WorldWideScience

Sample records for climate molecular insights

  1. Surviving historical Patagonian landscapes and climate: molecular insights from Galaxias maculatus

    Directory of Open Access Journals (Sweden)

    Carrea Cecilia

    2010-03-01

    Full Text Available Abstract Background The dynamic geological and climatic histories of temperate South America have played important roles in shaping the contemporary distributions and genetic diversity of endemic freshwater species. We use mitochondria and nuclear sequence variation to investigate the consequences of mountain barriers and Quaternary glacial cycles for patterns of genetic diversity in the diadromous fish Galaxias maculatus in Patagonia (~300 individuals from 36 locations. Results Contemporary populations of G. maculatus, east and west of the Andes in Patagonia, represent a single monophyletic lineage comprising several well supported groups. Mantel tests using control region data revealed a strong positive relationship when geographic distance was modeled according to a scenario of marine dispersal. (r = 0.69, P = 0.055. By contrast, direct distance between regions was poorly correlated with genetic distance (r = -0.05, P = 0.463. Hierarchical AMOVAs using mtDNA revealed that pooling samples according to historical (pre-LGM oceanic drainage (Pacific vs. Atlantic explained approximately four times more variance than pooling them into present-day drainage (15.6% vs. 3.7%. Further post-hoc AMOVA tests revealed additional genetic structure between populations east and west of the Chilean Coastal Cordillera (coastal vs. interior. Overall female effective population size appears to have remained relatively constant until roughly 0.5 Ma when population size rapidly increased several orders of magnitude [100× (60×-190×] to reach contemporary levels. Maximum likelihood analysis of nuclear alleles revealed a poorly supported gene tree which was paraphyletic with respect to mitochondrial-defined haplogroups. Conclusions First diversifying in the central/north-west region of Patagonia, G. maculatus extended its range into Argentina via the southern coastal regions that join the Pacific and Atlantic oceans. More recent gene flow between northern

  2. Extinction risks from climate change: macroecological and historical insights.

    Science.gov (United States)

    Jansson, Roland

    2009-06-09

    Human-induced climate change may threaten a large proportion of Earth's biota, but the uncertainties involved in projecting the future geographical distributions of species make quantitative predictions of extinction risk difficult to make. I discuss how insight from recent advances in macroecology and knowledge about species responses to past climate change can help predict extinction risks more accurately.

  3. Monoamine transporters: insights from molecular dynamics simulations

    Science.gov (United States)

    Grouleff, Julie; Ladefoged, Lucy Kate; Koldsø, Heidi; Schiøtt, Birgit

    2015-01-01

    The human monoamine transporters (MATs) facilitate the reuptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Imbalance in monoaminergic neurotransmission is linked to various diseases including major depression, attention deficit hyperactivity disorder, schizophrenia, and Parkinson’s disease. Inhibition of the MATs is thus an important strategy for treatment of such diseases. The MATs are sodium-coupled transport proteins belonging to the neurotransmitter/Na+ symporter (NSS) family, and the publication of the first high-resolution structure of a NSS family member, the bacterial leucine transporter LeuT, in 2005, proved to be a major stepping stone for understanding this family of transporters. Structural data allows for the use of computational methods to study the MATs, which in turn has led to a number of important discoveries. The process of substrate translocation across the membrane is an intrinsically dynamic process. Molecular dynamics simulations, which can provide atomistic details of molecular motion on ns to ms timescales, are therefore well-suited for studying transport processes. In this review, we outline how molecular dynamics simulations have provided insight into the large scale motions associated with transport of the neurotransmitters, as well as the presence of external and internal gates, the coupling between ion and substrate transport, and differences in the conformational changes induced by substrates and inhibitors. PMID:26528185

  4. Monoamine transporters: Insights from molecular dynamics simulations

    Directory of Open Access Journals (Sweden)

    Julie eGrouleff

    2015-10-01

    Full Text Available The human monoamine transporters facilitate the reuptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Imbalance in monoaminergic neurotransmission is linked to various diseases including major depression, attention deficit hyperactivity disorder, schizophrenia and Parkinson’s disease. Inhibition of the monoamine transporters is thus an important strategy for treatment of such diseases. The monoamine transporters are sodium-coupled transport proteins belonging to the neurotransmitter/Na+ symporter (NSS family, and the publication of the first high-resolution structure of a NSS family member, the bacterial leucine transporter LeuT, in 2005, proved to be a major stepping stone for understanding this family of transporters. Structural data allows for the use of computational methods to study the monoamine transporters, which in turn has led to a number of important discoveries. The process of substrate translocation across the membrane is an intrinsically dynamic process. Molecular dynamics simulations, which can provide atomistic details of molecular motion on ns to ms timescales, are therefore well-suited for studying transport processes. In this review, we outline how molecular dynamics simulations have provided insight into the large scale motions associated with transport of the neurotransmitters, as well as the presence of external and internal gates, the coupling between ion and substrate transport, and differences in the conformational changes induced by substrates and inhibitors.

  5. Male sex determination: insights into molecular mechanisms

    Institute of Scientific and Technical Information of China (English)

    Kathryn McClelland; Josephine Bowles; Peter Koopman

    2012-01-01

    Disorders of sex development often arise from anomalies in the molecular or cellular networks that guide the differentiation of the embryonic gonad into either a testis or an ovary,two functionally distinct organs.The activation of the Y-linked gene Sry(sexdetermining region Y) and its downstream target Sox9 (Sry box-containinggene 9) triggers testis differentiation by stimulating the differentiation of Sertoli cells,which then direct testis morphogenesis.Once engaged,a genetic pathway promotes the testis development while actively suppressing genes involved in ovarian development.This review focuses on the events of testis determination and the struggle to maintain male fate in the face of antagonistic pressure from the underlying female programme.

  6. Molecular dynamics insights into human aquaporin 2 water channel.

    Science.gov (United States)

    Binesh, A R; Kamali, R

    2015-12-01

    In this study, the first molecular dynamics simulation of the human aquaporin 2 is performed and for a better understanding of the aquaporin 2 permeability performance, the characteristics of water transport in this protein channel and key biophysical parameters of AQP2 tetramer including osmotic and diffusive permeability constants and the pore radius are investigated. For this purpose, recently recovered high resolution X-ray crystal structure of` the human aquaporin 2 is used to perform twenty nanosecond molecular dynamics simulation of fully hydrated tetramer of this protein embedded in a lipid bilayer. The resulting water permeability characteristics of this protein channel showed that the water permeability of the human AQP2 is in a mean range in comparison with other human aquaporins family. Finally, the results reported in this research demonstrate that molecular dynamics simulation of human AQP2 provided useful insights into the mechanisms of water permeation and urine concentration in the human kidney.

  7. Ice Formation on Kaolinite: Insights from Molecular Dynamics Simulations

    CERN Document Server

    Sosso, Gabriele C; Zen, Andrea; Pedevilla, Philipp; Michaelides, Angelos

    2016-01-01

    The formation of ice affects many aspects of our everyday life as well as technologies such as cryotherapy and cryopreservation. Foreign substances almost always aid water freezing through heterogeneous ice nucleation, but the molecular details of this process remain largely unknown. In fact, insight into the microscopic mechanism of ice formation on different substrates is difficult to obtain even via state-of-the-art experimental techniques. At the same time, atomistic simulations of heterogeneous ice nucleation frequently face extraordinary challenges due to the complexity of the water-substrate interaction and the long timescales that characterize nucleation events. Here, we have investigated several aspects of molecular dynamics simulations of heterogeneous ice nucleation considering as a prototypical ice nucleating material the clay mineral kaolinite, which is of relevance in atmospheric science. We show via seeded molecular dynamics simulations that ice nucleation on the hydroxylated (001) face of kaol...

  8. Pathogenesis of multiple sclerosis: insights from molecular and metabolic imaging.

    Science.gov (United States)

    Ciccarelli, Olga; Barkhof, Frederik; Bodini, Benedetta; De Stefano, Nicola; Golay, Xavier; Nicolay, Klaas; Pelletier, Daniel; Pouwels, Petra J W; Smith, Seth A; Wheeler-Kingshott, Claudia A M; Stankoff, Bruno; Yousry, Tarek; Miller, David H

    2014-08-01

    The mechanisms underlying the pathogenesis of multiple sclerosis induce the changes that underpin relapse-associated and progressive disability. Disease mechanisms can be investigated in preclinical models and patients with multiple sclerosis by molecular and metabolic imaging techniques. Many insights have been gained from such imaging studies: persisting inflammation in the absence of a damaged blood-brain barrier, activated microglia within and beyond lesions, increased mitochondrial activity after acute lesions, raised sodium concentrations in the brain, increased glutamate in acute lesions and normal-appearing white matter, different degrees of demyelination in different patients and lesions, early neuronal damage in grey matter, and early astrocytic proliferation and activation in lesions and white matter. Clinical translation of molecular and metabolic imaging and extension of these techniques will enable the assessment of novel drugs targeted at these disease mechanisms, and have the potential to improve health outcomes through the stratification of patients for treatments.

  9. Genomic and epigenetic insights into the molecular bases of heterosis.

    Science.gov (United States)

    Chen, Z Jeffrey

    2013-07-01

    Heterosis, also known as hybrid vigour, is widespread in plants and animals, but the molecular bases for this phenomenon remain elusive. Recent studies in hybrids and allopolyploids using transcriptomic, proteomic, metabolomic, epigenomic and systems biology approaches have provided new insights. Emerging genomic and epigenetic perspectives suggest that heterosis arises from allelic interactions between parental genomes, leading to altered programming of genes that promote the growth, stress tolerance and fitness of hybrids. For example, epigenetic modifications of key regulatory genes in hybrids and allopolyploids can alter complex regulatory networks of physiology and metabolism, thus modulating biomass and leading to heterosis. The conceptual advances could help to improve plant and animal productivity through the manipulation of heterosis.

  10. Ice formation on kaolinite: Insights from molecular dynamics simulations

    Science.gov (United States)

    Sosso, Gabriele C.; Tribello, Gareth A.; Zen, Andrea; Pedevilla, Philipp; Michaelides, Angelos

    2016-12-01

    The formation of ice affects many aspects of our everyday life as well as important technologies such as cryotherapy and cryopreservation. Foreign substances almost always aid water freezing through heterogeneous ice nucleation, but the molecular details of this process remain largely unknown. In fact, insight into the microscopic mechanism of ice formation on different substrates is difficult to obtain even if state-of-the-art experimental techniques are used. At the same time, atomistic simulations of heterogeneous ice nucleation frequently face extraordinary challenges due to the complexity of the water-substrate interaction and the long time scales that characterize nucleation events. Here, we have investigated several aspects of molecular dynamics simulations of heterogeneous ice nucleation considering as a prototypical ice nucleating material the clay mineral kaolinite, which is of relevance in atmospheric science. We show via seeded molecular dynamics simulations that ice nucleation on the hydroxylated (001) face of kaolinite proceeds exclusively via the formation of the hexagonal ice polytype. The critical nucleus size is two times smaller than that obtained for homogeneous nucleation at the same supercooling. Previous findings suggested that the flexibility of the kaolinite surface can alter the time scale for ice nucleation within molecular dynamics simulations. However, we here demonstrate that equally flexible (or non flexible) kaolinite surfaces can lead to very different outcomes in terms of ice formation, according to whether or not the surface relaxation of the clay is taken into account. We show that very small structural changes upon relaxation dramatically alter the ability of kaolinite to provide a template for the formation of a hexagonal overlayer of water molecules at the water-kaolinite interface, and that this relaxation therefore determines the nucleation ability of this mineral.

  11. Recent insights into the molecular genetics of the homocysteine metabolism.

    Science.gov (United States)

    Födinger, M; Wagner, O F; Hörl, W H; Sunder-Plassmann, G

    2001-02-01

    The homocysteine plasma level is determined by non-genetic and genetic factors. In recent years evidence has accumulated that the total homocysteine plasma level of patients under different forms of renal replacement therapy is influenced by a common mutation at nucleotide position 677 of the gene coding for 5,10-methylenetetrahydrofolate reductase (MTHFR 677C-->T). Furthermore, compound heterozygosity for the 677T allele and a novel A-->C polymorphism at nucleotide position 1298 of MTHFR is suggested to correlate with a decrease of folate plasma concentrations. Because polymorphisms of genes coding for proteins involved in the metabolism of homocysteine may contribute to elevated total homocysteine plasma concentrations, molecular genetic analyses of the homocysteine pathways experienced a drift towards screening for candidate genes with a putative relationship to total homocysteine plasma levels. One example is the cloning of the FOLR1 gene coding for the folate-binding protein (Folbp1), which has recently been inactivated in mice, thus representing an elegant model to investigate the consequence on the homocysteine metabolism. Furthermore, the recent characterization of the CUBN gene encoding the intrinsic factor-vitamin B12 receptor (cubilin) provides a basis to identify the causative mutations in patients suffering from a hereditary syndrome of hyperhomocysteinemia that presents with megaloblastic anemia and proteinuria. This review focuses on recent insights into the molecular genetics of MTHFR, FOLR1, and CUBN, and their relationships to the metabolism of the amino acid homocysteine.

  12. Molecular asymmetry in extraterrestrial chemistry: Insights from a pristine meteorite.

    Science.gov (United States)

    Pizzarello, Sandra; Huang, Yongsong; Alexandre, Marcelo R

    2008-03-11

    The nonracemic amino acids of meteorites provide the only natural example of molecular asymmetry measured so far outside the biosphere. Because extant life depends on chiral homogeneity for the structure and function of biopolymers, the study of these meteoritic compounds may offer insights into the establishment of prebiotic attributes in chemical evolution as well as the origin of terrestrial homochirality. However, all efforts to understand the origin, distribution, and scope of these amino acids' enantiomeric excesses (ee) have been frustrated by the ready exposure of meteorites to terrestrial contaminants and the ubiquitous homochirality of such contamination. We have analyzed the soluble organic composition of a carbonaceous meteorite from Antarctica that was collected and stored under controlled conditions, largely escaped terrestrial contamination and offers an exceptionally pristine sample of prebiotic material. Analyses of the meteorite diastereomeric amino acids alloisoleucine and isoleucine allowed us to show that their likely precursor molecules, the aldehydes, also carried a sizable molecular asymmetry of up to 14% in the asteroidal parent body. Aldehydes are widespread and abundant interstellar molecules; that they came to be present, survived, and evolved in the solar system carrying ee gives support to the idea that biomolecular traits such as chiral asymmetry could have been seeded in abiotic chemistry ahead of life.

  13. Insights from molecular dynamics simulations for computational protein design.

    Science.gov (United States)

    Childers, Matthew Carter; Daggett, Valerie

    2017-02-01

    A grand challenge in the field of structural biology is to design and engineer proteins that exhibit targeted functions. Although much success on this front has been achieved, design success rates remain low, an ever-present reminder of our limited understanding of the relationship between amino acid sequences and the structures they adopt. In addition to experimental techniques and rational design strategies, computational methods have been employed to aid in the design and engineering of proteins. Molecular dynamics (MD) is one such method that simulates the motions of proteins according to classical dynamics. Here, we review how insights into protein dynamics derived from MD simulations have influenced the design of proteins. One of the greatest strengths of MD is its capacity to reveal information beyond what is available in the static structures deposited in the Protein Data Bank. In this regard simulations can be used to directly guide protein design by providing atomistic details of the dynamic molecular interactions contributing to protein stability and function. MD simulations can also be used as a virtual screening tool to rank, select, identify, and assess potential designs. MD is uniquely poised to inform protein design efforts where the application requires realistic models of protein dynamics and atomic level descriptions of the relationship between dynamics and function. Here, we review cases where MD simulations was used to modulate protein stability and protein function by providing information regarding the conformation(s), conformational transitions, interactions, and dynamics that govern stability and function. In addition, we discuss cases where conformations from protein folding/unfolding simulations have been exploited for protein design, yielding novel outcomes that could not be obtained from static structures.

  14. Molecular insight into conformational transmission of human P-glycoprotein

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Shan-Yan [Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072 (China); Liu, Fu-Feng, E-mail: fufengliu@tju.edu.cn, E-mail: ysun@tju.edu.cn; Dong, Xiao-Yan; Sun, Yan, E-mail: fufengliu@tju.edu.cn, E-mail: ysun@tju.edu.cn [Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072 (China); Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072 (China)

    2013-12-14

    P-glycoprotein (P-gp), a kind of ATP-binding cassette transporter, can export candidates through a channel at the two transmembrane domains (TMDs) across the cell membranes using the energy released from ATP hydrolysis at the two nucleotide-binding domains (NBDs). Considerable evidence has indicated that human P-gp undergoes large-scale conformational changes to export a wide variety of anti-cancer drugs out of the cancer cells. However, molecular mechanism of the conformational transmission of human P-gp from the NBDs to the TMDs is still unclear. Herein, targeted molecular dynamics simulations were performed to explore the atomic detail of the conformational transmission of human P-gp. It is confirmed that the conformational transition from the inward- to outward-facing is initiated by the movement of the NBDs. It is found that the two NBDs move both on the two directions (x and y). The movement on the x direction leads to the closure of the NBDs, while the movement on the y direction adjusts the conformations of the NBDs to form the correct ATP binding pockets. Six key segments (KSs) protruding from the TMDs to interact with the NBDs are identified. The relative movement of the KSs along the y axis driven by the NBDs can be transmitted through α-helices to the rest of the TMDs, rendering the TMDs to open towards periplasm in the outward-facing conformation. Twenty eight key residue pairs are identified to participate in the interaction network that contributes to the conformational transmission from the NBDs to the TMDs of human P-gp. In addition, 9 key residues in each NBD are also identified. The studies have thus provided clear insight into the conformational transmission from the NBDs to the TMDs in human P-gp.

  15. Molecular insight into conformational transmission of human P-glycoprotein

    Science.gov (United States)

    Chang, Shan-Yan; Liu, Fu-Feng; Dong, Xiao-Yan; Sun, Yan

    2013-12-01

    P-glycoprotein (P-gp), a kind of ATP-binding cassette transporter, can export candidates through a channel at the two transmembrane domains (TMDs) across the cell membranes using the energy released from ATP hydrolysis at the two nucleotide-binding domains (NBDs). Considerable evidence has indicated that human P-gp undergoes large-scale conformational changes to export a wide variety of anti-cancer drugs out of the cancer cells. However, molecular mechanism of the conformational transmission of human P-gp from the NBDs to the TMDs is still unclear. Herein, targeted molecular dynamics simulations were performed to explore the atomic detail of the conformational transmission of human P-gp. It is confirmed that the conformational transition from the inward- to outward-facing is initiated by the movement of the NBDs. It is found that the two NBDs move both on the two directions (x and y). The movement on the x direction leads to the closure of the NBDs, while the movement on the y direction adjusts the conformations of the NBDs to form the correct ATP binding pockets. Six key segments (KSs) protruding from the TMDs to interact with the NBDs are identified. The relative movement of the KSs along the y axis driven by the NBDs can be transmitted through α-helices to the rest of the TMDs, rendering the TMDs to open towards periplasm in the outward-facing conformation. Twenty eight key residue pairs are identified to participate in the interaction network that contributes to the conformational transmission from the NBDs to the TMDs of human P-gp. In addition, 9 key residues in each NBD are also identified. The studies have thus provided clear insight into the conformational transmission from the NBDs to the TMDs in human P-gp.

  16. Sex Change in Clownfish: Molecular Insights from Transcriptome Analysis

    KAUST Repository

    Casas, Laura

    2016-10-17

    Sequential hermaphroditism is a unique reproductive strategy among teleosts that is displayed mainly in fish species living in the coral reef environment. The reproductive biology of hermaphrodites has long been intriguing; however, very little is known about the molecular pathways underlying their sex change. Here, we provide the first de novo transcriptome analyses of a hermaphrodite teleost´s undergoing sex change in its natural environment. Our study has examined relative gene expression across multiple groups—rather than just two contrasting conditions— and has allowed us to explore the differential expression patterns throughout the whole process. Our analysis has highlighted the rapid and complex genomic response of the brain associated with sex change, which is subsequently transmitted to the gonads, identifying a large number of candidate genes, some well-known and some novel, involved in the process. The present study provides strong evidence of the importance of the sex steroidogenic machinery during sex change in clownfish, with the aromatase gene playing a central role, both in the brain and the gonad. This work constitutes the first genome-wide study in a social sex-changing species and provides insights into the genetic mechanism governing social sex change and gonadal restructuring in protandrous hermaphrodites.

  17. Sex Change in Clownfish: Molecular Insights from Transcriptome Analysis

    Science.gov (United States)

    Casas, Laura; Saborido-Rey, Fran; Ryu, Taewoo; Michell, Craig; Ravasi, Timothy; Irigoien, Xabier

    2016-01-01

    Sequential hermaphroditism is a unique reproductive strategy among teleosts that is displayed mainly in fish species living in the coral reef environment. The reproductive biology of hermaphrodites has long been intriguing; however, very little is known about the molecular pathways underlying their sex change. Here, we provide the first de novo transcriptome analyses of a hermaphrodite teleost´s undergoing sex change in its natural environment. Our study has examined relative gene expression across multiple groups—rather than just two contrasting conditions— and has allowed us to explore the differential expression patterns throughout the whole process. Our analysis has highlighted the rapid and complex genomic response of the brain associated with sex change, which is subsequently transmitted to the gonads, identifying a large number of candidate genes, some well-known and some novel, involved in the process. The present study provides strong evidence of the importance of the sex steroidogenic machinery during sex change in clownfish, with the aromatase gene playing a central role, both in the brain and the gonad. This work constitutes the first genome-wide study in a social sex-changing species and provides insights into the genetic mechanism governing social sex change and gonadal restructuring in protandrous hermaphrodites. PMID:27748421

  18. Cognitive and psychological science insights to improve climate change data visualization

    Science.gov (United States)

    Harold, Jordan; Lorenzoni, Irene; Shipley, Thomas F.; Coventry, Kenny R.

    2016-12-01

    Visualization of climate data plays an integral role in the communication of climate change findings to both expert and non-expert audiences. The cognitive and psychological sciences can provide valuable insights into how to improve visualization of climate data based on knowledge of how the human brain processes visual and linguistic information. We review four key research areas to demonstrate their potential to make data more accessible to diverse audiences: directing visual attention, visual complexity, making inferences from visuals, and the mapping between visuals and language. We present evidence-informed guidelines to help climate scientists increase the accessibility of graphics to non-experts, and illustrate how the guidelines can work in practice in the context of Intergovernmental Panel on Climate Change graphics.

  19. Proteomic insight into the molecular function of the vitreous.

    Directory of Open Access Journals (Sweden)

    Jessica M Skeie

    Full Text Available The human vitreous contains primarily water, but also contains proteins which have yet to be fully characterized. To gain insight into the four vitreous substructures and their potential functions, we isolated and analyzed the vitreous protein profiles of three non-diseased human eyes. The four analyzed substructures were the anterior hyaloid, the vitreous cortex, the vitreous core, and the vitreous base. Proteins were separated by multidimensional liquid chromatography and identified by tandem mass spectrometry. Bioinformatics tools then extracted the expression profiles, signaling pathways, and interactomes unique to each tissue. From each substructure, a mean of 2,062 unique proteins were identified, with many being differentially expressed in a specific substructure: 278 proteins were unique to the anterior hyaloid, 322 to the vitreous cortex, 128 to the vitreous base, and 136 to the vitreous core. When the identified proteins were organized according to relevant functional pathways and networks, key patterns appeared. The blood coagulation pathway and extracellular matrix turnover networks were highly represented. Oxidative stress regulation and energy metabolism proteins were distributed throughout the vitreous. Immune functions were represented by high levels of immunoglobulin, the complement pathway, damage-associated molecular patterns (DAMPs, and evolutionarily conserved antimicrobial proteins. The majority of vitreous proteins detected were intracellular proteins, some of which originate from the retina, including rhodopsin (RHO, phosphodiesterase 6 (PDE6, and glial fibrillary acidic protein (GFAP. This comprehensive analysis uncovers a picture of the vitreous as a biologically active tissue, where proteins localize to distinct substructures to protect the intraocular tissues from infection, oxidative stress, and energy disequilibrium. It also reveals the retina as a potential source of inflammatory mediators. The vitreous proteome

  20. Molecular Insights into the Transmembrane Domain of the Thyrotropin Receptor.

    Directory of Open Access Journals (Sweden)

    Vanessa Chantreau

    Full Text Available The thyrotropin receptor (TSHR is a G protein-coupled receptor (GPCR that is member of the leucine-rich repeat subfamily (LGR. In the absence of crystal structure, the success of rational design of ligands targeting the receptor internal cavity depends on the quality of the TSHR models built. In this subfamily, transmembrane helices (TM 2 and 5 are characterized by the absence of proline compared to most receptors, raising the question of the structural conformation of these helices. To gain insight into the structural properties of these helices, we carried out bioinformatics and experimental studies. Evolutionary analysis of the LGR family revealed a deletion in TM5 but provided no information on TM2. Wild type residues at positions 2.58, 2.59 or 2.60 in TM2 and/or at position 5.50 in TM5 were substituted to proline. Depending on the position of the proline substitution, different effects were observed on membrane expression, glycosylation, constitutive cAMP activity and responses to thyrotropin. Only proline substitution at position 2.59 maintained complex glycosylation and high membrane expression, supporting occurrence of a bulged TM2. The TSHR transmembrane domain was modeled by homology with the orexin 2 receptor, using a protocol that forced the deletion of one residue in the TM5 bulge of the template. The stability of the model was assessed by molecular dynamics simulations. TM5 straightened during the equilibration phase and was stable for the remainder of the simulations. Our data support a structural model of the TSHR transmembrane domain with a bulged TM2 and a straight TM5 that is specific of glycoprotein hormone receptors.

  1. Estimating the limits of adaptation from historical behaviour: Insights from the American Climate Prospectus

    Science.gov (United States)

    Jina, A.; Hsiang, S. M.; Kopp, R. E., III; Rasmussen, D.; Rising, J.

    2014-12-01

    The American Climate Prospectus (ACP), the technical analysis underlying the Risky Business project, quantitatively assessed the climate risks posed to the United States' economy in a number of economic sectors [1]. The main analysis presents projections of climate impacts with an assumption of "no adaptation". Yet, historically, when the climate imposed an economic cost upon society, adaptive responses were taken to minimise these costs. These adaptive behaviours, both autonomous and planned, can be expected to occur as climate impacts increase in the future. To understand the extent to which adaptation might decrease some of the worst impacts of climate change, we empirically estimate adaptive responses. We do this in three sectors considered in the analysis - crop yield, crime, and mortality - and estimate adaptive capacity in two steps. First, looking at changes in climate impacts through time, we identify a historical rate of adaptation. Second, spatial differences in climate impacts are then used to stratify regions into more adapted or less adapted based on climate averages. As these averages change across counties in the US, we allow each to become more adapted at the rate identified in step one. We are then able to estimate the residual damages, assuming that only the historical adaptive behaviours have taken place (fig 1). Importantly, we are unable to estimate any costs associated with these adaptations, nor are we able to estimate more novel (for example, new technological discoveries) or more disruptive (for example, migration) adaptive behaviours. However, an important insight is that historical adaptive behaviours may not be capable of reducing the worst impacts of climate change. The persistence of impacts in even the most exposed areas indicates that there are non-trivial costs associated with adaptation that will need to be met from other sources or through novel behavioural changes. References: [1] T. Houser et al. (2014), American Climate

  2. The PICS Climate Insights 101 Courses: A Visual Approach to Learning About Climate Science, Mitigation and Adaptation

    Science.gov (United States)

    Pedersen, T. F.; Zwiers, F. W.; Breen, C.; Murdock, T. Q.

    2014-12-01

    The Pacific Institute for Climate Solutions (PICS) has now made available online three free, peer-reviewed, unique animated short courses in a series entitled "Climate Insights 101" that respectively address basic climate science, carbon-emissions mitigation approaches and opportunities, and adaptation. The courses are suitable for students of all ages, and use professionally narrated animations designed to hold a viewer's attention. Multiple issues are covered, including complex concerns like the construction of general circulation models, carbon pricing schemes in various countries, and adaptation approaches in the face of extreme weather events. Clips will be shown in the presentation. The first course (Climate Science Basics) has now been seen by over two hundred thousand individuals in over 80 countries, despite being offered in English only. Each course takes about two hours to work through, and in recognizing that that duration might pose an attention barrier to some students, PICS selected a number of short clips from the climate-science course and posted them as independent snippets on YouTube. A companion series of YouTube videos entitled, "Clear The Air", was created to confront the major global-warming denier myths. But a major challenge remains: despite numerous efforts to promote the availability of the free courses and the shorter YouTube pieces, they have yet to become widely known. Strategies to overcome that constraint will be discussed.

  3. Molecular Electronics: Insight from First-Principles Transport Simulations

    DEFF Research Database (Denmark)

    Paulsson, Magnus; Frederiksen, Thomas; Brandbyge, Mads

    2010-01-01

    Conduction properties of nanoscale contacts can be studied using first-principles simulations. Such calculations give insight into details behind the conductance that is not readily available in experiments. For example, we may learn how the bonding conditions of a molecule to the electrodes affect...

  4. Clinical and molecular insights into primary pediatric liver cancer

    NARCIS (Netherlands)

    V.B. Weeda

    2016-01-01

    This thesis aims to give insight into the clinical status quo of primary pediatric liver tumors and investigate signaling pathways that may be of importance for liver tumorigenesis. The most recent series of the International Childhood Liver Tumors Strategy Group (SIOPEL) of hepatocellular carcinoma

  5. Exploring soil organic matter-mineral interactions: mechanistic insights at the nanometer and molecular length scales

    Science.gov (United States)

    Newcomb, C.; Qafoku, N. P.; Grate, J. W.; Hufschmid, R.; Browning, N.; De Yoreo, J. J.

    2015-12-01

    With elevated levels of carbon dioxide in the atmosphere due to anthropogenic emissions and disruption to the carbon cycle, the effects of climate change are being accelerated. Approximately 80% of Earth's terrestrial organic carbon is stored in soil, and the residence time of this carbon can range from hours to millenia. Understanding the dynamics of this carbon pool in the carbon cycle is crucial to both predicting climate and sustaining ecosystem services. Soil organic carbon is known to be strongly associated with high surface area clay minerals. The nature of these interactions is not well understood primarily due to the heterogeneity of soil, as much of the current knowledge relies on experiments that take a top-down approach using bulk experimental measurements. Our work seeks to probe physical, chemical, and molecular-level interactions at the organic-mineral interface using a bottom-up approach that establishes a model system where complexity can be built in systematically. By performing in situ techniques such as dynamic force spectroscopy, a technique where organic molecules can be brought into contact with mineral surfaces in a controlled manner using an atomic force microscope, we demonstrate the ability to mechanistically probe the energy landscape of individual organic molecules with mineral surfaces. We demonstrate the ability to measure the binding energies of soil-inspired organic functional groups (including carboxylic acid, amine, methyl, and phosphate) with clay and mineral surfaces as a function of solution chemistry. This effort can provide researchers with both guiding principles about carbon dynamics at the sub-nanometer length scale and insights into early aggregation events, where organic-mineral interactions play a significant role.

  6. Molecular insights into the causes of male infertility

    Indian Academy of Sciences (India)

    Polani B Seshagiri

    2001-11-01

    Infertility is a reproductive health problem that affects many couples in the human population. About 13–18% of couple suffers from it and approximately one-half of all cases can be traced to either partner. Regardless of whether it is primary or secondary infertility, affected couples suffer from enormous emotional and psychological trauma and it can constitute a major life crisis in the social context. Many cases of idiopathic infertility have a genetic or molecular basis. The knowledge of the molecular genetics of male infertility is developing rapidly, new ``spermatogenic genes” are being discovered and molecular diagnostic approaches (DNA chips) established. This will immensely help diagnostic and therapeutic approaches to alleviate human infertility. The present review provides an overview of the causes of human infertility, particularly the molecular basis of male infertility and its implications for clinical practice.

  7. New insights into cystic fibrosis: molecular switches that regulate CFTR.

    Science.gov (United States)

    Guggino, William B; Stanton, Bruce A

    2006-06-01

    Cystic fibrosis transmembrane conductance regulator (CFTR), a Cl(-)-selective ion channel, is a prototypic member of the ATP-binding cassette transporter superfamily that is expressed in several organs. In these organs, CFTR assembles into large, dynamic macromolecular complexes that contain signalling molecules, kinases, transport proteins, PDZ-domain-containing proteins, myosin motors, Rab GTPases, and SNAREs. Understanding how these complexes regulate the intracellular trafficking and activity of CFTR provides a unique insight into the aetiology of cystic fibrosis and other diseases.

  8. Improving Public Engagement With Climate Change: Five "Best Practice" Insights From Psychological Science.

    Science.gov (United States)

    van der Linden, Sander; Maibach, Edward; Leiserowitz, Anthony

    2015-11-01

    Despite being one of the most important societal challenges of the 21st century, public engagement with climate change currently remains low in the United States. Mounting evidence from across the behavioral sciences has found that most people regard climate change as a nonurgent and psychologically distant risk-spatially, temporally, and socially-which has led to deferred public decision making about mitigation and adaptation responses. In this article, we advance five simple but important "best practice" insights from psychological science that can help governments improve public policymaking about climate change. Particularly, instead of a future, distant, global, nonpersonal, and analytical risk that is often framed as an overt loss for society, we argue that policymakers should (a) emphasize climate change as a present, local, and personal risk; (b) facilitate more affective and experiential engagement; (c) leverage relevant social group norms; (d) frame policy solutions in terms of what can be gained from immediate action; and (e) appeal to intrinsically valued long-term environmental goals and outcomes. With practical examples we illustrate how these key psychological principles can be applied to support societal engagement and climate change policymaking.

  9. The structure of biodiversity – insights from molecular phylogeography

    Directory of Open Access Journals (Sweden)

    Hewitt Godfrey M

    2004-10-01

    Full Text Available Abstract DNA techniques, analytical methods and palaeoclimatic studies are greatly advancing our knowledge of the global distribution of genetic diversity, and how it evolved. Such phylogeographic studies are reviewed from Arctic, Temperate and Tropical regions, seeking commonalities of cause in the resulting genetic patterns. The genetic diversity is differently patterned within and among regions and biomes, and is related to their histories of climatic changes. This has major implications for conservation science.

  10. Climate change and the molecular ecology of Arctic marine mammals.

    Science.gov (United States)

    O'Corry-Crowe, Gregory

    2008-03-01

    Key to predicting likely consequences of future climate change for Arctic marine mammals is developing a detailed understanding of how these species use their environment today and how they were affected by past climate-induced environmental change. Genetic analyses are uniquely placed to address these types of questions. Molecular genetic approaches are being used to determine distribution and migration patterns, dispersal and breeding behavior, population structure and abundance over time, and the effects of past and present climate change in Arctic marine mammals. A review of published studies revealed that population subdivision, dispersal, and gene flow in Arctic marine mammals was shaped primarily by evolutionary history, geography, sea ice, and philopatry to predictable, seasonally available resources. A meta-analysis of data from 38 study units across seven species found significant relationships between neutral genetic diversity and population size and climate region, revealing that small, isolated subarctic populations tend to harbor lower diversity than larger Arctic populations. A few small populations had substantially lower diversity than others. By contrast, other small populations retain substantial neutral diversity despite extensive population declines in the 19th and 20th centuries. The evolutionary and contemporary perspectives gained from these studies can be used to model the consequences of different climate projections for individual behavior and population structure and ultimately individual fitness and population viability. Future research should focus on: (1) the use of ancient-DNA techniques to directly reconstruct population histories through the analysis of historical and prehistorical material, (2) the use of genomic technologies to identify, map, and survey genes that directly influence fitness, (3) long-term studies to monitor populations and investigate evolution in contemporary time, (4) further Arctic-wide, multispecies analyses

  11. Chalcone Scaffold in Anticancer Armamentarium: A Molecular Insight

    Directory of Open Access Journals (Sweden)

    Manik Das

    2016-01-01

    Full Text Available Cancer is an inevitable matter of concern in the medicinal chemistry era. Chalcone is the well exploited scaffold in the anticancer domain. The molecular mechanism of chalcone at cellular level was explored in past decades. This mini review provides the most recent updates on anticancer potential of chalcones.

  12. Insights into molecular structure and digestion rate of oat starch.

    Science.gov (United States)

    Xu, Jinchuan; Kuang, Qirong; Wang, Kai; Zhou, Sumei; Wang, Shuo; Liu, Xingxun; Wang, Shujun

    2017-04-01

    The in vitro digestibility of oat starch and its relationship with starch molecular structure was investigated. The in vitro digestion results showed that the first-order kinetic constant (k) of oat starches (OS-1 and OS-2) was lower than that of rice starch. The size of amylose chains, amylose content and degree of branching (DB) of amylopectin in oat starch were significantly higher than the corresponding parameters in rice starch. The larger molecular size of oat starch may account for its lower digestion rate. The fine structure of amylopectin showed that oat starch had less chains of DP 6-12 and DP>36, which may explain the small difference in digestion rate between oat and rice starch. The biosynthesis model from oat amylopectin fine structure data suggested a lower starch branching enzyme (SBE) activity and/or a higher starch synthase (SS) activity, which may decrease the DB of oat starch and increase its digestion rate.

  13. Molecular Insight into Gut Microbiota and Rheumatoid Arthritis.

    Science.gov (United States)

    Wu, Xiaohao; He, Bing; Liu, Jin; Feng, Hui; Ma, Yinghui; Li, Defang; Guo, Baosheng; Liang, Chao; Dang, Lei; Wang, Luyao; Tian, Jing; Zhu, Hailong; Xiao, Lianbo; Lu, Cheng; Lu, Aiping; Zhang, Ge

    2016-03-22

    Rheumatoid arthritis (RA) is a systemic, inflammatory, and autoimmune disorder. Gut microbiota play an important role in the etiology of RA. With the considerable progress made in next-generation sequencing techniques, the identified gut microbiota difference between RA patients and healthy individuals provides an updated overview of the association between gut microbiota and RA. We reviewed the reported correlation and underlying molecular mechanisms among gut microbiota, the immune system, and RA. It has become known that gut microbiota contribute to the pathogenesis of RA via multiple molecular mechanisms. The progressive understanding of the dynamic interaction between gut microbiota and their host will help in establishing a highly individualized management for each RA patient, and achieve a better efficacy in clinical practice, or even discovering new drugs for RA.

  14. Buckling of microtubules: An insight by molecular and continuum mechanics

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Jin; Meguid, S. A., E-mail: meguid@mie.utoronto.ca [Mechanics and Aerospace Design Laboratory, Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario M5S 3G8 (Canada)

    2014-10-27

    The molecular structural mechanics method has been extended to investigate the buckling of microtubules (MTs) with various configurations. The results indicate that for relative short MTs the shear deformation effect, rather than the nonlocal effect, is mainly responsible for the limitation of their widely used Euler beam description and the observed length-dependence of their bending stiffness. In addition, the configuration effect of MTs is also studied and considered as an explanation for the large scattering of the critical buckling force and bending stiffness observed in existing experiments. This configuration effect is also found to mainly originate from the geometry of the MTs and is mainly determined by the protofilament number.

  15. Molecular insights into the premature aging disease progeria.

    Science.gov (United States)

    Vidak, Sandra; Foisner, Roland

    2016-04-01

    Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease presenting many features resembling the normal aging process. HGPS patients die before the age of 20 years due to cardiovascular problems and heart failure. HGPS is linked to mutations in the LMNA gene encoding the intermediate filament protein lamin A. Lamin A is a major component of the nuclear lamina, a scaffold structure at the nuclear envelope that defines mechanochemical properties of the nucleus and is involved in chromatin organization and epigenetic regulation. Lamin A is also present in the nuclear interior where it fulfills lamina-independent functions in cell signaling and gene regulation. The most common LMNA mutation linked to HGPS leads to mis-splicing of the LMNA mRNA and produces a mutant lamin A protein called progerin that tightly associates with the inner nuclear membrane and affects the dynamic properties of lamins. Progerin expression impairs many important cellular processes providing insight into potential disease mechanisms. These include changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence. In this review, we discuss these pathways and their potential contribution to the disease pathologies as well as therapeutic approaches used in preclinical and clinical tests.

  16. Insights of asphaltene aggregation mechanism from molecular dynamics simulation

    Directory of Open Access Journals (Sweden)

    Jennifer De León

    2015-01-01

    Full Text Available Se estudió el proceso de agregación de asfaltenos utilizando té cnicas de dinámica molecular. Se utilizaron cuatro estructuras diferentes. Las primeras tres moléculas tienen una estructura continental, con núcleos aromáticos condensador, mientras que la cuarta pose e una estructura tipo archipiélago, con pequeños grupos de anillos ar omáticos conectados con cadenas saturadas. Las moléculas fueron construidas de manera atomística, en la cual cada átomo se desc ribe individualmente. Se calcula ron las fuerzas de interacción a 300 K y 200 atm; las fuerzas de Van der W aals y las interacciones elect rostáticas fueron evaluadas separadamente. Se calculó el paráme tro de solubilidad para las cuatro molécu las. Se encontró que las inte racciones de Van der Waals asoc iadas a los anillos aromáticos y las fuerzas electrostáticas ocasionadas princ ipalmente por la presencia de heteroátomos como oxígeno, azufr e y nitrógeno, son igualmente r elevantes en la agregación de moléculas de asfalteno. Para todas las molé culas se encontró que los sistemas de asfaltenos tienen menor e nergía en estado de agregación que en estado monomérico. Para las estruct uras continentales, la presencia de largas cadenas obstruye el proceso de formación de agregados. Para las estructuras tipo archipiélago, la flexibilidad de las moléculas facilita la agregación con ot ras estructuras. La presencia de heteroátomos ocasiona una fuerza repulsiva que dificulta la agregación. El volumen molecular y la energía de c ohesión también son sensibles a la confi guración geométrica y la compos ición de las especies, lo cual afecta el parámetro de solubilidad.

  17. Turtle origins: insights from phylogenetic retrofitting and molecular scaffolds.

    Science.gov (United States)

    Lee, M S Y

    2013-12-01

    Adding new taxa to morphological phylogenetic analyses without substantially revising the set of included characters is a common practice, with drawbacks (undersampling of relevant characters) and potential benefits (character selection is not biased by preconceptions over the affinities of the 'retrofitted' taxon). Retrofitting turtles (Testudines) and other taxa to recent reptile phylogenies consistently places turtles with anapsid-grade parareptiles (especially Eunotosaurus and/or pareiasauromorphs), under both Bayesian and parsimony analyses. This morphological evidence for turtle-parareptile affinities appears to contradict the robust genomic evidence that extant (living) turtles are nested within diapsids as sister to extant archosaurs (birds and crocodilians). However, the morphological data are almost equally consistent with a turtle-archosaur clade: enforcing this molecular scaffold onto the morphological data does not greatly increase tree length (parsimony) or reduce likelihood (Bayesian inference). Moreover, under certain analytic conditions, Eunotosaurus groups with turtles and thus also falls within the turtle-archosaur clade. This result raises the possibility that turtles could simultaneously be most closely related to a taxon traditionally considered a parareptile (Eunotosaurus) and still have archosaurs as their closest extant sister group.

  18. Striped gold nanoparticles: New insights from molecular dynamics simulations

    Science.gov (United States)

    Velachi, Vasumathi; Bhandary, Debdip; Singh, Jayant K.; Cordeiro, M. Natália D. S.

    2016-06-01

    Recent simulations have improved our knowledge of the molecular-level structure and hydration properties of mixed self-assembled monolayers (SAMs) with equal and unequal alkyl thiols at three different arrangements, namely, random, patchy, and Janus. In our previous work [V. Vasumathi et al., J. Phys. Chem. C 119, 3199-3209 (2015)], we showed that the bending of longer thiols over shorter ones clearly depends on the thiols' arrangements and chemical nature of their terminal groups. In addition, such a thiol bending revealed to have a strong impact on the structural and hydration properties of SAMs coated on gold nanoparticles (AuNPs). In this paper, we extend our previous atomistic simulation study to investigate the bending of longer thiols by increasing the stripe thickness of mixed SAMs of equal and unequal lengths coated on AuNPs. We study also the effect of stripe thickness on the structural morphology and hydration of the coated SAMs. Our results show that the structural and hydration properties of SAMs are affected by the stripe thickness for mixtures of alkyl thiols with unequal chain length but not for equal length. Hence, the stability of the stripe configuration depends on the alkyl's chain length, the length difference between the thiol mixtures, and solvent properties.

  19. Embryonic stem cell biology: insights from molecular imaging.

    Science.gov (United States)

    Sallam, Karim; Wu, Joseph C

    2010-01-01

    Embryonic stem (ES) cells have therapeutic potential in disorders of cellular loss such as myocardial infarction, type I diabetes and neurodegenerative disorders. ES cell biology in living subjects was largely poorly understood until incorporation of molecular imaging into the field. Reporter gene imaging works by integrating a reporter gene into ES cells and using a reporter probe to induce a signal detectable by normal imaging modalities. Reporter gene imaging allows for longitudinal tracking of ES cells within the same host for a prolonged period of time. This has advantages over postmortem immunohistochemistry and traditional imaging modalities. The advantages include expression of reporter gene is limited to viable cells, expression is conserved between generations of dividing cells, and expression can be linked to a specific population of cells. These advantages were especially useful in studying a dynamic cell population such as ES cells and proved useful in elucidating the biology of ES cells. Reporter gene imaging identified poor integration of differentiated ES cells transplanted into host tissue as well as delayed donor cell death as reasons for poor long-term survival in vivo. This imaging technology also confirmed that ES cells indeed have immunogenic properties that factor into cell survival and differentiation. Finally, reporter gene imaging improved our understanding of the neoplastic risk of undifferentiated ES cells in forming teratomas. Despite such advances, much remains to be understood about ES cell biology to translate this technology to the bedside, and reporter gene imaging will certainly play a key role in formulating this understanding.

  20. Response of germinating barley seeds to Fusarium graminearum: The first molecular insight into Fusarium seedling blight

    DEFF Research Database (Denmark)

    Yang, Fen; Svensson, Birte; Finnie, Christine

    2011-01-01

    Fusarium seedling blight in cereals can result in significant reductions in plant establishment but has not received much attention. The disease often starts during seed germination due to sowing of the seeds infected by Fusarium spp. including Fusarium graminearum. In order to gain the first...... provides the first molecular insight into Fusarium seedling blight....

  1. Molecular Ecological Insights into Neotropical Bird-Tick Interactions.

    Directory of Open Access Journals (Sweden)

    Matthew J Miller

    Full Text Available In the tropics, ticks parasitize many classes of vertebrate hosts. However, because many tropical tick species are only identifiable in the adult stage, and these adults usually parasitize mammals, most attention on the ecology of tick-host interactions has focused on mammalian hosts. In contrast, immature Neotropical ticks are often found on wild birds, yet difficulties in identifying immatures hinder studies of birds' role in tropical tick ecology and tick-borne disease transmission. In Panama, we found immature ticks on 227 out of 3,498 individually-sampled birds representing 93 host species (24% of the bird species sampled, and 13% of the Panamanian land bird fauna. Tick parasitism rates did not vary with rainfall or temperature, but did vary significantly with several host ecological traits. Likewise, Neotropical-Nearctic migratory birds were significantly less likely to be infested than resident species. Using a molecular library developed from morphologically-identified adult ticks specifically for this study, we identified eleven tick species parasitizing birds, indicating that a substantial portion of the Panamanian avian species pool is parasitized by a diversity of tick species. Tick species that most commonly parasitized birds had the widest diversity of avian hosts, suggesting that immature tick species are opportunistic bird parasites. Although certain avian ecological traits are positively associated with parasitism, we found no evidence that individual tick species show specificity to particular avian host ecological traits. Finally, our data suggest that the four principal vectors of Rocky Mountain Spotted Fever in the Neotropics rarely, if ever, parasitize Panamanian birds. However, other tick species that harbor newly-discovered rickettsial parasites of unknown pathogenicity are frequently found on these birds. Given our discovery of broad interaction between Panamanian tick and avian biodiversity, future work on tick ecology

  2. Molecular insights into seed dispersal mutualisms driving plant population recruitment

    Science.gov (United States)

    García, Cristina; Grivet, Delphine

    2011-11-01

    Most plant species require mutualistic interactions with animals to fulfil their demographic cycle. In this regard frugivory (i.e., the intake of fruits by animals) enhances natural regeneration by mobilizing a large amount of seeds from source trees to deposition sites across the landscape. By doing so, frugivores move propagules, and the genotypes they harbour creating the spatial, ecological, and genetic environment under which subsequent recruitment proceeds. Recruitment patterns can be envisioned as the result of two density- and distance-dependent processes: seed dispersal and seed/seedling survival (the Janzen-Connell model). Population genetic studies add another layer of complexity for understanding the fate of dispersed propagules: the genetic relatedness among neighbouring seeds within a seed clump, a major outcome of frugivore activity, modifies their chances of germinating and surviving. Yet, we virtually ignore how the spatial distribution of maternal progenies and recruitment patterns relate with each other in frugivore-generated seed rains. Here we focus on the critical role of frugivore-mediated seed dispersal in shaping the spatial distribution of maternal progenies in the seed rain. We first examine which genetic mechanisms underlying recruitment are influenced by the spatial distribution of maternal progenies. Next, we examine those studies depicting the spatial distribution of maternal progenies in a frugivore-generated seed rain. In doing so, we briefly review the most suitable analytical approaches applied to track the contribution of fruiting trees to the seed rain based on molecular data. Then we look more specifically at the role of distinct frugivore guilds in determining maternal genetic correlations and their expected consequences for recruitment patterns. Finally we posit some general conclusions and suggest future research directions that would provide a more comprehensive understanding of the ecological and evolutionary consequences

  3. Molecular Ecological Insights into Neotropical Bird–Tick Interactions

    Science.gov (United States)

    Esser, Helen J.; Loaiza, Jose R.; Herre, Edward Allen; Aguilar, Celestino; Quintero, Diomedes; Alvarez, Eric; Bermingham, Eldredge

    2016-01-01

    In the tropics, ticks parasitize many classes of vertebrate hosts. However, because many tropical tick species are only identifiable in the adult stage, and these adults usually parasitize mammals, most attention on the ecology of tick-host interactions has focused on mammalian hosts. In contrast, immature Neotropical ticks are often found on wild birds, yet difficulties in identifying immatures hinder studies of birds’ role in tropical tick ecology and tick-borne disease transmission. In Panama, we found immature ticks on 227 out of 3,498 individually–sampled birds representing 93 host species (24% of the bird species sampled, and 13% of the Panamanian land bird fauna). Tick parasitism rates did not vary with rainfall or temperature, but did vary significantly with several host ecological traits. Likewise, Neotropical–Nearctic migratory birds were significantly less likely to be infested than resident species. Using a molecular library developed from morphologically–identified adult ticks specifically for this study, we identified eleven tick species parasitizing birds, indicating that a substantial portion of the Panamanian avian species pool is parasitized by a diversity of tick species. Tick species that most commonly parasitized birds had the widest diversity of avian hosts, suggesting that immature tick species are opportunistic bird parasites. Although certain avian ecological traits are positively associated with parasitism, we found no evidence that individual tick species show specificity to particular avian host ecological traits. Finally, our data suggest that the four principal vectors of Rocky Mountain Spotted Fever in the Neotropics rarely, if ever, parasitize Panamanian birds. However, other tick species that harbor newly–discovered rickettsial parasites of unknown pathogenicity are frequently found on these birds. Given our discovery of broad interaction between Panamanian tick and avian biodiversity, future work on tick ecology and the

  4. A Social Identity Analysis of Climate Change and Environmental Attitudes and Behaviors: Insights and Opportunities.

    Science.gov (United States)

    Fielding, Kelly S; Hornsey, Matthew J

    2016-01-01

    Environmental challenges are often marked by an intergroup dimension. Political conservatives and progressives are divided on their beliefs about climate change, farmers come into conflict with scientists and environmentalists over water allocation or species protection, and communities oppose big business and mining companies that threaten their local environment. These intergroup tensions are reminders of the powerful influence social contexts and group memberships can have on attitudes, beliefs, and actions relating to climate change and the environment more broadly. In this paper, we use social identity theory to help describe and explain these processes. We review literature showing, how conceiving of oneself in terms of a particular social identity influences our environmental attitudes and behaviors, how relations between groups can impact on environmental outcomes, and how the content of social identities can direct group members to act in more or less pro-environmental ways. We discuss the similarities and differences between the social identity approach to these phenomena and related theories, such as cultural cognition theory, the theory of planned behavior, and value-belief-norm theory. Importantly, we also advance social-identity based strategies to foster more sustainable environmental attitudes and behaviors. Although this theoretical approach can provide important insights and potential solutions, more research is needed to build the empirical base, especially in relation to testing social identity solutions.

  5. A social identity analysis of climate change and environmental attitudes and behaviors: Insights and opportunities

    Directory of Open Access Journals (Sweden)

    Kelly Shanene Fielding

    2016-02-01

    Full Text Available Environmental challenges are often marked by an intergroup dimension. Political conservatives and progressives are divided on their beliefs about climate change, farmers come into conflict with scientists and environmentalists over water allocation or species protection, and communities oppose big business and mining companies that threaten their local environment. These intergroup tensions are reminders of the powerful influence social contexts and group memberships can have on attitudes, beliefs, and actions relating to climate change and the environment more broadly. In this paper we use social identity theory to help describe and explain these processes. We review literature showing how conceiving of oneself in terms of a particular social identity influences our environmental attitudes and behaviors, how relations between groups can impact on environmental outcomes, and how the content of social identities can direct group members to act in more or less pro-environmental ways. We discuss the similarities and differences between the social identity approach to these phenomena and related theories such as cultural cognition theory, the theory of planned behavior and value-belief-norm theory. Importantly, we also advance social-identity based strategies to foster more sustainable environmental attitudes and behaviors. Although this theoretical approach can provide important insights and potential solutions, more research is needed to build the empirical base, especially in relation to testing social identity solutions.

  6. A Social Identity Analysis of Climate Change and Environmental Attitudes and Behaviors: Insights and Opportunities

    Science.gov (United States)

    Fielding, Kelly S.; Hornsey, Matthew J.

    2016-01-01

    Environmental challenges are often marked by an intergroup dimension. Political conservatives and progressives are divided on their beliefs about climate change, farmers come into conflict with scientists and environmentalists over water allocation or species protection, and communities oppose big business and mining companies that threaten their local environment. These intergroup tensions are reminders of the powerful influence social contexts and group memberships can have on attitudes, beliefs, and actions relating to climate change and the environment more broadly. In this paper, we use social identity theory to help describe and explain these processes. We review literature showing, how conceiving of oneself in terms of a particular social identity influences our environmental attitudes and behaviors, how relations between groups can impact on environmental outcomes, and how the content of social identities can direct group members to act in more or less pro-environmental ways. We discuss the similarities and differences between the social identity approach to these phenomena and related theories, such as cultural cognition theory, the theory of planned behavior, and value-belief-norm theory. Importantly, we also advance social-identity based strategies to foster more sustainable environmental attitudes and behaviors. Although this theoretical approach can provide important insights and potential solutions, more research is needed to build the empirical base, especially in relation to testing social identity solutions. PMID:26903924

  7. Alluvial fan response to climatic change: Insights from numerical modeling (Invited)

    Science.gov (United States)

    Pelletier, J. D.

    2009-12-01

    Alluvial fans in the western U.S. exhibit a regionally correlative sequence of Plio-Quaternary deposits. Cosmogenic and U-series dating has greatly improved the age control on these deposits and their associated terraces and generally strengthened the case for aggradation during humid-to-arid transitions. Still, the linkages between climate change, upland basin response, and alluvial fan response are not well constrained. Fans may fill and cut as a result of autogenetic processes/internal adjustments, changes in regional temperature (which controls snowmelt-induced flooding), changes in the frequency-size distribution of rainfall events, and/or changes in upslope vegetation. Here I describe the results of a numerical modeling study designed to better constrain the relationships between different end-member forcing mechanisms and the geologic record of alluvial fan deposits and terraces. The model solves the evolution of the fan topography using Exner's equation (conservation of mass) coupled with a nonlinear, threshold-controlled transport relation for sand and gravel. Bank retreat is modeled using an advection equation with a rate proportional to bank shear stress. I begin by considering the building of a fan under conditions of constant water and sediment supply. This simple system exhibits all of the complexity of fans developed under experimental conditions, and it provides insights into the mechanisms that control avulsions and it provides a baseline estimate for the within-fan relief that can result from autogenetic processes. Relationships between the magnitude and period of variations in the sediment-to-water ratio and the geomorphic response of fans are then discussed. I also consider the response of a coupled drainage basin-fan system to changes in climate, including the hydrologic and vegetation response of upland hillslopes. Fans can aggrade or incise in response to the same climatic event depending on the relief of the upstream drainage basin, which

  8. Molecular interaction of PCB153 to human serum albumin: Insights from spectroscopic and molecular modeling studies

    Energy Technology Data Exchange (ETDEWEB)

    Han, Chao; Fang, Senbiao; Cao, Huiming; Lu, Yan; Ma, Yaqiong [School of Pharmacy, Lanzhou University, Lanzhou 730000 (China); Wei, Dongfeng [Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700 (China); Xie, Xiaoyun [College of Earth and Environmental Science, Lanzhou University, Lanzhou 730000 (China); Liu, Xiaohua [School of Pharmacy, Lanzhou University, Lanzhou 730000 (China); Li, Xin [College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471003 (China); Fei, Dongqing [School of Pharmacy, Lanzhou University, Lanzhou 730000 (China); Zhao, Chunyan, E-mail: zhaochy07@lzu.edu.cn [School of Pharmacy, Lanzhou University, Lanzhou 730000 (China)

    2013-03-15

    Highlights: ► We identify the binding mode of PCB153 to human serum albumin (HSA). ► Spectroscopic and molecular modeling results reveal that PCB153 binds at the site II. ► The interaction is mainly governed by hydrophobic and hydrogen bond forces. ► The work helps to probe transporting, distribution and toxicity effect of PCBs. -- Abstract: Polychlorinated biphenyls (PCBs) possessed much potential hazard to environment because of its chemical stability and biological toxicity. Here, we identified the binding mode of a representative compound, PCB153, to human serum albumin (HSA) using fluorescence and molecular dynamics simulation methods. The fluorescence study showed that the intrinsic fluorescence of HSA was quenched by addition of PCB153 through a static quenching mechanism. The thermodynamic analysis proved the binding behavior was mainly governed by hydrophobic force. Furthermore, as evidenced by site marker displacement experiments using two probe compounds, it revealed that PCB153 acted exactly on subdomain IIIA (site II) of HSA. On the other hand, the molecular dynamics studies as well as free energy calculations made another important contribution to understand the conformational changes of HSA and the stability of HSA-PCB153 system. Molecular docking revealed PCB153 can bind in a large hydrophobic activity of subdomain IIIA by the hydrophobic interaction and hydrogen bond interactions between chlorine atoms and residue ASN391. The present work provided reasonable models helping us further understand the transporting, distribution and toxicity effect of PCBs when it spread into human blood serum.

  9. Application of molecular simulations: Insight into liquid bridging and jetting phenomena

    Directory of Open Access Journals (Sweden)

    I. Nezbeda

    2015-03-01

    Full Text Available Molecular dynamics simulations have been performed on pure liquid water, aqueous solutions of sodium chloride, and polymer solutions exposed to a strong external electric field with the goal to gain molecular insight into the structural response to the field. Several simulation methodologies have been used to elucidate the molecular mechanisms of the processes leading to the formation of liquid bridges and jets (in the production of nanofibers. It is shown that in the established nanoscale structures, the molecules form a chain with their dipole moments oriented parallel to the applied field throughout the entire sample volume. The presence of ions may disturb this structure leading to its ultimate disintegration into droplets; the concentration dependence of the threshold field required to stabilize a liquid column has been determined. Conformational changes of the polymer in the jetting process have also been observed.

  10. Insights into the molecular interactions between aminopeptidase and amyloid beta peptide using molecular modeling techniques.

    Science.gov (United States)

    Dhanavade, Maruti J; Sonawane, Kailas D

    2014-08-01

    Amyloid beta (Aβ) peptides play a central role in the pathogenesis of Alzheimer's disease. The accumulation of Aβ peptides in AD brain was caused due to overproduction or insufficient clearance and defects in the proteolytic degradation of Aβ peptides. Hence, Aβ peptide degradation could be a promising therapeutic approach in AD treatment. Recent experimental report suggests that aminopeptidase from Streptomyces griseus KK565 (SGAK) can degrade Aβ peptides but the interactive residues are yet to be known in detail at the atomic level. Hence, we developed the three-dimensional model of aminopeptidase (SGAK) using SWISS-MODEL, Geno3D and MODELLER. Model built by MODELLER was used for further studies. Molecular docking was performed between aminopeptidase (SGAK) with wild-type and mutated Aβ peptides. The docked complex of aminopeptidase (SGAK) and wild-type Aβ peptide (1IYT.pdb) shows more stability than the other complexes. Molecular docking and MD simulation results revealed that the residues His93, Asp105, Glu139, Glu140, Asp168 and His255 are involved in the hydrogen bonding with Aβ peptide and zinc ions. The interactions between carboxyl oxygen atoms of Glu139 of aminopeptidase (SGAK) with water molecule suggest that the Glu139 may be involved in the nucleophilic attack on Ala2-Glu3 peptide bond of Aβ peptide. Hence, amino acid Glu139 of aminopeptidase (SGAK) might play an important role to degrade Aβ peptides, a causative agent of Alzheimer's disease.

  11. Novel molecular fossils of bacteria: insights into hydrothermal origin of life.

    Science.gov (United States)

    Dai, Jianghong

    2012-10-01

    Hydrothermal vents, in particular, alkaline submarine vents, are potential systems for the origin of life. Early hydrothermal vents may have imprinted on biochemical processes and housekeeping proteins of life and have hallmarked key molecules. This essay introduces new information to this discussion by focusing on newly identified sulfur-modified DNA and a heretofore ignored anhydro bond of the cell wall peptidoglycan in bacteria. It is suggested that they are novel molecular fossils that are relevant to the settings of alkaline submarine vents and harbor clues of early life. As DNA and the cell wall are bound up with genetic information and the integrity of cell, respectively, these two molecular fossils may provide insights into hydrothermal origin of life from a new angle.

  12. Complex Reaction Environments and Competing Reaction Mechanisms in Zeolite Catalysis: Insights from Advanced Molecular Dynamics.

    Science.gov (United States)

    De Wispelaere, Kristof; Ensing, Bernd; Ghysels, An; Meijer, Evert Jan; Van Speybroeck, Veronique

    2015-06-22

    The methanol-to-olefin process is a showcase example of complex zeolite-catalyzed chemistry. At real operating conditions, many factors affect the reactivity, such as framework flexibility, adsorption of various guest molecules, and competitive reaction pathways. In this study, the strength of first principle molecular dynamics techniques to capture this complexity is shown by means of two case studies. Firstly, the adsorption behavior of methanol and water in H-SAPO-34 at 350 °C is investigated. Hereby an important degree of framework flexibility and proton mobility was observed. Secondly, the methylation of benzene by methanol through a competitive direct and stepwise pathway in the AFI topology was studied. Both case studies clearly show that a first-principle molecular dynamics approach enables unprecedented insights into zeolite-catalyzed reactions at the nanometer scale to be obtained.

  13. Structure of sulfamidase provides insight into the molecular pathology of mucopolysaccharidosis IIIA

    Energy Technology Data Exchange (ETDEWEB)

    Sidhu, Navdeep S. [University of Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen (Germany); University of Göttingen, Tammannstrasse 4, 37077 Göttingen (Germany); Schreiber, Kathrin [University of Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen (Germany); Pröpper, Kevin [University of Göttingen, Tammannstrasse 4, 37077 Göttingen (Germany); Becker, Stefan [Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen (Germany); Usón, Isabel [Instituto de Biologia Molecular de Barcelona (IBMB–CSIC), Barcelona Science Park, Baldiri Reixach 15, 08028 Barcelona (Spain); Institucio Catalana de Recerca i Estudis Avancats (ICREA), (Spain); Sheldrick, George M. [University of Göttingen, Tammannstrasse 4, 37077 Göttingen (Germany); Gärtner, Jutta; Krätzner, Ralph, E-mail: rkraetz@gwdg.de; Steinfeld, Robert, E-mail: rkraetz@gwdg.de [University of Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen (Germany)

    2014-05-01

    Mucopolysaccharidosis IIIA is a fatal neurodegenerative disease that typically manifests itself in childhood and is caused by mutations in the gene for the lysosomal enzyme sulfamidase. The first structure of this enzyme is presented, which provides insight into the molecular basis of disease-causing mutations, and the enzymatic mechanism is proposed. Mucopolysaccharidosis type IIIA (Sanfilippo A syndrome), a fatal childhood-onset neurodegenerative disease with mild facial, visceral and skeletal abnormalities, is caused by an inherited deficiency of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH; sulfamidase). More than 100 mutations in the SGSH gene have been found to reduce or eliminate its enzymatic activity. However, the molecular understanding of the effect of these mutations has been confined by a lack of structural data for this enzyme. Here, the crystal structure of glycosylated SGSH is presented at 2 Å resolution. Despite the low sequence identity between this unique N-sulfatase and the group of O-sulfatases, they share a similar overall fold and active-site architecture, including a catalytic formylglycine, a divalent metal-binding site and a sulfate-binding site. However, a highly conserved lysine in O-sulfatases is replaced in SGSH by an arginine (Arg282) that is positioned to bind the N-linked sulfate substrate. The structure also provides insight into the diverse effects of pathogenic mutations on SGSH function in mucopolysaccharidosis type IIIA and convincing evidence for the molecular consequences of many missense mutations. Further, the molecular characterization of SGSH mutations will lay the groundwork for the development of structure-based drug design for this devastating neurodegenerative disorder.

  14. A multi-layered governance framework for incorporating social science insights into adapting to the health impacts of climate change

    Directory of Open Access Journals (Sweden)

    Kathryn J. Bowen

    2013-09-01

    Full Text Available Background: Addressing climate change and its associated effects is a multi-dimensional and ongoing challenge. This includes recognizing that climate change will affect the health and wellbeing of all populations over short and longer terms, albeit in varied ways and intensities. That recognition has drawn attention to the need to take adaptive actions to lessen adverse impacts over the next few decades from unavoidable climate change, particularly in developing country settings. A range of sectors is responsible for appropriate adaptive policies and measures to address the health risks of climate change, including health services, water and sanitation, trade, agriculture, disaster management, and development. Objectives: To broaden the framing of governance and decision-making processes by using innovative methods and assessments to illustrate the multi-sectoral nature of health-related adaptation to climate change. This is a shift from sector-specific to multi-level systems encompassing sectors and actors, across temporal and spatial scales. Design: A review and synthesis of the current knowledge in the areas of health and climate change adaptation governance and decision-making processes. Results: A novel framework is presented that incorporates social science insights into the formulation and implementation of adaptation activities and policies to lessen the health risks posed by climate change. Conclusion: Clarification of the roles that different sectors, organizations, and individuals occupy in relation to the development of health-related adaptation strategies will facilitate the inclusion of health and wellbeing within multi-sector adaptation policies, thereby strengthening the overall set of responses to minimize the adverse health effects of climate change.

  15. Plant molecular stress responses face climate change. Trends in Plants

    NARCIS (Netherlands)

    Ahuja, I.; Vos, de R.C.H.; Bones, A.M.; Hall, R.D.

    2010-01-01

    Environmental stress factors such as drought, elevated temperature, salinity and rising CO2 affect plant growth and pose a growing threat to sustainable agriculture. This has become a hot issue due to concerns about the effects of climate change on plant resources, biodiversity and global food secur

  16. Livelihood adaptations to climate variability: insights from farming households in Ghana

    OpenAIRE

    Antwi-Agyei, P; Stringer, LC; Dougill, AJ

    2014-01-01

    Climate variability poses a significant threat to many sectors of Sub-Saharan Africa's economy. Agriculture is one of the most climate sensitive sectors because of its dependence on rain-fed cultivation. This paper identifies the main adaptation strategies used by farming households in the Sudan savannah and forest-savannah transitional agro-ecological zones of Ghana, in order to reduce the adverse impacts of climate variability on their livelihood activities. It combines questionnaire survey...

  17. Reactivity and Selectivity of Heterogenized Homogeneous Catalysts: Insights from Molecular Simulations

    Science.gov (United States)

    Malek, Kourosh; van Santen, Rutger A.

    Immobilized metal complexes on nanoporous materials have recently been proposed as a novel class of heterogeneous enantioselective catalyst for epoxidation of unfunctionalized olefins as well as hydrogenation, alkylation, and nitroaldol reactions. The porous hosted materials affect catalytic performance due to a cooperative interaction among the nanoporous solid, immobilizing linker, and metal complex asymmetry. The effects of mesoporous materials and immobilizing agents on chiral catalysis are not well understood, however, the catalysts confined in nanopores show comparable or even higher conversions and enantioselectivity compared to their homogeneous counterparts. This chapter highlights major scientific problems for fundamental understanding and design of heterogenized homogeneous catalysts. It describes in detail the pivotal role of a sound framework in physical theory and molecular modeling in systematic efforts towards better materials and catalytic performance optimization. The common threads of the various topics addressed is the wide range of scales that has to be considered in establishing relations between structure, physicochemical properties, and catalytic performance. Physical theory and modeling employ a variety of methods, encompassing ab-initio calculations, molecular simulations, and the continuum model of transport and reaction in nanoporous materials. We particularly describe how molecular simulations can be used to investigate the origin of enantioselectivity of an anchored metal complex in nanoporous materials. These studies provide new insights into the steric effects that relate to choices of substrate and linker and to the interplay with mesopore confinement. We also bring detailed example of employing molecular simulations to unravel the catalytic properties of metallomacrocyclics for the electrochemical reduction of molecular oxygen in aqueous media. We rationalize the importance of immobilization and show how it relates to the steric

  18. Molecular Insight into Affinities of Gallated and Nongallated Proanthocyanidins Dimers to Lipid Bilayers

    Science.gov (United States)

    Zhu, Wei; Xiong, Le; Peng, Jinming; Deng, Xiangyi; Gao, Jun; Li, Chun-Mei

    2016-11-01

    Experimental studies have proved the beneficial effects of proanthocyanidins (Pas) relating to interaction with the cell membrane. But the detailed mechanisms and structure-function relationship was unclear. In present study, molecular dynamics (MD) simulations were used to study the interactions of four PA dimers with a lipid bilayer composed of 1:1 mixed 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) and 1-palmitoyl-2-oleoyl phosphatidylethanolamine (POPE). The results showed that the gallated PA dimers had much higher affinities to the bilayer with lower binding free energies compared with nongallated PA dimers. The gallated PA dimers penetrated deeper into the bilayer and formed more hydrogen bonds (H-bonds) with bilayer oxygen atoms, especially the deeper oxygen atoms of the lipids simultaneously, thus inducing stronger lateral expansion of the membrane and lipid tails disorder. The present results provided molecular insights into the interactions between PA dimers and bio-membranes and agreed with our experimental results well. These molecular interactions helped to elucidate the structure-function relationship of the PA dimers and provided a foundation for a better understanding of the underlying mechanisms of the bioactivities of PA oligomers.

  19. Stimuli for municipal responses to climate adaptation: insights from Philadelphia – an early adapter

    NARCIS (Netherlands)

    Uittenbroek, C.J.; Janssen-Jansen, Leonie; Runhaar, H.A.C.

    2016-01-01

    An in-depth understanding of these stimuli is currently lacking in literature as most research has focussed on overcoming barriers to climate adaptation. The aim of this paper is to identify stimuli for municipal responses to climate adaptation and examine how they influence the governance approach

  20. Migration out of 1930s Rural Eastern Oklahoma: Insights for Climate Change Research

    Science.gov (United States)

    McLeman, Robert

    2006-01-01

    The question of how communities and individuals adapt to changing climatic conditions is of pressing concern to scientists and policymakers in light of the growing evidence that human activity has modified the Earth's climate. A number of authors have suggested that widespread changes in human settlement and migration patterns may occur in…

  1. Climate change, water stress, conflict and migration: Taking stock of current insights through a vulnerability lens

    NARCIS (Netherlands)

    Hermans, L.M.

    2011-01-01

    There is a growing awareness in international policy circles that climate change may be a driver of increased migration flows. In addition to political refugees and economic migrants, climate change-induced migration and environmental migrants are increasingly recognized as categories in human migra

  2. Protein Fibrillar Nanopolymers: Molecular-Level Insights into Their Structural, Physical and Mechanical Properties

    Science.gov (United States)

    Trusova, Valeriya M.

    2015-09-01

    Amyloid fibrils represent a generic class of mechanically strong and stable biomaterials with extremely advantageous properties. Although amyloids were initially associated only with severe neurological disorders, the role of these structures nowadays is shifting from health debilitating to highly beneficial both in biomedical and technological aspects. Intensive involvement of fibrillar assemblies into the wide range of pathogenic and functional processes strongly necessitate the molecular level characterization of the structural, physical and elastic features of protein nanofibrils. In the present contribution, we made an attempt to highlight the up-to-date progress in the understanding of amyloid properties from the polymer physics standpoint. The fundamental insights into protein fibril behavior are essential not only for development of therapeutic strategies to combat the protein misfolding disorders but also for rational and precise design of novel biodegradable protein-based nanopolymers.

  3. Crystal Structures of Human and Staphylococcus aureus Pyruvate Carboxylase and Molecular Insights into the Carboxyltransfer Reaction

    Energy Technology Data Exchange (ETDEWEB)

    Xiang,S.; Tong, L.

    2008-01-01

    Pyruvate carboxylase (PC) catalyzes the biotin-dependent production of oxaloacetate and has important roles in gluconeogenesis, lipogenesis, insulin secretion and other cellular processes. PC contains the biotin carboxylase (BC), carboxyltransferase (CT) and biotin-carboxyl carrier protein (BCCP) domains. We report here the crystal structures at 2.8-Angstroms resolution of full-length PC from Staphylococcus aureus and the C-terminal region (missing only the BC domain) of human PC. A conserved tetrameric association is observed for both enzymes, and our structural and mutagenesis studies reveal a previously uncharacterized domain, the PC tetramerization (PT) domain, which is important for oligomerization. A BCCP domain is located in the active site of the CT domain, providing the first molecular insights into how biotin participates in the carboxyltransfer reaction. There are dramatic differences in domain positions in the monomer and the organization of the tetramer between these enzymes and the PC from Rhizobium etli.

  4. Informing energy and climate policies using energy systems models insights from scenario analysis increasing the evidence base

    CERN Document Server

    Giannakidis, George; Ó Gallachóir, Brian; Tosato, GianCarlo

    2015-01-01

    This book highlights how energy-system models are used to underpin and support energy and climate mitigation policy decisions at national, multi-country and global levels. It brings together, for the first time in one volume, a range of methodological approaches and case studies of good modeling practice on a national and international scale from the IEA-ETSAP energy technology initiative. It provides insights for the reader into the rich and varied applications of energy-system models and the underlying methodologies and policy questions they can address. The book demonstrates how these mode

  5. Climate forcing and Neanderthal extinction in Southern Iberia: insights from a multiproxy marine record

    Science.gov (United States)

    Jiménez-Espejo, Francisco J.; Martínez-Ruiz, Francisca; Finlayson, Clive; Paytan, Adina; Sakamoto, Tatsuhiko; Ortega-Huertas, Miguel; Finlayson, Geraldine; Iijima, Koichi; Gallego-Torres, David; Fa, Darren

    2007-04-01

    Paleoclimate records from the western Mediterranean have been used to further understand the role of climatic changes in the replacement of archaic human populations inhabiting South Iberia. Marine sediments from the Balearic basin (ODP Site 975) was analysed at high resolution to obtain both geochemical and mineralogical data. These data were compared with climate records from nearby areas. Baexcces was used to characterize marine productivity and then related to climatic variability. Since variations in productivity were the consequence of climatic oscillations, climate/productivity events have been established. Sedimentary regime, primary marine productivity and oxygen conditions at the time of population replacement were reconstructed by means of a multiproxy approach. Climatic/oceanographic variations correlate well with Homo spatial and occupational patterns in Southern Iberia. It was found that low ventilation (U/Th), high river supply (Mg/Al), low aridity (Zr/Al) and low values of Baexcess coefficient of variation, may be linked with Neanderthal hospitable conditions. We attempt to support recent findings which claim that Neanderthals populations continued to inhabit southern Iberia between 30 and ˜28 ky cal BP and that this persistence was due to the specific characteristics of South Iberian climatic refugia. Comparisons of our data with other marine and continental records appear to indicate that conditions in South Iberia were highly inhospitable at ˜24 ky cal BP. Thus, it is proposed that the final disappearance of Neanderthals in this region could be linked with these extreme conditions.

  6. Can Payments for Ecosystem Services Contribute to Adaptation to Climate Change? Insights from a Watershed in Kenya

    Directory of Open Access Journals (Sweden)

    Isabel van de Sand

    2014-03-01

    Full Text Available Climate change presents new challenges for the management of social-ecological systems and the ecosystem services they provide. Although the instrument of payments for ecosystem services (PES has emerged as a promising tool to safeguard or enhance the provision of ecosystem services (ES, little attention has been paid to the potential role of PES in climate change adaptation. As an external stressor climate change has an impact on the social-ecological system in which PES takes place, including the various actors taking part in the PES scheme. Following a short description of the conceptual link between PES and adaptation to climate change, we provide practical insights into the relationship between PES and adaptation to climate change by presenting results from a case study of a rural watershed in Kenya. Drawing upon the results of a participatory vulnerability assessment among potential ecosystem service providers in Sasumua watershed north of Nairobi, we show that PES can play a role in enhancing adaptation to climate change by influencing certain elements of adaptive capacity and incentivizing adaptation measures. In addition, trade-offs and synergies between proposed measures under PES and adaptation to climate change are identified. Results show that although it may not be possible to establish PES schemes based on water utilities as the sole source of financing, embedding PES in a wider adaptation framework creates an opportunity for the development of watershed PES schemes in Africa and ensures their sustainability. We conclude that there is a need to embed PES in a wider institutional framework and that extra financial resources are needed to foster greater integration between PES and adaptation to climate change. This can be achieved through scaling up PES by bringing in other buyers and additional ecosystem services. PES can achieve important coadaptation benefits, but for more effective adaptation outcomes it needs to be combined

  7. Insight derived from molecular dynamics simulations into molecular motions, thermodynamics and kinetics of HIV-1 gp120.

