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Sample records for brain molecular conservation

  1. Tryptophan as an evolutionarily conserved signal to brain serotonin : Molecular evidence and psychiatric implications

    NARCIS (Netherlands)

    Russo, Sascha; Kema, Ido P.; Bosker, Fokko; Haavik, Jan; Korf, Jakob

    2009-01-01

    The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is evol

  2. Molecular contributions to conservation

    Science.gov (United States)

    Haig, Susan M.

    1998-01-01

    Recent advances in molecular technology have opened a new chapter in species conservation efforts, as well as population biology. DNA sequencing, MHC (major histocompatibility complex), minisatellite, microsatellite, and RAPD (random amplified polymorphic DNA) procedures allow for identification of parentage, more distant relatives, founders to new populations, unidentified individuals, population structure, effective population size, population-specific markers, etc. PCR (polymerase chain reaction) amplification of mitochondrial DNA, nuclear DNA, ribosomal DNA, chloroplast DNA, and other systems provide for more sophisticated analyses of metapopulation structure, hybridization events, and delineation of species, subspecies, and races, all of which aid in setting species recovery priorities. Each technique can be powerful in its own right but is most credible when used in conjunction with other molecular techniques and, most importantly, with ecological and demographic data collected from the field. Surprisingly few taxa of concern have been assayed with any molecular technique. Thus, rather than showcasing exhaustive details from a few well-known examples, this paper attempts to present a broad range of cases in which molecular techniques have been used to provide insight into conservation efforts.

  3. Conserved patterns of axogenesis in the panarthropod brain.

    Science.gov (United States)

    Boyan, George; Williams, Leslie; Liu, Yu

    2015-03-01

    Neuropils in the cerebral midline of Panarthropoda exhibit a wide spectrum of neuroarchitectures--from rudimentary to highly elaborated--and which at first sight defy a unifying neuroarchitectural principle. Developmental approaches have shown that in model arthropods such as insects, conserved cellular and molecular mechanisms first establish a simple axon scaffold in the brain. However, to be adapted for adult life, this immature ground plan is transformed by a developmental process--known in the grasshopper as "fascicle switching"--in which subsets of neurons systematically redirect their growth cones at stereotypic locations across the brain midline. A topographic system of choice points along the transverse brain axis where axons decussate features in all panarthropods studied even though different modes of neurogenesis and varying degrees of neuropilar elaboration are involved. This suggests that the molecular mechanisms regulating choice point selection may be conserved. In combination with recent cladistic interpretations of arthropod phylogeny based on nuclear protein-coding sequences the data argue for this topographic decussation as having evolved early and being a conserved feature of the Panarthropoda. Differences in elaboration likely reflect both the extent to which neuropilar reorganization has progressed during development and the lifestyle of the individual organism. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Amphibian molecular ecology and how it has informed conservation.

    Science.gov (United States)

    McCartney-Melstad, Evan; Shaffer, H Bradley

    2015-10-01

    Molecular ecology has become one of the key tools in the modern conservationist's kit. Here we review three areas where molecular ecology has been applied to amphibian conservation: genes on landscapes, within-population processes, and genes that matter. We summarize relevant analytical methods, recent important studies from the amphibian literature, and conservation implications for each section. Finally, we include five in-depth examples of how molecular ecology has been successfully applied to specific amphibian systems. © 2015 John Wiley & Sons Ltd.

  5. Molecular insights into melanoma brain metastases.

    Science.gov (United States)

    Westphal, Dana; Glitza Oliva, Isabella C; Niessner, Heike

    2017-06-01

    Substantial proportions of patients with metastatic melanoma develop brain metastases during the course of their disease, often resulting in significant morbidity and death. Despite recent advances with BRAF/MEK and immune-checkpoint inhibitors in the treatment of patients who have melanoma with extracerebral metastases, patients who have melanoma brain metastases still have poor overall survival, highlighting the need for further therapy options. A deeper understanding of the molecular pathways involved in the development of melanoma brain metastases is required to develop more brain-specific therapies. Here, the authors summarize the currently known preclinical data and describe steps involved in the development of melanoma brain metastases. Only by knowing the molecular background is it possible to design new therapeutic agents that can be used to improve the outcome of patients with melanoma brain metastases. Cancer 2017;123:2163-75. © 2017 American Cancer Society. © 2017 American Cancer Society.

  6. Energy conservation in molecular dynamics simulations of classical systems

    DEFF Research Database (Denmark)

    Toxværd, Søren; Heilmann, Ole; Dyre, J. C.

    2012-01-01

    Classical Newtonian dynamics is analytic and the energy of an isolated system is conserved. The energy of such a system, obtained by the discrete “Verlet” algorithm commonly used in molecular dynamics simulations, fluctuates but is conserved in the mean. This is explained by the existence...

  7. The Molecular Basis of Human Brain Evolution.

    Science.gov (United States)

    Enard, Wolfgang

    2016-10-24

    Humans are a remarkable species, especially because of the remarkable properties of their brain. Since the split from the chimpanzee lineage, the human brain has increased three-fold in size and has acquired abilities for vocal learning, language and intense cooperation. To better understand the molecular basis of these changes is of great biological and biomedical interest. However, all the about 16 million fixed genetic changes that occurred during human evolution are fully correlated with all molecular, cellular, anatomical and behavioral changes that occurred during this time. Hence, as humans and chimpanzees cannot be crossed or genetically manipulated, no direct evidence for linking particular genetic and molecular changes to human brain evolution can be obtained. Here, I sketch a framework how indirect evidence can be obtained and review findings related to the molecular basis of human cognition, vocal learning and brain size. In particular, I discuss how a comprehensive comparative approach, leveraging cellular systems and genomic technologies, could inform the evolution of our brain in the future. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Machine Learning of Accurate Energy-Conserving Molecular Force Fields

    CERN Document Server

    Chmiela, Stefan; Sauceda, Huziel E; Poltavsky, Igor; Schütt, Kristof; Müller, Klaus-Robert

    2016-01-01

    Using conservation of energy -- a fundamental property of closed classical and quantum mechanical systems -- we develop an efficient gradient-domain machine learning (GDML) approach to construct accurate molecular force fields using a restricted number of samples from ab initio molecular dynamics (AIMD) trajectories. The GDML implementation is able to reproduce global potential-energy surfaces of intermediate-size molecules with an accuracy of 0.3 kcal/mol for energies and 1 kcal/mol/{\\AA} for atomic forces using only 1000 conformational geometries for training. We demonstrate this accuracy for AIMD trajectories of molecules, including benzene, toluene, naphthalene, ethanol, uracil, and aspirin. The challenge of constructing conservative force fields is accomplished in our work by learning in a Hilbert space of vector-valued functions that obey the law of energy conservation. The GDML approach enables quantitative molecular dynamics simulations for molecules at a fraction of cost of explicit AIMD calculations...

  9. Amino acid properties conserved in molecular evolution.

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    Witold R Rudnicki

    Full Text Available That amino acid properties are responsible for the way protein molecules evolve is natural and is also reasonably well supported both by the structure of the genetic code and, to a large extent, by the experimental measures of the amino acid similarity. Nevertheless, there remains a significant gap between observed similarity matrices and their reconstructions from amino acid properties. Therefore, we introduce a simple theoretical model of amino acid similarity matrices, which allows splitting the matrix into two parts - one that depends only on mutabilities of amino acids and another that depends on pairwise similarities between them. Then the new synthetic amino acid properties are derived from the pairwise similarities and used to reconstruct similarity matrices covering a wide range of information entropies. Our model allows us to explain up to 94% of the variability in the BLOSUM family of the amino acids similarity matrices in terms of amino acid properties. The new properties derived from amino acid similarity matrices correlate highly with properties known to be important for molecular evolution such as hydrophobicity, size, shape and charge of amino acids. This result closes the gap in our understanding of the influence of amino acids on evolution at the molecular level. The methods were applied to the single family of similarity matrices used often in general sequence homology searches, but it is general and can be used also for more specific matrices. The new synthetic properties can be used in analyzes of protein sequences in various biological applications.

  10. An evolutionarily conserved sexual signature in the primate brain.

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    Björn Reinius

    2008-06-01

    Full Text Available The question of a potential biological sexual signature in the human brain is a heavily disputed subject. In order to provide further insight into this issue, we used an evolutionary approach to identify genes with sex differences in brain expression level among primates. We reasoned that expression patterns important to uphold key male and female characteristics may be conserved during evolution. We selected cortex for our studies because this specific brain region is responsible for many higher behavioral functions. We compared gene expression profiles in the occipital cortex of male and female humans (Homo sapiens, a great ape and cynomolgus macaques (Macaca fascicularis, an old world monkey, two catarrhine species that show abundant morphological sexual dimorphism, as well as in common marmosets (Callithrix Jacchus, a new world monkey which are relatively sexually monomorphic. We identified hundreds of genes with sex-biased expression patterns in humans and macaques, while fewer than ten were differentially expressed between the sexes in marmosets. In primates, a general rule is that many of the morphological and behavioral sexual dimorphisms seen in polygamous species, such as macaques, are typically less pronounced in monogamous species such as the marmosets. Our observations suggest that this correlation may also be reflected in the extent of sex-biased gene expression in the brain. We identified 85 genes with common sex-biased expression, in both human and macaque and 2 genes, X inactivation-specific transcript (XIST and Heat shock factor binding protein 1 (HSBP1, that were consistently sex-biased in the female direction in human, macaque, and marmoset. These observations imply a conserved signature of sexual gene expression dimorphism in cortex of primates. Further, we found that the coding region of female-biased genes is more evolutionarily constrained compared to the coding region of both male-biased and non sex-biased brain

  11. Cellular and molecular neurobiology of brain preconditioning.

    Science.gov (United States)

    Cadet, Jean Lud; Krasnova, Irina N

    2009-02-01

    The tolerant brain which is a consequence of adaptation to repeated nonlethal insults is accompanied by the upregulation of protective mechanisms and the downregulation of prodegenerative pathways. During the past 20 years, evidence has accumulated to suggest that protective mechanisms include increased production of chaperones, trophic factors, and other antiapoptotic proteins. In contrast, preconditioning can cause substantial dampening of the organism's metabolic state and decreased expression of proapoptotic proteins. Recent microarray analyses have also helped to document a role of several molecular pathways in the induction of the brain refractory state. The present review highlights some of these findings and suggests that a better understanding of these mechanisms will inform treatment of a number of neuropsychiatric disorders.

  12. Molecular Mechanisms of Neonatal Brain Injury

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    Claire Thornton

    2012-01-01

    Full Text Available Fetal/neonatal brain injury is an important cause of neurological disability. Hypoxia-ischemia and excitotoxicity are considered important insults, and, in spite of their acute nature, brain injury develops over a protracted time period during the primary, secondary, and tertiary phases. The concept that most of the injury develops with a delay after the insult makes it possible to provide effective neuroprotective treatment after the insult. Indeed, hypothermia applied within 6 hours after birth in neonatal encephalopathy reduces neurological disability in clinical trials. In order to develop the next generation of treatment, we need to know more about the pathophysiological mechanism during the secondary and tertiary phases of injury. We review some of the critical molecular events related to mitochondrial dysfunction and apoptosis during the secondary phase and report some recent evidence that intervention may be feasible also days-weeks after the insult.

  13. Non-conservation of excitons in finite molecular chain

    Energy Technology Data Exchange (ETDEWEB)

    Tosic, Bratislav, E-mail: btosic@yahoo.co [Vojvodina Academy of Science and Arts, 21000 Novi Sad, Dunavska 37 (Serbia); Sajfert, Vjekoslav, E-mail: sajfertv@nadlanu.co [University of Novi Sad, Technical Faculty ' M. Pupin' , 23000 Zrenjanin, Djure Djakovica bb (Serbia); Maskovic, Ljiljana, E-mail: maskovicm@yahoo.co.u [Academy of Criminalistic and Police Studies, 11000 Belgrade, Zemun (Serbia); Bednar, Nikola, E-mail: bednar.nikola@gmail.co [University of Novi Sad, Faculty of Technical Sciences, 21000 Novi Sad, Trg Dositeja Obradovica 6 (Serbia)

    2010-11-15

    We have analyzed a linear molecular chain with exciton excitations when the number of excitons is not conserved. The dispersion law depends on two independent variables and it is surfaced in a 3D plot. The same conclusion is valid for the concentrations of excitons and exciton pairs. As it was expected, physical characteristics of the finite chain depend on spatial coordinates. All results are compared to the corresponding results of an infinite chain.

  14. Machine learning of accurate energy-conserving molecular force fields

    Science.gov (United States)

    Chmiela, Stefan; Tkatchenko, Alexandre; Sauceda, Huziel E.; Poltavsky, Igor; Schütt, Kristof T.; Müller, Klaus-Robert

    2017-01-01

    Using conservation of energy—a fundamental property of closed classical and quantum mechanical systems—we develop an efficient gradient-domain machine learning (GDML) approach to construct accurate molecular force fields using a restricted number of samples from ab initio molecular dynamics (AIMD) trajectories. The GDML implementation is able to reproduce global potential energy surfaces of intermediate-sized molecules with an accuracy of 0.3 kcal mol−1 for energies and 1 kcal mol−1 Å̊−1 for atomic forces using only 1000 conformational geometries for training. We demonstrate this accuracy for AIMD trajectories of molecules, including benzene, toluene, naphthalene, ethanol, uracil, and aspirin. The challenge of constructing conservative force fields is accomplished in our work by learning in a Hilbert space of vector-valued functions that obey the law of energy conservation. The GDML approach enables quantitative molecular dynamics simulations for molecules at a fraction of cost of explicit AIMD calculations, thereby allowing the construction of efficient force fields with the accuracy and transferability of high-level ab initio methods. PMID:28508076

  15. Energy conservation in molecular dynamics simulations of classical systems.

    Science.gov (United States)

    Toxvaerd, Søren; Heilmann, Ole J; Dyre, Jeppe C

    2012-06-14

    Classical Newtonian dynamics is analytic and the energy of an isolated system is conserved. The energy of such a system, obtained by the discrete "Verlet" algorithm commonly used in molecular dynamics simulations, fluctuates but is conserved in the mean. This is explained by the existence of a "shadow Hamiltonian" H [S. Toxvaerd, Phys. Rev. E 50, 2271 (1994)], i.e., a Hamiltonian close to the original H with the property that the discrete positions of the Verlet algorithm for H lie on the analytic trajectories of H. The shadow Hamiltonian can be obtained from H by an asymptotic expansion in the time step length. Here we use the first non-trivial term in this expansion to obtain an improved estimate of the discrete values of the energy. The investigation is performed for a representative system with Lennard-Jones pair interactions. The simulations show that inclusion of this term reduces the standard deviation of the energy fluctuations by a factor of 100 for typical values of the time step length. Simulations further show that the energy is conserved for at least one hundred million time steps provided the potential and its first four derivatives are continuous at the cutoff. Finally, we show analytically as well as numerically that energy conservation is not sensitive to round-off errors.

  16. Molecular regionalization in the compact brain of the meiofaunal annelid Dinophilus gyrociliatus (Dinophilidae

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    Alexandra Kerbl

    2016-08-01

    Full Text Available Abstract Background Annelida is a morphologically diverse animal group that exhibits a remarkable variety in nervous system architecture (e.g., number and location of longitudinal cords, architecture of the brain. Despite this heterogeneity of neural arrangements, the molecular profiles related to central nervous system patterning seem to be conserved even between distantly related annelids. In particular, comparative molecular studies on brain and anterior neural region patterning genes have focused so far mainly on indirect-developing macrofaunal taxa. Therefore, analyses on microscopic, direct-developing annelids are important to attain a general picture of the evolutionary events underlying the vast diversity of annelid neuroanatomy. Results We have analyzed the expression domains of 11 evolutionarily conserved genes involved in brain and anterior neural patterning in adult females of the direct-developing meiofaunal annelid Dinophilus gyrociliatus. The small, compact brain shows expression of dimmed, foxg, goosecoid, homeobrain, nk2.1, orthodenticle, orthopedia, pax6, six3/6 and synaptotagmin-1. Although most of the studied markers localize to specific brain areas, the genes six3/6 and synaptotagmin-1 are expressed in nearly all perikarya of the brain. All genes except for goosecoid, pax6 and nk2.2 overlap in the anterior brain region, while the respective expression domains are more separated in the posterior brain. Conclusions Our findings reveal that the expression patterns of the genes foxg, orthodenticle, orthopedia and six3/6 correlate with those described in Platynereis dumerilii larvae, and homeobrain, nk2.1, orthodenticle and synaptotagmin-1 resemble the pattern of late larvae of Capitella teleta. Although data on other annelids are limited, molecular similarities between adult Dinophilus and larval Platynereis and Capitella suggest an overall conservation of molecular mechanisms patterning the anterior neural regions, independent

  17. Molecular regionalization in the compact brain of the meiofaunal annelid Dinophilus gyrociliatus (Dinophilidae)

    DEFF Research Database (Denmark)

    Kerbl, Alexandra; Martín-Durán, José M.; Worsaae, Katrine;

    2016-01-01

    BACKGROUND: Annelida is a morphologically diverse animal group that exhibits a remarkable variety in nervous system architecture (e.g., number and location of longitudinal cords, architecture of the brain). Despite this heterogeneity of neural arrangements, the molecular profiles related to central...... nervous system patterning seem to be conserved even between distantly related annelids. In particular, comparative molecular studies on brain and anterior neural region patterning genes have focused so far mainly on indirect-developing macrofaunal taxa. Therefore, analyses on microscopic, direct......-developing annelids are important to attain a general picture of the evolutionary events underlying the vast diversity of annelid neuroanatomy. RESULTS: We have analyzed the expression domains of 11 evolutionarily conserved genes involved in brain and anterior neural patterning in adult females of the direct...

  18. The molecular bases of the suicidal brain

    Science.gov (United States)

    Turecki, Gustavo

    2017-01-01

    Suicide ranks among the leading causes of death around the world, and takes a heavy emotional and public health toll on most societies. Both distal and proximal factors contribute to suicidal behaviour. Distal factors — such as familial and genetic predisposition, as well as early-life adversity — increase the lifetime risk of suicide. They alter responses to stress and other processes through epigenetic modification of genes and associated changes in gene expression, and through the regulation of emotional and behavioural traits. Proximal factors associate with the precipitation of a suicidal event and include alterations in key neurotransmitter systems, inflammatory changes and glial dysfunction in the brain. This Review explores the key molecular changes associated with suicidality, and presents some promising avenues for future research. PMID:25354482

  19. Molecular Genetics Techniques to Develop New Treatments for Brain Cancers

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    Fox, Jacob; Fathallan-Shaykh, Hassan

    2006-09-22

    The objectives of this report are: (1) to devise novel molecular gene therapies for malignant brain tumors, (2) advance our understanding of the immune system in the central nervous system; and (3) apply genomics to find molecular probes to diagnose brain tumors, predict prognosis, biological behavior and their response to treatment.

  20. Conserved Molecular Mechanisms Underlying Homeostasis of the Golgi Complex

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    Cathal Wilson

    2010-01-01

    Full Text Available The Golgi complex performs a central function in the secretory pathway in the sorting and sequential processing of a large number of proteins destined for other endomembrane organelles, the plasma membrane, or secretion from the cell, in addition to lipid metabolism and signaling. The Golgi apparatus can be regarded as a self-organizing system that maintains a relatively stable morphofunctional organization in the face of an enormous flux of lipids and proteins. A large number of the molecular players that operate in these processes have been identified, their functions and interactions defined, but there is still debate about many aspects that regulate protein trafficking and, in particular, the maintenance of these highly dynamic structures and processes. Here, we consider how an evolutionarily conserved underlying mechanism based on retrograde trafficking that uses lipids, COPI, SNAREs, and tethers could maintain such a homeodynamic system.

  1. Breast Conservation Therapy: The Influence of Molecular Subtype and Margins

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    Demirci, Senem, E-mail: senem.demirci@ege.edu.tr [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States); Department of Radiation Oncology, Ege University Faculty of Medicine, Izmir (Turkey); Broadwater, Gloria [Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Durham, NC (United States); Cancer and Leukemia Group B Statistical Center, Duke Cancer Institute, Durham, NC (United States); Marks, Lawrence B. [Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, NC (United States); Clough, Robert; Prosnitz, Leonard R. [Department of Radiation Oncology, Duke University Medical Center, Durham, NC (United States)

    2012-07-01

    Purpose: To evaluate treatment results and prognostic factors, especially margin status and molecular subtype, in early-stage breast cancer patients treated with breast conservation therapy (BCT). Methods and Materials: The records of 1,058 Stage I or II breast cancer patients treated with BCT (surgical excision plus radiotherapy) at Duke University Medical Center, Durham, North Carolina, from 1985-2005 were retrospectively reviewed. Conventional receptor analyses were used as surrogate markers for molecular subtype classification (luminal A, luminal B, Her2 positive, and basal like). Actuarial estimates of overall survival (OS), cause-specific survival (CSS), failure-free survival, and locoregional control (LRC) were computed by use of Kaplan-Meier plots. We analyzed prognostic variables for significance using Cox proportional hazards univariate and multivariate analysis. The study was approved by the Duke University Medical Center Institutional Review Board. Results: The median age of the patients was 56 years (range, 18-89 years). Of the patients, 80% had T1 disease and 66% N0 disease pathologically. With a median follow-up of 9.8 years, an in-breast recurrence developed in 53 patients and 10 patients had nodal failure. For all patients, the 10-year CSS rate was 94%; LRC rate, 94%; and failure-free survival rate, 88%. Luminal A patients had a CSS rate of 95% and LRC rate of 99%. Basal-type patients appeared to do worse, with regard to both CSS rate (74%) and LRC rate (76%), but the numbers were small and the difference was not statistically significant. LRC rates of patients with negative margins (widely negative, close, and extent of margin not known) were virtually identical (93%, 96%, and 94%, respectively). Those with positive margins appeared to fare slightly worse based on LRC rate (88%), but again, the numbers were small and the difference was not statistically significant. Conclusions: BCT remains the treatment of choice for early-stage breast cancer

  2. Comparative analysis of A-to-I editing in human and non-human primate brains reveals conserved patterns and context-dependent regulation of RNA editing.

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    O'Neil, Richard T; Wang, Xiaojing; Morabito, Michael V; Emeson, Ronald B

    2017-04-06

    A-to-I RNA editing is an important process for generating molecular diversity in the brain through modification of transcripts encoding several proteins important for neuronal signaling. We investigated the relationships between the extent of editing at multiple substrate transcripts (5HT2C, MGLUR4, CADPS, GLUR2, GLUR4, and GABRA3) in brain tissue obtained from adult humans and rhesus macaques. Several patterns emerged from these studies revealing conservation of editing across primate species. Additionally, variability in the human population allows us to make novel inferences about the co-regulation of editing at different editing sites and even across different brain regions.

  3. Molecular insights into human brain evolution.

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    Hill, Robert Sean; Walsh, Christopher A

    2005-09-01

    Rapidly advancing knowledge of genome structure and sequence enables new means for the analysis of specific DNA changes associated with the differences between the human brain and that of other mammals. Recent studies implicate evolutionary changes in messenger RNA and protein expression levels, as well as DNA changes that alter amino acid sequences. We can anticipate having a systematic catalogue of DNA changes in the lineage leading to humans, but an ongoing challenge will be relating these changes to the anatomical and functional differences between our brain and that of our ancient and more recent ancestors.

  4. Molecular dynamics algorithm enforcing energy conservation for microcanonical simulations.

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    Salueña, Clara; Avalos, Josep Bonet

    2014-05-01

    A reversible algorithm [enforced energy conservation (EEC)] that enforces total energy conservation for microcanonical simulations is presented. The key point is the introduction of the discrete-gradient method to define the forces from the conservative potentials, instead of the direct use of the force field at the actual position of the particle. We have studied the performance and accuracy of the EEC in two cases, namely Lennard-Jones fluid and a simple electrolyte model. Truncated potentials that usually induce inaccuracies in energy conservation are used. In particular, the reaction field approach is used in the latter. The EEC is able to preserve energy conservation for a long time, and, in addition, it performs better than the Verlet algorithm for these kinds of simulations.

  5. Searching for Conservation Laws in Brain Dynamics—BOLD Flux and Source Imaging

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    Henning U. Voss

    2014-07-01

    Full Text Available Blood-oxygen-level-dependent (BOLD imaging is the most important noninvasive tool to map human brain function. It relies on local blood-flow changes controlled by neurovascular coupling effects, usually in response to some cognitive or perceptual task. In this contribution we ask if the spatiotemporal dynamics of the BOLD signal can be modeled by a conservation law. In analogy to the description of physical laws, which often can be derived from some underlying conservation law, identification of conservation laws in the brain could lead to new models for the functional organization of the brain. Our model is independent of the nature of the conservation law, but we discuss possible hints and motivations for conservation laws. For example, globally limited blood supply and local competition between brain regions for blood might restrict the large scale BOLD signal in certain ways that could be observable. One proposed selective pressure for the evolution of such conservation laws is the closed volume of the skull limiting the expansion of brain tissue by increases in blood volume. These ideas are demonstrated on a mental motor imagery fMRI experiment, in which functional brain activation was mapped in a group of volunteers imagining themselves swimming. In order to search for local conservation laws during this complex cognitive process, we derived maps of quantities resulting from spatial interaction of the BOLD amplitudes. Specifically, we mapped fluxes and sources of the BOLD signal, terms that would appear in a description by a continuity equation. Whereas we cannot present final answers with the particular analysis of this particular experiment, some results seem to be non-trivial. For example, we found that during task the group BOLD flux covered more widespread regions than identified by conventional BOLD mapping and was always increasing during task. It is our hope that these results motivate more work towards the search for conservation

  6. [The application of DNA molecular markers in conservation of the rare and endangered medicinal plants].

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    Yan, Zhi-Feng; Zhang, Ben-Gang; Zhang, Zhao; Xia, Tian-Rui

    2005-12-01

    In this paper, the advance in DNA molecular markers techniques in recent years was reviewed. The application of DNA markers in conservation of the rare and endangered medicinal plants was explicated, of which included identification of germ-plasm resource, determination of the habitats unite which should be protected in situ, sampling strategies of ex-situ conservation, evaluation of the conservation effects of the rare and endangered medicinal plants, as well as elucidation of their endangered mechanism etc. The information could help drawing up conservation strategies and conservation measures for references.

  7. New Molecular Knowledge Towards the Trigemino-Cardiac Reflex as a Cerebral Oxygen-Conserving Reflex

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    N. Sandu

    2010-01-01

    Full Text Available The trigemino-cardiac reflex (TCR represents the most powerful of the autonomous reflexes and is a subphenomenon in the group of the so-called “oxygen-conserving reflexes”. Within seconds after the initiation of such a reflex, there is a powerful and differentiated activation of the sympathetic system with subsequent elevation in regional cerebral blood flow (CBF, with no changes in the cerebral metabolic rate of oxygen (CMRO2 or in the cerebral metabolic rate of glucose (CMRglc. Such an increase in regional CBF without a change of CMRO2 or CMRglc provides the brain with oxygen rapidly and efficiently. Features of the reflex have been discovered during skull base surgery, mediating reflex protection projects via currently undefined pathways from the rostral ventrolateral medulla oblongata to the upper brainstem and/or thalamus, which finally engage a small population of neurons in the cortex. This cortical center appears to be dedicated to transduce a neuronal signal reflexively into cerebral vasodilatation and synchronization of electrocortical activity; a fact that seems to be unique among autonomous reflexes. Sympathetic excitation is mediated by cortical-spinal projection to spinal preganglionic sympathetic neurons, whereas bradycardia is mediated via projections to cardiovagal motor medullary neurons. The integrated reflex response serves to redistribute blood from viscera to the brain in response to a challenge to cerebral metabolism, but seems also to initiate a preconditioning mechanism. Previous studies showed a great variability in the human TCR response, in special to external stimuli and individual factors. The TCR gives, therefore, not only new insights into novel therapeutic options for a range of disorders characterized by neuronal death, but also into the cortical and molecular organization of the brain.

  8. New molecular knowledge towards the trigemino-cardiac reflex as a cerebral oxygen-conserving reflex.

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    Sandu, N; Spiriev, T; Lemaitre, F; Filis, A; Schaller, B

    2010-05-04

    The trigemino-cardiac reflex (TCR) represents the most powerful of the autonomous reflexes and is a subphenomenon in the group of the so-called "oxygen-conserving reflexes". Within seconds after the initiation of such a reflex, there is a powerful and differentiated activation of the sympathetic system with subsequent elevation in regional cerebral blood flow (CBF), with no changes in the cerebral metabolic rate of oxygen (CMRO2) or in the cerebral metabolic rate of glucose (CMRglc). Such an increase in regional CBF without a change of CMRO2 or CMRglc provides the brain with oxygen rapidly and efficiently. Features of the reflex have been discovered during skull base surgery, mediating reflex protection projects via currently undefined pathways from the rostral ventrolateral medulla oblongata to the upper brainstem and/or thalamus, which finally engage a small population of neurons in the cortex. This cortical center appears to be dedicated to transduce a neuronal signal reflexively into cerebral vasodilatation and synchronization of electrocortical activity; a fact that seems to be unique among autonomous reflexes. Sympathetic excitation is mediated by cortical-spinal projection to spinal preganglionic sympathetic neurons, whereas bradycardia is mediated via projections to cardiovagal motor medullary neurons. The integrated reflex response serves to redistribute blood from viscera to the brain in response to a challenge to cerebral metabolism, but seems also to initiate a preconditioning mechanism. Previous studies showed a great variability in the human TCR response, in special to external stimuli and individual factors. The TCR gives, therefore, not only new insights into novel therapeutic options for a range of disorders characterized by neuronal death, but also into the cortical and molecular organization of the brain.

  9. Molecular Magnetic Resonance Imaging of Brain-immune Interactions

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    Maxime eGauberti

    2014-11-01

    Full Text Available Although the blood-brain barrier (BBB was thought to protect the brain from the effects of the immune system, immune cells can nevertheless migrate from the blood to the brain, either as a cause or as a consequence of central nervous system (CNS diseases, thus contributing to their evolution and outcome. Accordingly, as the interface between the CNS and the peripheral immune system, the BBB is critical during neuroinflammatory processes. In particular, endothelial cells are involved in the brain response to systemic or local inflammatory stimuli by regulating the cellular movement between the circulation and the brain parenchyma.While neuropathological conditions differ in etiology and in the way in which the inflammatory response is mounted and resolved, cellular mechanisms of neuroinflammation are probably similar. Accordingly, neuroinflammation is a hallmark and a decisive player of many CNS diseases. Thus, molecular magnetic resonance imaging (MRI of inflammatory processes is a central theme of research in several neurological disorders focusing on a set of molecules expressed by endothelial cells, such as adhesion molecules (VCAM-1, ICAM-1, P-Selectin, E-Selectin, …, which emerge as therapeutic targets and biomarkers for neurological diseases. In this review, we will present the most recent advances in the field of preclinical molecular MRI. Moreover, we will discuss the possible translation of molecular MRI to the clinical setting with a particular emphasis on myeloperoxidase imaging (MPO, autologous cell tracking and targeted iron oxide particles (USPIO, MPIO.

  10. Brain molecular aging, promotion of neurological disease and modulation by sirtuin 5 longevity gene polymorphism.

    Science.gov (United States)

    Glorioso, Christin; Oh, Sunghee; Douillard, Gaelle Guilloux; Sibille, Etienne

    2011-02-01

    Mechanisms determining characteristic age-of-onset for neurological diseases are largely unknown. Normal brain aging associates with robust and progressive transcriptome changes ("molecular aging"), but the intersection with disease pathways is mostly uncharacterized. Here, using cross-cohort microarray analysis of four human brain areas, we show that neurological disease pathways largely overlap with molecular aging and that subjects carrying a newly-characterized low-expressing polymorphism in a putative longevity gene (Sirtuin5; SIRT5(prom2)) have older brain molecular ages. Specifically, molecular aging was remarkably conserved across cohorts and brain areas, and included numerous developmental and transcription-regulator genes. Neurological disease-associated genes were highly overrepresented within age-related genes and changed almost unanimously in pro-disease directions, together suggesting an underlying genetic "program" of aging that progressively promotes disease. To begin testing this putative pathway, we developed and used an age-biosignature to assess five candidate longevity gene polymorphisms' association with molecular aging rates. Most robustly, aging was accelerated in cingulate, but not amygdala, of subjects carrying a SIRT5 promoter polymorphism (+9 years, p=0.004), in concordance with cingulate-specific decreased SIRT5 expression. This effect was driven by a set of core transcripts (+24 years, p=0.0004), many of which were mitochondrial, including Parkinson's disease genes, PINK-1 and DJ-1/PARK7, hence suggesting that SIRT5(prom2) may represent a risk factor for mitochondrial dysfunction-related diseases, including Parkinson's, through accelerated molecular aging of disease-related genes. Based on these results we speculate that a "common mechanism" may underlie age-of-onset across several neurological diseases. Confirming this pathway and its regulation by common genetic variants would provide new strategies for predicting, delaying, and

  11. Molecular aging of the brain, neuroplasticity, and vulnerability to depression and other brain-related disorders.

    Science.gov (United States)

    Sibille, Etienne

    2013-03-01

    The increased risk for neurodegenerative and neuropsychiatric disorders associated with extended lifespan has long suggested mechanistic links between chronological age and brain-related disorders, including depression, Recent characterizations of age-dependent gene expression changes now show that aging of the human brain engages a specific set of biological pathways along a continuous lifelong trajectory, and that the same genes that are associated with normal brain aging are also frequently and similarly implicated in depression and other brain-related disorders. These correlative observations suggest a model of age-by-disease molecular interactions, in which brain aging promotes biological changes associated with diseases, and additional environmental factors and genetic variability contribute to defining disease risk or resiliency trajectories. Here we review the characteristic features of brain aging in terms of changes in gene function over time, and then focus on evidence supporting accelerated molecular aging in depression. This proposed age-by-disease biological interaction model addresses the current gap in research between "normal" brain aging and its connection to late-life diseases. The implications of this model are profound, as it provides an investigational framework for identifying critical moderating factors, outlines opportunities for early interventions or preventions, and may form the basis for a dimensional definition of diseases that goes beyond the current categorical system.

  12. Dissecting molecular mechanisms in the living brain of dementia patients.

    Science.gov (United States)

    Barrio, Jorge R; Satyamurthy, Nagichettiar; Huang, Sung-Cheng; Petric, Andrej; Small, Gary W; Kepe, Vladimir

    2009-07-21

    Understanding the molecular mechanisms associated with the development of dementia is essential for designing successful interventions. Dementia, like cancer and cardiovascular disease, requires early detection to potentially arrest or prevent further disease progression. By the time a neurologist begins to manage clinical symptoms, the disease has often damaged the brain significantly. Because successful treatment is the logical goal, detecting the disease when brain damage is still limited is of the essence. The role of chemistry in this discovery process is critical. With the advent of molecular imaging, the understanding of molecular mechanisms in human neurodegenerative diseases has exploded. Traditionally, knowledge of enzyme and neurotransmitter function in humans has been extrapolated from animal studies, but now we can acquire data directly from both healthy and diseased human subjects. In this Account, we describe the use of molecular imaging probes to elucidate the biochemical and cellular bases of dementia (e.g., Alzheimer's disease) and the application of these discoveries to the design of successful therapeutic interventions. Molecular imaging permits observation and evaluation of the basic molecular mechanisms of disease progression in the living brains of patients. 2-Deoxy-2-[(18)F]fluoro-d-glucose is used to assess the effect of Alzheimer's disease progression on neuronal circuits projecting from and to the temporal lobe (one of the earliest metabolic signs of the disease). Recently, we have developed imaging probes for detection of amyloid neuropathology (both tau and beta-amyloid peptide deposits) and neuronal losses. These probes allow us to visualize the development of pathology in the living brain of dementia patients and its consequences, such as losses of critical neurons associated with memory deficits and other neuropsychiatric impairments. Because inflammatory processes are tightly connected to the brain degenerative processes

  13. Conserving GW scheme for nonequilibrium quantum transport in molecular contacts

    DEFF Research Database (Denmark)

    Thygesen, Kristian Sommer; Rubio, Angel

    2008-01-01

    We give a detailed presentation of our recent scheme to include correlation effects in molecular transport calculations using the nonequilibrium Keldysh formalism. The scheme is general and can be used with any quasiparticle self-energy, but for practical reasons, we mainly specialize to the so-c...

  14. Neurodevelopmental LincRNA Microsyteny Conservation and Mammalian Brain Size Evolution.

    Directory of Open Access Journals (Sweden)

    Eric Lewitus

    Full Text Available The mammalian neocortex has undergone repeated selection for increases and decreases in size and complexity, often over relatively short evolutionary time. But because probing developmental mechanisms across many species is experimentally unfeasible, it is unknown whether convergent morphologies in distantly related species are regulated by conserved developmental programs. In this work, we have taken advantage of the abundance of available mammalian genomes to find evidence of selection on genomic regions putatively regulating neurogenesis in large- versus small-brained species. Using published fetal human RNA-seq data, we show that the gene-neighborhood (i.e., microsynteny of long intergenic non-coding RNAs (lincRNAs implicated in cortical development is differentially conserved in large-brained species, lending support to the hypothesis that lincRNAs regulating neurogenesis are selectively lost in small-brained species. We provide evidence that this is not a phenomenon attributable to lincRNA expressed in all tissue types and is therefore likely to represent an adaptive function in the evolution of neurogenesis. A strong correlation between transcription factor-adjacency and lincRNA sequence conservation reinforces this conclusion.

  15. Neurodevelopmental LincRNA Microsyteny Conservation and Mammalian Brain Size Evolution.

    Science.gov (United States)

    Lewitus, Eric; Huttner, Wieland B

    2015-01-01

    The mammalian neocortex has undergone repeated selection for increases and decreases in size and complexity, often over relatively short evolutionary time. But because probing developmental mechanisms across many species is experimentally unfeasible, it is unknown whether convergent morphologies in distantly related species are regulated by conserved developmental programs. In this work, we have taken advantage of the abundance of available mammalian genomes to find evidence of selection on genomic regions putatively regulating neurogenesis in large- versus small-brained species. Using published fetal human RNA-seq data, we show that the gene-neighborhood (i.e., microsynteny) of long intergenic non-coding RNAs (lincRNAs) implicated in cortical development is differentially conserved in large-brained species, lending support to the hypothesis that lincRNAs regulating neurogenesis are selectively lost in small-brained species. We provide evidence that this is not a phenomenon attributable to lincRNA expressed in all tissue types and is therefore likely to represent an adaptive function in the evolution of neurogenesis. A strong correlation between transcription factor-adjacency and lincRNA sequence conservation reinforces this conclusion.

  16. In-vivo human brain molecular imaging with a brain-dedicated PET/MRI system.

    Science.gov (United States)

    Cho, Zang Hee; Son, Young Don; Choi, Eun Jung; Kim, Hang Keun; Kim, Jeong Hee; Lee, Sang Yoon; Ogawa, Seiji; Kim, Young Bo

    2013-02-01

    Advances in the new-generation of ultra-high-resolution, brain-dedicated positron emission tomography-magnetic resonance imaging (PET/MRI) systems have begun to provide many interesting insights into the molecular dynamics of the brain. First, the finely delineated structural information from ultra-high-field MRI can help us to identify accurate landmark structures, thereby making it easier to locate PET activation sites that are anatomically well-correlated with metabolic or ligand-specific organs in the neural structures in the brain. This synergistic potential of PET/MRI imaging is discussed in terms of neuroscience and neurological research from both translational and basic research perspectives. Experimental results from the hippocampus, thalamus, and brainstem obtained with (18)F-fluorodeoxyglucose and (11)C-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile are used to demonstrate the potential of this new brain PET/MRI system.

  17. [Molecular imaging of histamine receptors in the human brain].

    Science.gov (United States)

    Tashiro, Manabu; Yanai, Kazuhiko

    2007-03-01

    Brain histamine is involved in a wide range of physiological functions such as regulation of sleep-wake cycle, arousal, appetite control, cognition, learning and memory mainly through the 4 receptor subtypes: H1, H2, H3 and H4. Neurons producing histamine, histaminergic neurons, are exclusively located in the tuberomammillary nucleus of the posterior hypothalamus and are transmitting histamine to almost all regions of the brain. Roles of brain histamine have been studied using animals including knock-out mice and human subjects. For clinical studies, molecular imaging technique such as positron emission tomography (PET), with ligands such as [11C]doxepin and [11C]pyrilamine, has been a useful tool. A series of clinical studies on histamine H1 antagonists, or antihistamines, have demonstrated that antihistamines can be classified into sedative, mildly-sedative and non-sedative drugs according to their blood-brain barrier (BBB) permeability, showing apparent clinical usefulness regarding QOL, work efficiency and traffic safety of allergic patients. PET has also been used for elucidation of aging effects and pathophysiological roles of histaminergic nervous system in various neuropsychiatric disorders such as Alzheimer's disease, schizophrenia and depression, where H1 receptor binding potentials were lower than age-matched healthy controls. It has been also demonstrated that brain histamine functions as an endogenous anti-epileptic. In addition, H3 receptors are located in the presynaptic sites of not only histaminergic nerves but also in other nervous systems such as serotonergic, cholinergic and dopaminergic systems, and to be regulating secretion of various neurotransmitters. Nowadays, H3 receptors have been thought to be a new target of drug treatment of various neuropsychiatric disorders. There are still many research topics to be investigated regarding molecular imaging of histamine and histamine receptors. The authors hope that this line of research contributes

  18. Death Associated Protein Kinases: Molecular Structure and Brain Injury

    Directory of Open Access Journals (Sweden)

    Claire Thornton

    2013-07-01

    Full Text Available Perinatal brain damage underlies an important share of motor and neurodevelopmental disabilities, such as cerebral palsy, cognitive impairment, visual dysfunction and epilepsy. Clinical, epidemiological, and experimental studies have revealed that factors such as inflammation, excitotoxicity and oxidative stress contribute considerably to both white and grey matter injury in the immature brain. A member of the death associated protein kinase (DAPk family, DAPk1, has been implicated in cerebral ischemic damage, whereby DAPk1 potentiates NMDA receptor-mediated excitotoxicity through interaction with the NR2BR subunit. DAPk1 also mediate a range of activities from autophagy, membrane blebbing and DNA fragmentation ultimately leading to cell death. DAPk mRNA levels are particularly highly expressed in the developing brain and thus, we hypothesize that DAPk1 may play a role in perinatal brain injury. In addition to reviewing current knowledge, we present new aspects of the molecular structure of DAPk domains, and relate these findings to interacting partners of DAPk1, DAPk-regulation in NMDA-induced cerebral injury and novel approaches to blocking the injurious effects of DAPk1.

  19. Death associated protein kinases: molecular structure and brain injury.

    Science.gov (United States)

    Nair, Syam; Hagberg, Henrik; Krishnamurthy, Rajanikant; Thornton, Claire; Mallard, Carina

    2013-07-04

    Perinatal brain damage underlies an important share of motor and neurodevelopmental disabilities, such as cerebral palsy, cognitive impairment, visual dysfunction and epilepsy. Clinical, epidemiological, and experimental studies have revealed that factors such as inflammation, excitotoxicity and oxidative stress contribute considerably to both white and grey matter injury in the immature brain. A member of the death associated protein kinase (DAPk) family, DAPk1, has been implicated in cerebral ischemic damage, whereby DAPk1 potentiates NMDA receptor-mediated excitotoxicity through interaction with the NR2BR subunit. DAPk1 also mediate a range of activities from autophagy, membrane blebbing and DNA fragmentation ultimately leading to cell death. DAPk mRNA levels are particularly highly expressed in the developing brain and thus, we hypothesize that DAPk1 may play a role in perinatal brain injury. In addition to reviewing current knowledge, we present new aspects of the molecular structure of DAPk domains, and relate these findings to interacting partners of DAPk1, DAPk-regulation in NMDA-induced cerebral injury and novel approaches to blocking the injurious effects of DAPk1.

  20. Mandibular arch muscle identity is regulated by a conserved molecular process during vertebrate development.

    Science.gov (United States)

    Knight, Robert D; Mebus, Katharina; Roehl, Henry H

    2008-06-15

    Vertebrate head muscles exhibit a highly conserved pattern of innervation and skeletal connectivity and yet it is unclear whether the molecular basis of their development is likewise conserved. Using the highly conserved expression of Engrailed 2 (En2) as a marker of identity in the dorsal mandibular muscles of zebrafish, we have investigated the molecular signals and tissues required for patterning these muscles. We show that muscle En2 expression is not dependent on signals from the adjacent neural tube, pharyngeal endoderm or axial mesoderm and that early identity of head muscles does not require bone morphogenetic pathway, Notch or Hedgehog (Hh) signalling. However, constrictor dorsalis En2 expression is completely lost after a loss of fibroblast growth factor (Fgf) signalling and we show that is true throughout head muscle development. These results suggest that head muscle identity is dependent on Fgf signalling. Data from experiments performed in chick suggest a similar regulation of En2 genes by Fgf signalling revealing a conserved mechanism for specifying head muscle identity. We present evidence that another key gene important in the development of mouse head muscles, Tbx1, is also critical for specification of mandibular arch muscle identity and that this is independent of Fgf signalling. These data imply that dorsal mandibular arch muscle identity in fish, chick and mouse is specified by a highly conserved molecular process despite differing functions of these muscles in different lineages.

  1. Species-conserved reconfigurations of brain network topology induced by ketamine

    Science.gov (United States)

    Becker, R; Braun, U; Schwarz, A J; Gass, N; Schweiger, J I; Weber-Fahr, W; Schenker, E; Spedding, M; Clemm von Hohenberg, C; Risterucci, C; Zang, Z; Grimm, O; Tost, H; Sartorius, A; Meyer-Lindenberg, A

    2016-01-01

    Species-conserved (intermediate) phenotypes that can be quantified and compared across species offer important advantages for translational research and drug discovery. Here, we investigate the utility of network science methods to assess the pharmacological alterations of the large-scale architecture of brain networks in rats and humans. In a double-blind, placebo-controlled, cross-over study in humans and a placebo-controlled two-group study in rats, we demonstrate that the application of ketamine leads to a topological reconfiguration of large-scale brain networks towards less-integrated and more-segregated information processing in both the species. As these alterations are opposed to those commonly observed in patients suffering from depression, they might indicate systems-level correlates of the antidepressant effect of ketamine. PMID:27093068

  2. MOLECULAR MECHANISMS REGULATING LPS-INDUCED INFLAMMATION IN THE BRAIN

    Directory of Open Access Journals (Sweden)

    Olena eLykhmus

    2016-03-01

    Full Text Available Neuro-inflammation, one of the pathogenic causes of neurodegenerative diseases, is regulated through the cholinergic anti-inflammatory pathway via the 7 nicotinic acetylcholine receptor (7 nAChR. We previously showed that either bacterial lipopolysaccharide (LPS or immunization with the 7(1-208 nAChR fragment decrease 7 nAChRs density in the mouse brain, exacerbating chronic inflammation, beta-amyloid accumulation and episodic memory decline, which mimic the early stages of Alzheimer’s disease. To study the molecular mechanisms underlying the LPS and antibody effects in the brain, we employed an in vivo model of acute LPS-induced inflammation and an in vitro model of cultured glioblastoma U373 cells. Here, we report that LPS challenge decreased the levels of 7 nAChR RNA and protein and of acetylcholinesterase (AChE RNA and activity in distinct mouse brain regions, sensitized brain mitochondria to the apoptogenic effect of Ca2+ and modified brain microRNA profiles, including the cholinergic-regulatory CholinomiRs-132/212, in favor of anti-inflammatory and pro-apoptotic ones. Adding 7(1-208-specific antibodies to the LPS challenge prevented elevation of both the anti-inflammatory and pro-apoptotic miRNAs while supporting the resistance of brain mitochondria to Ca2+ and maintaining 7 nAChR/AChE decreases. In U373 cells, 7-specific antibodies and LPS both stimulated interleukin-6 production through the p38/Src-dependent pathway. Our findings demonstrate that acute LPS-induced inflammation induces the cholinergic anti-inflammatory pathway in the brain, that 7 nAChR down-regulation limits this pathway, and that 7-specific antibodies aggravate neuroinflammation by inducing the pro-inflammatory interleukin-6 and dampening anti-inflammatory miRNAs; however, these antibodies may protect brain mitochondria and decrease the levels of pro-apoptotic miRNAs, preventing LPS-induced neurodegeneration.

  3. Molecular Mechanisms Regulating LPS-Induced Inflammation in the Brain

    Science.gov (United States)

    Lykhmus, Olena; Mishra, Nibha; Koval, Lyudmyla; Kalashnyk, Olena; Gergalova, Galyna; Uspenska, Kateryna; Komisarenko, Serghiy; Soreq, Hermona; Skok, Maryna

    2016-01-01

    Neuro-inflammation, one of the pathogenic causes of neurodegenerative diseases, is regulated through the cholinergic anti-inflammatory pathway via the α7 nicotinic acetylcholine receptor (α7 nAChR). We previously showed that either bacterial lipopolysaccharide (LPS) or immunization with the α7(1–208) nAChR fragment decrease α7 nAChRs density in the mouse brain, exacerbating chronic inflammation, beta-amyloid accumulation and episodic memory decline, which mimic the early stages of Alzheimer’s disease (AD). To study the molecular mechanisms underlying the LPS and antibody effects in the brain, we employed an in vivo model of acute LPS-induced inflammation and an in vitro model of cultured glioblastoma U373 cells. Here, we report that LPS challenge decreased the levels of α7 nAChR RNA and protein and of acetylcholinesterase (AChE) RNA and activity in distinct mouse brain regions, sensitized brain mitochondria to the apoptogenic effect of Ca2+ and modified brain microRNA profiles, including the cholinergic-regulatory CholinomiRs-132/212, in favor of anti-inflammatory and pro-apoptotic ones. Adding α7(1–208)-specific antibodies to the LPS challenge prevented elevation of both the anti-inflammatory and pro-apoptotic miRNAs while supporting the resistance of brain mitochondria to Ca2+ and maintaining α7 nAChR/AChE decreases. In U373 cells, α7-specific antibodies and LPS both stimulated interleukin-6 production through the p38/Src-dependent pathway. Our findings demonstrate that acute LPS-induced inflammation induces the cholinergic anti-inflammatory pathway in the brain, that α7 nAChR down-regulation limits this pathway, and that α7-specific antibodies aggravate neuroinflammation by inducing the pro-inflammatory interleukin-6 and dampening anti-inflammatory miRNAs; however, these antibodies may protect brain mitochondria and decrease the levels of pro-apoptotic miRNAs, preventing LPS-induced neurodegeneration. PMID:27013966

  4. A systems biology strategy to identify molecular mechanisms of action and protein indicators of traumatic brain injury.

    Science.gov (United States)

    Yu, Chenggang; Boutté, Angela; Yu, Xueping; Dutta, Bhaskar; Feala, Jacob D; Schmid, Kara; Dave, Jitendra; Tawa, Gregory J; Wallqvist, Anders; Reifman, Jaques

    2015-02-01

    The multifactorial nature of traumatic brain injury (TBI), especially the complex secondary tissue injury involving intertwined networks of molecular pathways that mediate cellular behavior, has confounded attempts to elucidate the pathology underlying the progression of TBI. Here, systems biology strategies are exploited to identify novel molecular mechanisms and protein indicators of brain injury. To this end, we performed a meta-analysis of four distinct high-throughput gene expression studies involving different animal models of TBI. By using canonical pathways and a large human protein-interaction network as a scaffold, we separately overlaid the gene expression data from each study to identify molecular signatures that were conserved across the different studies. At 24 hr after injury, the significantly activated molecular signatures were nonspecific to TBI, whereas the significantly suppressed molecular signatures were specific to the nervous system. In particular, we identified a suppressed subnetwork consisting of 58 highly interacting, coregulated proteins associated with synaptic function. We selected three proteins from this subnetwork, postsynaptic density protein 95, nitric oxide synthase 1, and disrupted in schizophrenia 1, and hypothesized that their abundance would be significantly reduced after TBI. In a penetrating ballistic-like brain injury rat model of severe TBI, Western blot analysis confirmed our hypothesis. In addition, our analysis recovered 12 previously identified protein biomarkers of TBI. The results suggest that systems biology may provide an efficient, high-yield approach to generate testable hypotheses that can be experimentally validated to identify novel mechanisms of action and molecular indicators of TBI.

  5. 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.

  6. Laws of conservation as related to brain growth, aging, and evolution: symmetry of the minicolumn

    Directory of Open Access Journals (Sweden)

    Manuel F. Casanova

    2011-12-01

    Full Text Available Development, aging, and evolution offer different time scales regarding possible anatomical transformations of the brain. This article expands on the perspective that the cerebral cortex exhibits a modular architecture with invariant properties in regards to these time scales. These properties arise from morphometric relations of the ontogentic minicolumn as expressed in Noether’s first theorem, i.e., that for each continuous symmetry there is a conserved quantity. Whenever minicolumnar symmetry is disturbed by either developmental or aging processes the principle of least action limits the scope of morphometric alterations. Alternatively, local and global divergences from these laws apply to acquired processes when the system is no longer isolated from its environment. The underlying precepts to these physical laws can be expressed in terms of mathematical equations that are conservative of quantity. Invariant properties of the brain include the rotational symmetry of minicolumns, a scaling proportion or even expansion between pyramidal cells and core minicolumnar size, and the translation of neuronal elements from the main axis of the minicolumn. It is our belief that a significant portion of the architectural complexity of the cerebral cortex, its response to injury, and its evolutionary transformation, can all be captured by a small set of basic physical laws dictated by the symmetry of minicolumns. The putative preservations of parameters related to the symmetry of the minicolumn suggest that the development and final organization of the cortex follows a deterministic process.

  7. Molecular regionalization of the developing amphioxus neural tube challenges major partitions of the vertebrate brain.

    Science.gov (United States)

    Albuixech-Crespo, Beatriz; López-Blanch, Laura; Burguera, Demian; Maeso, Ignacio; Sánchez-Arrones, Luisa; Moreno-Bravo, Juan Antonio; Somorjai, Ildiko; Pascual-Anaya, Juan; Puelles, Eduardo; Bovolenta, Paola; Garcia-Fernàndez, Jordi; Puelles, Luis; Irimia, Manuel; Ferran, José Luis

    2017-04-01

    All vertebrate brains develop following a common Bauplan defined by anteroposterior (AP) and dorsoventral (DV) subdivisions, characterized by largely conserved differential expression of gene markers. However, it is still unclear how this Bauplan originated during evolution. We studied the relative expression of 48 genes with key roles in vertebrate neural patterning in a representative amphioxus embryonic stage. Unlike nonchordates, amphioxus develops its central nervous system (CNS) from a neural plate that is homologous to that of vertebrates, allowing direct topological comparisons. The resulting genoarchitectonic model revealed that the amphioxus incipient neural tube is unexpectedly complex, consisting of several AP and DV molecular partitions. Strikingly, comparison with vertebrates indicates that the vertebrate thalamus, pretectum, and midbrain domains jointly correspond to a single amphioxus region, which we termed Di-Mesencephalic primordium (DiMes). This suggests that these domains have a common developmental and evolutionary origin, as supported by functional experiments manipulating secondary organizers in zebrafish and mice.

  8. Surface migration of molecular adsorbates revisited: Morse-potential modeling based on bond-order conservation

    Science.gov (United States)

    Shustorovich, Evgeny

    1985-11-01

    Our bond-order-conservation model of surface migration of molecular AB adsorbates [J. Am. Chem. Soc. 106 (1984) 6479] has been generalized to provide for A-B bond-order changes under migration and to search for energy stationary points. The results are rigorous and well defined. The new conclusions corroborate most of the previous findings but also lead to important corrections (e.g., the mogration patterns of donor molecules) and new projections (e.g., monotonic destabilization of AB as its coordination increases without direct relevance to the heat of chemisorption and simple interrelations between molecular and atomic heats of chemisorption), in agreement with experiment.

  9. Molecular advances to treat cancer of the brain.

    Science.gov (United States)

    Fathallah-Shaykh, H M; Zhao, L J; Mickey, B; Kafrouni, A I

    2000-06-01

    Malignant primary and metastatic brain tumours continue to be associated with poor prognosis. Nevertheless, recent advances in molecular medicine, specifically in the strategies of gene therapy, targeting tumour cells, anti-angiogenesis and immunotherapy, have created novel tools that may be of therapeutic value. To date, gene therapy trials have not yet demonstrated clinical efficacy because of inherent defects in vector design. Despite this, advances in adenoviral technology, namely the helper-dependent adenoviral constructs (gutless) and the uncovering of brain parenchymal cells as effective and necessary targets for antitumour benefits of adenoviral-mediated gene transfer, suggest that developments in vector design may be approaching the point of clinical utility. Targeting tumour cells refers to strategies that destroy malignant but spare normal cells. A new assortment of oncolytic viruses have emerged, capable of specific lysis of cancer tissue while sparing normal cells and propagating until they reach the tumour borders. Furthermore, peptides have been transformed into bullets that specifically seek and destroy cancer cells. The concept of tumour angiogenesis has been challenged by new but still very controversial findings that tumour cells themselves may form blood channels. These results may lead to the redirecting of the molecular targets toward anti-angiogenesis in some tumours including glioblastoma multiform. Unfortunately, our knowledge regarding the immunological ignorance of the tumour is still limited. Even so, newly discovered molecules have shed light on novel pathways leading to the escape of the tumour from the immune system. Finally, significant limitations in our current experimental tumour models may soon be overcome by firstly, the development of models of reproducible organ-specific tumours in non-inbred animals and secondly applying genomics to individualize therapy for a particular tumour in a specific patient.

  10. A highly conserved program of neuronal microexons is misregulated in autistic brains.

    Science.gov (United States)

    Irimia, Manuel; Weatheritt, Robert J; Ellis, Jonathan D; Parikshak, Neelroop N; Gonatopoulos-Pournatzis, Thomas; Babor, Mariana; Quesnel-Vallières, Mathieu; Tapial, Javier; Raj, Bushra; O'Hanlon, Dave; Barrios-Rodiles, Miriam; Sternberg, Michael J E; Cordes, Sabine P; Roth, Frederick P; Wrana, Jeffrey L; Geschwind, Daniel H; Blencowe, Benjamin J

    2014-12-18

    Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide "microexons" display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein-interaction networks during neurogenesis, the misregulation of which is linked to autism.

  11. Distribution of iron in the parrot brain: conserved (pallidal) and derived (nigral) labeling patterns.

    Science.gov (United States)

    Roberts, T F; Brauth, S E; Hall, W S

    2001-12-01

    The distribution of iron in the brain of a vocal learning parrot, the budgerigar (Melopsittacus undulatus), was examined using iron histochemistry. In mammals, iron is a highly specific stain for the dorsal and ventral pallidal subdivision as well as specific cell groups in the brainstem, including the substantia nigra pars reticulata [Neuroscience 11 (1984) 595-603]. The purpose of this study was to compare the distribution of iron in the mammalian and avian brain focusing on pallidal and nigral cell groups. The results show that in the avian brain, iron stains oligodendrocytes, neurons and the neuropil. Cell staining changes dramatically along the rostrocaudal axis, with neuronal labeling confined to regions caudal to the thalamus and oligodendrocyte labeling denser in regions rostral to the dorsal thalamus. Many sensory forebrain regions contain appreciable iron labeling, including telencephalic vocal control nuclei. The dorsal and ventral subdivision of the avian pallidum, along with the basal ganglia component of the vocal control circuit, the magnicellular nucleus of the lobus parolfactorius, stain heavily for iron. Several brainstem regions, including nucleus rotundus, the medial spiriform nucleus (SpM), the principle nucleus of the trigeminal nerve, nucleus laminaris and scattered cell groups throughout the isthmus and pontine reticular formation stain intensely for iron. Within SpM neuronal labeling is more intense in the medial division while oligodendrocyte labeling is more intense in the lateral division. surprisingly no nigral iron staining was observed. Our results imply that iron is a conserved marker for the pallidum in birds and mammals, but that patterns of nigral staining have diverged in birds and mammals. Differences in iron staining patterns between birds and mammals may also reflect the relatively greater importance of the collothalamic visual pathways, pretectal-cerebellar pathways and specialized vocal learning circuitry in avian sensory

  12. Speeding up Monte Carlo molecular simulation by a non-conservative early rejection scheme

    KAUST Repository

    Kadoura, Ahmad Salim

    2015-04-23

    Monte Carlo (MC) molecular simulation describes fluid systems with rich information, and it is capable of predicting many fluid properties of engineering interest. In general, it is more accurate and representative than equations of state. On the other hand, it requires much more computational effort and simulation time. For that purpose, several techniques have been developed in order to speed up MC molecular simulations while preserving their precision. In particular, early rejection schemes are capable of reducing computational cost by reaching the rejection decision for the undesired MC trials at an earlier stage in comparison to the conventional scheme. In a recent work, we have introduced a ‘conservative’ early rejection scheme as a method to accelerate MC simulations while producing exactly the same results as the conventional algorithm. In this paper, we introduce a ‘non-conservative’ early rejection scheme, which is much faster than the conservative scheme, yet it preserves the precision of the method. The proposed scheme is tested for systems of structureless Lennard-Jones particles in both canonical and NVT-Gibbs ensembles. Numerical experiments were conducted at several thermodynamic conditions for different number of particles. Results show that at certain thermodynamic conditions, the non-conservative method is capable of doubling the speed of the MC molecular simulations in both canonical and NVT-Gibbs ensembles. © 2015 Taylor & Francis

  13. Conservation biological control of pests in the molecular era: new opportunities to address old constraints

    Directory of Open Access Journals (Sweden)

    Gurr eGeoff

    2016-01-01

    Full Text Available ABSTRACTBiological control has long been considered a potential alternative to pesticidal strategies for pest management but its impact and level of use globally remain modest and inconsistent. A rapidly expanding range of molecular – particularly DNA-related – techniques is currently revolutionizing many life sciences. This review identifies a series of constraints on the development and uptake of conservation biological control and considers the contemporary and likely future influence of molecular methods on these constraints. Molecular approaches are now often used to complement morphological taxonomic methods for the identification and study of biological control agents including microbes. A succession of molecular techniques has been applied to ‘who eats whom’ questions in food-web ecology. Polymerase chain reaction (PCR approaches have largely superseded immunological approaches such as enzyme-linked immunosorbent assay (ELISA and now – in turn – are being overtaken by next generation sequencing (NGS- based approaches that offer unparalleled power at a rapidly diminishing cost. There is scope also to use molecular techniques to manipulate biological control agents, which will be accelerated with the advent of gene editing tools, the CRISPR/Cas9 system in particular. Gene editing tools also offer unparalleled power to both elucidate and manipulate the plant defence mechanisms including those that involve natural enemy attraction to attacked plants. Rapid advances in technology will allow the development of still more novel pest management options for which uptake is likely to be limited chiefly by regulatory hurdles.

  14. Molecular Mechanisms of Cognitive Dysfunction following Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Kendall Rae Walker

    2013-07-01

    Full Text Available Traumatic brain injury (TBI results in significant disability due to cognitive deficits particularly in attention, learning and memory and higher-order executive functions. The role of TBI in chronic neurodegeneration and the development of neurodegenerative diseases including Alzheimer’s disease (AD, Parkinson’s disease (PD, Amyotrophic Lateral Sclerosis (ALS and most recently chronic traumatic encephalopathy (CTE is of particular importance. However, despite significant effort very few therapeutic options exist to prevent or reverse cognitive impairment following TBI. In this review we present experimental evidence of the known secondary injury mechanisms which contribute to neuronal cell loss, axonal injury and synaptic dysfunction and hence cognitive impairment both acutely and chronically following TBI. In particular we focus on the mechanisms linking TBI to the development of two forms of dementia: AD and CTE. We provide evidence of potential molecular mechanisms involved in modulating Aβ and Tau following TBI and provide evidence of the role of these mechanisms in AD pathology. Additionally we propose a mechanism by which Aβ generated as a direct result of TBI is capable of exacerbating secondary injury mechanisms thereby establishing a neurotoxic cascade that leads to chronic neurodegeneration.

  15. Energetic pulses in exciton-phonon molecular chains and conservative numerical methods for quasilinear Hamiltonian systems.

    Science.gov (United States)

    Lemesurier, Brenton

    2013-09-01

    The phenomenon of coherent energetic pulse propagation in exciton-phonon molecular chains such as α-helix protein is studied using an ODE system model of Davydov-Scott type, both with numerical studies using a new unconditionally stable fourth-order accurate energy-momentum conserving time discretization and with analytical explanation of the main numerical observations. Impulsive initial data associated with initial excitation of a single amide-I vibration by the energy released by ATP hydrolysis are used as well as the best current estimates of physical parameter values. In contrast to previous studies based on a proposed long-wave approximation by the nonlinear Schrödinger (NLS) equation and focusing on initial data resembling the soliton solutions of that equation, the results here instead lead to approximation by the third derivative nonlinear Schrödinger equation, giving a far better fit to observed behavior. A good part of the behavior is indeed explained well by the linear part of that equation, the Airy PDE, while other significant features do not fit any PDE approximation but are instead explained well by a linearized analysis of the ODE system. A convenient method is described for construction of the highly stable, accurate conservative time discretizations used, with proof of its desirable properties for a large class of Hamiltonian systems, including a variety of molecular models.

  16. A conservative and a hybrid early rejection schemes for accelerating Monte Carlo molecular simulation

    KAUST Repository

    Kadoura, Ahmad Salim

    2014-03-17

    Molecular simulation could provide detailed description of fluid systems when compared to experimental techniques. They can also replace equations of state; however, molecular simulation usually costs considerable computational efforts. Several techniques have been developed to overcome such high computational costs. In this paper, two early rejection schemes, a conservative and a hybrid one, are introduced. In these two methods, undesired configurations generated by the Monte Carlo trials are rejected earlier than it would when using conventional algorithms. The methods are tested for structureless single-component Lennard-Jones particles in both canonical and NVT-Gibbs ensembles. The computational time reduction for both ensembles is observed at a wide range of thermodynamic conditions. Results show that computational time savings are directly proportional to the rejection rate of Monte Carlo trials. The proposed conservative scheme has shown to be successful in saving up to 40% of the computational time in the canonical ensemble and up to 30% in the NVT-Gibbs ensemble when compared to standard algorithms. In addition, it preserves the exact Markov chains produced by the Metropolis scheme. Further enhancement for NVT-Gibbs ensemble is achieved by combining this technique with the bond formation early rejection one. The hybrid method achieves more than 50% saving of the central processing unit (CPU) time.

  17. Molecular mediators for raft-dependent endocytosis of syndecan-1, a highly conserved, multifunctional receptor.

    Science.gov (United States)

    Chen, Keyang; Williams, Kevin Jon

    2013-05-17

    Endocytosis via rafts has attracted considerable recent interest, but the molecular mediators remain incompletely characterized. Here, we focused on the syndecan-1 heparan sulfate proteoglycan, a highly conserved, multifunctional receptor that we previously showed to undergo raft-dependent endocytosis upon clustering. Alanine scanning mutagenesis of three to five consecutive cytoplasmic residues at a time revealed that a conserved juxtamembrane motif, MKKK, was the only region required for efficient endocytosis after clustering. Endocytosis of clustered syndecan-1 occurs in two phases, each requiring a kinase and a corresponding cytoskeletal partner. In the initial phase, ligands trigger rapid MKKK-dependent activation of ERK and the localization of syndecan-1 into rafts. Activation of ERK drives the dissociation of syndecan-1 from α-tubulin, a molecule that may act as an anchor for syndecan-1 at the plasma membrane in the basal state. In the second phase, Src family kinases phosphorylate tyrosyl residues within the transmembrane and cytoplasmic regions of syndecan-1, a process that also requires MKKK. Tyrosine phosphorylation of syndecan-1 triggers the robust recruitment of cortactin, which we found to be an essential mediator of efficient actin-dependent endocytosis. These findings represent the first detailed characterization of the molecular events that drive endocytosis of a raft-dependent receptor and identify a novel endocytic motif, MKKK. Moreover, the results provide new tools to study syndecan function and regulation during uptake of its biologically and medically important ligands, such as HIV-1, atherogenic postprandial remnant lipoproteins, and molecules implicated in Alzheimer disease.

  18. Evolutionary, behavioural and molecular ecology must meet to achieve long-term conservation goals.

    Science.gov (United States)

    Keogh, J Scott

    2009-09-01

    Founder populations in reintroduction programmes can experience a genetic bottleneck simply because of their small size. The influence of reproductive skew brought on by polygynous or polyandrous mating systems in these populations can exacerbate already difficult conservation genetic problems, such as inbreeding depression and loss of adaptive potential. Without an understanding of reproductive skew in a target species, and the effect it can have on genetic diversity retained over generations, long-term conservation goals will be compromised. In this issue of Molecular Ecology, Miller et al. (2009a) test how founder group size and variance in male reproductive success influence the maintenance of genetic diversity following reintroduction on a long-term scale. They evaluated genetic diversity in two wild populations of the iconic New Zealand tuatara (Fig. 1), which differ greatly in population size and genetic diversity, and compared this to genetic diversity in multiple founder populations sourced from both populations. Population viability analysis on the maintenance of genetic diversity over 400 years (10 generations) demonstrated that while the loss of heterozygosity was low when compared with both source populations (1-14%), the greater the male reproductive skew, the greater the predicted losses of genetic diversity. Importantly however, the loss of genetic diversity was ameliorated after population size exceeded 250 animals, regardless of the level of reproductive skew. This study demonstrates that highly informed conservation decisions could be made when you build on a solid foundation of demographic, natural history and behavioural ecology data. These data, when informed by modern population and genetic analysis, mean that fundamental applied conservation questions (how many animals should make up a founder population?) can be answered accurately and with an eye to the long-term consequences of management decisions.

  19. MOIL-opt: Energy-Conserving Molecular Dynamics on a GPU/CPU system.

    Science.gov (United States)

    Ruymgaart, A Peter; Cardenas, Alfredo E; Elber, Ron

    2011-08-26

    We report an optimized version of the molecular dynamics program MOIL that runs on a shared memory system with OpenMP and exploits the power of a Graphics Processing Unit (GPU). The model is of heterogeneous computing system on a single node with several cores sharing the same memory and a GPU. This is a typical laboratory tool, which provides excellent performance at minimal cost. Besides performance, emphasis is made on accuracy and stability of the algorithm probed by energy conservation for explicit-solvent atomically-detailed-models. Especially for long simulations energy conservation is critical due to the phenomenon known as "energy drift" in which energy errors accumulate linearly as a function of simulation time. To achieve long time dynamics with acceptable accuracy the drift must be particularly small. We identify several means of controlling long-time numerical accuracy while maintaining excellent speedup. To maintain a high level of energy conservation SHAKE and the Ewald reciprocal summation are run in double precision. Double precision summation of real-space non-bonded interactions improves energy conservation. In our best option, the energy drift using 1fs for a time step while constraining the distances of all bonds, is undetectable in 10ns simulation of solvated DHFR (Dihydrofolate reductase). Faster options, shaking only bonds with hydrogen atoms, are also very well behaved and have drifts of less than 1kcal/mol per nanosecond of the same system. CPU/GPU implementations require changes in programming models. We consider the use of a list of neighbors and quadratic versus linear interpolation in lookup tables of different sizes. Quadratic interpolation with a smaller number of grid points is faster than linear lookup tables (with finer representation) without loss of accuracy. Atomic neighbor lists were found most efficient. Typical speedups are about a factor of 10 compared to a single-core single-precision code.

  20. Brain Metastases from Colorectal Cancer: Microenvironment and Molecular Mechanisms

    Directory of Open Access Journals (Sweden)

    Yi-Wen Zang

    2012-11-01

    Full Text Available Colorectal cancer is one of the most common digestive tract malignancies in the world. Owing to the newer and more effective systemic therapies, the life of colorectal cancer patients can be remarkably prolonged, and the incidence of brain metastases is increasing. However, little is known about the underlying mechanisms of brain metastasis from colorectal cancer. Here we review the tumor microenvironment and metastasis associated molecules in brain metastases from colorectal cancer. A further understanding of these mechanisms will help us to propose better strategies for colorectal cancer patients with brain metastasis and improve their life quality.

  1. [Cellular and molecular mechanisms of radiation-induced brain injury: can peripheral markers be detected?].

    Science.gov (United States)

    Piskunov, A K; Nikitin, K V; Potapov, A A

    2015-01-01

    Investigation of the mechanisms of radiation-induced brain injury is a relevant fundamental objective of radiobiology and neuroradiology. Damage to the healthy brain tissue is the key factor limiting the application of radiation therapy in patients with nervous systems neoplasms. Furthermore, postradiation brain injury can be clinically indiscernible from continued tumor growth and requires differential diagnosis. Thus, there exists high demand for biomarkers of radiation effects on the brain in neurosurgery and radiobiology. These markers could be used for better understanding and quantifying the effects of ionizing radiation on brain tissues, as well as for elaborating personalized therapy. Despite the high demand, biomarkers of radiation-induced brain injury have not been identified thus far. The cellular and molecular mechanisms of the effect of ionizing radiation on the brain were analyzed in this review in order to identify potential biomarkers of radiation-induced injury to nervous tissue.

  2. GPU Accelerated Discrete Element Method (DEM) Molecular Dynamics for Conservative, Faceted Particle Simulations

    CERN Document Server

    Spellings, Matthew; Anderson, Joshua A; Glotzer, Sharon C

    2016-01-01

    Faceted shapes, such as polyhedra, are commonly found in systems of nanoscale, colloidal, and granular particles. Many interesting physical phenomena, like crystal nucleation and growth, vacancy motion, and glassy dynamics are challenging to model in these systems because they require detailed dynamical information at the individual particle level. Within the granular materials community the Discrete Element Method has been used extensively to model systems of anisotropic particles under gravity, with friction. We provide an implementation of this method intended for simulation of hard, faceted nanoparticles, with a conservative Weeks-Chandler-Andersen (WCA) interparticle potential, coupled to a thermodynamic ensemble. This method is a natural extension of classical molecular dynamics and enables rigorous thermodynamic calculations for faceted particles.