    Directory of Open Access Journals (Sweden)

    Peng Sang

    Full Text Available Although the crystal structures of the HIV-1 gp120 core bound and pre-bound by CD4 are known, the details of dynamics involved in conformational equilibrium and transition in relation to gp120 function have remained elusive. The homology models of gp120 comprising the N- and C-termini and loops V3 and V4 in the CD4-bound and CD4-unbound states were built and subjected to molecular dynamics (MD simulations to investigate the differences in dynamic properties and molecular motions between them. The results indicate that the CD4-bound gp120 adopted a more compact and stable conformation than the unbound form during simulations. For both the unbound and bound gp120, the large concerted motions derived from essential dynamics (ED analyses can influence the size/shape of the ligand-binding channel/cavity of gp120 and, therefore, were related to its functional properties. The differences in motion direction between certain structural components of these two forms of gp120 were related to the conformational interconversion between them. The free energy calculations based on the metadynamics simulations reveal a more rugged and complex free energy landscape (FEL for the unbound than for the bound gp120, implying that gp120 has a richer conformational diversity in the unbound form. The estimated free energy difference of ∼-6.0 kJ/mol between the global minimum free energy states of the unbound and bound gp120 indicates that gp120 can transform spontaneously from the unbound to bound states, revealing that the bound state represents a high-probability "ground state" for gp120 and explaining why the unbound state resists crystallization. Our results provide insight into the dynamics-and-function relationship of gp120, and facilitate understandings of the thermodynamics, kinetics and conformational control mechanism of HIV-1 gp120.

  8. Climate, history and neutrality as drivers of mammal beta diversity in Europe: insights from multiscale deconstruction

    DEFF Research Database (Denmark)

    Svenning, J.-C.; Fløjgaard, Camilla; Baselga, Andrés

    2011-01-01

    1. Environmental sorting, historical factors and neutral dynamics may all drive beta diversity (change in species composition across space), but their relative importance remains unresolved. In the case of European mammals, key potential drivers of large-scale beta diversity include current climate...... and regional (250 000 km2) scales. 3. We found continental-scale mammal beta diversity to be mainly caused by spatial turnover (99·9%), with only a small contribution (0·1%) from nestedness. 4. Current climate emerged as an important driver of beta diversity, given the strong continental-scale turnover...... diversity mainly reflects spatial turnover and only to a limited extent nestedness and is driven by current climate in combination with historical – and perhaps, neutral – dynamics. These findings suggest that a key challenge for climate-change predictive studies will be taking the influence of non...

  9. An improved dust emission model with insights into the global dust cycle's climate sensitivity

    Science.gov (United States)

    Kok, J. F.; Mahowald, N. M.; Albani, S.; Fratini, G.; Gillies, J. A.; Ishizuka, M.; Leys, J. F.; Mikami, M.; Park, M.-S.; Park, S.-U.; Van Pelt, R. S.; Ward, D. S.; Zobeck, T. M.

    2014-03-01

    Simulations of the global dust cycle and its interactions with a changing Earth system are hindered by the empirical nature of dust emission parameterizations in climate models. Here we take a step towards improving global dust cycle simulations by presenting a physically-based dust emission model. The resulting dust flux parameterization depends only on the wind friction speed and the soil's threshold friction speed, and can therefore be readily implemented into climate models. We show that our parameterization's functional form is supported by a compilation of quality-controlled vertical dust flux measurements, and that it better reproduces these measurements than existing parameterizations. Both our theory and measurements indicate that many climate models underestimate the dust flux's sensitivity to soil erodibility. This finding can explain why dust cycle simulations in many models are improved by using an empirical preferential sources function that shifts dust emissions towards the most erodible regions. In fact, implementing our parameterization in a climate model produces even better agreement against aerosol optical depth measurements than simulations that use such a source function. These results indicate that the need to use a source function is at least partially eliminated by the additional physics accounted for by our parameterization. Since soil erodibility is affected by climate changes, our results further suggest that many models have underestimated the climate sensitivity of the global dust cycle.

  10. New Insights into Molecular Organization of Human Neuraminidase-1: Transmembrane Topology and Dimerization Ability

    Science.gov (United States)

    Maurice, Pascal; Baud, Stéphanie; Bocharova, Olga V.; Bocharov, Eduard V.; Kuznetsov, Andrey S.; Kawecki, Charlotte; Bocquet, Olivier; Romier, Beatrice; Gorisse, Laetitia; Ghirardi, Maxime; Duca, Laurent; Blaise, Sébastien; Martiny, Laurent; Dauchez, Manuel; Efremov, Roman G.; Debelle, Laurent

    2016-01-01

    Neuraminidase 1 (NEU1) is a lysosomal sialidase catalyzing the removal of terminal sialic acids from sialyloconjugates. A plasma membrane-bound NEU1 modulating a plethora of receptors by desialylation, has been consistently documented from the last ten years. Despite a growing interest of the scientific community to NEU1, its membrane organization is not understood and current structural and biochemical data cannot account for such membrane localization. By combining molecular biology and biochemical analyses with structural biophysics and computational approaches, we identified here two regions in human NEU1 - segments 139–159 (TM1) and 316–333 (TM2) - as potential transmembrane (TM) domains. In membrane mimicking environments, the corresponding peptides form stable α-helices and TM2 is suited for self-association. This was confirmed with full-size NEU1 by co-immunoprecipitations from membrane preparations and split-ubiquitin yeast two hybrids. The TM2 region was shown to be critical for dimerization since introduction of point mutations within TM2 leads to disruption of NEU1 dimerization and decrease of sialidase activity in membrane. In conclusion, these results bring new insights in the molecular organization of membrane-bound NEU1 and demonstrate, for the first time, the presence of two potential TM domains that may anchor NEU1 in the membrane, control its dimerization and sialidase activity. PMID:27917893

  11. Molecular Insights into Aqueous NaCl Electrolytes Confined within Vertically-oriented Graphenes

    Science.gov (United States)

    Bo, Zheng; Yang, Huachao; Zhang, Shuo; Yang, Jinyuan; Yan, Jianhua; Cen, Kefa

    2015-10-01

    Vertically-oriented graphenes (VGs) are promising active materials for electric double layer capacitors (EDLCs) due to their unique morphological and structural features. This study, for the first time, reports the molecular dynamics (MD) simulations on aqueous NaCl electrolytes confined within VG channels with different surface charge densities and channel widths. Simulation results show that the accessibility of ions and the structure of EDLCs are determined by the ion type/size, surface charging, and VG channel width. For relatively narrow VG channels with the same width, the threshold charge density (to compensate the energy penalty for shedding hydration shell) and the dehydration rate of Cl- ions are larger than those of Na+ ions. To achieve the highest ion concentration coefficient, the effective VG channel width should be between the crystal and hydration diameters of the ions. The results are further quantified and elucidated by calculating the electrolyte density profiles. The molecular insights obtained in the current work are useful in guiding the design and fabrication of VGs for advancing their EDLC applications.

  12. First insight into the molecular epidemiology of Mycobacterium tuberculosis in Santa Catarina, southern Brazil.

    Science.gov (United States)

    Nogueira, Christiane Lourenço; Prim, Rodrigo Ivan; Senna, Simone Gonçalves; Rovaris, Darcita Büerger; Maurici, Rosemeri; Rossetti, Maria Lúcia; Couvin, David; Rastogi, Nalin; Bazzo, Maria Luiza

    2016-03-01

    Molecular epidemiology of Mycobacterium tuberculosis is useful for understanding disease transmission dynamics, and to establish strategic measures for TB control and prevention. The aim of this study was to analyze clinical, epidemiological and molecular characteristics of MTBC clinical isolates from Santa Catarina state, southern Brazil. During one-year period, 406 clinical isolates of MTBC were collected from Central Laboratory of Public Health and typed by spoligotyping. Demographic and clinical data were collected from the Brazilian National Mandatory Disease Reporting System. The majority of cases occurred in highest population densities regions and about 50% had some condition associated with TB. Among all isolates, 5.7% were MDR, which showed association with drug addiction. LAM was the most predominant lineage with 47.5%, followed by the T superfamily with 25.9% and Haarlem with 12.3%. The MST showed two major groups: the first was formed mainly by the LAM lineage and the second was mainly formed by the T and Haarlem lineages. Others lineages were distributed in peripheral positions. This study provides the first insight into the population structure of M. tuberculosis in SC State. Spoligotyping and other genotyping analyses are important to establish strategic measures for TB control and prevention.

  13. H2S biosynthesis and catabolism: new insights from molecular studies.

    Science.gov (United States)

    Rose, Peter; Moore, Philip K; Zhu, Yi Zhun

    2016-11-14

    Hydrogen sulfide (H2S) has profound biological effects within living organisms and is now increasingly being considered alongside other gaseous signalling molecules, such as nitric oxide (NO) and carbon monoxide (CO). Conventional use of pharmacological and molecular approaches has spawned a rapidly growing research field that has identified H2S as playing a functional role in cell-signalling and post-translational modifications. Recently, a number of laboratories have reported the use of siRNA methodologies and genetic mouse models to mimic the loss of function of genes involved in the biosynthesis and degradation of H2S within tissues. Studies utilising these systems are revealing new insights into the biology of H2S within the cardiovascular system, inflammatory disease, and in cell signalling. In light of this work, the current review will describe recent advances in H2S research made possible by the use of molecular approaches and genetic mouse models with perturbed capacities to generate or detoxify physiological levels of H2S gas within tissues.

  14. Molecular Insights into Division of Single Human Cancer Cells in On-Chip Transparent Microtubes

    Science.gov (United States)

    2016-01-01

    In vivo, mammalian cells proliferate within 3D environments consisting of numerous microcavities and channels, which contain a variety of chemical and physical cues. External environments often differ between normal and pathological states, such as the unique spatial constraints that metastasizing cancer cells experience as they circulate the vasculature through arterioles and narrow capillaries, where they can divide and acquire elongated cylindrical shapes. While metastatic tumors cause most cancer deaths, factors impacting early cancer cell proliferation inside the vasculature and those that can promote the formation of secondary tumors remain largely unknown. Prior studies investigating confined mitosis have mainly used 2D cell culture systems. Here, we mimic aspects of metastasizing tumor cells dividing inside blood capillaries by investigating single-cell divisions of living human cancer cells, trapped inside 3D rolled-up, transparent nanomembranes. We assess the molecular effects of tubular confinement on key mitotic features, using optical high- and super-resolution microscopy. Our experiments show that tubular confinement affects the morphology and dynamics of the mitotic spindle, chromosome arrangements, and the organization of the cell cortex. Moreover, we reveal that membrane blebbing and/or associated processes act as a potential genome-safety mechanism, limiting the extent of genomic instability caused by mitosis in confined circumstances, especially in tubular 3D microenvironments. Collectively, our study demonstrates the potential of rolled-up nanomembranes for gaining molecular insights into key cellular events occurring in tubular 3D microenvironments in vivo. PMID:27267364

  15. New Insights into Molecular Organization of Human Neuraminidase-1: Transmembrane Topology and Dimerization Ability

    Science.gov (United States)

    Maurice, Pascal; Baud, Stéphanie; Bocharova, Olga V.; Bocharov, Eduard V.; Kuznetsov, Andrey S.; Kawecki, Charlotte; Bocquet, Olivier; Romier, Beatrice; Gorisse, Laetitia; Ghirardi, Maxime; Duca, Laurent; Blaise, Sébastien; Martiny, Laurent; Dauchez, Manuel; Efremov, Roman G.; Debelle, Laurent

    2016-12-01

    Neuraminidase 1 (NEU1) is a lysosomal sialidase catalyzing the removal of terminal sialic acids from sialyloconjugates. A plasma membrane-bound NEU1 modulating a plethora of receptors by desialylation, has been consistently documented from the last ten years. Despite a growing interest of the scientific community to NEU1, its membrane organization is not understood and current structural and biochemical data cannot account for such membrane localization. By combining molecular biology and biochemical analyses with structural biophysics and computational approaches, we identified here two regions in human NEU1 - segments 139-159 (TM1) and 316-333 (TM2) - as potential transmembrane (TM) domains. In membrane mimicking environments, the corresponding peptides form stable α-helices and TM2 is suited for self-association. This was confirmed with full-size NEU1 by co-immunoprecipitations from membrane preparations and split-ubiquitin yeast two hybrids. The TM2 region was shown to be critical for dimerization since introduction of point mutations within TM2 leads to disruption of NEU1 dimerization and decrease of sialidase activity in membrane. In conclusion, these results bring new insights in the molecular organization of membrane-bound NEU1 and demonstrate, for the first time, the presence of two potential TM domains that may anchor NEU1 in the membrane, control its dimerization and sialidase activity.

  16. How does joint remodeling work?: new insights in the molecular regulation of the architecture of joints.

    Science.gov (United States)

    Schett, Georg

    2007-01-01

    Remodeling of joints is a key feature of inflammatory and degenerative joint disease. Bone erosion, cartilage degeneration and growth of bony spurs termed osteophytes are key features of structural joint pathology in the course of arthritis, which lead to impairment of joint function. Understanding their molecular mechanisms is essential to tailor targeted therapeutic approaches to protect joint architecture from inflammatory and mechanical stress. This addendum summarizes the new insights in the molecular regulation of bone formation in the joint and its relation to bone resorption. It describes how inflammatory cytokines impair bone formation and block the repair response of joints towards inflammatory stimuli. It particularly points out the key role of Dickkopf-1 protein, a regulator of the Wingless signaling and inhibitor of bone formation. This new link between inflammation and bone formation is also crucial for explaining the generation of osteophytes, bony spurs along joints, which are characterized by new bone and cartilage formation. This mechanism is largely dependent on an activation of wingless protein signaling and can lead to complete joint fusion. This addendum summarized the current concepts of joint remodeling in the limelight of these new findings.

  17. Plasmodium in the postgenomic era: new insights into the molecular cell biology of malaria parasites.

    Science.gov (United States)

    Garcia, Celia R S; de Azevedo, Mauro F; Wunderlich, Gerhard; Budu, Alexandre; Young, Jason A; Bannister, Lawrence

    2008-01-01

    In this review, we bring together some of the approaches toward understanding the cellular and molecular biology of Plasmodium species and their interaction with their host red blood cells. Considerable impetus has come from the development of new methods of molecular genetics and bioinformatics, and it is important to evaluate the wealth of these novel data in the context of basic cell biology. We describe how these approaches are gaining valuable insights into the parasite-host cell interaction, including (1) the multistep process of red blood cell invasion by the merozoite; (2) the mechanisms by which the intracellular parasite feeds on the red blood cell and exports parasite proteins to modify its cytoadherent properties; (3) the modulation of the cell cycle by sensing the environmental tryptophan-related molecules; (4) the mechanism used to survive in a low Ca(2+) concentration inside red blood cells; (5) the activation of signal transduction machinery and the regulation of intracellular calcium; (6) transfection technology; and (7) transcriptional regulation and genome-wide mRNA studies in Plasmodium falciparum.

  18. An insight into the isolation, enumeration and molecular detection of Listeria monocytogenes in food

    Directory of Open Access Journals (Sweden)

    Jodi Woan-Fei Law

    2015-11-01

    Full Text Available Listeria monocytogenes, a foodborne pathogen that can cause listeriosis through the consumption of food contaminated with this pathogen. The ability of L. monocytogenes to survive in extreme conditions and cause food contaminations have become a major concern. Hence, routine microbiological food testing is necessary to prevent food contamination and outbreaks of foodborne illness. This review provides insight into the methods for cultural detection, enumeration and molecular identification of L. monocytogenes in various food samples. There are a number of enrichment and plating media that can be used for the isolation of L. monocytogenes from food samples. Enrichment media such as buffered Listeria Enrichment Broth (BLEB, Fraser broth and University of Vermont Medium (UVM Listeria enrichment broth are recommended by regulatory agencies such as FDA-BAM, USDA-FSIS and ISO. Many plating media are available for the isolation of L. monocytogenes, for instance, PALCAM, Oxford and other chromogenic media. Besides, reference methods like FDA-BAM, ISO 11290 method and USDA-FSIS method are usually applied for the cultural detection or enumeration of L. monocytogenes. MPN technique is applied for the enumeration of L. monocytogenes in the case of low level contamination. Molecular methods including polymerase chain reaction (PCR, multiplex polymerase chain reaction (mPCR, real-time/quantitative polymerase chain reaction (qPCR, nucleic acid sequence-based amplification (NASBA, loop-mediated isothermal amplification (LAMP, DNA microarray and Next Generation Sequencing (NGS technology for the detection and identification of L. monocytogenes are discussed in this review. Overall, molecular methods are rapid, sensitive, specific, time- and labour-saving. In future, there are chances for the development of new techniques for the detection and identification of foodborne with improved features.

  19. Insights into the molecular basis of L-form formation and survival in Escherichia coli.

    Directory of Open Access Journals (Sweden)

    William A Glover

    Full Text Available L-forms have been shown to occur among many species of bacteria and are suspected to be involved in persistent infections. Since their discovery in 1935, numerous studies characterizing L-form morphology, growth, and pathogenic potential have been conducted. However, the molecular mechanisms underlying the formation and survival of L-forms remain unknown. Using unstable L-form colonies of Escherichia coli as a model, we performed genome-wide transcriptome analysis and screened a deletion mutant library to study the molecular mechanisms involved in formation and survival of L-forms. Microarray analysis of L-form versus classical colonies revealed many up-regulated genes of unknown function as well as multiple over-expressed stress pathways shared in common with persister cells and biofilms. Mutant screens identified three groups of mutants which displayed varying degrees of defects in L-form colony formation. Group 1 mutants, which showed the strongest defect in L-form colony formation, belonged to pathways involved in cell envelope stress, DNA repair, iron homeostasis, outer membrane biogenesis, and drug efflux/ABC transporters. Four (Group 1 mutants, rcsB, a positive response regulator of colanic acid capsule synthesis, ruvA, a recombinational junction binding protein, fur, a ferric uptake regulator and smpA a small membrane lipoprotein were selected for complementation. Complementation of the mutants using a high-copy overexpression vector failed, while utilization of a low-copy inducible vector successfully restored L-form formation. This work represents the first systematic genetic evaluation of genes and pathways involved in the formation and survival of unstable L-form bacteria. Our findings provide new insights into the molecular mechanisms underlying L-form formation and survival and have implications for understanding the emergence of antibiotic resistance, bacterial persistence and latent infections and designing novel drugs and

  20. Sensitivity of crop cover to climate variability: insights from two Indian agro-ecoregions.

    Science.gov (United States)

    Mondal, Pinki; Jain, Meha; DeFries, Ruth S; Galford, Gillian L; Small, Christopher

    2015-01-15

    Crop productivity in India varies greatly with inter-annual climate variability and is highly dependent on monsoon rainfall and temperature. The sensitivity of yields to future climate variability varies with crop type, access to irrigation and other biophysical and socio-economic factors. To better understand sensitivities to future climate, this study focuses on agro-ecological subregions in Central and Western India that span a range of crops, irrigation, biophysical conditions and socioeconomic characteristics. Climate variability is derived from remotely-sensed data products, Tropical Rainfall Measuring Mission (TRMM - precipitation) and Moderate Resolution Imaging Spectroradiometer (MODIS - temperature). We examined green-leaf phenologies as proxy for crop productivity using the MODIS Enhanced Vegetation Index (EVI) from 2000 to 2012. Using both monsoon and winter growing seasons, we assessed phenological sensitivity to inter-annual variability in precipitation and temperature patterns. Inter-annual EVI phenology anomalies ranged from -25% to 25%, with some highly anomalous values up to 200%. Monsoon crop phenology in the Central India site is highly sensitive to climate, especially the timing of the start and end of the monsoon and intensity of precipitation. In the Western India site, monsoon crop phenology is less sensitive to precipitation variability, yet shows considerable fluctuations in monsoon crop productivity across the years. Temperature is critically important for winter productivity across a range of crop and management types, such that irrigation might not provide a sufficient buffer against projected temperature increases. Better access to weather information and usage of climate-resilient crop types would play pivotal role in maintaining future productivity. Effective strategies to adapt to projected climate changes in the coming decades would also need to be tailored to regional biophysical and socio-economic conditions.

  1. Climate, history and neutrality as drivers of mammal beta diversity in Europe: insights from multiscale deconstruction.

    Science.gov (United States)

    Svenning, Jens-Christian; Fløjgaard, Camilla; Baselga, Andrés

    2011-03-01

    1. Environmental sorting, historical factors and neutral dynamics may all drive beta diversity (change in species composition across space), but their relative importance remains unresolved. In the case of European mammals, key potential drivers of large-scale beta diversity include current climate, neutral dynamics and two historical factors: Pleistocene glaciations and peninsular dynamics (immigration from extra-regional eastern faunal source areas and inter-linked relictual survival and evolutionary differentiation in isolated areas). 2. We assessed the relative importance of these drivers using a novel analytical framework to deconstruct beta diversity of non-volant mammals in Europe (138 species) into its turnover (change in species composition because of species replacements) and nestedness components (change in species composition because of species richness differences) at continental and regional (250,000 km(2) ) scales. 3. We found continental-scale mammal beta diversity to be mainly caused by spatial turnover (99·9%), with only a small contribution (0·1%) from nestedness. 4. Current climate emerged as an important driver of beta diversity, given the strong continental-scale turnover, particularly in north-south direction, i.e., in line with the latitudinal climate gradient, and, more directly, the strong correlation of climate with spatial turnover at both continental and regional scales. 5. However, there was also evidence for the importance of non-climatic drivers. Notably, the compositional variation purely accounted for by space was greater than that purely accounted for by environment for both the turnover and the nestedness component of beta diversity. Furthermore, the strong longitudinal turnover within Southern Europe is in accordance with the region's long-term climatic stability having allowed multiple refugia and local evolutionary diversification. As expected from peninsular dynamics, there was increasing dissimilarity with

  2. Parasite zoonoses and climate change: molecular tools for tracking shifting boundaries.

    Science.gov (United States)

    Polley, Lydden; Thompson, R C Andrew

    2009-06-01

    For human, domestic animal and wildlife health, key effects of directional climate change include the risk of the altered occurrence of infectious diseases. Many parasite zoonoses have high potential for vulnerability to the new climate, in part because their free-living life-cycle stages and ectothermic hosts are directly exposed to climatic conditions. For these zoonoses, climate change can shift boundaries for ecosystem components and processes integral to parasite transmission and persistence, and these shifts can impact host health. Vulnerable boundaries include those for spatial distributions, host-parasite assemblages, demographic rates, life-cycle phenologies, associations within ecosystems, virulence, and patterns of infection and disease. This review describes these boundary shifts and how molecular techniques can be applied to defining the new boundaries.

  3. Facilitating climate change adaptation through communication: Insights from the development of a visualization tool

    DEFF Research Database (Denmark)

    Glaas, Erik; Ballantyne, Anne Gammelgaard; Neset, Tina

    2015-01-01

    Climate change communication on anticipated impacts and adaptive responses is frequently presented as an effective means to facilitate implementation of adaptation to mitigate risks to residential buildings. However, it requires that communication is developed in a way that resonates...... with the context of the target audience, provides intelligible information and addresses perceived barriers to adaptation. In this paper we reflect upon criteria for useful climate change communication gained over a three year development process of a web-based tool - VisAdaptTM – aimed at increasing the adaptive...... capacity among Nordic homeowners. Based on the results from continuous user-testing and focus group interviews we outline lessons learned and key aspects to consider in the design of tools for communicating complex issues such as climate change effects and adaptive response measures....

  4. Topographic Evolution and Climate Aridification during Continental Collision: Insights from Computer Simulations.

    Directory of Open Access Journals (Sweden)

    Daniel Garcia-Castellanos

    Full Text Available How do the feedbacks between tectonics, sediment transport and climate work to shape the topographic evolution of the Earth? This question has been widely addressed via numerical models constrained with thermochronological and geomorphological data at scales ranging from local to orogenic. Here we present a novel numerical model that aims at reproducing the interaction between these processes at the continental scale. For this purpose, we combine in a single computer program: 1 a thin-sheet viscous model of continental deformation; 2 a stream-power surface-transport approach; 3 flexural isostasy allowing for the formation of large sedimentary foreland basins; and 4 an orographic precipitation model that reproduces basic climatic effects such as continentality and rain shadow. We quantify the feedbacks between these processes in a synthetic scenario inspired by the India-Asia collision and the growth of the Tibetan Plateau. We identify a feedback between erosion and crustal thickening leading locally to a <50% increase in deformation rates in places where orographic precipitation is concentrated. This climatically-enhanced deformation takes place preferentially at the upwind flank of the growing plateau, specially at the corners of the indenter (syntaxes. We hypothesize that this may provide clues for better understanding the mechanisms underlying the intriguing tectonic aneurisms documented in the Himalayas. At the continental scale, however, the overall distribution of topographic basins and ranges seems insensitive to climatic factors, despite these do have important, sometimes counterintuitive effects on the amount of sediments trapped within the continent. The dry climatic conditions that naturally develop in the interior of the continent, for example, trigger large intra-continental sediment trapping at basins similar to the Tarim Basin because they determine its endorheic/exorheic drainage. These complex climatic

  5. Global Deliberative Democracy and Climate Change: Insights from World Wide Views on Global Warming in Australia

    Directory of Open Access Journals (Sweden)

    Chris Riedy

    2011-12-01

    Full Text Available On 26 September 2009, approximately 4,000 citizens in 38 countries participated in World Wide Views on Global Warming (WWViews. WWViews was an ambitious first attempt to convene a deliberative mini-public at a global scale, giving people from around the world an opportunity to deliberate on international climate policy and to make recommendations to the decision-makers meeting at the United Nations Climate Change Conference in Copenhagen (COP-15 in December 2009. In this paper, we examine the role that deliberative mini-publics can play in facilitating the emergence of a global deliberative system for climate change response. We pursue this intent through a reflective evaluation of the Australian component of the World Wide Views on Global Warming project (WWViews. Our evaluation of WWViews is mixed. The Australian event was delivered with integrity and feedback from Australian participants was almost universally positive. Globally, WWViews demonstrated that it is feasible to convene a global mini-public to deliberate on issues of global relevance, such as climate change. On the other hand, the contribution of WWViews towards the emergence of a global deliberative system for climate change response was limited and it achieved little influence on global climate change policy. We identify lessons for future global mini-publics, including the need to prioritise the quality of deliberation and provide flexibility to respond to cultural and political contexts in different parts of the world. Future global mini-publics may be more influential if they seek to represent discourse diversity in addition to demographic profiles, use designs that maximise the potential for transmission from public to empowered space, run over longer time periods to build momentum for change and experiment with ways of bringing global citizens together in a single process instead of discrete national events.

  6. Informing climate change adaptation with insights from famine early warning (Invited)

    Science.gov (United States)

    Funk, C. C.; Verdin, J. P.

    2010-12-01

    Famine early warning systems provide a unique viewpoint for understanding the implications of climate change on food security, identifying the locations and seasons where millions of food insecure people are dependent upon climate-sensitive agricultural systems. The Famine Early Warning Systems Network (FEWS NET) is a decision support system sponsored by the Office of Food for Peace of the U.S. Agency for International Development (USAID), which distributes over two billion dollars of food aid to more than 40 countries each year. FEWS NET identifies the times and places where food aid is required by the most climatically sensitive and consequently food insecure populations of the developing world. As result, FEWS NET has developed its own "climate service", implemented by USGS, NOAA, and NASA, to support its decision making processes. The foundation of this climate service is the monitoring of current growing conditions for early identification of agricultural drought that might impact food security. Since station networks are sparse in the countries monitored, FEWS NET has a tradition (dating back to 1985) of reliance on satellite remote sensing of vegetation and rainfall. In the last ten years, climate forecasts have become an additional tool for food security assessment, extending the early warning perspective to include expected agricultural outcomes for the season ahead. More recently, research has expanded to include detailed analyses of recent observed climate trends, combined with diagnostic ocean-atmosphere studies. These studies are then used to develop interpretations of GCM scenarios and their implications for future patterns of precipitation and temperature, revealing trends towards warmer/drier climate conditions and increases in the relative frequency of drought. In some regions, like Eastern Africa, such changes seem to be already occurring, with an associated increase in food insecurity. Sub-national analyses for Kenya, for example, point to the

  7. Chemical insight from density functional modeling of molecular adsorption: Tracking the bonding and diffusion of anthracene derivatives on Cu(111) with molecular orbitals

    Science.gov (United States)

    Wyrick, Jonathan; Einstein, T. L.; Bartels, Ludwig

    2015-03-01

    We present a method of analyzing the results of density functional modeling of molecular adsorption in terms of an analogue of molecular orbitals. This approach permits intuitive chemical insight into the adsorption process. Applied to a set of anthracene derivates (anthracene, 9,10-anthraquinone, 9,10-dithioanthracene, and 9,10-diselenonanthracene), we follow the electronic states of the molecules that are involved in the bonding process and correlate them to both the molecular adsorption geometry and the species' diffusive behavior. We additionally provide computational code to easily repeat this analysis on any system.

  8. Chemical insight from density functional modeling of molecular adsorption: Tracking the bonding and diffusion of anthracene derivatives on Cu(111) with molecular orbitals

    Energy Technology Data Exchange (ETDEWEB)

    Wyrick, Jonathan; Bartels, Ludwig, E-mail: ludwig.bartels@ucr.edu [Pierce Hall, University of California-Riverside, Riverside, California 92521 (United States); Einstein, T. L. [Department of Physics and Condensed Matter Theory Center, University of Maryland, College Park, Maryland 20742-4111 (United States)

    2015-03-14

    We present a method of analyzing the results of density functional modeling of molecular adsorption in terms of an analogue of molecular orbitals. This approach permits intuitive chemical insight into the adsorption process. Applied to a set of anthracene derivates (anthracene, 9,10-anthraquinone, 9,10-dithioanthracene, and 9,10-diselenonanthracene), we follow the electronic states of the molecules that are involved in the bonding process and correlate them to both the molecular adsorption geometry and the species’ diffusive behavior. We additionally provide computational code to easily repeat this analysis on any system.

  9. Climate change threatens archaeologically significant ice patches: insights into their age, internal structure, mass balance and climate sensitivity

    Science.gov (United States)

    Strand Ødegård, Rune; Nesje, Atle; Isaksen, Ketil; Andreassen, Liss Marie; Eiken, Trond; Schwikowski, Margit; Uglietti, Chiara

    2017-01-01

    Despite numerous spectacular archaeological discoveries worldwide related to melting ice patches and the emerging field of glacial archaeology, governing processes related to ice patch development during the Holocene and their sensitivity to climate change are still largely unexplored. Here we present new results from an extensive 6-year (2009-2015) field experiment at the Juvfonne ice patch in Jotunheimen in central southern Norway. Our results show that the ice patch has existed continuously since the late Mesolithic period. Organic-rich layers and carbonaceous aerosols embedded in clear ice show ages spanning from modern at the surface to ca. 7600 cal years BP at the bottom. This is the oldest dating of ice in mainland Norway. The expanding ice patch covered moss mats appearing along the margin of Juvfonne about 2000 years ago. During the study period, the mass balance record showed a strong negative balance, and the annual balance is highly asymmetric over short distances. Snow accumulation is poorly correlated with estimated winter precipitation, and single storm events may contribute significantly to the total winter balance. Snow accumulation is approx. 20 % higher in the frontal area compared to the upper central part of the ice patch. There is sufficient meltwater to bring the permeable snowpack to an isothermal state within a few weeks in early summer. Below the seasonal snowpack, ice temperatures are between -2 and -4 °C. Juvfonne has clear ice stratification of isochronic origin.

  10. Tree Rings in the Tropics: Insights into the Ecology and Climate Sensitivity of Tropical Trees

    NARCIS (Netherlands)

    Brienen, R.J.W.; Schöngart, J.; Zuidema, P.A.

    2016-01-01

    Tree-ring studies provide important contributions to understanding the climate sensitivity of tropical trees and the effects of global change on tropical forests. This chapter reviews recent advances in tropical tree-ring research. In tropical lowlands, tree ring formation is mainly driven by season

  11. Reconciling collaborative action research with existing institutions: insights from Dutch and German climate knowledge programmes

    NARCIS (Netherlands)

    Termeer, C.J.A.M.; Buuren, van A.; Knieling, J.; Gottschick, M.

    2015-01-01

    Researchers and policymakers increasingly aim to set up collaborative research programmes to address the challenges of adaptation to climate change. This does not only apply for technical knowledge, but for governance knowledge also. Both the Netherlands and Germany have set up large scale collabora

  12. Planning for climate change in small islands: insights from national hurricane preparedness in the Cayman Islands

    Energy Technology Data Exchange (ETDEWEB)

    Tompkins, E.L. [University of East Anglia, Norwich (United Kingdom). School of Environmental Sciences

    2005-07-01

    This paper examines contemporary national scale responses to tropical storm risk in a small island in the Caribbean to derive lessons for adapting to climate change. There is little empirical evidence to guide national planners on how to adapt to climate change, and less still on how to build on past adaptation experiences. The paper investigates the construction of institutional resilience and the process of adaptation to tropical storm risk by the Cayman Islands' Government from 1988 to 2002. It explains the roles of persuasion, exposure and collective action as key components in developing the ability to buffer external disturbance using models of institutional economics and social resilience concepts. The study finds that self-efficacy, strong local and international support networks, combined with a willingness to act collectively and to learn from mistakes appear to have increased the resilience of the Cayman Islands' Government to tropical storm risk. The lessons learned from building resilience to storm risk can contribute to the creation of national level adaptive capacity to climate change, but climate change has to be prioritised before these lessons can be transferred. (author)

  13. Atomistic insight into the catalytic mechanism of glycosyltransferases by combined quantum mechanics/molecular mechanics (QM/MM) methods.

    Science.gov (United States)

    Tvaroška, Igor

    2015-02-11

    Glycosyltransferases catalyze the formation of glycosidic bonds by assisting the transfer of a sugar residue from donors to specific acceptor molecules. Although structural and kinetic data have provided insight into mechanistic strategies employed by these enzymes, molecular modeling studies are essential for the understanding of glycosyltransferase catalyzed reactions at the atomistic level. For such modeling, combined quantum mechanics/molecular mechanics (QM/MM) methods have emerged as crucial. These methods allow the modeling of enzymatic reactions by using quantum mechanical methods for the calculation of the electronic structure of the active site models and treating the remaining enzyme environment by faster molecular mechanics methods. Herein, the application of QM/MM methods to glycosyltransferase catalyzed reactions is reviewed, and the insight from modeling of glycosyl transfer into the mechanisms and transition states structures of both inverting and retaining glycosyltransferases are discussed.

  14. Molecular insights into the evolutionary pathway of Vibrio cholerae O1 atypical El Tor variants.

    Science.gov (United States)

    Kim, Eun Jin; Lee, Dokyung; Moon, Se Hoon; Lee, Chan Hee; Kim, Sang Jun; Lee, Jae Hyun; Kim, Jae Ouk; Song, Manki; Das, Bhabatosh; Clemens, John D; Pape, Jean William; Nair, G Balakrish; Kim, Dong Wook

    2014-09-01

    Pandemic V. cholerae strains in the O1 serogroup have 2 biotypes: classical and El Tor. The classical biotype strains of the sixth pandemic, which encode the classical type cholera toxin (CT), have been replaced by El Tor biotype strains of the seventh pandemic. The prototype El Tor strains that produce biotype-specific cholera toxin are being replaced by atypical El Tor variants that harbor classical cholera toxin. Atypical El Tor strains are categorized into 2 groups, Wave 2 and Wave 3 strains, based on genomic variations and the CTX phage that they harbor. Whole-genome analysis of V. cholerae strains in the seventh cholera pandemic has demonstrated gradual changes in the genome of prototype and atypical El Tor strains, indicating that atypical strains arose from the prototype strains by replacing the CTX phages. We examined the molecular mechanisms that effected the emergence of El Tor strains with classical cholera toxin-carrying phage. We isolated an intermediary V. cholerae strain that carried two different CTX phages that encode El Tor and classical cholera toxin, respectively. We show here that the intermediary strain can be converted into various Wave 2 strains and can act as the source of the novel mosaic CTX phages. These results imply that the Wave 2 and Wave 3 strains may have been generated from such intermediary strains in nature. Prototype El Tor strains can become Wave 3 strains by excision of CTX-1 and re-equipping with the new CTX phages. Our data suggest that inter-chromosomal recombination between 2 types of CTX phages is possible when a host bacterial cell is infected by multiple CTX phages. Our study also provides molecular insights into population changes in V. cholerae in the absence of significant changes to the genome but by replacement of the CTX prophage that they harbor.

  15. Mechanism for cocaine blocking the transport of dopamine: insights from molecular modeling and dynamics simulations.

    Science.gov (United States)

    Huang, Xiaoqin; Gu, Howard H; Zhan, Chang-Guo

    2009-11-12

    Molecular modeling and dynamics simulations have been performed to study how cocaine inhibits dopamine transporter (DAT) for the transport of dopamine. The computationally determined DAT-ligand binding mode is totally different from the previously proposed overlap binding mode in which cocaine- and dopamine-binding sites are the same (Beuming, T.; et al. Nat. Neurosci. 2008, 11, 780-789). The new cocaine-binding site does not overlap with, but is close to, the dopamine-binding site. Analysis of all results reveals that when cocaine binds to DAT, the initial binding site is likely the one modeled in this study because this binding site can naturally accommodate cocaine. Then cocaine may move to the dopamine-binding site after DAT makes some necessary conformational change and expands the binding site cavity. It has been demonstrated that cocaine may inhibit the transport of dopamine through both blocking the initial DAT-dopamine binding and reducing the kinetic turnover of the transporter following the DAT-dopamine binding. The relative contributions to the phenomenological inhibition of the transport of dopamine from blocking the initial binding and reducing the kinetic turnover can be different in different types of assays. The obtained general structural and mechanistic insights are consistent with available experimental data and could be valuable for guiding future studies toward understanding cocaine's inhibiting of other transporters.

  16. The topology and dynamics of protein complexes: insights from intra- molecular network theory.

    Science.gov (United States)

    Hu, Guang; Zhou, Jianhong; Yan, Wenying; Chen, Jiajia; Shen, Bairong

    2013-03-01

    Intra-molecular interactions within complex systems play a pivotal role in the biological function. They form a major challenge to computational structural proteomics. The network paradigm treats any system as a set of nodes linked by edges corresponding to the relations existing between the nodes. It offers a computationally efficient tool to meet this challenge. Here, we review the recent advances in the use of network theory to study the topology and dynamics of protein- ligand and protein-nucleic acid complexes. The study of protein complexes networks not only involves the topological classification in term of network parameters, but also reveals the consistent picture of intrinsic functional dynamics. Current dynamical analysis focuses on a plethora of functional phenomena: the process of allosteric communication, the binding induced conformational changes, prediction and identification of binding sites of protein complexes, which will give insights into intra-protein complexes interactions. Furthermore, such computational results may elucidate a variety of known biological processes and experimental data, and thereby demonstrate a huge potential for applications such as drug design and functional genomics. Finally we describe some web-based resources for protein complexes, as well as protein network servers and related bioinformatics tools.

  17. Improved insights into protein thermal stability: from the molecular to the structurome scale.

    Science.gov (United States)

    Pucci, Fabrizio; Rooman, Marianne

    2016-11-13

    Despite the intense efforts of the last decades to understand the thermal stability of proteins, the mechanisms responsible for its modulation still remain debated. In this investigation, we tackle this issue by showing how a multiscale perspective can yield new insights. With the help of temperature-dependent statistical potentials, we analysed some amino acid interactions at the molecular level, which are suggested to be relevant for the enhancement of thermal resistance. We then investigated the thermal stability at the protein level by quantifying its modification upon amino acid substitutions. Finally, a large scale analysis of protein stability-at the structurome level-contributed to the clarification of the relation between stability and natural evolution, thereby showing that the mutational profile of proteins differs according to their thermal properties. Some considerations on how the multiscale approach could help in unravelling the protein stability mechanisms are briefly discussed.This article is part of the themed issue 'Multiscale modelling at the physics-chemistry-biology interface'.

  18. New Insights into the Molecular Basis of Kidney Governing Bone Theory

    Directory of Open Access Journals (Sweden)

    Dong-feng Zhao

    2015-07-01

    Full Text Available Kidney governing bone theory plays an important role in treating bone metabolic disease such as osteoporosis, and many tonifying kidney prescriptions/herbs are widely used in Traditional Chinese Medicine (TCM. However, the exact biological basis of kidney governing bone theory in the context of new advances in biology is still not fully established. In this paper, the content of kidney governing bone theory in biology has been fully demonstrated from different aspects. We first propose that bone and kidney mutually affect each other in pathology and physiology, particularly through homeostasis of calcium, phosphorus and fibroblast growth factor-23(FGF-23. Next, we identify that tonifying kidney prescriptions/herbs exert bone protective effects, thus treating osteoporosis by regulating bone formation and bone resorption. Furthermore, the exact molecular mechanisms of tonifying kidney prescriptions, herbs and their effective components in treating osteoporosis have been systematically reviewed. Finally, we come into the conclusion that kidney regulating bone mineral homeostasis, bone protective effects of tonifying kidney herbs and regulatory effects on bone homeostasis are all the manifestations of kidney governing bone theory. Therefore, the new insights into kidney governing bone theory in biology will promote the development of clinical practices, and drugs discovery in treating osteoporosis.

  19. New Insights into the Molecular Basis of Kidney Governing Bone Theory

    Institute of Scientific and Technical Information of China (English)

    Dong-feng Zhao; Yong-jian Zhao; Cheng-long Wang; Yan-ping Yang; Yong-jun Wang

    2015-01-01

    Kidney governing bone theory plays an important role in treating bone metabolic disease such as osteoporosis, and many tonifying kidney prescriptions/herbs are widely used in Traditional Chinese Medicine (TCM). However, the exact biological basis of kidney governing bone theory in the context of new advances in biology is still not fully established. In this paper, the content of kidney governing bone theory in biology has been fully demonstrated from different aspects. We first propose that bone and kidney mutually affect each other in pathology and physiology, particularly through homeostasis of calcium, phosphorus and fibroblast growth factor-23(FGF-23). Next, we identify that tonifying kidney prescriptions/herbs exert bone protective effects, thus treating osteoporosis by regulating bone formation and bone resorption. Furthermore, the exact molecular mechanisms of tonifying kidney prescriptions, herbs and their effective components in treating osteoporosis have been systematically reviewed. Finally, we come into the conclusion that kidney regulating bone mineral homeostasis, bone protective effects of tonifying kidney herbs and regulatory effects on bone homeostasis are all the manifestations of kidney governing bone theory. Therefore, the new insights into kidney governing bone theory in biology will promote the development of clinical practices, and drugs discovery in treating osteoporosis.

  20. Mechanistic Insights into Molecular Targeting and Combined Modality Therapy for Aggressive, Localized Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Alan eDal Pra

    2016-02-01

    Full Text Available Radiation therapy (RT is one of the mainstay treatments for prostate cancer (PCa. The potentially curative approaches can provide satisfactory results for many patients with non-metastatic PCa; however, a considerable number of individuals may present disease recurrence and die from the disease. Exploiting the rich molecular biology of PCa will provide insights into how the most resistant tumor cells can be eradicated to improve treatment outcomes. Important for this biology-driven individualized treatment is a robust selection procedure. The development of predictive biomarkers for RT efficacy is therefore of utmost importance for a clinically exploitable strategy to achieve tumor-specific radiosensitization. This review highlights the current status and possible opportunities in the modulation of four key processes to enhance radiation response in PCa by targeting the: I. androgen signaling pathway; II. hypoxic tumor cells and regions; III. DNA damage response (DDR pathway; and IV. abnormal extra/intra-cell signaling pathways. In addition, we discuss how and which patients should be selected for biomarker-based clinical trials exploiting and validating these targeted treatment strategies with precision RT to improve cure rates in non-indolent, localized PCa.

  1. Dissecting the molecular structure of the Orion B cloud: insight from principal component analysis

    Science.gov (United States)

    Gratier, Pierre; Bron, Emeric; Gerin, Maryvonne; Pety, Jérôme; Guzman, Viviana V.; Orkisz, Jan; Bardeau, Sébastien; Goicoechea, Javier R.; Le Petit, Franck; Liszt, Harvey; Öberg, Karin; Peretto, Nicolas; Roueff, Evelyne; Sievers, Albrech; Tremblin, Pascal

    2017-03-01

    Context. The combination of wideband receivers and spectrometers currently available in (sub-)millimeter observatories deliver wide-field hyperspectral imaging of the interstellar medium. Tens of spectral lines can be observed over degree wide fields in about 50 h. This wealth of data calls for restating the physical questions about the interstellar medium in statistical terms. Aims: We aim to gain information on the physical structure of the interstellar medium from a statistical analysis of many lines from different species over a large field of view, without requiring detailed radiative transfer or astrochemical modeling. Methods: We coupled a non-linear rescaling of the data with one of the simplest multivariate analysis methods, namely the principal component analysis, to decompose the observed signal into components that we interpret first qualitatively and then quantitatively based on our deep knowledge of the observed region and of the astrochemistry at play. Results: We identify three principal components, linear compositions of line brightness temperatures, that are correlated at various levels with the column density, the volume density and the UV radiation field. Conclusions: When sampling a sufficiently diverse mixture of physical parameters, it is possible to decompose the molecular emission in order to gain physical insight on the observed interstellar medium. This opens a new avenue for future studies of the interstellar medium. Based on observations carried out at the IRAM-30 m single-dish telescope. IRAM is supported by INSU/CNRS (France), MPG (Germany) and IGN (Spain).

  2. Prolactin and teleost ionocytes: new insights into cellular and molecular targets of prolactin in vertebrate epithelia

    Science.gov (United States)

    Breves, Jason P.; McCormick, Stephen D.; Karlstrom, Rolf O.

    2014-01-01

    The peptide hormone prolactin is a functionally versatile hormone produced by the vertebrate pituitary. Comparative studies over the last six decades have revealed that a conserved function for prolactin across vertebrates is the regulation of ion and water transport in a variety of tissues including those responsible for whole-organism ion homeostasis. In teleost fishes, prolactin was identified as the “freshwater-adapting hormone”, promoting ion-conserving and water-secreting processes by acting on the gill, kidney, gut and urinary bladder. In mammals, prolactin is known to regulate renal, intestinal, mammary and amniotic epithelia, with dysfunction linked to hypogonadism, infertility, and metabolic disorders. Until recently, our understanding of the cellular mechanisms of prolactin action in fishes has been hampered by a paucity of molecular tools to define and study ionocytes, specialized cells that control active ion transport across branchial and epidermal epithelia. Here we review work in teleost models indicating that prolactin regulates ion balance through action on ion transporters, tight-junction proteins, and water channels in ionocytes, and discuss recent advances in our understanding of ionocyte function in the genetically and embryonically accessible zebrafish (Danio rerio). Given the high degree of evolutionary conservation in endocrine and osmoregulatory systems, these studies in teleost models are contributing novel mechanistic insight into how prolactin participates in the development, function, and dysfunction of osmoregulatory systems across the vertebrate lineage.

  3. Water oxidation with molecularly defined iridium complexes: insights into homogeneous versus heterogeneous catalysis.

    Science.gov (United States)

    Junge, Henrik; Marquet, Nicolas; Kammer, Anja; Denurra, Stefania; Bauer, Matthias; Wohlrab, Sebastian; Gärtner, Felix; Pohl, Marga-Martina; Spannenberg, Anke; Gladiali, Serafino; Beller, Matthias

    2012-10-01

    Molecularly defined Ir complexes and different samples of supported IrO(2) nanoparticles have been tested and compared in the catalytic water oxidation with cerium ammonium nitrate (CAN) as the oxidant. By comparing the activity of nano-scaled supported IrO(2) particles to the one of organometallic complexes it is shown that the overall activity of the homogeneous Ir precursors is defined by both the formation of the homogeneous active species and its conversion to Ir(IV)-oxo nanoparticles. In the first phase of the reaction the activity is dominated by the homogeneous active species. With increasing reaction time, the influence of nano-sized Ir-oxo particles becomes more evident. Notably, the different conversion rates of the homogeneous precursor into the active species as well as the conversion into Ir-oxo nanoparticles and the different particle sizes have a significant influence on the overall activity. In addition to the homogeneous systems, IrO(2)@MCM-41 has also been synthesized, which contains stabilized nanoparticles of between 1 and 3 nm in size. This latter system shows a similar activity to IrCl(3)⋅xH(2)O and complexes 4 and 5. Mechanistic insights were obtained by in situ X-ray absorption spectroscopy and scanning transmission electron microscopy.

  4. Insight to the thermodynamic stability of molecular crystals through crystallographic studies of a multipolymorph system.

    Science.gov (United States)

    Ng, Alicia T; Lai, Chiajen; Dabros, Marta; Gao, Qi

    2014-11-01

    Five solvent-free polymorphs of a pharmaceutical compound were discovered during polymorph screening. Out of the five polymorphs, only one has strong intermolecular N-H···N hydrogen bonding, whereas the others exhibit only weak C-H···N and π-π stacking interactions in addition to all the other weak C-H···X and van der Waals interactions. The relative thermodynamic stability relationships among the polymorphs are not intuitive and quite complex due to enantiotropic phase behavior. For instance, the polymorph with the most efficient packing (i.e., highest density) is not always the most thermodynamically stable form, and the polymorph with strong intermolecular interactions is not thermodynamically more stable than the polymorph with weak intermolecular interactions at all temperatures. Nevertheless, systematic examination and comparison of the molecular packing and intermolecular interactions of these polymorphs provide insight into the importance of H-bonding and packing efficiency to the thermodynamic stability of a crystalline form, and how these effects are dependent on temperature. This study seeks to correlate single-crystal structure features with experimentally established thermodynamic stability, and provides an example where a polymorph with only van der Waals forces and weak intermolecular interactions can be more stable than a polymorph that displays strong H-bonding in its structural make-up.

  5. Environmental gradients and grassland trait variation: Insight into the effects of climate change

    Science.gov (United States)

    Tardella, Federico M.; Piermarteri, Karina; Malatesta, Luca; Catorci, Andrea

    2016-10-01

    The research aim was to understand how variation of temperature and water availability drives trait assemblage of seminatural grasslands in sub-Mediterranean climate, where climate change is expected to intensify summer aridity. In the central Italy, we recorded species abundance and elevation, slope aspect and angle in 129 plots. The traits we analysed were life span, growth form, clonality, belowground organs, leaf traits, plant height, seed mass, and palatability. We used Ellenberg's indicators as a proxy to assess air temperature and soil moisture gradients. From productive to harsh conditions, we observed a shift from tolerance to avoidance strategies, and a change in resource allocation strategies to face competition and stress or that maximize exploitation of patchily distributed soil resource niches. In addition, we found that the increase of temperature and water scarcity leads to the establishment of regeneration strategies that enable plants to cope with the unpredictability of changes in stress intensity and duration. Since the dry habitats of higher elevations are also constrained by winter cold stress, we argue that, within the sub-Mediterranean bioclimate, climate change will likely lead to a variation in dominance inside plant communities rather than a shift upwards of species ranges. At higher elevations, drought-adaptive traits might become more abundant on south-facing slopes that are less stressed by winter low temperatures; traits related to productive conditions and cold stress would be replaced on north-facing slopes by those adapted to overcome both the drought and the cold stresses.

  6. Water accommodation on ice and organic surfaces: insights from environmental molecular beam experiments.

    Science.gov (United States)

    Kong, Xiangrui; Thomson, Erik S; Papagiannakopoulos, Panos; Johansson, Sofia M; Pettersson, Jan B C

    2014-11-26

    Water uptake on aerosol and cloud particles in the atmosphere modifies their chemistry and microphysics with important implications for climate on Earth. Here, we apply an environmental molecular beam (EMB) method to characterize water accommodation on ice and organic surfaces. The adsorption of surface-active compounds including short-chain alcohols, nitric acid, and acetic acid significantly affects accommodation of D2O on ice. n-Hexanol and n-butanol adlayers reduce water uptake by facilitating rapid desorption and function as inefficient barriers for accommodation as well as desorption of water, while the effect of adsorbed methanol is small. Water accommodation is close to unity on nitric-acid- and acetic-acid-covered ice, and accommodation is significantly more efficient than that on the bare ice surface. Water uptake is inefficient on solid alcohols and acetic acid but strongly enhanced on liquid phases including a quasi-liquid layer on solid n-butanol. The EMB method provides unique information on accommodation and rapid kinetics on volatile surfaces, and these studies suggest that adsorbed organic and acidic compounds need to be taken into account when describing water at environmental interfaces.

  7. What actually confers adaptive capacity? Insights from agro-climatic vulnerability of Australian wheat.

    Directory of Open Access Journals (Sweden)

    Brett A Bryan

    Full Text Available Vulnerability assessments have often invoked sustainable livelihoods theory to support the quantification of adaptive capacity based on the availability of capital--social, human, physical, natural, and financial. However, the assumption that increased availability of these capitals confers greater adaptive capacity remains largely untested. We quantified the relationship between commonly used capital indicators and an empirical index of adaptive capacity (ACI in the context of vulnerability of Australian wheat production to climate variability and change. We calculated ACI by comparing actual yields from farm survey data to climate-driven expected yields estimated by a crop model for 12 regions in Australia's wheat-sheep zone from 1991-2010. We then compiled data for 24 typical indicators used in vulnerability analyses, spanning the five capitals. We analyzed the ACI and used regression techniques to identify related capital indicators. Between regions, mean ACI was not significantly different but variance over time was. ACI was higher in dry years and lower in wet years suggesting that farm adaptive strategies are geared towards mitigating losses rather than capitalizing on opportunity. Only six of the 24 capital indicators were significantly related to adaptive capacity in a way predicted by theory. Another four indicators were significantly related to adaptive capacity but of the opposite sign, countering our theory-driven expectation. We conclude that the deductive, theory-based use of capitals to define adaptive capacity and vulnerability should be more circumspect. Assessments need to be more evidence-based, first testing the relevance and influence of capital metrics on adaptive capacity for the specific system of interest. This will more effectively direct policy and targeting of investment to mitigate agro-climatic vulnerability.

  8. Towards climate reconstruction on Mars using landscape analysis: Insights from terrestrial analogues

    Science.gov (United States)

    Hauber, E.; Ulrich, M.; Reiss, D.; Hiesinger, H.; Balme, M. R.; Gallagher, C. J.

    2011-12-01

    Many very young landforms on Mars resemble terrestrial glacial and periglacial surface features in permafrost regions and show a latitude-dependent geographic distribution. They include surface mantling, viscous flow features, polygonally fractured ground, patterned ground, fractured mounds, and gullies. Collectively, these landforms are hypothesized to represent the geomorphological surface record of Martian ice ages that were triggered by astronomical forcing and associated climate changes. Many previous studies of possible cold-climate features on Mars considered just one of them in isolation, e.g., polygons or fractured mounds. Such approaches do not consider the geomorphologic context of the landforms, and thus interpretations can be ambiguous due to the possible effect of equifinality. A more comprehensive investigation of the full assemblage of associated landforms (landscape analysis) has the potential to reduce this ambiguity. We use the permafrost landscape of Spitsbergen (Svalbard, Norway) as an analogue for the assemblage of cold-climate landforms that is typically found in mid-latitudes on Mars. Although relatively warm and wet as compared to other cold-climate analogues on Earth, Spitsbergen is a particularly instructive morphological analogue to Mars as it offers many surface features in a close spatial context that are strikingly similar to those on Mars. Based on this comparison, which uses remote sensing and field data from Svalbard, we identify similarities as well as differences, both of which are important in the use of analogues as a means to establish testable hypotheses. We then propose possible scenarios which may help to understand the evolution of Martian landforms into their present state. Of particular interest with respect to the habitability of Martian permafrost is whether liquid water was involved or not. Most phenomena on Mars, but not Svalbard, can plausibly be explained by "dry" permafrost scenarios without the need to invoke

  9. Quantitative analysis of oyster larval proteome provides new insights into the effects of multiple climate change stressors

    KAUST Repository

    Dineshram, Ramadoss

    2016-03-19

    The metamorphosis of planktonic larvae of the Pacific oyster (Crassostrea gigas) underpins their complex life-history strategy by switching on the molecular machinery required for sessile life and building calcite shells. Metamorphosis becomes a survival bottleneck, which will be pressured by different anthropogenically induced climate change-related variables. Therefore, it is important to understand how metamorphosing larvae interact with emerging climate change stressors. To predict how larvae might be affected in a future ocean, we examined changes in the proteome of metamorphosing larvae under multiple stressors: decreased pH (pH 7.4), increased temperature (30 °C), and reduced salinity (15 psu). Quantitative protein expression profiling using iTRAQ-LC-MS/MS identified more than 1300 proteins. Decreased pH had a negative effect on metamorphosis by down-regulating several proteins involved in energy production, metabolism, and protein synthesis. However, warming switched on these down-regulated pathways at pH 7.4. Under multiple stressors, cell signaling, energy production, growth, and developmental pathways were up-regulated, although metamorphosis was still reduced. Despite the lack of lethal effects, significant physiological responses to both individual and interacting climate change related stressors were observed at proteome level. The metamorphosing larvae of the C. gigas population in the Yellow Sea appear to have adequate phenotypic plasticity at the proteome level to survive in future coastal oceans, but with developmental and physiological costs. © 2016 John Wiley & Sons Ltd.

  10. Quantitative analysis of oyster larval proteome provides new insights into the effects of multiple climate change stressors.

    Science.gov (United States)

    Dineshram, Ramadoss; Chandramouli, Kondethimmanahalli; Ko, Ginger Wai Kuen; Zhang, Huoming; Qian, Pei-Yuan; Ravasi, Timothy; Thiyagarajan, Vengatesen

    2016-06-01

    The metamorphosis of planktonic larvae of the Pacific oyster (Crassostrea gigas) underpins their complex life-history strategy by switching on the molecular machinery required for sessile life and building calcite shells. Metamorphosis becomes a survival bottleneck, which will be pressured by different anthropogenically induced climate change-related variables. Therefore, it is important to understand how metamorphosing larvae interact with emerging climate change stressors. To predict how larvae might be affected in a future ocean, we examined changes in the proteome of metamorphosing larvae under multiple stressors: decreased pH (pH 7.4), increased temperature (30 °C), and reduced salinity (15 psu). Quantitative protein expression profiling using iTRAQ-LC-MS/MS identified more than 1300 proteins. Decreased pH had a negative effect on metamorphosis by down-regulating several proteins involved in energy production, metabolism, and protein synthesis. However, warming switched on these down-regulated pathways at pH 7.4. Under multiple stressors, cell signaling, energy production, growth, and developmental pathways were up-regulated, although metamorphosis was still reduced. Despite the lack of lethal effects, significant physiological responses to both individual and interacting climate change related stressors were observed at proteome level. The metamorphosing larvae of the C. gigas population in the Yellow Sea appear to have adequate phenotypic plasticity at the proteome level to survive in future coastal oceans, but with developmental and physiological costs.

  11. Dispersing perylene diimide/SWCNT hybrids: structural insights at the molecular level and fabricating advanced materials.

    Science.gov (United States)

    Tsarfati, Yael; Strauss, Volker; Kuhri, Susanne; Krieg, Elisha; Weissman, Haim; Shimoni, Eyal; Baram, Jonathan; Guldi, Dirk M; Rybtchinski, Boris

    2015-06-17

    The unique properties of carbon nanotubes (CNT) are advantageous for emerging applications. Yet, the CNT insolubility hampers their potential. Approaches based on covalent and noncovalent methodologies have been tested to realize stable dispersions of CNTs. Noncovalent approaches are of particular interest as they preserve the CNT's structures and properties. We report on hybrids, in which perylene diimide (PDI) amphiphiles are noncovalently immobilized onto single wall carbon nanotubes (SWCNT). The resulting hybrids were dispersed and exfoliated both in water and organic solvents in the presence of two different PDI derivatives, PP2b and PP3a. The dispersions were investigated using cryogenic transmission electron microscopy (cryo-TEM), providing unique structural insights into the exfoliation. A helical arrangement of PP2b assemblies on SWCNTs dominates in aqueous dispersions, while a single layer of PP2b and PP3a was found on SWCNTs in organic dispersions. The dispersions were probed by steady-state and time-resolved spectroscopies, revealing appreciable charge redistribution in the ground state, and an efficient electron transfer from SWCNTs to PDIs in the excited state. We also fabricated hybrid materials from the PP2b/SWCNT dispersions. A supramolecular membrane was prepared from aqueous dispersions and used for size-selective separation of gold nanoparticles. Hybrid buckypaper films were prepared from the organic dispersions. In the latter, high conductivity results from enhanced electronic communication and favorable morphology within the hybrid material. Our findings shed light onto SWCNT/dispersant molecular interactions, and introduce a versatile approach toward universal solution processing of SWCNT-based materials.

  12. Insights into the molecular evolution of HslU ATPase through biochemical and mutational analyses.

    Directory of Open Access Journals (Sweden)

    Kwang Hoon Sung

    Full Text Available The ATP-dependent HslVU complexes are found in all three biological kingdoms. A single HslV protease exists in each species of prokaryotes, archaea, and eukaryotes, but two HslUs (HslU1 and HslU2 are present in the mitochondria of eukaryotes. Previously, a tyrosine residue at the C-terminal tail of HslU2 has been identified as a key determinant of HslV activation in Trypanosoma brucei and a phenylalanine at the equivalent position to E. coli HslU is found in T. brucei HslU1. Unexpectedly, we found that an F441Y mutation in HslU enhanced the peptidase and caseinolytic activity of HslV in E. coli but it showed partially reduced ATPase and SulA degradation activity. Previously, only the C-terminal tail of HslU has been the focus of HslV activation studies. However, the Pro315 residue interacting with Phe441 in free HslU has also been found to be critical for HslV activation. Hence, our current biochemical analyses explore the importance of the loop region just before Pro315 for HslVU complex functionality. The proline and phenylalanine pair in prokaryotic HslU was replaced with the threonine and tyrosine pair from the functional eukaryotic HslU2. Sequence comparisons between multiple HslUs from three different biological kingdoms in combination with biochemical analysis of E. coli mutants have uncovered important new insights into the molecular evolutionary pathway of HslU.

  13. Vulnerability of the northern Mongolian steppe to climate change: insights from flower production and phenology.

    Science.gov (United States)

    Liancourt, Pierre; Spence, Laura A; Boldgiv, Bazartseren; Lkhagva, Ariuntsetseg; Helliker, Brent R; Casper, Brenda B; Petraitis, Peter S

    2012-04-01

    The semiarid, northern Mongolian steppe, which still supports pastoral nomads who have used the steppe for millennia, has experienced an average 1.7 degrees C temperature rise over the past 40 years. Continuing climate change is likely to affect flowering phenology and flower numbers with potentially important consequences for plant community composition, ecosystem services, and herder livelihoods. Over the growing seasons of 2009 and 2010, we examined flowering responses to climate manipulation using open-top passive warming chambers (OTCs) at two locations on a south-facing slope: one on the moister, cooler lower slope and the other on the drier, warmer upper slope, where a watering treatment was added in a factorial design with warming. Canonical analysis of principal coordinates (CAP) revealed that OTCs reduced flower production and delayed peak flowering in graminoids as a whole but only affected forbs on the upper slope, where peak flowering was also delayed. OTCs affected flowering phenology in seven of eight species, which were examined individually, either by altering the time of peak flowering and/or the onset and/or cessation of flowering, as revealed by survival analysis. In 2010, which was the drier year, OTCs reduced flower production in two grasses but increased production in an annual forb found only on the upper slope. The particular effects of OTCs on phenology, and whether they caused an extension or contraction of the flowering season, differed among species, and often depended on year, or slope, or watering treatment; however, a relatively strong pattern emerged for 2010 when four species showed a contraction of the flowering season in OTCs. Watering increased flower production in two species in 2010, but slope location more often affected flowering phenology than did watering. Our results show the importance of taking landscape-scale variation into account in climate change studies and also contrasted with those of several studies set in cold

  14. A Best Practices Notebook for Disaster Risk Reduction and Climate Change Adaptation: Guidance and Insights for Policy and Practice from the CATALYST Project

    NARCIS (Netherlands)

    Hare, M.; Bers, van C.; Mysiak, J.; Calliari, E.; Haque, A.; Warner, K.; Yuzva, K.; Zissener, M.; Jaspers, A.M.J.; Timmerman, J.G.

    2014-01-01

    This publication, A Best Practices Notebook for Disaster Risk Reduction and Climate Change Adaptation: Guidance and Insights for Policy and Practice from the CATALYST Project is one of two main CATALYST knowledge products that focus on the transformative approaches and measures that can support Disa

  15. Situating Climate Security, The Department of Defense's Role in Mitigating Climate Change's Causes and Dealing with its Effects; Strategic Insights; v. 9, issue 2 (Fall 2010) pp. 13-25.

    OpenAIRE

    CLAUSEN, Daniel; Clausen, Michael

    2010-01-01

    This article appeared in Strategic Insights, v.9, issue 2 (Fall 2010) pp. 13-25. Approved for public display, distribution unlimited An Emerging Security Focus: Climate Security. A new concern is circulating among policymakers, think tanks, and scholars: securing the planet’s climate. For those who debate what counts as “national security,” the question over whether climate change should be framed as a security issue has been argued along well-worn lines. For those who seek a more expan...

  16. The simulated climate of the Last Glacial Maximum and insights into the global marine carbon cycle

    Science.gov (United States)

    Buchanan, Pearse J.; Matear, Richard J.; Lenton, Andrew; Phipps, Steven J.; Chase, Zanna; Etheridge, David M.

    2016-12-01

    The ocean's ability to store large quantities of carbon, combined with the millennial longevity over which this reservoir is overturned, has implicated the ocean as a key driver of glacial-interglacial climates. However, the combination of processes that cause an accumulation of carbon within the ocean during glacial periods is still under debate. Here we present simulations of the Last Glacial Maximum (LGM) using the CSIRO Mk3L-COAL (Carbon-Ocean-Atmosphere-Land) earth system model to test the contribution of physical and biogeochemical processes to ocean carbon storage. For the LGM simulation, we find a significant global cooling of the surface ocean (3.2 °C) and the expansion of both minimum and maximum sea ice cover broadly consistent with proxy reconstructions. The glacial ocean stores an additional 267 Pg C in the deep ocean relative to the pre-industrial (PI) simulation due to stronger Antarctic Bottom Water formation. However, 889 Pg C is lost from the upper ocean via equilibration with a lower atmospheric CO2 concentration and a global decrease in export production, causing a net loss of carbon relative to the PI ocean. The LGM deep ocean also experiences an oxygenation ( > 100 mmol O2 m-3) and deepening of the calcite saturation horizon (exceeds the ocean bottom) at odds with proxy reconstructions. With modifications to key biogeochemical processes, which include an increased export of organic matter due to a simulated release from iron limitation, a deepening of remineralisation and decreased inorganic carbon export driven by cooler temperatures, we find that the carbon content of the glacial ocean can be sufficiently increased (317 Pg C) to explain the reduction in atmospheric and terrestrial carbon at the LGM (194 ± 2 and 330 ± 400 Pg C, respectively). Assuming an LGM-PI difference of 95 ppm pCO2, we find that 55 ppm can be attributed to the biological pump, 28 ppm to circulation changes and the remaining 12 ppm to solubility. The biogeochemical

  17. Oldest isotopically characterized fish otoliths provide insight to Jurassic continental climate of Europe

    Science.gov (United States)

    Patterson, William P.

    1999-03-01

    Large, shallow, epeiric seas and adjacent lagoons such as those described herein likely played a significant role in moderating Jurassic coastal and continental climate. Jurassic (Bathonian) ocean surface temperatures in Scotland have been calculated from δ18O(CaCO3) values of a suite of the oldest well-preserved fish otoliths analyzed to date. Otolith δ18O values range from -4.7‰ to -1.9‰ (Vienna Peedee belemnite, VPDB), while δ13C(CaCO3) values vary from -5.4‰ to +1.5‰ (VPDB), representing the oldest stable isotopic record of paleodiet, paleoecology, and fish migration to date. Using a global ocean δ18O(H2O) value of -1.0‰ (Vienna standard mean ocean water, VSMOW) for an ice-free Jurassic, fish species that migrated from estuarine to open marine water record time-averaged temperatures of 23 °C. Estuarine fish, assuming a similar temperature, record variation in δ18O(H2O) values from -3.7‰ to -2.0‰ (VSMOW). That significant mixing of fresh water and seawater occurred in the Jurassic in Scotland is in general agreement with data presented by others (molluscan fauna, lithostratigraphy, paleogeography, and paleocirculation models). The δ18O values and temperatures derived in this study correspond to the meteorologic and hydrologic parameters of a mid-latitude maritime climate with low seasonality, a mean temperature of 23 °C, and abundant precipitation and humidity. The δ18O(H2O) values calculated from estuarine fish indicate that rainfall must have a δ18O(H2O) value lower than -3.7‰ (VSMOW). Values of δ18O and δ13C suggest an environment hydrologically similar to that observed in the Everglades of south Florida or the estuaries of south Texas, both notable fish nurseries today. However, sea-surface temperatures were lower than those of modern Florida or Texas as evidenced by reduced evaporative enrichment of δ18O(H2O) values.

  18. Late Triassic tropical climate of Pangea: Carbon isotopic and other insights into the rise of dinosaurs

    Science.gov (United States)

    Whiteside, J. H.; Lindström, S.; Irmis, R. B.; Glasspool, I.; Schaller, M. F.; Dunlavey, M.; Nesbitt, S. J.; Smith, N. D.; Turner, A. H.

    2015-12-01

    The rarity and species-poor nature of early dinosaurs and their relatives at low paleolatitudes persisted for 30 million years after their origin and 10-15 million years after they became abundant and speciose at higher latitudes. New environmental reconstructions from stable carbon isotope ratios of preserved organic matter (δ13Corg), atmospheric pCO2 data based on the δ13C of soil carbonate, palynological, and wildfire data from charcoal from early dinosaur-bearing strata at low paleolatitudes in western North America show that variations in δ13Corg and palynomorph ecotypes are tightly correlated, displaying large and high-frequency excursions. These variations occurred within an environment characterized by elevated and increasing atmospheric pCO2, pervasive wildfires, and rapidly fluctuating extreme climatic conditions. Whereas pseudosuchian archosaur-dominated communities were able to persist in these same regions until the end-Triassic, the large-bodied, fast-growing tachymetabolic dinosaurian herbivores were not. We hypothesize that the greater resources required by the herbivores made it difficult from them to adapt to the unstable conditions at low paleolatitudes in the Late Triassic.

  19. Insight into glacier climate interaction: reconstruction of the mass balance field using ice extent data

    Science.gov (United States)

    Visnjevic, Vjeran; Herman, Frédéric; Licul, Aleksandar

    2016-04-01

    With the end of the Last Glacial Maximum (LGM), about 20 000 years ago, ended the most recent long-lasting cold phase in Earth's history. We recently developed a model that describes large-scale erosion and its response to climate and dynamical changes with the application to the Alps for the LGM period. Here we will present an inverse approach we have recently developed to infer the LGM mass balance from known ice extent data, focusing on a glacier or ice cap. The ice flow model is developed using the shallow ice approximation and the developed codes are accelerated using GPUs capabilities. The mass balance field is the constrained variable defined by the balance rate β and the equilibrium line altitude (ELA), where c is the cutoff value: b = max(βṡ(S(z) - ELA), c) We show that such a mass balance can be constrained from the observed past ice extent and ice thickness. We are also investigating several different geostatistical methods to constrain spatially variable mass balance, and derive uncertainties on each of the mass balance parameters.

  20. Structure and Dynamics of Glycosphingolipids in Lipid Bilayers: Insights from Molecular Dynamics Simulations

    Directory of Open Access Journals (Sweden)

    Ronak Y. Patel

    2011-01-01

    Full Text Available Glycolipids are important constituents of biological membranes, and understanding their structure and dynamics in lipid bilayers provides insights into their physiological and pathological roles. Experimental techniques have provided details into their behavior at model and biological membranes; however, computer simulations are needed to gain atomic level insights. This paper summarizes the insights obtained from MD simulations into the conformational and orientational dynamics of glycosphingolipids and their exposure, hydration, and hydrogen-bonding interactions in membrane environment. The organization of glycosphingolipids in raft-like membranes and their modulation of lipid membrane structure are also reviewed.

  1. Insights into molecular properties of the human monocarboxylate transporter 8 by combining functional with structural information

    Directory of Open Access Journals (Sweden)

    Kleinau Gunnar

    2011-08-01

    Full Text Available Abstract Background The monocarboxylate transporter 8 (MCT8 is a member of the major facilitator superfamily (MFS and transports specificly iodothyronines. MCT8 mutations are the underlying cause of a syndrome of severe X-linked psychomotor retardation known as the Allan-Herndon-Dudley syndrome. This syndrome is characterized by abnormally high T3, low/normal T4 serum levels and slightly elevated serum TSH. To date, more than 25 pathogenic mutations in hMCT8 are known and they are valuable indicators of important regions for structural and functional MCT8 properties. Methods We designed a structural human MCT8 model and studied reported pathogenic missense mutations with focus on the estimation of those amino acid positions which are probably sensitive for substrate transport. Furthermore, assuming similarities between determinants of T3 binding observed in the published crystal structure of the thyroid hormone receptor beta occupied by its ligand T3 and the structural MCT8 model, we explore potential T3 binding sites in the MCT8 substrate channel cavity. Results We found that all known pathogenic missense mutations are located exclusively in the transmembrane helices and to a high degree at conserved residues among the MCT family. Furthermore, mutations either of or to prolines/glycines are located mainly at helices 9-12 and are expected to cause steric clashes or structural misfolding. In contrast, several other mutations are close to the potential substrate channel and affected amino acids are likely involved in the switching mechanism between different transporter conformations. Finally, three potential substrate binding sites are predicted for MCT8. Conclusions Naturally occurring mutations of MCT8 provide molecular insights into protein regions important for protein folding, substrate binding and the switching mechanism during substrate transport. Future studies guided by this information should help to clarify structure

  2. Understanding impacts of climatic extremes on diarrheal disease epidemics: Insights from mechanistic disease propagation models

    Science.gov (United States)

    Jutla, A.; Akanda, A. S.; Colwell, R. R.

    2013-12-01

    increased climatic variability, such as acceleration of hydrological cycle, hydroclimatic hazards, etc on diarrheal disease outbreaks.

  3. Transcriptomic Changes in Coral Holobionts Provide Insights into Physiological Challenges of Future Climate and Ocean Change.

    Directory of Open Access Journals (Sweden)

    Paulina Kaniewska

    Full Text Available Tropical reef-building coral stress levels will intensify with the predicted rising atmospheric CO2 resulting in ocean temperature and acidification increase. Most studies to date have focused on the destabilization of coral-dinoflagellate symbioses due to warming oceans, or declining calcification due to ocean acidification. In our study, pH and temperature conditions consistent with the end-of-century scenarios of the Intergovernmental Panel on Climate Change (IPCC caused major changes in photosynthesis and respiration, in addition to decreased calcification rates in the coral Acropora millepora. Population density of symbiotic dinoflagellates (Symbiodinium under high levels of ocean acidification and temperature (Representative Concentration Pathway, RCP8.5 decreased to half of that found under present day conditions, with photosynthetic and respiratory rates also being reduced by 40%. These physiological changes were accompanied by evidence for gene regulation of calcium and bicarbonate transporters along with components of the organic matrix. Metatranscriptomic RNA-Seq data analyses showed an overall down regulation of metabolic transcripts, and an increased abundance of transcripts involved in circadian clock control, controlling the damage of oxidative stress, calcium signaling/homeostasis, cytoskeletal interactions, transcription regulation, DNA repair, Wnt signaling and apoptosis/immunity/ toxins. We suggest that increased maintenance costs under ocean acidification and warming, and diversion of cellular ATP to pH homeostasis, oxidative stress response, UPR and DNA repair, along with metabolic suppression, may underpin why Acroporid species tend not to thrive under future environmental stress. Our study highlights the potential increased energy demand when the coral holobiont is exposed to high levels of ocean warming and acidification.

  4. π-Hydrogen Bonding of Aromatics on the Surface of Aerosols: Insights from Ab Initio and Molecular Dynamics Simulation.

    Science.gov (United States)

    Feng, Ya-Juan; Huang, Teng; Wang, Chao; Liu, Yi-Rong; Jiang, Shuai; Miao, Shou-Kui; Chen, Jiao; Huang, Wei

    2016-07-14

    Molecular level insight into the interaction between volatile organic compounds (VOCs) and aerosols is crucial for improvement of atmospheric chemistry models. In this paper, the interaction between adsorbed toluene, one of the most significant VOCs in the urban atmosphere, and the aqueous surface of aerosols was studied by means of combined molecular dynamics simulations and ab initio quantum chemistry calculations. It is revealed that toluene can be stably adsorbed on the surface of aqueous droplets via hydroxyl-π hydrogen bonding between the H atoms of the water molecules and the C atoms in the aromatic ring. Further, significant modifications on the electrostatic potential map and frontier molecular orbital are induced by the solvation effect of surface water molecules, which would affect the reactivity and pathway of the atmospheric photooxidation of toluene. This study demonstrates that the surface interactions should be taken into consideration in the atmospheric chemical models on oxidation of aromatics.