  3. GPU accelerated Discrete Element Method (DEM) molecular dynamics for conservative, faceted particle simulations

    Science.gov (United States)

    Spellings, Matthew; Marson, Ryan L.; Anderson, Joshua A.; Glotzer, Sharon C.

    2017-04-01

    Faceted shapes, such as polyhedra, are commonly found in systems of nanoscale, colloidal, and granular particles. Many interesting physical phenomena, like crystal nucleation and growth, vacancy motion, and glassy dynamics are challenging to model in these systems because they require detailed dynamical information at the individual particle level. Within the granular materials community the Discrete Element Method has been used extensively to model systems of anisotropic particles under gravity, with friction. We provide an implementation of this method intended for simulation of hard, faceted nanoparticles, with a conservative Weeks-Chandler-Andersen (WCA) interparticle potential, coupled to a thermodynamic ensemble. This method is a natural extension of classical molecular dynamics and enables rigorous thermodynamic calculations for faceted particles.

  4. GPU accelerated Discrete Element Method (DEM) molecular dynamics for conservative, faceted particle simulations

    Energy Technology Data Exchange (ETDEWEB)

    Spellings, Matthew [Chemical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109 (United States); Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109 (United States); Marson, Ryan L. [Materials Science & Engineering, University of Michigan, 2300 Hayward St., Ann Arbor, MI 48109 (United States); Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109 (United States); Anderson, Joshua A. [Chemical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109 (United States); Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109 (United States); Glotzer, Sharon C., E-mail: sglotzer@umich.edu [Chemical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109 (United States); Materials Science & Engineering, University of Michigan, 2300 Hayward St., Ann Arbor, MI 48109 (United States); Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109 (United States)

    2017-04-01

    Faceted shapes, such as polyhedra, are commonly found in systems of nanoscale, colloidal, and granular particles. Many interesting physical phenomena, like crystal nucleation and growth, vacancy motion, and glassy dynamics are challenging to model in these systems because they require detailed dynamical information at the individual particle level. Within the granular materials community the Discrete Element Method has been used extensively to model systems of anisotropic particles under gravity, with friction. We provide an implementation of this method intended for simulation of hard, faceted nanoparticles, with a conservative Weeks–Chandler–Andersen (WCA) interparticle potential, coupled to a thermodynamic ensemble. This method is a natural extension of classical molecular dynamics and enables rigorous thermodynamic calculations for faceted particles.

  5. Conserved water molecules in family 1 glycosidases: a DXMS and molecular dynamics study.

    Science.gov (United States)

    Teze, David; Hendrickx, Johann; Dion, Michel; Tellier, Charles; Woods, Virgil L; Tran, Vinh; Sanejouand, Yves-Henri

    2013-08-27

    By taking advantage of the wealth of structural data available for family 1 glycoside hydrolases, a study of the conservation of internal water molecules found in this ubiquitous family of enzymes was undertaken. Strikingly, seven water molecules are observed in more than 90% of the known structures. To gain insight into their possible function, the water dynamics inside Thermus thermophilus β-glycosidase was probed using deuterium exchange mass spectroscopy, allowing the pinpointing of peptide L117-A125, which exchanges most of its amide hydrogens quickly in spite of the fact that it is for the most part buried in the crystal structure. To help interpret this result, a molecular dynamics simulation was performed whose analysis suggests that two water channels are involved in the process. The longest one (∼16 Å) extends between the protein surface and W120, whose side chain interacts with E164 (the acid-base residue involved in the catalytic mechanism), whereas the other channel allows for the exchange with the bulk of the highly conserved water molecules belonging to the hydration shell of D121, a deeply buried residue. Our simulation also shows that another chain of highly conserved water molecules, going from the protein surface to the bottom of the active site cleft close to the nucleophile residue involved in the catalytic mechanism, is able to exchange with the bulk on the nanosecond time scale. It is tempting to speculate that at least one of these three water channels could be involved in the function of family 1 glycoside hydrolases.

  6. [Molecular cytogenetic methods for studying interphase chromosomes in human brain cells].

    Science.gov (United States)

    Iurov, I Iu; Vorsanova, S G; Solov'ev, I V; Iurov, Iu B

    2010-09-01

    One of the main genetic factors determining the functional activity of the genome in somatic cells, including brain nerve cells, is the spatial organization of chromosomes in the interphase nucleus. For a long time, no studies of human brain cells were carried out until high-resolution methods of molecular cytogenetics were developed to analyze interphase chromosomes in nondividing somatic cells. The purpose of the present work was to assess the potential of high-resolution methods of interphase molecular cytogenetics for studying chromosomes and the nuclear organization in postmitotic brain cells. A high efficiency was shown by such methods as multiprobe and quantitative fluorescence in situ hybridization (Multiprobe FISH and QFISH), ImmunoMFISH (analysis of the chromosome organization in different types of brain cells), and interphase chromosome-specific multicolor banding (ICS-MCB). These approaches allowed studying the nuclear organization depending on the gene composition and types of repetitive DNA of specific chromosome regions in certain types of brain cells (in neurons and glial cells, in particular). The present work demonstrates a high potential of interphase molecular cytogenetics for studying the structural and functional organizations of the cell nucleus in highly differentiated nerve cells. Analysis of interphase chromosomes of brain cells in the normal and pathological states can be considered as a promising line of research in modern molecular cytogenetics and cell neurobiology, i. e., molecular neurocytogenetics.

  7. Death Associated Protein Kinases: Molecular Structure and Brain Injury

    OpenAIRE

    Claire Thornton; Carina Mallard; Rajanikant Krishnamurthy; Syam Nair; Henrik Hagberg

    2013-01-01

    Perinatal brain damage underlies an important share of motor and neurodevelopmental disabilities, such as cerebral palsy, cognitive impairment, visual dysfunction and epilepsy. Clinical, epidemiological, and experimental studies have revealed that factors such as inflammation, excitotoxicity and oxidative stress contribute considerably to both white and grey matter injury in the immature brain. A member of the death associated protein kinase (DAPk) family, DAPk1, has been implicated in cerebr...

  8. Adaptive multi-stage integrators for optimal energy conservation in molecular simulations

    CERN Document Server

    Fernández-Pendás, Mario; Sanz-Serna, J M

    2015-01-01

    We introduce a new Adaptive Integration Approach (AIA) to be used in a wide range of molecular simulations. Given a simulation problem and a step size, the method automatically chooses the optimal scheme out of an available family of numerical integrators. Although we focus on two-stage splitting integrators, the idea may be used with more general families. In each instance, the system-specific integrating scheme identified by our approach is optimal in the sense that it provides the best conservation of energy for harmonic forces. The AIA method has been implemented in the BCAM-modified GROMACS software package. Numerical tests in molecular dynamics and hybrid Monte Carlo simulations of constrained and unconstrained physical systems show that the method successfully realises the fail-safe strategy. In all experiments, and for each of the criteria employed, the AIA is at least as good as, and often significantly outperforms the standard Verlet scheme, as well as fixed parameter, optimized two-stage integrator...

  9. Adaptive multi-stage integrators for optimal energy conservation in molecular simulations

    Science.gov (United States)

    Fernández-Pendás, Mario; Akhmatskaya, Elena; Sanz-Serna, J. M.

    2016-12-01

    We introduce a new Adaptive Integration Approach (AIA) to be used in a wide range of molecular simulations. Given a simulation problem and a step size, the method automatically chooses the optimal scheme out of an available family of numerical integrators. Although we focus on two-stage splitting integrators, the idea may be used with more general families. In each instance, the system-specific integrating scheme identified by our approach is optimal in the sense that it provides the best conservation of energy for harmonic forces. The AIA method has been implemented in the BCAM-modified GROMACS software package. Numerical tests in molecular dynamics and hybrid Monte Carlo simulations of constrained and unconstrained physical systems show that the method successfully realizes the fail-safe strategy. In all experiments, and for each of the criteria employed, the AIA is at least as good as, and often significantly outperforms the standard Verlet scheme, as well as fixed parameter, optimized two-stage integrators. In particular, for the systems where harmonic forces play an important role, the sampling efficiency found in simulations using the AIA is up to 5 times better than the one achieved with other tested schemes.

  10. The evolutionarily conserved G protein-coupled receptor SREB2/GPR85 influences brain size, behavior, and vulnerability to schizophrenia

    Science.gov (United States)

    Matsumoto, Mitsuyuki; Straub, Richard E.; Marenco, Stefano; Nicodemus, Kristin K.; Matsumoto, Shun-ichiro; Fujikawa, Akihiko; Miyoshi, Sosuke; Shobo, Miwako; Takahashi, Shinji; Yarimizu, Junko; Yuri, Masatoshi; Hiramoto, Masashi; Morita, Shuji; Yokota, Hiroyuki; Sasayama, Takeshi; Terai, Kazuhiro; Yoshino, Masayasu; Miyake, Akira; Callicott, Joseph H.; Egan, Michael F.; Meyer-Lindenberg, Andreas; Kempf, Lucas; Honea, Robyn; Vakkalanka, Radha Krishna; Takasaki, Jun; Kamohara, Masazumi; Soga, Takatoshi; Hiyama, Hideki; Ishii, Hiroyuki; Matsuo, Ayako; Nishimura, Shintaro; Matsuoka, Nobuya; Kobori, Masato; Matsushime, Hitoshi; Katoh, Masao; Furuichi, Kiyoshi; Weinberger, Daniel R.

    2008-01-01

    The G protein-coupled receptor (GPCR) family is highly diversified and involved in many forms of information processing. SREB2 (GPR85) is the most conserved GPCR throughout vertebrate evolution and is expressed abundantly in brain structures exhibiting high levels of plasticity, e.g., the hippocampal dentate gyrus. Here, we show that SREB2 is involved in determining brain size, modulating diverse behaviors, and potentially in vulnerability to schizophrenia. Mild overexpression of SREB2 caused significant brain weight reduction and ventricular enlargement in transgenic (Tg) mice as well as behavioral abnormalities mirroring psychiatric disorders, e.g., decreased social interaction, abnormal sensorimotor gating, and impaired memory. SREB2 KO mice showed a reciprocal phenotype, a significant increase in brain weight accompanying a trend toward enhanced memory without apparent other behavioral abnormalities. In both Tg and KO mice, no gross malformation of brain structures was observed. Because of phenotypic overlap between SREB2 Tg mice and schizophrenia, we sought a possible link between the two. Minor alleles of two SREB2 SNPs, located in intron 2 and in the 3′ UTR, were overtransmitted to schizophrenia patients in a family-based sample and showed an allele load association with reduced hippocampal gray matter volume in patients. Our data implicate SREB2 as a potential risk factor for psychiatric disorders and its pathway as a target for psychiatric therapy. PMID:18413613

  11. Molecular mapping of brain areas involved in parrot vocal communication.

    Science.gov (United States)

    Jarvis, E D; Mello, C V

    2000-03-27

    Auditory and vocal regulation of gene expression occurs in separate discrete regions of the songbird brain. Here we demonstrate that regulated gene expression also occurs during vocal communication in a parrot, belonging to an order whose ability to learn vocalizations is thought to have evolved independently of songbirds. Adult male budgerigars (Melopsittacus undulatus) were stimulated to vocalize with playbacks of conspecific vocalizations (warbles), and their brains were analyzed for expression of the transcriptional regulator ZENK. The results showed that there was distinct separation of brain areas that had hearing- or vocalizing-induced ZENK expression. Hearing warbles resulted in ZENK induction in large parts of the caudal medial forebrain and in 1 midbrain region, with a pattern highly reminiscent of that observed in songbirds. Vocalizing resulted in ZENK induction in nine brain structures, seven restricted to the lateral and anterior telencephalon, one in the thalamus, and one in the midbrain, with a pattern partially reminiscent of that observed in songbirds. Five of the telencephalic structures had been previously described as part of the budgerigar vocal control pathway. However, functional boundaries defined by the gene expression patterns for some of these structures were much larger and different in shape than previously reported anatomical boundaries. Our results provide the first functional demonstration of brain areas involved in vocalizing and auditory processing of conspecific sounds in budgerigars. They also indicate that, whether or not vocal learning evolved independently, some of the gene regulatory mechanisms that accompany learned vocal communication are similar in songbirds and parrots.

  12. Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates.

    Science.gov (United States)

    Loryan, Irena; Sinha, Vikash; Mackie, Claire; Van Peer, Achiel; Drinkenburg, Wilhelmus H; Vermeulen, An; Heald, Donald; Hammarlund-Udenaes, Margareta; Wassvik, Carola M

    2015-02-01

    In the present work we sought to gain a mechanistic understanding of the physicochemical properties that influence the transport of unbound drug across the blood-brain barrier (BBB) as well as the intra- and extracellular drug exposure in the brain. Interpretable molecular descriptors that significantly contribute to the three key neuropharmacokinetic properties related to BBB drug transport (Kp,uu,brain), intracellular accumulation (Kp,uu,cell), and binding and distribution in the brain (Vu,brain) for a set of 40 compounds were identified using partial least-squares (PLS) analysis. The tailoring of drug properties for improved brain exposure includes decreasing the polarity and/or hydrogen bonding capacity. The design of CNS drug candidates with intracellular targets may benefit from an increase in basicity and/or the number of hydrogen bond donors. Applying this knowledge in drug discovery chemistry programs will allow designing compounds with more desirable CNS pharmacokinetic properties.

  13. Sex steroids and their receptors: molecular actions on brain cells.

    Science.gov (United States)

    Mannella, Paolo; Simoncini, Tommaso

    2012-03-01

    Sex steroids exert actions of paramount importance on brain cells. They contribute to shape the central nervous system during embryo development. They modulate the formation and the turnover of the interconnections between neurons. They control the function of glial cells. And they do it through a signaling machinery that is apparently simple, but that hides a level of complexity that has been unveiled only in part. Different receptor isoforms, different interactions between receptors and co-regulators, chains of events originating at the cell membrane and leading to effects in the nucleus (or the other way around) all interact to determine selective modulations of brain cells. All these actions end up in phenomenal effects on brain function that change through adolescence, pregnancy, adulthood, up to menopause and ageing. Many of these actions are relevant for degenerative processes and research may offer soon new strategies to counteract these diseases.

  14. Residue conservation and dimer-interface analysis of olfactory receptor molecular models

    Directory of Open Access Journals (Sweden)

    Ramanathan Sowdhamini

    2012-10-01

    Full Text Available Olfactory Receptors (ORs are members of the Class A rhodopsin like G-protein coupled receptors (GPCRs which are the initial players in the signal transduction cascade, leading to the generation of nerve impulses transmitted to the brain and resulting in the detection of odorant molecules. Despite the accumulation of thousands of olfactory receptor sequences, no crystal structures of ORs are known tο date. However, the recent availability of crystallographic models of a few GPCRs allows us to generate homology models of ORs and analyze their amino acid patterns, as there is a huge diversity in OR sequences. In this study, we have generated three-dimensional models of 100 representative ORs from Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans and Sacharomyces cerevisiae which were selected on the basis of a composite classification scheme and phylogenetic analysis. The crystal structure of bovine rhodopsin was used as a template and it was found that the full-length models have more than 90% of their residues in allowed regions of the Ramachandran plot. The structures were further used for analysis of conserved residues in the transmembrane and extracellular loop regions in order to identify functionally important residues. Several ORs are known to be functional as dimers and hence dimer interfaces were predicted for OR models to analyse their oligomeric functional state.

  15. Computational identification of conserved transcription factor binding sites upstream of genes induced in rat brain by transient focal ischemic stroke.

    Science.gov (United States)

    Pulliam, John V K; Xu, Zhenfeng; Ford, Gregory D; Liu, Cuimei; Li, Yonggang; Stovall, Kyndra C; Cannon, Virginetta S; Tewolde, Teclemichael; Moreno, Carlos S; Ford, Byron D

    2013-02-07

    Microarray analysis has been used to understand how gene regulation plays a critical role in neuronal injury, survival and repair following ischemic stroke. To identify the transcriptional regulatory elements responsible for ischemia-induced gene expression, we examined gene expression profiles of rat brains following focal ischemia and performed computational analysis of consensus transcription factor binding sites (TFBS) in the genes of the dataset. In this study, rats were sacrificed 24 h after middle cerebral artery occlusion (MCAO) stroke and gene transcription in brain tissues following ischemia/reperfusion was examined using Affymetrix GeneChip technology. The CONserved transcription FACtor binding site (CONFAC) software package was used to identify over-represented TFBS in the upstream promoter regions of ischemia-induced genes compared to control datasets. CONFAC identified 12 TFBS that were statistically over-represented from our dataset of ischemia-induced genes, including three members of the Ets-1 family of transcription factors (TFs). Microarray results showed that mRNA for Ets-1 was increased following tMCAO but not pMCAO. Immunohistochemical analysis of Ets-1 protein in rat brains following MCAO showed that Ets-1 was highly expressed in neurons in the brain of sham control animals. Ets-1 protein expression was virtually abolished in injured neurons of the ischemic brain but was unchanged in peri-infarct brain areas. These data indicate that TFs, including Ets-1, may influence neuronal injury following ischemia. These findings could provide important insights into the mechanisms that lead to brain injury and could provide avenues for the development of novel therapies. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options.

    Science.gov (United States)

    Yousefi, Meysam; Bahrami, Tayyeb; Salmaninejad, Arash; Nosrati, Rahim; Ghaffari, Parisa; Ghaffari, Seyed H

    2017-09-18

    Lung cancer is the most common cause of cancer-related mortality in humans. There are several reasons for this high rate of mortality, including metastasis to several organs, especially the brain. In fact, lung cancer is responsible for approximately 50% of all brain metastases, which are very difficult to manage. Understanding the cellular and molecular mechanisms underlying lung cancer-associated brain metastasis brings up novel therapeutic promises with the hope to ameliorate the severity of the disease. Here, we provide an overview of the molecular mechanisms underlying the pathogenesis of lung cancer dissemination and metastasis to the brain, as well as promising horizons for impeding lung cancer brain metastasis, including the role of cancer stem cells, the blood-brain barrier, interactions of lung cancer cells with the brain microenvironment and lung cancer-driven systemic processes, as well as the role of growth factor/receptor tyrosine kinases, cell adhesion molecules and non-coding RNAs. In addition, we provide an overview of current and novel therapeutic approaches, including radiotherapy, surgery and stereotactic radiosurgery, chemotherapy, as also targeted cancer stem cell and epithelial-mesenchymal transition (EMT)-based therapies, micro-RNA-based therapies and other small molecule or antibody-based therapies. We will also discuss the daunting potential of some combined therapies. The identification of molecular mechanisms underlying lung cancer metastasis has opened up new avenues towards their eradication and provides interesting opportunities for future research aimed at the development of novel targeted therapies.

  17. Molecular Mechanisms of Cannabis Signaling in the Brain.

    Science.gov (United States)

    Ronan, Patrick J; Wongngamnit, Narin; Beresford, Thomas P

    2016-01-01

    Cannabis has been cultivated and used by humans for thousands of years. Research for decades was focused on understanding the mechanisms of an illegal/addictive drug. This led to the discovery of the vast endocannabinoid system. Research has now shifted to understanding fundamental biological questions related to one of the most widespread signaling systems in both the brain and the body. Our understanding of cannabinoid signaling has advanced significantly in the last two decades. In this review, we discuss the state of knowledge on mechanisms of Cannabis signaling in the brain and the modulation of key brain neurotransmitter systems involved in both brain reward/addiction and psychiatric disorders. It is highly probable that various cannabinoids will be found to be efficacious in the treatment of a number of psychiatric disorders. However, while there is clearly much potential, marijuana has not been properly vetted by the medical-scientific evaluation process and there are clearly a range of potentially adverse side-effects-including addiction. We are at crossroads for research on endocannabinoid function and therapeutics (including the use of exogenous treatments such as Cannabis). With over 100 cannabinoid constituents, the majority of which have not been studied, there is much Cannabis research yet to be done. With more states legalizing both the medicinal and recreational use of marijuana the rigorous scientific investigation into cannabinoid signaling is imperative. Copyright © 2016. Published by Elsevier Inc.

  18. Exploring human brain lateralization with molecular genetics and genomics.

    Science.gov (United States)

    Francks, Clyde

    2015-11-01

    Lateralizations of brain structure and motor behavior have been observed in humans as early as the first trimester of gestation, and are likely to arise from asymmetrical genetic-developmental programs, as in other animals. Studies of gene expression levels in postmortem tissue samples, comparing the left and right sides of the human cerebral cortex, have generally not revealed striking transcriptional differences between the hemispheres. This is likely due to lateralization of gene expression being subtle and quantitative. However, a recent re-analysis and meta-analysis of gene expression data from the adult superior temporal and auditory cortex found lateralization of transcription of genes involved in synaptic transmission and neuronal electrophysiology. Meanwhile, human subcortical mid- and hindbrain structures have not been well studied in relation to lateralization of gene activity, despite being potentially important developmental origins of asymmetry. Genetic polymorphisms with small effects on adult brain and behavioral asymmetries are beginning to be identified through studies of large datasets, but the core genetic mechanisms of lateralized human brain development remain unknown. Identifying subtly lateralized genetic networks in the brain will lead to a new understanding of how neuronal circuits on the left and right are differently fine-tuned to preferentially support particular cognitive and behavioral functions. © 2015 New York Academy of Sciences.

  19. Molecular characterization of breast cancer CTCs associated with brain metastasis.

    Science.gov (United States)

    Boral, Debasish; Vishnoi, Monika; Liu, Haowen N; Yin, Wei; Sprouse, Marc L; Scamardo, Antonio; Hong, David S; Tan, Tuan Z; Thiery, Jean P; Chang, Jenny C; Marchetti, Dario

    2017-08-04

    The enumeration of EpCAM-positive circulating tumor cells (CTCs) has allowed estimation of overall metastatic burden in breast cancer patients. However, a thorough understanding of CTCs associated with breast cancer brain metastasis (BCBM) is necessary for early identification and evaluation of treatment response to BCBM. Here we report that BCBM CTCs is enriched in a distinct sub-population of cells identifiable by their biomarker expression and mutational content. Deriving from a comprehensive analysis of CTC transcriptomes, we discovered a unique "circulating tumor cell gene signature" that is distinct from primary breast cancer tissues. Further dissection of the circulating tumor cell gene signature identified signaling pathways associated with BCBM CTCs that may have roles in potentiating BCBM. This study proposes CTC biomarkers and signaling pathways implicated in BCBM that may be used either as a screening tool for brain micro-metastasis detection or for making rational treatment decisions and monitoring therapeutic response in patients with BCBM.Characterization of CTCs derived from breast cancer patients with brain metastasis (BCBM) may allow for early diagnosis of brain metastasis and/or help for treatment choice and its efficacy. In this study, the authors identify a unique signature, based on patient-derived CTCs transcriptomes, for BCBM- CTCs that is different from primary tumors.

  20. Molecular Characterization and Immune Protection of a New Conserved Hypothetical Protein of Eimeria tenella.

    Directory of Open Access Journals (Sweden)

    Qi Zhai

    Full Text Available The genome sequences of Eimeria tenella have been sequenced, but >70% of these genes are currently categorized as having an unknown function or annotated as conserved hypothetical proteins, and few of them have been studied. In the present study, a conserved hypothetical protein gene of E. tenella, designated EtCHP559, was cloned using rapid amplification of cDNA 5'-ends (5'RACE based on the expressed sequence tag (EST. The 1746-bp full-length cDNA of EtCHP559 contained a 1224-bp open reading frame (ORF that encoded a 407-amino acid polypeptide with the predicted molecular weight of 46.04 kDa. Real-time quantitative PCR analysis revealed that EtCHP559 was expressed at higher levels in sporozoites than in the other developmental stages (unsporulated oocysts, sporulated oocysts and second generation merozoites. The ORF was inserted into pCold-TF to produce recombinant EtCHP559. Using western blotting, the recombinant protein was successfully recognized by rabbit serum against E. tenella sporozoites. Immunolocalization by using EtCHP559 antibody showed that EtCHP559 was mainly distributed on the parasite surface in free sporozoites and became concentrated in the anterior region after sporozoites were incubated in complete medium. The EtCHP559 became uniformly dispersed in immature and mature schizonts. Inhibition of EtCHP559 function using anti-rEtCHP559 polyclonal antibody reduced the ability of E. tenella sporozoites to invade host cells by >70%. Animal challenge experiments demonstrated that the recombinant EtCHP559 significantly increased the average body weight gain, reduced the oocyst outputs, alleviated cecal lesions of the infected chickens, and resulted in anticoccidial index >160 against E. tenella. These results suggest that EtCHP559 plays an important role in sporozoite invasion and could be an effective candidate for the development of a new vaccine against E. tenella.

  1. Multi-scale coarse-graining of non-conservative interactions in molecular liquids

    Energy Technology Data Exchange (ETDEWEB)

    Izvekov, Sergei, E-mail: sergiy.izvyekov.civ@mail.mil; Rice, Betsy M. [U.S. Army Research Laboratory, Aberdeen Proving Ground, Maryland 21005 (United States)

    2014-03-14

    A new bottom-up procedure for constructing non-conservative (dissipative and stochastic) interactions for dissipative particle dynamics (DPD) models is described and applied to perform hierarchical coarse-graining of a polar molecular liquid (nitromethane). The distant-dependent radial and shear frictions in functional-free form are derived consistently with a chosen form for conservative interactions by matching two-body force-velocity and three-body velocity-velocity correlations along the microscopic trajectories of the centroids of Voronoi cells (clusters), which represent the dissipative particles within the DPD description. The Voronoi tessellation is achieved by application of the K-means clustering algorithm at regular time intervals. Consistently with a notion of many-body DPD, the conservative interactions are determined through the multi-scale coarse-graining (MS-CG) method, which naturally implements a pairwise decomposition of the microscopic free energy. A hierarchy of MS-CG/DPD models starting with one molecule per Voronoi cell and up to 64 molecules per cell is derived. The radial contribution to the friction appears to be dominant for all models. As the Voronoi cell sizes increase, the dissipative forces rapidly become confined to the first coordination shell. For Voronoi cells of two and more molecules the time dependence of the velocity autocorrelation function becomes monotonic and well reproduced by the respective MS-CG/DPD models. A comparative analysis of force and velocity correlations in the atomistic and CG ensembles indicates Markovian behavior with as low as two molecules per dissipative particle. The models with one and two molecules per Voronoi cell yield transport properties (diffusion and shear viscosity) that are in good agreement with the atomistic data. The coarser models produce slower dynamics that can be appreciably attributed to unaccounted dissipation introduced by regular Voronoi re-partitioning as well as by larger

  2. Molecular Mechanism of Adult Neurogenesis and its Association with Human Brain Diseases

    Science.gov (United States)

    Liu, He; Song, Ni

    2016-01-01

    Recent advances in neuroscience challenge the old dogma that neurogenesis occurs only during embryonic development. Mounting evidence suggests that functional neurogenesis occurs throughout adulthood. This review article discusses molecular factors that affect adult neurogenesis, including morphogens, growth factors, neurotransmitters, transcription factors, and epigenetic factors. Furthermore, we summarize and compare current evidence of associations between adult neurogenesis and human brain diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and brain tumors. PMID:27375363

  3. Perspectives on Molecular Biomarkers of Oxidative Stress and Antioxidant Strategies in Traumatic Brain Injury

    OpenAIRE

    André Mendes Arent; Luiz Felipe de Souza; Roger Walz; Alcir Luiz Dafre

    2014-01-01

    Traumatic brain injury (TBI) is frequently associated with abnormal blood-brain barrier function, resulting in the release of factors that can be used as molecular biomarkers of TBI, among them GFAP, UCH-L1, S100B, and NSE. Although many experimental studies have been conducted, clinical consolidation of these biomarkers is still needed to increase the predictive power and reduce the poor outcome of TBI. Interestingly, several of these TBI biomarkers are oxidatively modified to carbonyl group...

  4. The brain-uterus connection: brain derived neurotrophic factor (BDNF) and its receptor (Ntrk2) are conserved in the mammalian uterus.

    Science.gov (United States)

    Wessels, Jocelyn M; Wu, Liang; Leyland, Nicholas A; Wang, Hongmei; Foster, Warren G

    2014-01-01

    The neurotrophins are neuropeptides that are potent regulators of neurite growth and survival. Although mainly studied in the brain and nervous system, recent reports have shown that neurotrophins are expressed in multiple target tissues and cell types throughout the body. Additionally, dysregulation of neurotrophins has been linked to several disease conditions including Alzheimer's, Parkinson's, Huntington's, psychiatric disorders, and cancer. Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family that elicits its actions through the neurotrophic tyrosine receptor kinase type 2 (Ntrk2). Together BDNF and Ntrk2 are capable of activating the adhesion, angiogenesis, apoptosis, and proliferation pathways. These pathways are prominently involved in reproductive physiology, yet a cross-species examination of BDNF and Ntrk2 expression in the mammalian uterus is lacking. Herein we demonstrated the conserved nature of BDNF and Ntrk2 across several mammalian species by mRNA and protein sequence alignment, isolated BDNF and Ntrk2 transcripts in the uterus by Real-Time PCR, localized both proteins to the glandular and luminal epithelium, vascular smooth muscle, and myometrium of the uterus, determined that the major isoforms expressed in the human endometrium were pro-BDNF, and truncated Ntrk2, and finally demonstrated antibody specificity. Our findings suggest that BDNF and Ntrk2 are transcribed, translated, and conserved across mammalian species including human, mouse, rat, pig, horse, and the bat.

  5. The brain-uterus connection: brain derived neurotrophic factor (BDNF and its receptor (Ntrk2 are conserved in the mammalian uterus.

    Directory of Open Access Journals (Sweden)

    Jocelyn M Wessels

    Full Text Available The neurotrophins are neuropeptides that are potent regulators of neurite growth and survival. Although mainly studied in the brain and nervous system, recent reports have shown that neurotrophins are expressed in multiple target tissues and cell types throughout the body. Additionally, dysregulation of neurotrophins has been linked to several disease conditions including Alzheimer's, Parkinson's, Huntington's, psychiatric disorders, and cancer. Brain derived neurotrophic factor (BDNF is a member of the neurotrophin family that elicits its actions through the neurotrophic tyrosine receptor kinase type 2 (Ntrk2. Together BDNF and Ntrk2 are capable of activating the adhesion, angiogenesis, apoptosis, and proliferation pathways. These pathways are prominently involved in reproductive physiology, yet a cross-species examination of BDNF and Ntrk2 expression in the mammalian uterus is lacking. Herein we demonstrated the conserved nature of BDNF and Ntrk2 across several mammalian species by mRNA and protein sequence alignment, isolated BDNF and Ntrk2 transcripts in the uterus by Real-Time PCR, localized both proteins to the glandular and luminal epithelium, vascular smooth muscle, and myometrium of the uterus, determined that the major isoforms expressed in the human endometrium were pro-BDNF, and truncated Ntrk2, and finally demonstrated antibody specificity. Our findings suggest that BDNF and Ntrk2 are transcribed, translated, and conserved across mammalian species including human, mouse, rat, pig, horse, and the bat.

  6. Immunosignaturing can detect products from molecular markers in brain cancer.

    Directory of Open Access Journals (Sweden)

    Alexa K Hughes

    Full Text Available Immunosignaturing shows promise as a general approach to diagnosis. It has been shown to detect immunological signs of infection early during the course of disease and to distinguish Alzheimer's disease from healthy controls. Here we test whether immunosignatures correspond to clinical classifications of disease using samples from people with brain tumors. Blood samples from patients undergoing craniotomies for therapeutically naïve brain tumors with diagnoses of astrocytoma (23 samples, Glioblastoma multiforme (22 samples, mixed oligodendroglioma/astrocytoma (16 samples, oligodendroglioma (18 samples, and 34 otherwise healthy controls were tested by immunosignature. Because samples were taken prior to adjuvant therapy, they are unlikely to be perturbed by non-cancer related affects. The immunosignaturing platform distinguished not only brain cancer from controls, but also pathologically important features about the tumor including type, grade, and the presence or absence of O(6-methyl-guanine-DNA methyltransferase methylation promoter (MGMT, an important biomarker that predicts response to temozolomide in Glioblastoma multiformae patients.

  7. Molecular imaging of the brain. Using multi-quantum coherence and diagnostics of brain disorders

    Energy Technology Data Exchange (ETDEWEB)

    Kaila, M.M. [New South Wales Univ., Sydney, NSW (Australia). School of Physics; Kaila, Rakhi [Univ. of New South Wales, Sydney (Australia). School of Medicine

    2013-11-01

    Explains the basics of the MRI and its use in the diagnostics and the treatment of the human brain disorders. Examines multi-quantum magnetic resonance imaging methods and the diagnostics of brain disorders. Covers how in a non-invasive manner one can diagnose diseases of the brain. This book examines multi-quantum magnetic resonance imaging methods and the diagnostics of brain disorders. It consists of two Parts. The part I is initially devoted towards the basic concepts of the conventional single quantum MRI techniques. It is supplemented by the basic knowledge required to understand multi-quantum MRI. Practical illustrations are included both on recent developments in conventional MRI and the MQ-MRI. This is to illustrate the connection between theoretical concepts and their scope in the clinical applications. The Part II initially sets out the basic details about quadrupole charge distribution present in certain nuclei and their importance about the functions they perform in our brain. Some simplified final mathematical expressions are included to illustrate facts about the basic concepts of the quantum level interactions between magnetic dipole and the electric quadrupole behavior of useful nuclei present in the brain. Selected practical illustrations, from research and clinical practices are included to illustrate the newly emerging ideas and techniques. The reader should note that the two parts of the book are written with no interdependence. One can read them quite independently.

  8. QUANTITATIVE RT-PCR ANALYSES OF FIVE EVOLUTIONARY CONSERVED GENES IN ALLIGATOR BRAINS DURING DEVELOPMENT

    Science.gov (United States)

    Wilson, Sarah M.; Zhu, Tianli; Khanna, Rajesh; Pritz, Michael B.

    2011-01-01

    Gene expression was investigated in the major brain subdivisions (telencephalon, diencephalon, midbrain and hindbrain) in a representative reptile, Alligator mississipiensis, during the later stages of embryonic development. The following genes were examined: voltage-gated sodium channel isoforms: NaV1.1 and NaV1.2; synaptic vesicle 2a (SV2a); synaptophysin; and calbindin 2. With the exception of synaptophysin, which was only expressed in the telencephalon, all genes were expressed in all brain regions sampled at the time periods examined. For NaV1.1, gene expression varied according to brain area sampled. When compared with NaV1.1, the pattern of NaV1.2 gene expression differed appreciably. The gene expression of SV2a was the most robust of any of the genes examined. Of the other genes examined, although differences were noted, no statistically significant changes were found either between brain part or time interval. Although limited, the present analysis is the first quantitative mRNA gene expression study in any reptile during development. Together with future experiments of a similar nature, the present gene expression results should determine which genes are expressed in major brain areas at which times during development in Alligator. When compared with other amniotes, these results will prove useful for determining how gene expression during development influences adult brain structure. PMID:22379598

  9. Conservation of the glucan phosphatase laforin is linked to rates of molecular evolution and the glucan metabolism of the organism

    Directory of Open Access Journals (Sweden)

    Pace Rachel M

    2009-06-01

    Full Text Available Abstract Background Lafora disease (LD is a fatal autosomal recessive neurodegenerative disease. A hallmark of LD is cytoplasmic accumulation of insoluble glucans, called Lafora bodies (LBs. Mutations in the gene encoding the phosphatase laforin account for ~50% of LD cases, and this gene is conserved in all vertebrates. We recently demonstrated that laforin is the founding member of a unique class of phosphatases that dephosphorylate glucans. Results Herein, we identify laforin orthologs in a protist and two invertebrate genomes, and report that laforin is absent in the vast majority of protozoan genomes and it is lacking in all other invertebrate genomes sequenced to date. We biochemically characterized recombinant proteins from the sea anemone Nematostella vectensis and the amphioxus Branchiostoma floridae to demonstrate that they are laforin orthologs. We demonstrate that the laforin gene has a unique evolutionary lineage; it is conserved in all vertebrates, a subclass of protists that metabolize insoluble glucans resembling LBs, and two invertebrates. We analyzed the intron-exon boundaries of the laforin genes in each organism and determine, based on recently published reports describing rates of molecular evolution in Branchiostoma and Nematostella, that the conservation of laforin is linked to the molecular rate of evolution and the glucan metabolism of an organism. Conclusion Our results alter the existing view of glucan phosphorylation/dephosphorylation and strongly suggest that glucan phosphorylation is a multi-Kingdom regulatory mechanism, encompassing at least some invertebrates. These results establish boundaries concerning which organisms contain laforin. Laforin is conserved in all vertebrates, it has been lost in the vast majority of lower organisms, and yet it is an ancient gene that is conserved in a subset of protists and invertebrates that have undergone slower rates of molecular evolution and/or metabolize a carbohydrate

  10. Molecular Imaging of the Brain Using Multi-Quantum Coherence and Diagnostics of Brain Disorders

    CERN Document Server

    Kaila, M M

    2013-01-01

    This book examines multi-quantum magnetic resonance imaging methods and the diagnostics of brain disorders. It consists of two Parts. The part I is initially devoted towards the basic concepts of the conventional single quantum MRI techniques. It is supplemented by the basic knowledge required to understand multi-quantum MRI. Practical illustrations are included both on recent developments in conventional MRI and the MQ-MRI. This is to illustrate the connection between theoretical concepts and their scope in the clinical applications. The Part II initially sets out the basic details about quadrupole charge distribution present in certain nuclei and their importance about the functions they perform in our brain. Some simplified final mathematical expressions are included to illustrate facts about the basic concepts of the quantum level interactions between magnetic dipole and the electric quadrupole behavior of useful nuclei present in the brain. Selected practical illustrations, from research and clinical pra...

  11. Molecular imaging of brain tumors personal experience and review of the literature.

    Science.gov (United States)

    Schaller, Bernhard J; Cornelius, Jan F; Sandu, Nora; Buchfelder, Michael

    2008-12-01

    Non-invasive energy metabolism measurements in brain tumors in vivo are now performed widely as molecular imaging by positron emission tomography. This capability has developed from a large number of basic and clinical science investigations that have cross fertilized one another. Apart from precise anatomical localization and quantification, the most intriguing advantage of such imaging is the opportunity to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Most importantly, molecular imaging represents a key-technology in translational research, helping to develop experimental protocols that may later be applied to human patients. Common clinical indications for molecular imaging of primary brain tumors therefore contain (i) primary brain tumor diagnosis, (ii) identification of the metabolically most active brain tumor reactions (differentiation of viable tumor tissue from necrosis), and (iii) prediction of treatment response by measurement of tumor perfusion, or ischemia. The key-question remains whether the magnitude of biochemical alterations demonstrated by molecular imaging reveals prognostic value with respect to survival. Molecular imaging may identify early disease and differentiate benign from malignant lesions. Moreover, an early identification of treatment effectiveness could influence patient management by providing objective criteria for evaluation of therapeutic strategies for primary brain tumors. Specially, its novel potential to visualize metabolism and signal transduction to gene expression is used in reporter gene assays to trace the location and temporal level of expression of therapeutic and endogenous genes. The authors present here illustrative data of PET imaging: the thymidine kinase gene expression in experimentally transplanted F98 gliomas in cat brain indicates, that [(18)F]FHBG visualizes cells expressing TK-GFP gene in transduced gliomas as well as quantities and localizes transduced

  12. Whole brain N-acetylaspartate concentration is conserved throughout normal aging.

    Science.gov (United States)

    Wu, William E; Gass, Achim; Glodzik, Lidia; Babb, James S; Hirsch, Jochen; Sollberger, Marc; Achtnichts, Lutz; Amann, Michael; Monsch, Andreas U; Gonen, Oded

    2012-10-01

    We hypothesize that normal aging implies neuronal durability, reflected by age-independent concentrations of their marker--the amino acid derivative N-acetylaspartate (NAA). To test this, we obtained the whole-brain and whole-head N-acetylaspartate concentrations (WBNAA and WHNAA) with proton magnetic resonance (MR) spectroscopy; and the fractional brain parenchyma volume (fBPV)--a metric of atrophy, by segmenting the magnetic resonance image (MRI) from 42 (18 male) healthy young (31.9 ± 5.8 years old) and 100 (64 male, 72.6 ± 7.3 years old) cognitively normal elderly. The 12.8 ± 1.9 mM WBNAA of the young was not significantly different from the 13.1 ± 3.1 mM in the elderly (p > 0.05). In contrast, both fBPV (87.3 ± 4.7% vs. 74.8 ± 4.8%) and WHNAA (11.1 ± 1.7 mM vs. 9.8 ± 2.4 mM) were significantly higher in the young (approximately 14%; p normal aging apart suggests that neuronal integrity is maintained across the lifespan. Clinically, WBNAA could be used as a marker for normal (hence, also abnormal) brain aging. In contrast, WHNAA and fBPV seem age-related suggesting that brain atrophy may occur without compromising the remaining tissue.

  13. Molecular cloning, chromosomal mapping, and functional expression of human brain glutamate receptors

    Energy Technology Data Exchange (ETDEWEB)

    Sun, W.; Ferrer-Montiel, A.V.; Schinder, A.F.; Montal, M. (Univ. of California, San Diego, La Jolla (United States)); McPherson, J.P. (Univ. of California, Irvine (United States)); Evans, G.A. (Salk Inst. for Biological Studies, La Jolla, CA (United States))

    1992-02-15

    A full-length cDNA clone encoding a glutamate receptor was isolated from a human brain cDNA library, and the gene product was characterized after expression in Xenopus oocytes. Degenerate PCR primers to conserved regions of published rat brain glutamate receptor sequences amplified a 1-kilobase fragment from a human brain cDNA library. This fragment was used as a probe for subsequent hybridization screening. Two clones were isolated that, based on sequence information, code for different receptors: a 3-kilobase clone, HBGR1, contains a full-length glutamate receptor cDNA highly homologous to the rat brain clone GluR1, and a second clone, HBGR2, contains approximately two-thirds of the coding region of a receptor homologous to rat brain clone GluR2. Southern and PCr analysis of a somatic cell-hybrid panel mapped HBGR1 to human chromosome 5q31.3-33.3 and mapped HBGR2 to chromosome 4q25-34.3. Xenopus oocytes injected with in vitro-synthesized HBGR1 cRNA expressed currents activated by glutamate receptor agonists. These results indicate that clone HBGR1 codes for a glutamate receptor of the kainate subtype cognate to members of the glutamate receptor family from rodent brain.

  14. [Molecular-cellular and hormonal mechanisms of induced brain tolerance of extreme factors].

    Science.gov (United States)

    Samoĭlov, M O; Rybnikova, E A

    2012-01-01

    This review includes results of own studies and literature data on the topical problem of neurobiology and medicine: discovery of the mechanisms of increased brain resistance to extreme exposures. The emphasis is made on the molecular-cellular and hormonal mechanisms of hypoxic preconditioning-induced brain tolerance to injurious hypoxia, psychoemotional and traumatic stress. A role of basic hormonal and intracellular cascade pro-adaptive processes mediating the neuroprotective action of hypoxic preconditioning is reviewed. A dynamics of the mechanisms of development of induced susceptible brain areas (hippocampus, neocortex) tolerance which includes phases of induction, transformation and expression, is presented. New data on preconditioning-induced cross-tolerance providing increased brain resistance not only to hypoxia but also to other stresses are reported. For the first time neuroprotective effects of hypoxic postconditioning are described.

  15. Facial Morphogenesis: Physical and Molecular Interactions Between the Brain and the Face.

    Science.gov (United States)

    Marcucio, Ralph; Hallgrimsson, Benedikt; Young, Nathan M

    2015-01-01

    Morphogenesis of the brain and face is intrinsically linked by a number of factors. These include: origins of tissues, adjacency allowing their physical interactions, and molecular cross talk controlling growth. Neural crest cells that form the facial primordia originate on the dorsal neural tube. In the caudal pharyngeal arches, a Homeobox code regulates arch identity. In anterior regions, positional information is acquired locally. Second, the brain is a structural platform that influences positioning of the facial primordia, and brain growth influences the timing of primordia fusion. Third, the brain helps induce a signaling center, the frontonasal ectodermal zone, in the ectoderm, which participates in patterned growth of the upper jaw. Similarly, signals from neural crest cells regulate expression of fibroblast growth factor 8 in the anterior neural ridge, which controls growth of the anterior forebrain. Disruptions to these interactions have significant consequences for normal development of the craniofacial complex, leading to structural malformations and birth defects.

  16. A conservative region of the mercuric reductase gene (mera) as a molecular marker of bacterial mercury resistance

    Science.gov (United States)

    Sotero-Martins, Adriana; de Jesus, Michele Silva; Lacerda, Michele; Moreira, Josino Costa; Filgueiras, Ana Luzia Lauria; Barrocas, Paulo Rubens Guimarães

    2008-01-01

    The most common bacterial mercury resistance mechanism is based on the reduction of Hg(II) to Hg0, which is dependent of the mercuric reductase enzyme (MerA) activity. The use of a 431 bp fragment of a conservative region of the mercuric reductase (merA) gene was applied as a molecular marker of this mechanism, allowing the identification of mercury resistant bacterial strains. PMID:24031221

  17. Method for isolation and molecular characterization of extracellular microvesicles released from brain endothelial cells

    Directory of Open Access Journals (Sweden)

    Haqqani Arsalan S

    2013-01-01

    Full Text Available Abstract Background In addition to possessing intracellular vesicles, eukaryotic cells also produce extracellular microvesicles, ranging from 50 to 1000 nm in diameter that are released or shed into the microenvironment under physiological and pathological conditions. These membranous extracellular organelles include both exosomes (originating from internal vesicles of endosomes and ectosomes (originating from direct budding/shedding of plasma membranes. Extracellular microvesicles contain cell-specific collections of proteins, glycoproteins, lipids, nucleic acids and other molecules. These vesicles play important roles in intercellular communication by acting as carrier for essential cell-specific information to target cells. Endothelial cells in the brain form the blood–brain barrier, a specialized interface between the blood and the brain that tightly controls traffic of nutrients and macromolecules between two compartments and interacts closely with other cells forming the neurovascular unit. Therefore, brain endothelial cell extracellular microvesicles could potentially play important roles in ‘externalizing’ brain-specific biomarkers into the blood stream during pathological conditions, in transcytosis of blood-borne molecules into the brain, and in cell-cell communication within the neurovascular unit. Methods To study cell-specific molecular make-up and functions of brain endothelial cell exosomes, methods for isolation of extracellular microvesicles using mass spectrometry-compatible protocols and the characterization of their signature profiles using mass spectrometry -based proteomics were developed. Results A total of 1179 proteins were identified in the isolated extracellular microvesicles from brain endothelial cells. The microvesicles were validated by identification of almost 60 known markers, including Alix, TSG101 and the tetraspanin proteins CD81 and CD9. The surface proteins on isolated microvesicles could potentially

  18. Method for isolation and molecular characterization of extracellular microvesicles released from brain endothelial cells.

    Science.gov (United States)

    Haqqani, Arsalan S; Delaney, Christie E; Tremblay, Tammy-Lynn; Sodja, Caroline; Sandhu, Jagdeep K; Stanimirovic, Danica B

    2013-01-10

    In addition to possessing intracellular vesicles, eukaryotic cells also produce extracellular microvesicles, ranging from 50 to 1000 nm in diameter that are released or shed into the microenvironment under physiological and pathological conditions. These membranous extracellular organelles include both exosomes (originating from internal vesicles of endosomes) and ectosomes (originating from direct budding/shedding of plasma membranes). Extracellular microvesicles contain cell-specific collections of proteins, glycoproteins, lipids, nucleic acids and other molecules. These vesicles play important roles in intercellular communication by acting as carrier for essential cell-specific information to target cells. Endothelial cells in the brain form the blood-brain barrier, a specialized interface between the blood and the brain that tightly controls traffic of nutrients and macromolecules between two compartments and interacts closely with other cells forming the neurovascular unit. Therefore, brain endothelial cell extracellular microvesicles could potentially play important roles in 'externalizing' brain-specific biomarkers into the blood stream during pathological conditions, in transcytosis of blood-borne molecules into the brain, and in cell-cell communication within the neurovascular unit. To study cell-specific molecular make-up and functions of brain endothelial cell exosomes, methods for isolation of extracellular microvesicles using mass spectrometry-compatible protocols and the characterization of their signature profiles using mass spectrometry -based proteomics were developed. A total of 1179 proteins were identified in the isolated extracellular microvesicles from brain endothelial cells. The microvesicles were validated by identification of almost 60 known markers, including Alix, TSG101 and the tetraspanin proteins CD81 and CD9. The surface proteins on isolated microvesicles could potentially interact with both primary astrocytes and cortical neurons

  19. Molecular cytogenetic analysis in the study of brain tumors: findings and applications.

    Science.gov (United States)

    Bayani, Jane; Pandita, Ajay; Squire, Jeremy A

    2005-11-15

    Classic cytogenetics has evolved from black and white to technicolor images of chromosomes as a result of advances in fluorescence in situ hybridization (FISH) techniques, and is now called molecular cytogenetics. Improvements in the quality and diversity of probes suitable for FISH, coupled with advances in computerized image analysis, now permit the genome or tissue of interest to be analyzed in detail on a glass slide. It is evident that the growing list of options for cytogenetic analysis has improved the understanding of chromosomal changes in disease initiation, progression, and response to treatment. The contributions of classic and molecular cytogenetics to the study of brain tumors have provided scientists and clinicians alike with new avenues for investigation. In this review the authors summarize the contributions of molecular cytogenetics to the study of brain tumors, encompassing the findings of classic cytogenetics, interphase- and metaphase-based FISH studies, spectral karyotyping, and metaphase- and array-based comparative genomic hybridization. In addition, this review also details the role of molecular cytogenetic techniques in other aspects of understanding the pathogenesis of brain tumors, including xenograft, cancer stem cell, and telomere length studies.

  20. Therapeutic potential of brain-derived neurotrophic factor (BDNF) and a small molecular mimics of BDNF for traumatic brain injury

    Science.gov (United States)

    Wurzelmann, Mary; Romeika, Jennifer; Sun, Dong

    2017-01-01

    Traumatic brain injury (TBI) is a major health problem worldwide. Following primary mechanical insults, a cascade of secondary injuries often leads to further neural tissue loss. Thus far there is no cure to rescue the damaged neural tissue. Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration. The neurotrophin brain-derived neurotrophic factor (BDNF) has significant effect in both aspects, promoting neuronal survival, synaptic plasticity and neurogenesis. Recently, the flavonoid 7,8-dihydroxyflavone (7,8-DHF), a small TrkB agonist that mimics BDNF function, has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI. Compared to BDNF, 7,8-DHF has a longer half-life and much smaller molecular size, capable of penetrating the blood-brain barrier, which makes it possible for non-invasive clinical application. In this review, we summarize functions of the BDNF/TrkB signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.

  1. Therapeutic potential of brain-derived neurotrophic factor (BDNF) and a small molecular mimics of BDNF for traumatic brain injury.

    Science.gov (United States)

    Wurzelmann, Mary; Romeika, Jennifer; Sun, Dong

    2017-01-01

    Traumatic brain injury (TBI) is a major health problem worldwide. Following primary mechanical insults, a cascade of secondary injuries often leads to further neural tissue loss. Thus far there is no cure to rescue the damaged neural tissue. Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration. The neurotrophin brain-derived neurotrophic factor (BDNF) has significant effect in both aspects, promoting neuronal survival, synaptic plasticity and neurogenesis. Recently, the flavonoid 7,8-dihydroxyflavone (7,8-DHF), a small TrkB agonist that mimics BDNF function, has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI. Compared to BDNF, 7,8-DHF has a longer half-life and much smaller molecular size, capable of penetrating the blood-brain barrier, which makes it possible for non-invasive clinical application. In this review, we summarize functions of the BDNF/TrkB signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.

  2. Molecular evolution of vertebrate neurotrophins: co-option of the highly conserved nerve growth factor gene into the advanced snake venom arsenalf.

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    Kartik Sunagar

    Full Text Available Neurotrophins are a diverse class of structurally related proteins, essential for neuronal development, survival, plasticity and regeneration. They are characterized by major family members, such as the nerve growth factors (NGF, brain-derived neurotrophic factors (BDNF and neurotrophin-3 (NT-3, which have been demonstrated here to lack coding sequence variations and follow the regime of negative selection, highlighting their extremely important conserved role in vertebrate homeostasis. However, in stark contrast, venom NGF secreted as part of the chemical arsenal of the venomous advanced snake family Elapidae (and to a lesser extent Viperidae have characteristics consistent with the typical accelerated molecular evolution of venom components. This includes a rapid rate of diversification under the significant influence of positive-selection, with the majority of positively-selected sites found in the secreted β-polypeptide chain (74% and on the molecular surface of the protein (92%, while the core structural and functional residues remain highly constrained. Such focal mutagenesis generates active residues on the toxin molecular surface, which are capable of interacting with novel biological targets in prey to induce a myriad of pharmacological effects. We propose that caenophidian NGFs could participate in prey-envenoming by causing a massive release of chemical mediators from mast cells to mount inflammatory reactions and increase vascular permeability, thereby aiding the spread of other toxins and/or by acting as proapoptotic factors. Despite their presence in reptilian venom having been known for over 60 years, this is the first evidence that venom-secreted NGF follows the molecular evolutionary pattern of other venom components, and thus likely participates in prey-envenomation.

  3. Meta-coexpression conservation analysis of microarray data: a "subset" approach provides insight into brain-derived neurotrophic factor regulation

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    Timmusk Tõnis

    2009-09-01

    Full Text Available Abstract Background Alterations in brain-derived neurotrophic factor (BDNF gene expression contribute to serious pathologies such as depression, epilepsy, cancer, Alzheimer's, Huntington and Parkinson's disease. Therefore, exploring the mechanisms of BDNF regulation represents a great clinical importance. Studying BDNF expression remains difficult due to its multiple neural activity-dependent and tissue-specific promoters. Thus, microarray data could provide insight into the regulation of this complex gene. Conventional microarray co-expression analysis is usually carried out by merging the datasets or by confirming the re-occurrence of significant correlations across datasets. However, co-expression patterns can be different under various conditions that are represented by subsets in a dataset. Therefore, assessing co-expression by measuring correlation coefficient across merged samples of a dataset or by merging datasets might not capture all correlation patterns. Results In our study, we performed meta-coexpression analysis of publicly available microarray data using BDNF as a "guide-gene" introducing a "subset" approach. The key steps of the analysis included: dividing datasets into subsets with biologically meaningful sample content (e.g. tissue, gender or disease state subsets; analyzing co-expression with the BDNF gene in each subset separately; and confirming co- expression links across subsets. Finally, we analyzed conservation in co-expression with BDNF between human, mouse and rat, and sought for conserved over-represented TFBSs in BDNF and BDNF-correlated genes. Correlated genes discovered in this study regulate nervous system development, and are associated with various types of cancer and neurological disorders. Also, several transcription factor identified here have been reported to regulate BDNF expression in vitro and in vivo. Conclusion The study demonstrates the potential of the "subset" approach in co-expression conservation

  4. Multi-study integration of brain cancer transcriptomes reveals organ-level molecular signatures.

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    Jaeyun Sung

    Full Text Available We utilized abundant transcriptomic data for the primary classes of brain cancers to study the feasibility of separating all of these diseases simultaneously based on molecular data alone. These signatures were based on a new method reported herein--Identification of Structured Signatures and Classifiers (ISSAC--that resulted in a brain cancer marker panel of 44 unique genes. Many of these genes have established relevance to the brain cancers examined herein, with others having known roles in cancer biology. Analyses on large-scale data from multiple sources must deal with significant challenges associated with heterogeneity between different published studies, for it was observed that the variation among individual studies often had a larger effect on the transcriptome than did phenotype differences, as is typical. For this reason, we restricted ourselves to studying only cases where we had at least two independent studies performed for each phenotype, and also reprocessed all the raw data from the studies using a unified pre-processing pipeline. We found that learning signatures across multiple datasets greatly enhanced reproducibility and accuracy in predictive performance on truly independent validation sets, even when keeping the size of the training set the same. This was most likely due to the meta-signature encompassing more of the heterogeneity across different sources and conditions, while amplifying signal from the repeated global characteristics of the phenotype. When molecular signatures of brain cancers were constructed from all currently available microarray data, 90% phenotype prediction accuracy, or the accuracy of identifying a particular brain cancer from the background of all phenotypes, was found. Looking forward, we discuss our approach in the context of the eventual development of organ-specific molecular signatures from peripheral fluids such as the blood.

  5. The Morphological and Molecular Changes of Brain Cells Exposed to Direct Current Electric Field Stimulation

    OpenAIRE

    Pelletier, Simon J.; Lagacé, Marie; St-Amour, Isabelle; Arsenault, Dany; Cisbani, Giulia; Chabrat, Audrey; Fecteau, Shirley; Lévesque, Martin; Cicchetti, Francesca

    2015-01-01

    Background: The application of low-intensity direct current electric fields has been experimentally used in the clinic to treat a number of brain disorders, predominantly using transcranial direct current stimulation approaches. However, the cellular and molecular changes induced by such treatment remain largely unknown. Methods: Here, we tested various intensities of direct current electric fields (0, 25, 50, and 100V/m) in a well-controlled in vitro environment in order to investigate the r...

  6. Fluorescence microscopy studies of a peripheral-benzodiazepine-receptor-targeted molecular probe for brain tumor imaging

    Science.gov (United States)

    Marcu, Laura; Vernier, P. Thomas; Manning, H. Charles; Salemi, Sarah; Li, Aimin; Craft, Cheryl M.; Gundersen, Martin A.; Bornhop, Darryl J.

    2003-10-01

    This study investigates the potential of a new multi-modal lanthanide chelate complex for specifically targeting brain tumor cells. We report here results from ongoing studies of up-take, sub-cellular localization and binding specificity of this new molecular imaging probe. Fluorescence microscopy investigations in living rat C6 glioma tumor cells demonstrate that the new imaging agent has affinity for glioma cells and binds to mitochondria.

  7. Molecular and anatomical signatures of sleep deprivation in the mouse brain

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    Carol L Thompson

    2010-10-01

    Full Text Available Sleep deprivation (SD leads to a suite of cognitive and behavioral impairments, and yet the molecular consequences of SD in the brain are poorly understood. Using a systematic immediate-early gene mapping to detect neuronal activation, the consequences of SD were mapped primarily to forebrain regions. Sleep deprivation was found to both induce and suppress immediate early gene expression (and thus neuronal activity in subregions of neocortex, striatum, and other brain regions. Laser microdissection and cDNA microarrays were used to identify the molecular consequences of SD in 7 brain regions. In situ hybridization for 222 genes selected from the microarray data and other sources confirmed that robust molecular changes were largely restricted to the forebrain. Analysis of the ISH data for 222 genes (publicly accessible at http://sleep.alleninstitute.org provided a molecular and anatomic signature of the effects of SD on the brain. The SCN and the neocortex exhibited differential regulation of the same genes, such that in the SCN genes exhibited time-of-day effects while in the neocortex, genes exhibited only SD and W effects. In the neocortex, SD activated gene expression in areal-, layer-, and cell type-specific manner. In the forebrain, SD preferentially activated excitatory neurons, as demonstrated by double-labeling, except for striatum which consists primarily of inhibitory neurons. These data provide a characterization of the anatomical and cell-type specific signatures of SD on neuronal activity and gene expression that may account for the associated cognitive and behavioral effects.

  8. Achieving Energy Conservation in Poisson-Boltzmann Molecular Dynamics: Accuracy and Precision with Finite-Difference Algorithms

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    Wang, Jun; Cai, Qin; Li, Zhi-Lin; Zhao, Hong-Kai; Luo, Ray

    2009-01-01

    Violation of energy conservation in Poisson-Boltzmann molecular dynamics, due to the limited accuracy and precision of numerical methods, is a major bottleneck preventing its wide adoption in biomolecular simulations. We explored the ideas of enforcing interface conditions by the immerse interface method and of removing charge singularity to improve the finite-difference methods. Our analysis of these ideas on an analytical test system shows significant improvement in both energies and forces. Our analysis further indicates the need for more accurate force calculation, especially the boundary force calculation. PMID:20098487

  9. Conservative nature of oestradiol signalling pathways in the brain lobes of octopus vulgaris involved in reproduction, learning and motor coordination.

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    De Lisa, E; Paolucci, M; Di Cosmo, A

    2012-02-01

    Oestradiol plays crucial roles in the mammalian brain by modulating reproductive behaviour, neural plasticity and pain perception. The cephalopod Octopus vulgaris is considered, along with its relatives, to be the most behaviourally advanced invertebrate, although the neurophysiological basis of its behaviours, including pain perception, remain largely unknown. In the present study, using a combination of molecular and imaging techniques, we found that oestradiol up-regulated O. vulgaris gonadotrophin-releasing hormone (Oct-GnRH) and O. vulgaris oestrogen receptor (Oct-ER) mRNA levels in the olfactory lobes; in turn, Oct-ER mRNA was regulated by NMDA in lobes involved in learning and motor coordination. Fluorescence resonance energy transfer analysis revealed that oestradiol binds Oct-ER causing conformational modifications and nuclear translocation consistent with the classical genomic mechanism of the oestrogen receptor. Moreover, oestradiol triggered a calcium influx and cyclic AMP response element binding protein phosphorylation via membrane receptors, providing evidence for a rapid nongenomic action of oestradiol in O. vulgaris. In the present study, we demonstrate, for the first time, the physiological role of oestradiol in the brain lobes of O. vulgaris involved in reproduction, learning and motor coordination.

  10. Molecular dynamics analysis of conserved hydrophobic and hydrophilic bond-interaction networks in ErbB family kinases.

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    Shih, Andrew J; Telesco, Shannon E; Choi, Sung-Hee; Lemmon, Mark A; Radhakrishnan, Ravi

    2011-06-01

    The EGFR (epidermal growth factor receptor)/ErbB/HER (human EGFR) family of kinases contains four homologous receptor tyrosine kinases that are important regulatory elements in key signalling pathways. To elucidate the atomistic mechanisms of dimerization-dependent activation in the ErbB family, we have performed molecular dynamics simulations of the intracellular kinase domains of three members of the ErbB family (those with known kinase activity), namely EGFR, ErbB2 (HER2) and ErbB4 (HER4), in different molecular contexts: monomer against dimer and wild-type against mutant. Using bioinformatics and fluctuation analyses of the molecular dynamics trajectories, we relate sequence similarities to correspondence of specific bond-interaction networks and collective dynamical modes. We find that in the active conformation of the ErbB kinases, key subdomain motions are co-ordinated through conserved hydrophilic interactions: activating bond-networks consisting of hydrogen bonds and salt bridges. The inactive conformations also demonstrate conserved bonding patterns (albeit less extensive) that sequester key residues and disrupt the activating bond network. Both conformational states have distinct hydrophobic advantages through context-specific hydrophobic interactions. We show that the functional (activating) asymmetric kinase dimer interface forces a corresponding change in the hydrophobic and hydrophilic interactions that characterize the inactivating bond network, resulting in motion of the αC-helix through allostery. Several of the clinically identified activating kinase mutations of EGFR act in a similar fashion to disrupt the inactivating bond network. The present molecular dynamics study reveals a fundamental difference in the sequence of events in EGFR activation compared with that described for the Src kinase Hck.

  11. Heat of molecular chemisorption from bond-order-conservation viewpoint: Why morse potentials are so efficient

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    Shustorovich, Evgeny

    1987-03-01

    Our analytic Morse-potential model of chemisorption based on bond-order conservation [Surface Sci. 150 (1985) L115; 163 (1985) L730] has been extended to calculate the heat of chemisorption QAZ of molecules AZ coordinated parallel to a metal surface, where A and Z may be either the same or different atoms or atomic groups ("quasiatoms"). Examples include O 2, CO, H 2CCH 2, HCCH, H 2CO, and (CH 3) 2CO, where comparisons with the perpendicular AZ coordinations, considered earlier, are also made. The projected qualitative trends and quantitative estimates are in agreement with (scarce) experiment. It is argued that, within the bond-order-conservation framework, the efficiency of Morse potentials to describe the energetics of various chemisorption phenomena ultimately originates from the zero-energy gap between the occupied and vacant parts of the metal band.

  12. Molecular codes for neuronal individuality and cell assembly in the brain

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    Takeshi eYagi

    2012-04-01

    Full Text Available The brain contains an enormous, but finite, number of neurons. The ability of this limited number of neurons to produce nearly limitless neural information over a lifetime is typically explained by combinatorial explosion; that is, by the exponential amplification of each neuron’s contribution through its incorporation into cell assemblies and neural networks. In development, each neuron expresses diverse cellular recognition molecules that permit the formation of the appropriate neural cell assemblies to elicit various brain functions. The mechanism for generating neuronal assemblies and networks must involve molecular codes that give neurons individuality and allow them to recognize one another and join appropriate networks. The extensive molecular diversity of cell-surface proteins on neurons is likely to contribute to their individual identities. The cadherin-related neuronal receptors and clustered protocadherins (CNR/Pcdh is a large subfamily within the diverse cadherin superfamily. The CNR/Pcdh genes are encoded in tandem by three gene clusters, and are present in all known vertebrate genomes. The set of CNR/Pcdh genes is expressed in a random and combinatorial manner in each neuron. In addition, cis-tetramers composed of heteromultimeric CNR/Pcdh isoforms represent selective binding units for cell-cell interactions. Here I present the mathematical probabilities for neuronal individuality based on the random and combinatorial expression of CNR/Pcdh isoforms and their formation of cis-tetramers in each neuron. Notably, CNR/Pcdh gene products are known to play crucial roles in correct axonal projections, synaptic formation, and neuronal survival. Their molecular and biological features suggest that the diverse CNR/Pcdh molecules provide the molecular code by which neuronal individuality and cell assembly permit the combinatorial explosion of networks that supports enormous processing capability and plasticity of the brain.

  13. Molecular diversity in Coffea canephora germplasm conserved and cultivated in Brazil

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    Flávio de França Souza

    2013-12-01

    Full Text Available This work aimed to characterize accessions that represent the C. canephora germplasm conserved and cultivated in Brazil. A total of 130 accessions from germplasm banks of IAC (São Paulo, UFV (Minas Gerais and also collected in plantations of the State of Espírito Santo and Rondônia were evaluated with a set of 20 new microsatellite primers. Multivariate methods were used to estimate the relationship among the accessions. High level of polymorphism and two major diversity clusters were identified. First cluster was composed by the accessions conserved in the IAC and UFV collections and the second was formed by accessions collected in areas under cultivation. Accessions from Espírito Santo and Rondônia were clear separated, composing two subclusters. Despite the great polymorphism found in Brazilian plantations, the diversity may be increased, because a new threshold in the genetic gains is expected on breeding programs with the intensification of the use of conserved germplasm.

  14. Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia.

    Science.gov (United States)

    Imai, Kenji; Kotani, Tomomi; Tsuda, Hiroyuki; Mano, Yukio; Nakano, Tomoko; Ushida, Takafumi; Li, Hua; Miki, Rika; Sumigama, Seiji; Iwase, Akira; Hirakawa, Akihiro; Ohno, Kinji; Toyokuni, Shinya; Takeuchi, Hideyuki; Mizuno, Tetsuya; Suzumura, Akio; Kikkawa, Fumitaka

    2016-02-01

    Exposure to inflammation in utero is related to perinatal brain injury, which is itself associated with high rates of long-term morbidity and mortality in children. Novel therapeutic interventions during the perinatal period are required to prevent inflammation, but its pathogenesis is incompletely understood. Activated microglia are known to play a central role in brain injury by producing a variety of pro-inflammatory cytokines and releasing oxidative products. The study is aimed to investigate the preventative potential of molecular hydrogen (H2), which is an antioxidant and anti-inflammatory agent without mutagenicity. Pregnant ICR mice were injected with lipopolysaccharide (LPS) intraperitoneally on embryonic day 17 to create a model of perinatal brain injury caused by prenatal inflammation. In this model, the effect of maternal administration of hydrogen water (HW) on pups was also evaluated. The levels of pro-inflammatory cytokines, oxidative damage and activation of microglia were determined in the fetal brains. H2 reduced the LPS-induced expression of pro-inflammatory cytokines, oxidative damage and microglial activation in the fetal brains. Next, we investigated how H2 contributes to neuroprotection, focusing on microglia, using primary cultured microglia and neurons. H2 prevented LPS- or cytokine-induced generation of reactive oxidative species by microglia and reduced LPS-induced microglial neurotoxicity. Finally, we identified several molecules influenced by H2, involved in the process of activating microglia. These results suggested that H2 holds promise for the prevention of inflammation related to perinatal brain injury. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Molecular characterization and temporal expression profiling of presenilins in the developing porcine brain

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    Fredholm Merete

    2007-09-01

    Full Text Available Abstract Background The transmembrane presenilin (PSEN proteins, PSEN1 and PSEN2, have been proposed to be the catalytic components of the γ-secretase protein complex, which is an intramembranous multimeric protease involved in development, cell regulatory processes, and neurodegeneration in Alzheimer's disease. Here we describe the sequencing, chromosomal mapping, and polymorphism analysis of PSEN1 and PSEN2 in the domestic pig (Sus scrofa domesticus. Results The porcine presenilin proteins showed a high degree of homology over their entire sequences to the PSENs from mouse, bovine, and human. PSEN1 and PSEN2 transcription was examined during prenatal development of the brain stem, hippocampus, cortex, basal ganglia, and cerebellum at embryonic days 60, 80, 100, and 114, which revealed distinct temporal- and tissue-specific expression profiles. Furthermore, immunohistochemical analysis of PSEN1 and PSEN2 showed similar localization of the proteins predominantly in neuronal cells in all examined brain areas. Conclusion The data provide evidence for structural and functional conservation of PSENs in mammalian lineages, and may suggest that the high sequence similarity and colocalization of PSEN1 and PSEN2 in brain tissue reflect a certain degree of functional redundancy. The data show that pigs may provide a new animal model for detailed analysis of the developmental functions of the PSENs.

  16. Nitration of TRPM2 as a Molecular Switch Induces Autophagy During Brain Pericyte Injury.

    Science.gov (United States)

    Jiang, Quan; Gao, Yinping; Wang, Chengkun; Tao, Rongrong; Wu, Yan; Zhan, Kaiyu; Liao, Meihua; Lu, Nannan; Lu, Yingmei; Wilcox, Christopher S; Luo, Jianhong; Jiang, Lin-Hua; Yang, Wei; Han, Feng

    2017-04-18

    Dysfunction of neurovascular pericytes underlies breakdown of the blood-brain barrier, but the molecular mechanisms are largely unknown. In this study, we evaluated the role of the transient receptor potential melastatin-related 2 (TRPM2) channel and autophagy during brain pericyte injury both in vitro and in vivo. A rapid induction in autophagy in human brain vascular pericytes, in the zinc oxide nanoparticles (ZnO-NP)-induced cell stress model, was paralleled with an increase in the expression of the TRPM2-S truncated isoform, which was abolished by treatment with a nitric oxide synthase inhibitor and a peroxynitrite scavenger. Furthermore, Y1485 in the C-terminus of the TRPM2 protein was identified as the tyrosine nitration substrate by mass spectrometry. Overexpression of the Y1485S TRPM2 mutant reduced LC3-II accumulation and pericyte injury induced by ZnO-NP. Consistently, LC3-II accumulation was reduced and pericytes were better preserved in intact brain microvessels of the TRPM2 knockout mice after ZnO-NP-induced vascular injury. Innovation and Conclusions: Our present study has revealed a novel mechanism of autophagy disturbance secondary to nitrosative stress-induced tyrosine nitration of TRPM2 during pericyte injury. Antioxid. Redox Signal. 00, 000-000.

  17. Oxidative Stress in Ischemic Brain Damage: Mechanisms of Cell Death and Potential Molecular Targets for Neuroprotection

    Science.gov (United States)

    Chen, Hai; Yoshioka, Hideyuki; Kim, Gab Seok; Jung, Joo Eun; Okami, Nobuya; Sakata, Hiroyuki; Maier, Carolina M.; Narasimhan, Purnima; Goeders, Christina E.

    2011-01-01

    Abstract Significant amounts of oxygen free radicals (oxidants) are generated during cerebral ischemia/reperfusion, and oxidative stress plays an important role in brain damage after stroke. In addition to oxidizing macromolecules, leading to cell injury, oxidants are also involved in cell death/survival signal pathways and cause mitochondrial dysfunction. Experimental data from laboratory animals that either overexpress (transgenic) or are deficient in (knock-out) antioxidant proteins, mainly superoxide dismutase, have provided strong evidence of the role of oxidative stress in ischemic brain damage. In addition to mitochondria, recent reports demonstrate that NADPH oxidase (NOX), an important pro-oxidant enzyme, is also involved in the generation of oxidants in the brain after stroke. Inhibition of NOX is neuroprotective against cerebral ischemia. We propose that superoxide dismutase and NOX activity in the brain is a major determinant for ischemic damage/repair and that these major anti- and pro-oxidant enzymes are potential endogenous molecular targets for stroke therapy. Antioxid. Redox Signal. 14, 1505–1517. PMID:20812869

  18. Redox proteomics and the dynamic molecular landscape of the aging brain.

    Science.gov (United States)

    Perluigi, Marzia; Swomley, Aaron M; Butterfield, D Allan

    2014-01-01

    It is well established that the risk to develop neurodegenerative disorders increases with chronological aging. Accumulating studies contributed to characterize the age-dependent changes either at gene and protein expression level which, taken together, show that aging of the human brain results from the combination of the normal decline of multiple biological functions with environmental factors that contribute to defining disease risk of late-life brain disorders. Finding the "way out" of the labyrinth of such complex molecular interactions may help to fill the gap between "normal" brain aging and development of age-dependent diseases. To this purpose, proteomics studies are a powerful tool to better understand where to set the boundary line of healthy aging and age-related disease by analyzing the variation of protein expression levels and the major post translational modifications that determine "protein" physio/pathological fate. Increasing attention has been focused on oxidative modifications due to the crucial role of oxidative stress in aging, in addition to the fact that this type of modification is irreversible and may alter protein function. Redox proteomics studies contributed to decipher the complexity of brain aging by identifying the proteins that were increasingly oxidized and eventually dysfunctional as a function of age. The purpose of this review is to summarize the most important findings obtained by applying proteomics approaches to murine models of aging with also a brief overview of some human studies, in particular those related to dementia.