  5. Climatic vs. Seismic Controlled Rockglacier Advances in Northern Tien Shan - Insights from Lichenometry

    Science.gov (United States)

    Rosenwinkel, S.; Korup, O.; Landgraf, A.; Dzhumabaeva, A.

    2014-12-01

    patterns vary between the different locations and support the notion that the analyzed Tien Shan rockglaciers do not record climate-driven advances exclusively. We conclude by highlighting a number of constraints that may limit the use of lichenometry for dating rockglacier advances, and scope for future research on seismic triggers.

  6. Unraveling the molecular effects of mutation L270P on Wiskkot-Aldrich syndrome protein: insights from molecular dynamics approach.

    Science.gov (United States)

    Palaniappan, Chandrasekaran; Rao, Sethumadhavan; Ramalingam, Rajasekaran

    2016-09-01

    Missense mutation L270P disrupts the auto-inhibited state of "Wiskkot-Aldrich syndrome protein" (WASP), thereby constitutively activating the mutant structure, a key event for pathogenesis of X-linked neutropenia (XLN). In this study, we comprehensively deciphered the molecular feature of activated mutant structure by all atom molecular dynamics (MD) approach. MD analysis revealed that mutant structure exposed a wide variation in the spatial environment of atoms, resulting in enhanced residue flexibility. The increased flexibility of residues favored to decrease the number of intra-molecular hydrogen bonding interactions in mutant structure. The reduction of hydrogen bonds in the mutant structure resulted to disrupt the local folding of secondary structural elements that eventually affect the proper folding of mutants. The unfolded state of mutant structure established more number of inter-molecular hydrogen bonding interaction at interface level due to the conformational variability, thus mediated high binding affinity with its interacting partner, Cdc42.

  7. Molecular-Level Insights into Photocatalysis from Scanning Probe Microscopy Studies on TiO2(110)

    Energy Technology Data Exchange (ETDEWEB)

    Henderson, Michael A.; Lyubinetsky, Igor

    2013-06-12

    The field of heterogeneous photocatalysis has grown considerably in the decades since Fujishima and Honda's ground-breaking publications of photoelectrochemistry on TiO2. Numerous review articles continue to point to both progress made in the use of heterogeneous materials (such as TiO2) to perform photoconversion processes, and the many opportunities and challenges in heterogeneous photocatalysis research such as solar energy conversion and environmental remediation. The past decade has also seen an increase in the use of molecular-level approaches applied to model single crystal surfaces in an effort to obtain new insights into photocatalytic phenomena. In particular, scanning probe techniques (SPM) have enabled researchers to take a ‘nanoscale’ approach to photocatalysis that includes interrogation of the reactivities of specific sites and adsorbates on a model photocatalyst surface. The rutile TiO2(110) surface has become the prototypical oxide single crystal surface for fundamental studies of many interfacial phenomena. In particular, TiO2(110) has become an excellent model surface for probing photochemical and photocatalytic reactions at the molecular level. A variety of experimental approaches have emerged as being ideally suited for studying photochemical reactions on TiO2(110), including desorption-oriented approaches and electronic spectroscopies, but perhaps the most promising techniques for evaluating site-specific properties are those of SPM. In this review, we highlight the growing use of SPM techniques in providing molecular-level insights into surface photochemistry on the model photocatalyst surface of rutile TiO2(110). Our objective is to both illustrate the unique knowledge that scanning probe techniques have already provided the field of photocatalysis, and also to motivate a new generation of effort into the use of such approaches to obtain new insights into the molecular level details of photochemical events occurring at interfaces

  8. Sharing the cost of river basin adaptation portfolios to climate change: Insights from social justice and cooperative game theory

    Science.gov (United States)

    Girard, Corentin; Rinaudo, Jean-Daniel; Pulido-Velazquez, Manuel

    2016-10-01

    The adaptation of water resource systems to the potential impacts of climate change requires mixed portfolios of supply and demand adaptation measures. The issue is not only to select efficient, robust, and flexible adaptation portfolios but also to find equitable strategies of cost allocation among the stakeholders. Our work addresses such cost allocation problems by applying two different theoretical approaches: social justice and cooperative game theory in a real case study. First of all, a cost-effective portfolio of adaptation measures at the basin scale is selected using a least-cost optimization model. Cost allocation solutions are then defined based on economic rationality concepts from cooperative game theory (the Core). Second, interviews are conducted to characterize stakeholders' perceptions of social justice principles associated with the definition of alternatives cost allocation rules. The comparison of the cost allocation scenarios leads to contrasted insights in order to inform the decision-making process at the river basin scale and potentially reap the efficiency gains from cooperation in the design of river basin adaptation portfolios.

  9. Crater palaeolakes in the Tibesti mountains (Central Sahara, North Chad) - New insights into past Saharan climates

    Science.gov (United States)

    Kröpelin, Stefan; Dinies, Michèle; Sylvestre, Florence; Hoelzmann, Philipp

    2016-04-01

    For the first time continuous lacustrine sections were sampled from the volcanic Tibesti Mountains (Chad): In the 900 m deep crater of Trou au Natron at Pic Toussidé (3,315 m a.s.l.) and from the 800 m deep Era Kohor, the major sub-caldera of Emi Koussi (3,445 m a.s.l.). The remnant diatomites on their slopes are located 360 m (Trou au Natron) and 125 m (Era Kohor) above the present day bottom of the calderas. These sediments from highly continental positions in the central Sahara are keys for the reconstruction of the last climatic cycles (Kröpelin et al. 2015). We report first results from sedimentary-geochemical (total organic and total inorganic carbon contents; total nitrogen; major elements; mineralogy) and palynological analyses for palaeo-environmental interpretations. The diatomites from the Trou au Natron comprise 330 cm of mostly calcitic sediments with relatively low organic carbon (fern stands. Regional pollen rain-e.g. grasses and wormwood-is scarcely represented. Golden algae dominate in the lower section. The results of the first palynological samples suggest a small sedimentation basin. Two 14C-dated charcoals out of the upper part of the section indicate mid-Holocene ages and a linear extrapolation based on a sediment accumulation rate of 1.4mma-1 would lead to tentative dates of ~8650 cal a BP for basal lacustrine sediments and ~4450 cal a BP for the cessation of this lacustrine sequence. The diatomites from the Era Kohor reflect a suite of sections that in total sum up to 145 cm of mostly silica-based sediments with very low carbon contents (< 2% TC). Calcite dominated sediments are only present in the topmost 15 cm. Grasses and wormword are dominating throughout the sequence, probably reflecting the main constituents of the regional vegetation. Cattail (Typha/Sparganium) and especially milfoil (Myriophyllum) are recorded abundantly and continuously throughout the sequence. In combination with green algae like Pediastrum the first pollen

  10. Carbon nanotubes as nanodelivery systems an insight through molecular dynamics simulations

    CERN Document Server

    Lim, Melvin Choon Giap

    2013-01-01

    This book showcases the application of carbon nanotubes as nanodelivery systems for copper atoms, using molecular dynamics simulations as a means of investigation. The nanodelivery system of the carbon nanotube presents the possible usage of the carbon structure in many areas in the future. This book is comprehensive and informative, and serves as a guide for any reader who wishes to perform a molecular dynamics simulation of his own and to conduct an analytical study of a molecular system.

  11. Using Variation Theory with Metacognitive Monitoring to Develop Insights into How Students Learn from Molecular Visualizations

    Science.gov (United States)

    Kelly, Resa M.

    2014-01-01

    Molecular visualizations have been widely endorsed by many chemical educators as an efficient way to convey the dynamic and atomic-level details of chemistry events. Research indicates that students who use molecular visualizations are able to incorporate most of the intended features of the animations into their explanations. However, studies…

  12. Structural insight into RNA recognition motifs: versatile molecular Lego building blocks for biological systems.

    Science.gov (United States)

    Muto, Yutaka; Yokoyama, Shigeyuki

    2012-01-01

    'RNA recognition motifs (RRMs)' are common domain-folds composed of 80-90 amino-acid residues in eukaryotes, and have been identified in many cellular proteins. At first they were known as RNA binding domains. Through discoveries over the past 20 years, however, the RRMs have been shown to exhibit versatile molecular recognition activities and to behave as molecular Lego building blocks to construct biological systems. Novel RNA/protein recognition modes by RRMs are being identified, and more information about the molecular recognition by RRMs is becoming available. These RNA/protein recognition modes are strongly correlated with their biological significance. In this review, we would like to survey the recent progress on these versatile molecular recognition modules.

  13. Molecular taxonomy provides new insights into anopheles species of the neotropical arribalzagia series.

    Directory of Open Access Journals (Sweden)

    Giovan F Gómez

    Full Text Available Phylogenetic analysis of partial mitochondrial cytochrome oxidase c subunit I (COI and nuclear internal transcribed spacer 2 (ITS2 sequences were used to evaluate initial identification and to investigate phylogenetic relationships of seven Anopheles morphospecies of the Arribalzagia Series from Colombia. Phylogenetic trees recovered highly supported clades for An. punctimaculas.s., An. calderoni, An. malefactor s.l., An. neomaculipalpus, An. apicimacula s.l., An. mattogrossensis and An. peryassui. This study provides the first molecular confirmation of An. malefactorfrom Colombia and discovered conflicting patterns of divergence for the molecular markers among specimens from northeast and northern Colombia suggesting the presence of two previously unrecognized Molecular Operational Taxonomic Units (MOTUs. Furthermore, two highly differentiated An. apicimacula MOTUs previously found in Panama were detected. Overall, the combined molecular dataset facilitated the detection of known and new Colombian evolutionary lineages, and constitutes the baseline for future research on their bionomics, ecology and potential role as malaria vectors.

  14. Scombroid fishes provide novel insights into the trait/rate associations of molecular evolution.

    Science.gov (United States)

    Qiu, Fan; Kitchen, Andrew; Burleigh, J Gordon; Miyamoto, Michael M

    2014-06-01

    The study of which life history traits primarily affect molecular evolutionary rates is often confounded by the covariance of these traits. Scombroid fishes (billfishes, tunas, barracudas, and their relatives) are unusual in that their mass-specific metabolic rate is positively associated with body size. This study exploits this atypical pattern of trait variation, which allows for direct tests of whether mass-specific metabolic rate or body size is the more important factor of molecular evolutionary rates. We inferred a phylogeny for scombroids from a supermatrix of molecular and morphological characters and used new phylogenetic comparative approaches to assess the associations of body size and mass-specific metabolic rate with substitution rate. As predicted by the body size hypothesis, there is a negative correlation between body size and substitution rate. However, unexpectedly, we also find a negative association between mass-specific metabolic and substitution rates. These relationships are supported by analyses of the total molecular data, separate mitochondrial and nuclear genes, and individual loci, and they are robust to phylogenetic uncertainty. The molecular evolutionary rates of scombroids are primarily tied to body size. This study demonstrates that groups with novel patterns of trait variation can be particularly informative for identifying which life history traits are the primary factors of molecular evolutionary rates.

  15. Molecular interactions of UvrB protein and DNA from Helicobacter pylori: Insight into a molecular modeling approach.

    Science.gov (United States)

    Bavi, Rohit; Kumar, Raj; Rampogu, Shailima; Son, Minky; Park, Chanin; Baek, Ayoung; Kim, Hyong-Ha; Suh, Jung-Keun; Park, Seok Ju; Lee, Keun Woo

    2016-08-01

    Helicobacter pylori (H. pylori) persevere in the human stomach, an environment in which they encounter many DNA-damaging conditions, including gastric acidity. The pathogenicity of H. pylori is enhanced by its well-developed DNA repair mechanism, thought of as 'machinery,' such as nucleotide excision repair (NER). NER involves multi-enzymatic excinuclease proteins (UvrABC endonuclease), which repair damaged DNA in a sequential manner. UvrB is the central component in prokaryotic NER, essential for damage recognition. Therefore, molecular modeling studies of UvrB protein from H. pylori are carried out with homology modeling and molecular dynamics (MD) simulations. The results reveal that the predicted structure is bound to a DNA hairpin with 3-bp stem, an 11-nucleotide loop, and 3-nt 3' overhang. In addition, a mutation of the Y96A variant indicates reduction in the binding affinity for DNA. Free-energy calculations demonstrate the stability of the complex and help identify key residues in various interactions based on residue decomposition analysis. Stability comparative studies between wild type and mutant protein-DNA complexes indicate that the former is relatively more stable than the mutant form. This predicted model could also be useful in designing new inhibitors for UvrB protein, as well as preventing the pathogenesis of H. pylori.

  16. Molecular insight into amyloid oligomer destabilizing mechanism of flavonoid derivative 2-(4' benzyloxyphenyl)-3-hydroxy-chromen-4-one through docking and molecular dynamics simulations.

    Science.gov (United States)

    Kumar, Akhil; Srivastava, Swati; Tripathi, Shubhandra; Singh, Sandeep Kumar; Srikrishna, Saripella; Sharma, Ashok

    2016-06-01

    Aggregation of amyloid peptide (Aβ) has been shown to be directly related to progression of Alzheimer's disease (AD). Aβ is neurotoxic and its deposition and aggregation ultimately lead to cell death. In our previous work, we reported flavonoid derivative (compound 1) showing promising result in transgenic AD model of Drosophila. Compound 1 showed prevention of Aβ-induced neurotoxicity and neuroprotective efficacy in Drosophila system. However, mechanism of action of compound 1 and its effect on the amyloid is not known. We therefore performed molecular docking and atomistic, explicit-solvent molecular dynamics simulations to investigate the process of Aβ interaction, inhibition, and destabilizing mechanism. Results showed different preferred binding sites of compound 1 and good affinity toward the target. Through the course of 35 ns molecular dynamics simulation, conformations_5 of compound 1 intercalates into the hydrophobic core near the salt bridge and showed major structural changes as compared to other conformations. Compound 1 showed interference with the salt bridge and thus reducing the inter strand hydrogen bound network. This minimizes the side chain interaction between the chains A-B leading to disorder in oligomer. Contact map analysis of amino acid residues between chains A and B also showed lesser interaction with adjacent amino acids in the presence of compound 1 (conformations_5). The study provides an insight into how compound 1 interferes and disorders the Aβ peptide. These findings will further help to design better inhibitors for aggregation of the amyloid oligomer.

  17. Insight into the binding interactions of CYP450 aromatase inhibitors with their target enzyme: a combined molecular docking and molecular dynamics study.

    Science.gov (United States)

    Galeazzi, Roberta; Massaccesi, Luca

    2012-03-01

    CYP450 aromatase catalyzes the terminal and rate-determining step in estrogen synthesis, the aromatization of androgens, and its inhibition is an efficient approach to treating estrogen-dependent breast cancer. Insight into the molecular basis of the interaction at the catalytic site between CYP450 aromatase inhibitors and the enzyme itself is required in order to design new and more active compounds. Hence, a combined molecular docking-molecular dynamics study was carried out to obtain the structure of the lowest energy association complexes of aromatase with some third-generation aromatase inhibitors (AIs) and with other novel synthesized letrozole-derived compounds which showed high in vitro activity. The results obtained clearly demonstrate the role of the pharmacophore groups present in the azaheterocyclic inhibitors (NSAIs)-namely the triazolic ring and highly functionalized aromatic moieties carrying H-bond donor or acceptor groups. In particular, it was pointed out that all of them can contribute to inhibition activity by interacting with residues of the catalytic cleft, but the amino acids involved are different for each compound, even if they belong to the same class. Furthermore, the azaheterocyclic group strongly coordinates with the Fe(II) of heme cysteinate in the most active NSAI complexes, while it prefers to adopt another orientation in less active ones.

  18. Molecular dynamics insight to phase transition in n-alkanes with carbon nanofillers

    Directory of Open Access Journals (Sweden)

    Monisha Rastogi

    2015-05-01

    Full Text Available The present work aims to investigate the phase transition, dispersion and diffusion behavior of nanocomposites of carbon nanotube (CNT and straight chain alkanes. These materials are potential candidates for organic phase change materials(PCMs and have attracted flurry of research recently. Accurate experimental evaluation of the mass, thermal and transport properties of such composites is both difficult as well as economically taxing. Additionally it is crucial to understand the factors that results in modification or enhancement of their characteristic at atomic or molecular level. Classical molecular dynamics approach has been extended to elucidate the same. Bulk atomistic models have been generated and subjected to rigorous multistage equilibration. To reaffirm the approach, both canonical and constant-temperature, constant- pressure ensembles were employed to simulate the models under consideration. Explicit determination of kinetic, potential, non-bond and total energy assisted in understanding the enhanced thermal and transport property of the nanocomposites from molecular point of view. Crucial parameters including mean square displacement and simulated self diffusion coefficient precisely define the balance of the thermodynamic and hydrodynamic interactions. Radial distribution function also reflected the density variation, strength and mobility of the nanocomposites. It is expected that CNT functionalization could improve the dispersion within n-alkane matrix. This would further ameliorate the mass and thermal properties of the composite. Additionally, the determined density was in good agreement with experimental data. Thus, molecular dynamics can be utilized as a high throughput technique for theoretical investigation of nanocomposites PCMs.

  19. Molecular dynamics insight to phase transition in n-alkanes with carbon nanofillers

    Energy Technology Data Exchange (ETDEWEB)

    Rastogi, Monisha [School of Engineering, Indian Institute of Technology Mandi, Himachal Pradesh 175 001 (India); Vaish, Rahul, E-mail: rahul@iitmandi.ac.in [School of Engineering, Indian Institute of Technology Mandi, Himachal Pradesh 175 001 (India); Materials Research Centre, Indian Institute of Science, Bangalore 560 012 (India)

    2015-05-15

    The present work aims to investigate the phase transition, dispersion and diffusion behavior of nanocomposites of carbon nanotube (CNT) and straight chain alkanes. These materials are potential candidates for organic phase change materials(PCMs) and have attracted flurry of research recently. Accurate experimental evaluation of the mass, thermal and transport properties of such composites is both difficult as well as economically taxing. Additionally it is crucial to understand the factors that results in modification or enhancement of their characteristic at atomic or molecular level. Classical molecular dynamics approach has been extended to elucidate the same. Bulk atomistic models have been generated and subjected to rigorous multistage equilibration. To reaffirm the approach, both canonical and constant-temperature, constant- pressure ensembles were employed to simulate the models under consideration. Explicit determination of kinetic, potential, non-bond and total energy assisted in understanding the enhanced thermal and transport property of the nanocomposites from molecular point of view. Crucial parameters including mean square displacement and simulated self diffusion coefficient precisely define the balance of the thermodynamic and hydrodynamic interactions. Radial distribution function also reflected the density variation, strength and mobility of the nanocomposites. It is expected that CNT functionalization could improve the dispersion within n-alkane matrix. This would further ameliorate the mass and thermal properties of the composite. Additionally, the determined density was in good agreement with experimental data. Thus, molecular dynamics can be utilized as a high throughput technique for theoretical investigation of nanocomposites PCMs.

  20. Insight into the molecular regulation of the epithelial magnesium channel TRPM6.

    NARCIS (Netherlands)

    Cao, G.; Hoenderop, J.G.J.; Bindels, R.J.M.

    2008-01-01

    PURPOSE OF REVIEW: Recent studies have greatly increased our knowledge concerning the molecular mechanisms of renal magnesium handling. This review highlights the functional features of the newly identified transient receptor potential channel melastatin subtype 6 (TRPM6), which forms the gatekeeper

  1. Whole-genome duplication and molecular evolution in Cornus L. (Cornaceae) – Insights from transcriptome sequences

    Science.gov (United States)

    Yu, Yan; Xiang, Qiuyun; Manos, Paul S.; Soltis, Douglas E.; Soltis, Pamela S.; Song, Bao-Hua; Cheng, Shifeng; Liu, Xin; Wong, Gane

    2017-01-01

    The pattern and rate of genome evolution have profound consequences in organismal evolution. Whole-genome duplication (WGD), or polyploidy, has been recognized as an important evolutionary mechanism of plant diversification. However, in non-model plants the molecular signals of genome duplications have remained largely unexplored. High-throughput transcriptome data from next-generation sequencing have set the stage for novel investigations of genome evolution using new bioinformatic and methodological tools in a phylogenetic framework. Here we compare ten de novo-assembled transcriptomes representing the major lineages of the angiosperm genus Cornus (dogwood) and relevant outgroups using a customized pipeline for analyses. Using three distinct approaches, molecular dating of orthologous genes, analyses of the distribution of synonymous substitutions between paralogous genes, and examination of substitution rates through time, we detected a shared WGD event in the late Cretaceous across all taxa sampled. The inferred doubling event coincides temporally with the paleoclimatic changes associated with the initial divergence of the genus into three major lineages. Analyses also showed an acceleration of rates of molecular evolution after WGD. The highest rates of molecular evolution were observed in the transcriptome of the herbaceous lineage, C. canadensis, a species commonly found at higher latitudes, including the Arctic. Our study demonstrates the value of transcriptome data for understanding genome evolution in closely related species. The results suggest dramatic increase in sea surface temperature in the late Cretaceous may have contributed to the evolution and diversification of flowering plants. PMID:28225773

  2. Glioma-related edema: new insight into molecular mechanisms and their clinical implications

    Institute of Scientific and Technical Information of China (English)

    Zhi-Xiong Lin

    2013-01-01

    Glioma-related edema (GRE) is a significant contributor to morbidity and mortality from glioma.GRE is a complicated process involving not only peritumoral edema but also the water content of the tumor body.In terms of etiology,this condition derives from both GRE in the untreated state and GRE secondary to clinical intervention,and different cell types contribute to distinct components of GRE.Peritumoral edema was previously believed to loosen glioma tissue,facilitating tumor-cell invasion;however,the nutrition hypothesis of the tumor microecosystem suggests that tumor cells invade for the sake of nutrition.Edema is the pathologic consequence of the reconstructed trophic linkage within the tumor microecosystem.Glioma cells induce peritumoral brain edema via an active process that supplies a suitable niche for peritumoral invasive cells,suggesting that glioma-related peritumoral brain edema is determined by the invasive property of tumor cells.There are differences between pivotal molecular events and reactive molecular events in the development of GRE.Molecular therapy should target the former,as targeting reactive molecular events will produce undesired or even adverse results.At present,brain glioma angiogenesis models have not been translated into a new understanding of the features of brain images.The effect of these models on peritumoral brain edema is unclear.Clinical approaches should be transformed on the basis of new knowledge of the molecular mechanism underlying GRE.Exploring clinical assessment methods,optimizing the existing control strategy of GRE,and simultaneously developing new treatments are essential.

  3. Molecular and cellular insights into a distinct myopathy of Great Dane dogs.

    Science.gov (United States)

    Chang, Kin-Chow; McCulloch, Maj-Lis C; Anderson, Thomas James

    2010-03-01

    A myopathy in the Great Dane dog with characteristic pathological and molecular features is reported. Young adults present with progressive weakness and generalised muscle atrophy. To better define this condition, an investigation using histopathology, confocal microscopy, biochemistry and microarray analysis was undertaken. The skeletal muscles of affected dogs exhibited increased oxidative fibre phenotype and core fibre lesions characterised by the disruption of the sarcomeric architecture and the accumulation of mitochondrial organelles. Affected muscles displayed co-ordinated expression of genes consistent with a slow-oxidative phenotype, which was possibly a compensatory response to chronic muscle damage. There was disruption of Z-lines in affected muscles which, at the molecular level, manifested as transcriptional dysregulation of several Z-line associated genes, including alpha-actinin, myotilin, desmin, vimentin and telethonin. The pathology of this canine myopathy is distinct from that of human central core myopathies that are characterised by cores devoid of mitochondria and by the presence of myofibrillar breakdown products.

  4. Gene expression profiles give insight into the molecular pathology of bone in primary hyperparathyroidism

    DEFF Research Database (Denmark)

    Reppe, Sjur; Stilgren, Lis; Olstad, Ole K;

    2006-01-01

    Global gene expression profiling has been used to study the molecular mechanisms of increased bone remodeling caused by PHPT. This disease is a model for chronic over-stimulation of target organs by PTH due to an inappropriate overproduction of the hormone. Hyperactivity of osteoblasts and osteoc......Global gene expression profiling has been used to study the molecular mechanisms of increased bone remodeling caused by PHPT. This disease is a model for chronic over-stimulation of target organs by PTH due to an inappropriate overproduction of the hormone. Hyperactivity of osteoblasts...... and osteoclasts lead to increased calcium and phosphate mobilization from the skeleton and hypercalcaemia. The ensemble of genes that alter expression and thus is responsible for the effects of chronic PTH stimulation is today largely unknown. The differentiated gene expression profiles revealed characteristic...

  5. Whole Transcriptome Analysis Provides Insights into Molecular Mechanisms for Molting in Litopenaeus vannamei.

    Science.gov (United States)

    Gao, Yi; Zhang, Xiaojun; Wei, Jiankai; Sun, Xiaoqing; Yuan, Jianbo; Li, Fuhua; Xiang, Jianhai

    2015-01-01

    Molting is one of the most important biological processes in shrimp growth and development. All shrimp undergo cyclic molting periodically to shed and replace their exoskeletons. This process is essential for growth, metamorphosis, and reproduction in shrimp. However, the molecular mechanisms underlying shrimp molting remain poorly understood. In this study, we investigated global expression changes in the transcriptomes of the Pacific white shrimp, Litopenaeus vannamei, the most commonly cultured shrimp species worldwide. The transcriptome of whole L. vannamei was investigated by RNA-sequencing (RNA-seq) throughout the molting cycle, including the inter-molt (C), pre-molt (D0, D1, D2, D3, D4), and post-molt (P1 and P2) stages, and 93,756 unigenes were identified. Among these genes, we identified 5,117 genes differentially expressed (log2ratio ≥1 and FDR ≤0.001) in adjacent molt stages. The results were compared against the National Center for Biotechnology Information (NCBI) non-redundant protein/nucleotide sequence database, Swiss-Prot, PFAM database, the Gene Ontology database, and the Kyoto Encyclopedia of Genes and Genomes database in order to annotate gene descriptions, associate them with gene ontology terms, and assign them to pathways. The expression patterns for genes involved in several molecular events critical for molting, such as hormone regulation, triggering events, implementation phases, skelemin, immune responses were characterized and considered as mechanisms underlying molting in L. vannamei. Comparisons with transcriptomic analyses in other arthropods were also performed. The characterization of major transcriptional changes in genes involved in the molting cycle provides candidates for future investigation of the molecular mechanisms. The data generated in this study will serve as an important transcriptomic resource for the shrimp research community to facilitate gene and genome annotation and to characterize key molecular processes

  6. Novel Insights into the Molecular Mechanisms Governing Mdm2 Ubiquitination and Destruction

    OpenAIRE

    Fukushima, Hidefumi; Inuzuka, Hiroyuki; Shaik, Shavali; Wei, Wenyi

    2010-01-01

    The Mdm2/p53 pathway is compromised in more than 50% of all human cancers, therefore it is an intensive area of research to understand the upstream regulatory pathways governing Mdm2/p53 activity. Mdm2 is frequently overexpressed in human cancers while the molecular mechanisms underlying the timely destruction of Mdm2 remain unclear. We recently reported that Casein Kinase I phosphorylates Mdm2 at multiple sites to trigger Mdm2 interaction with, and subsequent ubiquitination and destruction b...

  7. Insights into diffusion of gases in zeolites gained from molecular dynamics simulations

    NARCIS (Netherlands)

    Krishna, R.; van Baten, J.M.

    2008-01-01

    The Maxwell-Stefan (M-S) diffusivities Đi of a variety of gases (He, Ne, Ar, Kr, H2, N2, CO2, CH4) in six different all-silica zeolite structures (MFI, AFI, FAU, CHA, DDR, and LTA) have been determined using molecular dynamics (MD) simulations for a range of molar loadings, qi. In all cases the Đi a

  8. Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design.

    Science.gov (United States)

    Zhang, Liang; Bhatnagar, Sumit; Deschenes, Emily; Thurber, Greg M

    2016-05-05

    Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake, and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Two in vitro experimental methods for estimating background signal in vivo are compared - non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents.

  9. Cellular and molecular drivers of differential organ growth: insights from the limbs of Monodelphis domestica.

    Science.gov (United States)

    Dowling, Anna; Doroba, Carolyn; Maier, Jennifer A; Cohen, Lorna; VandeBerg, John; Sears, Karen E

    2016-06-01

    A fundamental question in biology is "how is growth differentially regulated during development to produce organs of particular sizes?" We used a new model system for the study of differential organ growth, the limbs of the opossum (Monodelphis domestica), to investigate the cellular and molecular basis of differential organ growth in mammals. Opossum forelimbs grow much faster than hindlimbs, making opossum limbs an exceptional system with which to study differential growth. We first used the great differences in opossum forelimb and hindlimb growth to identify cellular processes and molecular signals that underlie differential limb growth. We then used organ culture and pharmacological addition of FGF ligands and inhibitors to test the role of the Fgf/Mitogen-activated protein kinases (MAPK) signaling pathway in driving these cellular processes. We found that molecular signals from within the limb drive differences in cell proliferation that contribute to the differential growth of the forelimb and hindlimbs of opossums. We also found that alterations in the Fgf/MAPK pathway can generate differences in cell proliferation that mirror those observed between wild-type forelimb and hindlimbs of opossums and that manipulation of Fgf/MAPK signaling affects downstream focal adhesion-extracellular matrix (FA-ECM) and Wnt signaling in opossum limbs. Taken together, these findings suggest that evolutionary changes in the Fgf/MAPK pathway could help drive the observed differences in cell behaviors and growth in opossum forelimb and hindlimbs.

  10. Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design

    Science.gov (United States)

    Zhang, Liang; Bhatnagar, Sumit; Deschenes, Emily; Thurber, Greg M.

    2016-05-01

    Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake, and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Two in vitro experimental methods for estimating background signal in vivo are compared - non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents.

  11. New insights from molecular characterization of the tick Rhipicephalus (Boophilus microplus in Brazil

    Directory of Open Access Journals (Sweden)

    Bárbara Guimarães Csordas

    Full Text Available Abstract The Rhipicephalus (Boophilus microplus complex currently consists of five taxa, namely R. australis, R. annulatus, R. (B. microplus clade A sensu, R. microplus clade B sensu, and R. (B. microplus clade C sensu. Mitochondrial DNA-based methods help taxonomists when they are facing the morpho-taxonomic problem of distinguishing members of the R. (B. microplus complex. The purpose of this study was to perform molecular characterization of ticks in all five regions of Brazil and infer their phylogenetic relationships. Molecular analysis characterized 10 haplotypes of the COX-1 gene. Molecular network analysis revealed that haplotype H-2 was the most dispersed of the studied populations (n = 11. Haplotype H-3 (n = 2 had the greatest genetic differentiation when compared to other Brazilian populations. A Bayesian phylogenetic tree of the COX-1 gene obtained strong support. In addition, it was observed that the population of R. (B. microplus haplotype H-3 exhibited diverging branches among the other Brazilian populations in the study. The study concludes that the different regions of Brazil have R. (B. microplus tick populations with distinct haplotypes.

  12. Photodynamic efficiency of cationic meso-porphyrins at lipid bilayers: insights from molecular dynamics simulations.

    Science.gov (United States)

    Cordeiro, Rodrigo M; Miotto, Ronei; Baptista, Maurício S

    2012-12-20

    Porphyrin derivatives have applications as photoactive drugs in photodynamic therapy. However, little is known about their interactions with phospholipid membranes at the molecular level. We employed molecular dynamics simulations to model the binding between a series of cationic meso-(N-methyl-4-pyridinium)phenylporphyrins and anionic phosphatidylglycerol lipid bilayers. This was done in the presence of molecular oxygen within the membrane. The ability of various porphyrins to cause photodamage was quantified in terms of their immersion depth and degree of exposition to a higher oxygen concentration inside the membrane. Simulations showed that the photodynamic efficiency could be improved as the number of hydrophobic phenyl substituents attached to the porphyrinic ring increased. In the specific case of porphyrins containing two hydrophobic and two charged substituents, the cis isomer was significantly more efficient than the trans. These results correlate well with previous experimental observations. They highlight the importance of both the total charge and amphiphilicity of the photosensitizer for its performance in photodynamic therapy.

  13. Exploring molecular insights into aggregation of hydrotrope sodium cumene sulfonate in aqueous solution: a molecular dynamics simulation study.

    Science.gov (United States)

    Das, Shubhadip; Paul, Sandip

    2015-02-19

    Hydrotropes are an important class of molecules that enhance the solubility of an otherwise insoluble or sparingly soluble solute in water. Besides this, hydrotropes are also known to self-assemble in aqueous solution and form aggregates. It is the hydrotrope aggregate that helps in solubilizing a solute molecule in water. In view of this, we try to understand the underlying mechanism of self-aggregation of hydrotrope sodium cumene sulfonate (SCS) in water. We have carried out classical molecular dynamics simulations of aqueous SCS solutions with a regime of concentrations. Moreover, to examine the effect of temperature change on SCS aggregation, if any, we consider four different temperatures ranging from 298 to 358 K. From the estimation of densities of different solutions we calculate apparent and partial molal volumes of the hydrotrope. The changes in these quantities increase sharply at a characteristic minimum hydrotrope concentration. The determination of molal expansibility at infinite dilution for different temperatures indicates the water structure breaking by SCS molecules, which is further confirmed by the calculations of water-water pair correlation functions. In comparison with typical surfactants in micelles, a slightly lower value of volumetric change upon aggregation per carbon atom suggests the formation of a more closely packed structure of hydrotrope aggregates. A close examination of different structural properties of hydrotrope solutions reveals that the hydrophobic interactions through their hydrophobic tails significantly contribute in hydrotrope aggregation,and the dehydration of hydrophobic tail at elevated temperatures is also visible. Remarkably, the aggregates have little or no impact on the average number of water-SCS hydrogen bonds.

  14. Molecular insights into the microbial formation of marine dissolved organic matter: recalcitrant or labile?

    Science.gov (United States)

    Koch, B. P.; Kattner, G.; Witt, M.; Passow, U.

    2014-08-01

    The degradation of marine dissolved organic matter (DOM) is an important control variable in the global carbon cycle. For our understanding of the kinetics of organic matter cycling in the ocean, it is crucial to achieve a mechanistic and molecular understanding of its transformation processes. A long-term microbial experiment was performed to follow the production of non-labile DOM by marine bacteria. Two different glucose concentrations and dissolved algal exudates were used as substrates. We monitored the bacterial abundance, concentrations of dissolved and particulate organic carbon (DOC, POC), nutrients, amino acids and transparent exopolymer particles (TEP) for 2 years. The molecular characterization of extracted DOM was performed by ultrahigh resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) after 70 days and after ∼2 years of incubation. Although glucose quickly degraded, a non-labile DOC background (5-9% of the initial DOC) was generated in the glucose incubations. Only 20% of the organic carbon from the algal exudate degraded within the 2 years of incubation. The degradation rates for the non-labile DOC background in the different treatments varied between 1 and 11 μmol DOC L-1 year-1. Transparent exopolymer particles, which are released by microorganisms, were produced during glucose degradation but decreased back to half of the maximum concentration within less than 3 weeks (degradation rate: 25 μg xanthan gum equivalents L-1 d-1) and were below detection in all treatments after 2 years. Additional glucose was added after 2 years to test whether labile substrate can promote the degradation of background DOC (co-metabolism; priming effect). A priming effect was not observed but the glucose addition led to a slight increase of background DOC. The molecular analysis demonstrated that DOM generated during glucose degradation differed appreciably from DOM transformed during the degradation of the algal exudates. Our

  15. Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency.

    Directory of Open Access Journals (Sweden)

    Laurent R Chiarelli

    Full Text Available Phosphoglycerate kinase (PGK catalyzes an important ATP-generating step in glycolysis. PGK1 deficiency is an uncommon X-linked inherited disorder, generally characterized by various combinations of non-spherocytic hemolytic anemia, neurological dysfunctions, and myopathies. Patients rarely exhibit all three clinical features. To provide a molecular framework to the different pathological manifestations, all known mutations were reviewed and 16 mutant enzymes, obtained as recombinant forms, were functionally and structurally characterized. Most mutations heavily affect thermal stability and to a different extent catalytic efficiency, in line with the remarkably low PGK activity clinically observed in the patients. Mutations grossly impairing protein stability, but moderately affecting kinetic properties (p.I47N, p.L89P, p.C316R, p.S320N, and p.A354P present the most homogeneous correlation with the clinical phenotype. Patients carrying these mutations display hemolytic anemia and neurological disorders, and,except for p.A354P variant, no myopaty. Variants highly perturbed in both catalytic efficiency (p.G158V, p.D164V, p.K191del, D285V, p.D315N, and p.T378P and heat stability (all, but p.T378P result to be mainly associated with myopathy alone. Finally, mutations faintly affecting molecular properties (p.R206P, p.E252A, p.I253T, p.V266M, and p.D268N correlate with a wide spectrum of clinical symptoms. These are the first studies that correlate the clinical symptoms with the molecular properties of the mutant enzymes. All findings indicate that the different clinical manifestations associated with PGK1 deficiency chiefly depend on the distinctive type of perturbations caused by mutations in the PGK1 gene, highlighting the need for determination of the molecular properties of PGK variants to assist in prognosis and genetic counseling. However, the clinical symptoms can not be understood only on the bases of molecular properties of the mutant enzyme

  16. Insights into the immuno-molecular biology of Angiostrongylus vasorum through transcriptomics--prospects for new interventions.

    Science.gov (United States)

    Ansell, Brendan R E; Schnyder, Manuela; Deplazes, Peter; Korhonen, Pasi K; Young, Neil D; Hall, Ross S; Mangiola, Stefano; Boag, Peter R; Hofmann, Andreas; Sternberg, Paul W; Jex, Aaron R; Gasser, Robin B

    2013-12-01

    Angiostrongylus vasorum is a metastrongyloid nematode of dogs and other canids of major clinical importance in many countries. In order to gain first insights into the molecular biology of this worm, we conducted the first large-scale exploration of its transcriptome, and predicted essential molecules linked to metabolic and biological processes as well as host immune responses. We also predicted and prioritized drug targets and drug candidates. Following Illumina sequencing (RNA-seq), 52.3 million sequence reads representing adult A. vasorum were assembled and annotated. The assembly yielded 20,033 contigs, which encoded proteins with 11,505 homologues in Caenorhabditis elegans, and additional 2252 homologues in various other parasitic helminths for which curated data sets were publicly available. Functional annotation was achieved for 11,752 (58.6%) proteins predicted for A. vasorum, including peptidases (4.5%) and peptidase inhibitors (1.6%), protein kinases (1.7%), G protein-coupled receptors (GPCRs) (1.5%) and phosphatases (1.2%). Contigs encoding excretory/secretory and immuno-modulatory proteins represented some of the most highly transcribed molecules, and encoded enzymes that digest haemoglobin were conserved between A. vasorum and other blood-feeding nematodes. Using an essentiality-based approach, drug targets, including neurotransmitter receptors, an important chemosensory ion channel and cysteine proteinase-3 were predicted in A. vasorum, as were associated small molecular inhibitors/activators. Future transcriptomic analyses of all developmental stages of A. vasorum should facilitate deep explorations of the molecular biology of this important parasitic nematode and support the sequencing of its genome. These advances will provide a foundation for exploring immuno-molecular aspects of angiostrongylosis and have the potential to underpin the discovery of new methods of intervention.

  17. New Insights into the Molecular Epidemiology and Population Genetics of Schistosoma mansoni in Ugandan Pre-school Children and Mothers

    Science.gov (United States)

    Betson, Martha; Sousa-Figueiredo, Jose C.; Kabatereine, Narcis B.; Stothard, J. Russell

    2013-01-01

    Significant numbers of pre-school children are infected with Schistosoma mansoni in sub-Saharan Africa and are likely to play a role in parasite transmission. However, they are currently excluded from control programmes. Molecular phylogenetic studies have provided insights into the evolutionary origins and transmission dynamics of S. mansoni, but there has been no research into schistosome molecular epidemiology in pre-school children. Here, we investigated the genetic diversity and population structure of S. mansoni in pre-school children and mothers living in lakeshore communities in Uganda and monitored for changes over time after praziquantel treatment. Parasites were sampled from children (<6 years) and mothers enrolled in the longitudinal Schistosomiasis Mothers and Infants Study at baseline and at 6-, 12- and 18-month follow-up surveys. 1347 parasites from 35 mothers and 45 children were genotyped by direct sequencing of the cytochrome c oxidase (cox1) gene. The cox1 region was highly diverse with over 230 unique sequences identified. Parasite populations were genetically differentiated between lakes and non-synonymous mutations were more diverse at Lake Victoria than Lake Albert. Surprisingly, parasite populations sampled from children showed a similar genetic diversity to those sampled from mothers, pointing towards a non-linear relationship between duration of exposure and accumulation of parasite diversity. The genetic diversity six months after praziquantel treatment was similar to pre-treatment diversity. Our results confirm the substantial genetic diversity of S. mansoni in East Africa and provide significant insights into transmission dynamics within young children and mothers, important information for schistosomiasis control programmes. PMID:24349589

  18. New insights into the molecular epidemiology and population genetics of Schistosoma mansoni in Ugandan pre-school children and mothers.

    Directory of Open Access Journals (Sweden)

    Martha Betson

    Full Text Available Significant numbers of pre-school children are infected with Schistosoma mansoni in sub-Saharan Africa and are likely to play a role in parasite transmission. However, they are currently excluded from control programmes. Molecular phylogenetic studies have provided insights into the evolutionary origins and transmission dynamics of S. mansoni, but there has been no research into schistosome molecular epidemiology in pre-school children. Here, we investigated the genetic diversity and population structure of S. mansoni in pre-school children and mothers living in lakeshore communities in Uganda and monitored for changes over time after praziquantel treatment. Parasites were sampled from children (<6 years and mothers enrolled in the longitudinal Schistosomiasis Mothers and Infants Study at baseline and at 6-, 12- and 18-month follow-up surveys. 1347 parasites from 35 mothers and 45 children were genotyped by direct sequencing of the cytochrome c oxidase (cox1 gene. The cox1 region was highly diverse with over 230 unique sequences identified. Parasite populations were genetically differentiated between lakes and non-synonymous mutations were more diverse at Lake Victoria than Lake Albert. Surprisingly, parasite populations sampled from children showed a similar genetic diversity to those sampled from mothers, pointing towards a non-linear relationship between duration of exposure and accumulation of parasite diversity. The genetic diversity six months after praziquantel treatment was similar to pre-treatment diversity. Our results confirm the substantial genetic diversity of S. mansoni in East Africa and provide significant insights into transmission dynamics within young children and mothers, important information for schistosomiasis control programmes.

  19. Cationic complexation with dissolved organic matter: Insights from molecular dynamics computer simulations and NMR spectroscopy

    Science.gov (United States)

    Kalinichev, A. G.; Xu, X.; Kirkpatrick, R.

    2006-12-01

    Dissolved organic matter (DOM) is ubiquitous in soil and surface water and plays many important geochemical and environmental roles acting as a proton donor/acceptor and pH buffer and interacting with metal ions, minerals and organic species to form water-soluble and water-insoluble complexes of widely differing chemical and biological stabilities. There are strong correlations among the concentration of DOM and the speciation, solubility and toxicity of many trace metals in soil and water due to metal-DOM interaction. DOM can also significantly negatively affect the performance of nanofiltration and reverse osmosis membranes used industrially for water purification and desalination, being one of the major causes of a so-called `membrane bio- fouling'. The molecular scale mechanisms and dynamics of the DOM interactions with metals and membranes are, however, quite poorly understood. Methods of computational molecular modeling, combined with element- specific nuclear magnetic resonance (NMR) spectroscopy, can serve as highly effective tools to probe and quantify on a fundamental molecular level the DOM interactions with metal cations in aqueous solutions, and to develop predictive models of the molecular mechanisms responsible for the metal-DOM complexation in the environment. This paper presents the results of molecular dynamics (MD) computer simulations of the interaction of DOM with dissolved Na+, Cs+, Mg2+, and Ca2+. Na+ forms only very weak outer-sphere complexes with DOM. These results and the results of other recent molecular modeling efforts (e.g., Sutton et al., Environmental Toxicology and Chemistry, 24, 1902-1911, 2005), clearly indicate that both the structural and dynamic aspects of the cation-DOM complexation follow a simple trend in terms of the charge/size ratio for the ions. Due to the competition between ion hydration in bulk aqueous solution and adsorption of these cations by the negatively charged DOM functional groups (primarily carboxylate

  20. Molecular Insights into the Genetic Diversity of Garcinia cambogia Germplasm Accessions

    Directory of Open Access Journals (Sweden)

    C Tharachand

    2015-10-01

    Full Text Available ABSTRACTIn this work, the genetic relationship among twelveGarcinia cambogia (Gaertn. Desr. accessions were evaluated using Random Amplified Polymorphic DNA markers. The samples were part of the germplasm collected and maintained at NBPGR Regional station, Thrissur, India. Out of thirty RAPD primers used for screening, seven primers produced a total of 128 polymorphic markers in twelve accessions. The Polymorphic Information Content (PIC ranged from 0.28 (OPA18 to 0.37 (OPA9 and Marker Index (MI ranged between 3.61 (OPA12 and 5.93 (OPA3 among the primers used. Jaccard's coefficient of genetic similarity ranged between 0.07 and 0.64. The dendrogram constructed based on the similarity matrix generated from the molecular and morphological data showed the genetic relationship among the sampled accessions. Mantel matrix test showed a positive correlation (r = 0.49 between the cluster analysis of RAPD data and morphological data. The clustering pattern in the molecular dendrogram and Principle Coordinate Analysis (PCoA showed that the genotypes were diverse, which was in congruence with the similarity index values and morphological dendrogram. High frequency of similarity values in the range of 0.11 to 0.17 suggested the existence of high genetic diversity among the accessions. The high level of genetic diversity among the studied accessions ofG.cambogia was also supported by the large variation in the morphological characters observed in the flowers, leaves, fruits and seeds of these sampled accessions. This is the first report for the molecular based genetic diversity studies for these accessions.

  1. Influences of subtropical jet and Tibetan Plateau on precipitation pattern in Asia : Insights from regional climate modeling

    NARCIS (Netherlands)

    Sato, Tomonori

    2009-01-01

    Large topographic features, like the Tibetan Plateau (TP) and the Rocky Mountains, have significant impacts on Earth's climate. Numerical experiments were carried out using a regional climate model in order to study the sensitivity of rainfall distribution to the TP's thermal/dynamic effects and mer

  2. Mitochondrial DNA disease—molecular insights and potential routes to a cure

    Energy Technology Data Exchange (ETDEWEB)

    Russell, Oliver; Turnbull, Doug, E-mail: doug.turnbull@newcastle.ac.uk

    2014-07-01

    Mitochondrial DNA diseases are common neurological conditions caused by mutations in the mitochondrial genome or nuclear genes responsible for its maintenance. Current treatments for these disorders are focussed on the management of the symptoms, rather than the correction of biochemical defects caused by the mutation. This review focuses on the molecular effects of mutations, the symptoms they cause and current work focusing on the development of targeted treatments for mitochondrial DNA disease. - Highlights: • We discuss several common disease causing mtDNA mutations. • We highlight recent work linking pathogenicity to deletion size and heteroplasmy. • We discuss recent advances in the development of targeted mtDNA disease treatments.

  3. Atomic level insights into realistic molecular models of dendrimer-drug complexes through MD simulations

    Science.gov (United States)

    Jain, Vaibhav; Maiti, Prabal K.; Bharatam, Prasad V.

    2016-09-01

    Computational studies performed on dendrimer-drug complexes usually consider 1:1 stoichiometry, which is far from reality, since in experiments more number of drug molecules get encapsulated inside a dendrimer. In the present study, molecular dynamic (MD) simulations were implemented to characterize the more realistic molecular models of dendrimer-drug complexes (1:n stoichiometry) in order to understand the effect of high drug loading on the structural properties and also to unveil the atomistic level details. For this purpose, possible inclusion complexes of model drug Nateglinide (Ntg) (antidiabetic, belongs to Biopharmaceutics Classification System class II) with amine- and acetyl-terminated G4 poly(amidoamine) (G4 PAMAM(NH2) and G4 PAMAM(Ac)) dendrimers at neutral and low pH conditions are explored in this work. MD simulation analysis on dendrimer-drug complexes revealed that the drug encapsulation efficiency of G4 PAMAM(NH2) and G4 PAMAM(Ac) dendrimers at neutral pH was 6 and 5, respectively, while at low pH it was 12 and 13, respectively. Center-of-mass distance analysis showed that most of the drug molecules are located in the interior hydrophobic pockets of G4 PAMAM(NH2) at both the pH; while in the case of G4 PAMAM(Ac), most of them are distributed near to the surface at neutral pH and in the interior hydrophobic pockets at low pH. Structural properties such as radius of gyration, shape, radial density distribution, and solvent accessible surface area of dendrimer-drug complexes were also assessed and compared with that of the drug unloaded dendrimers. Further, binding energy calculations using molecular mechanics Poisson-Boltzmann surface area approach revealed that the location of drug molecules in the dendrimer is not the decisive factor for the higher and lower binding affinity of the complex, but the charged state of dendrimer and drug, intermolecular interactions, pH-induced conformational changes, and surface groups of dendrimer do play an

  4. Molecular insights into the boundary conditions in the Stokes-Einstein relation.

    Science.gov (United States)

    Ishii, Yoshiki; Ohtori, Norikazu

    2016-05-01

    In order to mimic the Brownian particle in liquid, molecular dynamics calculations of dilute solutions of spherical fullerene molecules with various sizes in liquid Ar were performed. To establish the scaling equation for self-diffusion coefficient, D, of the fullerenes, the dependence of D was examined on the mass ratio of solute to solvent and on the energy-parameter ratio used in the Lennard-Jones potentials. The dependence on the energy-parameter ratio remains up to C_{540}, whereas D rapidly becomes independent of the mass ratio with increasing mass of the solute. The product of the scaling equations obtained for the D of the solute and for shear viscosity, η_{sv}, for the solvent gives a relation which replaces the Stokes-Einstein relation based on the hydrodynamics. The present expression does not need both the boundary conditions and the hydrodynamic particle size, but instead the energy-parameter ratio, packing fraction of solvent, and bare size of solute. From the viewpoint of the tackiness at the boundary, the cage correlation function around the diffusing particle was examined; it was found that the decay time of the function depends mainly on the the energy-parameter ratio. Therefore, the energy-parameter ratio accounts for the main part of both the boundary conditions and the hydrodynamic particle size in the Stokes equation, which have so far been ill-defined in any molecular theories.

  5. Nuclear magnetic shielding constants of liquid water: insights from hybrid quantum mechanics/molecular mechanics models.

    Science.gov (United States)

    Kongsted, Jacob; Nielsen, Christian B; Mikkelsen, Kurt V; Christiansen, Ove; Ruud, Kenneth

    2007-01-21

    We present a gauge-origin independent method for the calculation of nuclear magnetic shielding tensors of molecules in a structured and polarizable environment. The method is based on a combination of density functional theory (DFT) or Hartree-Fock wave functions with molecular mechanics. The method is unique in the sense that it includes three important properties that need to be fulfilled in accurate calculations of nuclear magnetic shielding constants: (i) the model includes electron correlation effects, (ii) the model uses gauge-including atomic orbitals to give gauge-origin independent results, and (iii) the effect of the environment is treated self-consistently using a discrete reaction-field methodology. The authors present sample calculations of the isotropic nuclear magnetic shielding constants of liquid water based on a large number of solute-solvent configurations derived from molecular dynamics simulations employing potentials which treat solvent polarization either explicitly or implicitly. For both the (17)O and (1)H isotropic shielding constants the best predicted results compare fairly well with the experimental data, i.e., they reproduce the experimental solvent shifts to within 4 ppm for the (17)O shielding and 1 ppm for the (1)H shielding.

  6. Nuclear magnetic shielding constants of liquid water: Insights from hybrid quantum mechanics/molecular mechanics models

    Science.gov (United States)

    Kongsted, Jacob; Nielsen, Christian B.; Mikkelsen, Kurt V.; Christiansen, Ove; Ruud, Kenneth

    2007-01-01

    We present a gauge-origin independent method for the calculation of nuclear magnetic shielding tensors of molecules in a structured and polarizable environment. The method is based on a combination of density functional theory (DFT) or Hartree-Fock wave functions with molecular mechanics. The method is unique in the sense that it includes three important properties that need to be fulfilled in accurate calculations of nuclear magnetic shielding constants: (i) the model includes electron correlation effects, (ii) the model uses gauge-including atomic orbitals to give gauge-origin independent results, and (iii) the effect of the environment is treated self-consistently using a discrete reaction-field methodology. The authors present sample calculations of the isotropic nuclear magnetic shielding constants of liquid water based on a large number of solute-solvent configurations derived from molecular dynamics simulations employing potentials which treat solvent polarization either explicitly or implicitly. For both the O17 and H1 isotropic shielding constants the best predicted results compare fairly well with the experimental data, i.e., they reproduce the experimental solvent shifts to within 4ppm for the O17 shielding and 1ppm for the H1 shielding.

  7. Insights into the structural stability of Bax from molecular dynamics simulations at high temperatures

    Science.gov (United States)

    Rosas-Trigueros, Jorge Luis; Correa-Basurto, José; Guadalupe Benítez-Cardoza, Claudia; Zamorano-Carrillo, Absalom

    2011-01-01

    Bax is a member of the Bcl-2 protein family that participates in mitochondrion-mediated apoptosis. In the early stages of the apoptotic pathway, this protein migrates from the cytosol to the outer mitochondrial membrane, where it is inserted and usually oligomerizes, making cytochrome c-compatible pores. Although several cellular and structural studies have been reported, a description of the stability of Bax at the molecular level remains elusive. This article reports molecular dynamics simulations of monomeric Bax at 300, 400, and 500 K, focusing on the most relevant structural changes and relating them to biological experimental results. Bax gradually loses its α-helices when it is submitted to high temperatures, yet it maintains its globular conformation. The resistance of Bax to adopt an extended conformation could be due to several interactions that were found to be responsible for maintaining the structural stability of this protein. Among these interactions, we found salt bridges, hydrophobic interactions, and hydrogen bonds. Remarkably, salt bridges were the most relevant to prevent the elongation of the structure. In addition, the analysis of our results suggests which conformational movements are implicated in the activation/oligomerization of Bax. This atomistic description might have important implications for understanding the functionality and stability of Bax in vitro as well as within the cellular environment. PMID:21936009

  8. G-protein-coupled receptor kinase 2 and endothelial dysfunction: molecular insights and pathophysiological mechanisms.

    Science.gov (United States)

    Taguchi, Kumiko; Matsumoto, Takayuki; Kobayashi, Tsuneo

    2015-01-01

    Smooth muscle cells (SMC) and endothelial cells are the major cell types in blood vessels. The principal function of vascular SMC in the body is to regulate blood flow and pressure through contraction and relaxation. The endothelium performs a crucial role in maintaining vascular integrity by achieving whole-organ metabolic homeostasis via the production of factors associated with vasoconstriction or vasorelaxation. In this review, we have focused on the production of nitric oxide (NO), a vasorelaxation factor. The extent of NO production represents a key marker in vascular health. A decrease in NO is capable of inducing pathological conditions associated with endothelial dysfunction, such as obesity, diabetes, cardiovascular disease, and atherosclerosis. Recent studies have strongly implicated the involvement of G-protein-coupled receptor kinase 2 (GRK2) in the progression of cardiovascular disease. Vasculature which is affected by insulin resistance and type 2 diabetes expresses high levels of GRK2, which may induce endothelial dysfunction by reducing intracellular NO. GRK2 activation also induces changes in the subcellular localization of GRK2 itself and also of β-arrestin 2, a downstream protein. In this review, we describe the pathophysiological mechanisms of insulin resistance and diabetes, focusing on the signal transduction for NO production via GRK2 and β-arrestin 2, providing novel insights into the potential field of translational investigation in the treatment of diabetic complications.

  9. Molecular genetics and mechanisms of disease in distal hereditary motor neuropathies: insights directing future genetic studies.

    Science.gov (United States)

    Drew, A P; Blair, I P; Nicholson, G A

    2011-11-01

    The distal hereditary motor neuropathies (dHMNs) are a clinically and genetically heterogeneous group of disorders that primarily affect motor neurons, without significant sensory involvement. New dHMN genes continue to be identified. There are now 11 causative genes described for dHMN, and an additional five genetic loci with unidentified genes. This genetic heterogeneity has further delineated the classification of dHMN, which was previously classified according to mode of inheritance, age at onset, and additional complicating features. Some overlap between phenotypically distinct forms of dHMN is also apparent. The mutated genes identified to-date in dHMN include HSPB1, HSPB8, HSPB3, DCTN1, GARS, PLEKHG5, BSCL2, SETX, IGHMBP2, ATP7A and TRPV4. The pathogenesis of mutations remains to be fully elucidated, however common pathogenic mechanisms are emerging. These include disruption of axonal transport, RNA processing defects, protein aggregation and inclusion body formation, disrupted calcium channel activity, and loss of neuroprotective signalling. Some of these dHMN genes are also mutated in Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA). This review examines the growing number of identified dHMN genes, discusses recent insights into the functions of these genes and possible pathogenic mechanisms, and looks at the increasing overlap between dHMN and the other neuropathies CMT2 and SMA.

  10. Human acid sphingomyelinase structures provide insight to molecular basis of Niemann–Pick disease

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Yan-Feng; Metcalf, Matthew C.; Garman, Scott C.; Edmunds, Tim; Qiu, Huawei; Wei, Ronnie R. (Sanofi Aventis); (UMASS, Amherst)

    2016-10-26

    Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and phosphocholine, essential components of myelin in neurons. Genetic alterations in ASM lead to ASM deficiency (ASMD) and have been linked to Niemann–Pick disease types A and B. Olipudase alfa, a recombinant form of human ASM, is being developed as enzyme replacement therapy to treat the non-neurological manifestations of ASMD. Here we present the human ASM holoenzyme and product bound structures encompassing all of the functional domains. The catalytic domain has a metallophosphatase fold, and two zinc ions and one reaction product phosphocholine are identified in a histidine-rich active site. The structures reveal the underlying catalytic mechanism, in which two zinc ions activate a water molecule for nucleophilic attack of the phosphodiester bond. Docking of sphingomyelin provides a model that allows insight into the selectivity of the enzyme and how the ASM domains collaborate to complete hydrolysis. Mapping of known mutations provides a basic understanding on correlations between enzyme dysfunction and phenotypes observed in ASMD patients.

  11. Human acid sphingomyelinase structures provide insight to molecular basis of Niemann–Pick disease

    Science.gov (United States)

    Zhou, Yan-Feng; Metcalf, Matthew C.; Garman, Scott C.; Edmunds, Tim; Qiu, Huawei; Wei, Ronnie R.

    2016-01-01

    Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and phosphocholine, essential components of myelin in neurons. Genetic alterations in ASM lead to ASM deficiency (ASMD) and have been linked to Niemann–Pick disease types A and B. Olipudase alfa, a recombinant form of human ASM, is being developed as enzyme replacement therapy to treat the non-neurological manifestations of ASMD. Here we present the human ASM holoenzyme and product bound structures encompassing all of the functional domains. The catalytic domain has a metallophosphatase fold, and two zinc ions and one reaction product phosphocholine are identified in a histidine-rich active site. The structures reveal the underlying catalytic mechanism, in which two zinc ions activate a water molecule for nucleophilic attack of the phosphodiester bond. Docking of sphingomyelin provides a model that allows insight into the selectivity of the enzyme and how the ASM domains collaborate to complete hydrolysis. Mapping of known mutations provides a basic understanding on correlations between enzyme dysfunction and phenotypes observed in ASMD patients. PMID:27725636

  12. Insights into Himalayan biogeography from geckos: a molecular phylogeny of Cyrtodactylus (Squamata: Gekkonidae).

    Science.gov (United States)

    Agarwal, Ishan; Bauer, Aaron M; Jackman, Todd R; Karanth, K Praveen

    2014-11-01

    The India-Asia collision profoundly influenced the climate, topography and biodiversity of Asia, causing the formation of the biodiverse Himalayas. The species-rich gekkonid genus Cyrtodactylus is an ideal clade for exploring the biological impacts of the India-Asia collision, as previous phylogenetic hypotheses suggest basal divergences occurred within the Himalayas and Indo-Burma during the Eocene. To this end, we sampled for Cyrtodactylus across Indian areas of the Himalayas and Indo-Burma Hotspots and used three genes to reconstruct relationships and estimate divergence times. Basal divergences in Cyrtodactylus, Hemidactylus and the Palaearctic naked-toed geckos were simultaneous with or just preceded the start of the India-Asia collision. Diversification within Cyrtodactylus tracks the India-Asia collision and subsequent geological events. A number of geographically concordant clades are resolved within Indo-Burmese Cyrtodactylus. Our study reveals 17 divergent lineages that may represent undescribed species, underscoring the previously undocumented diversity of the region. The importance of rocky habitats for Cyrtodactylus indicates the Indo-Gangetic flood plains and the Garo-Rajmahal Gap are likely to have been important historical barriers for this group.

  13. Role of ELA region in auto-activation of mutant KIT receptor: a molecular dynamics simulation insight.

    Science.gov (United States)

    Purohit, Rituraj

    2014-01-01

    KIT receptor is the prime target in gastrointestinal stromal tumor (GISTs) therapy. Second generation inhibitor, Sunitinib, binds to an inactivated conformation of KIT receptor and stabilizes it in order to prevent tumor formation. Here, we investigated the dynamic behavior of wild type and mutant D816H KIT receptor, and emphasized the extended A-loop (EAL) region (805-850) by conducting molecular dynamics simulation (∼100 ns). We analyzed different properties such as root mean square cutoff or deviation, root mean square fluctuation, radius of gyration, solvent-accessible surface area, hydrogen bonding network analysis, and essential dynamics. Apart from this, clustering and cross-correlation matrix approach was used to explore the conformational space of the wild type and mutant EAL region of KIT receptor. Molecular dynamics analysis indicated that mutation (D816H) was able to alter intramolecular hydrogen bonding pattern and affected the structural flexibility of EAL region. Moreover, flexible secondary elements, specially, coil and turns were dominated in EAL region of mutant KIT receptor during simulation. This phenomenon increased the movement of EAL region which in turn helped in shifting the equilibrium towards the active kinase conformation. Our atomic investigation of mutant KIT receptor which emphasized on EAL region provided a better insight into the understanding of Sunitinib resistance mechanism of KIT receptor and would help to discover new therapeutics for KIT-based resistant tumor cells in GIST therapy.

  14. Enhanced interfacial strength of carbon nanotube/copper nanocomposites via Ni-coating: Molecular-dynamics insights

    Science.gov (United States)

    Duan, Ke; Li, Li; Hu, Yujin; Wang, Xuelin

    2017-04-01

    The molecular bridging between carbon nanotube (CNT) within the meta matrix is hopeful for enhancing nanocomposite's mechanical performance. One of the main problems for nanocomposites is the inadequate bonding between nonstructural reinforcement and meta matrix. Ni-coating on CNT is an effective method to overcome the drawback of the inadequate strength, but the enhancing mechanism has not well interpreted yet. In this paper, the enhancing mechanism will be interpreted from the molecular-dynamics insights. The pullout process of CNT and Ni-coated CNT against copper matrix is investigated. The effects of geometric parameters, including CNT length and diameter, are taken into considerations and discussed. Results show that the interfacial strength is significantly improved after the Ni-coated CNT, which shows a good agreement with the experimental results available in the open literature. Besides, the sliding mechanism of Ni-coated CNTs against copper matrix is much more like a kind of friction sliding and directly related to the embedded zone. However, the pullout force of the CNT without Ni-coating is nearly proportional to its diameter, but independent of embedded length.

  15. Pancreatic acinar cells: molecular insight from studies of signal-transduction using transgenic animals.

    Science.gov (United States)

    Yule, David I

    2010-11-01

    Pancreatic acinar cells are classical exocrine gland cells. The apical regions of clusters of coupled acinar cells collectively form a lumen which constitutes the blind end of a tube created by ductal cells - a structure reminiscent of a "bunch of grapes". When activated by neural or hormonal secretagogues, pancreatic acinar cells are stimulated to secrete a variety of proteins. These proteins are predominately inactive digestive enzyme precursors called "zymogens". Acinar cell secretion is absolutely dependent on secretagogue-induced increases in intracellular free Ca(2+). The increase in [Ca(2+)](i) has precise temporal and spatial characteristics as a result of the exquisite regulation of the proteins responsible for Ca(2+) release, Ca(2+) influx and Ca(2+) clearance in the acinar cell. This brief review discusses recent studies in which transgenic animal models have been utilized to define in molecular detail the components of the Ca(2+) signaling machinery which contribute to these characteristics.

  16. Optimizing Water Transport through Graphene-Based Membranes: Insights from Nonequilibrium Molecular Dynamics.

    Science.gov (United States)

    Muscatello, Jordan; Jaeger, Frederike; Matar, Omar K; Müller, Erich A

    2016-05-18

    Recent experimental results suggest that stacked layers of graphene oxide exhibit strong selective permeability to water. To construe this observation, the transport mechanism of water permeating through a membrane consisting of layered graphene sheets is investigated via nonequilibrium and equilibrium molecular dynamics simulations. The effect of sheet geometry is studied by changing the offset between the entrance and exit slits of the membrane. The simulation results reveal that the permeability is not solely dominated by entrance effects; the path traversed by water molecules has a considerable impact on the permeability. We show that contrary to speculation in the literature, water molecules do not pass through the membrane as a hydrogen-bonded chain; instead, they form well-mixed fluid regions confined between the graphene sheets. The results of the present work are used to provide guidelines for the development of graphene and graphene oxide membranes for desalination and solvent separation.

  17. Insight into Substrate Preference of Two Chimeric Esterases by Combining Experiment and Molecular Simulation

    Institute of Scientific and Technical Information of China (English)

    ZHOU Xiao-li; HAN Wei-wei; ZHENG Bai-song; FENG Yan

    2013-01-01

    Better understanding of the relationship between the substrate preference and structural module of esterases is helpful to novel enzyme development.For this purpose,two chimeric esterases AAM7 and PAR,constructed via domain swapping between two ancient thermophilic esterases,were investigated on their molecular simulation(including homology modeling,substrates docking and substrate binding affinity validation) and enzymatic assay(specific activities and activation energies calculating).Our results indicate that the factors contributing to the substrate preference of many enzymes especially the broad-specificity enzymes like esterases are multiple and complicated,the substrate binding domains or binding pockets are important but not the only factor for substrate preference.

  18. Molecular insights into the taxonomy of Hypanis (Bivalvia, Cardiidae, Lymnocardiinae) in the Black Sea lagoons

    Science.gov (United States)

    Popa, Luis; Popa, Oana; Iorgu, Elena; Kelemen, Beatrice; Murariu, Dumitru

    2012-06-01

    In this study, we used data from morphology and three DNA markers to assess the taxonomic status of the putative bivalve species Hypanis colorata and Hypanis angusticostata in a Black Sea lagoon, the Razelm Lake in Romania. The morphological data (the shape of shell ribs and the multivariate analysis of morphometric variance of three variables constructed as the ratios between the main dimensions of the shell) confirmed that the two analyzed species are distinct morphological entities. Three molecular markers, one from the nuclear genome (18S rRNA) and two from the mitochondrial genome (16S rRNA and COI), showed extremely reduced sequence divergence (0-0.1%) between the two putative species. Based on these results, we suggest that H. angusticostata and H. colorata are morphotypes of a single species.

  19. UV-induced modification of fused silica: Insights from ReaxFF-based molecular dynamics simulations

    Science.gov (United States)

    Tian, Ye; Du, Jincheng; Zu, Xiaotao; Han, Wei; Yuan, Xiaodong; Zheng, Wanguo

    2016-09-01

    Atomic structural modification and defect processes of fused silica resulting from UV-laser irradiation are studied by a combination of molecular dynamics (MD) simulations and the Reactive Force Field (ReaxFF). Bond state transitions by laser excitation are modeled as the result of localized recoils during energy deposition. Computations of pair distribution functions and bond angle distributions of the irradiated structure reveal that fused silica undergoes significant changes in terms of Si-O, Si-Si pair distances and Si-O-Si bond angles, which are attributed to the formation of silicon and oxygen coordination defects. It is found that nonbridging oxygen is responsible for the decreased Si-O bond length, while laser-induced five-coordinated silicon leads to small Si-O-Si bond angles in 2-membered rings.

  20. Towards personalized therapy for patients with malignant melanoma: molecular insights into the biology of BRAF mutations.

    Science.gov (United States)

    Bradish, Joshua R; Montironi, Rodolfo; Lopez-Beltran, Antonio; Post, Kristin M; MacLennan, Gregory T; Cheng, Liang

    2013-02-01

    BRAF mutations have been identified as the most common oncogene mutation in melanomas, especially important in those originating on nonchronically sun-damaged skin. There is a large and continually growing body of evidence regarding the importance of this mutation in targeted therapy for melanoma. In this review, we outline these findings including: molecular pathways used by BRAF, the importance in nonmalignant neoplasms, histologic associations, the relationship of BRAF to KIT and NRAS mutations, and their impact on survival, as well as resistance mechanisms to BRAF inhibitors employed by melanoma. Understanding these topics and how they relate to one another may facilitate the development of new treatments and eventually improve the prognosis for those patients afflicted with this disease.

  1. Molecular developmental mechanism in polypterid fish provides insight into the origin of vertebrate lungs

    Science.gov (United States)

    Tatsumi, Norifumi; Kobayashi, Ritsuko; Yano, Tohru; Noda, Masatsugu; Fujimura, Koji; Okada, Norihiro; Okabe, Masataka

    2016-01-01

    The lung is an important organ for air breathing in tetrapods and originated well before the terrestrialization of vertebrates. Therefore, to better understand lung evolution, we investigated lung development in the extant basal actinopterygian fish Senegal bichir (Polypterus senegalus). First, we histologically confirmed that lung development in this species is very similar to that of tetrapods. We also found that the mesenchymal expression patterns of three genes that are known to play important roles in early lung development in tetrapods (Fgf10, Tbx4, and Tbx5) were quite similar to those of tetrapods. Moreover, we found a Tbx4 core lung mesenchyme-specific enhancer (C-LME) in the genomes of bichir and coelacanth (Latimeria chalumnae) and experimentally confirmed that these were functional in tetrapods. These findings provide the first molecular evidence that the developmental program for lung was already established in the common ancestor of actinopterygians and sarcopterygians. PMID:27466206

  2. Molecular-genetic insights in paediatric T-cell acute lymphoblastic leukaemia.

    Science.gov (United States)

    Van Vlierberghe, Pieter; Pieters, Rob; Beverloo, H Berna; Meijerink, Jules P P

    2008-10-01

    Paediatric T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy of thymocytes that accounts for about 15% of ALL cases and for which treatment outcome remains inferior compared to B-lineage acute leukaemias. In T-ALL, leukemic transformation of maturating thymocytes is caused by a multistep pathogenesis involving numerous genetic abnormalities that drive normal T-cells into uncontrolled cell growth and clonal expansion. This review provides an overview of the current knowledge on onco- and tumor suppressor genes in T-ALL and suggests a classification of these genetic defects into type A and type B abnormalities. Type A abnormalities may delineate distinct molecular-cytogenetic T-ALL subgroups, whereas type B abnormalities are found in all major T-ALL subgroups and synergize with these type A mutations during T-cell pathogenesis.

  3. Novel therapeutics in metastatic colorectal cancer: molecular insights and pharmacogenomic implications.

    Science.gov (United States)

    Hanna, Diana L; Lenz, Heinz-Josef

    2016-08-01

    Although the survival of metastatic colorectal cancer (mCRC) patients has improved five-fold over the last century, CRC remains a significant global health burden. Impressive strides have been made in identifying new regimens, employing maintenance strategies to limit treatment toxicities, and combining multidisciplinary approaches to achieve cure in oligometastatic disease. Attempts at personalized integration of targeted agents have been limited by the ability to identify molecularly enriched patient populations most likely to benefit. In this review, we discuss novel therapeutics and regimens recently approved and in development for mCRC. In addition, we discuss using older agents in novel combination and maintenance strategies, and highlight evidence for implementing pharmacogenomic data and non-invasive monitoring into the personalized management of mCRC patients.

  4. Molecular basis of epithelial Ca2+ and Mg2+ transport: insights from the TRP channel family

    DEFF Research Database (Denmark)

    Dimke, Henrik Anthony; Hoenderop, Joost G J; Bindels, René J M

    2011-01-01

    active transcellular movement of divalent cations from the lumen into the enterocyte. Furthermore, in bone, TRPV channels play important roles by influencing the osteoclastic resorption process, thereby contributing importantly to overall bone mineral content. The divalent cation-permeable TRPV5 and TRPM......Maintenance of plasma Ca(2+) and Mg(2+) levels is of vital importance for many physiological functions. This is achieved via a coordinated interplay between the intestine, bone and kidney by amending the rate of absorption, storage and excretion, respectively. Discovery of the transient receptor...... potential (TRP) family identified several new ion channels acting as gatekeepers of Ca(2+) and Mg(2+) transport in these epithelia, greatly increasing our understanding of the molecular processes that facilitate the movement of these minerals. In the intestine, TRP channels contribute to the saturable...

  5. Insights using a molecular approach into the life cycle of a tapeworm infecting great white sharks.

    Science.gov (United States)

    Randhawa, Haseeb S

    2011-04-01

    The great white shark Carcharodon carcharias Linnaeus, 1758 is a versatile and fierce predator (and responsible for many shark attacks on humans). This apex predator feeds on a wide range of organisms including teleosts, other elasmobranchs, cephalopods, pinnipeds, and cetaceans. Although much is known about its diet, no trophic links have been empirically identified as being involved in the transmission of its tapeworm parasites. Recently, the use of molecular tools combined with phylogenetics has proven useful to identify larval and immature stages of marine tapeworms; utilization of the technique has been increasing rapidly. However, the usefulness of this approach remains limited by the availability of molecular data. Here, I employed gene sequence data from the D2 region of the large subunit of ribosomal DNA to link adults of the tapeworm Clistobothrium carcharodoni Dailey and Vogelbein, 1990 (Cestoda: Tetraphyllidea) to larvae for which sequence data for this gene are available. The sequences from the adult tapeworms were genetically identical (0% sequence divergence) to those available on GenBank for "SP" 'small' Scolex pleuronectis recovered from the striped dolphin (Stenella coeruleoalba) and Risso's dolphin (Grampus griseus). This study is the first to provide empirical evidence linking the trophic interaction between great white sharks and cetaceans as a definitive route for the successful transmission of a tetraphyllidean tapeworm. Using the intensity of infection data from this shark and from cetaceans as proxies for the extent of predation, I estimate that this individual shark would have consumed between 9 to 83 G. griseus , fresh, dead, or both, in its lifetime.

  6. Immunoregulatory Effects Triggered by Lactic Acid Bacteria Exopolysaccharides: New Insights into Molecular Interactions with Host Cells

    Directory of Open Access Journals (Sweden)

    Jonathan Laiño

    2016-08-01

    Full Text Available Researchers have demonstrated that lactic acid bacteria (LAB with immunomodulatory capabilities (immunobiotics exert their beneficial effects through several molecules, including cell wall, peptidoglycan, and exopolysaccharides (EPS, that are able to interact with specific host cell receptors. EPS from LAB show a wide heterogeneity in its composition, meaning that biological properties depend on the strain and. therefore, only a part of the mechanism of action has been elucidated for these molecules. In this review, we summarize the current knowledge of the health-promoting actions of EPS from LAB with special focus on their immunoregulatory actions. In addition, we describe our studies using porcine intestinal epithelial cells (PIE cells as a model to evaluate the molecular interactions of EPS from two immunobiotic LAB strains and the host cells. Our studies showed that EPS from immunobiotic LAB have anti-inflammatory capacities in PIE cells since they are able to reduce the production of inflammatory cytokines in cells challenged with the Toll-like receptor (TLR-4-agonist lipopolysaccharide. The effects of EPS were dependent on TLR2, TLR4, and negative regulators of TLR signaling. We also reported that the radioprotective 105 (RP105/MD1 complex, a member of the TLR family, is partially involved in the immunoregulatory effects of the EPS from LAB. Our work described, for the first time, that LAB and their EPS reduce inflammation in intestinal epithelial cells in a RP105/MD1-dependent manner. A continuing challenge for the future is to reveal more effector-receptor relationships in immunobiotic-host interactions that contribute to the beneficial effects of these bacteria on mucosal immune homeostasis. A detailed molecular understanding should lead to a more rational use of immunobiotics in general, and their EPS in particular, as efficient prevention and therapies for specific immune-related disorders in humans and animals.

  7. Different mechanisms of action of antimicrobial peptides: insights from fluorescence spectroscopy experiments and molecular dynamics simulations.

    Science.gov (United States)

    Bocchinfuso, Gianfranco; Palleschi, Antonio; Orioni, Barbara; Grande, Giacinto; Formaggio, Fernando; Toniolo, Claudio; Park, Yoonkyung; Hahm, Kyung-Soo; Stella, Lorenzo

    2009-09-01

    Most antimicrobial peptides exert their activity by interacting with bacterial membranes, thus perturbing their permeability. They are investigated as a possible solution to the insurgence of bacteria resistant to the presently available antibiotic drugs. However, several different models have been proposed for their mechanism of membrane perturbation, and the molecular details of this process are still debated. Here, we compare fluorescence spectroscopy experiments and molecular dynamics (MD) simulations regarding the association with lipid bilayers and lipid perturbation for two different amphiphilic helical antimicrobial peptides, PMAP-23 and trichogin GA IV. PMAP-23, a cationic peptide member of the cathelicidin family, is considered to induce membrane permeability according to the Shai-Matsuzaki-Huang "carpet" model, while trichogin GA IV is a neutral peptide, member of the peptaibol family. Although several lines of evidence suggest a "barrel-stave" mechanism of pore formation for the latter peptide, its length is only half the normal thickness of a lipid bilayer. Both fluorescence spectroscopy experiments and MD simulations indicated that PMAP-23 associates with membranes close to their surface and parallel to it, and in this arrangement it causes a severe perturbation to the bilayer, both regarding its surface tension and lipid order. By contrast, trichogin GA IV can undergo a transition from a surface-bound state to a transmembrane orientation. In the first arrangement, it does not cause any strong membrane perturbation, while in the second orientation it might be able to span the bilayer from one side to the other, despite its relatively short length, by causing a significant thinning of the membrane.