  19. Effect of growth hormone and melatonin on the brain: from molecular mechanisms to structural changes.

    Science.gov (United States)

    Kireev, Roman A; Cuesta, Sara; Vara, Elena; Tresguerres, Jesus A F

    2011-10-01

    Aging of the brain causes important reductions in quality of life and has wide socio-economic consequences. An increase in oxidative stress, and the associated inflammation and apoptosis, could be responsible for the pathogenesis of aging associated brain lesions. Melatonin has neuroprotective effects, by limiting the negative effects of oxygen and nitrogen free radicals. Growth hormone (GH) might exert additional neuro-protective and or neurogenic effects on the brain. The molecular mechanisms of the protective effects of GH and melatonin on the aging brain have been investigated in young and old Wistar rats. A reduction in the total number of neurons in the hilus of the dentate gyrus was evident at 24 months of age and was associated with a significant increase in inflammation markers as well as in pro-apoptotic parameters, confirming the role of apoptosis in its reduction. Melatonin treatment was able to enhance neurogenesis in old rats without modification of the total number of neurons, whereas GH treatment increased the total number of neurons without enhancing neurogenesis. Both GH and melatonin were able to reduce inflammation and apoptosis in the hippocampus. In conclusion, neuroprotective effects demonstrated by GH and melatonin in the hippocampus were exerted by decreasing inflammation and apoptosis.

  20. The Importance of Brain Banks for Molecular Neuropathological Research: The New South Wales Tissue Resource Centre Experience

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    Antony Harding

    2009-01-01

    Full Text Available New developments in molecular neuropathology have evoked increased demands for postmortem human brain tissue. The New South Wales Tissue Resource Centre (TRC at The University of Sydney has grown from a small tissue collection into one of the leading international brain banking facilities, which operates with best practice and quality control protocols. The focus of this tissue collection is on schizophrenia and allied disorders, alcohol use disorders and controls. This review highlights changes in TRC operational procedures dictated by modern neuroscience, and provides examples of applications of modern molecular techniques to study the neuropathogenesis of many different brain disorders.

  1. Combined Proteomic-Molecular Epidemiology Approach to Identify Precision Targets in Brain Cancer.

    Science.gov (United States)

    Mostovenko, Ekaterina; Liu, Yanhong; Amirian, E Susan; Tsavachidis, Spiridon; Armstrong, Georgina N; Bondy, Melissa L; Nilsson, Carol L

    2017-07-11

    Primary brain tumors are predominantly malignant gliomas. Grade IV astrocytomas (glioblastomas, GBM) are among the most deadly of all tumors; most patients will succumb to their disease within 2 years of diagnosis despite standard of care. The grim outlook for brain tumor patients indicates that novel precision therapeutic targets must be identified. Our hypothesis is that the cancer proteomes of glioma tumors may contain protein variants that are linked to the aggressive pathology of the disease. To this end, we devised a novel workflow that combined variant proteomics with molecular epidemiological mining of public cancer data sets to identify 10 previously unrecognized variants linked to the risk of death in low grade glioma or GBM. We hypothesize that a subset of the protein variants may be successfully developed in the future as novel targets for malignant gliomas.

  2. Molecular Mechanisms of Allosteric Inhibition of Brain Glycogen Phosphorylase by Neurotoxic Dithiocarbamate Chemicals.

    Science.gov (United States)

    Mathieu, Cécile; Bui, Linh-Chi; Petit, Emile; Haddad, Iman; Agbulut, Onnik; Vinh, Joelle; Dupret, Jean-Marie; Rodrigues-Lima, Fernando

    2017-02-03

    Dithiocarbamates (DTCs) are important industrial chemicals used extensively as pesticides and in a variety of therapeutic applications. However, they have also been associated with neurotoxic effects and in particular with the development of Parkinson-like neuropathy. Although different pathways and enzymes (such as ubiquitin ligases or the proteasome) have been identified as potential targets of DTCs in the brain, the molecular mechanisms underlying their neurotoxicity remain poorly understood. There is increasing evidence that alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. Interestingly, recent studies with N,N-diethyldithiocarbamate suggest that brain glycogen phosphorylase (bGP) and glycogen metabolism could be altered by DTCs. Here, we provide molecular and mechanistic evidence that bGP is a target of DTCs. To examine this system, we first tested thiram, a DTC pesticide known to display neurotoxic effects, observing that it can react rapidly with bGP and readily inhibits its glycogenolytic activity (kinact = 1.4 × 10(5) m(-1) s(-1)). Using cysteine chemical labeling, mass spectrometry, and site-directed mutagenesis approaches, we show that thiram (and certain of its metabolites) alters the activity of bGP through the formation of an intramolecular disulfide bond (Cys(318)-Cys(326)), known to act as a redox switch that precludes the allosteric activation of bGP by AMP. Given the key role of glycogen metabolism in brain functions and neurodegeneration, impairment of the glycogenolytic activity of bGP by DTCs such as thiram may be a new mechanism by which certain DTCs exert their neurotoxic effects.

  3. Molecular mechanisms of increased cerebral vulnerability after repeated mild blast-induced traumatic brain injury

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    Alaa Kamnaksh

    2014-06-01

    Full Text Available The consequences of a mild traumatic brain injury can be especially severe if it is repeated within the period of increased cerebral vulnerability (ICV that follows the initial insult. To better understand the molecular mechanisms that contribute to ICV, we exposed rats to different levels of mild blast overpressure (5 exposures; total pressure range: 15.54–19.41 psi or 107.14–133.83 kPa at a rate of 1 per 30 min, monitored select physiological parameters, and assessed behavior. Two days post-injury or sham, we determined changes in protein biomarkers related to various pathologies in behaviorally relevant brain regions and in plasma. We found that oxygen saturation and heart rate were transiently depressed following mild blast exposure and that injured rats exhibited significantly increased anxiety- and depression-related behaviors. Proteomic analyses of the selected brain regions showed evidence of substantial oxidative stress and vascular changes, altered cell adhesion, and inflammation predominantly in the prefrontal cortex. Importantly, these pathological changes as well as indications of neuronal and glial cell loss/damage were also detected in the plasma of injured rats. Our findings illustrate some of the complex molecular changes that contribute to the period of ICV in repeated mild blast-induced traumatic brain injury. Further studies are needed to determine the functional and temporal relationship between the various pathomechanisms. The validation of these and other markers can help to diagnose individuals with ICV using a minimally invasive procedure and to develop evidence-based treatments for chronic neuropsychiatric conditions.

  4. Molecular genetic analysis of the yellow-breasted capuchin monkey: recommendations for ex situ conservation.

    Science.gov (United States)

    Oliveira, C G; Gaiotto, F A; Costa, M A; Martinez, R A

    2011-01-01

    The yellow-breasted capuchin monkey, Cebus xanthosternos, is one of the most endangered species of the Brazilian Atlantic Forest. In situ conservation for this species is problematic due to habitat destruction; therefore, captive conservation has been considered as an alternative strategy. A Studbook for C. xanthosternos has been kept for more than 20 years; however, no genetic data has been collected. Our aim was to provide a preliminary assessment of the genetic variability of C. xanthosternos in captivity in Brazil and compare it with data from the wild. Microsatellite and mtDNA sequencing were carried out in 40 samples from five Brazilian institutions registered in the international Studbook and compared with 8 samples collected in a wild population from REBIO-Una/BA. DNA for analysis was extracted from hair, feces and blood. Our results showed that two of the five captive groups assessed had a genetic variability comparable to wild animals. However, the other three groups apparently require urgent management to improve its genetic variability. Considering that inbreeding effects are more pronounced in captivity due to lack of gene flow, our data indicate a need to increase population size by introducing newly rescued individuals into these captive groups. Our results are the first attempt to provide genetic information for captive C. xanthosternos in Brazil.

  5. Molecular regionalization in the compact brain of the meiofaunal annelid Dinophilus gyrociliatus (Dinophilidae)

    DEFF Research Database (Denmark)

    Kerbl, Alexandra; Martín-Durán, José M.; Worsaae, Katrine;

    2016-01-01

    -developing annelids are important to attain a general picture of the evolutionary events underlying the vast diversity of annelid neuroanatomy. RESULTS: We have analyzed the expression domains of 11 evolutionarily conserved genes involved in brain and anterior neural patterning in adult females of the direct...

  6. Molecular mechanisms underlying the regulation of brain-derived neurotrophic factor (BDNF) translation in dendrites

    OpenAIRE

    Pinheiro, Vera Lúcia Margarido

    2010-01-01

    Dissertação de mestrado em Biologia Celular e Molecular apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra A especificidade espacial e temporal subjacente à diversidade de processos de plasticidade sináptica que ocorrem no sistema nervoso central está profundamente relacionada com a disponibilidade da proteína brain-derived neurotrophic factor (BDNF) em domínios sub-celulares distintos, especialmente na área pós-sinápti...

  7. Molecular mechanisms underlying the regulation of brain-derived neurotrophic factor (BDNF) translation in dendrites

    OpenAIRE

    Pinheiro, Vera Lúcia Margarido

    2010-01-01

    Dissertação de mestrado em Biologia Celular e Molecular apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra A especificidade espacial e temporal subjacente à diversidade de processos de plasticidade sináptica que ocorrem no sistema nervoso central está profundamente relacionada com a disponibilidade da proteína brain-derived neurotrophic factor (BDNF) em domínios sub-celulares distintos, especialmente na área pós-sinápti...

  8. Conservation of nucleotide sequences for molecular diagnosis of Middle East respiratory syndrome coronavirus, 2015.

    Science.gov (United States)

    Furuse, Yuki; Okamoto, Michiko; Oshitani, Hitoshi

    2015-11-01

    Infection due to the Middle East respiratory syndrome coronavirus (MERS-CoV) is widespread. The present study was performed to assess the protocols used for the molecular diagnosis of MERS-CoV by analyzing the nucleotide sequences of viruses detected between 2012 and 2015, including sequences from the large outbreak in eastern Asia in 2015. Although the diagnostic protocols were established only 2 years ago, mismatches between the sequences of primers/probes and viruses were found for several of the assays. Such mismatches could lead to a lower sensitivity of the assay, thereby leading to false-negative diagnosis. A slight modification in the primer design is suggested. Protocols for the molecular diagnosis of viral infections should be reviewed regularly after they are established, particularly for viruses that pose a great threat to public health such as MERS-CoV.

  9. Conservation of nucleotide sequences for molecular diagnosis of Middle East respiratory syndrome coronavirus, 2015

    Directory of Open Access Journals (Sweden)

    Yuki Furuse

    2015-11-01

    Full Text Available Infection due to the Middle East respiratory syndrome coronavirus (MERS-CoV is widespread. The present study was performed to assess the protocols used for the molecular diagnosis of MERS-CoV by analyzing the nucleotide sequences of viruses detected between 2012 and 2015, including sequences from the large outbreak in eastern Asia in 2015. Although the diagnostic protocols were established only 2 years ago, mismatches between the sequences of primers/probes and viruses were found for several of the assays. Such mismatches could lead to a lower sensitivity of the assay, thereby leading to false-negative diagnosis. A slight modification in the primer design is suggested. Protocols for the molecular diagnosis of viral infections should be reviewed regularly after they are established, particularly for viruses that pose a great threat to public health such as MERS-CoV.

  10. Some fundamental problems for an energy conserving adaptive resolution molecular dynamics scheme

    OpenAIRE

    Site, L. Delle

    2007-01-01

    Adaptive resolution molecular dynamics (MD) schemes allow for changing the number of degrees of freedom on the fly and preserve the free exchange of particles between regions of different resolution. There are two main alternatives on how to design the algorithm to switch resolution using auxiliary ''switching'' functions; force based and potential energy based approach. In this work we show that, in the framework of classical MD, the latter presents fundamental conceptual problems which make...

  11. Protocols for In Vitro Propagation, Conservation, Synthetic Seed Production, Microrhizome Production, and Molecular Profiling in Turmeric (Curcuma longa L.).

    Science.gov (United States)

    Nirmal Babu, K; Divakaran, Minoo; Pillai, Geetha S; Sumathi, V; Praveen, K; Raj, Rahul P; Akshita, H J; Ravindran, P N; Peter, K V

    2016-01-01

    Turmeric is a rhizomatous herbaceous perennial but cultivated as annual, belonging to the family Zingiberaceae. It is a native of India and South East Asia. The tuberous rhizomes or underground stems of turmeric are used from antiquity as condiments, a dye and as an aromatic stimulant in several medicines. Turmeric is an important crop in India and it is used as a spice, food preservative, coloring agent, cosmetic as well as for its medicinal properties. Propagation is done vegetatively with rhizome bits as seed materials. It is plagued by rhizome rot diseases most of which are mainly spread through infected seed rhizomes. Micropropagation will help in production of disease-free seed. Sexual reproduction is rare in turmeric, making recombinant breeding very difficult. In vitro technology can thus become the preferred choice and it can be utilized for multiplication, conservation of genetic resources, generating variability, gene transfer, molecular tagging, and their utility in crop improvement.

  12. Molecular studies of Callithrix pygmaea (Primates, Platyrrhini based on transferrin intronic and ND1 regions: implications for taxonomy and conservation

    Directory of Open Access Journals (Sweden)

    Tagliaro Claudia Helena

    2000-01-01

    Full Text Available Traditional classifications of Platyrrhini monkeys, based mainly on morphological features, are being contested by recent molecular data. The subfamily Callitrichinae (Platyrrhini, Primates consists of a diverse group of species, many of them considered endangered. Our analysis of two DNA regions, a mtDNA gene (ND1 and a nuclear gene (intronic regions of the transferrin gene, suggests that Callithrix pygmaea may have sufficient variability to justify the existence of subspecies or even separate species. Phylogenetic dendrograms based on the ND1 region show that this species is more closely related to Amazonian than to Atlantic forest marmosets. These results reopen the discussion about diversity and conservation programs based exclusively on traditional classifications.

  13. Discrete molecular states in the brain accompany changing responses to a vocal signal

    Science.gov (United States)

    Dong, Shu; Replogle, Kirstin L.; Hasadsri, Linda; Imai, Brian S.; Yau, Peter M.; Rodriguez-Zas, Sandra; Southey, Bruce R.; Sweedler, Jonathan V.; Clayton, David F.

    2009-01-01

    New experiences can trigger changes in gene expression in the brain. To understand this phenomenon better, we studied zebra finches hearing playbacks of birdsong. Earlier research had shown that initial playbacks of a novel song transiently increase the ZENK (ZIF-268, EGR1, NGFIA, KROX-24) mRNA in the auditory forebrain, but the response selectively habituates after repetition of the stimulus. Here, using DNA microarray analysis, we show that novel song exposure induces rapid changes in thousands of RNAs, with even more RNAs decreasing than increasing. Habituation training leads to the emergence of a different gene expression profile a day later, accompanied by loss of essentially all of the rapid “novel” molecular responses. The novel molecular profile is characterized by increases in genes involved in transcription and RNA processing and decreases in ion channels and putative noncoding RNAs. The “habituated” profile is dominated by changes in genes for mitochondrial proteins. A parallel proteomic analysis [2-dimensional difference gel electrophoresis (2D-DIGE) and sequencing by mass spectrometry] also detected changes in mitochondrial proteins, and direct enzyme assay demonstrated changes in both complexes I and IV in the habituated state. Thus a natural experience, in this case hearing the sound of birdsong, can lead to major shifts in energetics and macromolecular metabolism in higher centers in the brain. PMID:19541599

  14. Molecular phylogeny of OVOL genes illustrates a conserved C2H2 zinc finger domain coupled by hypervariable unstructured regions.

    Directory of Open Access Journals (Sweden)

    Abhishek Kumar

    Full Text Available OVO-like proteins (OVOL are members of the zinc finger protein family and serve as transcription factors to regulate gene expression in various differentiation processes. Recent studies have shown that OVOL genes are involved in epithelial development and differentiation in a wide variety of organisms; yet there is a lack of comprehensive studies that describe OVOL proteins from an evolutionary perspective. Using comparative genomic analysis, we traced three different OVOL genes (OVOL1-3 in vertebrates. One gene, OVOL3, was duplicated during a whole-genome-duplication event in fish, but only the copy (OVOL3b was retained. From early-branching metazoa to humans, we found that a core domain, comprising a tetrad of C2H2 zinc fingers, is conserved. By domain comparison of the OVOL proteins, we found that they evolved in different metazoan lineages by attaching intrinsically-disordered (ID segments of N/C-terminal extensions of 100 to 1000 amino acids to this conserved core. These ID regions originated independently across different animal lineages giving rise to different types of OVOL genes over the course of metazoan evolution. We illustrated the molecular evolution of metazoan OVOL genes over a period of 700 million years (MY. This study both extends our current understanding of the structure/function relationship of metazoan OVOL genes, and assembles a good platform for further characterization of OVOL genes from diverged organisms.

  15. Are Pharmaceuticals with Evolutionary Conserved Molecular Drug Targets More Potent to Cause Toxic Effects in Non-Target Organisms?

    Science.gov (United States)

    Furuhagen, Sara; Fuchs, Anne; Lundström Belleza, Elin; Breitholtz, Magnus; Gorokhova, Elena

    2014-01-01

    The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due to their design towards specific drug targets, pharmaceuticals may be therapeutically active already at low environmental concentrations. Several human drug targets are evolutionary conserved in aquatic organisms, raising concerns about effects of these pharmaceuticals in non-target organisms. In this study, we hypothesized that the toxicity of a pharmaceutical towards a non-target invertebrate depends on the presence of the human drug target orthologs in this species. This was tested by assessing toxicity of pharmaceuticals with (miconazole and promethazine) and without (levonorgestrel) identified drug target orthologs in the cladoceran Daphnia magna. The toxicity was evaluated using general toxicity endpoints at individual (immobility, reproduction and development), biochemical (RNA and DNA content) and molecular (gene expression) levels. The results provide evidence for higher toxicity of miconazole and promethazine, i.e. the drugs with identified drug target orthologs. At the individual level, miconazole had the lowest effect concentrations for immobility and reproduction (0.3 and 0.022 mg L−1, respectively) followed by promethazine (1.6 and 0.18 mg L−1, respectively). At the biochemical level, individual RNA content was affected by miconazole and promethazine already at 0.0023 and 0.059 mg L−1, respectively. At the molecular level, gene expression for cuticle protein was significantly suppressed by exposure to both miconazole and promethazine; moreover, daphnids exposed to miconazole had significantly lower vitellogenin expression. Levonorgestrel did not have any effects on any endpoints in the concentrations tested. These results highlight the importance of considering drug target conservation in environmental risk assessments of pharmaceuticals. PMID:25140792

  16. Are pharmaceuticals with evolutionary conserved molecular drug targets more potent to cause toxic effects in non-target organisms?

    Directory of Open Access Journals (Sweden)

    Sara Furuhagen

    Full Text Available The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due to their design towards specific drug targets, pharmaceuticals may be therapeutically active already at low environmental concentrations. Several human drug targets are evolutionary conserved in aquatic organisms, raising concerns about effects of these pharmaceuticals in non-target organisms. In this study, we hypothesized that the toxicity of a pharmaceutical towards a non-target invertebrate depends on the presence of the human drug target orthologs in this species. This was tested by assessing toxicity of pharmaceuticals with (miconazole and promethazine and without (levonorgestrel identified drug target orthologs in the cladoceran Daphnia magna. The toxicity was evaluated using general toxicity endpoints at individual (immobility, reproduction and development, biochemical (RNA and DNA content and molecular (gene expression levels. The results provide evidence for higher toxicity of miconazole and promethazine, i.e. the drugs with identified drug target orthologs. At the individual level, miconazole had the lowest effect concentrations for immobility and reproduction (0.3 and 0.022 mg L-1, respectively followed by promethazine (1.6 and 0.18 mg L-1, respectively. At the biochemical level, individual RNA content was affected by miconazole and promethazine already at 0.0023 and 0.059 mg L-1, respectively. At the molecular level, gene expression for cuticle protein was significantly suppressed by exposure to both miconazole and promethazine; moreover, daphnids exposed to miconazole had significantly lower vitellogenin expression. Levonorgestrel did not have any effects on any endpoints in the concentrations tested. These results highlight the importance of considering drug target conservation in environmental risk assessments of pharmaceuticals.

  17. Are pharmaceuticals with evolutionary conserved molecular drug targets more potent to cause toxic effects in non-target organisms?

    Science.gov (United States)

    Furuhagen, Sara; Fuchs, Anne; Lundström Belleza, Elin; Breitholtz, Magnus; Gorokhova, Elena

    2014-01-01

    The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due to their design towards specific drug targets, pharmaceuticals may be therapeutically active already at low environmental concentrations. Several human drug targets are evolutionary conserved in aquatic organisms, raising concerns about effects of these pharmaceuticals in non-target organisms. In this study, we hypothesized that the toxicity of a pharmaceutical towards a non-target invertebrate depends on the presence of the human drug target orthologs in this species. This was tested by assessing toxicity of pharmaceuticals with (miconazole and promethazine) and without (levonorgestrel) identified drug target orthologs in the cladoceran Daphnia magna. The toxicity was evaluated using general toxicity endpoints at individual (immobility, reproduction and development), biochemical (RNA and DNA content) and molecular (gene expression) levels. The results provide evidence for higher toxicity of miconazole and promethazine, i.e. the drugs with identified drug target orthologs. At the individual level, miconazole had the lowest effect concentrations for immobility and reproduction (0.3 and 0.022 mg L-1, respectively) followed by promethazine (1.6 and 0.18 mg L-1, respectively). At the biochemical level, individual RNA content was affected by miconazole and promethazine already at 0.0023 and 0.059 mg L-1, respectively. At the molecular level, gene expression for cuticle protein was significantly suppressed by exposure to both miconazole and promethazine; moreover, daphnids exposed to miconazole had significantly lower vitellogenin expression. Levonorgestrel did not have any effects on any endpoints in the concentrations tested. These results highlight the importance of considering drug target conservation in environmental risk assessments of pharmaceuticals.

  18. Molecular phylogenetics of geographically restricted Acropora species: implications for threatened species conservation.

    Science.gov (United States)

    Richards, Z T; Miller, D J; Wallace, C C

    2013-12-01

    To better understand the underlying causes of rarity and extinction risk in Acropora (staghorn coral), we contrast the minimum divergence ages and nucleotide diversity of an array of species with different range sizes and levels of threat. Time-calibrated Bayesian analyses based upon concatenated nuclear and mitochondrial sequence data implied contemporary range size and vulnerability are linked to species age. However, contrary to previous hypotheses that suggest geographically restricted Acropora species evolved in the Plio-Pleistocene, the molecular phylogeny depicts some Indo-Australian species have greater antiquity, diverging in the Miocene. Species age is not related to range size as a simple positive linear function and interpreting the precise tempo of evolution in this genus is greatly complicated by morphological homoplasy and a sparse fossil record. Our phylogenetic reconstructions provide new examples of how morphology conceals cryptic evolutionary relationships in this keystone genus, and offers limited support for the species groupings currently used in Acropora systematics. We hypothesize that in addition to age, other mechanisms (such as a reticulate ancestry) delimit the contemporary range of some Acropora species, as evidenced by the complex patterns of allele sharing and paraphyly we uncover. Overall, both new and ancient evolutionary information may be lost if geographically restricted and threatened Acropora species are forced to extinction. In order to protect coral biodiversity and resolve the evolutionary history of staghorn coral, further analyses based on comprehensive and heterogeneous morphological and molecular data utilizing reticulate models of evolution are needed. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. A molecular marker for in situ genetic resource conservation of Capsicum annuum var. acuminatum (Solanaceae).

    Science.gov (United States)

    Kaewdoungdee, N; Tanee, T

    2013-02-28

    The Thailand cultivar pepper 'phrik man bangchang' (Capsicum annuum var. acuminatum, Solanaceae) was originally cultivated in the Bangchang Subdistrict, Amphawa District in Samut Songkhram Province. The cultivated areas are limited; we verified its distribution in Thailand for in situ 'phrik man bangchang' genetic resource conservation. Samples were collected from the original cultivation area of Bangchang Subdistrict (Or) and were randomly explored in Ratchaburi Province (RB), Khon Kaen Province (KK), and Sakon Nakhon Province (SN). A pure line from The Tropical Vegetable Research Center at Kasetsart University was used as the standard indicator. Two more Capsicum species, C. chinensis and C. frutescens, and a species from another genus in the family, Solanum melongena, were included. A dendrogram constructed from random amplified polymorphic DNA fingerprints indicated that the Or, RB, KK, and SN samples were C. annuum var. acuminatum with supportive similarity coefficients of 0.79 to 0.98. Finally, DNA barcodes, from psbA-trnH spacer region, were provided for the 3 wild species, C. annuum var. acuminatum, C. chinensis, and C. frutescens under GenBank accession Nos. JQ087869-JQ087871. The nucleotide variations between species were 0.23 to 0.26. In summary, 'phrik man bangchang' is still being planted in Bangchang Subdistrict, but only in small areas. The distribution of planting areas is expected to be throughout Thailand.

  20. Molecular dialogues between the ischemic brain and the peripheral immune system: Dualistic roles in injury and repair

    Science.gov (United States)

    An, Chengrui; Shi, Yejie; Li, Peiying; Hu, Xiaoming; Gan, Yu; Stetler, Ruth A.; Leak, Rehana K.; Gao, Yanqin; Sun, Bao-Liang; Zheng, Ping; Chen, Jun

    2014-01-01

    Immune and inflammatory responses actively modulate the pathophysiological processes of acute brain injuries such as stroke. Soon after the onset of stroke, signals such as brain-derived antigens, danger-associated molecular patterns (DAMPs), cytokines, and chemokines are released from the injured brain into the systemic circulation. The injured brain also communicates with peripheral organs through the parasympathetic and sympathetic branches of the autonomic nervous system. Many of these diverse signals not only activate resident immune cells in the brain, but also trigger robust immune responses in the periphery. Peripheral immune cells then migrate toward the site of injury and release additional cytokines, chemokines, and other molecules, causing further disruptive or protective effects in the ischemic brain. Bidirectional communication between the injured brain and the peripheral immune system is now known to regulate the progression of stroke pathology as well as tissue repair. In the end, this exquisitely coordinated crosstalk helps determine the fate of animals after stroke. This article reviews the literature on ischemic brain-derived signals through which peripheral immune responses are triggered, and the potential impact of these peripheral responses on brain injury and repair. Pharmacological strategies and cell-based therapies that target the dialogue between the brain and peripheral immune system show promise as potential novel treatments for stroke. PMID:24374228

  1. Method for Systematic Assessment of Chemical Changes in Molecular Scaffolds with Conserved Topology and Application to the Analysis of Scaffold-Activity Relationships.

    Science.gov (United States)

    Hu, Ye; Zhang, Bijun; Bajorath, Jürgen

    2015-08-01

    Sets of scaffolds with conserved molecular topology are abundant among drugs and bioactive compounds. Core structure topology is one of the determinants of biological activity. Heteroatom replacements and/or bond order variation render topologically equivalent scaffolds chemically distinct and also contribute to differences in the biological activity of compounds containing these scaffolds. Relationships between core structure topology, chemical modifications, and observed activity profiles are difficult to analyze. A computational method is introduced to consistently assess chemical transformations that distinguish scaffolds with conserved topology. The methodology is applied to quantify chemical differences in conserved topological environments and systematically relate chemical changes in topologically equivalent scaffolds to associated activity profiles.

  2. Targeted Polymeric Nanoparticles for Brain Delivery of High Molecular Weight Molecules in Lysosomal Storage Disorders.

    Directory of Open Access Journals (Sweden)

    Marika Salvalaio

    Full Text Available Lysosomal Storage Disorders (LSDs are a group of metabolic syndromes, each one due to the deficit of one lysosomal enzyme. Many LSDs affect most of the organ systems and overall about 75% of the patients present neurological impairment. Enzyme Replacement Therapy, although determining some systemic clinical improvements, is ineffective on the CNS disease, due to enzymes' inability to cross the blood-brain barrier (BBB. With the aim to deliver the therapeutic enzymes across the BBB, we here assayed biodegradable and biocompatible PLGA-nanoparticles (NPs in two murine models for LSDs, Mucopolysaccharidosis type I and II (MPS I and MPS II. PLGA-NPs were modified with a 7-aminoacid glycopeptide (g7, yet demonstrated to be able to deliver low molecular weight (MW molecules across the BBB in rodents. We specifically investigated, for the first time, the g7-NPs ability to transfer a model drug (FITC-albumin with a high MW, comparable to the enzymes to be delivered for LSDs brain therapy. In vivo experiments, conducted on wild-type mice and knockout mouse models for MPS I and II, also included a whole series of control injections to obtain a broad preliminary view of the procedure efficiency. Results clearly showed efficient BBB crossing of albumin in all injected mice, underlying the ability of NPs to deliver high MW molecules to the brain. These results encourage successful experiments with enzyme-loaded g7-NPs to deliver sufficient amounts of the drug to the brain district on LSDs, where exerting a corrective effect on the pathological phenotype.

  3. Apert and Crouzon syndromes-Cognitive development, brain abnormalities, and molecular aspects.

    Science.gov (United States)

    Fernandes, Marilyse B L; Maximino, Luciana P; Perosa, Gimol B; Abramides, Dagma V M; Passos-Bueno, Maria Rita; Yacubian-Fernandes, Adriano

    2016-06-01

    Apert and Crouzon are the most common craniosynostosis syndromes associated with mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. We conducted a study to examine the molecular biology, brain abnormalities, and cognitive development of individuals with these syndromes. A retrospective longitudinal review of 14 patients with Apert and Crouzon syndromes seen at the outpatient Craniofacial Surgery Hospital for Rehabilitation of Craniofacial Anomalies in Brazil from January 1999 through August 2010 was performed. Patients between 11 and 36 years of age (mean 18.29 ± 5.80), received cognitive evaluations, cerebral magnetic resonance imaging, and molecular DNA analyses. Eight patients with Apert syndrome (AS) had full scale intelligence quotients (FSIQs) that ranged from 47 to 108 (mean 76.9 ± 20.2), and structural brain abnormalities were identified in five of eight patients. Six patients presented with a gain-of-function mutation (p.Ser252Trp) in FGFR2 and FSIQs in those patients ranged from 47 to78 (mean 67.2 ± 10.7). One patient with a gain-of-function mutation (p.Pro253Arg) had a FSIQ of 108 and another patient with an atypical splice mutation (940-2A →G) had a FSIQ of 104. Six patients with Crouzon syndrome had with mutations in exons IIIa and IIIc of FGFR2 and their FSIQs ranged from 82 to 102 (mean 93.5 ± 6.7). These reveal that molecular aspects are another factor that can be considered in studies of global and cognitive development of patients with Apert and Crouzon syndrome (CS). © 2016 Wiley Periodicals, Inc.

  4. Molecular size of benzodiazepine receptor in rat brain in situ: evidence for a functional dimer?

    Science.gov (United States)

    Doble, A.; Iversen, L. L.

    1982-02-01

    Benzodiazepine tranquillizers such as diazepam and chlordiazepoxide interact with high-affinity binding sites in nervous tissue1,2. The correlation between the affinities of various benzodiazepines for these sites with their clinical potencies and activity in behavioural and electrophysiological tests in animals suggests that the sites represent the functional `receptor' whereby benzodiazepines exert their effects3. The intimate involvement of benzodiazepines with γ-aminobutyric acid (GABA) and chloride channels raised the possibility that the benzodiazepine binding site (BDZ-R) may be a protein in the GABA receptor-effector complex4,5. GABA agonists enhance the affinity of BDZ-R for benzodiazepines6, although BDZ-R is distinct from the GABA receptor itself3. However, electrophysiological evidence suggests that the action of benzodiazepines is chloride channel, rather than receptor, directed7-10. Several attempts have been made to measure the molecular weight (Mr) of BDZ-R after solubilization from brain membranes: treatment with 1% Triton X-100 followed by assay of binding activity in solute fractions separated according to molecular weight suggested11 a value of ~200,000, photoaffinity labelling of BDZ-R with 3H-flunitrazepam (3H-FNZ) followed by more rigorous solubilization and gel chromatography indicated12,13 an apparent Mr of ~55,000 and a third approach14 a value of ~100,000. The measured molecular weight seems to depend critically on the solubilization procedure used. Chang et al.15 recently described the use of radiation inactivation to determine the size of BDZ-R in situ in calf brain membranes, and estimated a Mr, of 216,000. We have also used this approach; the results reported here indicate a Mr of between 90,000 and 100,000, but this is reduced to 60,000-63,000 in membranes pretreated with GABA, suggesting the disaggregation of a normally dimeric form.

  5. Endogenous recovery after brain damage: molecular mechanisms that balance neuronal life/death fate.

    Science.gov (United States)

    Tovar-y-Romo, Luis B; Penagos-Puig, Andrés; Ramírez-Jarquín, Josué O

    2016-01-01

    Neuronal survival depends on multiple factors that comprise a well-fueled energy metabolism, trophic input, clearance of toxic substances, appropriate redox environment, integrity of blood-brain barrier, suppression of programmed cell death pathways and cell cycle arrest. Disturbances of brain homeostasis lead to acute or chronic alterations that might ultimately cause neuronal death with consequent impairment of neurological function. Although we understand most of these processes well when they occur independently from one another, we still lack a clear grasp of the concerted cellular and molecular mechanisms activated upon neuronal damage that intervene in protecting damaged neurons from death. In this review, we summarize a handful of endogenously activated mechanisms that balance molecular cues so as to determine whether neurons recover from injury or die. We center our discussion on mechanisms that have been identified to participate in stroke, although we consider different scenarios of chronic neurodegeneration as well. We discuss two central processes that are involved in endogenous repair and that, when not regulated, could lead to tissue damage, namely, trophic support and neuroinflammation. We emphasize the need to construct integrated models of neuronal degeneration and survival that, in the end, converge in neuronal fate after injury. Under neurodegenerative conditions, endogenously activated mechanisms balance out molecular cues that determine whether neurons contend toxicity or die. Many processes involved in endogenous repair may as well lead to tissue damage depending on the strength of stimuli. Signaling mediated by trophic factors and neuroinflammation are examples of these processes as they regulate different mechanisms that mediate neuronal demise including necrosis, apoptosis, necroptosis, pyroptosis and autophagy. In this review, we discuss recent findings on balanced regulation and their involvement in neuronal death.

  6. Utilization of molecular markers for the conservation of blood cockles, Anadara granosa (Arcidae).

    Science.gov (United States)

    Chee, S Y; Azizah, M N S; Devakie, M N

    2011-06-28

    We examined genetic variation in blood cockles in an effort to obtain information useful for the sustainability, management, and the stability of this species as a major commodity in the fisheries sector. Ten populations of cockles were sampled from the north to the south of the west coast of peninsular Malaysia. The cockles were collected in collaboration with the Fisheries Research Institute, Penang. The population genetic analysis of the cockles were studied via RAPD-PCR and mtDNA sequencing. Three hundred individuals were analyzed with RAPD-PCR experiments. High gene diversity over all loci was observed (Shannon index = 0.549 ± 0.056 and Nei's gene diversity = 0.4852 ± 0.0430 among 35 loci). The second method, mtDNA sequencing, was employed to complement the information obtained from RAPD-PCR. The gene selected for mtDNA sequencing was cytochrome c oxidase I (COI). One hundred and fifty individuals were sequenced, yielding a partial gene of 585 bp. Statistical analysis showed homogeneity in general but did reveal some degree of variability between the populations in Johor and the rest of the populations. The Mantel test showed a positive but nonsignificant correlation between geographic and genetic distances (r = 0.2710, P = 0.622), as in the RAPD analysis. We propose that the homogeneity between distant populations is caused by two factors: 1) the translocation of the spats; 2) larvae are carried by current movement from the north of the peninsula to the south. The different genetic composition found in Johor could be due to pollution, mutagenic substances or physical factors such as the depth of the water column. This population genetic study is the first for this species in peninsular Malaysia. The data from this study have important implications for fishery management, conservation of blood cockles and translocation policies for aquaculture and stock enhancement programs.