  8. Insights into the molecular mechanism of RGL2-mediated inhibition of seed germination in Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Stamm Petra

    2012-10-01

    Full Text Available Abstract Background Seed germination is of immense significance for agriculture and has been studied for centuries. Yet, our understanding of the molecular mechanisms underlying regulation of dormancy and germination is still in its infancy. Gibberellins are the key phytohormones that promote germination, and the DELLA protein RGL2 is the main signalling intermediate involved in this response. Germination is completely inhibited if functional RGL2 is overexpressed and/or stabilized; however, the molecular mechanisms of RGL2 function are still largely unknown. We therefore attempted to shed light onto some of the genetic events downstream of RGL2. Results Gene ontology of the transcriptome differentially regulated by RGL2, as well as extensive cross-comparison with other available microarray data indicates that RGL2-mediated inhibition of germination causes seeds to enter a state of dormancy. RGL2 also appears to differentially regulate a number of transcription factors, many of which are known to be involved in light- or phytohormone-mediated aspects of germination. A promoter analysis of differentially expressed genes identified an enrichment of several motifs that can be bound by specific transcription factors, for example GAMYB, ARF1, or Dof-type zinc fingers. We show that Dof-binding motifs indeed play a role in RGL2-mediated transcription. Using Chromatin Immunoprecipitation (ChIP, we show that RGL2 directly downregulates at least one cell wall modifying enzyme, which is predicted to constrain cell growth thereby leading to inhibition of seed germination. Conclusions Our results reveal that RGL2 controls various aspects of germination. Through the repression of cell wall modifying enzymes, cell growth is directly constrained to inhibit germination. Furthermore, RGL2 likely interacts with various types of proteins to regulate transcription, and differentially regulates several transcription factors. Collectively, our data indicate that

  9. Molecular mechanisms of D-cycloserine in facilitating fear extinction: insights from RNAseq.

    Science.gov (United States)

    Malan-Müller, Stefanie; Fairbairn, Lorren; Daniels, Willie M U; Dashti, Mahjoubeh Jalali Sefid; Oakeley, Edward J; Altorfer, Marc; Kidd, Martin; Seedat, Soraya; Gamieldien, Junaid; Hemmings, Sîan Megan Joanna

    2016-02-01

    D-cycloserine (DCS) has been shown to be effective in facilitating fear extinction in animal and human studies, however the precise mechanisms whereby the co-administration of DCS and behavioural fear extinction reduce fear are still unclear. This study investigated the molecular mechanisms of intrahippocampally administered D-cycloserine in facilitating fear extinction in a contextual fear conditioning animal model. Male Sprague Dawley rats (n = 120) were grouped into four experimental groups (n = 30) based on fear conditioning and intrahippocampal administration of either DCS or saline. The light/dark avoidance test was used to differentiate maladapted (MA) (anxious) from well-adapted (WA) (not anxious) subgroups. RNA extracted from the left dorsal hippocampus was used for RNA sequencing and gene expression data was compared between six fear-conditioned + saline MA (FEAR + SALINE MA) and six fear-conditioned + DCS WA (FEAR + DCS WA) animals. Of the 424 significantly downregulated and 25 significantly upregulated genes identified in the FEAR + DCS WA group compared to the FEAR + SALINE MA group, 121 downregulated and nine upregulated genes were predicted to be relevant to fear conditioning and anxiety and stress-related disorders. The majority of downregulated genes transcribed immune, proinflammatory and oxidative stress systems molecules. These molecules mediate neuroinflammation and cause neuronal damage. DCS also regulated genes involved in learning and memory processes, and genes associated with anxiety, stress-related disorders and co-occurring diseases (e.g., cardiovascular diseases, digestive system diseases and nervous system diseases). Identifying the molecular underpinnings of DCS-mediated fear extinction brings us closer to understanding the process of fear extinction.

  10. New insight on FGFR3-related chondrodysplasias molecular physiopathology revealed by human chondrocyte gene expression profiling.

    Directory of Open Access Journals (Sweden)

    Laurent Schibler

    Full Text Available Endochondral ossification is the process by which the appendicular skeleton, facial bones, vertebrae and medial clavicles are formed and relies on the tight control of chondrocyte maturation. Fibroblast growth factor receptor (FGFR3 plays a role in bone development and maintenance and belongs to a family of proteins which differ in their ligand affinities and tissue distribution. Activating mutations of the FGFR3 gene lead to craniosynostosis and multiple types of skeletal dysplasia with varying degrees of severity: thanatophoric dysplasia (TD, achondroplasia and hypochondroplasia. Despite progress in the characterization of FGFR3-mediated regulation of cartilage development, many aspects remain unclear. The aim and the novelty of our study was to examine whole gene expression differences occurring in primary human chondrocytes isolated from normal cartilage or pathological cartilage from TD-affected fetuses, using Affymetrix technology. The phenotype of the primary cells was confirmed by the high expression of chondrocytic markers. Altered expression of genes associated with many cellular processes was observed, including cell growth and proliferation, cell cycle, cell adhesion, cell motility, metabolic pathways, signal transduction, cell cycle process and cell signaling. Most of the cell cycle process genes were down-regulated and consisted of genes involved in cell cycle progression, DNA biosynthesis, spindle dynamics and cytokinesis. About eight percent of all modulated genes were found to impact extracellular matrix (ECM structure and turnover, especially glycosaminoglycan (GAG and proteoglycan biosynthesis and sulfation. Altogether, the gene expression analyses provide new insight into the consequences of FGFR3 mutations in cell cycle regulation, onset of pre-hypertrophic differentiation and concomitant metabolism changes. Moreover, impaired motility and ECM properties may also provide clues about growth plate disorganization. These

  11. Human T-cell lymphotropic virus type 1 subtype C molecular variants among indigenous australians: new insights into the molecular epidemiology of HTLV-1 in Australo-Melanesia.

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    Olivier Cassar

    Full Text Available BACKGROUND: HTLV-1 infection is endemic among people of Melanesian descent in Papua New Guinea, the Solomon Islands and Vanuatu. Molecular studies reveal that these Melanesian strains belong to the highly divergent HTLV-1c subtype. In Australia, HTLV-1 is also endemic among the Indigenous people of central Australia; however, the molecular epidemiology of HTLV-1 infection in this population remains poorly documented. FINDINGS: Studying a series of 23 HTLV-1 strains from Indigenous residents of central Australia, we analyzed coding (gag, pol, env, tax and non-coding (LTR genomic proviral regions. Four complete HTLV-1 proviral sequences were also characterized. Phylogenetic analyses implemented with both Neighbor-Joining and Maximum Likelihood methods revealed that all proviral strains belong to the HTLV-1c subtype with a high genetic diversity, which varied with the geographic origin of the infected individuals. Two distinct Australians clades were found, the first including strains derived from most patients whose origins are in the North, and the second comprising a majority of those from the South of central Australia. Time divergence estimation suggests that the speciation of these two Australian clades probably occurred 9,120 years ago (38,000-4,500. CONCLUSIONS: The HTLV-1c subtype is endemic to central Australia where the Indigenous population is infected with diverse subtype c variants. At least two Australian clades exist, which cluster according to the geographic origin of the human hosts. These molecular variants are probably of very ancient origin. Further studies could provide new insights into the evolution and modes of dissemination of these retrovirus variants and the associated ancient migration events through which early human settlement of Australia and Melanesia was achieved.

  12. Molecular insights into the local anesthetic receptor within voltage-gated sodium channels using hydroxylated analogues of mexiletine

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    Jean-François eDesaphy

    2012-02-01

    Full Text Available We previously showed that the β-adrenoceptor modulators, clenbuterol and propranolol, directly blocked voltage-gated sodium channels, whereas salbutamol and nadolol did not (Desaphy et al., 2003, suggesting the presence of two hydroxyl groups on the aromatic moiety of the drugs as a molecular requisite for impeding sodium channel block. To verify such an hypothesis, we synthesized five new mexiletine analogues by adding one or two hydroxyl groups to the aryl moiety of the sodium channel blocker and tested these compounds on hNav1.4 channels expressed in HEK293 cells. Concentration-response relationships were constructed using an holding potential of -120 mV at 0.1 Hz (tonic block and 10 Hz (use-dependent block stimulation frequencies. The half-maximum inhibitory concentrations (IC50 were linearly correlated to drug lipophilicity: the less lipophilic the drug, minor was the block. The same compounds were also tested on F1586C and Y1593C hNav1.4 channel mutants, to gain further information on the molecular interactions of mexiletine with its receptor within the sodium channel pore. Alteration of tonic block suggests that the aryl moiety of mexiletine may interact either directly or indirectly with Phe1586 in the closed sodium channel to produce low-affinity binding block, and that this interaction depends on the electrostatic potential of the drug aromatic tail. Alteration of use-dependent block suggests that addition of hydroxyl groups to the aryl moiety may modify high-affinity binding of the drug ammine terminal to Phe1586 through cooperativity between the two pharmacophores, this effect being mainly related to drug lipophilicity. Mutation of Tyr1593 further impaired such cooperativity. In conclusion, these results confirm our former hypothesis showing that the presence of hydroxyl groups to the aryl moiety of mexiletine greatly reduced sodium channel block, and provide molecular insights into the intimate interaction of local anesthetics with

  13. New insight into the molecular mechanisms of the biological effects of DNA minor groove binders.

    Directory of Open Access Journals (Sweden)

    Xinbo Zhang

    Full Text Available BACKGROUND: Bisbenzimides, or Hoechst 33258 (H258, and its derivative Hoechst 33342 (H342 are archetypal molecules for designing minor groove binders, and widely used as tools for staining DNA and analyzing side population cells. They are supravital DNA minor groove binders with AT selectivity. H342 and H258 share similar biological effects based on the similarity of their chemical structures, but also have their unique biological effects. For example, H342, but not H258, is a potent apoptotic inducer and both H342 and H258 can induce transgene overexpression in in vitro studies. However, the molecular mechanisms by which Hoechst dyes induce apoptosis and enhance transgene overexpression are unclear. METHODOLOGY/PRINCIPAL FINDINGS: To determine the molecular mechanisms underlying different biological effects between H342 and H258, microarray technique coupled with bioinformatics analyses and multiple other techniques has been utilized to detect differential global gene expression profiles, Hoechst dye-specific gene expression signatures, and changes in cell morphology and levels of apoptosis-associated proteins in malignant mesothelioma cells. H342-induced apoptosis occurs in a dose-dependent fashion and is associated with morphological changes, caspase-3 activation, cytochrome c mitochondrial translocation, and cleavage of apoptosis-associated proteins. The antagonistic effect of H258 on H342-induced apoptosis indicates a pharmacokinetic basis for the two dyes' different biological effects. Differential global gene expression profiles induced by H258 and H342 are accompanied by unique gene expression signatures determined by DNA microarray and bioinformatics software, indicating a genetic basis for their different biological effects. CONCLUSIONS/SIGNIFICANCE: A unique gene expression signature associated with H342-induced apoptosis provides a new avenue to predict and classify the therapeutic class of minor groove binders in the drug

  14. Where and When did High Andean Relief Emerge?: Insights From Molecular Phylogenies of Andean Biota

    Science.gov (United States)

    Sempere, T.; Picard, D.; Plantard, O.

    2006-05-01

    Emergence of mountains along the Andean margin created new ecosystems and thus triggered a variety of adaptive biotic radiations, to the point that the Andes are to-day one of the world's major biodiversity hotspots. The rising Andes came to serve as a rain barrier: cloud forests developed along their eastern side due to orographic concentration of the westward-moving Amazonian moisture, and environments became drier in the west, with highland steppes extending above ~2-3 km. Relevant biologic data concerning Andean taxa adapted to these environments might therefore shed some light on the issue of Andean orogeny and surface uplift. Phylogeography (the analysis of phylogenetic trees in terms of biogeographic distributions) and phylochronology (the use of phylogenetic trees as molecular clocks) can be employed to reconstruct syn- orogenic radiations and estimate their timing, respectively. We use published molecular phylogenies that inform on the evolution of a variety of Andean animal and plant taxa, and therefore provide indirect means to assess and approximately date the acquisition of altitude. Phylogeographic analyses of 6 phylogenetic trees concerning unrelated Andean biota coincide in having their basal clades established in areas within the Central Andean Orocline (CAO), 5 of them clearly pointing to southern Peru and/or western Bolivia as the region of origin of the corresponding high-Andean taxa. A histogram of 9 phylochronologic estimates, based on trees concerning unrelated taxa (independently constructed and calibrated), suggests that the 2.0-2.5 km critical altitude was acquired during the 23-17 Ma or 26-16 Ma intervals (depending on the threshold used), confirming some geomorphic and geologic estimates (but conflicting with others). Although more data are needed, these results suggest that it was within the CAO and approximately during the early Miocene that the Andes acquired altitudes sufficient to trigger radiations of cold-adapted taxa, i.e. >~2 km

  15. The Growth Entrapment Model (GEM): New Insights from Molecular-Scale Simulations of Ti in Quartz

    Science.gov (United States)

    Watson, E. B.; Lanzillo, N. A.; Nayak, S. K.

    2011-12-01

    The growth entrapment model (GEM) put forth by Watson and Liang (Am. Min. 80, 1170-1187) and Watson (GCA 68, 1473-1488) offers a mechanism by which crystals can acquire non-equilibrium chemical or isotopic properties during growth from a uniform fluid medium. The GEM is based on the premise that the equilibrium properties of the near-surface region of a crystal differ from those of the bulk, much as the properties of nanocrystals differ from those of larger crystals of the same phase. In the GEM model, "capture" of the near-surface composition within a growing crystal-creating a non-equilibrium condition-depends upon the outcome of the competition between growth (which buries near-surface atoms) and diffusion (which attempts to restore equilibrium). In any application of the GEM model, the most uncertain input parameters are the near-surface diffusivity (D) and the equilibrium partition coefficient (F) between the near-surface region and the bulk lattice. Experimental measurement of these quantities is elusive because the relevant length scales are small (1-5 nm). However, molecular-scale simulations hold some promise for deducing relative values, as we illustrate here using Ti uptake in quartz as an example. We undertook ab initio molecular dynamics simulations based on a supercell approach to show that the binding energy of Ti^{4+} in quartz is a function of depth in the crystal within a few nanometers of the surface, confirming that F in the GEM model must differ from unity. We also show, using the meta-dynamics method to compute the unbiased diffusion path and corresponding energy barrier, that the activation energy for Ti^{4+} diffusion in the near-surface (2-3 nm deep) is substantially lower than that pertaining to the "deep" lattice diffusivity that is typically measured in diffusion experiments (which we also reproduced computationally). These findings substantiate the underlying phenomena upon which the GEM model is based, in addition to providing

  16. Solid-state NMR in macromolecular systems: insights on how molecular entities move.

    Science.gov (United States)

    Hansen, Michael Ryan; Graf, Robert; Spiess, Hans Wolfgang

    2013-09-17

    The function of synthetic and natural macromolecularsystems critically depends on the packing and dynamics of the individual components of a given system. Not only can solid-state NMR provide structural information with atomic resolution, but it can also provide a way to characterize the amplitude and time scales of motions over broad ranges of length and time. These movements include molecular dynamics, rotational and translational motions of the building blocks, and also the motion of the functional species themselves, such as protons or ions. This Account examines solid-state NMR methods for correlating dynamics and function in a variety of chemical systems. In the early days, scientists thought that the rotationalmotions reflected the geometry of the moving entities. They described these phenomena as jumps about well-defined axes, such as phenyl flips, even in amorphous polymers. Later, they realized that conformational transitions in macromolecules happen in a much more complex way. Because the individual entities do not rotate around well-defined axes, they require much less space. Only recently researchers have appreciated the relative importance of large angle fluctuations of polymers over rotational jumps. Researchers have long considered that cooperative motions might be at work, yet only recently they have clearly detected these motions by NMR in macromolecular and supramolecular systems. In correlations of dynamics and function, local motions do not always provide the mechanism of long-range transport. This idea holds true in ion conduction but also applies to chain transport in polymer melts and semicrystalline polymers. Similar chain motions and ion transport likewise occur in functional biopolymers, systems where solid-state NMR studies are also performed. In polymer science, researchers have appreciated the unique information on molecular dynamics available from advanced solid-state NMR at times, where their colleagues in the biomacromolecular

  17. Optimal drug cocktail design: methods for targeting molecular ensembles and insights from theoretical model systems.

    Science.gov (United States)

    Radhakrishnan, Mala L; Tidor, Bruce

    2008-05-01

    required. We also treated cases in which a subset of target variants was to be avoided, modeling the common challenge of closely related host molecules that may be implicated in drug toxicity. Such decoys generally increased the size of the required cocktail and more often resulted in infeasible optimizations. Taken together, this work provides practical optimization methods for the design of drug cocktails and a theoretical, physics-based framework through which useful insights can be achieved.

  18. The plastoquinol-plastoquinone exchange mechanism in photosystem II: insight from molecular dynamics simulations.

    Science.gov (United States)

    Zobnina, Veranika; Lambreva, Maya D; Rea, Giuseppina; Campi, Gaetano; Antonacci, Amina; Scognamiglio, Viviana; Giardi, Maria Teresa; Polticelli, Fabio

    2017-01-01

    In the photosystem II (PSII) of oxygenic photosynthetic organisms, the reaction center (RC) core mediates the light-induced electron transfer leading to water splitting and production of reduced plastoquinone molecules. The reduction of plastoquinone to plastoquinol lowers PSII affinity for the latter and leads to its release. However, little is known about the role of protein dynamics in this process. Here, molecular dynamics simulations of the complete PSII complex embedded in a lipid bilayer have been used to investigate the plastoquinol release mechanism. A distinct dynamic behavior of PSII in the presence of plastoquinol is observed which, coupled to changes in charge distribution and electrostatic interactions, causes disruption of the interactions seen in the PSII-plastoquinone complex and leads to the "squeezing out" of plastoquinol from the binding pocket. Displacement of plastoquinol closes the second water channel, recently described in a 2.9 Å resolution PSII structure (Guskov et al. in Nat Struct Mol Biol 16:334-342, 2009), allowing to rule out the proposed "alternating" mechanism of plastoquinol-plastoquinone exchange, while giving support to the "single-channel" one. The performed simulations indicated a pivotal role of D1-Ser264 in modulating the dynamics of the plastoquinone binding pocket and plastoquinol-plastoquinone exchange via its interaction with D1-His252 residue. The effects of the disruption of this hydrogen bond network on the PSII redox reactions were experimentally assessed in the D1 site-directed mutant Ser264Lys.

  19. ART and health: clinical outcomes and insights on molecular mechanisms from rodent studies.

    Science.gov (United States)

    Feuer, S K; Camarano, L; Rinaudo, P F

    2013-04-01

    Since the birth of the first IVF-conceived child in 1978, the use of assisted reproductive technologies (ART) has grown dramatically, contributing to the successful birth of 5 million individuals worldwide. However, there are several reported associations of ART with pregnancy complications, such as low birthweight (LBW), preterm birth, birth defects, epigenetic disorders, cancer and poor metabolic health. Whether this is attributed to ART procedures or to the subset of the population seeking ART remains a controversy, but the most relevant question today concerns the potential long-term implications of assisted conception. Recent evidence has emerged suggesting that ART-conceived children have distinct metabolic profiles that may predispose to cardiovascular pathologies in adulthood. Because the eldest IVF individuals are still too young to exhibit components of chronic middle-aged syndromes, the use of animal models has become particularly useful in describing the effects of unusual or stressful preimplantation experiences on adult fitness. Elucidating the molecular mechanisms by which embryos integrate environmental signals into development and metabolic gene expression programs will be essential for optimizing ART procedures such as in vitro culture conditions, embryo selection and transfer. In the future, additional animal studies to identify mechanisms underlying unfavorable ART outcomes, as well as more epidemiological reviews to monitor the long-term health of ART children are required, given that ART procedures have become routine medical practice.

  20. All-atom molecular dynamics insights on preQ1 riboswitch aptamer

    Science.gov (United States)

    Gong, Zhou; Zhao, Yunjie; Chen, Changjun; Xiao, Yi

    2012-02-01

    Recently, a series of experiments have focused on two types of preQ1 riboswitch with known smallest aptamer. One of them is from Bacillus subtilis, which have been discussed before. The other one comes from T. tengcongensis, and Jenkins et al recently release its crystal structure in both ligand-bound and free state. These two types of riboswitch aptamer have similar structures but totally different functions. Consequently, contrast studies of these two preQ1 riboswitches will help us to understand the regulation function of riboswitch better. Here, we study the dynamical properties of two types of preQ1 riboswitches using molecular dynamics simulation. We find that the unfolding pathway of the two preQ1 aptamer domains in bound state are both hierarchical and have an intermediate state. We believe that such conformation would be a good candidate structure for ligand binding. On the other hand, in the absent of ligand, the preQ1 riboswitch from Bacillus subtilis can only form the stable state with P1-L3 triplex, while the preQ1 riboswitch from T. tengcongensis can form the conformation with pseudoknot shape. We suggest that such intermediate structures may perform regulation functions in the absent of ligand.

  1. Insights into ligand binding to PreQ1 Riboswitch Aptamer from molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Zhou Gong

    Full Text Available Riboswitches play roles in transcriptional or translational regulation through specific ligand binding of their aptamer domains. Although a number of ligand-bound aptamer complex structures have been solved, it is important to know ligand-free conformations of the aptamers in order to understand the mechanism of specific binding by ligands. In this paper, preQ1 riboswitch aptamer domain from Bacillus subtilis is studied by overall 1.5 μs all-atom molecular dynamics simulations We found that the ligand-free aptamer has a stable state with a folded P1-L3 and open binding pocket. The latter forms a cytosine-rich pool in which the nucleotide C19 oscillates between close and open positions, making it a potential conformation for preQ1 entrance. The dynamic picture further suggests that the specific recognition of preQ1 by the aptamer domain is not only facilitated by the key nucleotide C19 but also aided and enhanced by other cytosines around the binding pocket. These results should help to understand the details of preQ1 binding.

  2. Molecular genetic insights on cheetah (Acinonyx jubatus) ecology and conservation in Namibia.

    Science.gov (United States)

    Marker, Laurie L; Pearks Wilkerson, Alison J; Sarno, Ronald J; Martenson, Janice; Breitenmoser-Würsten, Christian; O'Brien, Stephen J; Johnson, Warren E

    2008-01-01

    The extent and geographic patterns of molecular genetic diversity of the largest remaining free-ranging cheetah population were described in a survey of 313 individuals from throughout Namibia. Levels of relatedness, including paternity/maternity (parentage), were assessed across all individuals using 19 polymorphic microsatellite loci, and unrelated cheetahs (n = 89) from 7 regions were genotyped at 38 loci to document broad geographical patterns. There was limited differentiation among regions, evidence that this is a generally panmictic population. Measures of genetic variation were similar among all regions and were comparable with Eastern African cheetah populations. Parentage analyses confirmed several observations based on field studies, including 21 of 23 previously hypothesized family groups, 40 probable parent/offspring pairs, and 8 sibling groups. These results also verified the successful integration and reproduction of several cheetahs following natural dispersal or translocation. Animals within social groups (family groups, male coalitions, or sibling groups) were generally related. Within the main study area, radio-collared female cheetahs were more closely interrelated than similarly compared males, a pattern consistent with greater male dispersal. The long-term maintenance of current patterns of genetic variation in Namibia depends on retaining habitat characteristics that promote natural dispersal and gene flow of cheetahs.

  3. Towards New Insights in the Sterol/Amphotericin Nanochannels Formation: A Molecular Dynamic Simulation Study.

    Science.gov (United States)

    Boukari, Khaoula; Balme, Sébastien; Janot, Jean-Marc; Picaud, Fabien

    2016-06-01

    Amphotericin B (AmB) is a well-known polyene which self-organizes into membrane cell in order to cause the cell death. Its specific action towards fungal cell is not fully understood but was proved to become from sterol composition. The mechanism was shown experimentally to require the formation of stable sterol/polyene couples which could then organize in a nanochannel. This would allow the leakage of ions responsible for the death of fungal cells, only. In this present study, we investigate the arrangement of AmB/sterols in biological membrane using molecular dynamic simulations in order to understand the role of the sterol structure on the antifungal action of the polyene. We show in particular that the nanochannels tend to close up when cell was composed with cholesterol (animal cell) due to strong interaction between amphotericin and sterol. On the other side, with ergosterol (fungal cell) the largest interactions between amphotericin and lipid membrane lead to the appearance of large hole that could favor the important leakage of ions and thus, the fungal cell death. This work appears as a good complement in the extensive studies linked to the understanding of the antifungal molecules in membrane cells.

  4. Effect of temperature on DNA double helix: An insight from molecular dynamics simulation

    Indian Academy of Sciences (India)

    Sangeeta Kundu; Sanchita Mukherjee; Dhananjay Bhattacharyya

    2012-07-01

    The three-dimensional structure of DNA contains various sequence-dependent structural information, which control many cellular processes in life, such as replication, transcription, DNA repair, etc. For the above functions, DNA double helices need to unwind or melt locally, which is different from terminal melting, as often seen in molecular dynamics (MD) simulations or even in many DNA crystal structures. We have carried out detailed MD simulations of DNA double helices of regular oligonucleotide fragments as well as in polymeric constructs with water and charge-neutralizing counter-ions at several different temperatures. We wanted to eliminate the end-effect or terminal melting propensity by employing MD simulation of DNA oligonucleotides in such a manner that gives rise to properties of polymeric DNA of infinite length. The polymeric construct is expected to allow us to see local melting at elevated temperatures. Comparative structural analysis of oligonucleotides and its corresponding virtual polymer at various temperatures ranging from 300 K to 400 K is discussed. The general behaviour, such as volume expansion coefficients of both the simulations show high similarity, indicating polymeric construct, does not give many artificial constraints. Local melting of a polymer, even at elevated temperature, may need a high nucleation energy that was not available in the short (7 ns) simulations. We expected to observe such nucleation followed by cooperative melting of the polymers in longer MD runs. Such simulations of different polymeric sequences would facilitate us to predict probable melting origins in a polymeric DNA.

  5. Thermophysical properties of energetic ionic liquids/nitric acid mixtures: Insights from molecular dynamics simulationsa)

    Science.gov (United States)

    Hooper, Justin B.; Smith, Grant D.; Bedrov, Dmitry

    2013-09-01

    Molecular dynamics (MD) simulations of mixtures of the room temperature ionic liquids (ILs) 1-butyl-4-methyl imidazolium [BMIM]/dicyanoamide [DCA] and [BMIM][NO3-] with HNO3 have been performed utilizing the polarizable, quantum chemistry based APPLE&P® potential. Experimentally it has been observed that [BMIM][DCA] exhibits hypergolic behavior when mixed with HNO3 while [BMIM][NO3-] does not. The structural, thermodynamic, and transport properties of the IL/HNO3 mixtures have been determined from equilibrium MD simulations over the entire composition range (pure IL to pure HNO3) based on bulk simulations. Additional (non-equilibrium) simulations of the composition profile for IL/HNO3 interfaces as a function of time have been utilized to estimate the composition dependent mutual diffusion coefficients for the mixtures. The latter have been employed in continuum-level simulations in order to examine the nature (composition and width) of the IL/HNO3 interfaces on the millisecond time scale.

  6. Insights into molecular and metabolic events associated with fruit response to postharvest fungal pathogens

    Directory of Open Access Journals (Sweden)

    Noam eAlkan

    2015-10-01

    Full Text Available Due to postharvest losses more than 30% of harvested fruits will not reach the consumers’ plate. Fungal pathogens play a key role in those losses, as they cause most of the fruit rots and the customer complaints. Many of the fungal pathogens are already present in the unripe fruit but remain quiescent during fruit growth until a particular phase of fruit ripening and senescence. The pathogens sense the developmental change and switch into the devastating necrotrophic life style that causes fruit rotting. Colonization of unripe fruit by the fungus initiates defensive responses that limit fungal growth and development. However, during fruit ripening several physiological processes occur that correlate with increased fruit susceptibility. In contrast to plant defenses in unripe fruit, the defense posture of ripe fruit entails a different subset of defense responses that will end with fruit rotting and losses. This review will focus on several aspects of molecular and metabolic events associated with fleshy fruit responses induced by postharvest fungal pathogens during fruit ripening.

  7. Insights into molecular and metabolic events associated with fruit response to post-harvest fungal pathogens.

    Science.gov (United States)

    Alkan, Noam; Fortes, Ana M

    2015-01-01

    Due to post-harvest losses more than 30% of harvested fruits will not reach the consumers' plate. Fungal pathogens play a key role in those losses, as they cause most of the fruit rots and the customer complaints. Many of the fungal pathogens are already present in the unripe fruit but remain quiescent during fruit growth until a particular phase of fruit ripening and senescence. The pathogens sense the developmental change and switch into the devastating necrotrophic life style that causes fruit rotting. Colonization of unripe fruit by the fungus initiates defensive responses that limit fungal growth and development. However, during fruit ripening several physiological processes occur that correlate with increased fruit susceptibility. In contrast to plant defenses in unripe fruit, the defense posture of ripe fruit entails a different subset of defense responses that will end with fruit rotting and losses. This review will focus on several aspects of molecular and metabolic events associated with fleshy fruit responses induced by post-harvest fungal pathogens during fruit ripening.

  8. Molecular Background of miRNA Role in Asthma and COPD: An Updated Insight

    Directory of Open Access Journals (Sweden)

    Izabela Szymczak

    2016-01-01

    Full Text Available Inflammatory airway diseases are a significant health problems requiring new approaches to the existing therapies and addressing fundamental issues. Difficulties in developing effective therapeutic strategies might be caused by lack of understanding of their exact molecular mechanism. MicroRNAs (miRNAs are a class of regulators that already revolutionized the view of gene expression regulation. A cumulating number of investigations show a pivotal role of miRNAs in the pathogenesis of asthma, chronic obstructive pulmonary disease (COPD, or airway remodeling through the regulation of many pathways involved in their pathogenesis. Expression changes of several miRNAs have also been found to play a role in the development and/or improvement in asthma or COPD. Still, relatively little is known about the role of miRNAs in inflammatory disorders. The microRNA profiles may differ depending on the cell type or antigen-presenting cell. Based on the newest literature, this review discusses the current knowledge concerning miRNA contribution and influence on lung inflammation and chosen inflammatory airway diseases: asthma and COPD.

  9. Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Payel Das

    Full Text Available Knowledge of the detailed mechanism by which proteins such as human αB- crystallin and human lysozyme inhibit amyloid beta (Aβ peptide aggregation is crucial for designing treatment for Alzheimer's disease. Thus, unconstrained, atomistic molecular dynamics simulations in explicit solvent have been performed to characterize the Aβ17-42 assembly in presence of the αB-crystallin core domain and of lysozyme. Simulations reveal that both inhibitor proteins compete with inter-peptide interaction by binding to the peptides during the early stage of aggregation, which is consistent with their inhibitory action reported in experiments. However, the Aβ binding dynamics appear different for each inhibitor. The binding between crystallin and the peptide monomer, dominated by electrostatics, is relatively weak and transient due to the heterogeneous amino acid distribution of the inhibitor surface. The crystallin-bound Aβ oligomers are relatively long-lived, as they form more extensive contact surface with the inhibitor protein. In contrast, a high local density of arginines from lysozyme allows strong binding with Aβ peptide monomers, resulting in stable complexes. Our findings not only illustrate, in atomic detail, how the amyloid inhibitory mechanism of human αB-crystallin, a natural chaperone, is different from that of human lysozyme, but also may aid de novo design of amyloid inhibitors.

  10. Thyroid, brain and mood modulation in affective disorder: insights from molecular research and functional brain imaging.

    Science.gov (United States)

    Bauer, M; London, E D; Silverman, D H; Rasgon, N; Kirchheiner, J; Whybrow, P C

    2003-11-01

    The efficacy resulting from adjunctive use of supraphysiological doses of levothyroxine has emerged as a promising approach to therapy and prophylaxis for refractory mood disorders. Most patients with mood disorders who receive treatment with supraphysiological doses of levothyroxine have normal peripheral thyroid hormone levels, and also respond differently to the hormone and tolerate it better than healthy individuals and patients with primary thyroid diseases. Progress in molecular and functional brain imaging techniques has provided a new understanding of these phenomena, illuminating the relationship between thyroid function, mood modulation and behavior. Thyroid hormones are widely distributed in the brain and have a multitude of effects on the central nervous system. Notably many of the limbic system structures where thyroid hormone receptors are prevalent have been implicated in the pathogenesis of mood disorders. The influence of the thyroid system on neurotransmitters (particularly serotonin and norepinephrine), which putatively play a major role in the regulation of mood and behavior, may contribute to the mechanisms of mood modulation. Recent functional brain imaging studies using positron emission tomography (PET) with [ (18)F]-fluorodeoxyglucose demonstrated that thyroid hormone treatment with levothyroxine affects regional brain metabolism in patients with hypothyroidism and bipolar disorder. Theses studies confirm that thyroid hormones are active in modulating metabolic function in the mature adult brain, and provide intriging neuroanatomic clues that may guide future research.

  11. Effects of Structured Ionomer Interfaces on Water Diffusion: Molecular Dynamics Simulation Insight

    Science.gov (United States)

    Aryal, Dipak; Perahia, Dvora; Grest, Gary

    The dynamics of solvent molecules across structured ionomers interfaces is crucial to innovative technologies with selective controlled transport. These polymers consist of ionizable blocks facilitating transport tethered to mechanical stability enhancing ones, where their incompatibility drives compounded interfaces. Here water penetration through the interface of an A-B-C-B-A co-polymer is probed by atomistic molecular dynamics simulations where C is a randomly sulfonated polystyrene with sulfonation fractions f = 0 to 0.55, B is poly (ethylene-r-propylene) and A is poly (t-butyl styrene). For f>0, a two-step process with slow diffusion at the early stages is observed where water molecules transverse the hydrophobic rich surface before reaching the hydrophilic regime. Water molecules then diffuse along the percolating network of the ionic center block. Increasing the temperature and sulfonation fraction enhances both the rate of diffusion and the overall water uptake. This work is partially supported by DOE: DE-SC007908.

  12. The quantum nature of the hydrogen bond: insight from path-integral molecular dynamics

    Science.gov (United States)

    Walker, Brent; Li, Xin-Zheng; Michaelides, Angelos

    2011-03-01

    Hydrogen (H) bonds are weak, generally intermolecular bonds, that hold together much of soft matter, the condensed phases of water, network liquids, and many ferroelectric crystals. The small mass of H means H-bonds are inherently quantum mechanical; effects such as zero point motion and tunneling should be considered, although often are not. In particular, a consistent picture of quantum nuclear effects on the strength of H-bonds and consequently the structure of H-bonded systems is still absent. Here, we report ab initio path-integral molecular dynamics studies on the quantum nature of the H-bond. Systematic examination of a range of H-bonded systems shows that quantum nuclei weaken weak H-bonds but strengthen relatively strong ones. This correlation arises from a competition between anharmonic intermolecular bond bending and intramolecular bond stretching. A simple rule of thumb enables predictions to be made for H-bonded bonded materials in general with merely classical knowledge (e.g. H-bond strength or H-bond length). Our work rationalizes the contrasting influence of quantum nuclear dynamics on a wide variety of materials, including liquid water and HF, and highlights the need for flexible molecules in force-field based studies of quantum nuclear dynamics.

  13. Molecular insights into Adgra2/Gpr124 and Reck intracellular trafficking

    Directory of Open Access Journals (Sweden)

    Naguissa Bostaille

    2016-12-01

    Full Text Available Adgra2, formerly known as Gpr124, is a key regulator of cerebrovascular development in vertebrates. Together with the GPI-anchored glycoprotein Reck, this adhesion GPCR (aGPCR stimulates Wnt7-dependent Wnt/β-catenin signaling to promote brain vascular invasion in an endothelial cell-autonomous manner. Adgra2 and Reck have been proposed to assemble a receptor complex at the plasma membrane, but the molecular modalities of their functional synergy remain to be investigated. In particular, as typically found in aGPCRs, the ectodomain of Adgra2 is rich in protein-protein interaction motifs whose contributions to receptor function are unknown. In opposition to the severe ADGRA2 genetic lesions found in previously generated zebrafish and mouse models, the zebrafish ouchless allele encodes an aberrantly-spliced and inactive receptor lacking a single leucine-rich repeat (LRR unit within its N-terminus. By characterizing this allele we uncover that, in contrast to all other extracellular domains, the precise composition of the LRR domain determines proper receptor trafficking to the plasma membrane. Using CRISPR/Cas9 engineered cells, we further show that Adgra2 trafficking occurs in a Reck-independent manner and that, similarly, Reck reaches the plasma membrane irrespective of Adgra2 expression or localization, suggesting that the partners meet at the plasma membrane after independent intracellular trafficking events.

  14. Molecular Insights into Toluene Sensing in the TodS/TodT Signal Transduction System*

    Science.gov (United States)

    Koh, Serry; Hwang, Jungwon; Guchhait, Koushik; Lee, Eun-Gyeong; Kim, Sang-Yoon; Kim, Sujin; Lee, Sangmin; Chung, Jeong Min; Jung, Hyun Suk; Lee, Sang Jun; Ryu, Choong-Min; Lee, Seung-Goo; Oh, Tae-Kwang; Kwon, Ohsuk; Kim, Myung Hee

    2016-01-01

    TodS is a sensor kinase that responds to various monoaromatic compounds, which either cause an agonistic or antagonistic effect on phosphorylation of its cognate response regulator TodT, and controls tod operon expression in Pseudomonas putida strains. We describe a molecular sensing mechanism of TodS that is activated in response to toluene. The crystal structures of the TodS Per-Arnt-Sim (PAS) 1 sensor domain (residues 43–164) and its complex with toluene (agonist) or 1,2,4-trimethylbenzene (antagonist) show a typical β2α3β3 PAS fold structure (residues 45–149), forming a hydrophobic ligand-binding site. A signal transfer region (residues 150–163) located immediately after the canonical PAS fold may be intrinsically flexible and disordered in both apo-PAS1 and antagonist-bound forms and dramatically adapt an α-helix upon toluene binding. This structural change in the signal transfer region is proposed to result in signal transmission to activate the TodS/TodT two-component signal transduction system. Site-directed mutagenesis and β-galactosidase assays using a P. putida reporter strain system verified the essential residues involved in ligand sensing and signal transfer and suggest that the Phe46 residue acts as a ligand-specific switch. PMID:26903514

  15. Dynamics of biological water: insights from molecular modeling of light scattering in aqueous trehalose solutions.

    Science.gov (United States)

    Lupi, Laura; Comez, Lucia; Paolantoni, Marco; Fioretto, Daniele; Ladanyi, Branka M

    2012-06-28

    Extended depolarized light scattering (EDLS) measurements have been recently employed to investigate the dynamics of water solvating biological molecules, giving evidence of the presence of two different dynamical regimes among water molecules. An interpretation of EDLS has been proposed that provides an independent estimate of the retardation factor of slowdown with respect to fast water molecules and of the number of solvent molecules affected by this slowing down. Nevertheless this measure is an inherently complex one, due to the collective nature of the physical property probed. In the present work a molecular dynamics (MD) approach has been used to more deeply understand experimental results. Time correlation functions of the collective polarizability anisotropy have been calculated for the prototype disaccharide trehalose in aqueous solutions as a function of concentration. The unique capability of MD to disentangle the contributions to the dynamics arising from solute, solvent, and cross terms between the two allowed us to check the reliability of an interpretation that assumes a spectral separation of water and sugar dynamics, as well as to highlight the very presence of two distinct relaxation processes in water. The two processes have been attributed to the dynamics of bulk and hydration water, respectively. A retardation factor of ~5 and concentration dependent hydration numbers have been observed, in good agreement with experimental results [Paolantoni, M.; et al. J. Phys. Chem. B 2009, 113, 7874-7878].

  16. Cytochrome P450 structure-function: insights from molecular dynamics simulations.

    Science.gov (United States)

    Nair, Pramod C; McKinnon, Ross A; Miners, John O

    2016-08-01

    Cytochrome P450 (CYP) family 1, 2, and 3 enzymes play an essential role in the metabolic clearance and detoxification of a myriad of structurally and chemically diverse drugs and non-drug xenobiotics. The individual CYP enzymes exhibit distinct substrate and inhibitor selectivities, and hence differing patterns of inhibitory drug-drug interactions. In addition, CYP enzymes differ in terms of regulation of expression, genetic polymorphism, and environmental factors that alter activity. The availability of three-dimensional structures from X-ray crystallography have been invaluable for understanding the structural basis of the ligand selectivity of CYP enzymes. Moreover, the X-ray crystal structures demonstrate that CYP proteins exhibit marked flexibility, particularly around the active site, and the principle of ligand-induced conformational changes is now well accepted. Recent studies have demonstrated that molecular dynamics simulations (MDS) provide an additional approach for modeling the structural flexibility of CYP enzymes, both in the presence and absence of bound ligand, and understanding the functional consequences of plasticity. However, most of the MDS studies reported to date have utilized short simulation time scales, and few have validated the computationally-generated data experimentally (e.g. by site-directed mutagenesis and enzyme kinetic approaches). Although modeling approaches require further development and validation, MDS has the potential to provide a deeper understanding of CYP structure-function than is available from experimental techniques such as X-ray crystallography alone.

  17. Fullerene-based anchoring groups for molecular electronics: insights from theory

    Science.gov (United States)

    Bagrets, Alexei; Seiler, Christian; Meded, Velimir; Evers, Ferdinand

    2010-03-01

    Recent experiments [1] have explored the idea of using C60 as anchoring groups to increase the stability of single molecule junctions. To further explore this concept, we have performed elaborated electronic structure calculations based on the density functional theory. First, the influence of dispersive interactions on the location of C60 with respect to the electrode surface is carefully investigated. Second, the transmission of C60 and BDC60 [=1,4-bis(fullero[c]pyrrolidin-1-yl)benzene] junctions is obtained. We find that a mismatch of the chemical potential of Au electrodes and frontier molecular orbitals of C60 generates a tunneling barrier. As a consequence, BDC60 acts as a sequence of three weakly coupled quantum dots. Specifically, the small conductance values (˜10-3 -- 10-4 G0) observed experimentally [1], arise from the small broadening of the HOMO level of the inner molecule capped by C60 moieties. Third, electrode materials with a smaller work function (e.g. Ag instead of Au) are discussed, which might provide better matching to C60 and therefore establish more favorable conditions for electron transfer. [1] C.A. Martin, D. Ding, J.K. Sørensen, T. Bjørnholm, J. van Ruitenbeek, H.S.J. van der Zant, JACS 130, 13198-13199 (2008).

  18. Insight into the stability of cross-beta amyloid fibril from molecular dynamics simulation.

    Science.gov (United States)

    Chen, Yue; He, Yong-Jie; Wu, Maoying; Yan, Guanwen; Li, Yixue; Zhang, Jian; Chen, Hai-Feng

    2010-06-01

    Amyloid fibrils are considered to play causal roles in the pathogenesis of amyloid-related degenerative diseases such as Alzheimer's disease, type II diabetes mellitus, the transmissible spongiform encephalopathies, and prion disease. The mechanism of fibril formation is still hotly debated and remains an important open question. In this study, we utilized molecular dynamics (MD) simulation to analyze the stability of hexamer for eight class peptides. The MD results suggest that VEALYL and MVGGVV-1 are the most stable ones, then SNQNNY, followed by LYQLEN, MVGGVV-2, VQIVYK, SSTSAA, and GGVVIA. The statistics result indicates that hydrophobic residues play a key role in stabilizing the zipper interface. Single point and two linkage mutants of MVGGVV-1 confirmed that both Met1 and Val2 are key hydrophobic residues. This is consistent with the statistics analysis. The stability results of oligomer for MVGGVV-1 suggest that the intermediate state should be trimer (3-0) and tetramer (2-2). These methods can be used in stabilization study of other amyloid fibril.

  19. Insight into the mechanism of polyphenols on the activity of HMGR by molecular docking.

    Science.gov (United States)

    Islam, Barira; Sharma, Charu; Adem, Abdu; Aburawi, Elhadi; Ojha, Shreesh

    2015-01-01

    Statins are hypolipidemic drugs that are effective in the treatment of hypercholesterolemia by attenuating cholesterol synthesis in the liver via competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Recently, dietary changes associated with drug therapy have garnered attention as novel drugs to mitigate or ameliorate hypercholesterolemia. The present study was undertaken to observe different dietary polyphenols that can bind to the active site of HMGR and inhibit it. Results from the 12 dietary polyphenols tested reveal that polyphenols can bind to HMGR and block the binding of nicotinamide adenine dinucleotide phosphate (NADP(+)). We observed that the rigidity of phenolic rings prevents the polyphenols from docking to the enzyme activity site. The presence of an ester linkage between the phenolic rings in (-)-epigallocatechin-3-gallate (EGCG) and the alkyl chain in curcumin allows them to orient in the active site of the HMGR and bind to the catalytic residues. EGCG and curcumin showed binding to the active site residues with a low GRID score, which may be a potential inhibitor of HMGR. Kaempferol showed binding to HMG-CoA, but with low binding affinity. These observations provide a rationale for the consistent hypolipidemic effect of EGCG and curcumin, which has been previously reported in several epidemiological and animal studies. Therefore, this study substantiates the mechanism of polyphenols on the activity of HMGR by molecular docking and provides the impetus for drug design involving further structure-function relationship studies.

  20. Forced Desorption of Bovine Serum Albumin and Lysozyme from Graphite: Insights from Molecular Dynamics Simulation.

    Science.gov (United States)

    Mücksch, Christian; Urbassek, Herbert M

    2016-08-18

    We use molecular dynamics (MD) simulation to study the adsorption and desorption of two widely different proteins, bovine serum albumin (BSA) and lysozyme, on a graphite surface. The adsorption is modeled using accelerated MD to allow the proteins to find optimum conformations on the surface. Our results demonstrate that the "hard protein" lysozyme retains much of its secondary structure during adsorption, whereas BSA loses it almost completely. BSA has a considerably larger adsorption energy compared to that of lysozyme, which does not scale with chain length. Desorption simulations are carried out using classical steered MD. The BSA molecule becomes fully unzipped during pull-off, whereas several helices survive this process in lysozyme. The unzipping process shows up in the force-distance curve of BSA as a series of peaks, whereas only a single or few, depending on protein orientation, force peaks occur for lysozyme. The maximum desorption force is larger for BSA than for lysozyme, but only by a factor of about 2.3.

  1. Interaction of counterions with subtilisin in acetonitrile: insights from molecular dynamics simulations.

    Science.gov (United States)

    Lousa, Diana; Cianci, Michele; Helliwell, John R; Halling, Peter J; Baptista, António M; Soares, Cláudio M

    2012-05-24

    A recent X-ray structure has enabled the location of chloride and cesium ions on the surface of subtilisin Carlsberg in acetonitrile soaked crystals. (1) To complement the previous study and analyze the system in solution, molecular dynamics (MD) simulations, in acetonitrile, were performed using this structure. Additionally, Cl(-) and Cs(+) ions were docked on the protein surface and this system was also simulated. Our results indicate that chloride ions tend to stay close to the protein, whereas cesium ions frequently migrate to the solvent. The distribution of the ions around the enzyme surface is not strongly biased by their initial locations. Replacing cesium by sodium ions showed that the distribution of the two cations is similar, indicating that Cs(+) can be used to find the binding sites of cations like Na(+) and K(+), which, unlike Cs(+), have physiological and biotechnological roles. The Na(+)Cl(-) is more stable than the Cs(+)Cl(-) ion pair, decreasing the probability of interaction between Cl(-) and subtilisin. The comparison of water and acetonitrile simulations indicates that the solvent influences the distribution of the ions. This work provides an extensive theoretical analysis of the interaction between ions and the model enzyme subtilisin in a nonaqueous medium.

  2. From molecular insight to therapeutic strategy: The holistic approach for treating triple negative breast cancer.

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    Bhattacharya, Rittwika; Banerjee, Koyel; Mukherjee, Nupur; Sen, Minakshi; Mukhopadhyay, Ashis

    2017-03-01

    Aim of the present study was to analyze the molecular pathogenesis of TNBC, therapeutic practice, challenges, and future goals in treatment strategies. Based on the alterations of distinct pathways, Lehmann's subgroups of TNBCs were further categorized. Those with defective DNA damage repair and replication pathways, viz. Basal Like 1 & 2 (BL1, BL2) were found susceptible to DNA intercalating drugs while those with upregulated cell signalling & motility (mesenchymal (M), mesemchymal stem like (MSL)), cell survival (BL2, M, MSL), angiogenesis (BL2, MSL), T cell signalling (Immunomodulatory/IM) pathways required targeted therapies. Our Meta-analysis categorized 12 randomized previous trial cases, solely under the following drug regimens: [1] DNA destabilizers, [2] PARP inhibitors, [3] Microtubule stabilizers, [4] Angiogenesis inhibitors, [5] Antimetabolite, [6] T cell targeted therapy; as single or combinational therapy. Best therapeutic efficacies of DNA destabilizers with angiogenesis inhibitors in combination than monotherapy with either (OR: 5.011-7.286; p value<0.001) indicated a significant prevalence of BL1 type TNBCs in populations. Statistical significance with antimetabolites as combination therapy (OR: 2.343; p value: 0.018) and not with microtubule stabilizer (OR: 0.377) were observed. Thus, for best ORR in TNBC, personalized medicine should be the therapeutic choice for the clinicians.

  3. Molecular interactions of α-amino acids insight into aqueous β-cyclodextrin systems.

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    Ekka, Deepak; Roy, Mahendra Nath

    2013-10-01

    Qualitative and quantitative analysis of molecular interaction prevailing in glycine, L-alanine, L-valine and aqueous solution of β-cyclodextrin (β-CD) have been probed by thermophysical properties. Density (ρ), viscosity (η), and ultrasonic speed (u) measurements have been reported at different temperatures. The extent of interaction (solute-solvent interaction) is expressed in terms of the limiting apparent molar volume ([Formula: see text]), viscosity B-coefficient and limiting apparent molar adiabatic compressibility ([Formula: see text]). The changes on the enthalpy ([Formula: see text]) and entropy ([Formula: see text]) of the encapsulation analysis give information about the driving forces governing the inclusion. The temperature dependence behaviour of partial molar quantities and group contributions to partial molar volumes has been determined for the amino acids. The trends in transfer volumes, [Formula: see text], have been interpreted in terms of solute-cosolute interactions based on a cosphere overlap model. The role of the solvent (aqueous solution of β-CD) and the contribution of solute-solute and solute-solvent interactions to the solution complexes have also been analyzed through the derived properties.

  4. Nephrogenic diabetes insipidus: essential insights into the molecular background and potential therapies for treatment.

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    Moeller, Hanne B; Rittig, Søren; Fenton, Robert A

    2013-04-01

    The water channel aquaporin-2 (AQP2), expressed in the kidney collecting ducts, plays a pivotal role in maintaining body water balance. The channel is regulated by the peptide hormone arginine vasopressin (AVP), which exerts its effects through the type 2 vasopressin receptor (AVPR2). Disrupted function or regulation of AQP2 or the AVPR2 results in nephrogenic diabetes insipidus (NDI), a common clinical condition of renal origin characterized by polydipsia and polyuria. Over several years, major research efforts have advanced our understanding of NDI at the genetic, cellular, molecular, and biological levels. NDI is commonly characterized as hereditary (congenital) NDI, arising from genetic mutations in the AVPR2 or AQP2; or acquired NDI, due to for exmple medical treatment or electrolyte disturbances. In this article, we provide a comprehensive overview of the genetic, cell biological, and pathophysiological causes of NDI, with emphasis on the congenital forms and the acquired forms arising from lithium and other drug therapies, acute and chronic renal failure, and disturbed levels of calcium and potassium. Additionally, we provide an overview of the exciting new treatment strategies that have been recently proposed for alleviating the symptoms of some forms of the disease and for bypassing G protein-coupled receptor signaling.

  5. Molecular insights into the origin of the Hox-TALE patterning system.

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    Hudry, Bruno; Thomas-Chollier, Morgane; Volovik, Yael; Duffraisse, Marilyne; Dard, Amélie; Frank, Dale; Technau, Ulrich; Merabet, Samir

    2014-03-18

    Despite tremendous body form diversity in nature, bilaterian animals share common sets of developmental genes that display conserved expression patterns in the embryo. Among them are the Hox genes, which define different identities along the anterior-posterior axis. Hox proteins exert their function by interaction with TALE transcription factors. Hox and TALE members are also present in some but not all non-bilaterian phyla, raising the question of how Hox-TALE interactions evolved to provide positional information. By using proteins from unicellular and multicellular lineages, we showed that these networks emerged from an ancestral generic motif present in Hox and other related protein families. Interestingly, Hox-TALE networks experienced additional and extensive molecular innovations that were likely crucial for differentiating Hox functions along body plans. Together our results highlight how homeobox gene families evolved during eukaryote evolution to eventually constitute a major patterning system in Eumetazoans. DOI: http://dx.doi.org/10.7554/eLife.01939.001.

  6. Simple Indices Provide Insight to Climate Attributes Delineating the Geographic Range of Aedes albopictus (Diptera: Culicidae) Prior to Worldwide Invasion.

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    Mogi, Motoyoshi; Armbruster, Peter; Tuno, Nobuko; Campos, Raúl; Eritja, Roger

    2015-07-01

    Aedes albopictus (Skuse) has expanded its distribution worldwide during the past decades. Despite attempts to explain and predict its geographic occurrence, analyses of the distribution of Ae. albopictus in the context of broad climatic regions (biomes) has not been performed. We analyzed climate conditions at its distribution sites in the range before the worldwide invasions (from the easternmost Hawaii through westernmost Madagascar) by using thermal and aridity-humidity indices descriptive of major biomes. A significant advantage of this approach is that it uses simple indices clearly related to the population dynamics of Ae. albopictus. Although Ae. albopictus has been regarded as a forest species preferring humid climate, in areas with significant human habitation, the distribution sites extended from the perhumid, rain forest zone to the semiarid, steppe zone. This pattern was common from the tropics through the temperate zone. Across the distribution range, there was no seasonal discordance between temperature and precipitation; at sites where winter prevents Ae. albopictus reproduction (monthly means10°C) under the Asian summer monsoon. Absence of the species in northern and eastern coastal Australia and eastern coastal Africa was not attributable solely to climate conditions. However, Asia west of the summer monsoon range was climatically unsuitable because of low precipitation throughout the year or in warm months favorable to reproduction (concentration of precipitation in winter). We hypothesized that Ae. albopictus originated in continental Asia under the monsoon climate with distinct dry seasons and hot, wet summer, enabling rapid population growth.

  7. Molecular insights of genetic variation in Erianthus arundinaceus populations native to China.

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    Jianbo Zhang

    Full Text Available BACKGROUND: E. arundinaceus (Retz. Jeswiet is a warm-season, tall-growing perennial species native to much southern portion in China. The grass has been extensively used in sugarcane breeding and is recently targeted as a bioenergy feedstock crop. However, information on the genetic structure of the Chinese wild germplasm is limited. Knowledge of genetic variation within and among populations is essential for breeding new cultivars in the species. The major objective of this study was to quantify the magnitude of genetic variation among and within natural populations in China. METHODOLOGY/PRINCIPAL FINDINGS: In this experiment, we analyzed genetic variation of 164 individuals of 18 populations collected from natural habitats in six Chinese provinces using 20 sequence-related amplified polymorphism (SRAP primer pairs generating 277 polymorphic bands. Among and within the populations, the percentage of polymorphic bands (PPB was 80.00% and 27.07%, genetic diversity (HE was 0.245 and 0.099, effective number of alleles (NE was 1.350 and 1.170, and Shannon's information index (I was 0.340 and 0.147, respectively. The populations were clustered into six groups exhibiting a high level of genetic differentiation, which was highly associated with geographic origins of respective germplasm populations, but was not significantly associated with geographic distances between the populations. CONCLUSIONS/SIGNIFICANCE: This is the first report indicating that large genetic variation exists in the Chinese E. arundinaceus germplasm based on the SRAP molecular marker analysis of native populations. The genetic structure of populations in the species has been substantially affected by geographic landforms and environments. The diverse collection will be highly valuable in genetic improvement in the species per se and likely in sugarcane.

  8. Effects of oxidation on tensile deformation of iron nanowires: Insights from reactive molecular dynamics simulations

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    Aral, Gurcan; Wang, Yun-Jiang; Ogata, Shigenobu; van Duin, Adri C. T.

    2016-10-01

    The influence of oxidation on the mechanical properties of nanostructured metals is rarely explored and remains poorly understood. To address this knowledge gap, in this work, we systematically investigate the mechanical properties and changes in the metallic iron (Fe) nanowires (NWs) under various atmospheric conditions of ambient dry O2 and in a vacuum. More specifically, we focus on the effect of oxide shell layer thickness over Fe NW surfaces at room temperature. We use molecular dynamics (MD) simulations with the variable charge ReaxFF force field potential model that dynamically handles charge variation among atoms as well as breaking and forming of the chemical bonds associated with the oxidation reaction. The ReaxFF potential model allows us to study large length scale mechanical atomistic deformation processes under the tensile strain deformation process, coupled with quantum mechanically accurate descriptions of chemical reactions. To study the influence of an oxide layer, three oxide shell layer thicknesses of ˜4.81 Å, ˜5.33 Å, and ˜6.57 Å are formed on the pure Fe NW free surfaces. It is observed that the increase in the oxide layer thickness on the Fe NW surface reduces both the yield stress and the critical strain. We further note that the tensile mechanical deformation behaviors of Fe NWs are dependent on the presence of surface oxidation, which lowers the onset of plastic deformation. Our MD simulations show that twinning is of significant importance in the mechanical behavior of the pure and oxide-coated Fe NWs; however, twin nucleation occurs at a lower strain level when Fe NWs are coated with thicker oxide layers. The increase in the oxide shell layer thickness also reduces the external stress required to initiate plastic deformation.

  9. Insight into the mechanism of polyphenols on the activity of HMGR by molecular docking

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    Islam B

    2015-08-01

    Full Text Available Barira Islam,1,* Charu Sharma,2,* Abdu Adem,3 Elhadi Aburawi,1 Shreesh Ojha3 1Department of Paediatrics, 2Department of Internal Medicine, 3Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, Abu Dhabi, United Arab Emirates *These authors contributed equally to this work Abstract: Statins are hypolipidemic drugs that are effective in the treatment of hypercholesterolemia by attenuating cholesterol synthesis in the liver via competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA reductase. Recently, dietary changes associated with drug therapy have garnered attention as novel drugs to mitigate or ameliorate hypercholesterolemia. The present study was undertaken to observe different dietary polyphenols that can bind to the active site of HMGR and inhibit it. Results from the 12 dietary polyphenols tested reveal that polyphenols can bind to HMGR and block the binding of nicotinamide adenine dinucleotide phosphate (NADP+. We observed that the rigidity of phenolic rings prevents the polyphenols from docking to the enzyme activity site. The presence of an ester linkage between the phenolic rings in (–-epigallocatechin-3-gallate (EGCG and the alkyl chain in curcumin allows them to orient in the active site of the HMGR and bind to the catalytic residues. EGCG and curcumin showed binding to the active site residues with a low GRID score, which may be a potential inhibitor of HMGR. Kaempferol showed binding to HMG-CoA, but with low binding affinity. These observations provide a rationale for the consistent hypolipidemic effect of EGCG and curcumin, which has been previously reported in several epidemiological and animal studies. Therefore, this study substantiates the mechanism of polyphenols on the activity of HMGR by molecular docking and provides the impetus for drug design involving further structure–function relationship studies. Keywords: polyphenols

  10. Way back for fructose and liver metabolism: Bench side to molecular insights

    Institute of Scientific and Technical Information of China (English)

    Alba Rebollo; Núria Roglans; Marta Alegret; Juan C Laguna

    2012-01-01

    The World Health Organization recommends that the daily intake of added sugars should make up no more than 10% of total energy.The consumption of sugarsweetened beverages is the main source of added sugars.Fructose,together with glucose,as a component of high fructose corn syrups or as a component of the sucrose molecule,is one of the main sweeteners present in this kind of beverages.Data from prospective and intervention studies clearly point to high fructose consumption,mainly in the form of sweetened beverages,as a risk factor for several metabolic diseases in humans.The incidence of hypertension,nonalcoholic fatty liver disease (NAFLD),dyslipidemia (mainly hypertriglyceridemia),insulin resistance,type 2 diabetes mellitus,obesity,and the cluster of many of these pathologies in the form of metabolic syndrome is higher in human population segments that show high intake of fructose.Adolescent and young adults from lowincome families are especially at risk.We recently reviewed evidence from experimental animals and human data that confirms the deleterious effect of fructose on lipid and glucose metabolism.In this present review we update the information generated in the past 2 years about high consumption of fructose-enriched beverages and the occurrence of metabolic disturbances,especially NAFLD,type 2 diabetes mellitus,and metabolic syndrome.We have explored recent data from observational and experimental human studies,as well as experimental data from animal and cell models.Finally,using information generated in our laboratory and others,we provide a view of the molecular mechanisms that may be specifically involved in the development of liver lipid and glucose metabolic alterations after fructose consumption in liquid form.

  11. Mechanistic prospective for human PrPC conversion to PrPSc: Molecular dynamic insights

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    Nooshin Azari

    2013-12-01

    Full Text Available PrPC conversion to PrPSc isoform is the main known cause for prion diseases including Crutzfeldt-Jakob, Gerstmann-Sträussler-Sheinker syndrome and fatal familial insomnia in human. The precise mechanism underling this conversion is yet to be well understood. In the present work, using the coordinate file of PrPC (available on the Protein Data Bank as a starting structure, separate molecular dynamic simulations were carried out at neutral and acidic pH in an explicit water box at 37°C and 1 atmosphere pressure for 10ns second period. Results showed that the acidic pH accelerates PrPC conversion to PrPSc by decreasing the protein gyration radius, flexibility and protein-solvent hydrogen bonds. In acidic conditions, PrPC attains a more folded and less flexible tertiary structure compared to its native structure at neutral pH; otherwise, the decrease of protein-solvent hydrogen bonds at acidic pH will enhance the hydrophobic character of PrPC that may exhibit association as multimeric assemblies. It can also lower water solubility and increase resistance to proteolytic degradations. Data indicated that there was no sensible protein denaturation during this conversion. It is hypothesized that the formation of slightly misfolded conformations with minor structural changes in secondary and/or tertiary structures are enough to menace scrapie formation in PrPC. Our findings show that scrapie formation seems to be a theoretically reversible process.

  12. New insights into the mechanisms whereby low molecular weight CCR5 ligands inhibit HIV-1 infection.

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    Garcia-Perez, Javier; Rueda, Patricia; Staropoli, Isabelle; Kellenberger, Esther; Alcami, Jose; Arenzana-Seisdedos, Fernando; Lagane, Bernard

    2011-02-18

    CC chemokine receptor 5 (CCR5) is a G-protein-coupled receptor for the chemokines CCL3, -4, and -5 and a coreceptor for entry of R5-tropic strains of human immunodeficiency virus type 1 (HIV-1) into CD4(+) T-cells. We investigated the mechanisms whereby nonpeptidic, low molecular weight CCR5 ligands block HIV-1 entry and infection. Displacement binding assays and dissociation kinetics demonstrated that two of these molecules, i.e. TAK779 and maraviroc (MVC), inhibit CCL3 and the HIV-1 envelope glycoprotein gp120 binding to CCR5 by a noncompetitive and allosteric mechanism, supporting the view that they bind to regions of CCR5 distinct from the gp120- and CCL3-binding sites. We observed that TAK779 and MVC are full and weak inverse agonists for CCR5, respectively, indicating that they stabilize distinct CCR5 conformations with impaired abilities to activate G-proteins. Dissociation of [(125)I]CCL3 from CCR5 was accelerated by TAK779, to a lesser extent by MVC, and by GTP analogs, suggesting that inverse agonism contributes to allosteric inhibition of the chemokine binding to CCR5. TAK779 and MVC also promote dissociation of [(35)S]gp120 from CCR5 with an efficiency that correlates with their ability to act as inverse agonists. Displacement experiments revealed that affinities of MVC and TAK779 for the [(35)S]gp120-binding receptors are in the same range (IC(50) ∼6.4 versus 22 nm), although we found that MVC is 100-fold more potent than TAK779 for inhibiting HIV infection. This suggests that allosteric CCR5 inhibitors not only act by blocking gp120 binding but also alter distinct steps of CCR5 usage in the course of HIV infection.

  13. Insights into the interactions between maleimide derivates and GSK3β combining molecular docking and QSAR.

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    Luisa Quesada-Romero

    Full Text Available Many protein kinase (PK inhibitors have been reported in recent years, but only a few have been approved for clinical use. The understanding of the available molecular information using computational tools is an alternative to contribute to this process. With this in mind, we studied the binding modes of 77 maleimide derivates inside the PK glycogen synthase kinase 3 beta (GSK3β using docking experiments. We found that the orientations that these compounds adopt inside GSK3β binding site prioritize the formation of hydrogen bond (HB interactions between the maleimide group and the residues at the hinge region (residues Val135 and Asp133, and adopt propeller-like conformations (where the maleimide is the propeller axis and the heterocyclic substituents are two slanted blades. In addition, quantitative structure-activity relationship (QSAR models using CoMSIA methodology were constructed to explain the trend of the GSK3β inhibitory activities for the studied compounds. We found a model to explain the structure-activity relationship of non-cyclic maleimide (NCM derivatives (54 compounds. The best CoMSIA model (training set included 44 compounds included steric, hydrophobic, and HB donor fields and had a good Q(2 value of 0.539. It also predicted adequately the most active compounds contained in the test set. Furthermore, the analysis of the plots of the steric CoMSIA field describes the elements involved in the differential potency of the inhibitors that can be considered for the selection of suitable inhibitors.

  14. Molecular insights into DNA interference by CRISPR-associated nuclease-helicase Cas3.

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    Gong, Bei; Shin, Minsang; Sun, Jiali; Jung, Che-Hun; Bolt, Edward L; van der Oost, John; Kim, Jeong-Sun

    2014-11-18

    Mobile genetic elements in bacteria are neutralized by a system based on clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins. Type I CRISPR-Cas systems use a "Cascade" ribonucleoprotein complex to guide RNA specifically to complementary sequence in invader double-stranded DNA (dsDNA), a process called "interference." After target recognition by Cascade, formation of an R-loop triggers recruitment of a Cas3 nuclease-helicase, completing the interference process by destroying the invader dsDNA. To elucidate the molecular mechanism of CRISPR interference, we analyzed crystal structures of Cas3 from the bacterium Thermobaculum terrenum, with and without a bound ATP analog. The structures reveal a histidine-aspartate (HD)-type nuclease domain fused to superfamily-2 (SF2) helicase domains and a distinct C-terminal domain. Binding of ATP analog at the interface of the SF2 helicase RecA-like domains rearranges a motif V with implications for the enzyme mechanism. The HD-nucleolytic site contains two metal ions that are positioned at the end of a proposed nucleic acid-binding tunnel running through the SF2 helicase structure. This structural alignment suggests a mechanism for 3' to 5' nucleolytic processing of the displaced strand of invader DNA that is coordinated with ATP-dependent 3' to 5' translocation of Cas3 along DNA. In agreement with biochemical studies, the presented Cas3 structures reveal important mechanistic details on the neutralization of genetic invaders by type I CRISPR-Cas systems.

  15. New insights into the enigma of boron carbide inverse molecular behavior

    Energy Technology Data Exchange (ETDEWEB)

    Dera, Przemyslaw, E-mail: pdera@hawaii.edu [Hawaii Institute of Geophysics and Planetology, School of Ocean and Earth Science and Technology, University of Hawaii at Manoa, 1680 East West Road, POST Building, Honolulu, HI 96822 (United States); Manghnani, Murli H.; Hushur, Anwar; Hu, Yi [Hawaii Institute of Geophysics and Planetology, School of Ocean and Earth Science and Technology, University of Hawaii at Manoa, 1680 East West Road, POST Building, Honolulu, HI 96822 (United States); Tkachev, Sergey [Center for Advanced Radiation Sources, The University of Chicago, Argonne National Laboratory, 9700 S. Cass Avenue, Building 434, Argonne, IL 60439 (United States)

    2014-07-01

    Equation of state and compression mechanism of nearly stoichiometric boron carbide B{sub 4}C were investigated using diamond anvil cell single crystal synchrotron X-ray diffraction technique up to a maximum quasi-hydrostatic pressure of 74.0(1) GPa in neon pressure transmitting medium at ambient temperature. No signatures of structural phase transitions were observed on compression. Crystal structure refinements indicate that the icosahedral units are less compressible (13% volume reduction at 60 GPa) than the unit cell volume (18% volume reduction at 60 GPa), contrary to expectations based on the inverse molecular behavior hypothesis, but consistent with spectroscopic evidence and first principles calculations. The high-pressure crystallographic refinements reveal that the nature of the chemical bonds (two, versus three centered character) has marginal effect on the bond compressibility and the compression of the crystal is mainly governed by the force transfer between the rigid icosahedral structural units. - Graphical abstract: Single crystal measurements of equation of state and compression mechanism of B{sub 4}C show that the icosahedral units are less compressibe than the unit cell volume, despite the threei-ceneterd nature of some icosahedral bonds. - Highlights: • Equation of state and compression mechanism of B{sub 4}C were measured to 75 GPa. • No signatures of structural phase transitions were observed on compression. • Icosahedral units are less compressibe than the unit cell volume. • The nature of the chemical bonds has mariginal effect on the bond compressibility. • The compression is governed by force transfer between the rigid icosahedra.

  16. One or three species in Megadenia (Brassicaceae): insight from molecular studies.

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    Artyukova, E V; Kozyrenko, M M; Boltenkov, E V; Gorovoy, P G

    2014-08-01

    Megadenia Maxim. is a small genus of the Brassicaceae endemic to East Asia with three disjunct areas of distribution: the eastern edge of the Qinghai-Tibetan Plateau, the Eastern Sayan Mountains in southern Siberia, and Chandalaz Ridge in the southern Sikhote-Alin Mountains. Although distinct species (M. pygmaea Maxim., M. bardunovii Popov, and M. speluncarum Vorob., Vorosch. and Gorovoj) have been described from each area, they have lately been reduced to synonymy with M. pygmaea due to high morphological similarity. Here, we present the first molecular study of Megadenia. Using the sequences of 11 noncoding regions from the cytoplasmic (chloroplast and mitochondrial) and nuclear genomes, we assessed divergence within the genus and explored the relationships between Megadenia and Biscutella L. Although M. bardunovii, M. speluncarum, and M. pygmaea were found to be indiscernible with regard to the nuclear and mitochondrial markers studied, our data on the plastid genome revealed their distinctness and a clear subdivision of the genus into three lineages matching the three described species. All of the phylogenetic analyses of the chloroplast DNA sequences provide strong support for the inclusion of Megadenia and Biscutella in the tribe Biscutelleae. A dating analysis shows that the genus Megadenia is of Miocene origin and diversification within the genus, which has led to the three extant lineages, most likely occurred during the Early-Middle Pleistocene, in agreement with the vicariance pattern. Given the present-day distribution, differences in habitat preferences and in some anatomical traits, and lack of a direct genealogical relationship, M. pygmaea, M. bardunovii, and M. speluncarum should be treated as distinct species or at least subspecies.

  17. Binding of PFOS to serum albumin and DNA: insight into the molecular toxicity of perfluorochemicals

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    Ma Yin-Sheng

    2009-02-01

    Full Text Available Abstract Background Health risk from exposure of perfluorochemicals (PFCs to wildlife and human has been a subject of great interest for understanding their molecular mechanism of toxicity. Although much work has been done, the toxigenicity of PFCs remains largely unknown. In this work, the non-covalent interactions between perfluorooctane sulfonate (PFOS and serum albumin (SA and DNA were investigated under normal physiological conditions, aiming to elucidate the toxigenicity of PFCs. Results In equilibrium dialysis assay, the bindings of PFOS to SA correspond to the Langmuir isothermal model with two-step sequence model. The saturation binding number of PFOS was 45 per molecule of SA and 1 per three base-pairs of DNA, respectively. ITC results showed that all the interactions were spontaneous driven by entropy change. Static quenching of the fluorescence of SA was observed when interacting with PFOS, indicating PFOS bound Trp residue of SA. CD spectra of SA and DNA changed obviously in the presence of PFOS. At normal physiological conditions, 1.2 mmol/l PFOS reduces the binding ratio of Vitamin B2 to SA by more than 30%. Conclusion The ion bond, van der Waals force and hydrophobic interaction contributed to PFOS binding to peptide chain of SA and to the groove bases of DNA duplex. The non-covalent interactions of PFOS with SA and DNA alter their secondary conformations, with the physiological function of SA to transport Vitamin B2 being inhibited consequently. This work provides a useful experimental method for further studying the toxigenicity of PFCs.

  18. Molecular Mechanisms of Mild and Severe Pneumonia: Insights from RNA Sequencing.

    Science.gov (United States)

    Huang, Sai; Feng, Cong; Chen, Li; Huang, Zhi; Zhou, Xuan; Li, Bei; Wang, Li-Li; Chen, Wei; Lv, Fa-Qin; Li, Tan-Shi

    2017-04-06

    BACKGROUND This study aimed to uncover the molecular mechanisms underlying mild and severe pneumonia by use of mRNA sequencing (RNA-seq). MATERIAL AND METHODS RNA was extracted from the peripheral blood of patients with mild pneumonia, severe pneumonia, and healthy controls. Sequencing was performed on the HiSeq4000 platform. After filtering, clean reads were mapped to the human reference genome hg19. Differentially expressed genes (DEGs) were identified between the control group and the mild or severe group. A transcription factor-gene network was constructed for each group. Biological process (BP) terms enriched by DEGs in the network were analyzed and these genes were also mapped to the Connectivity map to search for small-molecule drugs. RESULTS A total of 199 and 560 DEGs were identified from the mild group and severe group, respectively. A transcription factor-gene network consisting of 215 nodes and another network consisting of 451 nodes were constructed in the mild group and severe group, respectively, and 54 DEGs (e.g., S100A9 and S100A12) were found to be common, with consistent differential expression changes in the 2 groups. Genes in the transcription factor-gene network for the mild group were mainly enriched in 13 BP terms, especially defense and inflammatory response (e.g., S100A8) and spermatogenesis, while the top BP terms enriched by genes in the severe group include response to oxidative stress (CCL5), wound healing, and regulation of cell differentiation (CCL5), and of the cellular protein metabolic process. CONCLUSIONS S100A9 and S100A12 may have a role in the pathogenesis of pneumonia: S100A9 and CXCL1 may contribute solely in mild pneumonia, and CCL5 and CXCL11 may contribute in severe pneumonia.

  19. Heterogeneous behavior of metalloproteins toward metal ion binding and selectivity: insights from molecular dynamics studies.

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    Gogoi, Prerana; Chandravanshi, Monika; Mandal, Suraj Kumar; Srivastava, Ambuj; Kanaujia, Shankar Prasad

    2016-07-01

    About one-third of the existing proteins require metal ions as cofactors for their catalytic activities and structural complexities. While many of them bind only to a specific metal, others bind to multiple (different) metal ions. However, the exact mechanism of their metal preference has not been deduced to clarity. In this study, we used molecular dynamics (MD) simulations to investigate whether a cognate metal (bound to the structure) can be replaced with other similar metal ions. We have chosen seven different proteins (phospholipase A2, sucrose phosphatase, pyrazinamidase, cysteine dioxygenase (CDO), plastocyanin, monoclonal anti-CD4 antibody Q425, and synaptotagmin 1 C2B domain) bound to seven different divalent metal ions (Ca(2+), Mg(2+), Zn(2+), Fe(2+), Cu(2+), Ba(2+), and Sr(2+), respectively). In total, 49 MD simulations each of 50 ns were performed and each trajectory was analyzed independently. Results demonstrate that in some cases, cognate metal ions can be exchanged with similar metal ions. On the contrary, some proteins show binding affinity specifically to their cognate metal ions. Surprisingly, two proteins CDO and plastocyanin which are known to bind Fe(2+) and Cu(2+), respectively, do not exhibit binding affinity to any metal ion. Furthermore, the study reveals that in some cases, the active site topology remains rigid even without cognate metals, whereas, some require them for their active site stability. Thus, it will be interesting to experimentally verify the accuracy of these observations obtained computationally. Moreover, the study can help in designing novel active sites for proteins to sequester metal ions particularly of toxic nature.