  7. Molecular Basis for Enzymatic Sulfite Oxidation -- HOW THREE CONSERVED ACTIVE SITE RESIDUES SHAPE ENZYME ACTIVITY

    Energy Technology Data Exchange (ETDEWEB)

    Bailey, Susan; Rapson, Trevor; Johnson-Winters, Kayunta; Astashkin, Andrei; Enemark, John; Kappler, Ulrike

    2008-11-10

    Sulfite dehydrogenases (SDHs) catalyze the oxidation and detoxification of sulfite to sulfate, a reaction critical to all forms of life. Sulfite-oxidizing enzymes contain three conserved active site amino acids (Arg-55, His-57, and Tyr-236) that are crucial for catalytic competency. Here we have studied the kinetic and structural effects of two novel and one previously reported substitution (R55M, H57A, Y236F) in these residues on SDH catalysis. Both Arg-55 and His-57 were found to have key roles in substrate binding. An R55M substitution increased Km(sulfite)(app) by 2-3 orders of magnitude, whereas His-57 was required for maintaining a high substrate affinity at low pH when the imidazole ring is fully protonated. This effect may be mediated by interactions of His-57 with Arg-55 that stabilize the position of the Arg-55 side chain or, alternatively, may reflect changes in the protonation state of sulfite. Unlike what is seen for SDHWT and SDHY236F, the catalytic turnover rates of SDHR55M and SDHH57A are relatively insensitive to pH (~;;60 and 200 s-1, respectively). On the structural level, striking kinetic effects appeared to correlate with disorder (in SDHH57A and SDHY236F) or absence of Arg-55 (SDHR55M), suggesting that Arg-55 and the hydrogen bonding interactions it engages in are crucial for substrate binding and catalysis. The structure of SDHR55M has sulfate bound at the active site, a fact that coincides with a significant increase in the inhibitory effect of sulfate in SDHR55M. Thus, Arg-55 also appears to be involved in enabling discrimination between the substrate and product in SDH.

  8. Computing the blood brain barrier (BBB) diffusion coefficient: A molecular dynamics approach

    Science.gov (United States)

    Shamloo, Amir; Pedram, Maysam Z.; Heidari, Hossein; Alasty, Aria

    2016-07-01

    Various physical and biological aspects of the Blood Brain Barrier (BBB) structure still remain unfolded. Therefore, among the several mechanisms of drug delivery, only a few have succeeded in breaching this barrier, one of which is the use of Magnetic Nanoparticles (MNPs). However, a quantitative characterization of the BBB permeability is desirable to find an optimal magnetic force-field. In the present study, a molecular model of the BBB is introduced that precisely represents the interactions between MNPs and the membranes of Endothelial Cells (ECs) that form the BBB. Steered Molecular Dynamics (SMD) simulations of the BBB crossing phenomenon have been carried out. Mathematical modeling of the BBB as an input-output system has been considered from a system dynamics modeling viewpoint, enabling us to analyze the BBB behavior based on a robust model. From this model, the force profile required to overcome the barrier has been extracted for a single NP from the SMD simulations at a range of velocities. Using this data a transfer function model has been obtained and the diffusion coefficient is evaluated. This study is a novel approach to bridge the gap between nanoscale models and microscale models of the BBB. The characteristic diffusion coefficient has the nano-scale molecular effects inherent, furthermore reducing the computational costs of a nano-scale simulation model and enabling much more complex studies to be conducted.

  9. Buffering by gene duplicates: an analysis of molecular correlates and evolutionary conservation

    Directory of Open Access Journals (Sweden)

    Vogel Christine

    2008-12-01

    Full Text Available Abstract Background One mechanism to account for robustness against gene knockouts or knockdowns is through buffering by gene duplicates, but the extent and general correlates of this process in organisms is still a matter of debate. To reveal general trends of this process, we provide a comprehensive comparison of gene essentiality, duplication and buffering by duplicates across seven bacteria (Mycoplasma genitalium, Bacillus subtilis, Helicobacter pylori, Haemophilus influenzae, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, and four eukaryotes (Saccharomyces cerevisiae (yeast, Caenorhabditis elegans (worm, Drosophila melanogaster (fly, Mus musculus (mouse. Results In nine of the eleven organisms, duplicates significantly increase chances of survival upon gene deletion (P-value ≤ 0.05, but only by up to 13%. Given that duplicates make up to 80% of eukaryotic genomes, the small contribution is surprising and points to dominant roles of other buffering processes, such as alternative metabolic pathways. The buffering capacity of duplicates appears to be independent of the degree of gene essentiality and tends to be higher for genes with high expression levels. For example, buffering capacity increases to 23% amongst highly expressed genes in E. coli. Sequence similarity and the number of duplicates per gene are weak predictors of the duplicate's buffering capacity. In a case study we show that buffering gene duplicates in yeast and worm are somewhat more similar in their functions than non-buffering duplicates and have increased transcriptional and translational activity. Conclusion In sum, the extent of gene essentiality and buffering by duplicates is not conserved across organisms and does not correlate with the organisms' apparent complexity. This heterogeneity goes beyond what would be expected from differences in experimental approaches alone. Buffering by duplicates contributes to robustness in several organisms

  10. Formation of body appendages during caudal regeneration in Platynereis dumerilii: adaptation of conserved molecular toolsets

    Directory of Open Access Journals (Sweden)

    Jan Grimmel

    2016-04-01

    Pdu-sp/btd expression is observed in Platynereis. Pdu-dpp shows an expression pattern not comparable to its expression in other taxa. Conclusions The expression patterns observed suggest conserved roles of these genes during appendage formation across different clades, but the underlying mechanisms utilizing this toolset might not be identical. Some genes show broad expression along the proximodistal axis indicating a possible role in proximodistal patterning of body appendages. Other genes exhibit expression patterns limited to specific parts and tissues of the growing parapodia, thus presumably being involved in formation of taxon-specific morphological differences.

  11. 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.

  12. Molecular phylogeny and biogeography of the weevil subfamily Platypodinae reveals evolutionarily conserved range patterns.

    Science.gov (United States)

    Jordal, Bjarte H

    2015-11-01

    Platypodinae is a peculiar weevil subfamily of species that cultivate fungi in tunnels excavated in dead wood. Their geographical distribution is generally restricted, with genera confined to a single continent or large island, which provides a useful system for biogeographical research. This study establishes the first detailed molecular phylogeny of the group, with the aim of testing hypotheses on classification, diversification, and biogeography. A phylogeny was reconstructed based on 3648 nucleotides from COI, EF-1α, CAD, ArgK, and 28S. Tree topology was well resolved and indicated a strong correlation with geography, more so than predicted by previous morphology-based classifications. Tesserocerini was paraphyletic, with Notoplatypus as the sister group to a clade consisting of three main lineages of Tesserocerini and the recently evolved Platypodini. Austroplatypus formed the sister group to all remaining Platypodini and hence confirmed its separate status from Platypus. The Indo-Australian genera of Platypodini were strikingly paraphyletic, suggesting that the taxonomy of this tribe needs careful revision. Ancestral-area reconstructions in Lagrange and S-DIVA were ambiguous for nodes roughly older than 80 Ma. More recent events were firmly assessed and involved post-Gondwanan long-distance dispersal. The Neotropics was colonized three times, all from the Afrotropical region, with the latest event less than 25 Ma that included the ancestor of all Neotropical Platypodini. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Conserved Molecular and Epigenetic Determinants of Aromatase Gene Induction by the Herbicide Atrazine in Human and Rat Cellular Models Relevant to Breast Cancer Risk

    OpenAIRE

    2011-01-01

    AbstractConserved Molecular and Epigenetic Determinants of Aromatase Gene Induction by the Herbicide Atrazine in Human and Rat Cellular Models Relevant to Breast Cancer Risk ByTheresa Ryan StueveDoctor of Philosophy in Molecular ToxicologyUniversity of California, BerkeleyProfessor Gary Firestone, Co-ChairProfessor Dale Leitman, Co-ChairFall 2011The widely-applied herbicide atrazine (ATR) is a potent endocrine disruptor that elicits anti-androgenic and estrogenic effects, often at concentrat...

  14. Computing the blood brain barrier (BBB) diffusion coefficient: A molecular dynamics approach

    Energy Technology Data Exchange (ETDEWEB)

    Shamloo, Amir, E-mail: shamloo@sharif.edu; Pedram, Maysam Z.; Heidari, Hossein; Alasty, Aria, E-mail: aalasti@sharif.edu

    2016-07-15

    Various physical and biological aspects of the Blood Brain Barrier (BBB) structure still remain unfolded. Therefore, among the several mechanisms of drug delivery, only a few have succeeded in breaching this barrier, one of which is the use of Magnetic Nanoparticles (MNPs). However, a quantitative characterization of the BBB permeability is desirable to find an optimal magnetic force-field. In the present study, a molecular model of the BBB is introduced that precisely represents the interactions between MNPs and the membranes of Endothelial Cells (ECs) that form the BBB. Steered Molecular Dynamics (SMD) simulations of the BBB crossing phenomenon have been carried out. Mathematical modeling of the BBB as an input-output system has been considered from a system dynamics modeling viewpoint, enabling us to analyze the BBB behavior based on a robust model. From this model, the force profile required to overcome the barrier has been extracted for a single NP from the SMD simulations at a range of velocities. Using this data a transfer function model has been obtained and the diffusion coefficient is evaluated. This study is a novel approach to bridge the gap between nanoscale models and microscale models of the BBB. The characteristic diffusion coefficient has the nano-scale molecular effects inherent, furthermore reducing the computational costs of a nano-scale simulation model and enabling much more complex studies to be conducted. - Highlights: • Molecular dynamics simulation of crossing nano-particles through the BBB membrane at different velocities. • Recording the position of nano-particle and the membrane-NP interaction force profile. • Identification of a frequency domain model for the membrane. • Calculating the diffusion coefficient based on MD simulation and identified model. • Obtaining a relation between continuum medium and discrete medium.

  15. Circadian oscillators in the mouse brain: molecular clock components in the neocortex and cerebellar cortex.

    Science.gov (United States)

    Rath, Martin F; Rovsing, Louise; Møller, Morten

    2014-09-01

    The circadian timekeeper of the mammalian brain resides in the suprachiasmatic nucleus of the hypothalamus (SCN), and is characterized by rhythmic expression of a set of clock genes with specific 24-h daily profiles. An increasing amount of data suggests that additional circadian oscillators residing outside the SCN have the capacity to generate peripheral circadian rhythms. We have recently shown the presence of SCN-controlled oscillators in the neocortex and cerebellum of the rat. The function of these peripheral brain clocks is unknown, and elucidating this could involve mice with conditional cell-specific clock gene deletions. This prompted us to analyze the molecular clockwork of the mouse neocortex and cerebellum in detail. Here, by use of in situ hybridization and quantitative RT-PCR, we show that clock genes are expressed in all six layers of the neocortex and the Purkinje and granular cell layers of the cerebellar cortex of the mouse brain. Among these, Per1, Per2, Cry1, Arntl, and Nr1d1 exhibit circadian rhythms suggesting that local running circadian oscillators reside within neurons of the mouse neocortex and cerebellar cortex. The temporal expression profiles of clock genes are similar in the neocortex and cerebellum, but they are delayed by 5 h as compared to the SCN, suggestively reflecting a master-slave relationship between the SCN and extra-hypothalamic oscillators. Furthermore, ARNTL protein products are detectable in neurons of the mouse neocortex and cerebellum, as revealed by immunohistochemistry. These findings give reason to further pursue the physiological significance of circadian oscillators in the mouse neocortex and cerebellum.

  16. Molecular mimicry by an F-box effector of Legionella pneumophila hijacks a conserved polyubiquitination machinery within macrophages and protozoa.

    Directory of Open Access Journals (Sweden)

    Christopher T Price

    2009-12-01

    Full Text Available The ability of Legionella pneumophila to proliferate within various protozoa in the aquatic environment and in macrophages indicates a remarkable evolution and microbial exploitation of evolutionarily conserved eukaryotic processes. Ankyrin B (AnkB of L. pneumophila is a non-canonical F-box-containing protein, and is the only known Dot/Icm-translocated effector of L. pneumophila essential for intra-vacuolar proliferation within both macrophages and protozoan hosts. We show that the F-box domain of AnkB and the (9L(10P conserved residues are essential for intracellular bacterial proliferation and for rapid acquisition of polyubiquitinated proteins by the Legionella-containing vacuole (LCV within macrophages, Dictyostelium discoideum, and Acanthamoeba. Interestingly, translocation of AnkB and recruitment of polyubiquitinated proteins in macrophages and Acanthamoeba is rapidly triggered by extracellular bacteria within 5 min of bacterial attachment. Ectopically expressed AnkB within mammalian cells is localized to the periphery of the cell where it co-localizes with host SKP1 and recruits polyubiquitinated proteins, which results in restoration of intracellular growth to the ankB mutant similar to the parental strain. While an ectopically expressed AnkB-(9L(10P/AA variant is localized to the cell periphery, it does not recruit polyubiquitinated proteins and fails to trans-rescue the ankB mutant intracellular growth defect. Direct in vivo interaction of AnkB but not the AnkB-(9L(10P/AA variant with the host SKP1 is demonstrated. Importantly, RNAi-mediated silencing of expression of SKP1 renders the cells non-permissive for intracellular proliferation of L. pneumophila. The role of AnkB in exploitation of the polyubiquitination machinery is essential for intrapulmonary bacterial proliferation in the mouse model of Legionnaires' disease. Therefore, AnkB exhibits a novel molecular and functional mimicry of eukaryotic F-box proteins that exploits

  17. Environmental effects on molecular biomarkers expression in pancreatic and brain cancer

    Science.gov (United States)

    Mensah, Lawrence; Mallidi, Srivalleesha; Massodi, Iqbal; Anbil, Sriram; Mai, Zhiming; Hasan, Tayyaba

    2013-03-01

    A complete understanding of the biological mechanisms regulating devastating disease such as cancer remains elusive. Pancreatic and brain cancers are primary among the cancer types with poor prognosis. Molecular biomarkers have emerged as group of proteins that are preferentially overexpressed in cancers and with a key role in driving disease progression and resistance to chemotherapy. The epidermal growth factor receptor (EGFR), a cell proliferative biomarker is particularly highly expressed in most cancers including brain and pancreatic cancers. The ability of EGFR to sustain prolong cell proliferation is augmented by biomarkers such as Bax, Bcl-XL and Bcl-2, proteins regulating the apoptotic process. To better understand the role and effect of the microenvironment on these biomarkers in pancreatic cancer (PaCa); we analysed two pancreatic tumor lines (AsPc-1 and MiaPaCa-2) in 2D, 3D in-vitro cultures and in orthotopic tumors at different growth stages. We also investigated in patient derived glioblastoma (GBM) tumor cultures, the ability to utilize the EGFR expression to specifically deliver photosensitizer to the cells for photodynamic therapy. Overall, our results suggest that (1) microenvironment changes affect biomarker expression; thereby it is critical to understand these effects prior to designing combination therapies and (2) EGFR expression in tumor cells indeed could serve as a reliable and a robust biomarker that could be used to design targeted and image-guided photodynamic therapy.

  18. Phylogeny and molecular signatures (conserved proteins and indels that are specific for the Bacteroidetes and Chlorobi species

    Directory of Open Access Journals (Sweden)

    Lorenzini Emily

    2007-05-01

    Full Text Available Abstract Background The Bacteroidetes and Chlorobi species constitute two main groups of the Bacteria that are closely related in phylogenetic trees. The Bacteroidetes species are widely distributed and include many important periodontal pathogens. In contrast, all Chlorobi are anoxygenic obligate photoautotrophs. Very few (or no biochemical or molecular characteristics are known that are distinctive characteristics of these bacteria, or are commonly shared by them. Results Systematic blast searches were performed on each open reading frame in the genomes of Porphyromonas gingivalis W83, Bacteroides fragilis YCH46, B. thetaiotaomicron VPI-5482, Gramella forsetii KT0803, Chlorobium luteolum (formerly Pelodictyon luteolum DSM 273 and Chlorobaculum tepidum (formerly Chlorobium tepidum TLS to search for proteins that are uniquely present in either all or certain subgroups of Bacteroidetes and Chlorobi. These studies have identified > 600 proteins for which homologues are not found in other organisms. This includes 27 and 51 proteins that are specific for most of the sequenced Bacteroidetes and Chlorobi genomes, respectively; 52 and 38 proteins that are limited to species from the Bacteroidales and Flavobacteriales orders, respectively, and 5 proteins that are common to species from these two orders; 185 proteins that are specific for the Bacteroides genus. Additionally, 6 proteins that are uniquely shared by species from the Bacteroidetes and Chlorobi phyla (one of them also present in the Fibrobacteres have also been identified. This work also describes two large conserved inserts in DNA polymerase III (DnaE and alanyl-tRNA synthetase that are distinctive characteristics of the Chlorobi species and a 3 aa deletion in ClpB chaperone that is mainly found in various Bacteroidales, Flavobacteriales and Flexebacteraceae, but generally not found in the homologs from other organisms. Phylogenetic analyses of the Bacteroidetes and Chlorobi species is also

  19. Molecular phylogeny of the genus Saguinus (Platyrrhini, Primates based on the ND1 mitochondrial gene and implications for conservation

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    Claudia Helena Tagliaro

    2005-03-01

    Full Text Available The systematics of the subfamily Callitrichinae (Platyrrhini, Primates, a group of small monkeys from South America and Panama, remains an area of considerable discussion despite many investigations, there being continuing controversy over subgeneric taxonomic classifications based on morphological characters. The purpose of our research was to help elucidate the phylogenetic relationships within the monkey genus Saguinus (Callitrichinae using a molecular approach to discover whether or not the two different sections containing hairy-faced and bare-faced species are monophyletic, whether Saguinus midas midas and Saguinus bicolor are more closely related than are S. midas midas and Saguinus midas niger, and if Saguinus fuscicollis melanoleucus and Saguinus fuscicollis weddelli really are different species. We sequenced the 957 bp ND1 mitochondrial gene of 21 Saguinus monkeys (belonging to six species and nine morphotypes and one Cebus monkey (the outgroup and constructed phylogenetic trees using maximum parsimony, neighbor joining, and maximum likelihood methods. The phylogenetic trees obtained divided the genus Saguinus into two groups, one containing the small-bodied species S. fuscicollis and the other, the large-bodied species S. mystax, S. leucopus, S. oedipus, S. midas, S. bicolor. The most derived taxa, S. midas and S. bicolor, grouped together, while S. fuscicollis melanoleucus and S. f. weddelli showed divergence values that did not support the division of these morphotypes into subspecies. On the other hand, S. midas individuals showed divergence compatible with the existence of three subspecies, two of them with the same morphotype as the subspecies S. midas niger. The results of our study suggest that there is at least one Saguinus subspecies that has not yet been described and that the conservation status of Saguinus species and subspecies should be carefully revised using modern molecular approaches.

  20. Etiologic subtypes of attention-deficit/hyperactivity disorder : Brain imaging, molecular genetic and environmental factors and the dopamine hypothesis

    NARCIS (Netherlands)

    Swanson, James M.; Kinsbourne, Marcel; Nigg, Joel; Lanphear, Bruce; Stefanatos, Gerry A.; Volkow, Nora; Taylor, Eric; Casey, B. J.; Castellanos, F. Xavier; Wadhwa, Pathik D.

    2007-01-01

    Multiple theories of Attention-Deficit/Hyperactivity Disorder (ADHD) have been proposed, but one that has stood the test of time is the dopamine deficit theory. We review the narrow literature from recent brain imaging and molecular genetic studies that has improved our understanding of the role of

  1. Molecular dynamics studies unravel role of conserved residues responsible for movement of ions into active site of DHBPS

    Science.gov (United States)

    Shinde, Ranajit Nivrutti; Karthikeyan, Subramanian; Singh, Balvinder

    2017-01-01

    3,4-dihydroxy-2-butanone-4-phosphate synthase (DHBPS) catalyzes the conversion of D-ribulose 5-phosphate (Ru5P) to L-3,4-dihydroxy-2-butanone-4-phosphate in the presence of Mg2+. Although crystal structures of DHBPS in complex with Ru5P and non-catalytic metal ions have been reported, structure with Ru5P along with Mg2+ is still elusive. Therefore, mechanistic role played by Mg2+ in the structure of DHBPS is poorly understood. In this study, molecular dynamics simulations of DHBPS-Ru5P complex along with Mg2+ have shown entry of Mg2+ from bulk solvent into active site. Presence of Mg2+ in active site has constrained conformations of Ru5P and has reduced flexibility of loop-2. Formation of hydrogen bonds among Thr-108 and residues - Gly-109, Val-110, Ser-111, and Asp-114 are found to be critical for entry of Mg2+ into active site. Subsequent in silico mutations of residues, Thr-108 and Asp-114 have substantiated the importance of these interactions. Loop-4 of one monomer is being proposed to act as a “lid” covering the active site of other monomer. Further, the conserved nature of residues taking part in the transfer of Mg2+ suggests the same mechanism being present in DHBPS of other microorganisms. Thus, this study provides insights into the functioning of DHBPS that can be used for the designing of inhibitors.

  2. The Morphological and Molecular Changes of Brain Cells Exposed to Direct Current Electric Field Stimulation

    Science.gov (United States)

    Pelletier, Simon J.; Lagacé, Marie; St-Amour, Isabelle; Arsenault, Dany; Cisbani, Giulia; Chabrat, Audrey; Fecteau, Shirley; Lévesque, Martin

    2015-01-01

    Background: The application of low-intensity direct current electric fields has been experimentally used in the clinic to treat a number of brain disorders, predominantly using transcranial direct current stimulation approaches. However, the cellular and molecular changes induced by such treatment remain largely unknown. Methods: Here, we tested various intensities of direct current electric fields (0, 25, 50, and 100V/m) in a well-controlled in vitro environment in order to investigate the responses of neurons, microglia, and astrocytes to this type of stimulation. This included morphological assessments of the cells, viability, as well as shape and fiber outgrowth relative to the orientation of the direct current electric field. We also undertook enzyme-linked immunosorbent assays and western immunoblotting to identify which molecular pathways were affected by direct current electric fields. Results: In response to direct current electric field, neurons developed an elongated cell body shape with neurite outgrowth that was associated with a significant increase in growth associated protein-43. Fetal midbrain dopaminergic explants grown in a collagen gel matrix also showed a reorientation of their neurites towards the cathode. BV2 microglial cells adopted distinct morphological changes with an increase in cyclooxygenase-2 expression, but these were dependent on whether they had already been activated with lipopolysaccharide. Finally, astrocytes displayed elongated cell bodies with cellular filopodia that were oriented perpendicularly to the direct current electric field. Conclusion: We show that cells of the central nervous system can respond to direct current electric fields both in terms of their morphological shape and molecular expression of certain proteins, and this in turn can help us to begin understand the mechanisms underlying the clinical benefits of direct current electric field. PMID:25522422

  3. The morphological and molecular changes of brain cells exposed to direct current electric field stimulation.

    Science.gov (United States)

    Pelletier, Simon J; Lagacé, Marie; St-Amour, Isabelle; Arsenault, Dany; Cisbani, Giulia; Chabrat, Audrey; Fecteau, Shirley; Lévesque, Martin; Cicchetti, Francesca

    2014-12-07

    The application of low-intensity direct current electric fields has been experimentally used in the clinic to treat a number of brain disorders, predominantly using transcranial direct current stimulation approaches. However, the cellular and molecular changes induced by such treatment remain largely unknown. Here, we tested various intensities of direct current electric fields (0, 25, 50, and 100V/m) in a well-controlled in vitro environment in order to investigate the responses of neurons, microglia, and astrocytes to this type of stimulation. This included morphological assessments of the cells, viability, as well as shape and fiber outgrowth relative to the orientation of the direct current electric field. We also undertook enzyme-linked immunosorbent assays and western immunoblotting to identify which molecular pathways were affected by direct current electric fields. In response to direct current electric field, neurons developed an elongated cell body shape with neurite outgrowth that was associated with a significant increase in growth associated protein-43. Fetal midbrain dopaminergic explants grown in a collagen gel matrix also showed a reorientation of their neurites towards the cathode. BV2 microglial cells adopted distinct morphological changes with an increase in cyclooxygenase-2 expression, but these were dependent on whether they had already been activated with lipopolysaccharide. Finally, astrocytes displayed elongated cell bodies with cellular filopodia that were oriented perpendicularly to the direct current electric field. We show that cells of the central nervous system can respond to direct current electric fields both in terms of their morphological shape and molecular expression of certain proteins, and this in turn can help us to begin understand the mechanisms underlying the clinical benefits of direct current electric field. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  4. RNA-seq of the aging brain in the short-lived fish N. furzeri - conserved pathways and novel genes associated with neurogenesis.

    Science.gov (United States)

    Baumgart, Mario; Groth, Marco; Priebe, Steffen; Savino, Aurora; Testa, Giovanna; Dix, Andreas; Ripa, Roberto; Spallotta, Francesco; Gaetano, Carlo; Ori, Michela; Terzibasi Tozzini, Eva; Guthke, Reinhard; Platzer, Matthias; Cellerino, Alessandro

    2014-12-01

    The brains of teleost fish show extensive adult neurogenesis and neuronal regeneration. The patterns of gene regulation during fish brain aging are unknown. The short-lived teleost fish Nothobranchius furzeri shows markers of brain aging including reduced learning performances, gliosis, and reduced adult neurogenesis. We used RNA-seq to quantify genome-wide transcript regulation and sampled five different time points to characterize whole-genome transcript regulation during brain aging of N. furzeri. Comparison with human datasets revealed conserved up-regulation of ribosome, lysosome, and complement activation and conserved down-regulation of synapse, mitochondrion, proteasome, and spliceosome. Down-regulated genes differ in their temporal profiles: neurogenesis and extracellular matrix genes showed rapid decay, synaptic and axonal genes a progressive decay. A substantial proportion of differentially expressed genes (~40%) showed inversion of their temporal profiles in the last time point: spliceosome and proteasome showed initial down-regulation and stress-response genes initial up-regulation. Extensive regulation was detected for chromatin remodelers of the DNMT and CBX families as well as members of the polycomb complex and was mirrored by an up-regulation of the H3K27me3 epigenetic mark. Network analysis showed extensive coregulation of cell cycle/DNA synthesis genes with the uncharacterized zinc-finger protein ZNF367 as central hub. In situ hybridization showed that ZNF367 is expressed in neuronal stem cell niches of both embryonic zebrafish and adult N. furzeri. Other genes down-regulated with age, not previously associated with adult neurogenesis and with similar patterns of expression are AGR2, DNMT3A, KRCP, MEX3A, SCML4, and CBX1. CBX7, on the other hand, was up-regulated with age.

  5. Conserved Molecular Superlattices in a Series of Homologous Synthetic Mycobacterial Cell-Wall Lipids Forming Interdigitated Bilayers.

    Science.gov (United States)

    Martin-Bertelsen, Birte; Yaghmur, Anan; Franzyk, Henrik; Justesen, Sarah; Kirkensgaard, Jacob J K; Foged, Camilla

    2016-12-06

    Synthetic analogues of the cell-wall lipid monomycoloyl glycerol (MMG) are promising as next-generation vaccine adjuvants. In the present study, the thermotropic phase behavior of an array of synthetic MMG analogues was examined by using simultaneous small- and wide-angle X-ray scattering under excess water conditions. The MMG analogues differed in the alkyl chain lengths and in the stereochemistry of the polar glycerol headgroup or of the lipid tails (native-like versus alternative compounds). All MMG analogues formed poorly hydrated lamellar phases at low temperatures and inverse hexagonal (H2) phases at higher temperatures prior to melting. MMG analogues with a native-like lipid acid configuration self-assembled into noninterdigitated bilayers whereas the analogues displaying an alternative lipid acid configuration formed interdigitated bilayers in a subgel (Lc') state. This is in contrast to previously described interdigitated phases for other lipids, which are usually in a gel (Lβ) state. All investigated MMG analogues displayed an abrupt direct temperature-induced phase transition from Lc' to H2. This transition is ultimately driven by the lipid chain melting and the accompanying change in molecular shape. No intermediate structures were found, but the entire array of MMG analogues displayed phase coexistence during the lamellar to H2 transition. The structural data also showed that the headgroups of the MMG analogues adopting the alternative lipid acid configuration were ordered and formed a two-dimensional molecular superlattice, which was conserved regardless of the lipid tail length. To our knowledge, the MMG analogues with an alternative lipid acid configuration represent the first example of a lipid system showing both interdigitation and superlattice formation, and as such could serve as an interesting model system for future studies. The MMG analogues are also relevant from a subunit vaccine perspective because they are well-tolerated and display

  6. Conserved cis-regulatory modules in promoters of genes encoding wheat high-molecular-weight glutenin subunits.

    Science.gov (United States)

    Ravel, Catherine; Fiquet, Samuel; Boudet, Julie; Dardevet, Mireille; Vincent, Jonathan; Merlino, Marielle; Michard, Robin; Martre, Pierre

    2014-01-01

    The concentration and composition of the gliadin and glutenin seed storage proteins (SSPs) in wheat flour are the most important determinants of its end-use value. In cereals, the synthesis of SSPs is predominantly regulated at the transcriptional level by a complex network involving at least five cis-elements in gene promoters. The high-molecular-weight glutenin subunits (HMW-GS) are encoded by two tightly linked genes located on the long arms of group 1 chromosomes. Here, we sequenced and annotated the HMW-GS gene promoters of 22 electrophoretic wheat alleles to identify putative cis-regulatory motifs. We focused on 24 motifs known to be involved in SSP gene regulation. Most of them were identified in at least one HMW-GS gene promoter sequence. A common regulatory framework was observed in all the HMW-GS gene promoters, as they shared conserved cis-regulatory modules (CCRMs) including all the five motifs known to regulate the transcription of SSP genes. This common regulatory framework comprises a composite box made of the GATA motifs and GCN4-like Motifs (GLMs) and was shown to be functional as the GLMs are able to bind a bZIP transcriptional factor SPA (Storage Protein Activator). In addition to this regulatory framework, each HMW-GS gene promoter had additional motifs organized differently. The promoters of most highly expressed x-type HMW-GS genes contain an additional box predicted to bind R2R3-MYB transcriptional factors. However, the differences in annotation between promoter alleles could not be related to their level of expression. In summary, we identified a common modular organization of HMW-GS gene promoters but the lack of correlation between the cis-motifs of each HMW-GS gene promoter and their level of expression suggests that other cis-elements or other mechanisms regulate HMW-GS gene expression.

  7. Insights into the molecular evolution of the PDZ/LIM family and identification of a novel conserved protein motif.

    Directory of Open Access Journals (Sweden)

    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.

  8. In vivo molecular imaging of the GABA/benzodiazepine receptor complex in the aged rat brain.

    Science.gov (United States)

    Hoekzema, Elseline; Rojas, Santiago; Herance, Raúl; Pareto, Deborah; Abad, Sergio; Jiménez, Xavier; Figueiras, Francisca P; Popota, Foteini; Ruiz, Alba; Flotats, Núria; Fernández, Francisco J; Rocha, Milagros; Rovira, Mariana; Víctor, Víctor M; Gispert, Juan D

    2012-07-01

    The GABA-ergic system, known to regulate neural tissue genesis during cortical development, has been postulated to play a role in cerebral aging processes. Using in vivo molecular imaging and voxel-wise quantification, we aimed to assess the effects of aging on the benzodiazepine (BDZ) recognition site of the GABA(A) receptor. To visualize BDZ site availability, [(11)C]-flumazenil microPET acquisitions were conducted in young and old rats. The data were analyzed and region of interest analyses were applied to validate the voxel-wise approach. We observed decreased [(11)C]-flumazenil binding in the aged rat brains in comparison with the young control group. More specifically, clusters of reduced radioligand uptake were detected in the bilateral hippocampus, cerebellum, midbrain, and bilateral frontal and parieto-occipital cortex. Our results support the pertinence of voxel-wise quantification in the analysis of microPET data. Moreover, these findings indicate that the aging process involves declines in neural BDZ recognition site availability, proposed to reflect alterations in GABA(A) receptor subunit polypeptide expression.

  9. A Silicon SPECT System for Molecular Imaging of the Mouse Brain.

    Science.gov (United States)

    Shokouhi, Sepideh; Fritz, Mark A; McDonald, Benjamin S; Durko, Heather L; Furenlid, Lars R; Wilson, Donald W; Peterson, Todd E

    2007-01-01

    We previously demonstrated the feasibility of using silicon double-sided strip detectors (DSSDs) for SPECT imaging of the activity distribution of iodine-125 using a 300-micrometer thick detector. Based on this experience, we now have developed fully customized silicon DSSDs and associated readout electronics with the intent of developing a multi-pinhole SPECT system. Each DSSD has a 60.4 mm × 60.4 mm active area and is 1 mm thick. The strip pitch is 59 micrometers, and the readout of the 1024 strips on each side gives rise to a detector with over one million pixels. Combining four high-resolution DSSDs into a SPECT system offers an unprecedented space-bandwidth product for the imaging of single-photon emitters. The system consists of two camera heads with two silicon detectors stacked one behind the other in each head. The collimator has a focused pinhole system with cylindrical-shaped pinholes that are laser-drilled in a 250 μm tungsten plate. The unique ability to collect projection data at two magnifications simultaneously allows for multiplexed data at high resolution to be combined with lower magnification data with little or no multiplexing. With the current multi-pinhole collimator design, our SPECT system will be capable of offering high spatial resolution, sensitivity and angular sampling for small field-of-view applications, such as molecular imaging of the mouse brain.

  10. Molecular mechanisms associated with ALA-PDT of brain tumor cells

    Science.gov (United States)

    Alqawi, Omar; Espiritu, Myrna; Singh, Gurmit

    2009-06-01

    Previous studies have shown that low-dose PDT using 5-aminolevulinic acid (ALA)-induced photoporphyrin IX (PpIX) can induce apoptosis in tumor cells without causing necrosis. In this study we investigated the molecular mechanisms associated with apoptosis after ALA-PDT treatment in two brain glioma cell lines: human U87, and rat CNS-1cells. We used high energy light at a short time (acute PDT) and low energy light at a long time of exposure (metronomic PDT) to treat both cell lines. The cells were treated with 0.25 mM ALA at 5 joules for energy. We found that CNS-1 cells were more resistant to ALA-PDT than U87 cells when treated by both acute and metronomic PDT. To screen possible apoptosis mechanisms associated with acute and metronomic PDT, microarray analysis of gene expression was performed on RNA from glioblastoma cells treated with either acute or metronomic ALA-PDT. Within the set of genes that were negatively or positively regulated by both treatments are tumor necrosis factor receptors. The expression of TNF receptors was investigated further by RT-PCR and western blotting. The apoptosis mechanism of the cell death occurred through different pathways including BCL-2 and TNF receptors, and in part caused by cleaving caspase 3. Interestingly, metronomic ALA-PDT inhibited the expression of LTβR and the transcription factor NFκB. This inhibition was ALA concentration dependent at low concentrations.

  11. Expression analysis of Egr-1 ortholog in metamorphic brain of honeybee (Apis mellifera L.): Possible evolutionary conservation of roles of Egr in eye development in vertebrates and insects.

    Science.gov (United States)

    Ugajin, Atsushi; Watanabe, Takayuki; Uchiyama, Hironobu; Sasaki, Tetsuhiko; Yajima, Shunsuke; Ono, Masato

    2016-09-16

    Specific genes quickly transcribed after extracellular stimuli without de novo protein synthesis are known as immediate early genes (IEGs) and are thought to contribute to learning and memory processes in the mature nervous system of vertebrates. A recent study revealed that the homolog of Early growth response protein-1 (Egr-1), which is one of the best-characterized vertebrate IEGs, shared similar properties as a neural activity-dependent gene in the adult brain of insects. With regard to the roles of vertebrate Egr-1 in neural development, the contribution to the development and growth of visual systems has been reported. However, in insects, the expression dynamics of the Egr-1 homologous gene during neural development remains poorly understood. Our expression analysis demonstrated that AmEgr, a honeybee homolog of Egr-1, was transiently upregulated in the developing brain during the early to mid pupal stages. In situ hybridization and 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry revealed that AmEgr was mainly expressed in post-mitotic cells in optic lobes, the primary visual center of the insect brain. These findings suggest the evolutionarily conserved role of Egr homologs in the development of visual systems in vertebrates and insects. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Bottom-up derivation of conservative and dissipative interactions for coarse-grained molecular liquids with the conditional reversible work method

    Energy Technology Data Exchange (ETDEWEB)

    Deichmann, Gregor; Marcon, Valentina; Vegt, Nico F. A. van der, E-mail: vandervegt@csi.tu-darmstadt.de [Center of Smart Interfaces, Technische Universität Darmstadt, Alarich-Weiss-Straße 10, 64287 Darmstadt (Germany)

    2014-12-14

    Molecular simulations of soft matter systems have been performed in recent years using a variety of systematically coarse-grained models. With these models, structural or thermodynamic properties can be quite accurately represented while the prediction of dynamic properties remains difficult, especially for multi-component systems. In this work, we use constraint molecular dynamics simulations for calculating dissipative pair forces which are used together with conditional reversible work (CRW) conservative forces in dissipative particle dynamics (DPD) simulations. The combined CRW-DPD approach aims to extend the representability of CRW models to dynamic properties and uses a bottom-up approach. Dissipative pair forces are derived from fluctuations of the direct atomistic forces between mapped groups. The conservative CRW potential is obtained from a similar series of constraint dynamics simulations and represents the reversible work performed to couple the direct atomistic interactions between the mapped atom groups. Neopentane, tetrachloromethane, cyclohexane, and n-hexane have been considered as model systems. These molecular liquids are simulated with atomistic molecular dynamics, coarse-grained molecular dynamics, and DPD. We find that the CRW-DPD models reproduce the liquid structure and diffusive dynamics of the liquid systems in reasonable agreement with the atomistic models when using single-site mapping schemes with beads containing five or six heavy atoms. For a two-site representation of n-hexane (3 carbons per bead), time scale separation can no longer be assumed and the DPD approach consequently fails to reproduce the atomistic dynamics.

  13. Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences

    Directory of Open Access Journals (Sweden)

    Redzic Zoran

    2011-01-01

    Full Text Available Abstract Efficient processing of information by the central nervous system (CNS represents an important evolutionary advantage. Thus, homeostatic mechanisms have developed that provide appropriate circumstances for neuronal signaling, including a highly controlled and stable microenvironment. To provide such a milieu for neurons, extracellular fluids of the CNS are separated from the changeable environment of blood at three major interfaces: at the brain capillaries by the blood-brain barrier (BBB, which is localized at the level of the endothelial cells and separates brain interstitial fluid (ISF from blood; at the epithelial layer of four choroid plexuses, the blood-cerebrospinal fluid (CSF barrier (BCSFB, which separates CSF from the CP ISF, and at the arachnoid barrier. The two barriers that represent the largest interface between blood and brain extracellular fluids, the BBB and the BCSFB, prevent the free paracellular diffusion of polar molecules by complex morphological features, including tight junctions (TJs that interconnect the endothelial and epithelial cells, respectively. The first part of this review focuses on the molecular biology of TJs and adherens junctions in the brain capillary endothelial cells and in the CP epithelial cells. However, normal function of the CNS depends on a constant supply of essential molecules, like glucose and amino acids from the blood, exchange of electrolytes between brain extracellular fluids and blood, as well as on efficient removal of metabolic waste products and excess neurotransmitters from the brain ISF. Therefore, a number of specific transport proteins are expressed in brain capillary endothelial cells and CP epithelial cells that provide transport of nutrients and ions into the CNS and removal of waste products and ions from the CSF. The second part of this review concentrates on the molecular biology of various solute carrier (SLC transport proteins at those two barriers and underlines

  14. Characterization of traumatic brain injury in human brains reveals distinct cellular and molecular changes in contusion and pericontusion.

    Science.gov (United States)

    Harish, Gangadharappa; Mahadevan, Anita; Pruthi, Nupur; Sreenivasamurthy, Sreelakshmi K; Puttamallesh, Vinuth N; Keshava Prasad, Thottethodi Subrahmanya; Shankar, Susarla Krishna; Srinivas Bharath, Muchukunte Mukunda

    2015-07-01

    Traumatic brain injury (TBI) contributes to fatalities and neurological disabilities worldwide. While primary injury causes immediate damage, secondary events contribute to long-term neurological defects. Contusions (Ct) are primary injuries correlated with poor clinical prognosis, and can expand leading to delayed neurological deterioration. Pericontusion (PC) (penumbra), the region surrounding Ct, can also expand with edema, increased intracranial pressure, ischemia, and poor clinical outcome. Analysis of Ct and PC can therefore assist in understanding the pathobiology of TBI and its management. This study on human TBI brains noted extensive neuronal, astroglial and inflammatory changes, alterations in mitochondrial, synaptic and oxidative markers, and associated proteomic profile, with distinct differences in Ct and PC. While Ct displayed petechial hemorrhages, thrombosis, inflammation, neuronal pyknosis, and astrogliosis, PC revealed edema, vacuolation of neuropil, axonal loss, and dystrophic changes. Proteomic analysis demonstrated altered immune response, synaptic, and mitochondrial dysfunction, among others, in Ct, while PC displayed altered regulation of neurogenesis and cytoskeletal architecture, among others. TBI brains displayed oxidative damage, glutathione depletion, mitochondrial dysfunction, and loss of synaptic proteins, with these changes being more profound in Ct. We suggest that analysis of markers specific to Ct and PC may be valuable in the evaluation of TBI pathobiology and therapeutics. We have characterized the primary injury in human traumatic brain injury (TBI). Contusions (Ct) - the injury core displayed hemorrhages, inflammation, and astrogliosis, while the surrounding pericontusion (PC) revealed edema, vacuolation, microglial activation, axonal loss, and dystrophy. Proteomic analysis demonstrated altered immune response, synaptic and mitochondrial dysfunction in Ct, and altered regulation of neurogenesis and cytoskeletal architecture in

  15. Molecular Imaging of Gene Expression and Efficacy following Adenoviral-Mediated Brain Tumor Gene Therapy

    Directory of Open Access Journals (Sweden)

    Alnawaz Rehemtulla

    2002-01-01

    Full Text Available Cancer gene therapy is an active area of research relying upon the transfer and subsequent expression of a therapeutic transgene into tumor cells in order to provide for therapeutic selectivity. Noninvasive assessment of therapeutic response and correlation of the location, magnitude, and duration of transgene expression in vivo would be particularly useful in the development of cancer gene therapy protocols by facilitating optimization of gene transfer protocols, vector development, and prodrug dosing schedules. In this study, we developed an adenoviral vector containing both the therapeutic transgene yeast cytosine deaminase (yCD along with an optical reporter gene (luciferase. Following intratumoral injection of the vector into orthotopic 9L gliomas, anatomical and diffusion-weighted MR images were obtained over time in order to provide for quantitative assessment of overall therapeutic efficacy and spatial heterogeneity of cell kill, respectively. In addition, bioluminescence images were acquired to assess the duration and magnitude of gene expression. MR images revealed significant reduction in tumor growth rates associated with yCD/5-fluorocytosine (5FC gene therapy. Significant increases in mean tumor diffusion values were also observed during treatment with 5FC. Moreover, spatial heterogeneity in tumor diffusion changes were also observed revealing that diffusion magnetic resonance imaging could detect regional therapeutic effects due to the nonuniform delivery and/or expression of the therapeutic yCD transgene within the tumor mass. In addition, in vivo bioluminescence imaging detected luciferase gene expression, which was found to decrease over time during administration of the prodrug providing a noninvasive surrogate marker for monitoring gene expression. These results demonstrate the efficacy of the yCD/5FC strategy for the treatment of brain tumors and reveal the feasibility of using multimodality molecular and functional imaging

  16. Molecular composition of staufen2-containing ribonucleoproteins in embryonic rat brain.

    Directory of Open Access Journals (Sweden)

    Marjolaine Maher-Laporte

    Full Text Available Messenger ribonucleoprotein particles (mRNPs are used to transport mRNAs along neuronal dendrites to their site of translation. Numerous mRNA-binding and regulatory proteins within mRNPs finely regulate the fate of bound-mRNAs. Their specific combination defines different types of mRNPs that in turn are related to specific synaptic functions. One of these mRNA-binding proteins, Staufen2 (Stau2, was shown to transport dendritic mRNAs along microtubules. Its knockdown expression in neurons was shown to change spine morphology and synaptic functions. To further understand the molecular mechanisms by which Stau2 modulates synaptic function in neurons, it is important to identify and characterize protein co-factors that regulate the fate of Stau2-containing mRNPs. To this end, a proteomic approach was used to identify co-immunoprecipitated proteins in Staufen2-containing mRNPs isolated from embryonic rat brains. The proteomic approach identified mRNA-binding proteins (PABPC1, hnRNP H1, YB1 and hsc70, proteins of the cytoskeleton (alpha- and beta-tubulin and RUFY3 a poorly characterized protein. While PABPC1 and YB1 associate with Stau2-containing mRNPs through RNAs, hsc70 is directly bound to Stau2 and this interaction is regulated by ATP. PABPC1 and YB1 proteins formed puncta in dendrites of embryonic rat hippocampal neurons. However, they poorly co-localized with Stau2 in the large dendritic complexes suggesting that they are rather components of Stau2-containing mRNA particles. All together, these results represent a further step in the characterization of Stau2-containing mRNPs in neurons and provide new tools to study and understand how Stau2-containing mRNPs are transported, translationally silenced during transport and/or locally expressed according to cell needs.

  17. Clinical and molecular characteristics of HNSCC patients with brain metastases: a retrospective study.

    Science.gov (United States)

    Bulut, Olcay Cem; Lindel, Katja; Hauswald, Henrik; Brandt, Regine; Klauschen, Frederick; Wolf, Janina; Wolf, Thomas; Plinkert, Peter K; Simon, Christian; Weichert, Wilko; Stenzinger, Albrecht

    2014-06-01

    Among the metastasis patterns of head and neck squamous cell carcinoma (HNSCC), intracranial spread is a rare but dreaded event. To date only very few cases have been reported and clinical and molecular data are sparse. We screened our archives for HNSCC patients from 1992 to 2005 who were diagnosed with brain metastases (BM). For retrospective analysis, all clinico-pathological data including disease-free survival (DFS), local progression-free survival (LPFS), and overall survival (OS) were compiled. Additionally, we assessed the mutational status of the TP53 gene and the prevalence of HPV serotypes by PCR and Sanger sequencing. Immunohistochemistry was applied to detect p16INK4A expression levels as surrogate marker for HPV infection. The prevalence rate of BM in our cohort comprising 193 patients with advanced HNSCC was 5.7%. Of 11 patients with BM, 3 were female and 9 were male. Seven of the primary tumors were of oropharyngeal origin (OPSCC). LPFS of the cohort was 11.8 months, DFS was 12.1 months and OS was 36.0 months. After the diagnosis of BM, survival was 10.5 months. Five tumors showed a mutation in the TP53 gene, while five of the seven OPSCC tumors had a positive HPV status displaying infection with serotype 16 in all cases. Compared with patients who harbored TP53wt/HPV-positive tumors, patients with TP53 mutations showed a poor prognosis. Compared with the whole cohort, the interval between diagnosis of the primary and the detection of BM was prolonged in the HPV-infected OPSCC subgroup (26.4 vs. 45.6 months). The prognosis of HNSCC patients with BM is poor. In our cohort, most tumors were OPSCC with the majority being HPV positive. Our study points toward a putatively unusual metastatic behavior of HPV-positive OPSCC.

  18. Molecular scaffolds underpinning macroglial polarization: an analysis of retinal Müller cells and brain astrocytes in mouse.

    Science.gov (United States)

    Enger, Rune; Gundersen, Georg Andreas; Haj-Yasein, Nadia Nabil; Eilert-Olsen, Martine; Thoren, Anna Elisabeth; Vindedal, Gry Fluge; Petersen, Pétur Henry; Skare, Øivind; Nedergaard, Maiken; Ottersen, Ole Petter; Nagelhus, Erlend A

    2012-12-01

    Key roles of macroglia are inextricably coupled to specialized membrane domains. The perivascular endfoot membrane has drawn particular attention, as this domain contains a unique complement of aquaporin-4 (AQP4) and other channel proteins that distinguishes it from perisynaptic membranes. Recent studies indicate that the polarization of macroglia is lost in a number of diseases, including temporal lobe epilepsy and Alzheimer's disease. A better understanding is required of the molecular underpinning of astroglial polarization, particularly when it comes to the significance of the dystrophin associated protein complex (DAPC). Here, we employ immunofluorescence and immunogold cytochemistry to analyze the molecular scaffolding in perivascular endfeet in macroglia of retina and three regions of brain (cortex, dentate gyrus, and cerebellum), using AQP4 as a marker. Compared with brain astrocytes, Müller cells (a class of retinal macroglia) exhibit lower densities of the scaffold proteins dystrophin and α-syntrophin (a DAPC protein), but higher levels of AQP4. In agreement, depletion of dystrophin or α-syntrophin--while causing a dramatic loss of AQP4 from endfoot membranes of brain astrocytes--had only modest or insignificant effect, respectively, on the AQP4 pool in endfoot membranes of Müller cells. In addition, while polarization of brain macroglia was less affected by dystrophin depletion than by targeted deletion of α-syntrophin, the reverse was true for retinal macroglia. These data indicate that the molecular scaffolding in perivascular endfeet is more complex than previously assumed and that macroglia are heterogeneous with respect to the mechanisms that dictate their polarization.

  19. Molecular mapping of movement-associated areas in the avian brain: a motor theory for vocal learning origin.

    Science.gov (United States)

    Feenders, Gesa; Liedvogel, Miriam; Rivas, Miriam; Zapka, Manuela; Horita, Haruhito; Hara, Erina; Wada, Kazuhiro; Mouritsen, Henrik; Jarvis, Erich D

    2008-03-12

    Vocal learning is a critical behavioral substrate for spoken human language. It is a rare trait found in three distantly related groups of birds-songbirds, hummingbirds, and parrots. These avian groups have remarkably similar systems of cerebral vocal nuclei for the control of learned vocalizations that are not found in their more closely related vocal non-learning relatives. These findings led to the hypothesis that brain pathways for vocal learning in different groups evolved independently from a common ancestor but under pre-existing constraints. Here, we suggest one constraint, a pre-existing system for movement control. Using behavioral molecular mapping, we discovered that in songbirds, parrots, and hummingbirds, all cerebral vocal learning nuclei are adjacent to discrete brain areas active during limb and body movements. Similar to the relationships between vocal nuclei activation and singing, activation in the adjacent areas correlated with the amount of movement performed and was independent of auditory and visual input. These same movement-associated brain areas were also present in female songbirds that do not learn vocalizations and have atrophied cerebral vocal nuclei, and in ring doves that are vocal non-learners and do not have cerebral vocal nuclei. A compilation of previous neural tracing experiments in songbirds suggests that the movement-associated areas are connected in a network that is in parallel with the adjacent vocal learning system. This study is the first global mapping that we are aware for movement-associated areas of the avian cerebrum and it indicates that brain systems that control vocal learning in distantly related birds are directly adjacent to brain systems involved in movement control. Based upon these findings, we propose a motor theory for the origin of vocal learning, this being that the brain areas specialized for vocal learning in vocal learners evolved as a specialization of a pre-existing motor pathway that controls

  20. Molecular mapping of movement-associated areas in the avian brain: a motor theory for vocal learning origin.

    Directory of Open Access Journals (Sweden)

    Gesa Feenders

    Full Text Available Vocal learning is a critical behavioral substrate for spoken human language. It is a rare trait found in three distantly related groups of birds-songbirds, hummingbirds, and parrots. These avian groups have remarkably similar systems of cerebral vocal nuclei for the control of learned vocalizations that are not found in their more closely related vocal non-learning relatives. These findings led to the hypothesis that brain pathways for vocal learning in different groups evolved independently from a common ancestor but under pre-existing constraints. Here, we suggest one constraint, a pre-existing system for movement control. Using behavioral molecular mapping, we discovered that in songbirds, parrots, and hummingbirds, all cerebral vocal learning nuclei are adjacent to discrete brain areas active during limb and body movements. Similar to the relationships between vocal nuclei activation and singing, activation in the adjacent areas correlated with the amount of movement performed and was independent of auditory and visual input. These same movement-associated brain areas were also present in female songbirds that do not learn vocalizations and have atrophied cerebral vocal nuclei, and in ring doves that are vocal non-learners and do not have cerebral vocal nuclei. A compilation of previous neural tracing experiments in songbirds suggests that the movement-associated areas are connected in a network that is in parallel with the adjacent vocal learning system. This study is the first global mapping that we are aware for movement-associated areas of the avian cerebrum and it indicates that brain systems that control vocal learning in distantly related birds are directly adjacent to brain systems involved in movement control. Based upon these findings, we propose a motor theory for the origin of vocal learning, this being that the brain areas specialized for vocal learning in vocal learners evolved as a specialization of a pre-existing motor

  1. Molecular cloning of an unusual bicistronic cholecystokinin receptor mRNA expressed in chicken brain: a structural and functional expression study.

    Science.gov (United States)

    Nilsson, Isabelle B M; Svensson, Samuel P S; Monstein, Hans-Jürg

    2003-06-15

    This report describes the molecular cloning and pharmacological characterization of a transiently expressed chicken brain cholecystokinin receptor (CCK-CHR) in COS-7 cells. A polymerase chain reaction (PCR)-based cloning strategy was applied using: (1) an initial PCR with deoxyinosine-containing primers designed to target conserved regions in CCK receptors, followed by (2) rapid amplification of cDNA ends (RACE), and (3) full-length PCR of the CCK-CHR cDNA. The full-length cloned bicistronic CCK-CHR cDNA contained a short upstream open reading frame (uORF) coding for a putative six-amino-acid-long peptide of unknown function, followed by a long open reading frame (lORF) encoding the 436-amino-acid-long CCK-CHR receptor protein. At the amino acid level, the CCK-CHR shared approximately 50% homology with mammalian and Xenopus laevis CCK receptors. The pharmacological profile of CCK-CHR resembled that of CCK-B receptors using agonists (CCK-8, CCK-4, gastrin-17), whereas CCK-CHR showed higher affinity for the CCK-A receptor antagonist, devazepide, than for the CCK-B receptor antagonist, L-365,260. To the best of our knowledge, this is the first description and functional expression study of a cloned chicken CCK receptor cDNA.

  2. Brain banks as key part of biochemical and molecular studies on cerebral cortex involvement in Parkinson's disease.

    Science.gov (United States)

    Ravid, Rivka; Ferrer, Isidro

    2012-04-01

    Exciting developments in basic and clinical neuroscience and recent progress in the field of Parkinson's disease (PD) are partly a result of the availability of human specimens obtained through brain banks. These banks have optimized the methodological, managerial and organizational procedures; standard operating procedures; and ethical, legal and social issues, including the code of conduct for 21st Century brain banking and novel protocols. The present minireview focuses on current brain banking organization and management, as well as the likely future direction of the brain banking field. We emphasize the potentials and pitfalls when using high-quality specimens of the human central nervous system for advancing PD research. PD is a generalized disease in which α-synuclein is not a unique component but, instead, is only one of the players accounting for the complex impairment of biochemical/molecular processes involved in metabolic pathways. This is particularly important in the cerebral cortex, where altered cognition has a complex neurochemical substrate. Mitochondria and energy metabolism impairment, abnormal RNA, microRNA, protein synthesis, post-translational protein modifications and alterations in the lipid composition of membranes and lipid rafts are part of these complementary factors. We have to be alert to the possible pitfalls of each specimen and its suitability for a particular study. Not all samples qualify for the study of DNA, RNA, proteins, post-translational modifications, lipids and metabolomes, although the use of carefully selected samples and appropriate methods minimizes pitfalls and errors and guarantees high-quality reserach.

  3. A Tool for Brain-Wide Quantitative Analysis of Molecular Data upon Projection into a Planar View of Choice

    Science.gov (United States)

    Vreysen, Samme; Scheyltjens, Isabelle; Laramée, Marie-Eve; Arckens, Lutgarde

    2017-01-01

    Several techniques, allowing the reconstruction and visualization of functional, anatomical or molecular information from tissue and organ slices, have been developed over the years. Yet none allow direct comparison without reprocessing the same slices. Alternative methods using publicly available reference maps like the Allen Brain Atlas lack flexibility with respect to age and species. We propose a new approach to reconstruct a segmented region of interest from serial slices by projecting the optical density values representing a given molecular signal to a plane of view of choice, and to generalize the results into a reference map, which is built from the individual maps of all animals under study. Furthermore, to allow quantitative comparison between experimental conditions, a non-parametric pseudo t-test has been implemented. This new mapping tool was applied, optimized and validated making use of an in situ hybridization dataset that represents the spatiotemporal expression changes for the neuronal activity reporter gene zif268, in relation to cortical plasticity induced by monocular enucleation, covering the entire mouse visual cortex. The created top view maps of the mouse brain allow precisely delineating and interpreting 11 extrastriate areas surrounding mouse V1. As such, and because of the opportunity to create a planar projection of choice, these molecular maps can in the future easily be compared with functional or physiological imaging maps created with other techniques such as Ca2+, flavoprotein and optical imaging. PMID:28144216

  4. First Molecular Identification of Sarcocystis ovicanis (Protozoa, Apicomplexa in the Brain of Sheep in Iran.

    Directory of Open Access Journals (Sweden)

    Mitra Salehi

    2014-06-01

    Full Text Available The objective of the present study was to survey the presence of Sarcocystis in sheep's brain in North Khorasan Province.In general, 80 samples of sheep's brain were collected from slaughtered sheep in slaughterhouses of North Khorasan Province. Tissue digestion method was used for observing bradyzoites in tissues. Histopathological processing tracing Sarcocystis and ensuing structural change in the brain tissue were conducted. PCR analysis was conducted on all the brain samples. Sequencing was done for one PCR product. Genotype was identified by Blast search and homology analysis.Sarcocystis spp. was found in one of the brain samples (1.25% using tissue digestion method. The presence of bradyzoite was also confirmed in the prepared histopathological sections. PCR analysis was positive in one of samples. Genotyping of one sample proved that Sarcocystis species was Sarcocystis ovicanis and the nucleotide sequence of this parasite was deposited in the GenBank database under accession number No.KF489431.Sarcocystis ovicanis can involve brain tissue of sheep and consequently causes clinical symptoms.

  5. Conservation genetics in transition to conservation genomics

    NARCIS (Netherlands)

    Ouborg, N. Joop; Pertoldi, Cino; Loeschcke, Volker; Bijlsma, R. (Kuke); Hedrick, Phil W.

    2010-01-01

    Over the past twenty years conservation genetics has progressed from being mainly a theory-based field of population biology to a full-grown empirical discipline. Technological developments in molecular genetics have led to extensive use of neutral molecular markers such as microsatellites in conser

  6. Airy-like pulses in models of large molecular chains, and conservative numerical methods for quasi-linear Hamiltonian systems

    CERN Document Server

    LeMesurier, Brenton

    2013-01-01

    The phenomenon of coherent energetic pulse propagation in macromolecular chains such as $\\alpha$-helix protein is studied using the Davydov-Scott model, with both numerical studies using a new unconditionally stable fourth order accurate energy-momentum conserving time discretization, and with analysis based on ideas of center manifold theory. It is shown that for physically natural impulsive initial data, the coherent traveling pulses seen have a form related to the Airy function, but with rapid variation of phase along the chain. This can be explained in terms of a new continuum limit approximation by the third derivative nonlinear Schr\\"odinger equation, which differs from the previous continuum limit approximations related to the standard NLS equation. A theorem is given describing the construction of such conservative time discretizations for a large class of Hamiltonian systems.

  7. Two cytosolic puromycin-sensitive aminopeptidase isozymes in chicken brain: molecular homology to brain-specific 14-3-3 protein.

    Science.gov (United States)

    Hui, K S; Saito, M; Hui, M; Saito, M; Lajtha, A; Yamamoto, K; Osawa, T

    1993-05-01

    Two puromycin-sensitive aminopeptidase isozymes (PSA-I and PSA-II) were isolated from chicken brain cytosol by ammonium sulfate fractionation followed by column chromatography on Cellex D and AH-Sepharose 4B and separated on Bio-Gel HTP. Each was purified to homogeneity on Sephadex G-200, Arg-Tyr-AH-Sepharose, Bio-Gel HTP, and preparative gel electrophoresis. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, PSA-I appeared to be a monomer with a molecular mass of 105 kDa, and PSA-II to be composed of two subunits of 25 kDa and 100 kDa. The tryptic maps of 100 kDa and 105 kDa protein in HPLC are different in peak frequency, height, and composition. The internal peptide sequence of PSA-I has a considerable homology to PSA-II. Both isozymes have repeated copies of common peptide segments and have no significant sequence homology to other peptidases and proteinases. These thio and Co(2+)-activated isozymes have a neutral pH optimum and are inhibited by puromycin and bestatin. PSA-II is more sensitive to trypsin and heat treatment, has a lower Km to Met-enkephalin, and is more active on Arg BNA and Pro BNA. Our results suggest that PSA-I and PSA-II derive from translation of two RNAs of a new gene family related to the brain-specific 14-3-3 protein.

  8. Behavioral and molecular processing of visceral pain in the brain of mice: impact of colitis and psychological stress

    Directory of Open Access Journals (Sweden)

    Piyush eJain

    2015-07-01

    Full Text Available Gastrointestinal disorders with abdominal pain are associated with central sensitization and psychopathologies that are often exacerbated by stress. Here we investigated the impact of colitis induced by dextran sulfate sodium (DSS and repeated water avoidance stress (WAS on spontaneous and nociception-related behavior and molecular signaling in the mouse brain. DSS increased the mechanical pain sensitivity of the abdominal skin while both WAS and DSS enhanced the mechanical and thermal pain sensitivity of the plantar skin. These manifestations of central sensitization were associated with augmented c-Fos expression in spinal cord, thalamus, hypothalamus, amygdala and prefrontal cortex. While WAS stimulated phosphorylation of mitogen-activated protein kinase (MAPK p42/44, DSS activated another signaling pathway, both of which converged on c-Fos. The DSS- and WAS-induced hyperalgesia in the abdominal and plantar skin and c-Fos expression in the brain disappeared when the mice were subjected to WAS+DSS treatment. Intrarectal allyl isothiocyanate (AITC evoked aversive behavior (freezing, reduction of locomotion and exploration in association with p42/44 MAPK and c-Fos activation in spinal cord and brain. These effects were inhibited by morphine, which attests to their relationship with nociception. DSS and WAS exerted opposite effects on AITC-evoked p42/44 MAPK and c-Fos activation, which indicates that these transduction pathways subserve different aspects of visceral pain processing in the brain. In summary, behavioral perturbations caused by colitis and psychological stress are associated with distinct alterations in cerebral signaling. These findings provide novel perspectives on central sensitization and the sensory and emotional processing of visceral pain stimuli in the brain.

  9. Behavioral and molecular processing of visceral pain in the brain of mice: impact of colitis and psychological stress

    Science.gov (United States)

    Jain, Piyush; Hassan, Ahmed M.; Koyani, Chintan N.; Mayerhofer, Raphaela; Reichmann, Florian; Farzi, Aitak; Schuligoi, Rufina; Malle, Ernst; Holzer, Peter

    2015-01-01

    Gastrointestinal disorders with abdominal pain are associated with central sensitization and psychopathologies that are often exacerbated by stress. Here we investigated the impact of colitis induced by dextran sulfate sodium (DSS) and repeated water avoidance stress (WAS) on spontaneous and nociception-related behavior and molecular signaling in the mouse brain. DSS increased the mechanical pain sensitivity of the abdominal skin while both WAS and DSS enhanced the mechanical and thermal pain sensitivity of the plantar skin. These manifestations of central sensitization were associated with augmented c-Fos expression in spinal cord, thalamus, hypothalamus, amygdala and prefrontal cortex. While WAS stimulated phosphorylation of mitogen-activated protein kinase (MAPK) p42/44, DSS activated another signaling pathway, both of which converged on c-Fos. The DSS- and WAS-induced hyperalgesia in the abdominal and plantar skin and c-Fos expression in the brain disappeared when the mice were subjected to WAS+DSS treatment. Intrarectal allyl isothiocyanate (AITC) evoked aversive behavior (freezing, reduction of locomotion and exploration) in association with p42/44 MAPK and c-Fos activation in spinal cord and brain. These effects were inhibited by morphine, which attests to their relationship with nociception. DSS and WAS exerted opposite effects on AITC-evoked p42/44 MAPK and c-Fos activation, which indicates that these transduction pathways subserve different aspects of visceral pain processing in the brain. In summary, behavioral perturbations caused by colitis and psychological stress are associated with distinct alterations in cerebral signaling. These findings provide novel perspectives on central sensitization and the sensory and emotional processing of visceral pain stimuli in the brain. PMID:26217204

  10. The optical theorem for the conservation of the electromagnetic helicity: Its significance for molecular transfer and enantiomeric discrimination by dichroism

    CERN Document Server

    Nieto-Vesperinas, Manuel

    2015-01-01

    We put forward the physical meaning of the conservation equation for the helicity on scattering of an electromagnetic field with a generally magnetodielectric bi-isotropic dipolar object. This is the optical theorem for the helicity that, as we find, plays a role for this quantity analogous to that of the optical thorem for energy. We discuss its consequences for helicity transfer between molecules and for new detection procedures of circular dichroism based on ellipsometric measurements.

  11. Molecular Mechanisms Responsible for Neuron-Derived Conditioned Medium (NCM)-Mediated Protection of Ischemic Brain.

    Science.gov (United States)

    Lin, Chi-Hsin; Wang, Chen-Hsuan; Hsu, Shih-Lan; Liao, Li-Ya; Lin, Ting-An; Hsueh, Chi-Mei

    2016-01-01

    The protective value of neuron-derived conditioned medium (NCM) in cerebral ischemia and the underlying mechanism(s) responsible for NCM-mediated brain protection against cerebral ischemia were investigated in the study. NCM was first collected from the neuronal culture growing under the in vitro ischemic condition (glucose-, oxygen- and serum-deprivation or GOSD) for 2, 4 or 6 h. Through the focal cerebral ischemia (bilateral CCAO/unilateral MCAO) animal model, we discovered that ischemia/reperfusion (I/R)-induced brain infarction was significantly reduced by NCM, given directly into the cistern magna at the end of 90 min of CCAO/MCAO. Immunoblocking and chemical blocking strategies were applied in the in vitro ischemic studies to show that NCM supplement could protect microglia, astrocytes and neurons from GOSD-induced cell death, in a growth factor (TGFβ1, NT-3 and GDNF) and p-ERK dependent manner. Brain injection with TGFβ1, NT3, GDNF and ERK agonist (DADS) alone or in combination, therefore also significantly decreased the infarct volume of ischemic brain. Moreover, NCM could inhibit ROS but stimulate IL-1β release from GOSD-treated microglia and limit the infiltration of IL-β-positive microglia into the core area of ischemic brain, revealing the anti-oxidant and anti-inflammatory activities of NCM. In overall, NCM-mediated brain protection against cerebral ischemia has been demonstrated for the first time in S.D. rats, due to its anti-apoptotic, anti-oxidant and potentially anti-glutamate activities (NCM-induced IL-1β can inhibit the glutamate-mediated neurotoxicity) and restriction upon the infiltration of inflammatory microglia into the core area of ischemic brain. The therapeutic potentials of NCM, TGFβ1, GDNF, NT-3 and DADS in the control of cerebral ischemia in human therefore have been suggested and require further investigation.

  12. Brain acetylcholinesterase and its molecular forms in a precocial murid, Acomys cahirinus, and rat during post-natal development.

    Science.gov (United States)

    Michalek, H; Pintor, A; Fortuna, S; Bisso, G M

    1984-01-01

    Brain acetylcholinesterase (AChE) and its molecular forms of a precocial murid, Acomys cahirinus, characterized by a large hippocampus, were measured during post-natal development and compared with rat. The activity of soluble AChE in Acomys increased slightly up to 4 weeks after birth. The total AChE activity increased somewhat more but, in rats, this increase was still greater. Three main molecular forms of AChE were separated by 7.5% polyacrylamide gel electrophoresis. Their close similarity to the rat AChE forms was assessed by gradient polyacrylamide gel electrophoresis and electrofocusing. Maturation of these forms, i.e., conversion of simple into more complex forms in the soluble fraction of AChE was, however, considerably delayed reaching only after 4 weeks the pattern comparable to that of rat.

  13. Diversified Structural Basis of a Conserved Molecular Mechanism for pH-Dependent Dimerization in Spider Silk N-Terminal Domains.

    Science.gov (United States)

    Otikovs, Martins; Chen, Gefei; Nordling, Kerstin; Landreh, Michael; Meng, Qing; Jörnvall, Hans; Kronqvist, Nina; Rising, Anna; Johansson, Jan; Jaudzems, Kristaps

    2015-08-17

    Conversion of spider silk proteins from soluble dope to insoluble fibers involves pH-dependent dimerization of the N-terminal domain (NT). This conversion is tightly regulated to prevent premature precipitation and enable rapid silk formation at the end of the duct. Three glutamic acid residues that mediate this process in the NT from Euprosthenops australis major ampullate spidroin 1 are well conserved among spidroins. However, NTs of minor ampullate spidroins from several species, including Araneus ventricosus ((Av)MiSp NT), lack one of the glutamic acids. Here we investigate the pH-dependent structural changes of (Av)MiSp NT, revealing that it uses the same mechanism but involves a non-conserved glutamic acid residue instead. Homology modeling of the structures of other MiSp NTs suggests that these harbor different compensatory residues. This indicates that, despite sequence variations, the molecular mechanism underlying pH-dependent dimerization of NT is conserved among different silk types. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. All-atom molecular dynamics simulations reveal significant differences in interaction between antimycin and conserved amino acid residues in bovine and bacterial bc1 complexes.

    Science.gov (United States)

    Kokhan, Oleksandr; Shinkarev, Vladimir P

    2011-02-02

    Antimycin A is the most frequently used specific and powerful inhibitor of the mitochondrial respiratory chain. We used all-atom molecular dynamics (MD) simulations to study the dynamic aspects of the interaction of antimycin A with the Q(i) site of the bacterial and bovine bc(1) complexes embedded in a membrane. The MD simulations revealed considerable conformational flexibility of antimycin and significant mobility of antimycin, as a whole, inside the Q(i) pocket. We conclude that many of the differences in antimycin binding observed in high-resolution x-ray structures may have a dynamic origin and result from fluctuations of protein and antimycin between multiple conformational states of similar energy separated by low activation barriers, as well as from the mobility of antimycin within the Q(i) pocket. The MD simulations also revealed a significant difference in interaction between antimycin and conserved amino acid residues in bovine and bacterial bc(1) complexes. The strong hydrogen bond between antimycin and conserved Asp-228 (bovine numeration) was observed to be frequently broken in the bacterial bc(1) complex and only rarely in the bovine bc(1) complex. In addition, the distances between antimycin and conserved His-201 and Lys-227 were consistently larger in the bacterial bc(1) complex. The observed differences could be responsible for a weaker interaction of antimycin with the bacterial bc(1) complex.

  15. Molecular clonality determination of ipsilateral recurrence of invasive breast carcinomas after breast-conserving therapy: comparison with clinical and biologic factors.

    Science.gov (United States)

    Goldstein, Neal S; Vicini, Frank A; Hunter, Susan; Odish, Eva; Forbes, Suzy; Kraus, Daniel; Kestin, Larry L

    2005-05-01

    We established clonality relationships between invasive ipsilateral breast failures (IBFs; local recurrences) and initial invasive carcinomas using a molecular polymerase chain reaction loss of heterozygosity (LOH) assay for 26 patients treated with breast-conserving therapy for invasive carcinoma with no distant metastases (DMs) before the IBE LOH was +/- 50% allelic loss. Eighteen IBFs (69%) were related clonally to initial carcinomas; 8 (31%) were clonally distinct, second primary carcinomas. IBFs and initial invasive carcinomas were morphologically similar in 6 (75%) of 8 clonally different cases. Clinical IBF classification and molecular assay results differed in 11 cases (42%). The mean intervals to IBF were 4.7 years in related and 8.7 years in different cases (P = .013). In 6 patients, DMs developed; 5 had related IBFs. In related IBF cases, the mean increase in fractional allelic loss (FAL) of IBFs associated with DMs was 18.9% compared with 7.6% in cases unassociated with DMs (P = .004). Molecular assays can accurately establish the clonality of most IBFs. Morphologic comparison and clinical IBF classification are unreliable methods of determining clonality. Clonally related IBFs occurred sooner than clonally different IBFs. Patients with clonally related IBFs are the main pool in which DMs occur Not all clonally related IBFs have the same DM association; those with large FAL gains were associated with DMs. Molecular clonality assays may provide a reliable means of identifying patients who might benefit from systemic chemotherapy at the time of IBF.