  20. Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets

    Directory of Open Access Journals (Sweden)

    Manuc TE

    2016-03-01

    Full Text Available Teodora-Ecaterina M Manuc,1 Mircea M Manuc,2 Mircea M Diculescu2 1Fundeni Clinical Institute, 2University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania Abstract: Chronic inflammatory bowel diseases (IBDs are a subject of great interest in gastroenterology, due to a pathological mechanism that is difficult to explain and an optimal therapeutic approach still undiscovered. Crohn's disease (CD is one of the main entities in IBD, characterized by clinical polymorphism and great variability in the treatment response. Modern theories on the pathogenesis of CD have proven that gut microbiome and environmental factors lead to an abnormal immune response in a genetically predisposed patient. Genome-wide association studies in patients with CD worldwide revealed several genetic mutations that increase the risk of IBD and that predispose to a more severe course of disease. Gut microbiota is considered a compulsory and an essential part in the pathogenesis of CD. Intestinal dysmicrobism with excessive amounts of different bacterial strains can be found in all patients with IBD. The discovery of Escherichia coli entero-invasive on resection pieces in patients with CD now increases the likelihood of antimicrobial or vaccine-type treatments. Recent studies targeting intestinal immunology and its molecular activation pathways provide new possibilities for therapeutics. In addition to antitumor necrosis factor molecules, which were a breakthrough in IBD, improving mucosal healing and resection-free survival rate, other classes of therapeutic agents come to focus. Leukocyte adhesion inhibitors block the leukocyte homing mechanism and prevent cellular immune response. In addition to anti-integrin antibodies, chemokine receptor antagonists and SMAD7 antisense oligonucleotides have shown encouraging results in clinical trials. Micro-RNAs have demonstrated their role as disease biomarkers but it could also become useful for the treatment of IBD

  1. Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

    Directory of Open Access Journals (Sweden)

    Monica Marzagalli

    2016-10-01

    Full Text Available Cutaneous melanoma is an aggressive tumor with its incidence increasing faster than any other cancer in the past decades. Melanoma is a heterogeneous tumor, with most patients harboring mutations in the BRAF or NRAS oncogenes, leading to the overactivation of the MAPK/ERK and PI3K/Akt pathways. The current therapeutic approaches are based on therapies targeting mutated BRAF and the downstream pathway, and on monoclonal antibodies against the immune checkpoint blockade. However, treatment resistance and side effects are common events of these therapeutic strategies.Increasing evidence supports that melanoma is a hormone-related cancer. Melanoma incidence is higher in males than in females and females have a significant survival advantage over men. Estrogens exert their effects through estrogen receptors (ER and ERβ that exert opposite effects on cancer growth: ER is associated with a proliferative action and ERβ with an anticancer effect. ERβ is the predominant estrogen receptor in melanoma and its expression decreases in melanoma progression, supporting its role as a tumor suppressor. Thus, ERβ is now considered as an effective molecular target for melanoma treatment. 17β-estradiol was reported to inhibit melanoma cells proliferation. However, clinical trials did not provide the expected survival benefits. In vitro studies demonstrate that ERβ ligands inhibit the proliferation of melanoma cells harboring the NRAS (but not the BRAF mutation, suggesting that ERβ activation might impair melanoma development through the inhibition of the PI3K/Akt pathway. These data suggest that ERβ agonists might be considered as an effective treatment strategy, in combination with MAPK inhibitors, for NRAS mutant melanomas. In an era of personalized medicine, pretreatment evaluation of the expression of ER isoforms together with the concurrent oncogenic mutations should be considered before selecting the most appropriate therapeutic intervention

  2. An unusual H2 sorption mechanism in PCN-14: insights from molecular simulation.

    Science.gov (United States)

    Pham, Tony; Forrest, Katherine A; Space, Brian

    2016-08-01

    Simulations of H2 sorption were performed in PCN-14, a metal-organic framework (MOF) that consists of Cu(2+) ions coordinated to 5,5'-(9,10-anthracenediyl)diisophthalate (adip) linkers. This MOF displays an excess H2 uptake of 2.70 wt% at 77 K and 1.0 atm and an initial H2Qst value of 8.6 kJ mol(-1) according to previous experimental measurements. The experimental H2 sorption isotherms and Qst values in PCN-14 were reproduced in simulations using well-known H2 potentials that have been widely used for MOF-H2 theoretical studies. H2 sorption in PCN-14 was dominated by repulsion/dispersion energetics; this allowed the experimental observables to be reproduced by a model that includes only Lennard-Jones parameters. The most energetically favorable H2 sorption site in PCN-14 corresponds to sorption within a small cage that is enclosed by three [Cu2(O2CR)4] units and three adip linkers. The anthracenyl rings of the adip linkers represent the secondary sorption sites within the MOF. In contrast to expectations, sorption of H2 onto the Cu(2+) ions of the copper paddlewheels was not observed within the simulations at low loading. The simulations revealed that the open-metal sites in PCN-14 were occupied at high loading. Control simulations of H2 sorption in PCN-14 for different cases in which the partial positive charge of one of the paddlewheel Cu(2+) ions was increased relative to the other revealed that sorption onto the open-metal sites can be captured if there is a very high positive charge on the metal. Otherwise, the calculated partial charge for the Cu(2+) ions in PCN-14 in this work was not high enough in magnitude to facilitate strong H2-metal interactions in simulation. This study shows the power of using molecular simulations to elucidate an unusual H2 sorption behavior in a MOF.

  3. Conduction and Reactivity in Heterogeneous-Molecular Catalysis: New Insights in Water Oxidation Catalysis by Phosphate Cobalt Oxide Films.

    Science.gov (United States)

    Costentin, Cyrille; Porter, Thomas R; Savéant, Jean-Michel

    2016-05-04

    Cyclic voltammetry of phosphate cobalt oxide (CoPi) films catalyzing O2-evolution from water oxidation as a function of scan rate, phosphate concentration and film thickness allowed for new insights into the coupling between charge transport and catalysis. At pH = 7 and low buffer concentrations, the film is insulating below 0.8 (V vs SHE) but becomes conductive above 0.9 (V vs SHE). Between 1.0 to 1.3 (V vs SHE), the mesoporous structure of the film gives rise to a large thickness-dependent capacitance. At higher buffer concentrations, two reversible proton-coupled redox couples appear over the capacitive response with 0.94 and 1.19 (V vs SHE) pH = 7 standard potentials. The latter is, at most, very weakly catalytic and not responsible for the large catalytic current observed at higher potentials. CV-response analysis showed that the amount of redox-active cobalt-species in the film is small, less than 10% of total. The catalytic process involves a further proton-coupled-electron-transfer and is so fast that it is controlled by diffusion of phosphate, the catalyst cofactor. CV-analysis with newly derived relationships led to a combination of the catalyst standard potential with the catalytic rate constant and a lower-limit estimation of these parameters. The large currents resulting from the fast catalytic reaction result in significant potential losses related to charge transport through the film. CoPi films appear to combine molecular catalysis with semiconductor-type charge transport. This mode of heterogeneous molecular catalysis is likely to occur in many other catalytic films.

  4. Biophysical and molecular docking insight into the interaction of cytosine β-D arabinofuranoside with human serum albumin

    Energy Technology Data Exchange (ETDEWEB)

    Alam, Parvez; Chaturvedi, Sumit Kumar [Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, UP (India); Anwar, Tamanna [Center of Bioinformatics Research and Technology, Aligarh 202002 (India); Siddiqi, Mohammad Khursheed; Ajmal, Mohd Rehan [Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, UP (India); Badr, Gamal [Laboratory of Immunology & Molecular Physiology, Zoology Department, Faculty of Science, Assiut University, 71516 Assiut (Egypt); Mahmoud, Mohamed H. [Food Science and Nutrition Department, National Research Center, Dokki, Cairo (Egypt); Deanship of Scientific Research, King Saud University, Riyadh (Saudi Arabia); Hasan Khan, Rizwan, E-mail: rizwanhkhan@hotmail.com [Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, UP (India)

    2015-08-15

    Interaction of pharmacologically important anticancer drug cytosine β-D arabinofuranoside with human serum albumin (HSA) at physiological pH 7.4 has been studied by utilizing various spectroscopic and molecular docking strategies. Fluorescence results revealed that cytosine β-D arabinofuranoside interacts with HSA through static quenching mechanism with binding affinity of 2.4×10{sup 3} M{sup −1}. The average binding distance between drug and Trp{sup 214} of HSA was found to be 2.23 nm on the basis of the theory of Förster's energy transfer. Synchronous fluorescence data indicated that interaction of drug with HSA changed the microenvironment around the tryptophan residue. UV–visible spectroscopy and circular dichroism results deciphered the complex formation and conformational alterations in the HSA respectively. Dynamic light scattering was utilized to understand the topology of protein in absence and presence of drug. Thermodynamic parameters obtained from isothermal titration calorimetry (ΔH=−26.01 kJ mol{sup −1} and TΔS=6.5 kJ mol{sup −1}) suggested the involvement of van der Waal interaction and hydrogen bonding. Molecular docking and displacement study with site specific markers suggested that cytosine β-D arabinofuranoside binds to subdomain IB of HSA which is also known as the hemin binding site. This study will be helpful to understand the binding mechanism of cytosine β-D arabinofuranoside with HSA and associated alterations. - Highlights: • Comprehensive insight into the interaction of CBDA with HSA. • The interaction process is spontaneous and exothermic. • The main governing forces for stabilizing HSA–CBDA complex are van der Waal interaction and hydrogen bonding. • CBDA binds at subdomain IB on HSA.

  5. Reactivity of aldehydes at the air-water interface. Insights from molecular dynamics simulations and ab initio calculations.

    Science.gov (United States)

    Martins-Costa, Marilia T C; García-Prieto, Francisco F; Ruiz-López, Manuel F

    2015-02-14

    Understanding the influence of solute-solvent interactions on chemical reactivity has been a subject of intense research in the last few decades. Theoretical studies have focused on bulk solvation phenomena and a variety of models and methods have been developed that are now widely used by both theoreticians and experimentalists. Much less attention has been paid, however, to processes that occur at liquid interfaces despite the important role such interfaces play in chemistry and biology. In this study, we have carried out sequential molecular dynamics simulations and quantum mechanical calculations to analyse the influence of the air-water interface on the reactivity of formaldehyde, acetaldehyde and benzaldehyde, three simple aldehydes of atmospheric interest. The calculated free-energy profiles exhibit a minimum at the interface, where the average reactivity indices may display large solvation effects. The study emphasizes the role of solvation dynamics, which are responsible for large fluctuations of some molecular properties. We also show that the photolysis rate constant of benzaldehyde in the range 290-308 nm increases by one order of magnitude at the surface of a water droplet, from 2.7 × 10(-5) s(-1) in the gas phase to 2.8 × 10(-4) s(-1) at the air-water interface, and we discuss the potential impact of this result on the chemistry of the troposphere. Experimental data in this domain are still scarce and computer simulations like those presented in this work may provide some insights that can be useful to design new experiments.

  6. Climate, people, fire and vegetation: new insights into vegetation dynamics in the Eastern Mediterranean since the 1st century AD

    Directory of Open Access Journals (Sweden)

    J. Bakker

    2012-08-01

    Full Text Available Anatolia forms a bridge between Europe, Africa and Asia and is influenced by all three continents in terms of climate, vegetation and human civilisation. Unfortunately, well dated palynological records focussing on the period from the end of the classical Roman period until subrecent times are rare for Anatolia and completely absent for southwest Turkey, resulting in a lacuna in knowledge concerning the interactions of climatic change, human impact, and environmental change in this important region. Two well dated palaeoecological records from the Western Taurus Mountains, Turkey, provide a first relatively detailed record of vegetation dynamics from late Roman times until the present in SW Turkey. Combining pollen, non-pollen palynomorphs, charcoal, sedimentological, archaeological data, and newly developed multivariate numerical analyses, allows for the disentangling of climatic and anthropogenic influences on vegetation change. Results show both the regional pollen signal as well as local soil sediment characteristics respond accurately to shifts in regional climatic conditions. Both climatic as well as anthropogenic change had a strong influence on vegetation dynamics and land use. A moist environmental trend during the late 3rd century caused an increase in marshes and wetlands in the moister valley floors, limiting possibilities for intensive crop cultivation at such locations. A mid 7th century shift to pastoralism coincided with a climatic deterioration as well as the start of Arab incursions into the region, the former driving the way in which the vegetation developed afterwards. Resurgence in agriculture was observed in the study during the mid 10th century AD, coinciding with the Medieval Climate Anomaly. An abrupt mid 12th century decrease in agriculture is linked to socio-political change, rather than the onset of the Little Ice Age. Similarly, gradual deforestation occurring from the 16th century onwards has been linked to changes

  7. Mechanistic insights into Mg2+-independent prenylation by CloQ from classical molecular mechanics and hybrid quantum mechanics/molecular mechanics molecular dynamics simulations.

    Science.gov (United States)

    Bayse, Craig A; Merz, Kenneth M

    2014-08-05

    Understanding the mechanism of prenyltransferases is important to the design of engineered proteins capable of synthesizing derivatives of naturally occurring therapeutic agents. CloQ is a Mg(2+)-independent aromatic prenyltransferase (APTase) that transfers a dimethylallyl group to 4-hydroxyphenylpyruvate in the biosynthetic pathway for clorobiocin. APTases consist of a common ABBA fold that defines a β-barrel containing the reaction cavity. Positively charged basic residues line the inside of the β-barrel of CloQ to activate the pyrophosphate leaving group to replace the function of the Mg(2+) cofactor in other APTases. Classical molecular dynamics simulations of CloQ, its E281G and F68S mutants, and the related NovQ were used to explore the binding of the 4-hydroxyphenylpyruvate (4HPP) and dimethylallyl diphosphate substrates in the reactive cavity and the role of various conserved residues. Hybrid quantum mechanics/molecular mechanics potential of mean force (PMF) calculations show that the effect of the replacement of the Mg(2+) cofactor with basic residues yields a similar activation barrier for prenylation to Mg(2+)-dependent APTases like NphB. The topology of the binding pocket for 4HPP is important for selective prenylation at the ortho position of the ring. Methylation at this position alters the conformation of the substrate for O-prenylation at the phenol group. Further, a two-dimensional PMF scan shows that a "reverse" prenylation product may be a possible target for protein engineering.

  8. Molecular docking and molecular dynamics simulation study of inositol phosphorylceramide synthase – inhibitor complex in leishmaniasis: Insight into the structure based drug design [version 2; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Vineetha Mandlik

    2016-09-01

    Full Text Available Inositol phosphorylceramide synthase (IPCS has emerged as an important, interesting and attractive target in the sphingolipid metabolism of Leishmania. IPCS catalyzes the conversion of ceramide to IPC which forms the most predominant sphingolipid in Leishmania. IPCS has no mammalian equivalent and also plays an important role in maintaining the infectivity and viability of the parasite. The present study explores the possibility of targeting IPCS; development of suitable inhibitors for the same would serve as a treatment strategy for the infectious disease leishmaniasis. Five coumarin derivatives were developed as inhibitors of IPCS protein. Molecular dynamics simulations of the complexes of IPCS with these inhibitors were performed which provided insights into the binding modes of the inhibitors. In vitro screening of the top three compounds has resulted in the identification of one of the compounds (compound 3 which shows little cytotoxic effects. This compound therefore represents a good starting point for further in vivo experimentation and could possibly serve as an important drug candidate for the treatment of leishmaniasis.

  9. Low-Latitude Western North Atlantic Climate Variability During the Past Millennium: Insights from Proxies and Models

    Science.gov (United States)

    2009-09-01

    Birdwhistell, and Simon Thorrold. Andy Solow , Nathalie Goodkin, and Peter Huybers provided valuable insights into the statistical analysis. We thank...latitude North Atlantic since 1552 Casey Saenger1*, Anne L. Cohen2, Delia W. Oppo2, Robert B. Halley3 and Jessica E. Carilli4 Sea surface temperature

  10. Insights into rapid climate change: A high resolution, compound-specific n-alkane δD study of the 8.2 ka event (Tenaghi Philippon, Greece)

    Science.gov (United States)

    Schemmel, F.; Niedermeyer, E.; Schwab, V.; Pross, J.; Mulch, A.

    2013-12-01

    Despite being characterized as remarkably stable, the Holocene climate has experienced a number of abrupt, relatively short-term climate changes. Arguably the most prominent climate perturbation, the 8.2 ka event, was caused by the catastrophic drainage of the ice-dammed Laurentide ice-lake into the North Atlantic, leading to a severe weakening of thermohaline circulation, causing a decline in temperature and significant changes in atmospheric circulation in the Northern Hemisphere, especially in the North Atlantic realm and Europe. Being located between the climate systems of the higher and lower latitudes, the Mediterranean region is particularly susceptible to rapid climate change. Available proxy data and climate models provide first-order insight into the impact of the 8.2 ka event in this area but often lack the temporal resolution to supply information about changes in seasonality, hence severely hindering the understanding of rapid climate changes and revealing the need for high resolution terrestrial archives. Here, we present a multi-proxy, high resolution stable isotope study across the 8.2 ka event on a peat core from the classical site of Tenaghi Philippon (NE Greece). We aim to characterize the effects of changing temperature and rainfall patterns by using compound-specific δD values of the long-chain n-alkanes as a proxy for terrestrial (summer) precipitation. We compare changes in hydrogen isotopic composition to the concentration of the long-chain n-alkanes as well as to δ13Cbulk measurements of the organic material and high-resolution palynomorphic data from the same core. Analysis of 35 samples of telmatic peat shows significant decreases in concentration of the long-chain n-alkanes along with strong positive shifts in δD (over 40 ‰ in δDC29) during the 8.2 ka event. The general trend of δD of the n-Alkanes n-C27, n-C29 and n-C31 coincides with changes in δ13Cbulk, and to some degree reflects changes in moisture availability. We attribute

  11. Reduction of α,β-Unsaturated Ketones by Old Yellow Enzymes: Mechanistic Insights from Quantum Mechanics/Molecular Mechanics Calculations.

    Science.gov (United States)

    Lonsdale, Richard; Reetz, Manfred T

    2015-11-25

    Enoate reductases catalyze the reduction of activated C═C bonds with high enantioselectivity. The oxidative half-reaction, which involves the addition of a hydride and a proton to opposite faces of the C═C bond, has been studied for the first time by hybrid quantum mechanics/molecular mechanics (QM/MM). The reduction of 2-cyclohexen-1-one by YqjM from Bacillus subtilis was selected as the model system. Two-dimensional QM/MM (B3LYP-D/OPLS2005) reaction pathways suggest that the hydride and proton are added as distinct steps, with the former step preceding the latter. Furthermore, we present interesting insights into the reactivity of this enzyme, including the weak binding of the substrate in the active site, the role of the two active site histidine residues for polarization of the substrate C═O bond, structural details of the transition states to hydride and proton transfer, and the role of Tyr196 as proton donor. The information presented here will be useful for the future design of enantioselective YqjM mutants for other substrates.

  12. Denudational slope processes and slope response to global climate changes and other disturbances: insights from the Nepal Himalayas.

    Science.gov (United States)

    Fort, Monique

    2016-04-01

    Hillslope geomorphology results from a large range of denudational processes mainly controlled by relief, structure, lithology, climate, land-cover and land use. In most areas of the world, the "critical zone" concept is a good integrator of denudation that operates on a long-term scale. However, in large and high mountain areas, short-time scale factors often play a significant role in the denudational pattern, accelerating and/or delaying the transfer of denudation products and fluxes, and creating specific, spatially limited disturbances. We focus on the Nepal Himalayas, where the wide altitudinal range of bio-climatic zones and the intense geodynamic activity create a complex mosaic of landforms, as expressed by the present geomorphology of mountain slopes. On the basis of examples selected in the different Himalayan mountain belts (Siwaliks hills, middle mountains, High Himalaya), we illustrate different types of slopes and disturbances induced by active tectonics, climate extremes, and climate warming trends. Special attention is paid to recent events, such as landslide damming, triggered by either intense rainfalls (Kali Gandaki and Sun Kosi valleys) or the last April-May 2015 Gorkha seismic sequence (southern Khumbu). Lastly, references to older, larger events show that despite the highly dynamic environment, landforms caused by large magnitude disturbances may persist in the landscape in the long term.

  13. Value of traditional oral narratives in building climate-change resilience: insights from rural communities in Fiji

    Directory of Open Access Journals (Sweden)

    Shaiza Z. Janif

    2016-06-01

    Full Text Available In the interests of improving engagement with Pacific Island communities to enable development of effective and sustainable adaptation strategies to climate change, we looked at how traditional oral narratives in rural/peripheral Fiji communities might be used to inform such strategies. Interviews were undertaken and observations made in 27 communities; because the custodians of traditional knowledge were targeted, most interviewees were 70-79 years old. The view that oral traditions, particularly those referring to environmental history and the observations/precursors of environmental change, were endangered was widespread and regretted. Interviewees' personal experiences of extreme events (natural disasters were commonplace but no narratives of historical (unwitnessed by interviewees events were found. In contrast, experiences of previous village relocations attributable (mainly to environmental change were recorded in five communities while awareness of environmentally driven migration was more common. Questions about climate change elicited views dominated by religious/fatalist beliefs but included some more pragmatic ones; the confusion of climate change with climate variability, which is part of traditional knowledge, was widespread. The erosion of traditional environmental knowledge in the survey communities over recent decades has been severe and is likely to continue apace, which will reduce community self-sufficiency and resilience. Ways of conserving such knowledge and incorporating it into adaptation planning for Pacific Island communities in rural/peripheral locations should be explored.

  14. Southern African continental climate since the late Pleistocene: Insights from biomarker analyses of Kalahari salt pan sediments

    Science.gov (United States)

    Belz, Lukas; Schüller, Irka; Wehrmann, Achim; Wilkes, Heinz

    2016-04-01

    The climate system of sub-tropical southern Africa is mainly controlled by large scale atmospheric and marine circulation processes and, therefore, very sensitive to global climate change. This underlines the importance of paleoenvironmental reconstructions in order to estimate regional implications of current global changes. However, the majority of studies on southern African paleoclimate are based on the investigation of marine sedimentary archives and past climate development especially in continental areas is still poorly understood. This emphasizes the necessity of continental proxy-data from this area. Proxy datasets from local geoarchives especially of the southwestern Kalahari region are still scarce. A main problem is the absence of conventional continental climatic archives, due to the lack of lacustrine systems. In this study we are exploring the utility of sediments from western Kalahari salt pans, i.e. local depressions which are flooded temporarily during rainfall events. An age model based on 14C dating of total organic carbon (TOC) shows evidence that sedimentation predominates over erosional processes with respect to pan formation. Besides the analyses of basic geochemical bulk parameters including TOC, δ13CTOC, total inorganic carbon, δ13CTIC, δ18OTIC, total nitrogen and δ15N, our paleo-climatic approach focuses on reconstruction of local vegetation assemblages to identify changes in the ecosystem. This is pursued using plant biomarkers, particularly leaf wax n-alkanes and n-alcohols and their stable carbon and hydrogen isotopic signatures. Results show prominent shifts in n-alkane and n-alkanol distributions and compound specific carbon isotope values, pointing to changes to a more grass dominated environment during Heinrich Stadial 1 (18.5-14.6 ka BP), while hydrogen isotope values suggest wetter phases during Holocene and LGM. This high variability indicates the local vulnerability to global change.

  15. Response of lightning NOx emissions and ozone production to climate change:Insights from the Atmospheric Chemistry and Climate Model Intercomparison Project

    OpenAIRE

    2016-01-01

    Results from an ensemble of models are used to investigate the response of lightning nitrogen oxide emissions to climate change and the consequent impacts on ozone production. Most models generate lightning using a parameterization based on cloud top height. With this approach and a present-day global emission of 5 TgN, we estimate a linear response with respect to changes in global surface temperature of +0.44 ± 0.05 TgN K−1. However, two models using alternative approaches give +0.14 and −0...

  16. Bromine soil/sediment enrichment in tidal salt marshes as a potential indicator of climate changes driven by solar activity: New insights from W coast Portuguese estuaries.

    Science.gov (United States)

    Moreno, J; Fatela, F; Leorri, E; Moreno, F; Freitas, M C; Valente, T; Araújo, M F; Gómez-Navarro, J J; Guise, L; Blake, W H

    2017-02-15

    This paper aims at providing insight about bromine (Br) cycle in four Portuguese estuaries: Minho, Lima (in the NW coast) and Sado, Mira (in the SW coast). The focus is on their tidal marsh environments, quite distinct with regard to key biophysicochemical attributes. Regardless of the primary bromide (Br(-)) common natural source, i.e., seawater, the NW marshes present relatively higher surface soil/sediment Br concentrations than the ones from SW coast. This happens in close connection with organic matter (OM) content, and is controlled by their main climatic contexts. Yet, the anthropogenic impact on Br concentrations cannot be discarded. Regarding [Br] spatial patterns across the marshes, the results show a general increase from tidal flat toward high marsh. Maxima [Br] occur in the upper driftline zone, at transition from highest low marsh to high marsh, recognized as a privileged setting for OM accumulation. Based on the discovery of OM ubiquitous bromination in marine and transitional environments, it is assumed that this Br occurs mainly as organobromine. Analysis of two dated sediment cores indicates that, despite having the same age (AD ~1300), the Caminha salt marsh (Minho estuary) evidences higher Br enrichment than the Casa Branca salt marsh (Mira estuary). This is related to a greater Br storage ability, which is linked to OM build-up and rate dynamics under different climate scenarios. Both cores evidence a fairly similar temporal Br enrichment pattern, and may be interpreted in light of the sun-climate coupling. Thereby, most of the well-known Grand Solar Minima during the Little Ice Age appear to have left an imprint on these marshes, supported by higher [Br] in soils/sediments. Besides climate changes driven by solar activity and impacting marsh Br biogeodynamics, those Br enrichment peaks might also reflect inputs of enhanced volcanic activity covarying with Grand Solar Minima.

  17. Influence of climate warming on arctic mammals? New insights from ancient DNA studies of the collared lemming Dicrostonyx torquatus.

    Directory of Open Access Journals (Sweden)

    Stefan Prost

    Full Text Available BACKGROUND: Global temperature increased by approximately half a degree (Celsius within the last 150 years. Even this moderate warming had major impacts on Earth's ecological and biological systems, especially in the Arctic where the magnitude of abiotic changes even exceeds those in temperate and tropical biomes. Therefore, understanding the biological consequences of climate change on high latitudes is of critical importance for future conservation of the species living in this habitat. The past 25,000 years can be used as a model for such changes, as they were marked by prominent climatic changes that influenced geographical distribution, demographic history and pattern of genetic variation of many extant species. We sequenced ancient and modern DNA of the collared lemming (Dicrostonyx torquatus, which is a key species of the arctic biota, from a single site (Pymva Shor, Northern Pre Urals, Russia to see if climate warming events after the Last Glacial Maximum had detectable effects on the genetic variation of this arctic rodent species, which is strongly associated with a cold and dry climate. RESULTS: Using three dimensional network reconstructions we found a dramatic decline in genetic diversity following the LGM. Model-based approaches such as Approximate Bayesian Computation and Markov Chain Monte Carlo based Bayesian inference show that there is evidence for a population decline in the collared lemming following the LGM, with the population size dropping to a minimum during the Greenland Interstadial 1 (Bølling/Allerød warming phase at 14.5 kyrs BP. CONCLUSION: Our results show that previous climate warming events had a strong influence on genetic diversity and population size of collared lemmings. Due to its already severely compromised genetic diversity a similar population reduction as a result of the predicted future climate change could completely abolish the remaining genetic diversity in this population. Local population

  18. Climate, people, fire and vegetation: new insights into vegetation dynamics in the Eastern Mediterranean since the 1st century AD

    Directory of Open Access Journals (Sweden)

    J. Bakker

    2013-01-01

    Full Text Available Anatolia forms a bridge between Europe, Africa and Asia and is influenced by all three continents in terms of climate, vegetation and human civilisation. Unfortunately, well-dated palynological records focussing on the period from the end of the classical Roman period until subrecent times are rare for Anatolia and completely absent for southwest Turkey, resulting in a lacuna in knowledge concerning the interactions of climatic change, human impact, and environmental change in this important region. Two well-dated palaeoecological records from the Western Taurus Mountains, Turkey, provide a first relatively detailed record of vegetation dynamics from late Roman times until the present in SW Turkey. Combining pollen, non-pollen palynomorphs, charcoal, sedimentological, archaeological data, and newly developed multivariate numerical analyses allows for the disentangling of climatic and anthropogenic influences on vegetation change. Results show changes in both the regional pollen signal as well as local soil sediment characteristics match shifts in regional climatic conditions. Both climatic as well as anthropogenic change had a strong influence on vegetation dynamics and land use. A moist environmental trend during the late-3rd century caused an increase in marshes and wetlands in the moister valley floors, limiting possibilities for intensive crop cultivation at such locations. A mid-7th century shift to pastoralism coincided with a climatic deterioration as well as the start of Arab incursions into the region, the former driving the way in which the vegetation developed afterwards. Resurgence in agriculture was observed in the study during the mid-10th century AD, coinciding with the Medieval Climate Anomaly. An abrupt mid-12th century decrease in agriculture is linked to socio-political change, rather than the onset of the Little Ice Age. Similarly, gradual deforestation occurring from the 16th century onwards has been linked to changes in

  19. The record of Miocene climatic events in AND-2A drill core (Antarctica): Insights from provenance analyses of basement clasts

    Science.gov (United States)

    Sandroni, Sonia; Talarico, Franco M.

    2011-01-01

    This paper includes the results of a detailed quantitative provenance investigation on gravel-size clasts occurring within the late Early to Late Miocene sedimentary glacimarine section recovered for the first time by the AND-2A core in the SW sector of the Ross Sea (southern McMurdo Sound, Antarctica). This period of time is of crucial interest, as it includes two of the major Cenozoic events in the global climatic evolution: the mid-Miocene climatic optimum and the middle Miocene climate transition. Petrographical and mineral chemistry data on basement clasts allow to individuate two different diagnostic clast assemblages, which clearly suggest two specific sectors of southern Victoria Land as the most likely sources: the Mulock-Skelton glacier and the Koettlitz-Blue glacier regions. Distribution patterns reveal high fluctuations of the detritus source areas throughout the investigated core interval, variations which can be interpreted as the direct result of an evolving McMurdo Sound paleogeography during the late Early to Late Miocene. Consistently with sedimentological studies, gravel-fraction clast distribution patterns clearly testify that the Antarctic ice sheet experienced a dramatic contraction at ca. 17.35 ± 0.14 Ma (likely correlated to the onset of the climatic optimum), and in a gravel-fraction clasts show that the variations of paleoenvironmental drivers characterising this period were able to exert deep transformation of the Antarctic ice sheet and reveal the methodology to be a powerful tool for the reconstruction of paleo-glacial-flow direction and paleogeographic scenarios.

  20. Decadal-to-centennial-scale climate variability: Insights into the rise and fall of the Great Salt Lake

    Science.gov (United States)

    Mann, Michael E.; Lall, Upmanu; Saltzman, Barry

    1995-01-01

    We demonstrate connections between decadal and secular global climatic variations, and historical variations in the volume of the Great Salt Lake. The decadal variations correspond to a low-frequency shifting of storm tracks which influence winter precipitation and explain nearly 18% of the interannual and longer-term variance in the record of monthly volume change. The secular trend accounts for a more modest approximately 1.5% of the variance.

  1. Insights on the role of accurate state estimation in coupled model parameter estimation by a conceptual climate model study

    Science.gov (United States)

    Yu, Xiaolin; Zhang, Shaoqing; Lin, Xiaopei; Li, Mingkui

    2017-03-01

    The uncertainties in values of coupled model parameters are an important source of model bias that causes model climate drift. The values can be calibrated by a parameter estimation procedure that projects observational information onto model parameters. The signal-to-noise ratio of error covariance between the model state and the parameter being estimated directly determines whether the parameter estimation succeeds or not. With a conceptual climate model that couples the stochastic atmosphere and slow-varying ocean, this study examines the sensitivity of state-parameter covariance on the accuracy of estimated model states in different model components of a coupled system. Due to the interaction of multiple timescales, the fast-varying atmosphere with a chaotic nature is the major source of the inaccuracy of estimated state-parameter covariance. Thus, enhancing the estimation accuracy of atmospheric states is very important for the success of coupled model parameter estimation, especially for the parameters in the air-sea interaction processes. The impact of chaotic-to-periodic ratio in state variability on parameter estimation is also discussed. This simple model study provides a guideline when real observations are used to optimize model parameters in a coupled general circulation model for improving climate analysis and predictions.

  2. Molecular, ethno-spatial epidemiology of leprosy in China: novel insights for tracing leprosy in endemic and non endemic provinces.

    Science.gov (United States)

    Weng, Xiaoman; Xing, Yan; Liu, Jian; Wang, Yonghong; Ning, Yong; Li, Ming; Wu, Wenbin; Zhang, Lianhua; Li, Wei; Vander Heiden, Jason; Vissa, Varalakshmi

    2013-03-01

    Leprosy continues to be detected at near stable rates in China even with established control programs, necessitating new knowledge and alternative methods to interrupt transmission. A molecular epidemiology investigation of 190 patients was undertaken to define Mycobacterium leprae strain types and discern genetic relationships and clusters in endemic and non-endemic regions spanning seventeen provinces and two autonomous regions. The findings support multiple locus variable number of tandem repeat (VNTR) analysis as a useful tool in uncovering characteristic patterns across the multiethnic and divergent geographic landscape of China. Several scenarios of clustering of leprosy from township to provincial to regional levels were recognized, while recent occupational or remote migration showed geographical separation of certain strains. First, prior studies indicated that of the four major M. leprae subtypes defined by single nucleotide polymorphisms (SNPs), only type 3 was present in China, purportedly entering from Europe/West/Central Asia via the Silk Road. However, this study revealed VNTR linked strains that are of type 1 in Guangdong, Fujian and Guangxi in southern China. Second, a subset of VNTR distinguishable strains of type 3, co-exist in these provinces. Third, type 3 strains with rpoT VNTR allele of 4, detected in Japan and Korea were discovered in Jiangsu and Anhui in the east and in western Sichuan bordering Tibet. Fourth, considering the overall genetic diversity, strains of endemic counties of Qiubei, Yunnan; Xing Yi, Guizhou; and across Sichuan in southwest were related. However, closer inspection showed distinct local strains and clusters. Altogether, these insights, primarily derived from VNTR typing, reveal multiple and overlooked paths for spread of leprosy into, within and out of China and invoke attention to historic maritime routes in the South and East China Sea. More importantly, new concepts and approaches for prospective case finding and

  3. Mutant analysis in Arabidopsis provides insight into the molecular mode of action of the auxinic herbicide dicamba.

    Directory of Open Access Journals (Sweden)

    Cynthia Gleason

    Full Text Available Herbicides that mimic the natural auxin indole-3-acetic acid are widely used in weed control. One common auxin-like herbicide is dicamba, but despite its wide use, plant gene responses to dicamba have never been extensively studied. To further understand dicamba's mode of action, we utilized Arabidopsis auxin-insensitive mutants and compared their sensitivity to dicamba and the widely-studied auxinic herbicide 2,4-dichlorophenoxyacetic acid (2,4-D. The mutant axr4-2, which has disrupted auxin transport into cells, was resistant to 2,4-D but susceptible to dicamba. By comparing dicamba resistance in auxin signalling F-box receptor mutants (tir1-1, afb1, afb2, afb3, and afb5, only tir1-1 and afb5 were resistant to dicamba, and this resistance was additive in the double tir1-1/afb5 mutant. Interestingly, tir1-1 but not afb5 was resistant to 2,4-D. Whole genome analysis of dicamba-induced gene expression showed that 10 hours after application, dicamba stimulated many stress-responsive and signalling genes, including those involved in biosynthesis or signalling of auxin, ethylene, and abscisic acid (ABA, with TIR1 and AFB5 required for the dicamba-responsiveness of some genes. Research into dicamba-regulated gene expression and the selectivity of auxin receptors has provided molecular insight into dicamba-regulated signalling and could help in the development of novel herbicide resistance in crop plants.

  4. Histopathological and molecular insights into the ovicidal activities of two entomopathogenic fungi against two-spotted spider mite.

    Science.gov (United States)

    Zhang, Lei; Shi, Wei-Bing; Feng, Ming-Guang

    2014-03-01

    Entomopathogenic fungi can infect and kill spider mite eggs but their ovicidal activities are poorly understood. Here we gain histopathogenical and molecular insights into the ovicidal activities of Beauveria bassiana and Isaria fumosorosea against the two-spotted spider mite, Tetranychus urticae. Scanning electronic microscopy indicated successful adhesion and germination of fungal conidia on egg shell at 24h post-spray (HPS). Germ tubes of both fungi could penetrate into egg shell with penetration pegs at 48 HPS. Interestingly, the germ tubes of B. bassiana may elongate on egg surface to locate appropriate sites for penetration, acting as 'searching' hyphae. Aside from the normal penetration, the germ tubes of I. fumosorosea can be completely or partially embedded into egg shell for a distance of extension, forming shell humps. Light microscopy of ultrathin sections of infected eggs showed shrunken (affected) or disrupted embryos at 48-96 HPS despite little effect on egg cleavage at 24 HPS. However, distinguishable hyphal cells were hardly found inside the embryos lacking oxygen although fungal outgrowths were abundant on unhatched (killed) eggs. In PCR with specific probes, the 18S rDNA signals of B. bassiana (412 bp) and I. fumosorosea (454 bp) in the DNA extracts from surface-cleaned mite eggs increased at 0-96 HPS, confirming fungal colonization in the infected eggs. We consider that the colonization on shell surface and underside could rely upon extending hyphae for uptake of egg nutrition, resulting in embryo disruption. Our observations add knowledge to microbial control of spider mites.

  5. New molecular insights into modulation of platelet reactivity in aspirin-treated patients using a network-based approach.

    Science.gov (United States)

    Zufferey, Anne; Ibberson, Mark; Reny, Jean-Luc; Nolli, Séverine; Schvartz, Domitille; Docquier, Mylène; Xenarios, Ioannis; Sanchez, Jean-Charles; Fontana, Pierre

    2016-04-01

    Platelet reactivity (PR) is variable between individuals and modulates clinical outcome in cardiovascular (CV) patients treated with antiplatelet drugs. Although several data point to a genetic control of platelet reactivity, the genes contributing to the modulation of this phenotype are not clearly identified. Integration of data derived from high-throughput technologies may yield novel insights into the molecular mechanisms that govern platelet reactivity. The aim of this study is to identify candidate genes modulating platelet reactivity in aspirin-treated CV patients using an integrative network-based approach. Patients with extreme high (n = 6) or low PR (n = 6) were selected and data derived from quantitative proteomic of platelets and platelet sub-cellular fractions, as well as from transcriptomic analysis were integrated with a network biology approach. Two modules within the network containing 123 and 182 genes were identified. We then specifically assessed the level of miRNAs in these two groups of patients. Among the 12 miRNAs differentially expressed, 2 (miR-135a-5p and miR-204-5p) correlated with PR. The predicted targets of these miRNAs were mapped onto the network, allowing the identification of seven overlapping genes (THBS1, CDC42, CORO1C, SPTBN1, TPM3, GTPBP2, and MAPRE2), suggesting a synergistic effect of these two miRNAs on these predicted targets. Integration of several omics data sets allowed the identification of 2 candidate miRNAs and 7 candidate genes regulating platelet reactivity in aspirin-treated CV patients.

  6. Functional and structural insights revealed by molecular dynamics simulations of an essential RNA editing ligase in Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Rommie E Amaro

    Full Text Available RNA editing ligase 1 (TbREL1 is required for the survival of both the insect and bloodstream forms of Trypanosoma brucei, the parasite responsible for the devastating tropical disease African sleeping sickness. The type of RNA editing that TbREL1 is involved in is unique to the trypanosomes, and no close human homolog is known to exist. In addition, the high-resolution crystal structure revealed several unique features of the active site, making this enzyme a promising target for structure-based drug design. In this work, two 20 ns atomistic molecular dynamics (MD simulations are employed to investigate the dynamics of TbREL1, both with and without the ATP substrate present. The flexibility of the active site, dynamics of conserved residues and crystallized water molecules, and the interactions between TbREL1 and the ATP substrate are investigated and discussed in the context of TbREL1's function. Differences in local and global motion upon ATP binding suggest that two peripheral loops, unique to the trypanosomes, may be involved in interdomain signaling events. Notably, a significant structural rearrangement of the enzyme's active site occurs during the apo simulations, opening an additional cavity adjacent to the ATP binding site that could be exploited in the development of effective inhibitors directed against this protozoan parasite. Finally, ensemble averaged electrostatics calculations over the MD simulations reveal a novel putative RNA binding site, a discovery that has previously eluded scientists. Ultimately, we use the insights gained through the MD simulations to make several predictions and recommendations, which we anticipate will help direct future experimental studies and structure-based drug discovery efforts against this vital enzyme.

  7. A tale of two spartinas: Climatic, photobiological and isotopic insights on the fitness of non-indigenous versus native species

    Science.gov (United States)

    Duarte, B.; Baeta, A.; Rousseau-Gueutin, M.; Ainouche, M.; Marques, J. C.; Caçador, I.

    2015-12-01

    Salt marshes are facing a new threat: the invasion by non-indigenous species (NIS), Although its introduction time is not established yet, in 1999 Spartina versicolor was already identified as a NIS in the Mediterranean marshes, significantly spreading its area of colonization. Using the Mediterranean native Spartina maritima as a reference, the present research studied the ecophysiological fitness of this NIS in its new environment, as a tool to understand its potential invasiveness. It was found that Spartina versicolor had a stable photobiological pattern, with only minor fluctuations during an annual cycle, and lower efficiencies comparated to S. maritima. The NIS seems to be rather insensitive to the observed abiotic factors fluctuations (salinity and pH of the sediment), and thus contrasts with the native S. maritima, known to be salinity dependent with higher productivity values in higher salinity environments. Most of the differences observed between the photobiology of these species could be explained by their nitrogen nutrition (here evaluated by the δ15N stable isotope) and directly related with the Mediterranean climate. Enhanced by a higher N availability during winter, the primary production of S. maritima which lead to dilution of the foliar δ15N concentration in the newly formed biomass, similarly to what is observed along a rainfall gradient. On the other hand, S. versicolor showed an increased δ15N in its tissues along the annual rainfall gradient, probably due to a δ15N concentration effect during low biomass production periods (winter and autumn). Together with the photobiological traits, these isotopic data point out to a climatic misfit of S. versicolor to the Mediterranean climate compared to the native S. maritima. This appears to be the major constrain shaping the ecophysiological fitness of this NIS, its primary production and consequently, its spreading rate along the Mediterranean marshes.

  8. Significance of pre-Quaternary climate change for montane species diversity: insights from Asian salamanders (Salamandridae: Pachytriton).

    Science.gov (United States)

    Wu, Yunke; Wang, Yuezhao; Jiang, Ke; Hanken, James

    2013-01-01

    Despite extensive focus on the genetic legacy of Pleistocene glaciation, impacts of earlier climatic change on biodiversity are poorly understood. Because amphibians are highly sensitive to variations in precipitation and temperature, we use a genus of Chinese montane salamanders (Salamandridae: Pachytriton) to study paleoclimatic change in East Asia, which experienced intensification of its monsoon circulation in the late Miocene associated with subsequent Pliocene warming. Using both nuclear and mitochondrial DNA sequences, we reconstruct the species tree under a coalescent model and demonstrate that all major lineages originated before the Quaternary. Initial speciation within the genus occurred after the summer monsoon entered a stage of substantial intensification. Heavy summer precipitation established temporary water connectivity through overflows between adjacent stream systems, which may facilitate geographic range expansion by aquatic species such as Pachytriton. Species were formed in allopatry likely through vicariant isolation during or after range expansion. To evaluate the influence of Pliocene warming on these cold-adapted salamanders, we construct a novel temperature buffer-zone model, which suggests widespread physiological stress or even extinction during the warming period. A significant deceleration of species accumulation rate is consistent with Pliocene range contraction, which affected P. granulosus and P. archospotus the most because they lack large temperature buffer zones. In contrast, demographic growth occurred in species for which refugia persist. The buffer-zone model reveals the Huangshan Mountain as a potential climatic refugium, which is similar to that found for other East Asian organisms. Our approach can incorporate future climatic data to evaluate the potential impact of ongoing global warming on montane species (particularly amphibians) and to predict possible population declines.

  9. Molecular targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) within the zebrafish ovary: Insights into TCDD-induced endocrine disruption and reproductive toxicity

    OpenAIRE

    2007-01-01

    TCDD is a reproductive toxicant and endocrine disruptor, yet the mechanisms by which it causes these reproductive alterations are not fully understood. In order to provide additional insight into the molecular mechanisms that underlie TCDD’s reproductive toxicity, we assessed TCDD-induced transcriptional changes in the ovary as they relate to previously described impacts on serum estradiol concentrations and altered follicular development in zebrafish. In-silico computational approaches were ...

  10. The Pleistocene vermicular red earth in South China signaling the global climatic change: The molecular fossil record

    Institute of Scientific and Technical Information of China (English)

    XIE; Shucheng; (谢树成); YI; Yi; (易; 轶); LIU; Yuyan; (刘育燕); GU; Yansheng; (顾延生); MA; Zhenxing; (马振兴); LIN; Wenjiao; (林文姣); WANG; Xianyan; (王先彦); LIU; Gang; (刘; 刚); LIANG; Bin; (梁; 斌); ZHU; Zongmin; (朱宗敏)

    2003-01-01

    The trace molecular fossils identified in the Pleistocene vermicular red earth by using the gas chromatography-mass spectrometry (GC/MS) analysis include n-alkanes, n-alkanoic acids, n-alkanols and n-alkan-2-ones. The variations of the n-alkane parameters appear to bear significant climate information, in striking contrast to the oxygen-bearing molecules (n-alkanoic acids and n-alkanols) believed to be more easily reworked by post-depositional processes. Of importance in paleoclimate reconstruction are the ratios of C27/C31 n-alkane indicative of the replacement of woody plants by grassy vegetation, and C15-21/C22-33 n-alkane representative of the relative abundance between microorganisms and higher plants. The profile trends of the two n-alkane ratios are comparable to the marine oxygen isotope record among stages 4-20. These molecular fossil records implicate that the Pleistocene vermicular red earth widespread in South China was formed in coupling to the global climatic change and could be an important climate carrier.

  11. Translating Scientific Judgment, Technological Insight and Economic Theory Into Practical Policy Lessons: The Case of Climate Regulation in the United States

    Science.gov (United States)

    Mignone, B. K.

    2008-12-01

    Effective solutions to the climate change problem will require unprecedented cooperation across space, continuity across time and coordination between disciplines. One well-known methodology for synthesizing the lessons of physical science, energy engineering and economics is integrated assessment. Typically, integrated assessment models use scientific and technological relationships as physical constraints in a larger macroeconomic optimization that is designed to either balance the costs and benefits of climate change mitigation or find the least-cost path to an exogenously prescribed endpoint (e.g. atmospheric CO2 stabilization). The usefulness of these models depends to a large extent on the quality of the assumptions and the relevance of the outcome metrics chosen by the user. In this study, I show how a scientifically-based emissions reduction scenario can be combined with engineering-based assumptions about the energy system (e.g. estimates of the marginal cost premium of carbon-free technology) to yield insights about the price path of CO2 under a future regulatory regime. I then show how this outcome metric (carbon price) relates to key decisions about the design of a future cap-and-trade system and the way in which future carbon markets may be regulated.

  12. Climate Warming and Soil Carbon in Tropical Forests: Insights from an Elevation Gradient in the Peruvian Andes

    Science.gov (United States)

    Nottingham, Andrew T.; Whitaker, Jeanette; Turner, Benjamin L.; Salinas, Norma; Zimmermann, Michael; Malhi, Yadvinder; Meir, Patrick

    2015-01-01

    The temperature sensitivity of soil organic matter (SOM) decomposition in tropical forests will influence future climate. Studies of a 3.5-kilometer elevation gradient in the Peruvian Andes, including short-term translocation experiments and the examination of the long-term adaptation of biota to local thermal and edaphic conditions, have revealed several factors that may regulate this sensitivity. Collectively this work suggests that, in the absence of a moisture constraint, the temperature sensitivity of decomposition is regulated by the chemical composition of plant debris (litter) and both the physical and chemical composition of preexisting SOM: higher temperature sensitivities are found in litter or SOM that is more chemically complex and in SOM that is less occluded within aggregates. In addition, the temperature sensitivity of SOM in tropical montane forests may be larger than previously recognized because of the presence of “cold-adapted” and nitrogen-limited microbial decomposers and the possible future alterations in plant and microbial communities associated with warming. Studies along elevation transects, such as those reviewed here, can reveal factors that will regulate the temperature sensitivity of SOM. They can also complement and guide in situ soil-warming experiments, which will be needed to understand how this vulnerability to temperature may be mediated by altered plant productivity under future climatic change. PMID:26955086

  13. How will coral reef fish communities respond to climate-driven disturbances? Insight from landscape-scale perturbations.

    Science.gov (United States)

    Adam, Thomas C; Brooks, Andrew J; Holbrook, Sally J; Schmitt, Russell J; Washburn, Libe; Bernardi, Giacomo

    2014-09-01

    Global climate change is rapidly altering disturbance regimes in many ecosystems including coral reefs, yet the long-term impacts of these changes on ecosystem structure and function are difficult to predict. A major ecosystem service provided by coral reefs is the provisioning of physical habitat for other organisms, and consequently, many of the effects of climate change on coral reefs will be mediated by their impacts on habitat structure. Therefore, there is an urgent need to understand the independent and combined effects of coral mortality and loss of physical habitat on reef-associated biota. Here, we use a unique series of events affecting the coral reefs around the Pacific island of Moorea, French Polynesia to differentiate between the impacts of coral mortality and the degradation of physical habitat on the structure of reef fish communities. We found that, by removing large amounts of physical habitat, a tropical cyclone had larger impacts on reef fish communities than an outbreak of coral-eating sea stars that caused widespread coral mortality but left the physical structure intact. In addition, the impacts of declining structural complexity on reef fish assemblages accelerated as structure became increasingly rare. Structure provided by dead coral colonies can take up to decades to erode following coral mortality, and, consequently, our results suggest that predictions based on short-term studies are likely to grossly underestimate the long-term impacts of coral decline on reef fish communities.

  14. Response of lightning NOx emissions and ozone production to climate change: Insights from the Atmospheric Chemistry and Climate Model Intercomparison Project

    Science.gov (United States)

    Finney, D. L.; Doherty, R. M.; Wild, O.; Young, P. J.; Butler, A.

    2016-05-01

    Results from an ensemble of models are used to investigate the response of lightning nitrogen oxide emissions to climate change and the consequent impacts on ozone production. Most models generate lightning using a parameterization based on cloud top height. With this approach and a present-day global emission of 5 TgN, we estimate a linear response with respect to changes in global surface temperature of +0.44 ± 0.05 TgN K-1. However, two models using alternative approaches give +0.14 and -0.55 TgN K-1 suggesting that the simulated response is highly dependent on lightning parameterization. Lightning NOx is found to have an ozone production efficiency of 6.5 ± 4.7 times that of surface NOx sources. This wide range of efficiencies across models is partly due to the assumed vertical distribution of the lightning source and partly to the treatment of nonmethane volatile organic compound (NMVOC) chemistry. Careful consideration of the vertical distribution of emissions is needed, given its large influence on ozone production.

  15. Climatic Factors Drive Population Divergence and Demography: Insights Based on the Phylogeography of a Riparian Plant Species Endemic to the Hengduan Mountains and Adjacent Regions.

    Science.gov (United States)

    Wang, Zhi-Wei; Chen, Shao-Tian; Nie, Ze-Long; Zhang, Jian-Wen; Zhou, Zhuo; Deng, Tao; Sun, Hang

    2015-01-01

    Quaternary climatic factors have played a significant role in population divergence and demography. Here we investigated the phylogeography of Osteomeles schwerinae, a dominant riparian plant species of the hot/warm-dry river valleys of the Hengduan Mountains (HDM), Qinling Mountains (QLM) and Yunnan-Guizhou Plateau (YGP). Three chloroplast DNA (cpDNA) regions (trnD-trnT, psbD-trnT, petL-psbE), one single copy nuclear gene (glyceraldehyde 3-phosphate dehydrogenase; G3pdh), and climatic data during the Last Interglacial (LIG; c. 120-140 ka), Last Glacial Maximum (LGM; c. 21 ka), and Current (c. 1950-2000) periods were used in this study. Six cpDNA haplotypes and 15 nuclear DNA (nDNA) haplotypes were identified in the 40 populations of O. schwerinae. Spatial Analysis of Molecular Variance, median-joining networks, and Bayesian phylogenetic trees based on the cpDNA and nDNA datasets, all suggested population divergence between the QLM and HDM-YGP regions. Our climatic analysis identified significant heterogeneity of the climatic factors in the QLM and HDM-YGP regions during the aforementioned three periods. The divergence times based on cpDNA and nDNA haplotypes were estimated to be 466.4-159.4 ka and 315.8-160.3 ka, respectively, which coincide with the time of the weakening of the Asian monsoons in these regions. In addition, unimodal pairwise mismatch distribution curves, expansion times, and Ecological Niche Modeling suggested a history of population expansion (rather than contraction) during the last glaciation. Interestingly, the expansion times were found being well consistent with the intensification of the Asian monsoons during this period. We inferred that the divergence between the two main lineages is probably caused by disruption of more continuous distribution because of weakening of monsoons/less precipitation, whilst subsequent intensification of the Asian monsoons during the last glaciation facilitated the expansion of O. schwerinae populations.

  16. The relationships between temperature changes and reproductive investment in a Mediterranean goby: Insights for the assessment of climate change effects

    Science.gov (United States)

    Zucchetta, M.; Cipolato, G.; Pranovi, F.; Antonetti, P.; Torricelli, P.; Franzoi, P.; Malavasi, S.

    2012-04-01

    The relationships between changes in water temperature and the timing and level of reproductive investment were investigated in an estuarine fish, inhabiting the Venice lagoon: the grass goby Zosterisessor ophiocephalus. A time series of the mean monthly values of gonado-somatic index was coupled with thermal profiles of lagoon water temperatures over 14 years, from 1997 to 2010. Results showed that the reproductive investment was positively affected by water temperature changes, both in terms of monthly thermal anomalies and cumulative degree days. A predictive model was also developed to assess the temporal shift of reproductive peaks as a response to inter-annual thermal fluctuations. This model allowed the detection of deviations from the median level, indicating that during warmer years, the reproductive peak tended to occur earlier than during colder years. The model is therefore proposed as a tool to predict anticipated consequences of climate change on fish phenology in transitional waters, regarding recurrent biological phenomena, such as reproduction and recruitment.

  17. Contextual and interdependent causes of climate change adaptation barriers: Insights from water management institutions in Himachal Pradesh, India.

    Science.gov (United States)

    Azhoni, Adani; Holman, Ian; Jude, Simon

    2017-01-15

    Research on adaptation barriers is increasing as the need for climate change adaptation becomes evident. However, empirical studies regarding the emergence, causes and sustenance of adaptation barriers remain limited. This research identifies key contextual causes of adaptation barriers in water institutions in the mountainous Himalayan state of Himachal Pradesh in northern India. Semi-structured interviews were carried out with representatives from twenty-six key governmental, non-governmental, academic and research institutions in the State with responsibilities spanning domestic water supply, irrigation and hydropower generation, environmental monitoring and research. It identified low knowledge capacity and resources, policy implementation gaps, normative attitudes, and unavailability and inaccessibility of data and information compounded with weak interinstitutional networks as key adaptation barriers. Although these barriers are similar to those reported elsewhere, they have important locally-contextual root causes. For instance, inadequate resources result from fragmented resources allocation due to competing developmental priorities and the desire of the political leadership to please diverse electors, rather than climate scepticism. The identified individual barriers are found to be highly inter-dependent and closely intertwined which enables the identification of leverage points for interventions to maximise barrier removal. For instance, breaking down key barriers hindering accessibility to data and information, which are shaped by systemic bureaucracies and cultural attitudes, will involve attitudinal change through sensitisation to the importance of accurate and accessible data and information and the building trust between different actors, in addition to institutional structural changes through legislation and inter-institutional agreements. Approaching barriers as a system of contextually interconnected cultural, systemic, geographical and political

  18. Centennial-scale vegetation and climate changes in the Middle Atlas, Morocco: new insights from multi-proxy investigations at Lake Sidi Ali

    Science.gov (United States)

    Fletcher, William; Campbell, Jennifer; Joannin, Sebastien; Mischke, Steffen; Zielhofer, Christoph; de Batist, Marc; Mikdad, Abdes

    2016-04-01

    The karstic lakes of the Middle Atlas, Morocco, represent a valuable archive of environmental and climatic change for Northwest Africa. Here we present the results of centennial-scale palynological and charcoal analyses as part of a multiproxy palaeolimnological study of sediment cores from Lake Sidi Ali in the Middle Atlas, Morocco (33° 03 N, 05° 00 W; 2,080 m a.s.l.). Supported by absolute dating including 23 more than twenty AMS 14C dates on pollen concentrates, the record covers the entire Holocene and offers insights into vegetation and climate change at a regionally unprecedented centennial-scale. Pollen assemblages are dominated by steppic herbs, evergreen oaks (Quercus), junipers (Cupressaceae) and Atlantic cedar (Cedrus atlantica). A long-term evolution of the montane vegetation is recorded, reflecting progressive changes in the dominant arboreal taxa and leading to the full establishment of the emblematic cedar forests of the area during the mid-Holocene by 6000 cal BP. Orbital-scale changes in seasonality and growing season moisture availability linked to declining summer insolation are implicated, with a transition from (a) warm, dry summers associated with summer drought tolerant taxa especially evergreen Quercus, high algal productivity in the lake, and high background levels of microcharcoal reflecting distant fire activity during the early Holocene, to (b) cool, relatively humid summers with dominance of montane conifers, declining algal productivity in the lake, and episodic local fire activity during the mid- to late Holocene. Superimposed on the long-term environmental changes are recurrent centennial-scale fluctuations in vegetation composition, reflecting competitive dynamics between the major taxa, initially between steppic and arboreal elements, and later between the major tree taxa. Parallels with hydrological proxies including stable O and C isotopes suggest common responses to climatic drivers (fluctuations in moisture sources and

  19. Stratigraphic reconstruction of two debris avalanche deposits at Colima Volcano (Mexico): Insights into pre-failure conditions and climate influence

    Science.gov (United States)

    Roverato, M.; Capra, L.; Sulpizio, R.; Norini, G.

    2011-10-01

    Throughout its history, Colima Volcano has experienced numerous partial edifice collapses with associated emplacement of debris avalanche deposits of contrasting volume, morphology and texture. A detailed stratigraphic study in the south-eastern sector of the volcano allowed the recognition of two debris avalanche deposits, named San Marcos (> 28,000 cal yr BP, V = ~ 1.3 km 3) and Tonila (15,000-16,000 cal yr BP, V = ~ 1 km 3 ). This work sheds light on the pre-failure conditions of the volcano based primarily on a detailed textural study of debris avalanche deposits and their associated pyroclastic and volcaniclastic successions. Furthermore, we show how the climate at the time of the Tonila collapse influenced the failure mechanisms. The > 28,000 cal yr BP San Marcos collapse was promoted by edifice steep flanks and ongoing tectonic and volcanotectonic deformation, and was followed by a magmatic eruption that emplaced pyroclastic flow deposits. In contrast, the Tonila failure occurred just after the Last Glacial Maximum (22,000-18,000 cal BP) and, in addition to the typical debris avalanche textural characteristics (angular to sub-angular clasts, coarse matrix, jigsaw fit) it shows a hybrid facies characterized by debris avalanche blocks embedded in a finer, homogenous and partially cemented matrix, a texture more characteristic of debris flow deposits. The Tonila debris avalanche is directly overlain by a 7-m thick hydromagmatic pyroclastic succession. Massive debris flow deposits, often more than 10 m thick and containing large amounts of tree trunk logs, represent the top unit in the succession. Fluvial deposits also occur throughout all successions; these represent periods of highly localized stream reworking. All these lines of evidence point to the presence of water in the edifice prior to the Tonila failure, suggesting it may have been a weakening factor. The Tonila failure appears to represent an anomalous event related to the particular climatic

  20. How will precipitation change in extratropical cyclones as the planet warms? Insights from a large initial condition climate model ensemble

    Science.gov (United States)

    Yettella, Vineel; Kay, Jennifer E.

    2016-10-01

    The extratropical precipitation response to global warming is investigated within a 30-member initial condition climate model ensemble. As in observations, modeled cyclonic precipitation contributes a large fraction of extratropical precipitation, especially over the ocean and in the winter hemisphere. When compared to present day, the ensemble projects increased cyclone-associated precipitation under twenty-first century business-as-usual greenhouse gas forcing. While the cyclone-associated precipitation response is weaker in the near-future (2016-2035) than in the far-future (2081-2100), both future periods have similar patterns of response. Though cyclone frequency changes are important regionally, most of the increased cyclone-associated precipitation results from increased within-cyclone precipitation. Consistent with this result, cyclone-centric composites show statistically significant precipitation increases in all cyclone sectors. Decomposition into thermodynamic (mean cyclone water vapor path) and dynamic (mean cyclone wind speed) contributions shows that thermodynamics explains 92 and 95% of the near-future and far-future within-cyclone precipitation increases respectively. Surprisingly, the influence of dynamics on future cyclonic precipitation changes is negligible. In addition, the forced response exceeds internal variability in both future time periods. Overall, this work suggests that future cyclonic precipitation changes will result primarily from increased moisture availability in a warmer world, with secondary contributions from changes in cyclone frequency and cyclone dynamics.

  1. Insights into Ocean Acidification During the Middle Eocene Climatic Optimum from Boron Isotopes at Southern Ocean Site 738

    Science.gov (United States)

    Moebius, I.; Hoenisch, B.; Friedrich, O.

    2015-12-01

    The Middle Eocene Climatic Optimum (MECO) is a ~650-kyr interval of global warming, with a brief ~50 ky long peak warming interval, and an abrupt termination. Deep sea and surface ocean temperature evolution across this interval are fairly well constrained, but thus far we have little understanding of the mechanisms responsible for the gradual warming and rapid recovery. Carbonate mass accumulation rates suggest a shoaling of the carbonate compensation depth, and studies on alkenones indicate increasing atmospheric CO2 levels during the MECO. This suggests an increase in surface ocean CO2, and consequently ocean acidification. However, the severity and timing of the proposed ocean acidification with respect to the onset, peak warming and the termination are currently not well resolved. The boron isotopic composition (δ11B) recorded in planktic foraminifer shells offers an opportunity to infer oceanic pH across this interval. We are working on a boron isotope reconstruction from Southern Ocean IODP site 738 and South Atlantic IODP site 1263, covering 42.0 to 38.5 Ma. These sites are characterized by good carbonate preservation and well-defined age models have been established. Additionally, ecology, nutrient content and bottom-water oxygenation have been shown to change significantly across the event towards a more eutrophic, periodically oxygen-depleted environment supporting different biological communities. We selected the planktic foraminifera species Acarinina spinuloinflata for this study because it is symbiont-bearing, suggesting a near-surface habitat and little vertical migration in the water column, and because of its abundance in the samples. δ11B data will be translated to surface ocean pH and atmospheric pCO2 will be approximated to refine knowledge about the carbon cycle during this time. Parallel analysis of two core sites will help to evaluate the tenacity of the data.

  2. Using next-generation sequencing for molecular reconstruction of past Arctic vegetation and climate

    DEFF Research Database (Denmark)

    Sønstebø, J H; Gielly, L; Brysting, A K

    2010-01-01

    Palaeoenvironments and former climates are typically inferred from pollen and macrofossil records. This approach is time-consuming and suffers from low taxonomic resolution and biased taxon sampling. Here, we test an alternative DNA-based approach utilizing the P6 loop in the chloroplast trnL (UA...

  3. Environment and climate of the last 51,000 years - new insights from the Potrok Aike maar lake Sediment Archive Drilling prOject (PASADO)

    Science.gov (United States)

    Zolitschka, B.; Anselmetti, F.; Ariztegui, D.; Corbella, H.; Francus, P.; Lücke, A.; Maidana, N. I.; Ohlendorf, C.; Schäbitz, F.; Wastegård, S.

    2013-07-01

    In this introductory paper we summarize the history and achievements of the Potrok Aike maar lake Sediment Archive Drilling prOject (PASADO), an interdisciplinary project embedded in the International Continental Scientific Drilling Program (ICDP). The stringent multiproxy approach adopted in this research combined with radiocarbon and luminescence dating provided the opportunity to synthesize a large body of hydrologically relevant data from Laguna Potrok Aike (southern Patagonia, Argentina). At this site, lake level was high from 51 ka until the early Holocene when the Southern Hemisphere Westerlies (SHW) were located further to the north. At 9.3 ka cal. BP the SHW moved southward and over the latitude of the study area (52°S) causing a pronounced negative water balance with a lake level decrease of more than 50 m. Two millennia later, the SHW diminished in intensity and lake level rose to a subsequent maximum during the Little Ice Age. Since the 20th century, a strengthening of the SHW increased the evaporative stress resulting in a more negative water balance. A comparison of our data with other hydrological fluctuations at a regional scale in south-eastern Patagonia, provides new insights and also calls for better chronologies and high-resolution records of climate variability.

  4. Molecular-level Insight into Unusual Low Pressure CO2 Affinity in Pillared Metal-Organic Frameworks

    NARCIS (Netherlands)

    Burtch, N.C.; Jasuja, H.; Dubbeldam, D.; Walton, K.S.

    2013-01-01

    Fundamental insight into how low pressure adsorption properties are affected by chemical functionalization is critical to the development of next-generation porous materials for postcombustion CO2 capture. In this work, we present a systematic approach to understanding low pressure CO2 affinity in i

  5. Climate adaption and post-fire restoration of a foundational perennial in cold desert: Insights from intraspecific variation in response to weather

    Science.gov (United States)

    Brabec, Martha M.; Germino, Matthew; Richardson, Bryce A.

    2017-01-01

    responses among subspecies/cytotypes were not as strong and did not relate to survival patterns. 5.Synthesis and applications. Low temperature responses are a key axis defining climate adaptation in young sagebrush seedlings and vary more with cytotype than with subspecies, which contrasts with the traditional emphases on (i) water limitations to explain establishment in these deserts, and (ii) subspecies in selecting restoration seedings. These important and novel insights on climate adaptation are critical for seed selection and parameterizing seed transfer zones, and were made possible by incorporating weather data with survival statistics. The survival/weather statistics used here could be applied to any restoration planting or seeding to help elucidate factors contributing to success and enable adaptive management.

  6. Molecular modeling and competition binding study of Br-noscapine and colchicine provides insight into noscapinoid-tubulin binding site

    OpenAIRE

    Naik, Pradeep K.; Santoshi, Seneha; Rai, Ankit; Joshi, Harish C.

    2011-01-01

    We have previously discovered the tubulin-binding anti-cancer properties of noscapine and its derivatives (noscapinoids). Here, we present three lines of evidence that noscapinoids bind at or near the well studied colchicine binding site of tubulin: 1) In silico molecular docking studies of Br-noscapine and noscapine yield highest docking score with the well characterised colchicine-binding site from the co-crystal structure; 2) the molecular mechanics-generalized Born/surface area (MM-GB/SA)...

  7. Calorimetry is not color-blind.Molecular insights on association processes in surfactant-polymer mixtures derived from calorimetric experiments

    Institute of Scientific and Technical Information of China (English)

    LOH Watson; BRINATTI Cesar

    2012-01-01

    This comment will review and discuss recent results obtained with the use of calorimetry in assessing molecular information from complex phenomena such as association in surfactant/polymer mixtures.These examples were selected to support the view that it is possible to ally the great sensitivity of modern calorimeters with carefully planned experiments and,sometimes,ancillary techniques in order to derive detailed information on molecular interactions.

  8. Insight into the interactive residues between two domains of human somatic Angiotensin-converting enzyme and Angiotensin II by MM-PBSA calculation and steered molecular dynamics simulation.

    Science.gov (United States)

    Guan, Shan-shan; Han, Wei-wei; Zhang, Hao; Wang, Song; Shan, Ya-ming

    2016-01-01

    Angiotensin-converting enzyme (ACE), a membrane-bound zinc metallopeptidase, catalyzes the formation of Angiotensin-II (AngII) and the deactivation of bradykinin in the renin-angiotensin-aldosterone and kallikrein-kinin systems. As a hydrolysis product of ACE, AngII is regarded as an inhibitor and displays stronger competitive inhibition in the C-domain than the N-domain of ACE. However, the AngII binding differences between the two domains and the mechanisms behind AngII dissociation from the C-domain are rarely explored. In this work, molecular docking, Molecular Mechanics/Poisson-Boltzmann Surface Area calculation, and steered molecular dynamics (SMD) are applied to explore the structures and interactions in the binding or unbinding of AngII with the two domains of human somatic ACE. Calculated free energy values suggest that the C-domain-AngII complex is more stable than the N-domain-AngII complex, consistent with available experimental data. SMD simulation results imply that electrostatic interaction is dominant in the dissociation of AngII from the C-domain. Moreover, Gln106, Asp121, Glu123, and Tyr213 may be the key residues in the unbinding pathway of AngII. The simulation results in our work provide insights into the interactions between the two domains of ACE and its natural peptide inhibitor AngII at a molecular level. Moreover, the results provide theoretical clues for the design of new inhibitors.

  9. Molecular characterization and evolutionary insights into potential sex-determination genes in the western orchard predatory mite Metaseiulus occidentalis (Chelicerata: Arachnida: Acari: Phytoseiidae).

    Science.gov (United States)

    Pomerantz, Aaron F; Hoy, Marjorie A; Kawahara, Akito Y

    2015-01-01

    Little is known about the process of sex determination at the molecular level in species belonging to the subclass Acari, a taxon of arachnids that contains mites and ticks. The recent sequencing of the transcriptome and genome of the western orchard predatory mite Metaseiulus occidentalis allows investigation of molecular mechanisms underlying the biological processes of sex determination in this predator of phytophagous pest mites. We identified four doublesex-and-mab-3-related transcription factor (dmrt) genes, one transformer-2 gene, one intersex gene, and two fruitless-like genes in M. occidentalis. Phylogenetic analyses were conducted to infer the molecular relationships to sequences from species of arthropods, including insects, crustaceans, acarines, and a centipede, using available genomic data. Comparative analyses revealed high sequence identity within functional domains and confirmed that the architecture for certain sex-determination genes is conserved in arthropods. This study provides a framework for identifying potential target genes that could be implicated in the process of sex determination in M. occidentalis and provides insight into the conservation and change of the molecular components of sex determination in arthropods.

  10. Entanglements in P3HT and their influence on thin-film mechanical properties: Insights from molecular dynamics simulations

    KAUST Repository

    Tummala, Naga Rajesh

    2015-04-01

    Due to their inherent mechanical flexibility and stretchability, organic-based electronic devices have garnered a great deal of academic and industrial interest. Here, molecular-dynamics simulations are used to examine the molecular-scale details that govern the relationships among molecular weight, chain entanglement, persistence length, and the elastic characteristics of the widely studied π-conjugated polymer poly-(3-hexyl thiophene), P3HT. Oligomers containing at least 50 monomer units are required in the simulations to observe elastic behavior in P3HT, while much longer chains are required to ensure description of appropriate levels of entanglement: only when the molecular weight is greater than 50 kDa, that is, oligomers with approximately 400 monomer units, is truly entangled behavior observed. Interestingly, results from primitive path analysis of amorphous P3HT matches well with the observed onsets of inter-chain excitonic coherence with increased molecular weight. The simulations also indicate that the P3HT modulus saturates at 1.6 GPa for chain lengths of 50–100 monomers, a result that compares well with experimental results. This work highlights the care that needs to be taken to accurately model P3HT morphologies in relation to experimental measurements. © 2015 The Authors. Journal of Polymer Science Part B: Polymer Physics Published by Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015

  11. New insights into the molecular mechanism of E-cadherin-mediated cell adhesion by free energy calculations

    DEFF Research Database (Denmark)

    Doro, Fabio; Saladino, Giorgio; Belvisi, Laura

    2015-01-01

    swapping to mediate cell adhesion. However, despite its importance, the molecular mechanism of domain swapping is still debated. Here, we study the conformational changes that lead to activation and dimerization via domain swapping of E-cadherin. Using state-of-the-art enhanced sampling atomistic...

  12. Predictive molecular markers for EGFR-TKI in non-small cell lung cancer patients: new insights and critical aspects

    Directory of Open Access Journals (Sweden)

    Paola Ulivi

    2010-07-01

    Full Text Available In recent years, a number of novel agents have been investigated that target specific molecular pathways in non-small cell lung cancer (NSCLC. A great deal of effort has been focused on identifying specific markers that predict treatment response, given that a tailored approach would maximize both the therapeutic index and the cost-effectiveness. The epidermal growth factor receptor (EGFR pathway has emerged as a key regulator of cancer cell proliferation and invasion, and several specific EGFR inhibitors have been examined. Gefitinib and erlotinib are selective EGFR tyrosine kinase inhibitors (EGFR-TKIs, demonstrating good results in selected cases both in terms of objective response rate and of overall survival. At present, EGFR gene mutations are the best positive predictive factors for TKI therapy, and a number of other potential biomarkers are being investigated as additional positive or negative predictors of response. The correct selection of patients that could benefit from these innovative therapies, based on an accurate molecular characterization, is mandatory to provide the best clinical management. Currently, the main factor limiting the characterization of metastatic NSCLC patients is the small quantity of tumor cells available for molecular analysis. In this paper we provide an overview of the most important molecular predictive markers for EGFR-TKIs therapy in NSCLC patients, and focus attention on biological samples suitable for analysis and alternative sampling approaches such as plasma- or serum-derived DNA.

  13. New Insights into the Molecular Distinction of Dysplastic Nevi and Common Melanocytic Nevi-Highlighting the Keratinocyte-Melanocyte Relationship.

    Science.gov (United States)

    Eliades, Philip; Tsao, Hensin

    2016-10-01

    Mitsui et al. approach the problem of differentiating dysplastic nevi from common melanocytic nevi through a molecular lens. Whereas most of the literature on this topic shines the spotlight toward melanocytes, the focus of this paper is shifted to the tumor microenvironment. Using microarrays, reverse transcriptase-PCR, and immunohistochemistry, their results emphasize the role of keratinocyte dysplasia within dysplastic nevi.

  14. Quaternary association in -prism I fold plant lectins: Insights from X-ray crystallography, modelling and molecular dynamics

    Indian Academy of Sciences (India)

    Alok Sharma; Mamannamana Vijayan

    2011-12-01

    Dimeric banana lectin and calsepa, tetrameric artocarpin and octameric heltuba are mannose-specific -prism I fold lectins of nearly the same tertiary structure. MD simulations on individual subunits and the oligomers provide insights into the changes in the structure brought about in the protomers on oligomerization, including swapping of the N-terminal stretch in one instance. The regions that undergo changes also tend to exhibit dynamic flexibility during MD simulations. The internal symmetries of individual oligomers are substantially retained during the calculations. Energy minimization and simulations were also carried out on models using all possible oligomers by employing the four different protomers. The unique dimerization pattern observed in calsepa could be traced to unique substitutions in a peptide stretch involved in dimerization. The impossibility of a specific mode of oligomerization involving a particular protomer is often expressed in terms of unacceptable steric contacts or dissociation of the oligomer during simulations. The calculations also led to a rationale for the observation of a heltuba tetramer in solution although the lectin exists as an octamer in the crystal, in addition to providing insights into relations among evolution, oligomerization and ligand binding.

  15. Tailored novolak resins for advanced photoresists by a two-step procedure: new insight into the molecular structure is achieved by coupling GPC and MALDI-TOF-MS

    Science.gov (United States)

    Reuther, Freimut; Krueger, Ralph-Peter; Schulz, Guenter; Baehr, Guenther; Westerwelle, Ulrich; Gruetzner, Gabi

    2000-06-01

    Synthesis and structure of novolaks continue to be investigated due to their significant influence on the performance of photoresists. Previously a two-step procedure was reported which enables the manufacturer to vary the monomer composition and order in novolak molecules in a wide range which then allows for the tailoring of the resin properties. Recent reinvestigation of the molecular structure of these novolaks applying gel permeation chromatography and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry has given very interesting new insight into the molecular structure of the two-step synthesis novolaks. Coupling of the two analytical methods provides a new powerful tool to get detailed information on the molecular architecture which cannot be deduced by other methods. Three species of novolak chains have been found. This analytical approach can generally be applied to explore the structure of novolaks made of monomers differing in their molar masses. Using the two- step novolaks high resolution positive and negative tone photoresists for MEMS applications and lift-off processes, respectively, with high alkaline and etch resistance can be produced.

  16. Permafrost Meta-Omics and Climate Change

    Science.gov (United States)

    Mackelprang, Rachel; Saleska, Scott R.; Jacobsen, Carsten Suhr; Jansson, Janet K.; Taş, Neslihan

    2016-06-01

    Permanently frozen soil, or permafrost, covers a large portion of the Earth's terrestrial surface and represents a unique environment for cold-adapted microorganisms. As permafrost thaws, previously protected organic matter becomes available for microbial degradation. Microbes that decompose soil carbon produce carbon dioxide and other greenhouse gases, contributing substantially to climate change. Next-generation sequencing and other -omics technologies offer opportunities to discover the mechanisms by which microbial communities regulate the loss of carbon and the emission of greenhouse gases from thawing permafrost regions. Analysis of nucleic acids and proteins taken directly from permafrost-associated soils has provided new insights into microbial communities and their functions in Arctic environments that are increasingly impacted by climate change. In this article we review current information from various molecular -omics studies on permafrost microbial ecology and explore the relevance of these insights to our current understanding of the dynamics of permafrost loss due to climate change.

  17. Surface grafted chitosan gels. Part I. Molecular insight into the formation of chitosan and poly(acrylic acid) multilayers

    DEFF Research Database (Denmark)

    Liu, Chao; Thormann, Esben; Claesson, Per M.

    2014-01-01

    Composite polyelectrolyte multilayers of chitosan and low molecular weight poly(acrylic acid) (PAA) have been assembled by sequential adsorption as a first step toward building a surface anchored chitosan gel. Silane chemistry was used to graft the first chitosan layer to prevent film detachment...... and decomposition. The assembly process is characterized by nonlinear growth behavior, with different adsorption kinetics for chitosan and PAA. In situ analysis of the multilayer by means of surface sensitive total internal reflection Raman (TIRR) spectroscopy, combined with target factor analysis of the spectra...... molecular weight chitosan shows a similar behavior, although to a much lower extent. Our data demonstrate that the charged monomeric units of chitosan are mainly compensated by carboxylate ions from PAA. Furthermore, the morphology and mechanical properties of the multilayers were investigated in situ using...

  18. Molecular methods for the detection of human papillomavirus infection: new insights into their role in diagnostics and epidemiological surveillance

    Directory of Open Access Journals (Sweden)

    Andrea Piana

    2009-06-01

    Full Text Available Human papillomaviruses (HPVs comprise more than 180 genotypes. HPV infection is mainly diagnosed by molecular methods. The aim of our study was to review the main molecular methods used to diagnose HPV infection, underscoring their characteristics. Several methods have been developed for molecular diagnosis of Papilloma infection, such as those based on PCR technique. Another commercial non-PCR based diagnostic method is Hybrid Capture test; it is the only commercially available HPV DNA detection test approved by the FDA. Several Authors have suggested that viral load and E6/E7 transcripts could be used as surrogate markers of persistent HPV infection, being more specific predictors of progressive disease than the simple presence of HPV DNA. Validating clinical sensitivity and specificity of each technique and improving the interpretation of the results are essential; consequently, there is a clear need for well characterized international quality control panels to compare the various diagnostic methods. HPV DNA testing could be useful both as a primary screening test, alone or in combination with a Pap smear, for the early detection of cervical cancer precursors, and as triage test to select women with minor cytological abnormalities who will need further follow-up and to predict possible treatment failure in women with diagnosed high-grade intraepithelial lesions who have undergone excisional therapy. In the next future surveillance for HPV infections, based on these molecular methods, could represent an important step for the development of primary and secondary prophylactic interventions, such as new vaccines targeted to genotypes who might replace those previously prevalent.

  19. Molecular Radiocarbon Dating of Tropical Lake Sediments: Insights into the Chronology of Leaf Wax Stable Isotope Records

    Science.gov (United States)

    Douglas, P. M.; Pagani, M.; Eglinton, T. I.; Brenner, M.; Curtis, J. H.; Hodell, D. A.

    2010-12-01

    Leaf wax δD and δ13C measurements in marine and lacustrine sediment cores are promising proxies for past climatic and environmental change. However, a number of studies of marine sediments indicate centennial to millennial scale offsets between the radiocarbon ages of leaf waxes and the age of surrounding sediments due to long-term storage of these lipids in soils. These offsets present a complication for the interpretation of leaf wax stable isotope records that has not been thoroughly addressed. We present leaf wax δD, δ13C and Δ14C values for a sediment core from Lake Chichancanab in southeastern Mexico. This lake was previously studied using mineralogical (gypsum) and carbonate isotopic (δ18O) climate proxies, which indicated a sequence of severe droughts from 750 to 1000 AD, coincident with the collapse of the Classic Maya civilization. A suite of leaf wax δD values was plotted against the original sediment core chronology, which was developed using radiocarbon dates on terrestrial macrofossils. The leaf wax results also indicated major hydrological variability over the past 3000 years, but were not temporally coherent with the other climate proxy records. Leaf wax radiocarbon ages are 400 to 1200 years older than terrestrial macrofossil radiocarbon ages from the same depths, suggesting that leaf waxes are retained in the watershed for extended periods prior to deposition in the lake. We fit a 2nd-order polynomial equation to the depth profile of leaf wax radiocarbon ages (r2 =0.99) and refit the leaf wax δD profile to this “leaf wax age model”. This approach yielded much greater coherence with mineralogical and carbonate isotopic proxy records, including evidence for a period of severe drought (35‰ D-enrichment) from 750 to 1000 A.D. Our results indicate that long-term storage of leaf waxes in drainage basin soils can lead to temporal inaccuracies in leaf wax stable isotope records. These inaccuracies, however, can be corrected using a

  20. New insights into heat induced structural changes of pectin methylesterase on fluorescence spectroscopy and molecular modeling basis

    Science.gov (United States)

    Nistor, Oana Viorela; Stănciuc, Nicoleta; Aprodu, Iuliana; Botez, Elisabeta

    2014-07-01

    Heat-induced structural changes of Aspergillus oryzae pectin methylesterase (PME) were studied by means of fluorescence spectroscopy and molecular modeling, whereas the functional enzyme stability was monitored by inactivation studies. The fluorescence spectroscopy experiments were performed at two pH value (4.5 and 7.0). At both pH values, the phase diagrams were linear, indicating the presence of two molecular species induced by thermal treatment. A red shift of 7 nm was observed at neutral pH by increasing temperature up to 60 °C, followed by a blue shift of 4 nm at 70 °C, suggesting significant conformational rearrangements. The quenching experiments using acrylamide and iodide demonstrate a more flexible conformation of enzyme with increasing temperature, especially at neutral pH. The experimental results were complemented with atomic level observations on PME model behavior after performing molecular dynamics simulations at different temperatures. The inactivation kinetics of PME in buffer solutions was fitted using a first-order kinetics model, resulting in activation energy of 241.4 ± 7.51 kJ mol-1.

  1. Inactivation of TEM-1 by avibactam (NXL-104): insights from quantum mechanics/molecular mechanics metadynamics simulations.

    Science.gov (United States)

    Sgrignani, Jacopo; Grazioso, Giovanni; De Amici, Marco; Colombo, Giorgio

    2014-08-12

    The fast and constant development of drug-resistant bacteria represents a serious medical emergence. To overcome this problem, the development of drugs with new structures and modes of action is urgently needed. In this context, avibactam represents a promising, innovative inhibitor of beta-lactamases with a novel molecular structure compared to previously developed inhibitors, showing a promising inhibitory activity toward a significant number of beta-lactamase enzymes. In this work, we studied, at the atomistic level, the mechanisms of formation of the covalent complex between avibactam and TEM-1, an experimentally well-characterized class A beta-lactamase, using classical and quantum mechanics/molecular mechanics (QM/MM) simulations combined with metadynamics. Our simulations provide a detailed structural and energetic picture of the molecular steps leading to the formation of the avibactam/TEM-1 covalent adduct. In particular, they support a mechanism in which the rate-determining step is the water-assisted Glu166 deprotonation by Ser70. In this mechanistic framework, the predicted activation energy is in good agreement with experimental kinetic measurements. Additionally, our simulations highlight the important role of Lys73 in assisting the Ser70 and Ser130 deprotonations. While based on the specific case of the avibactam/TEM-1, the simple protocol we present here can be immediately extended and applied to the study of covalent complex formation in different enzyme-inhibitor pairs.

  2. Predicting ecological regime shift under climate change:New modelling techniques and potential of molecular-based approaches

    Institute of Scientific and Technical Information of China (English)

    Richard STAFFORD; V.Anne SMITH; Dirk HUSMEIER; Thomas GRIMA; Barbara-ann GUINN

    2013-01-01

    Ecological regime shift is the rapid transition from one stable community structure to another,often ecologically inferior,stable community.Such regime shifts are especially common in shallow marine communities,such as the transition of kelp forests to algal turfs that harbour far lower biodiversity.Stable regimes in communities are a result of balanced interactions between species,and predicting new regimes therefore requires an evaluation of new species interactions,as well as the resilience of the ‘stable' position.While computational optimisation techniques can predict new potential regimes,predicting the most likely community state of the various options produced is currently educated guess work.In this study we integrate a stable regime optimisation approach with a Bayesian network used to infer prior knowledge of the likely stress of climate change (or,in practice,any other disturbance) on each component species of a representative rocky shore community model.Combining the results,by calculating the product of the match between resilient computational predictions and the posterior probabilities of the Bayesian network,gives a refined set of model predictors,and demonstrates the use of the process in determining community changes,as might occur through processes such as climate change.To inform Bayesian priors,we conduct a review of molecular approaches applied to the analysis of the transcriptome of rocky shore organisms,and show how such an approach could be linked to measureable stress variables in the field.Hence species-specific microarrays could be designed as biomarkers of in situ stress,and used to inform predictive modelling approaches such as those described here.

  3. Predicting ecological regime shift under climate change: New modelling techniques and potential of molecular-based approaches

    Directory of Open Access Journals (Sweden)

    Richard STAFFORD, V. Anne SMITH, Dirk HUSMEIER, Thomas GRIMA, Barbara-ann GUINN

    2013-06-01

    Full Text Available Ecological regime shift is the rapid transition from one stable community structure to another, often ecologically inferior, stable community. Such regime shifts are especially common in shallow marine communities, such as the transition of kelp forests to algal turfs that harbour far lower biodiversity. Stable regimes in communities are a result of balanced interactions between species, and predicting new regimes therefore requires an evaluation of new species interactions, as well as the resilience of the ‘stable’ position. While computational optimisation techniques can predict new potential regimes, predicting the most likely community state of the various options produced is currently educated guess work. In this study we integrate a stable regime optimisation approach with a Bayesian network used to infer prior knowledge of the likely stress of climate change (or, in practice, any other disturbance on each component species of a representative rocky shore community model. Combining the results, by calculating the product of the match between resilient computational predictions and the posterior probabilities of the Bayesian network, gives a refined set of model predictors, and demonstrates the use of the process in determining community changes, as might occur through processes such as climate change. To inform Bayesian priors, we conduct a review of molecular approaches applied to the analysis of the transcriptome of rocky shore organisms, and show how such an approach could be linked to measureable stress variables in the field. Hence species-specific microarrays could be designed as biomarkers of in situ stress, and used to inform predictive modelling approaches such as those described here [Current Zoology 59 (3: 403–417, 2013].

  4. The role of Phe82 and Phe351 in auxin-induced substrate perception by TIR1 ubiquitin ligase: a novel insight from molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Ge-Fei Hao

    Full Text Available It is well known that Auxin plays a key role in controlling many aspects of plant growth and development. Crystal structures of Transport inhibitor response 1 (TIR1, a true receptor of auxin, were very recently determined for TIR1 alone and in complexes with auxin and different synthetic analogues and an Auxin/Indole-3-Acetic Acid (Aux/IAA substrate peptide. However, the dynamic conformational changes of the key residues of TIR1 that take place during the auxin and substrate perception by TIR1 and the detailed mechanism of these changes are still unclear. In the present study, various computational techniques were integrated to uncover the detailed molecular mechanism of the auxin and Aux/IAA perception process; these simulations included molecular dynamics (MD simulations on complexes and the free enzyme, the molecular mechanics Poisson Boltzmann surface area (MM-PBSA calculations, normal mode analysis, and hydrogen bond energy (HBE calculations. The computational simulation results provided a reasonable explanation for the structure-activity relationships of auxin and its synthetic analogues in view of energy. In addition, a more detailed model for auxin and Aux/IAA perception was also proposed, indicating that Phe82 and Phe351 played a pivotal role in Aux/IAA perception. Upon auxin binding, Phe82 underwent conformational changes to accommodate the subsequent binding of Aux/IAA. As a result, auxin enhances the TIR1-Aux/IAA interactions by acting as a "molecular glue". Besides, Phe351 acts as a "fastener" to further improve the substrate binding. The structural and mechanistic insights obtained from the present study will provide valuable clues for the future design of promising auxin analogues.

  5. Environmental effects on molecular and phenotypic variation in populations of Eruca sativa across a steep climatic gradient.

    Science.gov (United States)

    Westberg, Erik; Ohali, Shachar; Shevelevich, Anatoly; Fine, Pinchas; Barazani, Oz

    2013-08-01

    climatic gradient. In addition to molecular marker data, we made use of phenotypic evaluation from common garden experiments, and a broad GIS based environmental data with edaphic information gathered in the field. This study, among others, lead to the identification of an outlier locus with an association to trichome formation and herbivore defense, and its ecological adaptive value is discussed.

  6. Molecular adaptation in flowering and symbiotic recognition pathways: insights from patterns of polymorphism in the legume Medicago truncatula

    Directory of Open Access Journals (Sweden)

    Ronfort Joëlle

    2011-08-01

    Full Text Available Abstract Background We studied patterns of molecular adaptation in the wild Mediterranean legume Medicago truncatula. We focused on two phenotypic traits that are not functionally linked: flowering time and perception of symbiotic microbes. Phenology is an important fitness component, especially for annual plants, and many instances of molecular adaptation have been reported for genes involved in flowering pathways. While perception of symbiotic microbes is also integral to adaptation in many plant species, very few reports of molecular adaptation exist for symbiotic genes. Here we used data from 57 individuals and 53 gene fragments to quantify the overall strength of both positive and purifying selection in M. truncatula and asked if footprints of positive selection can be detected at key genes of rhizobia recognition pathways. Results We examined nucleotide variation among 57 accessions from natural populations in 53 gene fragments: 5 genes involved in nitrogen-fixing bacteria recognition, 11 genes involved in flowering, and 37 genes used as control loci. We detected 1757 polymorphic sites yielding an average nucleotide diversity (pi of 0.003 per site. Non-synonymous variation is under sizable purifying selection with 90% of amino-acid changing mutations being strongly selected against. Accessions were structured in two groups consistent with geographical origins. Each of these two groups harboured an excess of rare alleles, relative to expectations of a constant-sized population, suggesting recent population expansion. Using coalescent simulations and an approximate Bayesian computation framework we detected several instances of genes departing from selective neutrality within each group and showed that the polymorphism of two nodulation and four flowering genes has probably been shaped by recent positive selection. Conclusion We quantify the intensity of purifying selection in the M. truncatula genome and show that putative footprints of

  7. Insights into the phylogeny of sporadotrichid ciliates (Protozoa, Ciliophora: Hypotricha) based on genealogical analyses of multiple molecular markers

    Institute of Scientific and Technical Information of China (English)

    HU Xiaoyan; HU Xiaozhong; Khaled A. S. AL-RASHEID; Saieh A. AL-FARRAJ; SONG Weibo

    2011-01-01

    The sporadotrichid ciliates are an especially diverse group. A number of investigators have studied the morphological, morphogenetic, and molecular relationships among members of this group. Despite this, a consistent classification is still lacking and several important questions about the phylogenetic relationships within this group remain unsolved. To improve our understanding of these relationships, we constructed phylogenetic trees using the nucleotide sequences of the small-subunit rRNA (SSrRNA) gene and amino acid sequences of actin I and -αtubulin. Analyses of SSrRNA gene sequences indicated that: 1) the Sporadotrichida sensu Lynn (2008) and the Oxytrichidae are polyphyletic; 2) the Uroleptus species, which are classified to urostylids, formed a sister group with the oxytrichids; 3) Halteria grandinella, which is grouped morphologically with oligotrich species, clustered within the oxytrichids. These results are congruent with previous studies based on SSrRNA gene sequences. However, the amino acid sequences of actin I and α-tubulin yielded different topologies. The main results are: 1) in all phylogenetic trees, the genus Oxylricha was paraphyletic; 2) Uroleptus was sister to a subset of Urostyla and Holosticha, albeit with low supporting values; 3) Halteria grandinella was separated distantly from the Oxytrichidae in trees inferred from actin I amino acid sequences but clustered with oligotrichids in the α-tubulin analysis. The inconsistency among the trees inferred from these different molecular markers may be caused by rapidly accumulated genetic characterizations of ciliates. Further studies with additional molecular markers and sampling of more taxa are expected to better address the relationships among sporadotrichids.

  8. Equilibrium magnesium isotope fractionation between aqueous Mg2+ and carbonate minerals: Insights from path integral molecular dynamics

    Science.gov (United States)

    Pinilla, Carlos; Blanchard, Marc; Balan, Etienne; Natarajan, Suresh K.; Vuilleumier, Rodolphe; Mauri, Francesco

    2015-08-01

    The theoretical determination of the isotopic fractionation between an aqueous solution and a mineral is of utmost importance in Earth sciences. While for crystals, it is well established that equilibrium isotopic fractionation factors can be calculated using a statistical thermodynamic approach based on the vibrational properties, several theoretical methods are currently used to model ions in aqueous solution. In this work, we present a systematic study to determine the reduced partition function ratio (β-factor) of aqueous Mg2+ using several levels of theory within the simulations. In particular, using an empirical force field, we compare and discuss the performance of the exact results obtained from path integral molecular dynamics (PIMD) simulations, with respect to the more traditional methods based on vibrational properties and the cluster approximation. The results show the importance of including configurational disorder for the estimation of the equilibrium isotope fractionation factor. We also show that using the vibrational frequencies computed from snapshots taken from equilibrated classical molecular dynamics represents a good approximation for the study of aqueous ions. Based on these conclusions, the β-factor of aqueous Mg2+ have been estimated from a Car-Parrinello molecular dynamics (CPMD) simulation with an ab initio force field, and combined with the β-factors of carbonate minerals (magnesite, dolomite, calcite and aragonite). Mg β-factor of Mg-bearing aragonite, calculated here for the first time, displays a lower value than the three other carbonate minerals. This is explained by a strong distortion of the cationic site leading to a decrease of the coordination number during Ca-Mg substitution. Overall, the equilibrium magnesium isotope fractionation factors between aqueous Mg2+ and carbonate minerals that derive from this methodological study support the previous theoretical results obtained from embedded cluster models.

  9. Static and dynamic length scales in supercooled liquids: insights from molecular dynamics simulations of water and tri-propylene oxide.

    Science.gov (United States)

    Klameth, F; Henritzi, P; Vogel, M

    2014-04-14

    We perform molecular dynamics simulations to study static and dynamic length scales in molecular supercooled liquids, in particular, water. For a determination of these scales, we use equilibrium configurations and pin appropriate subsets of molecules so as to obtain random matrices, cylindrical pores, and slit confinements. Static length scales ξ(s) are determined by analyzing overlap correlation functions for various fractions of pinned molecules or distances to the confining walls. For water in all confinements and for propylene oxide trimers in random geometry, a linear increase of ξ(s) with inverse temperature is found. Dynamic length scales ξ(d) are determined by analogous analysis of fraction-dependent or position-resolved correlation times of structural relaxation. While ξ(d) continuously grows upon cooling in the cylindrical and slit confinements, we find no evidence for a temperature dependence in random matrices, implying that molecular dynamics in parsed volumes is qualitatively different from that in bulk liquids. Finally, we study possible connections between the growth of the static and dynamic length scales and the slowdown of the structural relaxation of the supercooled bulk liquids. For water, we observe a linear relation between ln τ(α) and ξ(s)²/T in the whole accessible range down to the critical temperature of mode-coupling theory, T(c). In the weakly supercooled regime, the same relation holds also for ξ(d), as obtained from cylindrical and slit confinements, but deviations from this behavior are observed near T(c). The results are discussed in connection with random first-order theory and experimental studies of liquid dynamics in nanoscopic confinements and binary mixtures.

  10. Insights into the phylogeny of sporadotrichid ciliates (Protozoa, Ciliophora: Hypotricha) based on genealogical analyses of multiple molecular markers

    Science.gov (United States)

    Hu, Xiaoyan; Hu, Xiaozhong; Al-Rasheid, Khaled A. S.; Al-Farraj, Saleh A.; Song, Weibo

    2011-01-01

    The sporadotrichid ciliates are an especially diverse group. A number of investigators have studied the morphological, morphogenetic, and molecular relationships among members of this group. Despite this, a consistent classification is still lacking and several important questions about the phylogenetic relationships within this group remain unsolved. To improve our understanding of these relationships, we constructed phylogenetic trees using the nucleotide sequences of the small-subunit rRNA (SSrRNA) gene and amino acid sequences of actin I and α-tubulin. Analyses of SSrRNA gene sequences indicated that: 1) the Sporadotrichida sensu Lynn (2008) and the Oxytrichidae are polyphyletic; 2) the Uroleptus species, which are classified to urostylids, formed a sister group with the oxytrichids; 3) Halteria grandinella, which is grouped morphologically with oligotrich species, clustered within the oxytrichids. These results are congruent with previous studies based on SSrRNA gene sequences. However, the amino acid sequences of actin I and α-tubulin yielded different topologies. The main results are: 1) in all phylogenetic trees, the genus Oxytricha was paraphyletic; 2) Uroleptus was sister to a subset of Urostyla and Holosticha, albeit with low supporting values; 3) Halteria grandinella was separated distantly from the Oxytrichidae in trees inferred from actin I amino acid sequences but clustered with oligotrichids in the α-tubulin analysis. The inconsistency among the trees inferred from these different molecular markers may be caused by rapidly accumulated genetic characterizations of ciliates. Further studies with additional molecular markers and sampling of more taxa are expected to better address the relationships among sporadotrichids.

  11. Are characiform fishes Gondwanan in origin? Insights from a time-scaled molecular phylogeny of the Citharinoidei (Ostariophysi: Characiformes.

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    Jairo Arroyave

    Full Text Available Fishes of the order Characiformes are a diverse and economically important teleost clade whose extant members are found exclusively in African and Neotropical freshwaters. Although their transatlantic distribution has been primarily attributed to the Early Cretaceous fragmentation of western Gondwana, vicariance has not been tested with temporal information beyond that contained in their fragmentary fossil record and a recent time-scaled phylogeny focused on the African family Alestidae. Because members of the suborder Citharinoidei constitute the sister lineage to the entire remaining Afro-Neotropical characiform radiation, we inferred a time-calibrated molecular phylogeny of citharinoids using a popular Bayesian approach to molecular dating in order to assess the adequacy of current vicariance hypotheses and shed light on the early biogeographic history of characiform fishes. Given that the only comprehensive phylogenetic treatment of the Citharinoidei has been a morphology-based analysis published over three decades ago, the present study also provided an opportunity to further investigate citharinoid relationships and update the evolutionary framework that has laid the foundations for the current classification of the group. The inferred chronogram is robust to changes in calibration priors and suggests that the origins of citharinoids date back to the Turonian (ca 90 Ma of the Late Cretaceous. Most modern citharinoid genera, however, appear to have originated and diversified much more recently, mainly during the Miocene. By reconciling molecular-clock- with fossil-based estimates for the origins of the Characiformes, our results provide further support for the hypothesis that attributes the disjunct distribution of the order to the opening of the South Atlantic Ocean. The striking overlap in tempo of diversification and biogeographic patterns between citharinoids and the African-endemic family Alestidae suggests that their evolutionary

  12. Response of the seagrass Posidonia oceanica to different light environments: Insights from a combined molecular and photo-physiological study.

    Science.gov (United States)

    Dattolo, E; Ruocco, M; Brunet, C; Lorenti, M; Lauritano, C; D'Esposito, D; De Luca, P; Sanges, R; Mazzuca, S; Procaccini, G

    2014-10-01

    Here we investigated mechanisms underlying the acclimation to light in the marine angiosperm Posidonia oceanica, along its bathymetric distribution (at -5 m and -25 m), combining molecular and photo-physiological approaches. Analyses were performed during two seasons, summer and autumn, in a meadow located in the Island of Ischia (Gulf of Naples, Italy), where a genetic distinction between plants growing above and below the summer thermocline was previously revealed. At molecular level, analyses carried out using cDNA-microarray and RT-qPCR, revealed the up-regulation of genes involved in photoacclimation (RuBisCO, ferredoxin, chlorophyll binding proteins), and photoprotection (antioxidant enzymes, xanthophyll-cycle related genes, tocopherol biosynthesis) in the upper stand of the meadow, indicating that shallow plants are under stressful light conditions. However, the lack of photo-damage, indicates the successful activation of defense mechanisms. This conclusion is also supported by several responses at physiological level as the lower antenna size, the higher number of reaction centers and the higher xanthophyll cycle pigment pool, which are common plant responses to high-light adaptation/acclimation. Deep plants, despite the lower available light, seem to be not light-limited, thanks to some shade-adaptation strategies (e.g. higher antenna size, lower Ek values). Furthermore, also at the molecular level there were no signs of stress response, indicating that, although the lower energy available, low-light environments are more favorable for P. oceanica growth. Globally, results of whole transcriptome analysis displayed two distinct gene expression signatures related to depth distribution, reflecting the different light-adaptation strategies adopted by P. oceanica along the depth gradient. This observation, also taking into account the genetic disjunction of clones along the bathymetry, might have important implications for micro-evolutionary processes

  13. Are characiform fishes Gondwanan in origin? Insights from a time-scaled molecular phylogeny of the Citharinoidei (Ostariophysi: Characiformes).

    Science.gov (United States)

    Arroyave, Jairo; Denton, John S S; Stiassny, Melanie L J

    2013-01-01

    Fishes of the order Characiformes are a diverse and economically important teleost clade whose extant members are found exclusively in African and Neotropical freshwaters. Although their transatlantic distribution has been primarily attributed to the Early Cretaceous fragmentation of western Gondwana, vicariance has not been tested with temporal information beyond that contained in their fragmentary fossil record and a recent time-scaled phylogeny focused on the African family Alestidae. Because members of the suborder Citharinoidei constitute the sister lineage to the entire remaining Afro-Neotropical characiform radiation, we inferred a time-calibrated molecular phylogeny of citharinoids using a popular Bayesian approach to molecular dating in order to assess the adequacy of current vicariance hypotheses and shed light on the early biogeographic history of characiform fishes. Given that the only comprehensive phylogenetic treatment of the Citharinoidei has been a morphology-based analysis published over three decades ago, the present study also provided an opportunity to further investigate citharinoid relationships and update the evolutionary framework that has laid the foundations for the current classification of the group. The inferred chronogram is robust to changes in calibration priors and suggests that the origins of citharinoids date back to the Turonian (ca 90 Ma) of the Late Cretaceous. Most modern citharinoid genera, however, appear to have originated and diversified much more recently, mainly during the Miocene. By reconciling molecular-clock- with fossil-based estimates for the origins of the Characiformes, our results provide further support for the hypothesis that attributes the disjunct distribution of the order to the opening of the South Atlantic Ocean. The striking overlap in tempo of diversification and biogeographic patterns between citharinoids and the African-endemic family Alestidae suggests that their evolutionary histories could have

  14. Molecular Insights for Giardia, Cryptosporidium, and Soil-Transmitted Helminths from a Facility-Based Surveillance System in Guatemala

    Science.gov (United States)

    Velasquez, Daniel E.; Arvelo, Wences; Cama, Vitaliano A.; López, Beatriz; Reyes, Lissette; Roellig, Dawn M.; Kahn, Geoffrey D.; Lindblade, Kimberly A.

    2011-01-01

    We molecularly characterized samples with Giardia, Cryptosporidium, and soil-transmitted helminths from a facility-based surveillance system for diarrhea in Santa Rosa, Guatemala. The DNA sequence analysis determined the presence of Giardia assemblages A (N = 7) and B (N = 12) and, Cryptosporidium hominis (N = 2) and Cryptosporidium parvum (N = 2), suggestive of different transmission cycles. All 41 samples with soil-transmitted helminths did not have the β-tubulin mutation described for benzimidazole resistance, suggesting potential usefulness in mass drug administration campaigns. PMID:22144459

  15. The molecular mechanism of bisphenol A (BPA as an endocrine disruptor by interacting with nuclear receptors: insights from molecular dynamics (MD simulations.

    Directory of Open Access Journals (Sweden)

    Lanlan Li

    Full Text Available Bisphenol A (BPA can interact with nuclear receptors and affect the normal function of nuclear receptors in very low doses, which causes BPA to be one of the most controversial endocrine disruptors. However, the detailed molecular mechanism about how BPA interferes the normal function of nuclear receptors is still undiscovered. Herein, molecular dynamics simulations were performed to explore the detailed interaction mechanism between BPA with three typical nuclear receptors, including hERα, hERRγ and hPPARγ. The simulation results and calculated binding free energies indicate that BPA can bind to these three nuclear receptors. The binding affinities of BPA were slightly lower than that of E2 to these three receptors. The simulation results proved that the binding process was mainly driven by direct hydrogen bond and hydrophobic interactions. In addition, structural analysis suggested that BPA could interact with these nuclear receptors by mimicking the action of natural hormone and keeping the nuclear receptors in active conformations. The present work provided the structural evidence to recognize BPA as an endocrine disruptor and would be important guidance for seeking safer substitutions of BPA.

  16. Molecular insight in the purification of immunoglobulin by pseudobiospecific ligand l-histidine and histidyl moieties in histidine ligand affinity chromatography (HLAC) by molecular docking.

    Science.gov (United States)

    Savane, Tushar S; Kumar, Sanjit; Janakiraman, Vignesh Narasimhan; Kamalanathan, Agamudi S; Vijayalakshmi, Mookambeswaran A

    2016-05-15

    Pseudobiospecific ligand l-histidine is an inexpensive, highly stable, non-toxic ligand explored successfully over the last twenty years for the purification of immunoglobulins in immobilised histidine ligand affinity chromatography. It is of great interest to know the molecular recognition sites of IgG to immobilized l-histidine. Here, we have used an in silico approach to explore the molecular recognition of l-histidine by IgG. We have assessed the feasible binding modes of histidine and its moieties at different sites of IgG and considered only those binding conformations which are exhibited via the imidazole ring NH group or any other OH donating group apart from the ones which are terminally conjugated with the support matrix. We categorised binding site into two categories; category I: inner binding groove and category II: surface binding groove and observed that the hinge region of IgG has most favourable binding pocket for l-histidine and histidyl moieties. Ser and Tyr residues on the hinge region make several significant interactions with l-histidine and histidyl moieties. In case of Fc region of IgG, l-histidine and histidyl moieties closely resemble the binding modes of Protein A, biomimetic ligand 22/8 and B domain of SpA to IgG. In addition to these we have also observed a significant binding site for l-histidine and histidyl moieties at Fab region of IgG.

  17. Comparative Analyses of the β-Tubulin Gene and Molecular Modeling Reveal Molecular Insight into the Colchicine Resistance in Kinetoplastids Organisms

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    Luis Luis

    2013-01-01

    Full Text Available Differential susceptibility to microtubule agents has been demonstrated between mammalian cells and kinetoplastid organisms such as Leishmania spp. and Trypanosoma spp. The aims of this study were to identify and characterize the architecture of the putative colchicine binding site of Leishmania spp. and investigate the molecular basis of colchicine resistance. We cloned and sequenced the β-tubulin gene of Leishmania (Viannia guyanensis and established the theoretical 3D model of the protein, using the crystallographic structure of the bovine protein as template. We identified mutations on the Leishmania  β-tubulin gene sequences on regions related to the putative colchicine-binding pocket, which generate amino acid substitutions and changes in the topology of this region, blocking the access of colchicine. The same mutations were found in the β-tubulin sequence of kinetoplastid organisms such as Trypanosoma cruzi, T. brucei, and T. evansi. Using molecular modelling approaches, we demonstrated that conformational changes include an elongation and torsion of an α-helix structure and displacement to the inside of the pocket of one β-sheet that hinders access of colchicine. We propose that kinetoplastid organisms show resistance to colchicine due to amino acids substitutions that generate structural changes in the putative colchicine-binding domain, which prevent colchicine access.

  18. Insights into the folding and unfolding processes of wild-type and mutated SH3 domain by molecular dynamics and replica exchange molecular dynamics simulations.

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    Wen-Ting Chu

    Full Text Available Src-homology regions 3 (SH3 domain is essential for the down-regulation of tyrosine kinase activity. Mutation A39V/N53P/V55L of SH3 is found to be relative to the urgent misfolding diseases. To gain insight, the human and gallus SH3 domains (PDB ID: 1NYG and 2LP5, including 58 amino acids in each protein, were selected for MD simulations (Amber11, ff99SB force field and cluster analysis to investigate the influence of mutations on the spatial structure of the SH3 domain. It is found that the large conformational change of mutations mainly exists in three areas in the vicinity of protein core: RT loop, N-src loop, distal β-hairpin to 310 helix. The C-terminus of the mutated gallus SH3 is disordered after simulation, which represents the intermediate state of aggregation. The disappeared strong Hbond net in the mutated human and gallus systems will make these mutated proteins looser than the wild-type proteins. Additionally, by performing the REMD simulations on the gallus SH3 domain, the mutated domain is found to have an obvious effect on the unfolding process. These studies will be helpful for further aggregation mechanisms investigations on SH3 family.

  19. Molecular phylogeography of East Asian Kirengeshoma (Hydrangeaceae) in relation to quaternary climate change and landbridge configurations.

    Science.gov (United States)

    Qiu, Ying-Xiong; Sun, Yi; Zhang, Xiao-Ping; Lee, Joongku; Fu, Cheng-Xin; Comes, Hans Peter

    2009-01-01

    Kirengeshoma comprises two species inhabiting warm temperate-deciduous forests in East China/South Japan (Kirengeshoma palmata) and South Korea (Kirengeshoma koreana). A survey of chloroplast (cp) DNA and inter-simple sequence repeats (ISSRs) variation in Kirengeshoma was carried out to determine the population history of a plant taxon around the East China Sea (ECS). CpDNA and ISSRs revealed lower genetic divergence between China and Japan relative to the other contrasts, in line with intrageneric classification. Molecular dating suggests that K. koreana diverged at the Plio-Pleistocene boundary from the Japanese populations, whereas the latter migrated into China during the early-to-mid Pleistocene via the ECS basin. Vicariant segregation of Chinese and Japanese populations likely occurred during the mid-Pleistocene. Mismatch distributions and neutrality tests indicated that Chinese populations expanded their range during the Late Pleistocene, probably during a cold period, whereas those from Japan showed no significant population growth. We conclude that the current distribution and differentiation of components of presently isolated warm temperate-deciduous forests in China, Japan and Korea likely resulted from a combination of relatively ancient vicariant and immigration events, and those from Japan were particularly sensitive to range fragmentation and long-term refugial isolation throughout the Late Pleistocene.

  20. Temperature-accelerated molecular dynamics gives insights into globular conformations sampled in the free state of the AC catalytic domain.

    Science.gov (United States)

    Selwa, Edithe; Huynh, Tru; Ciccotti, Giovanni; Maragliano, Luca; Malliavin, Thérèse E

    2014-10-01

    The catalytic domain of the adenyl cyclase (AC) toxin from Bordetella pertussis is activated by interaction with calmodulin (CaM), resulting in cAMP overproduction in the infected cell. In the X-ray crystallographic structure of the complex between AC and the C terminal lobe of CaM, the toxin displays a markedly elongated shape. As for the structure of the isolated protein, experimental results support the hypothesis that more globular conformations are sampled, but information at atomic resolution is still lacking. Here, we use temperature-accelerated molecular dynamics (TAMD) simulations to generate putative all-atom models of globular conformations sampled by CaM-free AC. As collective variables, we use centers of mass coordinates of groups of residues selected from the analysis of standard molecular dynamics (MD) simulations. Results show that TAMD allows extended conformational sampling and generates AC conformations that are more globular than in the complexed state. These structures are then refined via energy minimization and further unrestrained MD simulations to optimize inter-domain packing interactions, thus resulting in the identification of a set of hydrogen bonds present in the globular conformations.

  1. Insights into the Tunnel Mechanism of Cholesteryl Ester Transfer Protein through All-atom Molecular Dynamics Simulations.

    Science.gov (United States)

    Lei, Dongsheng; Rames, Matthew; Zhang, Xing; Zhang, Lei; Zhang, Shengli; Ren, Gang

    2016-07-01

    Cholesteryl ester transfer protein (CETP) mediates cholesteryl ester (CE) transfer from the atheroprotective high density lipoprotein (HDL) cholesterol to the atherogenic low density lipoprotein cholesterol. In the past decade, this property has driven the development of CETP inhibitors, which have been evaluated in large scale clinical trials for treating cardiovascular diseases. Despite the pharmacological interest, little is known about the fundamental mechanism of CETP in CE transfer. Recent electron microscopy (EM) experiments have suggested a tunnel mechanism, and molecular dynamics simulations have shown that the flexible N-terminal distal end of CETP penetrates into the HDL surface and takes up a CE molecule through an open pore. However, it is not known whether a CE molecule can completely transfer through an entire CETP molecule. Here, we used all-atom molecular dynamics simulations to evaluate this possibility. The results showed that a hydrophobic tunnel inside CETP is sufficient to allow a CE molecule to completely transfer through the entire CETP within a predicted transfer time and at a rate comparable with those obtained through physiological measurements. Analyses of the detailed interactions revealed several residues that might be critical for CETP function, which may provide important clues for the effective development of CETP inhibitors and treatment of cardiovascular diseases.

  2. Insights into cytochrome bc 1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling

    Science.gov (United States)

    Sodero, Ana Carolina Rennó; Abrahim-Vieira, Bárbara; Torres, Pedro Henrique Monteiro; Pascutti, Pedro Geraldo; Garcia, Célia RS; Ferreira, Vitor Francisco; da Rocha, David Rodrigues; Ferreira, Sabrina Baptista; Silva, Floriano Paes

    2017-01-01

    BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc 1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity. METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite. PMID:28327793

  3. Confocal imaging of whole vertebrate embryos reveals novel insights into molecular and cellular mechanisms of organ development

    Science.gov (United States)

    Hadel, Diana M.; Keller, Bradley B.; Sandell, Lisa L.

    2014-03-01

    Confocal microscopy has been an invaluable tool for studying cellular or sub-cellular biological processes. The study of vertebrate embryology is based largely on examination of whole embryos and organs. The application of confocal microscopy to immunostained whole mount embryos, combined with three dimensional (3D) image reconstruction technologies, opens new avenues for synthesizing molecular, cellular and anatomical analysis of vertebrate development. Optical cropping of the region of interest enables visualization of structures that are morphologically complex or obscured, and solid surface rendering of fluorescent signal facilitates understanding of 3D structures. We have applied these technologies to whole mount immunostained mouse embryos to visualize developmental morphogenesis of the mammalian inner ear and heart. Using molecular markers of neuron development and transgenic reporters of neural crest cell lineage we have examined development of inner ear neurons that originate from the otic vesicle, along with the supporting glial cells that derive from the neural crest. The image analysis reveals a previously unrecognized coordinated spatial organization between migratory neural crest cells and neurons of the cochleovestibular nerve. The images also enable visualization of early cochlear spiral nerve morphogenesis relative to the developing cochlea, demonstrating a heretofore unknown association of neural crest cells with extending peripheral neurite projections. We performed similar analysis of embryonic hearts in mouse and chick, documenting the distribution of adhesion molecules during septation of the outflow tract and remodeling of aortic arches. Surface rendering of lumen space defines the morphology in a manner similar to resin injection casting and micro-CT.

  4. Insights into the structure of the LC13 TCR/HLA-B8-EBV peptide complex with molecular dynamics simulations.

    Science.gov (United States)

    Stavrakoudis, Athanassios

    2011-07-01

    One key step in the immune response against infected or tumor cells is the recognition of the T-cell receptor (TCR) by class I major histocompatibility complexes. The complex between the HLA-B8 molecule and the immunodominant peptide with sequence FLRGRAYGL, derived from the Epstein-Barr virus, with the LC13 TCR has been determined by X-ray diffraction. The complex has been used as a starting point in a molecular dynamics study in order to investigate the dynamics of the complex association and to explore the specific interactions of the complex formation. The analyzed structures provided evidence that the peptide adopts an open type β-turn conformation close to C-terminal part, which dominates peptide/TCR interactions. Conformational energy landscape analysis indicated the presence of two conformational clusters in the peptide's structure, underlying the backbone flexibility of the peptide despite being surrounded by two receptors. The peptide/MHC/TCR interface was found to hold significant number of solvent molecules, more specifically the peptide has been found to have approximately seventeen hydrogen bonds with water molecules. The molecular dynamics simulation indicated the disruption of some MHC/TCR contacts, mainly with the CDR1α loop. However, several other interactions emerged that resulted in a stable association during the 20 ns trajectory, as revealed by the buried surface area analysis.

  5. Molecular modelling and competition binding study of Br-noscapine and colchicine provide insight into noscapinoid-tubulin binding site.

    Science.gov (United States)

    Naik, Pradeep K; Santoshi, Seneha; Rai, Ankit; Joshi, Harish C

    2011-06-01

    We have previously discovered the tubulin-binding anti-cancer properties of noscapine and its derivatives (noscapinoids). Here, we present three lines of evidence that noscapinoids bind at or near the well studied colchicine binding site of tubulin: (1) in silico molecular docking studies of Br-noscapine and noscapine yield highest docking score with the well characterised colchicine-binding site from the co-crystal structure; (2) the molecular mechanics-generalized Born/surface area (MM-GB/SA) scoring results ΔΔG(bind-cald) for both noscapine and Br-noscapine (3.915 and 3.025 kcal/mol) are in reasonably good agreement with our experimentally determined binding affinity (ΔΔG(bind-Expt) of 3.570 and 2.988 kcal/mol, derived from K(d) values); and (3) Br-noscapine competes with colchicine binding to tubulin. The simplest interpretation of these collective data is that Br-noscapine binds tubulin at a site overlapping with, or very close to colchicine-binding site of tubulin. Although we cannot rule out a formal possibility that Br-noscapine might bind to a site distinct and distant from the colchicine-binding site that might negatively influence the colchicine binding to tubulin.

  6. In Silico Docking, Molecular Dynamics and Binding Energy Insights into the Bolinaquinone-Clathrin Terminal Domain Binding Site

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    Mohammed K. Abdel-Hamid

    2014-05-01

    Full Text Available Clathrin-mediated endocytosis (CME is a process that regulates selective internalization of important cellular cargo using clathrin-coated vesicles. Perturbation of this process has been linked to many diseases including cancer and neurodegenerative conditions. Chemical proteomics identified the marine metabolite, 2-hydroxy-5-methoxy-3-(((1S,4aS,8aS-1,4a,5-trimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-2-ylmethylcyclohexa- 2,5-diene-1,4-dione (bolinaquinone as a clathrin inhibitor. While being an attractive medicinal chemistry target, the lack of data about bolinaquinone’s mode of binding to the clathrin enzyme represents a major limitation for its structural optimization. We have used a molecular modeling approach to rationalize the observed activity of bolinaquinone and to predict its mode of binding with the clathrin terminal domain (CTD. The applied protocol started by global rigid-protein docking followed by flexible docking, molecular dynamics and linear interaction energy calculations. The results revealed the potential of bolinaquinone to interact with various pockets within the CTD, including the clathrin-box binding site. The results also highlight the importance of electrostatic contacts over van der Waals interactions for proper binding between bolinaquinone and its possible binding sites. This study provides a novel model that has the potential to allow rapid elaboration of bolinaquinone analogues as a new class of clathrin inhibitors.

  7. Carbon dioxide and methane transport in DDR zeolite: insights from molecular simulations into carbon dioxide separations in small pore zeolites

    Science.gov (United States)

    Jee, Sang Eun; Sholl, David

    2009-03-01

    Zeolites are good candidates as a membranes for chemical separations because of their excellent chemical and thermal stability. Cage type zeolites are promising materials for gas separation since their narrow windows are expected to control molecular transport. DDR is one of the strongest candidates for light gas separations because of its narrow 8MR window. In our study, we examined the separation selectivity of DDR for CO2/CH4 separation using atomistic simulation methods. We introduced new force fields which can reproduce experimental single component adsorption and diffusion data for this material for the first time. Previously interatomic potentials that have been applied to DDR overestimate experimental diffusivities at least one order of magnitude. We characterized single-component and binary adsorption using Grand Canonical Monte Carlo, and single-component. diffusion using a combination of Molecular Dynamics and Transition State Theory. The most important observation from our calculation is that CO2/CH4 diffusion in DDR is very different from the usual situation in nanoporous materials, where the presence of a slowly diffusing species retards transport rates of a more rapidly diffusing species. In DDR, we show that CO2 diffusion rates are only weakly affected by the presence of CH4, despite the very slow diffusion of the latter species. The physical origins of this unusual behavior are explained by analyzing the adsorption sites and diffusion mechanism for each species.

  8. TP53 alterations in pancreatic acinar cell carcinoma: new insights into the molecular pathology of this rare cancer.

    Science.gov (United States)

    La Rosa, Stefano; Bernasconi, Barbara; Frattini, Milo; Tibiletti, Maria Grazia; Molinari, Francesca; Furlan, Daniela; Sahnane, Nora; Vanoli, Alessandro; Albarello, Luca; Zhang, Lizhi; Notohara, Kenji; Casnedi, Selenia; Chenard, Marie-Pierre; Adsay, Volkan; Asioli, Sofia; Capella, Carlo; Sessa, Fausto

    2016-03-01

    The molecular alterations of pancreatic acinar cell carcinomas (ACCs) are poorly understood and have been reported as being different from those in ductal adenocarcinomas. Loss of TP53 gene function in the pathogenesis of ACCs is controversial since contradictory findings have been published. A comprehensive analysis of the different possible genetic and epigenetic mechanisms leading to TP53 alteration in ACC has never been reported and hence the role of TP53 in the pathogenesis and/or progression of ACC remains unclear. We investigated TP53 alterations in 54 tumor samples from 44 patients, including primary and metastatic ACC, using sequencing analysis, methylation-specific multiplex ligation probe amplification, fluorescence in situ hybridization, and immunohistochemistry. TP53 mutations were found in 13 % of primary ACCs and in 31 % of metastases. Primary ACCs and metastases showed the same mutational profile, with the exception of one case, characterized by a wild-type sequence in the primary carcinoma and a mutation in the corresponding metastasis. FISH analysis revealed deletion of the TP53 region in 53 % of primary ACCs and in 50 % of metastases. Promoter hypermethylation was found in one case. The molecular alterations correlated well with the immunohistochemical findings. A statistically significant association was found between the combination of mutation of one allele and loss of the other allele of TP53 and worse survival.

  9. Insights into the structure and inhibition of Giardia intestinalis arginine deiminase: homology modeling, docking, and molecular dynamics studies.

    Science.gov (United States)

    Trejo-Soto, Pedro Josué; Aguayo-Ortiz, Rodrigo; Yépez-Mulia, Lilián; Hernández-Campos, Alicia; Medina-Franco, José Luis; Castillo, Rafael

    2016-01-01

    Giardia intestinalis arginine deiminase (GiADI) is an important metabolic enzyme involved in the energy production and defense of this protozoan parasite. The lack of this enzyme in the human host makes GiADI an attractive target for drug design against G. intestinalis. One approach in the design of inhibitors of GiADI could be computer-assisted studies of its crystal structure, such as docking; however, the required crystallographic structure of the enzyme still remains unresolved. Because of its relevance, in this work, we present a three-dimensional structure of GiADI obtained from its amino acid sequence using the homology modeling approximation. Furthermore, we present an approximation of the most stable dimeric structure of GiADI identified through molecular dynamics simulation studies. An in silico analysis of druggability using the structure of GiADI was carried out in order to know if it is a good target for design and optimization of selective inhibitors. Potential GiADI inhibitors were identified by docking of a set of 3196 commercial and 19 in-house benzimidazole derivatives, and molecular dynamics simulation studies were used to evaluate the stability of the ligand-enzyme complexes.

  10. An insight to conserved water molecular dynamics of catalytic and structural Zn(+2) ions in matrix metalloproteinase 13 of human.

    Science.gov (United States)

    Chakrabarti, Bornali; Bairagya, Hridoy R; Mallik, Payel; Mukhopadhyay, Bishnu P; Bera, Asim K

    2011-02-01

    Matrix Metalloproteinase (MMP)--13 or Collagenase--3 plays a significant role in the formation and remodeling of bone, tumor invasion and causes osteoarthritis. Water molecular dynamic studies of the five (1XUC, 1XUD, 1XUR, 456C, 830C) PDB and solvated structures of MMP-13 in human have been carried out upto 5 ns on assigning the differential charges (+2, +1, +0.5 e) to both the Zinc ions. The MM and MD-studies have revealed the coordination of three water molecules (W(H), W(I) and W(S)) to Zn(c) and one water to Zn(s). The transition of geometry around the Znc from tetrahedral to octahedral via trigonal bipyramidal, and for Zn(s) from tetrahedral to trigonal bipyramidal are seem interesting. Recognition of two zinc ions through water molecular bridging (Zn(c) - W(H) (W(1))...W(2)....W(3)....H(187) Zn(s)) and the stabilization of variable coordination geometries around metal ions may indicate the possible involvement of Zn(c) ...Zn(s) coupled mechanism in the catalytic process. So the hydrophilic topology and stereochemistry of water mediated coupling between Zn-ions may provide some plausible hope towards the design of some bidentate/polydentate bridging ligands or inhibitors for MMP-13.

  11. Insight derived from molecular dynamics simulation into substrate-induced changes in protein motions of proteinase K.

    Science.gov (United States)

    Tao, Yan; Rao, Zi-He; Liu, Shu-Qun

    2010-10-01

    Because of the significant industrial, agricultural and biotechnological importance of serine protease proteinase K, it has been extensively investigated using experimental approaches such as X-ray crystallography, site-directed mutagenesis and kinetic measurement. However, detailed aspects of enzymatic mechanism such as substrate binding, release and relevant regulation remain unstudied. Molecular dynamics (MD) simulations of the proteinase K alone and in complex with the peptide substrate AAPA were performed to investigate the effect of substrate binding on the dynamics/molecular motions of proteinase K. The results indicate that during simulations the substrate-complexed proteinase K adopt a more compact and stable conformation than the substrate-free form. Further essential dynamics (ED) analysis reveals that the major internal motions are confined within a subspace of very small dimension. Upon substrate binding, the overall flexibility of the protease is reduced; and the noticeable displacements are observed not only in substrate-binding regions but also in regions opposite the substrate-binding groove/pockets. The dynamic pockets caused by the large concerted motions are proposed to be linked to the substrate recognition, binding, orientation and product release; and the significant displacements in regions opposite the binding groove/pockets are considered to play a role in modulating the dynamics of enzyme-substrate interaction. Our simulation results complement the biochemical and structural studies, highlighting the dynamic mechanism of the functional properties of proteinase K.

  12. Molecular insights into evolution of the vertebrate gut: focus on stomach and parietal cells in the marsupial, Macropus eugenii.

    Science.gov (United States)

    Kwek, Joly; De Iongh, Robbert; Nicholas, Kevin; Familari, Mary

    2009-09-15

    Gastrulation in vertebrate embryos results in the formation of the primary germ layers: ectoderm, mesoderm and endoderm, which contain the progenitors of the tissues of the entire fetal body. Extensive studies undertaken in Xenopus, zebrafish and mouse have revealed a high degree of conservation in the genes and cellular mechanisms regulating endoderm formation. Nodal, Mix and Sox gene factor families have been implicated in the specification of the endoderm across taxa. Considerably less is known about endoderm development in marsupials. In this study we review what is known about the molecular aspects of endoderm development, focusing on evolution and development of the stomach and parietal cells and highlight recent studies on parietal cells in the stomach of Tammar Wallaby, Macropus eugenii. Although the regulation of parietal cells has been extensively studied, very little is known about the regulation of parietal cell differentiation. Intriguingly, during late-stage forestomach maturation in M. eugenii, there is a sudden and rapid loss of parietal cells, compared with the sharp increase in parietal cell numbers in the hindstomach region. This has provided a unique opportunity to study the development and regulation of parietal cell differentiation. A PCR-based subtractive hybridization strategy was used to identify candidate genes involved in this phenomenon. This will allow us to dissect the molecular mechanisms that underpin regulation of parietal cell development and differentiation, which have been a difficult process to study and provide markers that can be used to study the evolutionary origin of these cells in vertebrates.

  13. Molecular insights into the pH-dependent adsorption and removal of ionizable antibiotic oxytetracycline by adsorbent cyclodextrin polymers.

    Directory of Open Access Journals (Sweden)

    Yu Zhang

    Full Text Available Effects of pH on adsorption and removal efficiency of ionizable organic compounds (IOCs by environmental adsorbents are an area of debate, because of its dual mediation towards adsorbents and adsorbate. Here, we probe the pH-dependent adsorption of ionizable antibiotic oxytetracycline (comprising OTCH2 (+, OTCH(±, OTC(-, and OTC(2- onto cyclodextrin polymers (CDPs with the nature of molecular recognition and pH inertness. OTCH(± commonly has high adsorption affinity, OTC(- exhibits moderate affinity, and the other two species have negligible affinity. These species are evidenced to selectively interact with structural units (e.g., CD cavity, pore channel, and network of the polymers and thus immobilized onto the adsorbents to different extents. The differences in adsorption affinity and mechanisms of the species account for the pH-dependent adsorption of OTC. The mathematical equations are derived from the multiple linear regression (MLR analysis of quantitatively relating adsorption affinity of OTC at varying pH to adsorbent properties. A combination of the MLR analysis for OTC and molecular recognition of adsorption of the species illustrates the nature of the pH-dependent adsorption of OTC. Based on this finding, γ-HP-CDP is chosen to adsorb and remove OTC at pH 5.0 and 7.0, showing high removal efficiency and strong resistance to the interference of coexisting components.

  14. Amid the possible causes of a very famous foxing: molecular and microscopic insight into Leonardo da Vinci's self‐portrait

    Science.gov (United States)

    Tafer, Hakim; Sterflinger, Katja; Pinzari, Flavia

    2015-01-01

    Summary Leonardo da Vinci's self‐portrait is affected by foxing spots. The portrait has no fungal or bacterial infections in place, but is contaminated with airborne spores and fungal material that could play a role in its disfigurement. The knowledge of the nature of the stains is of great concern because future conservation treatments should be derived from scientific investigations. The lack of reliable scientific data, due to the non‐culturability of the microorganisms inhabiting the portrait, prompted the investigation of the drawing using non‐invasive and micro‐invasive sampling, in combination with scanning electron microscope (SEM) imaging and molecular techniques. The fungus E urotium halophilicum was found in foxing spots using SEM analyses. Oxalates of fungal origin were also documented. Both findings are consistent with the hypothesis that tonophilic fungi germinate on paper metabolizing organic acids, oligosaccharides and proteic compounds, which react chemically with the material at a low water activity, forming brown products and oxidative reactions resulting in foxing spots. Additionally, molecular techniques enabled a screening of the fungi inhabiting the portrait and showed differences when different sampling techniques were employed. Swabs samples showed a high abundance of lichenized Ascomycota, while the membrane filters showed a dominance of A cremonium sp. colonizing the drawing. PMID:26111623

  15. Mechanisms underlying autoimmune synaptic encephalitis leading to disorders of memory, behavior and cognition: insights from molecular, cellular and synaptic studies.

    Science.gov (United States)

    Moscato, Emilia H; Jain, Ankit; Peng, Xiaoyu; Hughes, Ethan G; Dalmau, Josep; Balice-Gordon, Rita J

    2010-07-01

    Recently, several novel, potentially lethal and treatment-responsive syndromes that affect hippocampal and cortical function have been shown to be associated with auto-antibodies against synaptic antigens, notably glutamate or GABA-B receptors. Patients with these auto-antibodies, sometimes associated with teratomas and other neoplasms, present with psychiatric symptoms, seizures, memory deficits and decreased levels of consciousness. These symptoms often improve dramatically after immunotherapy or tumor resection. Here we review studies of the cellular and synaptic effects of these antibodies in hippocampal neurons in vitro and preliminary work in rodent models. Our work suggests that patient antibodies lead to rapid and reversible removal of neurotransmitter receptors from synaptic sites, leading to changes in synaptic and circuit function that in turn are likely to lead to behavioral deficits. We also discuss several of the many questions raised by these and related disorders. Determining the mechanisms underlying these novel anti-neurotransmitter receptor encephalopathies will provide insights into the cellular and synaptic bases of the memory and cognitive deficits that are hallmarks of these disorders, and potentially suggest avenues for therapeutic intervention.

  16. Acute and chronic wound fluids inversely influence adipose-derived stem cell function: molecular insights into impaired wound healing.

    Science.gov (United States)

    Koenen, Paola; Spanholtz, Timo A; Maegele, Marc; Stürmer, Ewa; Brockamp, Thomas; Neugebauer, Edmund; Thamm, Oliver C

    2015-02-01

    Wound healing is a complex biological process that requires a well-orchestrated interaction of mediators as well as resident and infiltrating cells. In this context, mesenchymal stem cells play a crucial role as they are attracted to the wound site and influence tissue regeneration by various mechanisms. In chronic wounds, these processes are disturbed. In a comparative approach, adipose-derived stem cells (ASC) were treated with acute and chronic wound fluids (AWF and CWF, respectively). Proliferation and migration were investigated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test and transwell migration assay. Gene expression changes were analysed using quantitative real time-polymerase chain reaction. AWF had a significantly stronger chemotactic impact on ASC than CWF (77·5% versus 59·8% migrated cells). While proliferation was stimulated by AWF up to 136·3%, CWF had a negative effect on proliferation over time (80·3%). Expression of b-FGF, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 was strongly induced by CWF compared with a mild induction by AWF. These results give an insight into impaired ASC function in chronic wounds. The detected effect of CWF on proliferation and migration of ASC might be one reason for an insufficient healing process in chronic wounds.

  17. Molecular interaction between natural IgG and ficolin - mechanistic insights on adaptive-innate immune crosstalk

    Science.gov (United States)

    Panda, Saswati; Zhang, Jing; Yang, Lifeng; Anand, Ganesh S.; Ding, Jeak L.

    2014-01-01

    Recently, we found that natural IgG (nIgG; a non-specific immunoglobulin of adaptive immunity) is not quiescent, but plays a crucial role in immediate immune defense by collaborating with ficolin (an innate immune protein). However, how the nIgG and ficolin interplay and what factors control the complex formation during infection is unknown. Here, we found that mild acidosis and hypocalcaemia induced by infection- inflammation condition increased the nIgG:ficolin complex formation. Hydrogen-deuterium exchange mass spectrometry delineated the binding interfaces to the CH2-CH3 region of nIgG Fc and P-subdomain of ficolin FBG domain. Infection condition exposes novel binding sites. Site-directed mutagenesis and surface plasmon resonance analyses of peptides, derived from nIgG and ficolin, defined the interacting residues between the proteins. These results provide mechanistic insights on the interaction between two molecules representing the adaptive and innate immune pathways, prompting potential development of immunomodulatory/prophylactic peptides tunable to prevailing infection conditions.

  18. Molecular insight into the role of the N-terminal extension in the maturation, substrate recognition, and catalysis of a bacterial alginate lyase from polysaccharide lyase family 18.

    Science.gov (United States)

    Dong, Sheng; Wei, Tian-Di; Chen, Xiu-Lan; Li, Chun-Yang; Wang, Peng; Xie, Bin-Bin; Qin, Qi-Long; Zhang, Xi-Ying; Pang, Xiu-Hua; Zhou, Bai-Cheng; Zhang, Yu-Zhong

    2014-10-24

    Bacterial alginate lyases, which are members of several polysaccharide lyase (PL) families, have important biological roles and biotechnological applications. The mechanisms for maturation, substrate recognition, and catalysis of PL18 alginate lyases are still largely unknown. A PL18 alginate lyase, aly-SJ02, from Pseudoalteromonas sp. 0524 displays a β-jelly roll scaffold. Structural and biochemical analyses indicated that the N-terminal extension in the aly-SJ02 precursor may act as an intramolecular chaperone to mediate the correct folding of the catalytic domain. Molecular dynamics simulations and mutational assays suggested that the lid loops over the aly-SJ02 active center serve as a gate for substrate entry. Molecular docking and site-directed mutations revealed that certain conserved residues at the active center, especially those at subsites +1 and +2, are crucial for substrate recognition. Tyr(353) may function as both a catalytic base and acid. Based on our results, a model for the catalysis of aly-SJ02 in alginate depolymerization is proposed. Moreover, although bacterial alginate lyases from families PL5, 7, 15, and 18 adopt distinct scaffolds, they share the same conformation of catalytic residues, reflecting their convergent evolution. Our results provide the foremost insight into the mechanisms of maturation, substrate recognition, and catalysis of a PL18 alginate lyase.

  19. Probing the role of chemical enhancers in facilitating drug release from patches: Mechanistic insights based on FT-IR spectroscopy, molecular modeling and thermal analysis.

    Science.gov (United States)

    Song, Wenting; Quan, Peng; Li, Shanshan; Liu, Chao; Lv, Siji; Zhao, Yongshan; Fang, Liang

    2016-04-10

    In patches, a drug must release from patches prior to its percutaneous absorption. Chemical enhancers have been used for several decades, but their roles in drug release from patches are poorly understood. In this work, the roles of chemical enhancers in bisoprolol tartrate (BSP-T) release from patches were probed in vitro and in vivo. More importantly, an innovative mechanism insight of chemical enhancers in drug release process was provided at molecular level. FT-IR spectroscopy and molecular modeling were employed to investigate the influence of chemical enhancers on drug-adhesive interaction. The results showed chemical enhancers like Span 80, which had a strong ability forming hydrogen bonds, could decrease drug-adhesive interaction leading to the release of drug from adhesive of patches. Thermal analysis was conducted to research the influence of chemical enhancers on the thermodynamic properties of patch system. It showed that chemical enhancers promoted the formation of free volume of adhesive, which facilitated drug release process. By contrast, the influence on the thermodynamic properties of BSP-T was less effective in influencing BSP-T release process. In conclusion, chemical enhancers played an important role in facilitating BSP-T release from the adhesive DURO-TAK® 87-2287 of patches by decreasing drug-adhesive interaction and promoting the formation of free volume of adhesive. This work may be an important step in understanding the important roles of chemical enhancers in drug release process.

  20. Insights into the molecular mechanisms underlying mammalian P2X7 receptor functions and contributions in diseases, revealed by structural modeling and single nucleotide polymorphisms

    Directory of Open Access Journals (Sweden)

    Lin-Hua eJiang

    2013-05-01

    Full Text Available The mammalian P2X7 receptors (P2X7Rs, a member of the ionotropic P2X receptor family with distinctive functional properties, play an important part in mediating extracellular ATP signaling in health and disease. A clear delineation of the molecular mechanisms underlying the key receptor properties, such as ATP-binding, ion permeation, and large pore formation of the mammalian P2X7Rs, is still lacking, but such knowledge is crucial for a better understanding of their physiological functions and contributions in diseases and for development of therapeutics. The recent breakthroughs in determining the atomic structures of the zebrafish P2X4.1R in the closed and ATP-bound open states have provided the long-awaited structural information. The human P2RX7 gene is abundant with non-synonymous single nucleotide polymorphisms (NS-SNPs, which generate a repertoire of human P2X7Rs with point mutations. Characterizations of the NS-SNPs identified in patients of various disease conditions and the resulting mutations have informed previously unknown molecular mechanisms determining the mammalian P2X7R functions and diseases. In this review, we will discuss the new insights into such mechanisms provided by structural modeling and recent functional and genetic linkage studies of NS-SNPs.

  1. Molecular docking and dynamic studies of human growth factor receptorbound protein (Grb 2 insights to identify novel inhibitors

    Directory of Open Access Journals (Sweden)

    Sandeep S

    2016-10-01

    Full Text Available Background: Human growth factor receptor bound protein-2 (Grb 2 involves in initiation of kinase signaling by Son of Sevenless (SOS and activates mitogen activated protein kinase pathway. Grb2 overexpress during cancerous condition hence it emerged as a potent target for various cancers. Material and Methods: Seven pharmacophores were developed from seven co-crystal structures of Grb2 and applied for common pharmacophore hypothesis. Two common pharmacophore hypothesis (CPH models were screened and hits were applied for docking and free energy [G] calculations. Results: Two leads were proposed from docking and G analysis. Energy of the system, RMSD, RMSF, hydrogen bonds and water bridges of lead1 was better than the co-crystal ligand during 50 ns molecular dynamics simulations. Discussion: Two leads are interacting with Src homology 2 (SH2 domain of Grb2 and blocking the function of Grb2.

  2. New insights into the biological properties of Crocus sativus L.: chemical modifications, human monoamine oxidases inhibition and molecular modeling studies.

    Science.gov (United States)

    De Monte, Celeste; Carradori, Simone; Chimenti, Paola; Secci, Daniela; Mannina, Luisa; Alcaro, Francesca; Petzer, Anél; N'Da, Clarina I; Gidaro, Maria Concetta; Costa, Giosuè; Alcaro, Stefano; Petzer, Jacobus P

    2014-07-23

    Although there are clinical trials and in vivo studies in literature regarding the anxiolytic and antidepressant activities of the components of Crocus sativus L., their effects on the human monoamine oxidases (hMAO-A and hMAO-B), enzymes which are involved in mental disorders and neurodegenerative diseases, have not yet been investigated. We have thus examined the hMAO inhibitory activities of crocin and safranal (the most important active principles in saffron) and, subsequently, designed a series of safranal derivatives to evaluate which chemical modifications confer enhanced inhibition of the hMAO isoforms. Docking simulations were performed in order to identify key molecular recognitions of these inhibitors with both isoforms of hMAO. In this regard, different mechanisms of action were revealed. This study concludes that safranal and crocin represent useful leads for the discovery of novel hMAO inhibitors for the clinical management of psychiatric and neurodegenerative disorders.

  3. Combining the Many-Body GW Formalism with Classical Polarizable Models: Insights on the Electronic Structure of Molecular Solids.

    Science.gov (United States)

    Li, Jing; D'Avino, Gabriele; Duchemin, Ivan; Beljonne, David; Blase, Xavier

    2016-07-21

    We present an original hybrid QM/MM scheme merging the many-body Green's function GW formalism with classical discrete polarizable models and its application to the paradigmatic case of a pentacene crystal. Our calculated transport gap is found to be in excellent agreement with reference periodic bulk GW calculations, together with properly parametrized classical microelectrostatic calculations, and with photoionization measurements at crystal surfaces. More importantly, we prove that the gap is insensitive to the partitioning of pentacene molecules in QM and MM subsystems, as a result of the mutual compensation of quantum and classical polarizabilities, clarifying the relation between polarization energy and delocalization. The proposed hybrid method offers a computationally attractive strategy to compute the full spectrum of charged excitations in complex molecular environments, accounting for both QM and MM contributions to the polarization energy, a crucial requirement in the limit of large QM subsystems.

  4. Insights into the molecular recognition of the granuphilin C2A domain with PI(4,5)P2.

    Science.gov (United States)

    Wan, Chanjuan; Wu, Bo; Song, Zhenwei; Zhang, Jiahai; Chu, Huiying; Wang, Aoli; Liu, Qingsong; Shi, Yunyu; Li, Guohui; Wang, Junfeng

    2015-02-01

    Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is a key player in regulating the process of excytosis, including insulin secretion. Granuphilin, a tandem C2 domain containing protein, mediates the docking of insulin granules onto plasma membrane. The C2A domain plays key roles in this process through interaction with PI(4,5)P2. In this study, we have investigated the molecular recognition mechanism of granuphilin-C2A domain to PI(4,5)P2 head group, and further to PI(4,5)P2-nanodisc by NMR, ITC, MST and SEC methods. Our results demonstrate that PI(4,5)P2 binds to the concave surface of granuphilin-C2A domain. The key residues involved in the binding were validated by mutation analysis.

  5. Molecular Theory of Detonation Initiation: Insight from First Principles Modeling of the Decomposition Mechanisms of Organic Nitro Energetic Materials.

    Science.gov (United States)

    Tsyshevsky, Roman V; Sharia, Onise; Kuklja, Maija M

    2016-02-19

    This review presents a concept, which assumes that thermal decomposition processes play a major role in defining the sensitivity of organic energetic materials to detonation initiation. As a science and engineering community we are still far away from having a comprehensive molecular detonation initiation theory in a widely agreed upon form. However, recent advances in experimental and theoretical methods allow for a constructive and rigorous approach to design and test the theory or at least some of its fundamental building blocks. In this review, we analyzed a set of select experimental and theoretical articles, which were augmented by our own first principles modeling and simulations, to reveal new trends in energetic materials and to refine known existing correlations between their structures, properties, and functions. Our consideration is intentionally limited to the processes of thermally stimulated chemical reactions at the earliest stage of decomposition of molecules and materials containing defects.

  6. How do trehalose, maltose and sucrose influence some structural and dynamical properties of lysozyme ? An insight from Molecular Dynamics simulations

    CERN Document Server

    Lerbret, A; Affouard, F; Hedoux, A; Guinet, Y; Descamps, M

    2007-01-01

    The influence of three well-known disaccharides, namely trehalose, maltose and sucrose, on some structural and dynamical properties of lysozyme has been investigated by means of molecular dynamics computer simulations in the 37-60 wt % concentration range. The effects of sugars on the protein conformation are found relatively weak, in agreement with the preferential hydration of lysozyme. Conversely, sugars seem to increase significantly the relaxation times of the protein. These effects are shown to be correlated to the fractional solvent accessibilities of lysozyme residues and further support the slaving of protein dynamics. Moreover, a significant increase in the relaxation times of lysozyme, sugars and water molecules is observed within the studied concentration range and may result from the percolation of the hydrogen-bond network of sugar molecules. This percolation appears to be of primary importance to explain the influence of sugars on the dynamical properties of lysozyme and water.

  7. Molecular Theory of Detonation Initiation: Insight from First Principles Modeling of the Decomposition Mechanisms of Organic Nitro Energetic Materials

    Directory of Open Access Journals (Sweden)

    Roman V. Tsyshevsky

    2016-02-01

    Full Text Available This review presents a concept, which assumes that thermal decomposition processes play a major role in defining the sensitivity of organic energetic materials to detonation initiation. As a science and engineering community we are still far away from having a comprehensive molecular detonation initiation theory in a widely agreed upon form. However, recent advances in experimental and theoretical methods allow for a constructive and rigorous approach to design and test the theory or at least some of its fundamental building blocks. In this review, we analyzed a set of select experimental and theoretical articles, which were augmented by our own first principles modeling and simulations, to reveal new trends in energetic materials and to refine known existing correlations between their structures, properties, and functions. Our consideration is intentionally limited to the processes of thermally stimulated chemical reactions at the earliest stage of decomposition of molecules and materials containing defects.

  8. Insights into the phosphatase and the synthase activities of human bisphosphoglycerate mutase: a quantum mechanics/molecular mechanics simulation.

    Science.gov (United States)

    Chu, Wen-Ting; Zheng, Qing-Chuan; Zhang, Hong-Xing

    2014-03-07

    Bisphosphoglycerate mutase (BPGM) is a multi-activity enzyme. Its main function is to synthesize the 2,3-bisphosphoglycerate, the allosteric effector of hemoglobin. This enzyme can also catalyze the 2,3-bisphosphoglycerate to the 3-phosphoglycerate. In this study, the reaction mechanisms of both the phosphatase and the synthase activities of human bisphosphoglycerate mutase were theoretically calculated by using the quantum mechanics/molecular mechanics method based on the metadynamics and umbrella sampling simulations. The simulation results not only show the free energy curve of the phosphatase and the synthase reactions, but also reveal the important role of some residues in the active site. Additionally, the energy barriers of the two reactions indicate that the activity of the synthase in human bisphosphoglycerate mutase is much higher than that of the phosphatase. The estimated reaction barriers are consistent with the experimental data. Therefore, our work can give important information to understand the catalytic mechanism of the bisphosphoglycerate mutase family.

  9. Structural analysis of prolyl oligopeptidases using molecular docking and dynamics: insights into conformational changes and ligand binding.

    Directory of Open Access Journals (Sweden)

    Swati Kaushik

    Full Text Available Prolyl oligopeptidase (POP is considered as an important pharmaceutical target for the treatment of numerous diseases. Despite enormous studies on various aspects of POPs structure and function still some of the questions are intriguing like conformational dynamics of the protein and interplay between ligand entry/egress. Here, we have used molecular modeling and docking based approaches to unravel questions like differences in ligand binding affinities in three POP species (porcine, human and A. thaliana. Despite high sequence and structural similarity, they possess different affinities for the ligands. Interestingly, human POP was found to be more specific, selective and incapable of binding to a few planar ligands which showed extrapolation of porcine POP in human context is more complicated. Possible routes for substrate entry and product egress were also investigated by detailed analyses of molecular dynamics (MD simulations for the three proteins. Trajectory analysis of bound and unbound forms of three species showed differences in conformational dynamics, especially variations in β-propeller pore size, which was found to be hidden by five lysine residues present on blades one and seven. During simulation, β-propeller pore size was increased by ∼2 Å in porcine ligand-bound form which might act as a passage for smaller product movement as free energy barrier was reduced, while there were no significant changes in human and A. thaliana POPs. We also suggest that these differences in pore size could lead to fundamental differences in mode of product egress among three species. This analysis also showed some functionally important residues which can be used further for in vitro mutagenesis and inhibitor design. This study can help us in better understanding of the etiology of POPs in several neurodegenerative diseases.

  10. Adsorption of Synthetic Cationic Polymers on Model Phospholipid Membranes: Insight from Atomic-Scale Molecular Dynamics Simulations.

    Science.gov (United States)

    Kostritskii, Andrei Yu; Kondinskaia, Diana A; Nesterenko, Alexey M; Gurtovenko, Andrey A

    2016-10-11

    Although synthetic cationic polymers represent a promising class of effective antibacterial agents, the molecular mechanisms behind their antimicrobial activity remain poorly understood. To this end, we employ atomic-scale molecular dynamics simulations to explore adsorption of several linear cationic polymers of different chemical structure and protonation (polyallylamine (PAA), polyethylenimine (PEI), polyvinylamine (PVA), and poly-l-lysine (PLL)) on model bacterial membranes (4:1 mixture of zwitterionic phosphatidylethanolamine (PE) and anionic phosphatidylglycerol (PG) lipids). Overall, our findings show that binding of polycations to the anionic membrane surface effectively neutralizes its charge, leading to the reorientation of water molecules close to the lipid/water interface and to the partial release of counterions to the water phase. In certain cases, one has even an overcharging of the membrane, which was shown to be a cooperative effect of polymer charges and lipid counterions. Protonated amine groups of polycations are found to interact preferably with head groups of anionic lipids, giving rise to formation of hydrogen bonds and to a noticeable lateral immobilization of the lipids. While all the above findings are mostly defined by the overall charge of a polymer, we found that the polymer architecture also matters. In particular, PVA and PEI are able to accumulate anionic PG lipids on the membrane surface, leading to lipid segregation. In turn, PLL whose charge twice exceeds charges of PVA/PEI does not induce such lipid segregation due to its considerably less compact architecture and relatively long side chains. We also show that partitioning of a polycation into the lipid/water interface is an interplay between its protonation level (the overall charge) and hydrophobicity of the backbone. Therefore, a possible strategy in creating highly efficient antimicrobial polymeric agents could be in tuning these polycation's properties through proper

  11. Platelet-type von Willebrand disease: new insights into the molecular pathophysiology of a unique platelet defect.

    Science.gov (United States)

    Othman, Maha; Kaur, Harmanpreet; Emsley, Jonas

    2013-09-01

    Compared with coagulation factor defects, little attention is given to defects of platelet function as causes of rare bleeding disorders. Platelet-type von Willebrand disease (PT-VWD) is an autosomal dominant bleeding disorder and is unique among platelet disorders because it is characterized by platelet hyperresponsiveness rather than decreased function. The disease is caused by gain-of-function mutations in the platelet GP1BA gene, which codes for the platelet von Willebrand factor (VWF) receptor, GPIbα. Only five mutations (four missense and one deletion) have so far been reported. Affected patients suffer from mild to moderate mucocutaneous bleeding, low VWF activity compared with antigen, decreased high-molecular-weight VWF multimers, variable degree of thrombocytopenia and typically platelet aggregation in response to low concentrations of ristocetin. All reported PT-VWD missense mutations occur within the R-loop of GPIbα and it was speculated that the introduction of short branched chain mutations such as Val in PT-VWD stabilized the extended β-hairpin. Examination of this theory by surveying all the available GPIbα structures showed that a distinct conformation predominates for the R-loop when GPIbα is not bound to VWF-A1 and this provides the framework of a new hypothesis for the molecular basis of PT-VWD. Worldwide efforts to improve diagnosis of PT-VWD continue, and international systematic studies are required to further our understanding of the phenotype and the influence of the hyperresponsive GPIbα beyond hemostasis.

  12. Insights into the complex formed by matrix metalloproteinase-2 and alloxan inhibitors: molecular dynamics simulations and free energy calculations.

    Directory of Open Access Journals (Sweden)

    Ilenia Giangreco

    Full Text Available Matrix metalloproteinases (MMP are well-known biological targets implicated in tumour progression, homeostatic regulation, innate immunity, impaired delivery of pro-apoptotic ligands, and the release and cleavage of cell-surface receptors. Hence, the development of potent and selective inhibitors targeting these enzymes continues to be eagerly sought. In this paper, a number of alloxan-based compounds, initially conceived to bias other therapeutically relevant enzymes, were rationally modified and successfully repurposed to inhibit MMP-2 (also named gelatinase A in the nanomolar range. Importantly, the alloxan core makes its debut as zinc binding group since it ensures a stable tetrahedral coordination of the catalytic zinc ion in concert with the three histidines of the HExxHxxGxxH metzincin signature motif, further stabilized by a hydrogen bond with the glutamate residue belonging to the same motif. The molecular decoration of the alloxan core with a biphenyl privileged structure allowed to sample the deep S(1' specificity pocket of MMP-2 and to relate the high affinity towards this enzyme with the chance of forming a hydrogen bond network with the backbone of Leu116 and Asn147 and the side chains of Tyr144, Thr145 and Arg149 at the bottom of the pocket. The effect of even slight structural changes in determining the interaction at the S(1' subsite of MMP-2 as well as the nature and strength of the binding is elucidated via molecular dynamics simulations and free energy calculations. Among the herein presented compounds, the highest affinity (pIC(50 = 7.06 is found for BAM, a compound exhibiting also selectivity (>20 towards MMP-2, as compared to MMP-9, the other member of the gelatinases.

  13. Structural insight into tetrameric hTRPV1 from homology modeling, molecular docking, molecular dynamics simulation, virtual screening, and bioassay validations.

    Science.gov (United States)

    Feng, Zhiwei; Pearce, Larry V; Xu, Xiaomeng; Yang, Xiaole; Yang, Peng; Blumberg, Peter M; Xie, Xiang-Qun

    2015-03-23

    The transient receptor potential vanilloid type 1 (TRPV1) is a heat-activated cation channel protein, which contributes to inflammation, acute and persistent pain. Antagonists of human TRPV1 (hTRPV1) represent a novel therapeutic approach for the treatment of pain. Developing various antagonists of hTRPV1, however, has been hindered by the unavailability of a 3D structure of hTRPV1. Recently, the 3D structures of rat TRPV1 (rTRPV1) in the presence and absence of ligand have been reported as determined by cryo-EM. rTRPV1 shares 85.7% sequence identity with hTRPV1. In the present work, we constructed and reported the 3D homology tetramer model of hTRPV1 based on the cryo-EM structures of rTRPV1. Molecular dynamics (MD) simulations, energy minimizations, and prescreen were applied to select and validate the best model of hTRPV1. The predicted binding pocket of hTRPV1 consists of two adjacent monomers subunits, which were congruent with the experimental rTRPV1 data and the cyro-EM structures of rTRPV1. The detailed interactions between hTRPV1 and its antagonists or agonists were characterized by molecular docking, which helped us to identify the important residues. Conformational changes of hTRPV1 upon antagonist/agonist binding were also explored by MD simulation. The different movements of compounds led to the different conformational changes of monomers in hTRPV1, indicating that TRPV1 works in a concerted way, resembling some other channel proteins such as aquaporins. We observed that the selective filter was open when hTRPV1 bound with an agonist during MD simulation. For the lower gate of hTRPV1, we observed large similarities between hTRPV1 bound with antagonist and with agonist. A five-point pharmacophore model based on several antagonists was established, and the structural model was used to screen in silico for new antagonists for hTRPV1. By using the 3D TRPV1 structural model above, the pilot in silico screening has begun to yield promising hits with

  14. The transcriptome of Trichuris suis--first molecular insights into a parasite with curative properties for key immune diseases of humans.

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    Cinzia Cantacessi

    Full Text Available BACKGROUND: Iatrogenic infection of humans with Trichuris suis (a parasitic nematode of swine is being evaluated or promoted as a biological, curative treatment of immune diseases, such as inflammatory bowel disease (IBD and ulcerative colitis, in humans. Although it is understood that short-term T. suis infection in people with such diseases usually induces a modified Th2-immune response, nothing is known about the molecules in the parasite that induce this response. METHODOLOGY/PRINCIPAL FINDINGS: As a first step toward filling the gaps in our knowledge of the molecular biology of T. suis, we characterised the transcriptome of the adult stage of this nematode employing next-generation sequencing and bioinformatic techniques. A total of ∼65,000,000 reads were generated and assembled into ∼20,000 contiguous sequences ( = contigs; ∼17,000 peptides were predicted and classified based on homology searches, protein motifs and gene ontology and biological pathway mapping. CONCLUSIONS: These analyses provided interesting insights into a number of molecular groups, particularly predicted excreted/secreted molecules (n = 1,288, likely to be involved in the parasite-host interactions, and also various molecules (n = 120 linked to chemokine, T-cell receptor and TGF-β signalling as well as leukocyte transendothelial migration and natural killer cell-mediated cytotoxicity, which are likely to be immuno-regulatory or -modulatory in the infected host. This information provides a conceptual framework within which to test the immunobiological basis for the curative effect of T. suis infection in humans against some immune diseases. Importantly, the T. suis transcriptome characterised herein provides a curated resource for detailed studies of the immuno-molecular biology of this parasite, and will underpin future genomic and proteomic explorations.

  15. Insights into regioselective metabolism of mefenamic acid by cytochrome P450 BM3 mutants through crystallography, docking, molecular dynamics, and free energy calculations.

    Science.gov (United States)

    Capoferri, Luigi; Leth, Rasmus; ter Haar, Ernst; Mohanty, Arun K; Grootenhuis, Peter D J; Vottero, Eduardo; Commandeur, Jan N M; Vermeulen, Nico P E; Jørgensen, Flemming Steen; Olsen, Lars; Geerke, Daan P

    2016-03-01

    Cytochrome P450 BM3 (CYP102A1) mutant M11 is able to metabolize a wide range of drugs and drug-like compounds. Among these, M11 was recently found to be able to catalyze formation of human metabolites of mefenamic acid and other nonsteroidal anti-inflammatory drugs (NSAIDs). Interestingly, single active-site mutations such as V87I were reported to invert regioselectivity in NSAID hydroxylation. In this work, we combine crystallography and molecular simulation to study the effect of single mutations on binding and regioselective metabolism of mefenamic acid by M11 mutants. The heme domain of the protein mutant M11 was expressed, purified, and crystallized, and its X-ray structure was used as template for modeling. A multistep approach was used that combines molecular docking, molecular dynamics (MD) simulation, and binding free-energy calculations to address protein flexibility. In this way, preferred binding modes that are consistent with oxidation at the experimentally observed sites of metabolism (SOMs) were identified. Whereas docking could not be used to retrospectively predict experimental trends in regioselectivity, we were able to rank binding modes in line with the preferred SOMs of mefenamic acid by M11 and its mutants by including protein flexibility and dynamics in free-energy computation. In addition, we could obtain structural insights into the change in regioselectivity of mefenamic acid hydroxylation due to single active-site mutations. Our findings confirm that use of MD and binding free-energy calculation is useful for studying biocatalysis in those cases in which enzyme binding is a critical event in determining the selective metabolism of a substrate.

  16. The biogeography of kelps (Laminariales, Phaeophyceae): a global analysis with new insights from recent advances in molecular phylogenetics

    Science.gov (United States)

    Bolton, John J.

    2010-12-01

    Despite their ecological and economic importance, no summary of kelp global biogeography has been produced for almost two decades. The circumscription of the order Laminariales and familial and generic relationships in the group have changed considerably recently, in the light of molecular data. A global summary and geographical analysis of kelp species and their distributions (112 species in 33 genera) is presented. These data are analysed and discussed from the perspective of the new consensus of relationships within the group, and likely evolutionary events. The putative ancestors of the kelps occur and are overwhelmingly most diverse, in the cooler waters of northern Japan. The biogeographical evidence suggests three main lines of subsequent evolution: (a) a diversification producing the four ‘derived’ families Alariaceae, Costariceae, Laminariaceae, and Lessoniaceae and most extant genera in the temperate northern Pacific, probably during the Miocene. (b) The evolution of an Arctic flora which invaded the North Atlantic following the opening of the Bering Strait ca. 5.5 Ma. (c) At least four separate crossings, by different genera, of tropical regions from Northern to Southern Hemisphere (and one in the opposite direction). The recorded impacts of man on these distributions have thus far been minimal, with the notable exceptions of Undaria pinnatifida and species of Saccharina (grown in aquaculture systems for human food). Most genera are monospecific, with many confined to either the western or eastern temperate North Pacific, whereas the distribution of the most species-rich genera ( Alaria, Laminaria, Saccharina) includes the Arctic, and they are widespread in the North Atlantic. This rapid species-level evolution is hypothesised to have been promoted by the relatively recent invasion of the Atlantic by these taxa. The crossing of the tropics has occurred in warm-temperate species some of which occur and are sometimes abundant, in deeper water in today

  17. Focused examination of the intestinal lamina propria yields greater molecular insight into mechanisms underlying SIV induced immune dysfunction.

    Directory of Open Access Journals (Sweden)

    Mahesh Mohan

    Full Text Available BACKGROUND: The Gastrointestinal (GI tract is critical to AIDS pathogenesis as it is the primary site for viral transmission and a major site of viral replication and CD4(+ T cell destruction. Consequently GI disease, a major complication of HIV/SIV infection can facilitate translocation of lumenal bacterial products causing localized/systemic immune activation leading to AIDS progression. METHODOLOGY/PRINCIPAL FINDINGS: To better understand the molecular mechanisms underlying GI disease we analyzed global gene expression profiles sequentially in the intestine of the same animals prior to and at 21 and 90d post SIV infection (PI. More importantly we maximized information gathering by examining distinct mucosal components (intraepithelial lymphocytes, lamina propria leukocytes [LPL], epithelium and fibrovascular stroma separately. The use of sequential intestinal resections combined with focused examination of distinct mucosal compartments represents novel approaches not previously attempted. Here we report data pertaining to the LPL. A significant increase (±1.7-fold in immune defense/inflammation, cell adhesion/migration, cell signaling, transcription and cell division/differentiation genes were observed at 21 and 90d PI. Genes associated with the JAK-STAT pathway (IL21, IL12R, STAT5A, IL10, SOCS1 and T-cell activation (NFATc1, CDK6, Gelsolin, Moesin were notably upregulated at 21d PI. Markedly downregulated genes at 21d PI included IL17D/IL27 and IL28B/IFNγ3 (anti-HIV/viral, activation induced cytidine deaminase (B-cell function and approximately 57 genes regulating oxidative phosphorylation, a critical metabolic shift associated with T-cell activation. The 90d transcriptome revealed further augmentation of inflammation (CXCL11, chitinase-1, JNK3, immune activation (CD38, semaphorin7A, CD109, B-cell dysfunction (CD70, intestinal microbial translocation (Lipopolysaccharide binding protein and mitochondrial antiviral signaling (NLRX1 genes

  18. Non-destructive foraminiferal paleoclimatic proxies: A brief insight

    Digital Repository Service at National Institute of Oceanography (India)

    Saraswat, R.

    Non-Destructive Foraminiferal Paleoclimatic Proxies: A Brief Insight The knowledge of past climate can help us to understand imminent climatic changes. Oceans are the vast archives of past climate. Various indirect techniques termed as proxies...

  19. The Nucleotide Capture Region of Alpha Hemolysin: Insights into Nanopore Design for DNA Sequencing from Molecular Dynamics Simulations

    Science.gov (United States)

    Manara, Richard M. A.; Tomasio, Susana; Khalid, Syma

    2015-01-01

    Nanopore technology for DNA sequencing is constantly being refined and improved. In strand sequencing a single strand of DNA is fed through a nanopore and subsequent fluctuations in the current are measured. A major hurdle is that the DNA is translocated through the pore at a rate that is too fast for the current measurement systems. An alternative approach is “exonuclease sequencing”, in which an exonuclease is attached to the nanopore that is able to process the strand, cleaving off one base at a time. The bases then flow through the nanopore and the current is measured. This method has the advantage of potentially solving the translocation rate problem, as the speed is controlled by the exonuclease. Here we consider the practical details of exonuclease attachment to the protein alpha hemolysin. We employ molecular dynamics simulations to determine the ideal (a) distance from alpha-hemolysin, and (b) the orientation of the monophosphate nucleotides upon release from the exonuclease such that they will enter the protein. Our results indicate an almost linear decrease in the probability of entry into the protein with increasing distance of nucleotide release. The nucleotide orientation is less significant for entry into the protein.

  20. Grazers, shredders and filtering carnivores--the evolution of feeding ecology in Drusinae (Trichoptera: Limnephilidae): insights from a molecular phylogeny.

    Science.gov (United States)

    Pauls, Steffen U; Graf, Wolfram; Haase, Peter; Lumbsch, H Thorsten; Waringer, Johann

    2008-02-01

    We examined the phylogenetic relationships between species and genera within the caddisfly subfamily Drusinae (Trichoptera: Limnephilidae) using sequence data from two mitochondrial loci (cytochrome oxidase 1, large subunit rRNA) and one nuclear gene (wingless). Sequence data were analysed for 28 species from five genera from the subfamily. We analysed individual and combined data sets using a Bayesian Markov Chain Monte Carlo and a maximum parsimony approach and compared the performance of each partition for resolving phylogenetic relationships at this level. In terms of resolution and phylogenetic utility wingless outperformed the two mitochondrial gene partitions. Using both Shimodaira-Hasegawa and expected likelihood weights tests we tested several hypotheses of relationships previously inferred based on adult morphological characters. The data did not support the generic concept, or many previously proposed species groupings, based on adult morphology. In contrast, the molecular data correlated with the morphology and feeding ecology of larvae. Using Bayesian ancestral character state reconstructions we inferred the evolution of feeding ecology and relevant larval morphological characters. Our analyses showed that within the subfamily Drusinae two derived feeding types evolved. One of these--grazing epilithic algae--is otherwise unusual in the Limnephilidae and may have promoted the high degree of diversity in the Drusinae.

  1. The Nucleotide Capture Region of Alpha Hemolysin: Insights into Nanopore Design for DNA Sequencing from Molecular Dynamics Simulations.

    Science.gov (United States)

    Manara, Richard M A; Tomasio, Susana; Khalid, Syma

    2015-01-27

    Nanopore technology for DNA sequencing is constantly being refined and improved. In strand sequencing a single strand of DNA is fed through a nanopore and subsequent fluctuations in the current are measured. A major hurdle is that the DNA is translocated through the pore at a rate that is too fast for the current measurement systems. An alternative approach is "exonuclease sequencing", in which an exonuclease is attached to the nanopore that is able to process the strand, cleaving off one base at a time. The bases then flow through the nanopore and the current is measured. This method has the advantage of potentially solving the translocation rate problem, as the speed is controlled by the exonuclease. Here we consider the practical details of exonuclease attachment to the protein alpha hemolysin. We employ molecular dynamics simulations to determine the ideal (a) distance from alpha-hemolysin, and (b) the orientation of the monophosphate nucleotides upon release from the exonuclease such that they will enter the protein. Our results indicate an almost linear decrease in the probability of entry into the protein with increasing distance of nucleotide release. The nucleotide orientation is less significant for entry into the protein.

  2. Structural insights into the interactions of xpt riboswitch with novel guanine analogues: a molecular dynamics simulation study.

    Science.gov (United States)

    Jain, Swapan S; Sonavane, Uddhavesh B; Uppuladinne, Mallikarjunachari V N; McLaughlin, Emily C; Wang, Weiqing; Black, Sheneil; Joshi, Rajendra R

    2015-01-01

    Ligand recognition in purine riboswitches is a complex process requiring different levels of conformational changes. Recent efforts in the area of purine riboswitch research have focused on ligand analogue binding studies. In the case of the guanine xanthine phosphoribosyl transferase (xpt) riboswitch, synthetic analogues that resemble guanine have the potential to tightly bind and subsequently influence the genetic expression of xpt mRNA in prokaryotes. We have carried out 25 ns Molecular Dynamics (MD) simulation studies of the aptamer domain of the xpt G-riboswitch in four different states: guanine riboswitch in free form, riboswitch bound with its cognate ligand guanine, and with two guanine analogues SJ1 and SJ2. Our work reveals novel interactions of SJ1 and SJ2 ligands with the binding core residues of the riboswitch. The ligands proposed in this work bind to the riboswitch with greater overall stability and lower root mean square deviations and fluctuations compared to guanine ligand. Reporter gene assay data demonstrate that the ligand analogues, upon binding to the RNA, lower the genetic expression of the guanine riboswitch. Our work has important implications for future ligand design and binding studies in the exciting field of riboswitches.

  3. On the structure of crystalline and molten cryolite: Insights from the ab initio molecular dynamics in NpT ensemble

    Science.gov (United States)

    Bučko, Tomáš; Šimko, František

    2016-02-01

    Ab initio molecular dynamics simulations in isobaric-isothermal ensemble have been performed to study the low- and the high-temperature crystalline and liquid phases of cryolite. The temperature induced transitions from the low-temperature solid (α) to the high-temperature solid phase (β) and from the phase β to the liquid phase have been simulated using a series of MD runs performed at gradually increasing temperature. The structure of crystalline and liquid phases is analysed in detail and our computational approach is shown to reliably reproduce the available experimental data for a wide range of temperatures. Relatively frequent reorientations of the AlF6 octahedra observed in our simulation of the phase β explain the thermal disorder in positions of the F- ions observed in X-ray diffraction experiments. The isolated AlF63-, AlF52-, AlF4-, as well as the bridged Al 2 Fm 6 - m ionic entities have been identified as the main constituents of cryolite melt. In accord with the previous high-temperature NMR and Raman spectroscopic experiments, the compound AlF5 2 - has been shown to be the most abundant Al-containing species formed in the melt. The characteristic vibrational frequencies for the AlFn 3 - n species in realistic environment have been determined and the computed values have been found to be in a good agreement with experiment.

  4. Molecular phylogenetics of cixiid planthoppers (Hemiptera: Fulgoromorpha): new insights from combined analyses of mitochondrial and nuclear genes.

    Science.gov (United States)

    Ceotto, Paula; Kergoat, Gaël J; Rasplus, Jean-Yves; Bourgoin, Thierry

    2008-08-01

    The planthopper family Cixiidae (Hemiptera: Fulgoromorpha) comprises approximately 160 genera and 2000 species divided in three subfamilies: Borystheninae, Bothriocerinae and Cixiinae, the later with 16 tribes. The current paper represents the first attempt to estimate phylogenetic relationships within Cixiidae based on molecular data. We use a total of 3652bp sequence alignment of four genes: the mitochondrial coding genes Cytochrome c Oxidase subunit 1 (Cox1) and Cytochrome b (Cytb), a portion of the nuclear 18S rDNA and two non-contiguous portions of the nuclear 28S rDNA. The phylogenetic relationships of 72 terminal specimens were reconstructed using both maximum parsimony and Bayesian inference methods. Through the analysis of this empirical dataset, we also provide comparisons among different a priori partitioning strategies and the use of mixture models in a Bayesian framework. Our comparisons suggest that mixture models overcome the benefits obtained by partitioning the data according to codon position and gene identity, as they provide better accuracy in phylogenetic reconstructions. The recovered maximum parsimony and Bayesian inference phylogenies suggest that the family Cixiidae is paraphyletic in respect with Delphacidae. The paraphyly of the subfamily Cixiinae is also recovered by both approaches. In contrast to a morphological phylogeny recently proposed for cixiids, subfamilies Borystheninae and Bothriocerinae form a monophyletic group.

  5. Colonization and diversification in the African 'sky islands': insights from fossil-calibrated molecular dating of Lychnis (Caryophyllaceae).

    Science.gov (United States)

    Gizaw, Abel; Brochmann, Christian; Nemomissa, Sileshi; Wondimu, Tigist; Masao, Catherine Aloyce; Tusiime, Felly Mugizi; Abdi, Ahmed Abdikadir; Oxelman, Bengt; Popp, Magnus; Dimitrov, Dimitar

    2016-07-01

    The flora on the isolated high African mountains or 'sky islands' is remarkable for its peculiar adaptations, local endemism and striking biogeographical connections to remote parts of the world. Ages of the plant lineages and the timing of their radiations have frequently been debated but remain contentious as there are few estimates based on explicit models and fossil-calibrated molecular clocks. We used the plastid region maturaseK (matK) and a Caryophylloflora paleogenica fossil to infer the age of the genus Lychnis, and constructed a data set of three plastid (matK; a ribosomal protein S16 (rps16); and an intergenic spacer (psbE-petL)) and two nuclear (internal transcribed spacer (ITS) and a region spanning exon 18-24 in the second largest subunit of RNA polymerase II (RPB2)) loci for joint estimation of the species tree and divergence time of the African representatives. The time of divergence of the African high-altitude Lychnis was placed in the late Miocene to early Pliocene. A single speciation event was inferred in the early Pliocene; subsequent speciation took place sporadically from the late Pliocene to the middle Pleistocene. We provide further support for a Eurasian origin of the African 'sky islands' floral elements, which seem to have been recruited via dispersals at different times: some old, as in Lychnis, and others very recent. We show that dispersal and diversification within Africa play an important role in shaping these isolated plant communities.

  6. Structural analysis of the human SYCE2-TEX12 complex provides molecular insights into synaptonemal complex assembly.

    Science.gov (United States)

    Davies, Owen R; Maman, Joseph D; Pellegrini, Luca

    2012-07-01

    The successful completion of meiosis is essential for all sexually reproducing organisms. The synaptonemal complex (SC) is a large proteinaceous structure that holds together homologous chromosomes during meiosis, providing the structural framework for meiotic recombination and crossover formation. Errors in SC formation are associated with infertility, recurrent miscarriage and aneuploidy. The current lack of molecular information about the dynamic process of SC assembly severely restricts our understanding of its function in meiosis. Here, we provide the first biochemical and structural analysis of an SC protein component and propose a structural basis for its function in SC assembly. We show that human SC proteins SYCE2 and TEX12 form a highly stable, constitutive complex, and define the regions responsible for their homotypic and heterotypic interactions. Biophysical analysis reveals that the SYCE2-TEX12 complex is an equimolar hetero-octamer, formed from the association of an SYCE2 tetramer and two TEX12 dimers. Electron microscopy shows that biochemically reconstituted SYCE2-TEX12 complexes assemble spontaneously into filamentous structures that resemble the known physical features of the SC central element (CE). Our findings can be combined with existing biological data in a model of chromosome synapsis driven by growth of SYCE2-TEX12 higher-order structures within the CE of the SC.

  7. Computational Insight to Improve the Thermal Isomerisation Performance of Overcrowded Alkene-Based Molecular Motors through Structural Redesign.

    Science.gov (United States)

    Oruganti, Baswanth; Wang, Jun; Durbeej, Bo

    2016-11-04

    Synthetic overcrowded alkene-based molecular motors achieve 360° unidirectional rotary motion of one motor half (rotator) relative to the other (stator) through sequential photochemical and thermal isomerisation steps. In order to facilitate and expand the use of these motors for various applications, it is important to investigate ways to increase the rates and efficiencies of the reactions governing the rotary motion. Here, we use computational methods to explore whether the thermal isomerisation performance of some of the fastest available motors of this type can be further improved by reducing the sizes of the motor halves. Presenting three new redesigned motors that combine an indanylidene rotator with a cyclohexadiene, pyran or thiopyran stator, we first use multiconfigurational quantum chemical methods to verify that the photoisomerisations of these motors sustain unidirectional rotary motion. Then, by performing density functional calculations, we identify both stepwise and concerted mechanisms for the thermal isomerisations of the motors and show that the rate-determining free-energy barriers of these processes are up to 25 kJ mol(-1) smaller than those of the original motors. Furthermore, the thermal isomerisations of the redesigned motors proceed in fewer steps. Altogether, the results suggest that the redesigned motors are useful templates for improving the thermal isomerisation performance of existing overcrowded alkene-based motors.

  8. Mechanical operation and intersubunit coordination of ring-shaped molecular motors: insights from single-molecule studies.

    Science.gov (United States)

    Liu, Shixin; Chistol, Gheorghe; Bustamante, Carlos

    2014-05-06

    Ring NTPases represent a large and diverse group of proteins that couple their nucleotide hydrolysis activity to a mechanical task involving force generation and some type of transport process in the cell. Because of their shape, these enzymes often operate as gates that separate distinct cellular compartments to control and regulate the passage of chemical species across them. In this manner, ions and small molecules are moved across membranes, biopolymer substrates are segregated between cells or moved into confined spaces, double-stranded nucleic acids are separated into single strands to provide access to the genetic information, and polypeptides are unfolded and processed for recycling. Here we review the recent advances in the characterization of these motors using single-molecule manipulation and detection approaches. We describe the various mechanisms by which ring motors convert chemical energy to mechanical force or torque and coordinate the activities of individual subunits that constitute the ring. We also examine how single-molecule studies have contributed to a better understanding of the structural elements involved in motor-substrate interaction, mechanochemical coupling, and intersubunit coordination. Finally, we discuss how these molecular motors tailor their operation-often through regulation by other cofactors-to suit their unique biological functions.

  9. Molecular Evidence for Convergence and Parallelism in Evolution of Complex Brains of Cephalopod Molluscs: Insights from Visual Systems.

    Science.gov (United States)

    Yoshida, M A; Ogura, A; Ikeo, K; Shigeno, S; Moritaki, T; Winters, G C; Kohn, A B; Moroz, L L

    2015-12-01

    Coleoid cephalopods show remarkable evolutionary convergence with vertebrates in their neural organization, including (1) eyes and visual system with optic lobes, (2) specialized parts of the brain controlling learning and memory, such as vertical lobes, and (3) unique vasculature supporting such complexity of the central nervous system. We performed deep sequencing of eye transcriptomes of pygmy squids (Idiosepius paradoxus) and chambered nautiluses (Nautilus pompilius) to decipher the molecular basis of convergent evolution in cephalopods. RNA-seq was complemented by in situ hybridization to localize the expression of selected genes. We found three types of genomic innovations in the evolution of complex brains: (1) recruitment of novel genes into morphogenetic pathways, (2) recombination of various coding and regulatory regions of different genes, often called "evolutionary tinkering" or "co-option", and (3) duplication and divergence of genes. Massive recruitment of novel genes occurred in the evolution of the "camera" eye from nautilus' "pinhole" eye. We also showed that the type-2 co-option of transcription factors played important roles in the evolution of the lens and visual neurons. In summary, the cephalopod convergent morphological evolution of the camera eyes was driven by a mosaic of all types of gene recruitments. In addition, our analysis revealed unexpected variations of squids' opsins, retinochromes, and arrestins, providing more detailed information, valuable for further research on intra-ocular and extra-ocular photoreception of the cephalopods.

  10. Structural insights for designed alanine-rich helices: Comparing NMR helicity measures and conformational ensembles from molecular dynamics simulation

    Science.gov (United States)

    Song, Kun; Stewart, James M.; Fesinmeyer, R. Matthew

    2013-01-01

    The temperature dependence of helical propensities for the peptides Ac-ZGG-(KAAAA)3X-NH2 (Z = Y or G, X = A, K, and d-Arg) were studied both experimentally and by molecular dynamics simulations. Good agreement is observed in both the absolute helical propensities as well as relative helical content along the sequence; the global minimum on the calculated free energy landscape corresponds to a single α-helical conformation running from K4 – A18 with some terminal fraying, particularly at the C-terminus. Energy component analysis shows that the single helix state has favorable intramolecular electrostatic energy due to hydrogen bonds, and that less-favorable two-helix globular states have favorable solvation energy. The central lysine residues do not appear to increase helicity; however, both experimental and simulation studies show increasing helicity in the series X = Ala → Lys → d-Arg. This C-capping preference was also experimentally confirmed in Ac-(KAAAA)3X-GY-NH2 and (KAAAA)3X-GY-NH2 sequences. The roles of the C-capping groups, and of lysines throughout the sequence, in the MD-derived ensembles are analyzed in detail. PMID:18428207

  11. Zucchini tigré mosaic virus is a distinct potyvirus in the papaya ringspot virus cluster: molecular and biological insights.

    Science.gov (United States)

    Romay, G; Lecoq, H; Desbiez, C

    2014-02-01

    In recent years, three new potyviruses have been described in the papaya ringspot virus (PRSV) cluster. In addition, two types of PRSV are recognized, type W, infecting cucurbit plants, and type P, infecting papaya and also cucurbits. A third type, PRSV-T, was also partially described in Guadeloupe. Complete genome sequencing of four PRSV-T isolates showed that this virus is a related virus that is distinct from PRSV, and the name zucchini tigré mosaic virus (ZTMV) is proposed, in reference to the typical symptoms observed in zucchini squash. Eleven other viral isolates from different geographic origins were confirmed as ZTMV isolates using the complete sequence of the cylindrical inclusion (CI) coding region, whereas pairwise sequence similarities in the coat protein (CP) coding region did not unambiguously distinguish ZTMV isolates from PRSV isolates. The use of the CI coding region for species demarcation appears more suitable than the CP coding region for closely related viruses. Principal coordinates analysis based on the biological behavior of the viral isolates studied clustered PRSV-P, PRSV-W and ZTMV isolates into three different groups. Therefore, ZTMV is different from PRSV in its molecular and biological properties.

  12. Molecular Origin of Gerstmann-Str ussler-Scheinker Syndrome: Insight from Computer Simulation of an Amyloidogenic Prion Peptide

    Energy Technology Data Exchange (ETDEWEB)

    Diadone, Isabella [University of L' Aquila, L' Aquila, Italy; DiNola, Alfredo [University of Rome; Smith, Jeremy C [ORNL

    2011-01-01

    Prion proteins become pathogenic through misfolding. Here, we characterize the folding of a peptide consisting of residues 109 122 of the Syrian hamster prion protein (the H1 peptide) and of a more amyloidogenic A117V point mutant that leads in humans to an inheritable form of the Gerstmann-Straeussler-Scheinker syndrome. Atomistic molecular dynamics simulations are performed for 2.5 s. Both peptides lose their -helical starting conformations and assume a -hairpin that is structurally similar in both systems. In each simulation several unfolding/refolding events occur, leading to convergence of the thermodynamics of the conformational states to within 1 kJ/mol. The similar stability of the -hairpin relative to the unfolded state is observed in the two peptides. However, substantial differences are found between the two unfolded states. A local minimum is found within the free energy unfolded basin of the A117V mutant populated by misfolded collapsed conformations of comparable stability to the -hairpin state, consistent with increased amyloidogenicity. This population, in which V117 stabilizes a hydrophobic core, is absent in the wild-type peptide. These results are supported by simulations of oligomers showing a slightly higher stability of the associated structures and a lower barrier to association for the mutated peptide. Hence, a single point mutation carrying only two additional methyl groups is here shown to be responsible for rather dramatic differences of structuring within the unfolded (misfolded) state.

  13. Molecular Dynamics Simulation of the Crystallizable Fragment of IgG1—Insights for the Design of Fcabs

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    Balder Lai

    2014-01-01

    Full Text Available An interesting format in the development of therapeutic monoclonal antibodies uses the crystallizable fragment of IgG1 as starting scaffold. Engineering of its structural loops allows generation of an antigen binding site. However, this might impair the molecule’s conformational stability, which can be overcome by introducing stabilizing point mutations in the CH3 domains. These point mutations often affect the stability and unfolding behavior of both the CH2 and CH3 domains. In order to understand this cross-talk, molecular dynamics simulations of the domains of the Fc fragment of human IgG1 are reported. The structure of human IgG1-Fc obtained from X-ray crystallography is used as a starting point for simulations of the wild-type protein at two different pH values. The stabilizing effect of a single point mutation in the CH3 domain as well as the impact of the hinge region and the glycan tree structure connected to the CH2 domains is investigated. Regions of high local flexibility were identified as potential sites for engineering antigen binding sites. Obtained data are discussed with respect to the available X-ray structure of IgG1-Fc, directed evolution approaches that screen for stability and use of the scaffold IgG1-Fc in the design of antigen binding Fc proteins.

  14. Insights into the Thiamine Diphosphate Enzyme Activation Mechanism: Computational Model for Transketolase Using a Quantum Mechanical/Molecular Mechanical Method.

    Science.gov (United States)

    Nauton, Lionel; Hélaine, Virgil; Théry, Vincent; Hecquet, Laurence

    2016-04-12

    We propose the first computational model for transketolase (TK), a thiamine diphosphate (ThDP)-dependent enzyme, using a quantum mechanical/molecular mechanical method on the basis of crystallographic TK structures from yeast and Escherichia coli, together with experimental kinetic data reported in the literature with wild-type and mutant TK. This model allowed us to define a new route for ThDP activation in the enzyme environment. We evidenced a strong interaction between ThDP and Glu418B of the TK active site, itself stabilized by Glu162A. The crucial point highlighted here is that deprotonation of ThDP C2 is not performed by ThDP N4' as reported in the literature, but by His481B, involving a HOH688A molecule bridge. Thus, ThDP N4' is converted from an amino form to an iminium form, ensuring the stabilization of the C2 carbanion or carbene. Finally, ThDP activation proceeds via an intermolecular process and not by an intramolecular one as reported in the literature. More generally, this proposed ThDP activation mechanism can be applied to some other ThDP-dependent enzymes and used to define the entire TK mechanism with donor and acceptor substrates more accurately.

  15. Systems biology provides new insights into the molecular mechanisms that control the fate of embryonic stem cells.

    Science.gov (United States)

    Mallanna, Sunil K; Rizzino, Angie

    2012-01-01

    During the last 5 years there has been enormous progress in developing a deeper understanding of the molecular mechanisms that control the self-renewal and pluripotency of embryonic stem cells (ESC). Early progress resulted from studying individual transcription factors and signaling pathways. Unexpectedly, these studies demonstrated that small changes in the levels of master regulators, such as Oct4 and Sox2, promote the differentiation of ESC. More recently, impressive progress has been made using technologies that provide a global view of the signaling pathways and the gene regulatory networks that control the fate of ESC. This review provides an overview of the progress made using several different high-throughput technologies and focuses on proteomic studies, which provide the first glimpse of the protein-protein interaction networks used by ESC. The latter studies indicate that transcription factors required for the self-renewal of ESC are part of a large, highly integrated protein-protein interaction landscape, which helps explain why the levels of master regulators need to be regulated precisely in ESC.

  16. Surface complexation of heavy metal cations on clay edges: insights from first principles molecular dynamics simulation of Ni(II)

    Science.gov (United States)

    Zhang, Chi; Liu, Xiandong; Lu, Xiancai; He, Mengjia; Jan Meijer, Evert; Wang, Rucheng

    2017-04-01

    Aiming at an atomistic mechanism of heavy metal cation complexing on clay surfaces, we carried out systematic first principles molecular dynamics (FPMD) simulations to investigate the structures, free energies and acidity constants of Ni(II) complexes formed on edge surfaces of 2:1 phyllosilicates. Three representative complexes were studied, including monodentate complex on the tbnd SiO site, bidentate complex on the tbnd Al(OH)2 site, and tetradentate complex on the octahedral vacancy where Ni(II) fits well into the lattice. The complexes structures were characterized in detail. Computed free energy values indicate that the tetradentate complex is significantly more stable than the other two. The calculated acidity constants indicate that the tetradentate complex can get deprotonated (pKa = 8.4) at the ambient conditions whereas the other two hardly deprotonate due to extremely high pKa values. By comparing with the 2 Site Protolysis Non Electrostatic Surface Complexation and Cation Exchange (2SPNE SC/CE) model, the vacant site has been assigned to the strong site and the other two to the weak site, respectively. Thus a link has been built between atomistic simulations and macroscopic experiments and it is deduced that this should also apply to other heavy metal cations based on additional simulations of Co(II) and Cu(II) and previous simulations of Fe(II) and Cd(II)). This study forms a physical basis for understanding the transport and fixation of heavy metal elements in many geologic environments.

  17. The evolution of antibiotic resistance: insight into the roles of molecular mechanisms of resistance and treatment context.

    Science.gov (United States)

    Maclean, R Craig; Hall, Alex R; Perron, Gabriel G; Buckling, Angus

    2010-08-01

    The widespread use of antibiotics has markedly improved public health over the last 60 years. However, the efficacy of antibiotic treatment is rapidly decreasing as a result of the continual spread of antibiotic resistance in pathogen populations. The evolution of antibiotic resistance is an amazingly simple example of adaptation by natural selection, and there is growing interest among evolutionary biologists in using evolutionary principles to help understand and combat the spread of resistance in pathogen populations. In this article, we review recent progress in our understanding of the underlying evolutionary forces that drive antibiotic resistance. Recent work has shown that both the mechanisms of antibiotic action and resistance, as well as the treatment context in which resistance evolves, influence the evolution of resistance in predictable ways. We argue that developing predictive models of resistance evolution that can be used to prevent the spread of resistance in pathogen populations requires integrating the treatment context and the molecular biology of resistance into the same evolutionary framework.

  18. Comparative proteome analysis of psychrophilic versus mesophilic bacterial species: Insights into the molecular basis of cold adaptation of proteins

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    Reddy Boojala

    2009-01-01

    Full Text Available Abstract Background Cold adapted or psychrophilic organisms grow at low temperatures, where most of other organisms cannot grow. This adaptation requires a vast array of sequence, structural and physiological adjustments. To understand the molecular basis of cold adaptation of proteins, we analyzed proteomes of psychrophilic and mesophilic bacterial species and compared the differences in amino acid composition and substitution patterns to investigate their likely association with growth temperatures. Results In psychrophilic bacteria, serine, aspartic acid, threonine and alanine are overrepresented in the coil regions of secondary structures, whilst glutamic acid and leucine are underrepresented in the helical regions. Compared to mesophiles, psychrophiles comprise a significantly higher proportion of amino acids that contribute to higher protein flexibility in the coil regions of proteins, such as those with tiny/small or neutral side chains. Amino acids with aliphatic, basic, aromatic and hydrophilic side chains are underrepresented in the helical regions of proteins of psychrophiles. The patterns of amino acid substitutions between the orthologous proteins of psychrophiles versus mesophiles are significantly different for several amino acids when compared to their substitutions in orthologous proteins of within the mesophiles or psychrophiles. Conclusion Current results provide quantitative substitution preferences (or avoidance of amino acids that lead to the adaptation of proteins to cold temperatures. These finding would help future efforts in selecting mutations for rational design of proteins with enhanced psychrophilic properties.

  19. Insights on the molecular mechanism for the recalcitrance of biochars: interactive effects of carbon and silicon components.

    Science.gov (United States)

    Guo, Jianhua; Chen, Baoliang

    2014-08-19

    Few studies have investigated the effects of structural heterogeneity (particularly the interactions of silicon and carbon) on the mechanisms for the recalcitrance of biochar. In this study, the molecular mechanisms for the recalcitrance of biochars derived from rice straw at 300, 500, and 700 °C (named RS300, RS500, and RS700, respectively) were elucidated. Short-term (24 h) and long-term (240 h) oxidation kinetics experiments were conducted under different concentrations of H2O2 to distinguish the stable carbon pools in the biochars. We discovered that the stabilities of the biochars were influenced not only by their aromaticity but also through possible protection by silicon encapsulation, which is regulated by pyrolysis temperatures. The aromatic components and recalcitrance of the biochars increased with increasing pyrolysis temperatures. The morphologies of the carbon forms in all of the biochars were also greatly associated with those of silica. Silica-encapsulation protection only occurred for RS500, not for RS300 and RS700. In RS300, carbon and silica were both amorphous, and they were easily decomposed by H2O2. The separation of crystalline silica from condensed aromatic carbon in RS700 eliminated the protective role of silicon on carbon. The effect of the biochar particle size on the stability of the biochar was greatly influenced by C-Si interactions and by the oxidation intensities. A novel silicon-and-carbon-coupled framework model was proposed to guide biochar carbon sequestration.

  20. Insight into the topology effect on the diffusion of ethene and propene in zeolites: A molecular dynamics simulation study

    Institute of Scientific and Technical Information of China (English)

    Chuanming; Wang; Bowei; Li; Yangdong; Wang; Zaiku; Xie

    2013-01-01

    Selectivity control is a difficult scientific and industrial challenge in methanol-to-olefins(MTO)conversion.It has been experimentally established that the topology of zeolite catalysts influenced the distribution of products.Besides the topology effect on reaction kinetics,the topology influences the diffusion of reactants and products in catalysts as well.In this work,by using COMPASS force-field molecular dynamics method,we investigated the intracrystalline diffusion of ethene and propene in four different zeolites,CHA,MFI,BEA and FAU,at different temperatures.The self-diffusion coefficients and diffusion activation barriers were calculated.A strong restriction on the diffusion of propene in CHA was observed because the self-diffusion coefficient ratio of ethene to propene is larger than 18 and the diffusion activation barrier of propene is more than 20 kJ/mol in CHA.This ratio decreases with the increase of temperature in the four investigated zeolites.The shape selectivity on products from diffusion perspective can provide some implications on the understanding of the selectivity difference between HSAPO-34 and HZSM-5 catalysts for the MTO conversion.

  1. Structure and function of cytochrome P450S in insect adaptation to natural and synthetic toxins: insights gained from molecular modeling.

    Science.gov (United States)

    Schuler, Mary A; Berenbaum, May R

    2013-09-01

    Over evolutionary time, insect herbivores have adapted to the presence of natural toxins and more recently to synthetic insecticides in or on the plants they consume. Biochemical analyses and molecular modeling of the cytochrome P450 monooxygenases (P450s) that metabolize these compounds have provided insight into the many variations affecting their catalytic activity. Phylogenetically distinct P450s may metabolize similar substrates, and phylogenetically similar P450s may metabolize different substrates; as well, some P450s process broad arrays of both phytochemicals and synthetic insecticides, while closely related P450s are restricted to a narrow range of phytochemicals. Mapped on the predicted three-dimensional structures of insect P450s developed from available mammalian P450 crystal structures, differences in multiple regions of the insect proteins reveal the evolutionary processes occurring as P450 genes have duplicated and diverged. Analyses of site-directed mutants in select lepidopteran and dipteran P450s demonstrate that slight changes in the catalytic site, the putative product release channel, and the proximal surface (interacting with electron transfer partners such as cytochrome P450 reductase and cytochrome b5) yield pronounced activity differences. Additionally, changes in the catalytic site and in the linker region preceding the proline-hinge influence P450 folding. With predicted structures available for many mammalian P450s involved in metabolism of xenobiotics, it is possible to record allelic variation relative to catalytically important regions in the overall P450 structure and to predict functionally critical differences. Together with information on the relative levels of allelic variant transcripts, comprehensive characterization of the mechanisms that modulate metabolism of natural and synthetic xenobiotics in insects can yield insights into plant-insect coevolution and into novel approaches for chemical pest management.

  2. Molecular Level Insights into Thermally Induced [alpha]-Chymotrypsinogen A Amyloid Aggregation Mechanism and Semiflexible Protofibril Morphology

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Aming; Jordan, Jacob L.; Ivanova, Magdalena I.; Weiss, IV., William F.; Roberts, Christopher J.; Fernandez, Erik J. (UCLA); (Delaware); (UV)

    2010-12-07

    Understanding nonnative protein aggregation is critical not only to a number of amyloidosis disorders but also for the development of effective and safe biopharmaceuticals. In a series of previous studies [Weiss et al. (2007) Biophys. J. 93, 4392-4403; Andrews et al. (2007) Biochemistry 46, 7558-7571; Andrews et al. (2008) Biochemistry 47, 2397-2403], {alpha}-chymotrypsinogen A (aCgn) and bovine granulocyte colony stimulating factor (bG-CSF) have been shown to exhibit the kinetic and morphological features of other nonnative aggregating proteins at low pH and ionic strength. In this study, we investigated the structural mechanism of aCgn aggregation. The resultant aCgn aggregates were found to be soluble and exhibited semiflexible filamentous aggregate morphology under transmission electron microscopy. In addition, the filamentous aggregates were demonstrated to possess amyloid characteristics by both Congo red binding and X-ray diffraction. Peptide level hydrogen exchange (HX) analysis suggested that a buried native {beta}-sheet comprised of three peptide segments (39-46, 51-64, and 106-114) reorganizes into the cross-{beta} amyloid core of aCgn aggregates and that at least 50% of the sequence adopts a disordered structure in the aggregates. Furthermore, the equimolar, bimodal HX labeling distribution observed for three reported peptides (65-102, 160-180, and 229-245) suggested a heterogeneous assembly of two molecular conformations in aCgn aggregates. This demonstrates that extended {beta}-sheet interactions typical of the amyloid are sufficiently strong that a relatively small fraction of polypeptide sequence can drive formation of filamentous aggregates even under conditions favoring colloidal stability.

  3. Phylogenetic and molecular insights into the evolution of multidrug-resistant porcine enterotoxigenic Escherichia coli in Australia.

    Science.gov (United States)

    Abraham, Sam; Trott, Darren J; Jordan, David; Gordon, David M; Groves, Mitchell D; Fairbrother, John M; Smith, Matthew G; Zhang, Ren; Chapman, Toni A

    2014-08-01

    This study investigated the phylogeny and molecular epidemiology of Australian porcine enterotoxigenic Escherichia coli (ETEC) isolates (n=70) by performing multilocus sequence typing (MLST), random amplified polymorphic DNA (RAPD) analysis, virulence gene analysis, plasmid, bacteriocin, integron and antimicrobial resistance gene typing, and antimicrobial susceptibility phenotyping. Isolates of the most commonly observed O serogroup (O149) were highly clonal with a lower frequency of antimicrobial resistance compared with the less common O141 serogroup isolates, which were more genetically diverse and resistant to a greater array of antimicrobials. The O149 and O141 isolates belonged to sequence types (STs) ST100 and ST1260, respectively. A small number of new STs were identified for the least common serogroups, including O157 (ST4245), O138 (ST4244), O139 (ST4246) and O8 (ST4247). A high frequency of plasmid replicons was observed among all ETEC isolates. However, O149 isolates predominantly carried IncFIB, I1, HI1 and FIC, whereas O141 isolates carried a more varied array, including IncI1, FIB, FIC, HI1, I1, Y and, most significantly, A/C. O141 isolates also possessed a greater diversity of bacteriocins, with almost one-half of the isolates carrying colicin E3 (44.4%; 12/27) and E7 (48.1%; 13/27). This study shows that Australian porcine ETEC are distinct from isolates obtained in other parts of the world with respect to the MLST profile and the absence of resistance to critically important antimicrobials, including third-generation cephalosporins and fluoroquinolones.

  4. Insights into the molecular evolution of the PDZ/LIM family and identification of a novel conserved protein motif.

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    Aartjan J W Te Velthuis

    Full Text Available The PDZ and LIM domain-containing protein family is encoded by a diverse group of genes whose phylogeny has currently not been analyzed. In mammals, ten genes are found that encode both a PDZ- and one or several LIM-domains. These genes are: ALP, RIL, Elfin (CLP36, Mystique, Enigma (LMP-1, Enigma homologue (ENH, ZASP (Cypher, Oracle, LMO7 and the two LIM domain kinases (LIMK1 and LIMK2. As conventional alignment and phylogenetic procedures of full-length sequences fell short of elucidating the evolutionary history of these genes, we started to analyze the PDZ and LIM domain sequences themselves. Using information from most sequenced eukaryotic lineages, our phylogenetic analysis is based on full-length cDNA-, EST-derived- and genomic- PDZ and LIM domain sequences of over 25 species, ranging from yeast to humans. Plant and protozoan homologs were not found. Our phylogenetic analysis identifies a number of domain duplication and rearrangement events, and shows a single convergent event during evolution of the PDZ/LIM family. Further, we describe the separation of the ALP and Enigma subfamilies in lower vertebrates and identify a novel consensus motif, which we call 'ALP-like motif' (AM. This motif is highly-conserved between ALP subfamily proteins of diverse organisms. We used here a combinatorial approach to define the relation of the PDZ and LIM domain encoding genes and to reconstruct their phylogeny. This analysis allowed us to classify the PDZ/LIM family and to suggest a meaningful model for the molecular evolution of the diverse gene architectures found in this multi-domain family.

  5. Molecular docking simulations provide insights in the substrate binding sites and possible substrates of the ABCC6 transporter.

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    Mohammad Jakir Hosen

    Full Text Available The human ATP-binding cassette family C member 6 (ABCC6 gene encodes an ABC transporter protein (ABCC6, primarily expressed in liver and kidney. Mutations in the ABCC6 gene cause pseudoxanthoma elasticum (PXE, an autosomal recessive connective tissue disease characterized by ectopic mineralization of the elastic fibers. The pathophysiology underlying PXE is incompletely understood, which can at least partly be explained by the undetermined nature of the ABCC6 substrates as well as the unknown substrate recognition and binding sites. Several compounds, including anionic glutathione conjugates (N-ethylmaleimide; NEM-GS and leukotriene C4 (LTC4 were shown to be modestly transported in vitro; conversely, vitamin K3 (VK3 was demonstrated not to be transported by ABCC6. To predict the possible substrate binding pockets of the ABCC6 transporter, we generated a 3D homology model of ABCC6 in both open and closed conformation, qualified for molecular docking and virtual screening approaches. By docking 10 reported in vitro substrates in our ABCC6 3D homology models, we were able to predict the substrate binding residues of ABCC6. Further, virtual screening of 4651 metabolites from the Human Serum Metabolome Database against our open conformation model disclosed possible substrates for ABCC6, which are mostly lipid and biliary secretion compounds, some of which are found to be involved in mineralization. Docking of these possible substrates in the closed conformation model also showed high affinity. Virtual screening expands this possibility to explore more compounds that can interact with ABCC6, and may aid in understanding the mechanisms leading to PXE.

  6. Insight on Mutation-Induced Resistance from Molecular Dynamics Simulations of the Native and Mutated CSF-1R and KIT

    Science.gov (United States)

    Da Silva Figueiredo Celestino Gomes, Priscila; Chauvot De Beauchêne, Isaure; Panel, Nicolas; Lopez, Sophie; De Sepulveda, Paulo; Geraldo Pascutti, Pedro; Solary, Eric; Tchertanov, Luba

    2016-01-01

    The receptors tyrosine kinases (RTKs) for the colony stimulating factor-1, CSF-1R, and for the stem cell factor, SCFR or KIT, are important mediators of signal transduction. The abnormal function of these receptors, promoted by gain-of-function mutations, leads to their constitutive activation, associated with cancer or other proliferative diseases. A secondary effect of the mutations is the alteration of receptors’ sensitivity to tyrosine kinase inhibitors, compromising effectiveness of these molecules in clinical treatment. In particular, the mutation V560G in KIT increases its sensitivity to Imatinib, while the D816V in KIT, and D802V in CSF-1R, triggers resistance to the drug. We analyzed the Imatinib binding affinity to the native and mutated KIT (mutations V560G, S628N and D816V) and CSF-1R (mutation D802V) by using molecular dynamics simulations and energy calculations of Imatinib•target complexes. Further, we evaluated the sensitivity of the studied KIT receptors to Imatinib by measuring the inhibition of KIT phosphorylation. Our study showed that (i) the binding free energy of Imatinib to the targets is highly correlated with their experimentally measured sensitivity; (ii) the electrostatic interactions are a decisive factor affecting the binding energy; (iii) the most deleterious impact to the Imatinib sensitivity is promoted by D802V (CSF-1R) and D816V (KIT) mutations; (iv) the role of the juxtamembrane region, JMR, in the imatinib binding is accessory. These findings contribute to a better description of the mutation-induced effects alternating the targets sensitivity to Imatinib. PMID:27467080

  7. Employing conformational analysis in the molecular modeling of agrochemicals: insights on QSAR parameters of 2,4-D

    Directory of Open Access Journals (Sweden)

    Matheus Puggina de Freitas

    2013-12-01

    Full Text Available A common practice to compute ligand conformations of compounds with various degrees of freedom to be used in molecular modeling (QSAR and docking studies is to perform a conformational distribution based on repeated random sampling, such as Monte-Carlo methods. Further calculations are often required. This short review describes some methods used for conformational analysis and the implications of using selected conformations in QSAR. A case study is developed for 2,4-dichlorophenoxyacetic acid (2,4-D, a widely used herbicide which binds to TIR1 ubiquitin ligase enzyme. The use of such an approach and semi-empirical calculations did not achieve all possible minima for 2,4-D. In addition, the conformations and respective energies obtained by the semi-empirical AM1 method do not match the calculated trends obtained by a high level DFT method. Similar findings were obtained for the carboxylate anion, which is the bioactive form. Finally, the crystal bioactive structure of 2,4-D was not found as a minimum when using Monte-Carlo/AM1 and is similarly populated with another conformer in implicit water solution according to optimization at the B3LYP/aug-cc-pVDZ level. Therefore, quantitative structure-activity relationship (QSAR methods based on three dimensional chemical structures are not fundamental to provide predictive models for 2,4-D congeners as TIR1 ubiquitin ligase ligands, since they do not necessarily reflect the bioactive conformation of this molecule. This probably extends to other systems.

  8. Spinning gland transcriptomics from two main clades of spiders (order: Araneae--insights on their molecular, anatomical and behavioral evolution.

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    Francisco Prosdocimi

    Full Text Available Characterized by distinctive evolutionary adaptations, spiders provide a comprehensive system for evolutionary and developmental studies of anatomical organs, including silk and venom production. Here we performed cDNA sequencing using massively parallel sequencers (454 GS-FLX Titanium to generate ∼80,000 reads from the spinning gland of Actinopus spp. (infraorder: Mygalomorphae and Gasteracantha cancriformis (infraorder: Araneomorphae, Orbiculariae clade. Actinopus spp. retains primitive characteristics on web usage and presents a single undifferentiated spinning gland while the orbiculariae spiders have seven differentiated spinning glands and complex patterns of web usage. MIRA, Celera Assembler and CAP3 software were used to cluster NGS reads for each spider. CAP3 unigenes passed through a pipeline for automatic annotation, classification by biological function, and comparative transcriptomics. Genes related to spider silks were manually curated and analyzed. Although a single spidroin gene family was found in Actinopus spp., a vast repertoire of specialized spider silk proteins was encountered in orbiculariae. Astacin-like metalloproteases (meprin subfamily were shown to be some of the most sampled unigenes and duplicated gene families in G. cancriformis since its evolutionary split from mygalomorphs. Our results confirm that the evolution of the molecular repertoire of silk proteins was accompanied by the (i anatomical differentiation of spinning glands and (ii behavioral complexification in the web usage. Finally, a phylogenetic tree was constructed to cluster most of the known spidroins in gene clades. This is the first large-scale, multi-organism transcriptome for spider spinning glands and a first step into a broad understanding of spider web systems biology and evolution.

  9. Molecular phylogeny of the Afroedura nivaria (Reptilia: Gekkonidae) species complex in South Africa provides insight on cryptic speciation.

    Science.gov (United States)

    Makhubo, Buyisile G; Tolley, Krystal A; Bates, Michael F

    2015-01-01

    The Afroedura nivaria species complex (A. nivaria, A. karroica, A. amatolica, A. tembulica and A. halli) is a morphologically conservative group of medium-sized flat geckos endemic to South Africa and Lesotho. Species are allopatric, as are some populations within species that are separated by large expanses of unsuitable habitat. Because of this isolation of populations we hypothesised that several cryptic species may be present. To investigate this hypothesis we constructed a molecular phylogeny using multiple markers, and included representatives of other Afroedura species. Bayesian inference and maximum likelihood analyses (439bp 16S, 593bp ND4, 948bp RAG1) strongly supported the genetic distinctiveness of the five described species. However, the A. nivaria species complex as currently described is not monophyletic, as A. karroica was positioned outside a clade containing all other Afroedura species, and A. pondolia (which was presumed to belong to a different species complex) was recovered within the A. nivaria complex. Several distinct clades within A. halli and A. nivaria were also recovered, and the narrowly-distributed A. amatolica consisted of two highly divergent clades. We also conducted a multivariate analysis using 19 morphological characters to investigate whether the clades recovered by the phylogeny were distinct in terms of head, body and limb shape. The analysis showed some variation between clades in terms of locomotor apparatus (forelimbs and feet), head and body dimensions, but overall the morphological differences were minor. This morphological conservatism in the A. nivaria complex may be a result of adaptation to similar microhabitats. Exclusive of A. karroica, the results suggest that there are at least nine species in this complex, of which four are cryptic and undescribed.

  10. New insights into the molecular epidemiology of Trichinella infection in domestic pigs, wild boars, and bears in Romania.

    Science.gov (United States)

    Nicorescu, Isabela Madalina Dragoi; Ionita, Mariana; Ciupescu, Laurentiu; Buzatu, Cristian Vasile; Tanasuica, Rodica; Mitrea, Ioan Liviu

    2015-09-15

    Trichinellosis is a food-borne zoonosis caused by the parasitic nematode Trichinella, characterized by an extremely wide host range and geographical distribution. In Romania, it is recognized as one of the most serious zoonotic diseases. A cross-sectional study, covering all regions of Romania, was conducted in 2014 to investigate and update the prevalence of Trichinella infection among domestic pigs, wild boars, and bears. Additional, molecular identification of Trichinella species circulating among these animals was performed in order to establish the biogeography of Trichinella species within the seven geographical regions of Romania. For this, a total of 113,383 pigs raised in non-controlled housing conditions (backyards), 5596 hunted wild boars and 147 hunted bears were subjected to Trichinella analysis. The highest prevalence of Trichinella infections was found in bears (12.93%), followed by wild boars (1.66%) and domestic pigs (0.20%). Of 294 Trichinella isolates that tested positive by multiplex PCR, 219 (74.49%) were identified as Trichinella spiralis, 66 (22.45%) as Trichinella britovi, and 9 isolates (3.06%) as mixed infections of T. spiralis and T. britovi. T. spiralis was more prevalent in domestic pigs (165/228; 72.37%) than in game (63/228; 27.63%), while T. britovi showed a higher prevalence in game (50/75; 66.66%) than in domestic pigs (25/75; 33.33%). Moreover, the present study revealed a significant host- and area- related distribution of Trichinella species within the seven regions of Romania. Therefore, these findings are of epidemiological relevance, updating data on the prevalence and distribution of Trichinella species circulating among domestic and wild animals in South-Eastern Europe.

  11. High molecular weight organic compounds (HMW-OCs) in severe winter haze: Direct observation and insights on the formation mechanism.

    Science.gov (United States)

    Duan, F K; He, K B; Ma, Y L; Ihozaki, T; Kawasaki, H; Arakawa, R; Kitayama, S; Tujimoto, K; Huang, T; Kimoto, T; Furutani, H; Toyoda, M

    2016-11-01

    High molecular weight organic compounds (HMW-OCs), formed as secondary organic aerosols (SOA), have been reported in many laboratory studies. However, little evidence of HMW-OCs formation, in particular during winter season in the real atmosphere, has been reported. In January 2013, Beijing faced historically severe haze pollution, in which the hourly PM2.5 concentration reached as high as 974 μg m(-3). Four typical haze events (HE1 to HE4) were identified, and HE2 (Jan. 9-16) was the most serious of these. Based on the hourly observed chemical composition of PM2.5 and the daily organic composition analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), we found that abundant ion peaks in m/z 200-850 appeared on heavy haze days, whereas these were negligible on a clear day, indicating the existence of HMW-OCs in the wintertime haze. A negative nonlinear correlation between HMW-OCs and O3 suggested that gas oxidation was not likely to be the dominant mechanism for HMW-OCs formation. During the heavy haze events, the relative humidity and mass ratio of H2O/PM2.5 reached as high as 80% and 0.2, respectively. The high water content and its good positive correlation with HMW-OCs indicated that an aqueous-phase process may be a significant pathway in wintertime. The evidence that acidity was much higher during HE2 (0.37 μg m(-3)) than on other days, as well as its strong correlation with HMW-OCs, indicated that acid-catalyzed reactions likely resulted in HMW-OCs formation during the heavy winter haze in Beijing.

  12. Insights into the olfactory system of the ectoparasite Caligus rogercresseyi: molecular characterization and gene transcription analysis of novel ionotropic receptors.

    Science.gov (United States)

    Núñez-Acuña, Gustavo; Valenzuela-Muñoz, Valentina; Marambio, Jorge Pino; Wadsworth, Simon; Gallardo-Escárate, Cristian

    2014-10-01

    Although various elements of the olfactory system have been elucidated in insects, it remains practically unstudied in crustaceans at a molecular level. Among crustaceans, some species are classified as ectoparasites that impact the finfish aquaculture industry. Thus, there is an urgent need to identify and comprehend the signaling pathways used by these in host recognition. The present study, through RNA-seq and qPCR analyses, found novel transcripts involved in the olfactory system of Caligus rogercresseyi, in addition to the transcriptomic patterns expressed during different stages of salmon lice development. From a transcriptomic library generated by Illumina sequencing, contigs that annotated for ionotropic receptors and other genes implicated in the olfactory system were identified and extracted. Full length mRNA was obtained for the ionotropic glutamate receptor 25, which had 3923 bp, and for the glutamate receptor ionotropic kainate 2, which had 2737 bp. Furthermore, two other transcripts identified as glutamate receptor, ionotropic kainate 2-like were found. In silico analysis was performed for the transcription expression from different stages of development in C. rogercresseyi, and clusters according to RPKM values were constructed. Gene transcription data were validated through qPCR assays in ionotropic receptors, and showed an expression of glutamate receptor 25 associated with the copepodid stage whereas adults, especially male adults, were associated with the kainate 2 and kainate 2-like transcripts. Additionally, gene transcription analysis of the ionotropic receptors showed an overexpression in response to the presence of masking compounds and immunostimulant in salmon diets. This response correlated to a reduction in sea lice infection following in vivo challenge. Diets with masking compounds showed a decrease of lice infestation of up to 25%. This work contributes to the available knowledge on chemosensory systems in this ectoparasite, providing

  13. Molecular simulation insights on the in vacuo adsorption of amino acids on graphene oxide surfaces with varying surface oxygen densities

    Science.gov (United States)

    Rahmani, Farzin; Nouranian, Sasan; Mahdavi, Mina; Al-Ostaz, Ahmed

    2016-11-01

    In this fundamental study, a series of molecular dynamics simulations were performed in vacuo to investigate the energetics and select geometries of 20 standard amino acids (AAs) on pristine graphene (PG) and graphene oxide (GO) surfaces as a function of graphene surface oxygen density. These interactions are of key interest to graphene/biomolecular systems. Our results indicate that aromatic AAs exhibit the strongest total interactions with the PG surfaces due to π-π stacking. Tryptophan (Trp) has the highest aromaticity due to its indole side chain and, hence, has the strongest interaction among all AAs (-16.66 kcal/mol). Aliphatic, polar, and charged AAs show various levels of affinity to the PG sheets depending on the strength of their side chain hydrophobic interactions. For example, arginine (Arg) with its guanidinium side chain exhibits the strongest interaction with the PG sheets (-13.81 kcal/mol) following aromatic AAs. Also, glycine (Gly; a polar AA) has the weakest interaction with the PG sheets (-7.29 kcal/mol). When oxygen-containing functional groups are added to the graphene sheets, the π-π stacking in aromatic AAs becomes disrupted and perfect parallelism of the aromatic rings is lost. Moreover, hydrogen bonding and/or electrostatic interactions become more pronounced. Charged AAs exhibit the strongest interactions with the GO surfaces. In general, the AA-GO interactions increase with increasing surface oxygen density, and the effect is more pronounced at higher O/C ratios. This study provides a quantitative measure of AA-graphene interactions for the design and tuning of biomolecular systems suitable for biosensing, drug delivery, and gene delivery applications.

  14. Insights into organogelation and its kinetics from Hansen solubility parameters. Toward a priori predictions of molecular gelation.

    Science.gov (United States)

    Diehn, Kevin K; Oh, Hyuntaek; Hashemipour, Reza; Weiss, Richard G; Raghavan, Srinivasa R

    2014-04-21

    particular solvent or a blend of solvents. The above framework can be readily extended to many other gelators, including those with molecular structures very different from that of DBS. We have developed a MATLAB program that will be freely available (upon request) to the scientific community to replicate and extend this approach to other gelators of interest.

  15. Perturbation of hydration layer in solvated proteins by external electric and electromagnetic fields: Insights from non-equilibrium molecular dynamics

    Science.gov (United States)

    Nandi, Prithwish K.; Futera, Zdenek; English, Niall J.

    2016-11-01

    Given the fundamental role of water in governing the biochemistry of enzymes, and in regulating their wider biological activity (e.g., by local water concentration surrounding biomolecules), the influence of extraneous electric and electromagnetic (e/m) fields thereon is of central relevance to biophysics and, more widely, biology. With the increase in levels of local and atmospheric microwave-frequency radiation present in modern life, as well as other electric-field exposure, the impact upon hydration-water layers surrounding proteins, and biomolecules generally, becomes a particularly pertinent issue. Here, we present a (non-equilibrium) molecular-dynamics-simulation study on a model protein (hen egg-white lysozyme) hydrated in water, in which we determine, inter alia, translational self-diffusivities for both hen egg-white lysozyme and its hydration layer together with relaxation dynamics of the hydrogen-bond network between the protein and its hydration-layer water molecules on a residue-per-residue basis. Crucially, we perform this analysis both above and below the dynamical-transition temperature (at ˜220 K), at 300 and 200 K, respectively, and we compare the effects of external static-electric and e/m fields with linear-response-régime (r.m.s.) intensities of 0.02 V/Å. It was found that the translational self-diffusivity of hen egg-white lysozyme and its hydration-water layer are increased substantially in static fields, primarily due to the induced electrophoretic motion, whilst the water-protein hydrogen-bond-network-rearrangement kinetics can also undergo rather striking accelerations, primarily due to the enhancement of a larger-amplitude local translational and rotational motion by charged and dipolar residues, which serves to promote hydrogen-bond breakage and re-formation kinetics. These external-field effects are particularly evident at 200 K, where they serve to induce the protein- and solvation-layer-response effects redolent of dynamical

  16. Structural dynamics of Casein Kinase I (CKI) from malarial parasite Plasmodium falciparum (Isolate 3D7): Insights from theoretical modelling and molecular simulations.

    Science.gov (United States)

    Dehury, Budheswar; Behera, Santosh Kumar; Mahapatra, Namita

    2017-01-01

    The protein kinases (PKs), belonging to serine/threonine kinase (STKs), are important drug targets for a wide spectrum of diseases in human. Among protein kinases, the Casein Kinases (CKs) are vastly expanded in various organisms, where, the malarial parasite Plasmodium falciparum possesses a single member i.e., PfCKI, which can phosphorylate various proteins in parasite extracts in vitro condition. But, the structure-function relationship of PfCKI and dynamics of ATP binding is yet to be understood. Henceforth, an attempt was made to study the dynamics, stability, and ATP binding mechanisms of PfCKI through computational modelling, docking, molecular dynamics (MD) simulations, and MM/PBSA binding free energy estimation. Bi-lobed catalytic domain of PfCKI shares a high degree of secondary structure topology with CKI domains of rice, human, and mouse indicating co-evolution of these kinases. Molecular docking study revealed that ATP binds to the active site where the glycine-rich ATP-binding motif (G16-X-G18-X-X-G21) along with few conserved residues plays a crucial role maintaining stability of the complex. Structural superposition of PfCKI with close structural homologs depicted that the location and length of important loops are different, indicating the dynamic properties of these loops among CKIs, which is consistent with principal component analysis (PCA). PCA displayed that the overall global motion of ATP-bound form is comparatively higher than that of apo form. The present study provides insights into the structural features of PfCKI, which could contribute towards further understanding of related protein structures, dynamics of catalysis and phosphorylation mechanism in these important STKs from malarial parasite in near future.

  17. Homology modeling and molecular dynamics simulation of N-myristoyltransferase from protozoan parasites: active site characterization and insights into rational inhibitor design

    Science.gov (United States)

    Sheng, Chunquan; Ji, Haitao; Miao, Zhenyuan; Che, Xiaoyin; Yao, Jianzhong; Wang, Wenya; Dong, Guoqiang; Guo, Wei; Lü, Jiaguo; Zhang, Wannian

    2009-06-01

    Myristoyl-CoA:protein N-myristoyltransferase (NMT) is a cytosolic monomeric enzyme that catalyzes the transfer of the myristoyl group from myristoyl-CoA to the N-terminal glycine of a number of eukaryotic cellular and viral proteins. Recent experimental data suggest NMT from parasites could be a promising new target for the design of novel antiparasitic agents with new mode of action. However, the active site topology and inhibitor specificity of these enzymes remain unclear. In this study, three-dimensional models of NMT from Plasmodium falciparum (PfNMT), Leishmania major (LmNMT) and Trypanosoma brucei (TbNMT) were constructed on the basis of the crystal structures of fungal NMTs using homology modeling method. The models were further refined by energy minimization and molecular dynamics simulations. The active sites of PfNMT, LmNMT and TbNMT were characterized by multiple copy simultaneous search (MCSS). MCSS functional maps reveal that PfNMT, LmNMT and TbNMT share a similar active site topology, which is defined by two hydrophobic pockets, a hydrogen-bonding (HB) pocket, a negatively-charged HB pocket and a positively-charged HB pocket. Flexible docking approaches were then employed to dock known inhibitors into the active site of PfNMT. The binding mode, structure-activity relationships and selectivity of inhibitors were investigated in detail. From the results of molecular modeling, the active site architecture and certain key residues responsible for inhibitor binding were identified, which provided insights for the design of novel inhibitors of parasitic NMTs.

  18. Structures of Human Cyctochrome P450 2E1: Insights Into the Binding of Inhibitors And Both Small Molecular Weight And Fatty Acid Substrates

    Energy Technology Data Exchange (ETDEWEB)

    Porubsky, P.R.; Meneely, K.M.; Scott, E.E.

    2009-05-21

    Human microsomal cytochrome P-450 2E1 (CYP2E1) monooxygenates >70 low molecular weight xenobiotic compounds, as well as much larger endogenous fatty acid signaling molecules such as arachidonic acid. In the process, CYP2E1 can generate toxic or carcinogenic compounds, as occurs with acetaminophen overdose, nitrosamines in cigarette smoke, and reactive oxygen species from uncoupled catalysis. Thus, the diverse roles that CYP2E1 has in normal physiology, toxicity, and drug metabolism are related to its ability to metabolize diverse classes of ligands, but the structural basis for this was previously unknown. Structures of human CYP2E1 have been solved to 2.2 {angstrom} for an indazole complex and 2.6 {angstrom} for a 4-methylpyrazole complex. Both inhibitors bind to the heme iron and hydrogen bond to Thr{sup 303} within the active site. Complementing its small molecular weight substrates, the hydrophobic CYP2E1 active site is the smallest yet observed for a human cytochrome P-450. The CYP2E1 active site also has two adjacent voids: one enclosed above the I helix and the other forming a channel to the protein surface. Minor repositioning of the Phe{sup 478} aromatic ring that separates the active site and access channel would allow the carboxylate of fatty acid substrates to interact with conserved {sup 216}QXXNN{sup 220} residues in the access channel while positioning the hydrocarbon terminus in the active site, consistent with experimentally observed {omega}-1 hydroxylation of saturated fatty acids. Thus, these structures provide insights into the ability of CYP2E1 to effectively bind and metabolize both small molecule substrates and fatty acids.

  19. Comparative transcripts profiling reveals new insight into molecular processes regulating lycopene accumulation in a sweet orange (Citrus sinensis red-flesh mutant

    Directory of Open Access Journals (Sweden)

    Zhang Jianchen

    2009-11-01

    Full Text Available Abstract Background Interest in lycopene metabolism and regulation is growing rapidly because accumulative studies have suggested an important role for lycopene in human health promotion. However, little is known about the molecular processes regulating lycopene accumulation in fruits other than tomato so far. Results On a spontaneous sweet orange bud mutant with abnormal lycopene accumulation in fruits and its wild type, comparative transcripts profiling was performed using Massively Parallel Signature Sequencing (MPSS. A total of 6,877,027 and 6,275,309 reliable signatures were obtained for the wild type (WT and the mutant (MT, respectively. Interpretation of the MPSS signatures revealed that the total number of transcribed gene in MT is 18,106, larger than that in WT 17,670, suggesting that newly initiated transcription occurs in the MT. Further comparison of the transcripts abundance between MT and WT revealed that 3,738 genes show more than two fold expression difference, and 582 genes are up- or down-regulated at 0.05% significance level by more than three fold difference. Functional assignments of the differentially expressed genes indicated that 26 reliable metabolic pathways are altered in the mutant; the most noticeable ones are carotenoid biosynthesis, photosynthesis, and citrate cycle. These data suggest that enhanced photosynthesis and partial impairment of lycopene downstream flux are critical for the formation of lycopene accumulation trait in the mutant. Conclusion This study provided a global picture of the gene expression changes in a sweet orange red-flesh mutant as compared to the wild type. Interpretation of the differentially expressed genes revealed new insight into the molecular processes regulating lycopene accumulation in the sweet orange red-flesh mutant.

  20. Analysis of Swedish Forest Owners' Information and Knowledge-Sharing Networks for Decision-Making: Insights for Climate Change Communication and Adaptation.

    Science.gov (United States)

    André, Karin; Baird, Julia; Gerger Swartling, Åsa; Vulturius, Gregor; Plummer, Ryan

    2017-03-08

    To further the understanding of climate change adaptation processes, more attention needs to be paid to the various contextual factors that shape whether and how climate-related knowledge and information is received and acted upon by actors involved. This study sets out to examine the characteristics of forest owners' in Sweden, the information and knowledge-sharing networks they draw upon for decision-making, and their perceptions of climate risks, their forests' resilience, the need for adaptation, and perceived adaptive capacity. By applying the concept of ego-network analysis, the empirical data was generated by a quantitative survey distributed to 3000 private forest owners' in Sweden in 2014 with a response rate of 31%. The results show that there is a positive correlation, even though it is generally weak, between forest owner climate perceptions and (i) network features, i.e. network size and heterogeneity, and (ii) presence of certain alter groups (i.e. network members or actors). Results indicate that forest owners' social networks currently serve only a minimal function of sharing knowledge of climate change and adaptation. Moreover, considering the fairly infrequent contact between respondents and alter groups, the timing of knowledge sharing is important. In conclusion we suggest those actors that forest owners' most frequently communicate with, especially forestry experts providing advisory services (e.g. forest owner associations, companies, and authorities) have a clear role to communicate both the risks of climate change and opportunities for adaptation. Peers are valuable in connecting information about climate risks and adaptation to the actual forest property.

  1. Novel microduplications at Xp11.22 including HUWE1: clinical and molecular insights into these genomic rearrangements associated with intellectual disability.

    Science.gov (United States)

    Santos-Rebouças, Cíntia Barros; de Almeida, Luciana Guedes; Belet, Stefanie; Dos Santos, Suely Rodrigues; Ribeiro, Márcia Gonçalves; da Silva, Antônio Francisco Alves; Medina-Acosta, Enrique; Dos Santos, Jussara Mendonça; Gonçalves, Andressa Pereira; Bahia, Paulo Roberto Valle; Pimentel, Márcia Mattos Gonçalves; Froyen, Guy

    2015-04-01

    Recently, we defined a minimal overlapping region for causal Xp11.22 copy number gains in males with intellectual disability (ID), and identified HECT, UBA and WWE domain-containing protein-1 (HUWE1) as the primary dosage-sensitive gene, whose overexpression leads to ID. In the present study, we used this minimal interval to search for HUWE1 copy number variations by quantitative polymerase chain reaction in a large cohort of Brazilian males with idiopathic ID. We detected two unrelated sporadic individuals with syndromic ID carrying unique overlapping duplications encompassing HUWE1. Breakpoint junction analysis showed a simple tandem duplication in the first patient, which has probably arisen by microhomology-mediated break-induced repair mechanism. In the second patient, the rearrangement is complex having an insertion of an intrachromosomal sequence at its junction. This kind of rearrangement has not been reported in Xp11.22 duplications and might have emerged by a replication- or recombination-based mechanism. Furthermore, the presence of infantile seizures in the second family suggests a potential role of increased KDM5C expression on epilepsy. Our findings highlight the importance of microduplications at Xp11.22 to ID, even in sporadic cases, and reveal new clinical and molecular insight into HUWE1 copy number gains.

  2. Mature salivary gland rests within sonic hedgehog-positive medulloblastoma: case report and insights into the molecular genetics and embryopathology of ectopic intracranial salivary gland analogs.

    Science.gov (United States)

    Shammassian, Berje; Manjila, Sunil; Cox, Efrem; Onwuzulike, Kaine; Wang, Dehua; Rodgers, Mark; Stearns, Duncan; Selman, Warren R

    2016-12-01

    Intracranial ectopic salivary gland rests within dural-based lesions are reported very infrequently in the literature. The authors report the unique case of a 12-year-old boy with a cerebellar medulloblastoma positive for sonic hedgehog (Shh) that contained intraaxial mature ectopic salivary gland rests. The patient underwent clinical and radiological monitoring postoperatively, until he died of disseminated disease. An autopsy showed no evidence of salivary glands within disseminated lesions. The intraaxial presence of salivary gland rests and concomitant Shh positivity of the described tumor point to a disorder in differentiation as opposed to ectopic developmental foci, which are uniformly dural based in the described literature. The authors demonstrate the characteristic "papilionaceous" appearance of the salivary glands with mucicarmine stain and highlight the role of Shh signaling in explaining the intraaxial presence of seromucous gland analogs. This article reports the first intraaxial posterior fossa tumor with heterotopic salivary gland rests, and it provides molecular and embryopathological insights into the development of these lesions.

  3. Insight into the molecular composition of laboratory organic residues produced from interstellar/pre-cometary ice analogues using very high resolution mass spectrometry

    Science.gov (United States)

    Danger, G.; Fresneau, A.; Abou Mrad, N.; de Marcellus, P.; Orthous-Daunay, F.-R.; Duvernay, F.; Vuitton, V.; Le Sergeant d'Hendecourt, L.; Thissen, R.; Chiavassa, T.

    2016-09-01

    Experimental simulations in the laboratory may provide important information about the chemical evolution occurring in various astrophysical objects such as extraterrestrial ices. Interstellar or (pre)cometary ice analogues made of H2O, CH3OH, and NH3 at 77 K, when subjected to an energetic process (VUV photons, electrons or ions) and then warmed-up to room temperature, lead, in the laboratory, to the formation of an organic residue. In this paper we expand our previous analysis of the residues in order to obtain a better insight into their molecular content. Data analyses show that three different chemical groups are present in the residue in the negative electrospray ionization (ESI) mode: CHN, CHO and CHNOsbnd whereas only two groups are detected in the positive ESI mode: CHN and CHNO. In both cases, the CHNO group is the most abundant. The application of specific data treatment shows that residue mainly contains aliphatic linear molecules or cyclic structures connected to unsaturated chemical functions such as esters, carboxylic acids, amides or aldehydes. In lower abundances, some molecules do present aromatic structures. The comparison of our residue with organic compounds detected in the Murchison meteorite gives an interesting match, which suggests that laboratory simulation of interstellar ice chemistry is relevant to understand astrophysical organic matter evolution.

  4. Potential Prepore Trimer Formation by the Bacillus thuringiensis Mosquito-specific Toxin: MOLECULAR INSIGHTS INTO A CRITICAL PREREQUISITE OF MEMBRANE-BOUND MONOMERS.

    Science.gov (United States)

    Sriwimol, Wilaiwan; Aroonkesorn, Aratee; Sakdee, Somsri; Kanchanawarin, Chalermpol; Uchihashi, Takayuki; Ando, Toshio; Angsuthanasombat, Chanan

    2015-08-21

    The insecticidal feature of the three-domain Cry δ-endotoxins from Bacillus thuringiensis is generally attributed to their capability to form oligomeric pores, causing lysis of target larval midgut cells. However, the molecular description of their oligomerization process has not been clearly defined. Here a stable prepore of the 65-kDa trypsin-activated Cry4Ba mosquito-specific toxin was established through membrane-mimetic environments by forming an ∼200-kDa octyl-β-D-glucoside micelle-induced trimer. The SDS-resistant trimer caused cytolysis to Sf9 insect cells expressing Aedes-mALP (a Cry4Ba receptor) and was more effective than a toxin monomer in membrane perturbation of calcein-loaded liposomes. A three-dimensional model of toxin trimer obtained by negative-stain EM in combination with single-particle reconstruction at ∼5 nm resolution showed a propeller-shaped structure with 3-fold symmetry. Fitting the three-dimensional reconstructed EM map with a 100-ns molecular dynamics-simulated Cry4Ba structure interacting with an octyl-β-D-glucoside micelle showed relative positioning of individual domains in the context of the trimeric complex with a major protrusion from the pore-forming domain. Moreover, high-speed atomic force microscopy imaging at nanometer resolution and a subsecond frame rate demonstrated conformational transitions from a propeller-like to a globularly shaped trimer upon lipid membrane interactions, implying prepore-to-pore conversion. Real-time trimeric arrangement of monomers associated with L-α-dimyristoylphosphatidylcholine/3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonic acid bicelle membranes was also envisaged by successive high-speed atomic force microscopy imaging, depicting interactions among three individual subunits toward trimer formation. Together, our data provide the first pivotal insights into the structural requirement of membrane-induced conformational changes of Cry4Ba toxin monomers for the

  5. Amine oxidation mediated by lysine-specific demethylase 1: quantum mechanics/molecular mechanics insights into mechanism and role of lysine 661.

    Science.gov (United States)

    Karasulu, Bora; Patil, Mahendra; Thiel, Walter

    2013-09-11

    We report classical molecular dynamics (MD) simulations and combined quantum mechanics/molecular mechanics (QM/MM) calculations to elucidate the catalytic mechanism of the rate-determining amine oxidation step in the lysine-specific demethylase 1 (LSD1)-catalyzed demethylation of the histone tail lysine (H3K4), with flavin adenine dinucleotide (FAD) acting as cofactor. The oxidation of substrate lysine (sLys) involves the cleavage of an α-CH bond accompanied by the transfer of a hydride ion equivalent to FAD, leading to an imine intermediate. This hydride transfer pathway is shown to be clearly favored for sLys oxidation over other proposed mechanisms, including the radical (or single-electron transfer) route as well as carbanion and polar-nucleophilic mechanisms. MD simulations on six NVT ensembles (covering different protonation states of sLys and K661 as well as the K661M mutant) identify two possible orientations of the reacting sLys and FAD subunits (called "downward" and "upward"). Calculations at the QM(B3LYP-D/6-31G*)/CHARMM22 level provide molecular-level insights into the mechanism, helping to understand how LSD1 achieves the activation of the rather inert methyl-CH bond in a metal-free environment. Factors such as proper alignment of sLys (downward orientation), transition-state stabilization (due to the protein environment and favorable orbital interactions), and product stabilization via adduct formation are found to be crucial for facilitating the oxidative α-CH bond cleavage. The current study also sheds light on the role of important active-site residues (Y761, K661, and W695) and of the conserved water-bridge motif. The steric influence of Y761 helps to position the reaction partners properly, K661 is predicted to get deprotonated prior to substrate binding and to act as an active-site base that accepts a proton from sLys to enable the subsequent amine oxidation, and the water bridge that is stabilized by K661 and W695 mediates this proton

  6. Early to middle Miocene climate evolution: New insights from IODP Sites U1335, U1337 and U1338 (eastern equatorial Pacific Ocean)

    Science.gov (United States)

    Kochhann, Karlos G. D.; Holbourn, Ann; Kuhnt, Wolfgang; Lyle, Mitch; Raffi, Isabella; Channell, James E.; Andersen, Nils

    2015-04-01

    The lower to middle Miocene (~20 to 13 Ma) carbonate-rich sedimentary successions recovered at Integrated Ocean Drilling Program (IODP) Sites U1335, U1337 and U1338 allow unsurpassed resolution over the Climatic Optimum (16.9-14.7 Ma) and the transition into a colder climate mode after 13.9 Ma with re-establishment of permanent Antarctic ice sheets. High-resolution (1-10 kyr) stable carbon (δ13C) and oxygen (δ18O) isotopes of well-preserved epibenthic foraminifera (Cibicidoides mundulus and Planulina wuellerstorfi) from these three sites show that the Climatic Optimum was characterized by high-amplitude climate variations and intense perturbations of the carbon cycle. Episodes of peak warmth coincided with transient shoaling of the carbonate compensation depth and enhanced carbonate dissolution in the deep ocean. The U1335 and U1337 records additionally reveal that the rapid global warming and/or polar ice melting event, marking the onset of the Climatic Optimum at ~16.9 Ma, was coupled to a massive increase in carbonate dissolution, indicated by sharp drops in carbonate percentages and accumulation rates and by the fragmentation or complete dissolution of planktonic foraminifers. After ~14.7 Ma, stepwise global cooling, culminating with extensive ice growth over Antarctica at ~13.8 Ma, coincide with enhanced opal and benthic foraminiferal accumulation rates, suggesting that increased siliceous productivity and organic carbon burial may have contributed to CO2 drawdown. Integration of age models derived from orbitally-tuned, high-resolution isotopes, biostratigraphic data and magnetic reversals allows further constraints on the temporal sequence of events and helps unravel the drivers of early to middle Miocene climate variations.

  7. Climatic change from a social perspective. Insights from the VAM research programme; Klimaatverandering vanuit sociaal perspectief. Inzichten uit het VAM-onderzoeksprogramma

    Energy Technology Data Exchange (ETDEWEB)

    Martens, P. [International Centre for Integrated Assessment and Sustainable Development ICIS, Maastricht University, Maastricht (Netherlands); Amelung, B. [Amelung Advies, Amsterdam (Netherlands)

    2010-09-15

    Climate change has fundamental societal causes and consequences. Nevertheless, social sciences are still playing a subordinate role in climate research today. The research program financed by NOW 'Vulnerability, Adaptation and Mitigation' (VAM) tries to change this situation. This article provides an overview of the main results of the VAM program. [Dutch] Klimaatverandering heeft fundamentele maatschappelijke oorzaken en gevolgen. Toch spelen de sociale wetenschappen tot op de dag van vandaag een ondergeschikte rol in het klimaatonderzoek. Het door NWO gefinancierde onderzoeksprogramma 'Vulnerability, Adaptation and Mitigation' (VAM) probeert hierin verandering te brengen. Dit artikel geeft een overzicht van de belangrijkste resultaten van het VAM-programma.

  8. Oxygen isotope ratios (18O/16O) of hemicellulose-derived sugar biomarkers in plants, soils and sediments as paleoclimate proxy II: Insight from a climate transect study

    Science.gov (United States)

    Tuthorn, Mario; Zech, Michael; Ruppenthal, Marc; Oelmann, Yvonne; Kahmen, Ansgar; Valle, Héctor Francisco del; Wilcke, Wolfgang; Glaser, Bruno

    2014-02-01

    The oxygen isotopic composition of precipitation (δ18Oprec) is well known to be a valuable (paleo-)climate proxy. Paleosols and sediments and hemicelluloses therein have the potential to serve as archives recording the isotopic composition of paleoprecipitation. In a companion paper (Zech et al., 2014) we investigated δ18Ohemicellulose values of plants grown under different climatic conditions in a climate chamber experiment. Here we present results of compound-specific δ18O analyses of arabinose, fucose and xylose extracted from modern topsoils (n = 56) along a large humid-arid climate transect in Argentina in order to answer the question whether hemicellulose biomarkers in soils reflect δ18Oprec. The results from the field replications indicate that the homogeneity of topsoils with regard to δ18Ohemicellulose is very high for most of the 20 sampling sites. Standard deviations for the field replications are 1.5‰, 2.2‰ and 1.7‰, for arabinose, fucose and xylose, respectively. Furthermore, all three hemicellulose biomarkers reveal systematic and similar trends along the climate gradient. However, the δ18Ohemicellulose values (mean of the three sugars) do not correlate positively with δ18Oprec (r = -0.54, p fucose and xylose do not simply reflect δ18Oprec but rather δ18Oleaf water. The correlation between measured δ18Ohemicellulose and modeled δ18Oleaf water is highly significant (r = 0.81, p < 0.001, n = 20). This finding can be attributed to the evaporative 18O enrichment of leaf water during transpiration. Model sensitivity tests using a Péclet-modified Craig-Gordon (PMCG) model corroborate that relative air humidity is a very rigorous climate parameter influencing δ18Oleaf water, whereas temperature is of minor importance. While oxygen exchange and degradation effects on δ18O values of hemicelluloses sugar biomarkers seem to be negligible (Zech et al., 2012), further effects that need to be considered when interpreting δ18Ohemicellulose

  9. Terrestrial carbon cycle responses to drought and climate stress: New insights using atmospheric observations of CO2 and delta13C

    Science.gov (United States)

    Alden, Caroline B.

    Atmospheric concentrations of carbon dioxide (CO2) continue to rise well into the second decade of the new millennium, in spite of broad-scale human understanding of the impacts of fossil fuel emissions on the earth's climate. Natural sinks for CO2 that are relevant on human time scales---the world's oceans and land biosphere---appear to have kept pace with emissions. The continuously increasing strength of the land biosphere sink for CO2 is surpassing expectations given our understanding of the CO2 fertilization and warming effects on the balance between photosynthesis and respiration, especially in the face of ongoing forest degradation. The climate and carbon cycle links between the atmosphere and land biosphere are not well understood, especially at regional (100 km to 10,000 km) scales. The climate modulating effects of changing plant stomatal conductance in response to temperature and water availability is a key area of uncertainty. Further, the differential response to climate change of C3 and C4 plant functional types is not well known at regional scales. This work outlines the development of a novel application of atmospheric observations of delta13C of CO2 to investigate the links between climate and water and carbon cycling and the integrated responses of C3 and C4 ecosystems to climate variables. A two-step Bayesian batch inversion for 3-hourly, 1x1º CO2 fluxes (step one), and for 3-hourly 1x1º delta13C of recently assimilated carbon (step two) is created here for the first time, and is used to investigate links between regional climate indicators and changes in delta13C of the biosphere. Results show that predictable responses of regional-scale, integrated plant discrimination to temperature, precipitation and relative humidity anomalies can be recovered from atmospheric signals. Model development, synthetic data simulations to test sensitivity, and results for the year 2010 are presented here. This dissertation also includes two other applications

  10. Simulating the effects of climate change on the distribution of an invasive plant, using a high resolution, local scale, mechanistic approach: challenges and insights.

    Science.gov (United States)

    Fennell, Mark; Murphy, James E; Gallagher, Tommy; Osborne, Bruce

    2013-04-01

    The growing economic and ecological damage associated with biological invasions, which will likely be exacerbated by climate change, necessitates improved projections of invasive spread. Generally, potential changes in species distribution are investigated using climate envelope models; however, the reliability of such models has been questioned and they are not suitable for use at local scales. At this scale, mechanistic models are more appropriate. This paper discusses some key requirements for mechanistic models and utilises a newly developed model (PSS[gt]) that incorporates the influence of habitat type and related features (e.g., roads and rivers), as well as demographic processes and propagule dispersal dynamics, to model climate induced changes in the distribution of an invasive plant (Gunnera tinctoria) at a local scale. A new methodology is introduced, dynamic baseline benchmarking, which distinguishes climate-induced alterations in species distributions from other potential drivers of change. Using this approach, it was concluded that climate change, based on IPCC and C4i projections, has the potential to increase the spread-rate and intensity of G. tinctoria invasions. Increases in the number of individuals were primarily due to intensification of invasion in areas already invaded or in areas projected to be invaded in the dynamic baseline scenario. Temperature had the largest influence on changes in plant distributions. Water availability also had a large influence and introduced the most uncertainty in the projections. Additionally, due to the difficulties of parameterising models such as this, the process has been streamlined by utilising methods for estimating unknown variables and selecting only essential parameters.

  11. Climate change and human disturbance can lead to local extinction of Alpine rock ptarmigan: new insight from the western Italian Alps.

    Directory of Open Access Journals (Sweden)

    Simona Imperio

    Full Text Available Alpine grouses are particularly vulnerable to climate change due to their adaptation to extreme conditions and to their relict distributions in the Alps where global warming has been particularly marked in the last half century. Grouses are also currently threatened by habitat modification and human disturbance, and an assessment of the impact of multiple stressors is needed to predict the fate of Alpine populations of these birds in the next decades. We estimated the effect of climate change and human disturbance on a rock ptarmigan population living in the western Italian Alps by combining an empirical population modelling approach and stochastic simulations of the population dynamics under the a1B climate scenario and two different disturbance scenarios, represented by the development of a ski resort, through 2050.The early appearance of snow-free ground in the previous spring had a favorable effect on the rock ptarmigan population, probably through a higher reproductive success. On the contrary, delayed snowfall in autumn had a negative effect possibly due to a mismatch in time to molt to white winter plumage which increases predation risk. The regional climate model PROTHEUS does not foresee any significant change in snowmelt date in the study area, while the start date of continuous snow cover is expected to be significantly delayed. The net effect in the stochastic projections is a more or less pronounced (depending on the model used decline in the studied population. The addition of extra-mortality due to collision with ski-lift wires led the population to fatal consequences in most projections. Should these results be confirmed by larger studies the conservation of Alpine populations would deserve more attention. To counterbalance the effects of climate change, the reduction of all causes of death should be pursued, through a strict preservation of the habitats in the present area of occurrence.

  12. Climate change and human disturbance can lead to local extinction of Alpine rock ptarmigan: new insight from the western Italian Alps.

    Science.gov (United States)

    Imperio, Simona; Bionda, Radames; Viterbi, Ramona; Provenzale, Antonello

    2013-01-01

    Alpine grouses are particularly vulnerable to climate change due to their adaptation to extreme conditions and to their relict distributions in the Alps where global warming has been particularly marked in the last half century. Grouses are also currently threatened by habitat modification and human disturbance, and an assessment of the impact of multiple stressors is needed to predict the fate of Alpine populations of these birds in the next decades. We estimated the effect of climate change and human disturbance on a rock ptarmigan population living in the western Italian Alps by combining an empirical population modelling approach and stochastic simulations of the population dynamics under the a1B climate scenario and two different disturbance scenarios, represented by the development of a ski resort, through 2050.The early appearance of snow-free ground in the previous spring had a favorable effect on the rock ptarmigan population, probably through a higher reproductive success. On the contrary, delayed snowfall in autumn had a negative effect possibly due to a mismatch in time to molt to white winter plumage which increases predation risk. The regional climate model PROTHEUS does not foresee any significant change in snowmelt date in the study area, while the start date of continuous snow cover is expected to be significantly delayed. The net effect in the stochastic projections is a more or less pronounced (depending on the model used) decline in the studied population. The addition of extra-mortality due to collision with ski-lift wires led the population to fatal consequences in most projections. Should these results be confirmed by larger studies the conservation of Alpine populations would deserve more attention. To counterbalance the effects of climate change, the reduction of all causes of death should be pursued, through a strict preservation of the habitats in the present area of occurrence.

  13. Criminality and climate change

    Science.gov (United States)

    White, Rob

    2016-08-01

    The impacts of climate change imply a reconceptualization of environment-related criminality. Criminology can offer insight into the definitions and dynamics of this behaviour, and outline potential areas of redress.

  14. Structural insights into the MDP binding and CARD-CARD interaction in zebrafish (Danio rerio) NOD2: a molecular dynamics approach.

    Science.gov (United States)

    Maharana, Jitendra; Patra, Mahesh Chandra; De, Bidhan Chandra; Sahoo, Bikash Ranjan; Behera, Bijay Kumar; De, Sachinandan; Pradhan, Sukanta Kumar

    2014-05-01

    Nucleotide binding and oligomerization domain (NOD2) is a key component of innate immunity that is highly specific for muramyl dipeptide (MDP)-a peptidoglycan component of bacterial cell wall. MDP recognition by NOD2-leucine rich repeat (LRR) domain activates NF-κB signaling through a protein-protein interaction between caspase activating and recruitment domains (CARDs) of NOD2 and downstream receptor interacting and activating protein kinase 2 (RIP2). Due to the lack of crystal/NMR structures, MDP recognition and CARD-CARD interaction are poorly understood. Herein, we have predicted the probable MDP and CARD-CARD binding surfaces in zebrafish NOD2 (zNOD2) using various in silico methodologies. The results show that the conserved residues Phe819, Phe871, Trp875, Trp929, Trp899, and Arg845 located at the concave face of zNOD2-LRR confer MDP recognition by hydrophobic and hydrogen bond (H-bond) interactions. Molecular dynamics simulations reveal a stable association between the electropositive surface on zNOD2-CARDa and the electronegative surface on zRIP2-CARD reinforced mostly by H-bonds and electrostatic interactions. Importantly, a 3.5 Å salt bridge is observed between Arg60 of zNOD2-CARDa and Asp494 of zRIP2-CARD. Arg11 and Lys53 of zNOD2-CARDa and Ser498 and Glu508 of zRIP2-CARD are critical residues for CARD-CARD interaction and NOD2 signaling. The 2.7 Å H-bond between Lys104 of the linker and Glu508 of zRIP2-CARD suggests a possible role of the linker for shaping CARD-CARD interaction. These findings are consistent with existing mutagenesis data. We provide first insight into MDP recognition and CARD-CARD interaction in the zebrafish that will be useful to understand the molecular basis of NOD signaling in a broader perspective.

  15. COOH-Terminal Clustering of Autoantibody and T-Cell Determinants on the Structure of GAD65 Provide Insights Into the Molecular Basis of Autoreactivity

    Energy Technology Data Exchange (ETDEWEB)

    Fenalti, Gustavo; Hampe, Christiane S.; Arafat, Yasir; Law, Ruby H.P.; Banga, J. Paul; Mackay, Ian R.; Whisstock, James C.; Buckle, Ashley M.; Rowley, Merrill J. (UWASH); (King’s College); (Monash)

    2008-11-19

    To gain structural insights into the autoantigenic properties of GAD65 in type 1 diabetes, we analyzed experimental epitope mapping data in the context of the recently determined crystal structures of GAD65 and GAD67, to allow 'molecular positioning' of epitope sites for B- and T-cell reactivity. Data were assembled from analysis of reported effects of mutagenesis of GAD65 on its reactivity with a panel of 11 human monoclonal antibodies (mAbs), supplemented by use of recombinant Fab to cross-inhibit reactivity with GAD65 by radioimmunoprecipitation of the same mAbs. COOH-terminal region on GAD65 was the major autoantigenic site. B-cell epitopes were distributed within two separate clusters around different faces of the COOH-terminal domain. Inclusion of epitope sites in the pyridoxal phosphate- and NH{sub 2}-terminal domains was attributed to the juxtaposition of all three domains in the crystal structure. Epitope preferences of different mAbs to GAD65 aligned with different clinical expressions of type 1 diabetes. Epitopes for four of five known reactive T-cell sequences restricted by HLA DRB1*0401 were aligned to solvent-exposed regions of the GAD65 structure and colocalized within the two B-cell epitope clusters. The continuous COOH-terminal epitope region of GAD65 was structurally highly flexible and therefore differed markedly from the equivalent region of GAD67. Structural features could explain the differing antigenicity, and perhaps immunogenicity, of GAD65 versus GAD67. The proximity of B- and T-cell epitopes within the GAD65 structure suggests that antigen-antibody complexes may influence antigen processing by accessory cells and thereby T-cell reactivity.

  16. Insight into the intermolecular recognition mechanism between Keap1 and IKKβ combining homology modelling, protein-protein docking, molecular dynamics simulations and virtual alanine mutation.

    Directory of Open Access Journals (Sweden)

    Zheng-Yu Jiang

    Full Text Available Degradation of certain proteins through the ubiquitin-proteasome pathway is a common strategy taken by the key modulators responsible for stress responses. Kelch-like ECH-associated protein-1(Keap1, a substrate adaptor component of the Cullin3 (Cul3-based ubiquitin E3 ligase complex, mediates the ubiquitination of two key modulators, NF-E2-related factor 2 (Nrf2 and IκB kinase β (IKKβ, which are involved in the redox control of gene transcription. However, compared to the Keap1-Nrf2 protein-protein interaction (PPI, the intermolecular recognition mechanism of Keap1 and IKKβ has been poorly investigated. In order to explore the binding pattern between Keap1 and IKKβ, the PPI model of Keap1 and IKKβ was investigated. The structure of human IKKβ was constructed by means of the homology modeling method and using reported crystal structure of Xenopus laevis IKKβ as the template. A protein-protein docking method was applied to develop the Keap1-IKKβ complex model. After the refinement and visual analysis of docked proteins, the chosen pose was further optimized through molecular dynamics simulations. The resulting structure was utilized to conduct the virtual alanine mutation for the exploration of hot-spots significant for the intermolecular interaction. Overall, our results provided structural insights into the PPI model of Keap1-IKKβ and suggest that the substrate specificity of Keap1 depend on the interaction with the key tyrosines, namely Tyr525, Tyr574 and Tyr334. The study presented in the current project may be useful to design molecules that selectively modulate Keap1. The selective recognition mechanism of Keap1 with IKKβ or Nrf2 will be helpful to further know the crosstalk between NF-κB and Nrf2 signaling.

  17. Insight into the intermolecular recognition mechanism between Keap1 and IKKβ combining homology modelling, protein-protein docking, molecular dynamics simulations and virtual alanine mutation.

    Science.gov (United States)

    Jiang, Zheng-Yu; Chu, Hong-Xi; Xi, Mei-Yang; Yang, Ting-Ting; Jia, Jian-Min; Huang, Jing-Jie; Guo, Xiao-Ke; Zhang, Xiao-Jin; You, Qi-Dong; Sun, Hao-Peng

    2013-01-01

    Degradation of certain proteins through the ubiquitin-proteasome pathway is a common strategy taken by the key modulators responsible for stress responses. Kelch-like ECH-associated protein-1(Keap1), a substrate adaptor component of the Cullin3 (Cul3)-based ubiquitin E3 ligase complex, mediates the ubiquitination of two key modulators, NF-E2-related factor 2 (Nrf2) and IκB kinase β (IKKβ), which are involved in the redox control of gene transcription. However, compared to the Keap1-Nrf2 protein-protein interaction (PPI), the intermolecular recognition mechanism of Keap1 and IKKβ has been poorly investigated. In order to explore the binding pattern between Keap1 and IKKβ, the PPI model of Keap1 and IKKβ was investigated. The structure of human IKKβ was constructed by means of the homology modeling method and using reported crystal structure of Xenopus laevis IKKβ as the template. A protein-protein docking method was applied to develop the Keap1-IKKβ complex model. After the refinement and visual analysis of docked proteins, the chosen pose was further optimized through molecular dynamics simulations. The resulting structure was utilized to conduct the virtual alanine mutation for the exploration of hot-spots significant for the intermolecular interaction. Overall, our results provided structural insights into the PPI model of Keap1-IKKβ and suggest that the substrate specificity of Keap1 depend on the interaction with the key tyrosines, namely Tyr525, Tyr574 and Tyr334. The study presented in the current project may be useful to design molecules that selectively modulate Keap1. The selective recognition mechanism of Keap1 with IKKβ or Nrf2 will be helpful to further know the crosstalk between NF-κB and Nrf2 signaling.

  18. Insights into nucleotide recognition by cell division protein FtsZ from a mant-GTP competition assay and molecular dynamics.

    Science.gov (United States)

    Schaffner-Barbero, Claudia; Gil-Redondo, Rubén; Ruiz-Avila, Laura B; Huecas, Sonia; Läppchen, Tilman; den Blaauwen, Tanneke; Diaz, J Fernando; Morreale, Antonio; Andreu, Jose M

    2010-12-14

    Essential cell division protein FtsZ forms the bacterial cytokinetic ring and is a target for new antibiotics. FtsZ monomers bind GTP and assemble into filaments. Hydrolysis to GDP at the association interface between monomers leads to filament disassembly. We have developed a homogeneous competition assay, employing the fluorescence anisotropy change of mant-GTP upon binding to nucleotide-free FtsZ, which detects compounds binding to the nucleotide site in FtsZ monomers and measures their affinities within the millimolar to 10 nM range. We have employed this method to determine the apparent contributions of the guanine, ribose, and the α-, β-, and γ-phosphates to the free energy change of nucleotide binding. Similar relative contributions have also been estimated through molecular dynamics and binding free energy calculations, employing the crystal structures of FtsZ-nucleotide complexes. We find an energetically dominant contribution of the β-phosphate, comparable to the whole guanosine moiety. GTP and GDP bind with similar observed affinity to FtsZ monomers. Loss of the regulatory γ-phosphate results in a predicted accommodation of GDP which has not been observed in the crystal structures. The binding affinities of a series of C8-substituted GTP analogues, known to inhibit FtsZ but not eukaryotic tubulin assembly, correlate with their inhibitory capacity on FtsZ polymerization. Our methods permit testing of FtsZ inhibitors targeting its nucleotide site, as well as compounds from virtual screening of large synthetic libraries. Our results give insight into the FtsZ-nucleotide interactions, which could be useful in the rational design of new inhibitors, especially GTP phosphate mimetics.

  19. Characterization of a 1-cysteine peroxiredoxin from big-belly seahorse (Hippocampus abdominalis); insights into host antioxidant defense, molecular profiling and its expressional response to septic conditions.

    Science.gov (United States)

    Godahewa, G I; Perera, N C N; Elvitigala, Don Anushka Sandaruwan; Jayasooriya, R G P T; Kim, Gi-Young; Lee, Jehee

    2016-10-01

    1-cysteine peroxiredoxin (Prx6) is an antioxidant enzyme that protects cells by detoxifying multiple peroxide species. This study aimed to describe molecular features, functional assessments and potential immune responses of Prx6 identified from the big-belly seahorse, Hippocampus abdominalis (HaPrx6). The complete ORF (666 bp) of HaPrx6 encodes a polypeptide (24 kDa) of 222 amino acids, and harbors a prominent peroxiredoxin super-family domain, a peroxidatic catalytic center, and a peroxidatic cysteine. The deduced amino acid sequence of HaPrx6 shares a relatively high amino acid sequence similarity and close evolutionary relationship with Oplegnathus fasciatus Prx6. The purified recombinant HaPrx6 protein (rHaPrx6) was shown to protect plasmid DNA in the Metal Catalyzed Oxidation (MCO) assay and, together with 1,4-Dithiothreitol (DTT), protected human leukemia THP-1 cells from extracellular H2O2-mediated cell death. In addition, quantitative real-time PCR revealed that HaPrx6 mRNA was constitutively expressed in 14 different tissues, with the highest expression observed in liver tissue. Inductive transcriptional responses were observed in liver and kidney tissues of fish after treating them with bacterial stimuli, including LPS, Edwardsiella tarda, and Streptococcus iniae. These results suggest that HaPrx6 may play an important role in the immune response of the big-belly seahorse against microbial infection. Collectively, these findings provide structural and functional insights into HaPrx6.

  20. Structural models of zebrafish (Danio rerio NOD1 and NOD2 NACHT domains suggest differential ATP binding orientations: insights from computational modeling, docking and molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Jitendra Maharana

    Full Text Available Nucleotide-binding oligomerization domain-containing protein 1 (NOD1 and NOD2 are cytosolic pattern recognition receptors playing pivotal roles in innate immune signaling. NOD1 and NOD2 recognize bacterial peptidoglycan derivatives iE-DAP and MDP, respectively and undergoes conformational alternation and ATP-dependent self-oligomerization of NACHT domain followed by downstream signaling. Lack of structural adequacy of NACHT domain confines our understanding about the NOD-mediated signaling mechanism. Here, we predicted the structure of NACHT domain of both NOD1 and NOD2 from model organism zebrafish (Danio rerio using computational methods. Our study highlighted the differential ATP binding modes in NOD1 and NOD2. In NOD1, γ-phosphate of ATP faced toward the central nucleotide binding cavity like NLRC4, whereas in NOD2 the cavity was occupied by adenine moiety. The conserved 'Lysine' at Walker A formed hydrogen bonds (H-bonds and Aspartic acid (Walker B formed electrostatic interaction with ATP. At Sensor 1, Arg328 of NOD1 exhibited an H-bond with ATP, whereas corresponding Arg404 of NOD2 did not. 'Proline' of GxP motif (Pro386 of NOD1 and Pro464 of NOD2 interacted with adenine moiety and His511 at Sensor 2 of NOD1 interacted with γ-phosphate group of ATP. In contrast, His579 of NOD2 interacted with the adenine moiety having a relatively inverted orientation. Our findings are well supplemented with the molecular interaction of ATP with NLRC4, and consistent with mutagenesis data reported for human, which indicates evolutionary shared NOD signaling mechanism. Together, this study provides novel insights into ATP binding mechanism, and highlights the differential ATP binding modes in zebrafish NOD1 and NOD2.

  1. Influence of high-order mechanics on simulation of glacier response to climate change: insights from Haig Glacier, Canadian Rocky Mountains

    OpenAIRE

    S. Adhikari; Marshall, S. J.

    2013-01-01

    Evolution of glaciers in response to climate change has mostly been simulated using simplified dynamical models. Because these models do not account for the influence of high-order physics, corresponding results may exhibit some biases. For Haig Glacier in the Canadian Rocky Mountains, we test this hypothesis by comparing simulation results obtained from 3-D numerical models that deal with different assumptions concerning physics, ranging ...

  2. Freshwater lenses as archive of climate, groundwater recharge, and hydrochemical evolution: Insights from depth-specific water isotope analysis and age determination on the island of Langeoog, Germany

    Science.gov (United States)

    Houben, Georg J.; Koeniger, Paul; Sültenfuß, Jürgen

    2014-10-01

    The age stratification of a freshwater lens on the island of Langeoog, Germany, was reconstructed through depth-specific sampling and groundwater dating using the tritium-helium method. The stratification is strongly affected by the land use and resulting differences in recharge rates. Infiltration at the dune tops is significantly lower than in the valleys, due to repellency of the dry sand. Dune valleys contribute up to four times more groundwater recharge per area than other areas. Housing development in dune areas might therefore significantly decrease the available fresh groundwater. The freshwater column shows a distinct increase of stable isotope values with decreasing depths. Hence, the freshwater lens contains a climate archive which reflects changing environmental conditions at the time of recharge. Combined with tritium-helium dating, this pattern could be matched to climate records which show an increase of the temperature at the time of recharge and rainfall rates during the last 50 years. The spatial and temporal developments of water chemistry during the passage through the lens follow a marked pattern from a sodium and chloride-dominated rainwater of low conductivity to a more mineralized sodium bicarbonate water type, caused by dissolution of carbonate shells close to the surface and subsequent ion exchange of calcium for sodium in the deeper parts.

  3. Influence of high-order mechanics on simulation of glacier response to climate change: insights from Haig Glacier, Canadian Rocky Mountains

    Directory of Open Access Journals (Sweden)

    S. Adhikari

    2013-04-01

    Full Text Available Evolution of glaciers in response to climate change has mostly been simulated using simplified dynamical models. Because these models do not account for the influence of high-order physics, corresponding results may exhibit some biases. For Haig Glacier in the Canadian Rocky Mountains, we test this hypothesis by comparing simulation results obtained from 3-D numerical models that deal with different assumptions concerning ice-flow physics, ranging from simple shear-deformation to comprehensive Stokes flow. In glacier retreat scenarios, we find a minimal role of high-order mechanics in glacier evolution, as geometric effects at our site (the presence of an overdeepened bed result in limited horizontal movement of ice (flow speed on the order of a few meters per year. Consequently, high-order and reduced models all predict that Haig Glacier ceases to exist by ca. 2080 under ongoing climate warming. The influence of high-order mechanics is evident, however, in glacier advance scenarios, where ice speeds are greater and ice dynamical effects become more important. To generalize these findings for other glacier applications, we advise that high-order mechanics are important and therefore should be considered while modelling the evolution of active glaciers. Reduced model predictions may, however, be adequate for other glaciologic and topographic settings, particularly where flow speeds are low.

  4. Influence of high-order mechanics on simulation of glacier response to climate change: insights from Haig Glacier, Canadian Rocky Mountains

    Directory of Open Access Journals (Sweden)

    S. Adhikari

    2013-09-01

    Full Text Available Evolution of glaciers in response to climate change has mostly been simulated using simplified dynamical models. Because these models do not account for the influence of high-order physics, corresponding results may exhibit some biases. For Haig Glacier in the Canadian Rocky Mountains, we test this hypothesis by comparing simulation results obtained from 3-D numerical models that deal with different assumptions concerning physics, ranging from simple shear deformation to comprehensive Stokes flow. In glacier retreat scenarios, we find a minimal role of high-order mechanics in glacier evolution, as geometric effects at our site (the presence of an overdeepened bed result in limited horizontal movement of ice (flow speed on the order of a few meters per year. Consequently, high-order and reduced models all predict that Haig Glacier ceases to exist by ca. 2080 under ongoing climate warming. The influence of high-order mechanics is evident, however, in glacier advance scenarios, where ice speeds are greater and ice dynamical effects become more important. Although similar studies on other glaciers are essential to generalize such findings, we advise that high-order mechanics are important and therefore should be considered while modeling the evolution of active glaciers. Reduced model predictions may be adequate for other glaciologic and topographic settings, particularly where flow speeds are low and where mass balance changes dominate over ice dynamics in determining glacier geometry.

  5. Response of an ombrotrophic peat to a regional climatic event revealed by macrofossil, molecular, and isotopic data

    NARCIS (Netherlands)

    Sinninghe Damsté, J.S.; Pancost, R.D.; Baas, B.; Geel, B. van

    2003-01-01

    We examined the variations in vegetation, organic carbon isotopic compositions and biomarker distributions spanning a well-constrained climatic shift in a Sub-Boreal Dutch raised bog. The macrofossils record a vegetation shift from a predominance of degraded Ericaceae rootlets to a predominance of w

  6. Molecular characterization of UGT94F2 and UGT86C4, two glycosyltransferases from Picrorhiza kurrooa: comparative structural insight and evaluation of substrate recognition.

    Directory of Open Access Journals (Sweden)

    Wajid Waheed Bhat

    Full Text Available Uridine diphosphate glycosyltransferases (UGTs are pivotal in the process of glycosylation for decorating natural products with sugars. It is one of the versatile mechanisms in determining chemical complexity and diversity for the production of suite of pharmacologically active plant natural products. Picrorhiza kurrooa is a highly reputed medicinal herb known for its hepato-protective properties which are attributed to a novel group of iridoid glycosides known as picrosides. Although the plant is well studied in terms of its pharmacological properties, very little is known about the biosynthesis of these important secondary metabolites. In this study, we identified two family-1 glucosyltransferases from P. kurrooa. The full length cDNAs of UGT94F4 and UGT86C4 contained open reading frames of 1455 and 1422 nucleotides, encoding polypeptides of 484 and 473 amino acids respectively. UGT94F2 and UGT86C4 showed differential expression pattern in leaves, rhizomes and inflorescence. To elucidate whether the differential expression pattern of the two Picrorhiza UGTs correlate with transcriptional regulation via their promoters and to identify elements that could be recognized by known iridoid-specific transcription factors, upstream regions of each gene were isolated and scanned for putative cis-regulatory elements. Interestingly, the presence of cis-regulatory elements within the promoter regions of each gene correlated positively with their expression profiles in response to different phytohormones. HPLC analysis of picrosides extracted from different tissues and elicitor-treated samples showed a significant increase in picroside levels, corroborating well with the expression profile of UGT94F2 possibly indicating its implication in picroside biosynthesis. Using homology modeling and molecular docking studies, we provide an insight into the donor and acceptor specificities of both UGTs identified in this study. UGT94F2 was predicted to be an iridoid

  7. Insights into resistance mechanism of the macrolide biosensor protein MphR(A) binding to macrolide antibiotic erythromycin by molecular dynamics simulation.

    Science.gov (United States)

    Feng, Tingting; Zhang, Yanjun; Ding, Jing-Na; Fan, Song; Han, Ju-Guang

    2015-12-01

    Macrolide biosensor protein MphR(A) has been known as a key regulatory protein in metabolite sensing and genetic expression regulating. MphR(A) protein binds to macrolide antibiotic erythromycin (Ery) and releases the gene operon, thus activates expression of the mphA gene and initiates Ery resistance. The two mutant amino acid residues (V66L and V126L) might potentially disrupt Ery binding to MphR(A). In these studies, the binding of macrolide antibiotic Ery to wild type (Wt) MphR(A) and double mutant (V66L/V126L) MphR(A) are explored by molecular dynamics simulations. Compared to the Apo-MphR(A) protein and Wt-MphR(A)-Ery complex, many interesting effects owing to the double mutant (V66L/V126L) are discovered. In the case of Ery, Helix I which plays an important role in transcription shows itself a right-hand α helix in Wt-MphR(A)-Ery, whereas the activated helix is broken down in double mutant-V66L/V126L-MphR(A)-Ery. The calculated results exhibit that the double mutant V66L/V126L reduces the binding affinity of the V66L/V126L-MphR(A) to Ery, resulting in the block of Ery resistance. The binding free energy decomposition analysis reveals that the decrease of the binding affinity for the variant V66L/V126L-MphR(A)-Ery is mainly attributed to the gas phase electrostatic energies. The residue Leu66, Thr154, and Arg122 enhance the binding affinity of V66L/V126L-MphR(A) to Ery. The residues Tyr103 and His147 contributes mainly to binding energies in the Wt-MphR(A)-Ery complex, whereas the two residues have no contribution to the binding free energy inV66L/V126L-MphR(A)-Ery complex. Our study gives useful insights into the nature of amino acids mutation effect, the mechanism of blocking drug resistance at the atomic level and the characteristics in binding affinity for Ery to double mutant (V66L/V126L) MphR(A), which will contribute to the design of more effective macrolide antibiotics.

  8. Molecular insights into how a deficiency of amylose affects carbon allocation – carbohydrate and oil analyses and gene expression profiling in the seeds of a rice waxy mutant

    Directory of Open Access Journals (Sweden)

    Zhang Ming-Zhou

    2012-12-01

    Full Text Available Abstract Background Understanding carbon partitioning in cereal seeds is of critical importance to develop cereal crops with enhanced starch yields for food security and for producing specified end-products high in amylose, β-glucan, or fructan, such as functional foods or oils for biofuel applications. Waxy mutants of cereals have a high content of amylopectin and have been well characterized. However, the allocation of carbon to other components, such as β-glucan and oils, and the regulation of the altered carbon distribution to amylopectin in a waxy mutant are poorly understood. In this study, we used a rice mutant, GM077, with a low content of amylose to gain molecular insight into how a deficiency of amylose affects carbon allocation to other end products and to amylopectin. We used carbohydrate analysis, subtractive cDNA libraries, and qPCR to identify candidate genes potentially responsible for the changes in carbon allocation in GM077 seeds. Results Carbohydrate analysis indicated that the content of amylose in GM077 seeds was significantly reduced, while that of amylopectin significantly rose as compared to the wild type BP034. The content of glucose, sucrose, total starch, cell-wall polysaccharides and oil were only slightly affected in the mutant as compared to the wild type. Suppression subtractive hybridization (SSH experiments generated 116 unigenes in the mutant on the wild-type background. Among the 116 unigenes, three, AGP, ISA1 and SUSIBA2-like, were found to be directly involved in amylopectin synthesis, indicating their possible roles in redirecting carbon flux from amylose to amylopectin. A bioinformatics analysis of the putative SUSIBA2-like binding elements in the promoter regions of the upregulated genes indicated that the SUSIBA2-like transcription factor may be instrumental in promoting the carbon reallocation from amylose to amylopectin. Conclusion Analyses of carbohydrate and oil fractions and gene expression

  9. Solubilization Behavior of Polyene Antibiotics in Nanomicellar System: Insights from Molecular Dynamics Simulation of the Amphotericin B and Nystatin Interactions with Polysorbate 80

    Directory of Open Access Journals (Sweden)

    Meysam Mobasheri

    2015-12-01

    Full Text Available Amphotericin B (AmB and Nystatin (Nys are the drugs of choice for treatment of systemic and superficial mycotic infections, respectively, with their full clinical potential unrealized due to the lack of high therapeutic index formulations for their solubilized delivery. In the present study, using a coarse-grained (CG molecular dynamics (MD simulation approach, we investigated the interaction of AmB and Nys with Polysorbate 80 (P80 to gain insight into the behavior of these polyene antibiotics (PAs in nanomicellar solution and derive potential implications for their formulation development. While the encapsulation process was predominantly governed by hydrophobic forces, the dynamics, hydration, localization, orientation, and solvation of PAs in the micelle were largely controlled by hydrophilic interactions. Simulation results rationalized the experimentally observed capability of P80 in solubilizing PAs by indicating (i the dominant kinetics of drugs encapsulation over self-association; (ii significantly lower hydration of the drugs at encapsulated state compared with aggregated state; (iii monomeric solubilization of the drugs; (iv contribution of drug-micelle interactions to the solubilization; (v suppressed diffusivity of the encapsulated drugs; (vi high loading capacity of the micelle; and (vii the structural robustness of the micelle against drug loading. Supported from the experimental data, our simulations determined the preferred location of PAs to be the core-shell interface at the relatively shallow depth of 75% of micelle radius. Deeper penetration of PAs was impeded by the synergistic effects of (i limited diffusion of water; and (ii perpendicular orientation of these drug molecules with respect to the micelle radius. PAs were solvated almost exclusively in the aqueous poly-oxyethylene (POE medium due to the distance-related lack of interaction with the core, explaining the documented insensitivity of Nys solubilization to drug

  10. Insights into resistance mechanism of the macrolide biosensor protein MphR(A) binding to macrolide antibiotic erythromycin by molecular dynamics simulation

    Science.gov (United States)

    Feng, Tingting; Zhang, Yanjun; Ding, Jing-Na; Fan, Song; Han, Ju-Guang

    2015-12-01

    Macrolide biosensor protein MphR(A) has been known as a key regulatory protein in metabolite sensing and genetic expression regulating. MphR(A) protein binds to macrolide antibiotic erythromycin (Ery) and releases the gene operon, thus activates expression of the mphA gene and initiates Ery resistance. The two mutant amino acid residues (V66L and V126L) might potentially disrupt Ery binding to MphR(A). In these studies, the binding of macrolide antibiotic Ery to wild type (Wt) MphR(A) and double mutant (V66L/V126L) MphR(A) are explored by molecular dynamics simulations. Compared to the Apo-MphR(A) protein and Wt-MphR(A)-Ery complex, many interesting effects owing to the double mutant (V66L/V126L) are discovered. In the case of Ery, Helix I which plays an important role in transcription shows itself a right-hand α helix in Wt-MphR(A)-Ery, whereas the activated helix is broken down in double mutant-V66L/V126L-MphR(A)-Ery. The calculated results exhibit that the double mutant V66L/V126L reduces the binding affinity of the V66L/V126L-MphR(A) to Ery, resulting in the block of Ery resistance. The binding free energy decomposition analysis reveals that the decrease of the binding affinity for the variant V66L/V126L-MphR(A)-Ery is mainly attributed to the gas phase electrostatic energies. The residue Leu66, Thr154, and Arg122 enhance the binding affinity of V66L/V126L-MphR(A) to Ery. The residues Tyr103 and His147 contributes mainly to binding energies in the Wt-MphR(A)-Ery complex, whereas the two residues have no contribution to the binding free energy inV66L/V126L-MphR(A)-Ery complex. Our study gives useful insights into the nature of amino acids mutation effect, the mechanism of blocking drug resistance at the atomic level and the characteristics in binding affinity for Ery to double mutant (V66L/V126L) MphR(A), which will contribute to the design of more effective macrolide antibiotics.

  11. Discussion on sea level fluctuations along the Adriatic coasts coupling to climate indices forced by solar activity: Insights into the future of Venice

    Science.gov (United States)

    Zanchettin, Davide; Traverso, Pietro; Tomasino, Mario

    2006-04-01

    The North Atlantic Oscillation (NAO), which is a dominant circulation pattern in Northern Hemisphere winter, is known to affect sea-level variability in the Mediterranean Sea mainly through the hydrostatic response of water masses to pressure anomalies and changes in evaporation/precipitation budgets. In this study the influence of the NAO on sea levels along the Adriatic coasts is re-assessed in the attempt to uncover the potential causes of the observed high sensitivity of the northern basin to NAO fluctuations. The investigation is focused on the role of the NAO as forcing factor of the winds blowing in the area and of the freshwaters input from the Po River, both of which influence the hydrodynamics of the Northern Adriatic. In addition, some insights into the future of Venice are discussed on the basis of the hypothesis that NAO phases are modulated by the varying solar activity through the intensity of the Earth's geomagnetic activity.

  12. Charred wood remains in the natufian sequence of el-Wad terrace (Israel): New insights into the climatic, environmental and cultural changes at the end of the Pleistocene

    Science.gov (United States)

    Caracuta, Valentina; Weinstein-Evron, Mina; Yeshurun, Reuven; Kaufman, Daniel; Tsatskin, Alexander; Boaretto, Elisabetta

    2016-01-01

    The major social and economic changes associated with the rise of a sedentary lifestyle and the gradual transition to food production in the southern Levant are often considered to have been triggered by climate changes at the end of the Pleistocene (∼20,000-11,000 years BP). This explanation, however, is biased by the scarcity of high-resolution climate records directly associated with human activity and the lack of refined palaeoecological studies from multi-stratified sites in the area. Here, we present the results of an anthracological analysis, carried out on charcoals collected along a continuous column of archaeological sediments in the Natufian site of el-Wad Terrace (Mount Carmel, Israel). We also present the carbon isotopes analysis of 14C-dated archaeological remains of Amygdalus sp. The analyses of charcoal shows the predominance of an oak forest including Quercus calliprinos and ithaburensis around the site during the Early Natufian building phase (∼14,600-13,700 cal BP), and the values of Δ13C point to a high rainfall rate. This period is followed by a marked decrease in the local rainfall between ∼13,700 and 12,000 cal BP). The reduction, culturally associated with the latest Early Natufian and the Late Natufian, is independently recorded by the speleothems of the region: Soreq Cave and Jerusalem Cave. This period incorporates an increase in drought tolerant species such as Amygdalus sp. Thermo-Mediterranean species, such as Olea europaea and Ceratonia siliqua, as well as Pistacia palaestina, which dominate the modern landscape, become established in the Holocene. We conclude that the Natufian settlement at el-Wad Terrace flourished in the context of oak forests, and subsequently occupation intensity decreased in concurrence to the drying trend. This shift does not correspond to the cultural typology (i.e. Early Natufian vs. Late Natufian). Human response to climate change at the terminal Pleistocene Levant was multifaceted and localized. Its

  13. Insights into MIS 3 and 4 climate in the Alps from the Baumkirchen paleo-lake site: Results of pollen analysis

    Science.gov (United States)

    Barrett, Samuel; Drescher-Schneider, Ruth; Starnberger, Reinhard; Spötl, Christoph

    2016-04-01

    The well-known Baumkirchen site of western Austria has recently been the focus of a renewed research effort. New drilling has greatly extended the length of the known lacustrine sequence to over 250 m. Luminescence dating has corroborated the late MIS 3 radiocarbon dates for the upper part of the sequence and revealed two lake phases: the upper extending from late MIS 3 back to mid MIS 3, and the lower covering late MIS 4 or early MIS 3 back possibly as far as MIS 5a. X-ray fluorescence core scanning analysis confirmed the presence of two phases which have different geochemical signals, and provided a chemistry-based stratigraphy in the visually monotonous sediments. In these uniform sediments, the only clear indication of climatic conditions from the sediments themselves is a short sequence of ice-rafted debris corresponding to the end of MIS 4. However, given their age and location within the Alps, these sediments provide an important archive of Alpine climate in the last glacial cycle. We present new results from pollen analysis and discuss them in the context of previously reported findings. Due to high sedimentation rates, pollen counts were very low. However, two stadials and two interstadials were identified. The entire lower lake phase corresponding to MIS 4 was identified as a stadial, being characterised by a very low total pollen concentrations, a dominance of herb over tree pollen and significant reworking of pre-Quaternary forms and wood fragments. The upper lake phase contains two interstadials split by an intervening stadial. The interstadials are characterised by higher total pollen concentrations and proportion of woody species including the sporadic presence of relatively warm climate species with the upper of the two appearing better developed with these indicators more strongly expressed. This upper interstadial corresponds to the location of well dated plant remains putting its age around 35 ka cal BP, strongly suggesting a correlation to

  14. Vegetation and climate in Southern Hemisphere mid-latitudes since 210 ka: new insights from marine and terrestrial pollen records from New Zealand

    Science.gov (United States)

    Ryan, M. T.; Dunbar, G. B.; Vandergoes, M. J.; Neil, H. L.; Hannah, M. J.; Newnham, R. M.; Bostock, H.; Alloway, B. V.

    2012-08-01

    Paleo-vegetation records developed from marine sedimentary sequences offer considerable potential for examining changes in terrestrial climate beyond the range of 14C dating because they can be independently dated by δ18O stratigraphy. Here we present the first pollen record of vegetation from a marine core site in the Tasman Sea, TAN0513-14 (42°18'S, 169°53'E), ˜110 km west of New Zealand's South Island. An independent chronology provided by correlating the Globigerina bulloides δ18O record at TAN0513-14 to a global isotope stack shows that the record extends back to 210 ka. Glacial to interglacial changes in palynomorph content are characterised by shrub and podocarp-broadleaf forest taxa respectively and are correlated with similar changes in the ca 150 kyr-long terrestrial pollen record from Okarito Pakihi (bog), 110 km to the south southeast. Both records are placed on the same timescale by matching variations in Dacrydium cupressinum and Fuscospora between sites, with a unique tie point provided by the ca 25.4 ka Kawakawa Tephra. Our Southern Hemisphere mid-latitude vegetation records show forest extent is greatest during periods of low ice volume, high mean annual sea surface temperature (MASST) and anti-phased with local insolation intensity. However, there are several features not attributable to changes in mean annual temperature. First, a fundamental change in forest composition occurred at Termination II (TII), with a loss of southern beech (Nothofagus) from the study area. Second, the amplitude of MASST change through MIS 5 is not reflected in corresponding changes in forest extent, suggesting other feature(s) of regional climate (seasonality, frostiness, ice cover) exert important controls over vegetation patterns at these latitudes.

  15. What can scientific practice look like in a classroom? Insights from scientists' critique of high school students' climate change argumentation practice

    Science.gov (United States)

    Walsh, E.; McGowan, V. C.

    2015-12-01

    The Next Generation Science Standards promote a vision in which learners engage in authentic knowledge in practice to tackle personally consequential science problems in the classroom. However, there is not yet a clear understanding amongst researchers and educators of what authentic practice looks like in a classroom and how this can be accomplished. This study explores these questions by examining interactions between scientists and students on a social media platform during two pilot enactments of a project-based curriculum focusing on the ecological impacts of climate change. During this unit, scientists provided feedback to students on infographics, visual representations of scientific information meant to communicate to an audience about climate change. We conceptualize the feedback and student work as boundary objects co-created by students and scientists moving between the school and scientific contexts, and analyze the structure and content of the scientists' feedback. We find that when giving feedback on a particular practice (e.g. argumentation), scientists would provide avenues, critiques and questions that incorporated many other practices (e.g. data analysis, visual communication); thus, scientists encouraged students to participate systemically in practices instead of isolating one particular practice. In addition, scientists drew attention to particular habits of mind that are valued in the scientific community and noted when students' work aligned with scientific values. In this way, scientists positioned students as capable of participating "scientifically." While traditionally, incorporating scientific inquiry in a classroom has emphasized student experimentation and data generation, in this work, we found that engaging with scientists around established scientific texts and data sets provided students with a platform for developing expertise in other important scientific practices during argment construction.

  16. Litter decomposition over broad spatial and long time scales investigated by advanced solid-state NMR: insight into effects of climate, litter quality, and time

    Science.gov (United States)

    Mao, J.; Chen, N.; Harmon, M. E.; Li, Y.; Cao, X.; Chappell, M.

    2012-12-01

    Advanced 13C solid-state NMR techniques were employed to study the chemical structural changes of litter decomposition across broad spatial and long time scales. The fresh and decomposed litter samples of four species (Acer saccharum (ACSA), Drypetes glauca (DRGL), Pinus resinosa (PIRE), and Thuja plicata (THPL)) incubated for up to 10 years at four sites under different climatic conditions (from Arctic to tropical forest) were examined. Decomposition generally led to an enrichment of cutin and surface wax materials, and a depletion of carbohydrates causing overall composition to become more similar compared with original litters. However, the changes of main constituents in the four litters were inconsistent with the four litters following different pathways of decomposition at the same site. As decomposition proceeded, waxy materials decreased at the early stage and then gradually increased in PIRE; DRGL showed a significant depletion of lignin and tannin while the changes of lignin and tannin were relative small and inconsistent for ACSA and THPL. In addition, the NCH groups, which could be associated with either fungal cell wall chitin or bacterial wall petidoglycan, were enriched in all litters except THPL. Contrary to the classic lignin-enrichment hypothesis, DRGL with low-quality C substrate had the highest degree of composition changes. Furthermore, some samples had more "advanced" compositional changes in the intermediate stage of decomposition than in the highly-decomposed stage. This pattern might be attributed to the formation of new cross-linking structures, that rendered substrates more complex and difficult for enzymes to attack. Finally, litter quality overrode climate and time factors as a control of long-term changes of chemical composition.

  17. Pleistocene uplift, climate and morphological segmentation of the Northern Chile coasts (24°S-32°S): Insights from cosmogenic 10Be dating of paleoshorelines

    Science.gov (United States)

    Martinod, Joseph; Regard, Vincent; Riquelme, Rodrigo; Aguilar, German; Guillaume, Benjamin; Carretier, Sébastien; Cortés-Aranda, Joaquín; Leanni, Laetitia; Hérail, Gérard

    2016-12-01

    We present new cosmogenic (10Be) exposure ages obtained on Pleistocene marine abrasion shore terraces of Northern Chile between 24°S and 32°S in order to evaluate the temporal and spatial variability of uplift rates along the coastal forearc. Both the dispersion of cosmogenic concentrations in samples from the same terrace and data obtained in vertical profiles show that onshore erosion rates, following emergence of paleoshorelines, approached 1 m/Myr. Therefore, minimum ages calculated without considering onshore erosion may be largely underestimated for Middle Pleistocene terraces. The elevation of the last interglacial (MIS-5) paleoshoreline is generally between 25 and 45 m amsl, suggesting that the entire coast of the study area has been uplifting during the Upper Pleistocene at rates approaching 0.3 mm/yr. Available ages for Middle Pleistocene terraces suggest similar uplift rates, except in the Altos de Talinay area where uplift may have been accelerated by the activity of the Puerto Aldea Fault. The maximum elevation of Pleistocene paleoshorelines is generally close to 250 m and there is no higher older Neogene marine sediment, which implies that uplift accelerated during the Pleistocene following a period of coastal stability or subsidence. We observe that the coastal morphology largely depends on the latitudinal climatic variability. North of 26.75°S, the coast is characterized by the presence of a high scarp associated with small and poorly preserved paleoshorelines at its foot. The existence of the coastal scarp in the northern part of the study area is permitted by the hyper-arid climate of the Atacama Desert. This particular morphology may explain why paleoshorelines evidencing coastal uplift are poorly preserved between 26.75°S and 24°S despite Upper Pleistocene uplift rates being comparable with those prevailing in the southern part of the study area.

  18. Probabilistic Projections of Future Sea-Level Change and Their Implications for Flood Risk Management: Insights from the American Climate Prospectus

    Science.gov (United States)

    Kopp, R. E., III; Delgado, M.; Horton, R. M.; Houser, T.; Little, C. M.; Muir-Wood, R.; Oppenheimer, M.; Rasmussen, D. M., Jr.; Strauss, B.; Tebaldi, C.

    2014-12-01

    Global mean sea level (GMSL) rise projections are insufficient for adaptation planning; local decisions require local projections that characterize risk over a range of timeframes and tolerances. We present a global set of local sea level (LSL) projections to inform decisions on timescales ranging from the coming decades through the 22nd century. We present complete probability distributions, informed by a combination of expert community assessment, expert elicitation, and process modeling [1]. We illustrate the application of this framework by estimating the joint distribution of future sea-level change and coastal flooding, and associated economic costs [1,2]. In much of the world in the current century, differences in median LSL projections are due primarily to varying levels of non-climatic uplift or subsidence. In the 22nd century and in the high-end tails, larger ice sheet contributions, particularly from the Antarctic ice sheet (AIS), contribute significantly to site-to-site differences. Uncertainty in GMSL and most LSL projections is dominated by the uncertain AIS component. Sea-level rise dramatically reshapes flood risk. For example, at the New York City (Battery) tide gauge, our projections indicate a likely (67% probability) 21st century LSL rise under RCP 8.5 of 65--129 cm (1-in-20 chance of exceeding 154 cm). Convolving the distribution of projected sea-level rise with the extreme value distribution of flood return periods indicates that this rise will cause the current 1.80 m `1-in-100 year' flood event to occur an expected nine times over the 21st century -- equivalent to the expected number of `1-in-11 year' floods in the absence of sea-level change. Projected sea-level rise for 2100 under RCP 8.5 would likely place 80-160 billion of current property in New York below the high tide line, with a 1-in-20 chance of losses >190 billion. Even without accounting for potential changes in storms themselves, it would likely increase average annual storm

  19. The climate of the Late Cretaceous: New insights from the application of the carbonate clumped isotope thermometer to Western Interior Seaway macrofossil

    Science.gov (United States)

    Dennis, K. J.; Cochran, J. K.; Landman, N. H.; Schrag, D. P.

    2013-01-01

    We apply the carbonate clumped isotope thermometer (Δ47) to macrofossils from the Baculites compressus (˜73.5 Ma) and the Hoploscaphites nebrascensis (˜67 Ma) ammonite zones of the Western Interior Seaway (WIS) of North America, and nearby coeval terrestrial and open marine environments. The carbonate clumped isotope thermometer is based on a single-phase isotope exchange equilibrium that promotes the 'clumping' of two heavy isotopes together within a single carbonate molecule as temperature decreases. Due to the thermometer's isotopic independence from water, coupled measurements of Δ47 and the bulk oxygen isotopic composition of a carbonate (δ18Oc) enable the reconstruction of both paleotemperature and the isotopic composition of the water in which the organisms grew. Before applying the technique to the aragonite shells of fossil marine organisms (mostly ammonites, but also some gastropods, bivalves, and one belemnite), we measure the clumped isotopic composition of modern nautilus and cuttlefish, two of the nearest living relatives to the Cretaceous ammonites. Modern cephalopods exhibit disequilibrium isotope effects with respect to Δ47, but not δ18Oc, therefore a simple correctional scheme is applied to the Late Cretaceous macrofossil data before reconstructing paleotemperatures. Diagenesis is also assessed by visual preservation and previously measured Sr concentrations (Cochran et al., 2003). Temperatures reconstructed for the Late Cretaceous Western Interior Seaway range from 16.4±3.5 °C for an offshore Interior Seaway environment from the H. nebrascensis zone to 24.2±0.4 °C for the B. compressus ammonite zone. The seaway itself has an isotopic composition of approximately -1‰ (relative to VSMOW), the expectation for an ice-free global ocean average, while a nearby freshwater environment has an isotopic composition approaching -20‰. We compare the attributes of the reconstructed climate to predictions based on Late Cretaceous climate models

  20. Surviving in mountain climate refugia: new insights from the genetic diversity and structure of the relict shrub Myrtus nivellei (Myrtaceae) in the Sahara Desert.

    Science.gov (United States)

    Migliore, Jérémy; Baumel, Alex; Juin, Marianick; Fady, Bruno; Roig, Anne; Duong, Nathalie; Médail, Frédéric

    2013-01-01

    The identification of past glacial refugia has become a key topic for conservation under environmental change, since they contribute importantly to shaping current patterns of biodiversity. However, little attention has been paid so far to interglacial refugia despite their key role for the survival of relict species currently occurring in climate refugia. Here, we focus on the genetic consequences of range contraction on the relict populations of the evergreen shrub Myrtus nivellei, endemic in the Saharan mountains since at least the end of the last Green Sahara period, around 5.5 ka B.P. Multilocus genotypes (nuclear microsatellites and AFLP) were obtained from 215 individuals collected from 23 wadis (temporary rivers) in the three main mountain ranges in southern Algeria (the Hoggar, Tassili n'Ajjer and Tassili n'Immidir ranges). Identical genotypes were found in several plants growing far apart within the same wadis, a pattern taken as evidence of clonality. Multivariate analyses and Bayesian clustering revealed that genetic diversity was mainly structured among the mountain ranges, while low isolation by distance was observed within each mountain range. The range contraction induced by the last episode of aridification has likely increased the genetic isolation of the populations of M. nivellei, without greatly affecting the genetic diversity of the species as a whole. The pattern of genetic diversity observed here suggests that high connectivity may have prevailed during humid periods, which is consistent with recent paleoenvironmental reconstructions.

  1. Climate-relevant physical properties of molecular constituents relevant for isoprene-derived secondary organic aerosol material

    Directory of Open Access Journals (Sweden)

    M. A. Upshur

    2014-06-01

    Full Text Available Secondary organic aerosol (SOA particles, formed from gas-phase biogenic volatile organic compounds (BVOCs, contribute large uncertainties to the radiative forcing that is associated with aerosols in the climate system. Reactive uptake of surface-active organic oxidation products of BVOCs at the gas–aerosol interface can potentially decrease the overall aerosol surface tension and therefore influence their propensity to act as cloud condensation nuclei (CCN. Here, we synthesize and measure some climate-relevant physical properties of SOA particle constituents consisting of the isoprene oxidation products α-, δ-, and cis- and {trans-β-IEPOX (isoprene epoxide, as well as syn- and anti-2-methyltetraol. Following viscosity measurements, we use octanol-water partition coefficients to quantify the relative hydrophobicity of the oxidation products while dynamic surface tension measurements indicate that aqueous solutions of α- and trans-β-IEPOX exhibit significant surface tension depression. We hypothesize that the surface activity of these compounds may enhance aerosol CCN activity, and that trans-β-IEPOX may be highly relevant for surface chemistry of aerosol particles relative to other IEPOX isomers.

  2. Spatial Self-Organization of Vegetation Subject to Climatic Stress-Insights from a System Dynamics-Individual-Based Hybrid Model.

    Science.gov (United States)

    Vincenot, Christian E; Carteni, Fabrizio; Mazzoleni, Stefano; Rietkerk, Max; Giannino, Francesco

    2016-01-01

    In simulation models of populations or communities, individual plants have often been obfuscated in favor of aggregated vegetation. This simplification comes with a loss of biological detail and a smoothing out of the demographic noise engendered by stochastic individual-scale processes and heterogeneities, which is significant among others when studying the viability of small populations facing challenging fluctuating environmental conditions. This consideration has motivated the development of precise plant-centered models. The accuracy gained in the representation of plant biology has then, however, often been balanced by the disappearance in models of important plant-soil interactions (esp. water dynamics) due to the inability of most individual-based frameworks to simulate complex continuous processes. In this study, we used a hybrid modeling approach, namely integrated System Dynamics (SD)-Individual-based (IB), to illustrate the importance of individual plant dynamics to explain spatial self-organization of vegetation in arid environments. We analyzed the behavior of this model under different parameter sets either related to individual plant properties (such as seed dispersal distance and reproductive age) or the environment (such as intensity and yearly distribution of precipitation events). While the results of this work confirmed the prevailing theory on vegetation patterning, they also revealed the importance therein of plant-level processes that cannot be rendered by reaction-diffusion models. Initial spatial distribution of plants, reproductive age, and average seed dispersal distance, by impacting patch size and vegetation aggregation, affected pattern formation and population survival under climatic variations. Besides, changes in precipitation regime altered the demographic structure and spatial organization of vegetation patches by affecting plants differentially depending on their age and biomass. Water availability influenced non-linearly total

  3. Spatial Self-Organization of Vegetation Subject to Climatic Stress—Insights from a System Dynamics—Individual-Based Hybrid Model

    Science.gov (United States)

    Vincenot, Christian E.; Carteni, Fabrizio; Mazzoleni, Stefano; Rietkerk, Max; Giannino, Francesco

    2016-01-01

    In simulation models of populations or communities, individual plants have often been obfuscated in favor of aggregated vegetation. This simplification comes with a loss of biological detail and a smoothing out of the demographic noise engendered by stochastic individual-scale processes and heterogeneities, which is significant among others when studying the viability of small populations facing challenging fluctuating environmental conditions. This consideration has motivated the development of precise plant-centered models. The accuracy gained in the representation of plant biology has then, however, often been balanced by the disappearance in models of important plant-soil interactions (esp. water dynamics) due to the inability of most individual-based frameworks to simulate complex continuous processes. In this study, we used a hybrid modeling approach, namely integrated System Dynamics (SD)—Individual-based (IB), to illustrate the importance of individual plant dynamics to explain spatial self-organization of vegetation in arid environments. We analyzed the behavior of this model under different parameter sets either related to individual plant properties (such as seed dispersal distance and reproductive age) or the environment (such as intensity and yearly distribution of precipitation events). While the results of this work confirmed the prevailing theory on vegetation patterning, they also revealed the importance therein of plant-level processes that cannot be rendered by reaction-diffusion models. Initial spatial distribution of plants, reproductive age, and average seed dispersal distance, by impacting patch size and vegetation aggregation, affected pattern formation and population survival under climatic variations. Besides, changes in precipitation regime altered the demographic structure and spatial organization of vegetation patches by affecting plants differentially depending on their age and biomass. Water availability influenced non

  4. Evaluation of the biointeraction of colorant flavazin with human serum albumin: insights from multiple spectroscopic studies, in silico docking and molecular dynamics simulation.

    Science.gov (United States)

    Peng, Wei; Ding, Fei; Jiang, Yu-Ting; Sun, Ying; Peng, Yu-Kui

    2014-06-01

    Azo compounds are the largest chemical class of agents frequently used as colorants in a variety of consumer goods and farm produce; therefore, they may become a hazard to public health, because numerous azo compounds and their metabolites are proven to be carcinogens and mutagens. Herein several qualitative and quantitative analytical techniques, including steady state and time-resolved fluorescence, circular dichroism (CD), computer-aided molecular docking as well as molecular dynamics simulation, were employed to ascertain the molecular recognition between the principal vehicle of ligands in human plasma, albumin and a model azo compound, flavazin. The results show that the albumin spatial structure was changed in the presence of flavazin with a decrease of α-helix suggesting partial protein destabilization/self-regulation, as derived from steady state fluorescence, far-UV CD and detailed analyses of three-dimensional fluorescence spectra. Time-resolved fluorescence further evinced that the recognition mechanism is related to albumin-flavazin adduct formation with an association intensity of 10(4) M(-1), and the driving forces were found to be chiefly π-π interactions, hydrophobic interactions and hydrogen bonds. The specific binding domain of flavazin in protein was defined from molecular docking; subdomain IIA (Sudlow's site I) was found to retain high affinity for the ligand flavazin. This finding corroborates the results of competitive ligand displacement experiments, a hydrophobic 8-anilino-1-naphthalenesulfonic acid probe study and protein denaturation results, placing flavazin at the warfarin-azapropazone site. Based on molecular dynamics simulation, it can be said with certainty that the results of molecular docking are credible, and the key amino acid residues participating in the molecular recognition of flavazin by protein are clearly Trp-214, Arg-222 and Lys-436. The outcomes presented here will help to further comprehend the molecular recognition

  5. Joint analysis of phenotypic and molecular diversity provides new insights on the genetic variability of the Brazilian physic nut germplasm bank.

    Science.gov (United States)

    Alves, Alexandre Alonso; Bhering, Leonardo Lopes; Rosado, Tatiana Barbosa; Laviola, Bruno Galvêas; Formighieri, Eduardo Fernandes; Cruz, Cosme Damião

    2013-09-01

    The genetic variability of the Brazilian physic nut (Jatropha curcas) germplasm bank (117 accessions) was assessed using a combination of phenotypic and molecular data. The joint dissimilarity matrix showed moderate correlation with the original matrices of phenotypic and molecular data. However, the correlation between the phenotypic dissimilarity matrix and the genotypic dissimilarity matrix was low. This finding indicated that molecular markers (RAPD and SSR) did not adequately sample the genomic regions that were relevant for phenotypic differentiation of the accessions. The dissimilarity values of the joint dissimilarity matrix were used to measure phenotypic + molecular diversity. This diversity varied from 0 to 1.29 among the 117 accessions, with an average dissimilarity among genotypes of 0.51. Joint analysis of phenotypic and molecular diversity indicated that the genetic diversity of the physic nut germplasm was 156% and 64% higher than the diversity estimated from phenotypic and molecular data, respectively. These results show that Jatropha genetic variability in Brazil is not as limited as previously thought.

  6. Consumer Insights

    Institute of Scientific and Technical Information of China (English)

    JANKOT

    2004-01-01

    Fang Jun, the head of consumer and market insights of Unilever Shanghai, has summarized his early life as a market in two sentences: rush about to study market changes;act all day to observe consumer behavior. And now?"Tell stories, conduct interviews and piece together different data; calculate numbers,build models and write reports."

  7. Temperature, vegetation and precipitation variability in the Nile River drainage during the past 27,000 years: Insights from molecular and isotopic proxies

    Science.gov (United States)

    Castañeda, Isla; Schouten, Stefan; Pätzold, Jürgen; Schefuß, Enno

    2013-04-01

    The paleoclimate history of the Eastern Mediterranean (EM) region is of much interest due to its long history of human occupation. To date, much of our knowledge of past climate in the EM region comes from marine sedimentary records. These indicate that since the Last Glacial Maximum, major and sometimes abrupt sea surface temperature (SST) fluctuations occurred in response to global climate events including the Younger Dryas (YD), the Bølling-Allerød, and Heinrich Event 1 (H1). In comparison, less is known regarding continental paleoclimate conditions in this region due to a scarcity of well-dated continuous climate archives, particularly from Saharan North Africa. Here, we present new reconstructions of continental precipitation (plant leaf wax δD), C3 vs. C4 vegetation (plant leaf wax δ13C) and soil temperature (MBT/CBT paleothermometer) in the Nile River catchment in conjunction with previously published U37k' and TEX86SST reconstructions from the EM Sea. Our multiproxy records indicate that relative to the present, the LGM was characterized by arid conditions with cooler SST and soil temperatures in the catchment. The H1 event stands out as a major excursion in nearly all proxies and is characterized by an abrupt decrease in SST and the most arid conditions of the past 27,000 years. The African Humid Period (AHP) of the early Holocene is the wettest interval of the entire record and is observed from ~10,000 to 5,500 cal BP, with maximum wet conditions noted at ~8,000 cal BP. Interestingly, a rather abrupt cooling is noted in the MBT/CBT record at ~5.5 cal kyr, coinciding with the end of the AHP off west Africa; however, the transition out of the AHP is more gradual in the δD record. Overall both the continental and marine climate records indicate millennial scale climate variability. Our records also shed light on shifting sources of organic matter in response to the sequential cessation and re-initiation of different tributaries to the main flow of the

  8. Insight into the Mechanism of Hydrolysis of Meropenem by OXA-23 Serine-β-lactamase Gained by Quantum Mechanics/Molecular Mechanics Calculations.

    Science.gov (United States)

    Sgrignani, Jacopo; Grazioso, Giovanni; De Amici, Marco

    2016-09-13

    The fast and constant development of drug resistant bacteria represents a serious medical emergency. To overcome this problem, the development of drugs with new structures and modes of action is urgently needed. In this work, we investigated, at the atomistic level, the mechanisms of hydrolysis of Meropenem by OXA-23, a class D β-lactamase, combining unbiased classical molecular dynamics and umbrella sampling simulations with classical force field-based and quantum mechanics/molecular mechanics potentials. Our calculations provide a detailed structural and dynamic picture of the molecular steps leading to the formation of the Meropenem-OXA-23 covalent adduct, the subsequent hydrolysis, and the final release of the inactive antibiotic. In this mechanistic framework, the predicted activation energy is in good agreement with experimental kinetic measurements, validating the expected reaction path.

  9. Insights into the Molecular Pathogenesis of Activated B-Cell-like Diffuse Large B-Cell Lymphoma and Its Therapeutic Implications

    Energy Technology Data Exchange (ETDEWEB)

    Lenz, Georg [Translational Oncology, Department of Medicine A, Albert-Schweitzer Campus 1, University Hospital Münster, 48149 Münster (Germany); Cluster of Excellence EXC 1003, Cells in Motion, 48149 Münster (Germany)

    2015-05-22

    Within the last couple of years, the understanding of the molecular mechanisms that drive the pathogenesis of diffuse large B-cell lymphoma (DLBCL) has significantly improved. Large-scale gene expression profiling studies have led to the discovery of several molecularly defined subtypes that are characterized by specific oncogene addictions and significant differences in their outcome. Next generation sequencing efforts combined with RNA interference screens frequently identify crucial oncogenes that lead to constitutive activation of various signaling pathways that drive lymphomagenesis. This review summarizes our current understanding of the molecular pathogenesis of the activated B-cell-like (ABC) DLBCL subtype that is characterized by poor prognosis. A special emphasis is put on findings that might impact therapeutic strategies of affected patients.

  10. Historical Associations of Molecular Measurements of Escherichia coli and Enterococci to Anthropogenic Activities and Climate Variables in Freshwater Sediment Cores.

    Science.gov (United States)

    Brooks, Yolanda M; Baustian, Melissa M; Baskaran, Mark; Ostrom, Nathaniel E; Rose, Joan B

    2016-07-05

    This study investigated the long-term associations of anthropogenic (sedimentary P, C, and N concentrations, and human population in the watershed), and climatic variables (air temperature, and river discharge) with Escherichia coli uidA and enterococci 23S rRNA concentrations in sediment cores from Anchor Bay (AB) in Lake St. Clair, and near the mouth of the Clinton River (CR), Michigan. Calendar year was estimated from vertical abundances of (137)Cs. The AB and CR cores spanned c.1760-2012 and c.1895-2012, respectively. There were steady state concentrations of enterococci in AB during c.1760-c.1860 and c.1910-c.2003 at ∼0.1 × 10(5) and ∼2.0 × 10(5) cell equivalents (CE) per g-dry wt, respectively. Enterococci concentrations in CR increased toward present day, and ranged from ∼0.03 × 10(5) to 9.9 × 10(5) CE/g-dry wt. The E. coli concentrations in CR and AB increased toward present day, and ranged from 0.14 × 10(7) to 1.7 × 10(7) CE/g-dry wt, and 1.8 × 10(6) to 8.5 × 10(6) CE/g-dry wt, respectively. Enterococci was associated with population and river discharge, while E. coli was associated with population, air temperature, and N and C concentrations (p < 0.05). Sediments retain records of the abundance of fecal indicator bacteria, and offer a way to evaluate responses to increased population, nutrient loading, and environmental policies.

  11. Molecular interaction studies of green tea catechins as multitarget drug candidates for the treatment of Parkinson's disease: computational and structural insights.

    Science.gov (United States)

    Azam, Faizul; Mohamed, Najah; Alhussen, Fatma

    2015-01-01

    Green tea catechins have extensively been studied for their imminent role in reducing the risk of various neurodegenerative diseases such as Parkinson's disease (PD). Understanding the molecular interaction of these compounds with various anti-Parkinsonian drug targets is of interest. The present study is intended to explore binding modes of catechins with molecular targets having potential role in PD. Lamarckian genetic algorithm methodology was adopted for molecular docking simulations employing AutoDock 4.2 program. Toxicity potential and molecular properties responsible for good pharmacokinetic profile were calculated by Osiris property explorer and Molinspiration online toolkit, respectively. A strong correlation coefficient (r(2) = 0.893) was obtained between experimentally reported and docking predicted activities of native co-crystallized ligands of the 18 target receptors used in current study. Analysis of docked conformations revealed monoamine oxidase-B as most promising, while N-methyl-D-aspartate receptor was recognized as the least favorable target for catechins. Benzopyran skeleton with a phenyl group substituted at the 2-position and a hydroxyl (or ester) function at the 3-position has been identified as common structural requirements at majority of the targets. The present findings suggest that epigallocatechin gallate is the most promising lead to be developed as multitarget drug for the design and development of novel anti-Parkinsonian agents.

  12. Insight into the structural requirements of protoporphyrinogen oxidase inhibitors: molecular modeling and CoMFA of diphenyl ether, isoxazole phenyl, and pyrazole phenyl ether

    Science.gov (United States)

    Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is one of the most significant targets for a large family of inhibitors that may be used as herbicide, bactericide, fungicide, or photosensitizing activator to treat cancer through photodynamic therapy (PDT). Molecular modeling and CoMFA were combined in ...

  13. First principles molecular dynamics simulation of a task-specific ionic liquid based on silver-olefin complex: atomistic insight into separation process

    CERN Document Server

    Jiang, De-en

    2008-01-01

    First principles molecular dynamics based on density functional theory is applied to a hypothetical ionic liquid whose cations and anions are silver-ethylene complex [Ag(C2H4)2+] and tetrafluoroborate [BF4-], respectively. This ionic liquid represents a group of task-specific silver complex-based ionic liquids synthesized recently. Molecular dynamics simulations at two temperatures are performed for five picoseconds. Events of association, dissociation, exchange, and recombination of ethylene with silver cation are observed. A mechanism of ethylene transfer similar to the Grotthus type of proton transfer in water is identified, where a silver cation accepts one ethylene molecule and donates another to a neighboring silver cation. This mechanism may contribute to fast transport of olefins through ionic liquid membranes based on silver complexes for olefin/paraffin separation.

  14. First principles molecular dynamics simulation of a task-specif