  16. Molecular conservation of estrogen-response associated with cell cycle regulation, hormonal carcinogenesis and cancer in zebrafish and human cancer cell lines

    Directory of Open Access Journals (Sweden)

    Govindarajan Kunde R

    2011-05-01

    Full Text Available Abstract Background The zebrafish is recognized as a versatile cancer and drug screening model. However, it is not known whether the estrogen-responsive genes and signaling pathways that are involved in estrogen-dependent carcinogenesis and human cancer are operating in zebrafish. In order to determine the potential of zebrafish model for estrogen-related cancer research, we investigated the molecular conservation of estrogen responses operating in both zebrafish and human cancer cell lines. Methods Microarray experiment was performed on zebrafish exposed to estrogen (17β-estradiol; a classified carcinogen and an anti-estrogen (ICI 182,780. Zebrafish estrogen-responsive genes sensitive to both estrogen and anti-estrogen were identified and validated using real-time PCR. Human homolog mapping and knowledge-based data mining were performed on zebrafish estrogen responsive genes followed by estrogen receptor binding site analysis and comparative transcriptome analysis with estrogen-responsive human cancer cell lines (MCF7, T47D and Ishikawa. Results Our transcriptome analysis captured multiple estrogen-responsive genes and signaling pathways that increased cell proliferation, promoted DNA damage and genome instability, and decreased tumor suppressing effects, suggesting a common mechanism for estrogen-induced carcinogenesis. Comparative analysis revealed a core set of conserved estrogen-responsive genes that demonstrate enrichment of estrogen receptor binding sites and cell cycle signaling pathways. Knowledge-based and network analysis led us to propose that the mechanism involving estrogen-activated estrogen receptor mediated down-regulation of human homolog HES1 followed by up-regulation cell cycle-related genes (human homologs E2F4, CDK2, CCNA, CCNB, CCNE, is highly conserved, and this mechanism may involve novel crosstalk with basal AHR. We also identified mitotic roles of polo-like kinase as a conserved signaling pathway with multiple entry

  17. Molecular Imaging Provides Novel Insights on Estrogen Receptor Activity in Mouse Brain

    Directory of Open Access Journals (Sweden)

    Alessia Stell

    2008-11-01

    Full Text Available Estrogen receptors have long been known to be expressed in several brain areas in addition to those directly involved in the control of reproductive functions. Investigations in humans and in animal models suggest a strong influence of estrogens on limbic and motor functions, yet the complexity and heterogeneity of neural tissue have limited our approaches to the full understanding of estrogen activity in the central nervous system. The aim of this study was to examine the transcriptional activity of estrogen receptors in the brain of male and female mice. Exploiting the ERE-Luc reporter mouse, we set up a novel, bioluminescence-based technique to study brain estrogen receptor transcriptional activity. Here we show, for the first time, that estrogen receptors are similarly active in male and female brains and that the estrous cycle affects estrogen receptor activity in regions of the central nervous system not known to be associated with reproductive functions. Because of its reproducibility and sensitivity, this novel bioluminescence application stands as a candidate as an innovative methodology for the study and development of drugs targeting brain estrogen receptors.

  18. Molecular cloning, expression and in situ hybridization of rat brain glutamic acid decarboxylase messenger RNA.

    Science.gov (United States)

    Julien, J F; Legay, F; Dumas, S; Tappaz, M; Mallet, J

    1987-01-14

    A cDNA library was generated in the expression vector lambda GT11 from rat brain poly(A)+ RNAs and screened with a GAD antiserum. Two clones reacted positively. One of them was shown to express a GAD activity which was specifically trapped on anti-GAD immunogel and was inhibited by gamma-acetylenic-GABA. Blot hybridization analysis of RNAs from rat brain revealed a single 4 kilobases band. Preliminary in situ hybridizations showed numerous cells labelled by the GAD probe such as the Purkinje and stellate cells in the cerebellar cortex and the cells of the reticular thalamic nucleus.

  19. Screening of biochemical and molecular mechanisms of secondary injury and repair in the brain after experimental blast-induced traumatic brain injury in rats.

    Science.gov (United States)

    Kochanek, Patrick M; Dixon, C Edward; Shellington, David K; Shin, Samuel S; Bayır, Hülya; Jackson, Edwin K; Kagan, Valerian E; Yan, Hong Q; Swauger, Peter V; Parks, Steven A; Ritzel, David V; Bauman, Richard; Clark, Robert S B; Garman, Robert H; Bandak, Faris; Ling, Geoffrey; Jenkins, Larry W

    2013-06-01

    Abstract Explosive blast-induced traumatic brain injury (TBI) is the signature insult in modern combat casualty care and has been linked to post-traumatic stress disorder, memory loss, and chronic traumatic encephalopathy. In this article we report on blast-induced mild TBI (mTBI) characterized by fiber-tract degeneration and axonal injury revealed by cupric silver staining in adult male rats after head-only exposure to 35 psi in a helium-driven shock tube with head restraint. We now explore pathways of secondary injury and repair using biochemical/molecular strategies. Injury produced ∼25% mortality from apnea. Shams received identical anesthesia exposure. Rats were sacrificed at 2 or 24 h, and brain was sampled in the hippocampus and prefrontal cortex. Hippocampal samples were used to assess gene array (RatRef-12 Expression BeadChip; Illumina, Inc., San Diego, CA) and oxidative stress (OS; ascorbate, glutathione, low-molecular-weight thiols [LMWT], protein thiols, and 4-hydroxynonenal [HNE]). Cortical samples were used to assess neuroinflammation (cytokines, chemokines, and growth factors; Luminex Corporation, Austin, TX) and purines (adenosine triphosphate [ATP], adenosine diphosphate, adenosine, inosine, 2'-AMP [adenosine monophosphate], and 5'-AMP). Gene array revealed marked increases in astrocyte and neuroinflammatory markers at 24 h (glial fibrillary acidic protein, vimentin, and complement component 1) with expression patterns bioinformatically consistent with those noted in Alzheimer's disease and long-term potentiation. Ascorbate, LMWT, and protein thiols were reduced at 2 and 24 h; by 24 h, HNE was increased. At 2 h, multiple cytokines and chemokines (interleukin [IL]-1α, IL-6, IL-10, and macrophage inflammatory protein 1 alpha [MIP-1α]) were increased; by 24 h, only MIP-1α remained elevated. ATP was not depleted, and adenosine correlated with 2'-cyclic AMP (cAMP), and not 5'-cAMP. Our data reveal (1) gene-array alterations similar to disorders of

  20. Integrative Proteomics and Metabolomics Analysis of Insect Larva Brain: Novel Insights into the Molecular Mechanism of Insect Wandering Behavior.

    Science.gov (United States)

    Li, Yi; Wang, Xin; Hou, Yong; Zhou, Xiaoying; Chen, Quanmei; Guo, Chao; Xia, Qingyou; Zhang, Yan; Zhao, Ping

    2016-01-04

    Before metamorphosis, most holometabolous insects, such as the silkworm studied here, undergo a special phase called the wandering stage. Insects in this stage often display enhanced locomotor activity (ELA). ELA is vital because it ensures that the insect finds a safe and suitable place to live through the pupal stage. The physiological mechanisms of wandering behavior are still unclear. Here, we integrated proteomics and metabolomics approaches to analyze the brain of the lepidopteran insect, silkworm, at the feeding and wandering stages. Using LC-MS/MS and GC-MS, in all we identified 3004 proteins and 37 metabolites at these two stages. Among them, 465 proteins and 22 metabolites were changed. Neural signal transduction proteins and metabolites, such as neurofilament, dopaminergic synapse related proteins, and glutamic acid, were significantly altered, which suggested that active neural conduction occurred in the brain at the wandering stage. We also found decreased dopamine degradation at the wandering stage. The proposed changes in active neural conduction and increased dopamine concentration might induce ELA. In addition, proteins involved in the ubiquitin proteasome system and lysosome pathway were upregulated, revealing that the brain experiences morphological remodeling during metamorphosis. These findings yielded novel insights into the molecular mechanism underlying insect wandering behavior.

  1. Molecular cloning of partial cDNAs for rat DNA topoisomerase II isoforms and their differential expression in brain development.

    Science.gov (United States)

    Tsutsui, K; Tsutsui, K; Okada, S; Watanabe, M; Shohmori, T; Seki, S; Inoue, Y

    1993-09-05

    cDNA segments for DNA topoisomerase II were amplified from rat brain RNA after reverse transcription by the polymerase chain reaction, using degenerate oligonucleotide primers deduced from the conserved regions of topoisomerase II of higher eukaryotes. The cDNA product from a successful amplification was homogeneous in length but heterogeneous in sequence. Restriction mapping of the cloned cDNA fragments revealed that they consisted of two distinct sequence groups. DNA sequencing of representative clones from each group, designated A and B, showed that they are highly homologous to cDNAs of human topoisomerase II isoforms, alpha and beta, respectively. Northern blot analysis indicated that the transcript level for rat topoisomerase II alpha was high in embryonic brain and in the cerebellum of 2-day newborns, followed by rapid decrease to a undetectable level at 4 weeks after birth. In contrast, rat topoisomerase II beta transcript was present throughout the embryonic and postnatal stages. In the developing cerebellum, cells expressing topoisomerase II alpha were confirmed exclusively to the outer mitotic zone of the external granular layer, whereas the transcript of topoisomerase II beta was detected over the entire cortical region. These results clearly indicate that the isoform alpha is expressed only in proliferating cells. The differential expression of topoisomerase II isozymes was also observed among developed tissues. Therefore, the isozymes are most likely to be involved in the following different physiological processes: topoisomerase II alpha in cell proliferation, and topoisomerase II beta in some processes unrelated to cell proliferation.

  2. New neurons in aging brains: molecular control by small non-coding RNAs.

    NARCIS (Netherlands)

    M. Schouten; M.R. Buijink; P.J. Lucassen; C.P. Fitzsimons

    2012-01-01

    Adult neurogenesis generates functional neurons from neural stem cells present in specific brain regions. It is largely confined to two main regions: the subventricular zone of the lateral ventricle, and the subgranular zone of the dentate gyrus (DG), in the hippocampus. With age, the function of th

  3. New neurons in aging brains: molecular control by small non-coding RNAs.

    NARCIS (Netherlands)

    Schouten, M.; Buijink, M.R.; Lucassen, P.J.; Fitzsimons, C.P.

    2012-01-01

    Adult neurogenesis generates functional neurons from neural stem cells present in specific brain regions. It is largely confined to two main regions: the subventricular zone of the lateral ventricle, and the subgranular zone of the dentate gyrus (DG), in the hippocampus. With age, the function of

  4. A fatal case of Nocardia otitidiscaviarum pulmonary infection and brain abscess: taxonomic characterization by molecular techniques

    Directory of Open Access Journals (Sweden)

    Aranaz Carlos

    2009-04-01

    Full Text Available Abstract We report on a rare case of pulmonary Nocardiosis and brain abscess caused by Nocardia otitidiscaviarum in an elderly woman with chronic obstructive pulmonary disease. Taxonomic identification involved phenotypic testing, restriction fragment length polymorphism (RFLP, and complete 16S rRNA gene sequencing.

  5. Large-scale analysis of conserved rare codon clusters suggests an involvement in co-translational molecular recognition events.

    Science.gov (United States)

    Chartier, Matthieu; Gaudreault, Francis; Najmanovich, Rafael

    2012-06-01

    An increasing amount of evidence from experimental and computational analysis suggests that rare codon clusters are functionally important for protein activity. Most of the studies on rare codon clusters were performed on a limited number of proteins or protein families. In the present study, we present the Sherlocc program and how it can be used for large scale protein family analysis of evolutionarily conserved rare codon clusters and their relation to protein function and structure. This large-scale analysis was performed using the whole Pfam database covering over 70% of the known protein sequence universe. Our program Sherlocc, detects statistically relevant conserved rare codon clusters and produces a user-friendly HTML output. Statistically significant rare codon clusters were detected in a multitude of Pfam protein families. The most statistically significant rare codon clusters were predominantly identified in N-terminal Pfam families. Many of the longest rare codon clusters are found in membrane-related proteins which are required to interact with other proteins as part of their function, for example in targeting or insertion. We identified some cases where rare codon clusters can play a regulating role in the folding of catalytically important domains. Our results support the existence of a widespread functional role for rare codon clusters across species. Finally, we developed an online filter-based search interface that provides access to Sherlocc results for all Pfam families. The Sherlocc program and search interface are open access and are available at http://bcb.med.usherbrooke.ca

  6. Protecting Neural Structures and Cognitive Function During Prolonged Space Flight by Targeting the Brain Derived Neurotrophic Factor Molecular Network

    Science.gov (United States)

    Schmidt, M. A.; Goodwin, T. J.

    2014-01-01

    Brain derived neurotrophic factor (BDNF) is the main activity-dependent neurotrophin in the human nervous system. BDNF is implicated in production of new neurons from dentate gyrus stem cells (hippocampal neurogenesis), synapse formation, sprouting of new axons, growth of new axons, sprouting of new dendrites, and neuron survival. Alterations in the amount or activity of BDNF can produce significant detrimental changes to cortical function and synaptic transmission in the human brain. This can result in glial and neuronal dysfunction, which may contribute to a range of clinical conditions, spanning a number of learning, behavioral, and neurological disorders. There is an extensive body of work surrounding the BDNF molecular network, including BDNF gene polymorphisms, methylated BDNF gene promoters, multiple gene transcripts, varied BDNF functional proteins, and different BDNF receptors (whose activation differentially drive the neuron to neurogenesis or apoptosis). BDNF is also closely linked to mitochondrial biogenesis through PGC-1alpha, which can influence brain and muscle metabolic efficiency. BDNF AS A HUMAN SPACE FLIGHT COUNTERMEASURE TARGET Earth-based studies reveal that BDNF is negatively impacted by many of the conditions encountered in the space environment, including oxidative stress, radiation, psychological stressors, sleep deprivation, and many others. A growing body of work suggests that the BDNF network is responsive to a range of diet, nutrition, exercise, drug, and other types of influences. This section explores the BDNF network in the context of 1) protecting the brain and nervous system in the space environment, 2) optimizing neurobehavioral performance in space, and 3) reducing the residual effects of space flight on the nervous system on return to Earth

  7. Molecular and biochemical analysis of rainbow trout LCK suggests a conserved mechanism for T-cell signaling in gnathostomes

    Science.gov (United States)

    Laing, K.J.; Dutton, S.; Hansen, J.D.

    2007-01-01

    Two genes were identified in rainbow trout that display high sequence identity to vertebrate Lck. Both of the trout Lck transcripts are associated with lymphoid tissues and were found to be highly expressed in IgM-negative lymphocytes. In vitro analysis of trout lymphocytes indicates that trout Lck mRNA is up-regulated by T-cell mitogens, supporting an evolutionarily conserved function for Lck in the signaling pathways of T-lymphocytes. Here, we describe the generation and characterization of a specific monoclonal antibody raised against the N-terminal domains of recombinant trout Lck that can recognize Lck protein(s) from trout thymocyte lysates that are similar in size (???57 kDa) to mammalian Lck. This antibody also reacted with permeabilized lymphocytes during FACS analysis, indicating its potential usage for cellular analyses of trout lymphocytes, thus representing an important tool for investigations of salmonid T-cell function.

  8. Large-scale analysis of conserved rare codon clusters suggests an involvement in co-translational molecular recognition events

    Science.gov (United States)

    Chartier, Matthieu; Gaudreault, Francis; Najmanovich, Rafael

    2012-01-01

    Motivation: An increasing amount of evidence from experimental and computational analysis suggests that rare codon clusters are functionally important for protein activity. Most of the studies on rare codon clusters were performed on a limited number of proteins or protein families. In the present study, we present the Sherlocc program and how it can be used for large scale protein family analysis of evolutionarily conserved rare codon clusters and their relation to protein function and structure. This large-scale analysis was performed using the whole Pfam database covering over 70% of the known protein sequence universe. Our program Sherlocc, detects statistically relevant conserved rare codon clusters and produces a user-friendly HTML output. Results: Statistically significant rare codon clusters were detected in a multitude of Pfam protein families. The most statistically significant rare codon clusters were predominantly identified in N-terminal Pfam families. Many of the longest rare codon clusters are found in membrane-related proteins which are required to interact with other proteins as part of their function, for example in targeting or insertion. We identified some cases where rare codon clusters can play a regulating role in the folding of catalytically important domains. Our results support the existence of a widespread functional role for rare codon clusters across species. Finally, we developed an online filter-based search interface that provides access to Sherlocc results for all Pfam families. Availability: The Sherlocc program and search interface are open access and are available at http://bcb.med.usherbrooke.ca Contact: rafael.najmanovich@usherbrooke.ca Supplementary information: Supplementary data are available at Bioinformatics online. PMID:22467916

  9. Molecular fingerprint of neuropeptide S-producing neurons in the mouse brain

    DEFF Research Database (Denmark)

    Liu, Xiaobin; Zeng, Joanne; Zhou, Anni

    2011-01-01

    Neuropeptide S (NPS) has been associated with a number of complex brain functions, including anxiety-like behaviors, arousal, sleep-wakefulness regulation, drug-seeking behaviors, and learning and memory. In order to better understand how NPS influences these functions in a neuronal network context....../EGFP-transgenic mice show anatomically correct and overlapping expression of both NPS and EGFP. A total number of ~500 NPS/EGFP-positive neurons are present in the mouse brain, located in the pericoerulear region and the Kölliker-Fuse nucleus. NPS and transgene expression is first detectable around E14, indicating...... network of orexin/hypocretin neuronal projections contacting pericoerulear NPS-producing neurons was observed by immunostaining. Expression of a distinct repertoire of metabotropic and ionotropic receptor genes was identified in both NPS neuronal clusters that will allow for detailed investigations...

  10. Molecular fingerprint of neuropeptide S-producing neurons in the mouse brain

    DEFF Research Database (Denmark)

    Liu, Xiaobin; Zeng, Joanne; Zhou, Anni

    2011-01-01

    Neuropeptide S (NPS) has been associated with a number of complex brain functions, including anxiety-like behaviors, arousal, sleep-wakefulness regulation, drug-seeking behaviors, and learning and memory. In order to better understand how NPS influences these functions in a neuronal network context....../EGFP-transgenic mice show anatomically correct and overlapping expression of both NPS and EGFP. A total number of ∼500 NPS/EGFP-positive neurons are present in the mouse brain, located in the pericoerulear region and the Kölliker-Fuse nucleus. NPS and transgene expression is first detectable around E14, indicating...... network of orexin/hypocretin neuronal projections contacting pericoerulear NPS-producing neurons was observed by immunostaining. Expression of a distinct repertoire of metabotropic and ionotropic receptor genes was identified in both NPS neuronal clusters that will allow for detailed investigations...

  11. Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity.

    Science.gov (United States)

    Angoa-Pérez, Mariana; Kane, Michael J; Briggs, Denise I; Sykes, Catherine E; Shah, Mrudang M; Francescutti, Dina M; Rosenberg, David R; Thomas, David M; Kuhn, Donald M

    2012-06-01

    Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g. obsessive-compulsive disorder; OCD) and impulse-control (e.g. impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2-/-), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2-/- mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2-/- mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2-/- mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis.

  12. Cross-generational trans fat intake facilitates mania-like behavior: oxidative and molecular markers in brain cortex.

    Science.gov (United States)

    Trevizol, F; Roversi, Kr; Dias, V T; Roversi, K; Barcelos, R C S; Kuhn, F T; Pase, C S; Golombieski, R; Veit, J C; Piccolo, J; Pochmann, D; Porciúncula, L O; Emanuelli, T; Rocha, J B T; Bürger, M E

    2015-02-12

    Since that fast food consumption have raised concerns about people's health, we evaluated the influence of trans fat consumption on behavioral, biochemical and molecular changes in the brain-cortex of second generation rats exposed to a model of mania. Two successive generations of female rats were supplemented with soybean oil (SO, rich in n-6 FA, control group), fish oil (FO, rich in n-3 FA) and hydrogenated vegetable fat (HVF, rich in trans FA) from pregnancy, lactation to adulthood, when male rats from 2nd generation received amphetamine (AMPH-4 mg/kg-i.p., once a day, for 14 days) treatment. AMPH increased locomotor index in all animals, which was higher in the HVF group. While the FO group showed increased n-3 polyunsaturated fatty acid (PUFA) incorporation and reduced n-6/n-3 PUFA ratio, HVF allowed trans fatty acid (TFA) incorporation and increased n-6/n-3 PUFA ratio in the brain-cortex. In fact, the FO group showed minor AMPH-induced hyperactivity, decreased reactive species (RS) generation per se, causing no changes in protein carbonyl (PC) levels and dopamine transporter (DAT). FO supplementation showed molecular changes, since proBDNF was increased per se and reduced by AMPH, decreasing the brain-derived neurotrophic factor (BDNF) level following drug treatment. Conversely, HVF was related to increased hyperactivity, higher PC level per se and higher AMPH-induced PC level, reflecting on DAT, whose levels were decreased per se as well as in AMPH-treated groups. In addition, while HVF increased BDNF-mRNA per se, AMPH reduced this value, acting on BDNF, whose level was lower in the same AMPH-treated experimental group. ProBDNF level was influenced by HVF supplementation, but it was not sufficient to modify BDNF level. These findings reinforce that prolonged consumption of trans fat allows TFA incorporation in the cortex, facilitating hyperactive behavior, oxidative damages and molecular changes. Our study is a warning about cross-generational consumption

  13. Regulation of Drosophila Brain Wiring by Neuropil Interactions via a Slit-Robo-RPTP Signaling Complex.

    Science.gov (United States)

    Oliva, Carlos; Soldano, Alessia; Mora, Natalia; De Geest, Natalie; Claeys, Annelies; Erfurth, Maria-Luise; Sierralta, Jimena; Ramaekers, Ariane; Dascenco, Dan; Ejsmont, Radoslaw K; Schmucker, Dietmar; Sanchez-Soriano, Natalia; Hassan, Bassem A

    2016-10-24

    The axonal wiring molecule Slit and its Round-About (Robo) receptors are conserved regulators of nerve cord patterning. Robo receptors also contribute to wiring brain circuits. Whether molecular mechanisms regulating these signals are modified to fit more complex brain wiring processes is unclear. We investigated the role of Slit and Robo receptors in wiring Drosophila higher-order brain circuits and identified differences in the cellular and molecular mechanisms of Robo/Slit function. First, we find that signaling by Robo receptors in the brain is regulated by the Receptor Protein Tyrosine Phosphatase RPTP69d. RPTP69d increases membrane availability of Robo3 without affecting its phosphorylation state. Second, we detect no midline localization of Slit during brain development. Instead, Slit is enriched in the mushroom body, a neuronal structure covering large areas of the brain. Thus, a divergent molecular mechanism regulates neuronal circuit wiring in the Drosophila brain, partly in response to signals from the mushroom body.

  14. Protocols for In Vitro Propagation, Conservation, Synthetic Seed Production, Embryo Rescue, Microrhizome Production, Molecular Profiling, and Genetic Transformation in Ginger (Zingiber officinale Roscoe.).

    Science.gov (United States)

    Nirmal Babu, K; Samsudeen, K; Divakaran, Minoo; Pillai, Geetha S; Sumathi, V; Praveen, K; Ravindran, P N; Peter, K V

    2016-01-01

    Ginger is a rhizomatous plant that belongs to the family Zingiberaceae. It is a herbaceous perennial but cultivated as annual, with crop duration of 7-10 months. Ginger is native to India and Tropical South Asia. The tuberous rhizomes or underground stems of ginger are used as condiment, an aromatic stimulant, and food preservative as well as in traditional medicine. Ginger is propagated vegetatively with rhizome bits as seed material. Cultivation of ginger is plagued by rhizome rot diseases, most of which are mainly spread through infected seed rhizomes. Micropropagation will help in production of disease-free planting material. Sexual reproduction is absent in ginger, making recombinant breeding very impossible. In vitro technology can thus become the preferred choice as it can be utilized for multiplication, conservation of genetic resources, generating variability, gene transfer, molecular tagging, and their utility in crop improvement of these crops.

  15. A highly conserved N-terminal sequence for teleost vitellogenin with potential value to the biochemistry, molecular biology and pathology of vitellogenesis

    Science.gov (United States)

    Folmar, L.D.; Denslow, N.D.; Wallace, R.A.; LaFleur, G.; Gross, T.S.; Bonomelli, S.; Sullivan, C.V.

    1995-01-01

    N-terminal amino acid sequences for vitellogenin (Vtg) from six species of teleost fish (striped bass, mummichog, pinfish, brown bullhead, medaka, yellow perch and the sturgeon) are compared with published N-terminal Vtg sequences for the lamprey, clawed frog and domestic chicken. Striped bass and mummichog had 100% identical amino acids between positions 7 and 21, while pinfish, brown bullhead, sturgeon, lamprey, Xenopus and chicken had 87%, 93%, 60%, 47%, 47-60%) for four transcripts and had 40% identical, respectively, with striped bass for the same positions. Partial sequences obtained for medaka and yellow perch were 100% identical between positions 5 to 10. The potential utility of this conserved sequence for studies on the biochemistry, molecular biology and pathology of vitellogenesis is discussed.

  16. Conserving the linear momentum in stochastic dynamics: Dissipative particle dynamics as a general strategy to achieve local thermostatization in molecular dynamics simulations.

    Science.gov (United States)

    Passler, Peter P; Hofer, Thomas S

    2017-02-15

    Stochastic dynamics is a widely employed strategy to achieve local thermostatization in molecular dynamics simulation studies; however, it suffers from an inherent violation of momentum conservation. Although this short-coming has little impact on structural and short-time dynamic properties, it can be shown that dynamics in the long-time limit such as diffusion is strongly dependent on the respective thermostat setting. Application of the methodically similar dissipative particle dynamics (DPD) provides a simple, effective strategy to ensure the advantages of local, stochastic thermostatization while at the same time the linear momentum of the system remains conserved. In this work, the key parameters to employ the DPD thermostats in the framework of periodic boundary conditions are investigated, in particular the dependence of the system properties on the size of the DPD-region as well as the treatment of forces near the cutoff. Structural and dynamical data for light and heavy water as well as a Lennard-Jones fluid have been compared to simulations executed via stochastic dynamics as well as via use of the widely employed Nose-Hoover chain and Berendsen thermostats. It is demonstrated that a small size of the DPD region is sufficient to achieve local thermalization, while at the same time artifacts in the self-diffusion characteristic for stochastic dynamics are eliminated. © 2016 Wiley Periodicals, Inc.

  17. Analysis and validation of genome-specific DNA variations in 5' flanking conserved sequences of wheat low-molecular-weight glutenin subunit genes

    Institute of Scientific and Technical Information of China (English)

    LONG; Hai; WEI; Yuming

    2006-01-01

    The thirty-three 5' flanking conserved sequences of the known low-molecular-weight subunit (LMW-GS) genes have been divided into eight clusters, which was in agreement with the classification based on the deduced N-terminal protein sequences. The DNA polymorphism between the eight clusters was obtained by sequence alignment, and a total of 34 polymorphic positions were observed in the approximately 200 bp regions, among which 18 polymorphic positions were candidate SNPs. Seven cluster-specific primer sets were designed for seven out of eight clusters containing cluster-specific bases, with which the genomic DNA of the ditelosomic lines of group 1 chromosomes of a wheat variety 'Chinese Spring' was employed to carry out chromosome assignment. The subsequent cloning and DNA sequencing of PCR fragments validated the sequences specificity of the 5' flanking conserved sequences between LMW-GS gene groups in different genomes. These results suggested that the coding and 5' flanking regions of LMW-GS genes are likely to have evolved in a concerted fashion. The seven primer sets developed in this study could be used to isolate the complete ORFs of seven groups of LMW-GS genes, respectively, and therefore possess great value for further research in the contributions of a single LMW-GS gene to wheat quality in the complex genetic background and the efficient selections of quality-related components in breeding programs.

  18. Molecular dissection of a contiguous gene syndrome: Frequent submicroscopic deletions, evolutionarily conserved sequences, and a hypomethylated island in the Miller-Dieker chromosome region

    Energy Technology Data Exchange (ETDEWEB)

    Ledbetter, D.H.; Ledbetter, S.A.; vanTuinen, P.; Summers, K.M.; Robinson, T.J.; Nakamura, Yusuke; Wolff, R.; White, R.; Barker, D.F.; Wallace, M.R.; Collins, F.S.; Dobyns, W.B. (Baylor College of Medicine, Houston, TX (USA))

    1989-07-01

    The Miller-Dieker syndrome (MDS), composed of characteristic facial abnormalities and a severe neuronal migration disorder affecting the cerebral cortex, is caused by visible or submicroscopic deletions of chromosome band 17p13. Twelve anonymous DNA markers were tested against a panel of somatic cell hybrids containing 17p deletions from seven MDS patients. All patients, including three with normal karyotypes, are deleted for a variable set of 5-12 markers. Two highly polymorphic VNTR (variable number of tandem repeats) probes, YNZ22 and YNH37, are codeleted in all patients tested and make molecular diagnosis for this disorder feasible. By pulsed-field gel electrophoresis, YNZ22 and YNH37 were shown to be within 30 kilobases (kb) of each other. Cosmid clones containing both VNTR sequences were identified, and restriction mapping showed them to be <15 kb apart. Three overlapping cosmids spanning >100 kb were completely deleted in all patients, providing a minimum estimate of the size of the MDS critical region. A hypomethylated island and evolutionarily conserved sequences were identified within this 100-kb region, indications of the presence of one or more expressed sequences potentially involved in the pathophysiology of this disorder. The conserved sequences were mapped to mouse chromosome 11 by using mouse-rat somatic cell hybrids, extending the remarkable homology between human chromosome 17 and mouse chromosome 11 by 30 centimorgans, into the 17p telomere region.

  19. 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.

  20. MALDI mass spectrometry based molecular phenotyping of CNS glial cells for prediction in mammalian brain tissue

    DEFF Research Database (Denmark)

    Hanrieder, Jørg; Wicher, Grzegorz; Bergquist, Jonas

    2011-01-01

    and straightforward methodology for direct characterization of rodent CNS glial cells using MALDI-MS-based intact cell mass spectrometry (ICMS). This molecular phenotyping approach enables monitoring of cell growth stages, (stem) cell differentiation, as well as probing cellular responses towards different...

  1. Generation and molecular characterization of a monoclonal antibody reactive with conserved epitope in sphingomyelinases D from Loxosceles spider venoms.

    Science.gov (United States)

    Dias-Lopes, C; Felicori, L; Rubrecht, L; Cobo, S; Molina, L; Nguyen, C; Galéa, P; Granier, C; Molina, F; Chávez-Olortegui, C

    2014-04-11

    We report the production of a neutralizing monoclonal antibody able to recognize the venoms of three major medically important species of Loxosceles spiders in Brazil. The mAb was produced by immunization of mice with a toxic recombinant L. intermedia sphingomyelinase D {SMases D isoform (rLiD1)} [1] and screened by enzyme-linked immunosorbent assay (ELISA) using L. intermedia, L. laeta and L. gaucho venoms as antigens. One clone (LiD1mAb16) out of seventeen anti-rLiD1 hybridomas was cross-reactive with the three whole Loxosceles venoms. 2D Western blot analysis indicated that LiD1mAb16 was capable of interacting with 34 proteins of 29-36kDa in L. intermedia, 33 in L. gaucho and 27 in L. laeta venoms. The results of immunoassays with cellulose-bound peptides revealed that the LiD1mAb16 recognizes a highly conserved linear epitope localized in the catalytic region of SMases D toxins. The selected mAb displayed in vivo protective activity in rabbits after challenge with rLiD1. These results show the potential usefulness of monoclonal antibodies for future therapeutic approaches and also opens up the perspective of utilization of these antibodies for immunodiagnostic assays in loxoscelism.

  2. Blood-brain barrier transport studies, aggregation, and molecular dynamics simulation of multiwalled carbon nanotube functionalized with fluorescein isothiocyanate.

    Science.gov (United States)

    Shityakov, Sergey; Salvador, Ellaine; Pastorin, Giorgia; Förster, Carola

    2015-01-01

    In this study, the ability of a multiwalled carbon nanotube functionalized with fluorescein isothiocyanate (MWCNT-FITC) was assessed as a prospective central nervous system-targeting drug delivery system to permeate the blood-brain barrier. The results indicated that the MWCNT-FITC conjugate is able to penetrate microvascular cerebral endothelial monolayers; its concentrations in the Transwell(®) system were fully equilibrated after 48 hours. Cell viability test, together with phase-contrast and fluorescence microscopies, did not detect any signs of MWCNT-FITC toxicity on the cerebral endothelial cells. These microscopic techniques also revealed presumably the intracellular localization of fluorescent MWCNT-FITCs apart from their massive nonfluorescent accumulation on the cellular surface due to nanotube lipophilic properties. In addition, the 1,000 ps molecular dynamics simulation in vacuo discovered the phenomenon of carbon nanotube aggregation driven by van der Waals forces via MWCNT-FITC rapid dissociation as an intermediate phase.

  3. Molecular characterization of a putative K-Cl cotransporter in rat brain. A neuronal-specific isoform.

    Science.gov (United States)

    Payne, J A; Stevenson, T J; Donaldson, L F

    1996-07-05

    Using a combination of data base searching, polymerase chain reaction, and library screening, we have identified a putative K-Cl cotransporter isoform (KCC2) in rat brain that is specifically localized in neurons. A cDNA of 5566 bases was obtained from overlapping clones and encoded a protein of 1116 amino acids with a deduced molecular mass of 123.6 kDa. Over its full length, the amino acid sequence of KCC2 is 67% identical to the widely distributed K-Cl cotransporter isoform (KCC1) identified in rat brain and rabbit kidney (Gillen, C., Brill, S., Payne, J.A., and Forbush, B., III(1996) J. Biol. Chem. 271, 16237-16244) but only approximately25% identical to other members of the cation-chloride cotransporter gene family, including "loop" diuretic-sensitive Na-K-Cl cotransport and thiazide-sensitive Na-Cl cotransport. Based on analysis of the primary structure as well as homology with other cation-chloride cotransporters, we predict 12 transmembrane segments bounded by N- and C-terminal cytoplasmic regions. Four sites for N-linked glycosylation are predicted on an extracellular intermembrane loop between putative transmembrane segments 5 and 6. Northern blot analysis using a KCC2-specific cDNA probe revealed a very highly expressed approximately5.6-kilobase transcript only in brain. Reverse transcriptase-polymerase chain reaction revealed that KCC1 was present in rat primary astrocytes and rat C6 glioma cells but that KCC2 was completely absent from these cells, suggesting KCC2 was not of glial cell origin. In situ hybridization studies demonstrated that the KCC2 transcript was expressed at high levels in neurons throughout the central nervous system, including CA1-CA4 pyramidal neurons of the hippocampus, granular cells and Purkinje neurons of the cerebellum, and many groups of neurons throughout the brainstem.

  4. 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.

  5. Molecular Mechanisms for Exercise Training-Induced Changes in Vascular Structure and Function: Skeletal Muscle, Cardiac Muscle, and the Brain.

    Science.gov (United States)

    Olver, T Dylan; Ferguson, Brian S; Laughlin, M Harold

    2015-01-01

    Compared with resting conditions, during incremental exercise, cardiac output in humans is elevated from ~5 to 25 L min(-1). In conjunction with this increase, the proportion of cardiac output directed toward skeletal muscle increases from ~20% to 85%, while blood flow to cardiac muscle increases 500% and blood flow to specific brain structures increases nearly 200%. Based on existing evidence, researchers believe that blood flow in these tissues is matched to the increases in metabolic rate during exercise. This phenomenon, the matching of blood flow to metabolic requirement, is often referred to as functional hyperemia. This chapter summarizes mechanical and metabolic factors that regulate functional hyperemia as well as other exercise-induced signals, which are also potent stimuli for chronic adaptations in vascular biology. Repeated exposure to exercise-induced increases in shear stress and the induction of angiogenic factors alter vascular cell gene expression and mediate changes in vascular volume and blood flow control. The magnitude and regulation of this coordinated response appear to be tissue specific and coupled to other factors such as hypertrophy and hyperplasia. The cumulative effects of these adaptations contribute to increased exercise capacity, reduced relative challenge of a given submaximal exercise bout and ameliorated vascular outcomes in patient populations with pathological conditions. In the subsequent discussion, this chapter explores exercise as a regulator of vascular biology and summarizes the molecular mechanisms responsible for exercise training-induced changes in vascular structure and function in skeletal and cardiac muscle as well as the brain.

  6. Studies on the molecular correlates of genomic stability in rat brain cells following Amalakirasayana therapy.

    Science.gov (United States)

    Swain, Umakanta; Sindhu, Kiran Kumar; Boda, Ushasri; Pothani, Suresh; Giridharan, Nappan V; Raghunath, Manchala; Rao, Kalluri Subba

    2012-04-01

    Adult Wistar NIN (WNIN) rats (6 months old) of both sexes were orally fed Amalakirasayana at a dose of 4.5 g per kg body weight, five days in a week. The Amalakirasayana was prepared by Arya Vaidya Sala, Kottakkal, Kerala, India, which is considered as gold standard. After 3, 9 and 15 months of such therapeutic regime, rats were sacrificed and various tissues including brain were removed. Isolated cell suspensions of neurons and astroglia were prepared from the cerebral cortex. DNA damage, as a prime indicator of the status of genomic stability was measured in terms of single (SSBs) and double strand breaks (DSBs) through (a). The "comet" assay and (b). The biochemical methods utilizing the unique properties of Escherichia coli DNA polymerase I (pol I) and calf thymus terminal transferase. The results convincingly indicate that while in control animals, there was a distinct increase in DNA damage with age in neurons and astrocytes, rasayana fed animals showed significantly less DNA damage in brain cells demonstrating beneficial effects of Rasayana therapy towards maintenance of genomic stability. DNA-damage may be the proximal cause of aging and strategies to reduce the rate of aging could be based on this fact.

  7. The Prognostic Impact of Molecular Subtypes and Very Young Age on Breast Conserving Surgery in Early Stage Breast Cancer

    Science.gov (United States)

    McGuire, Kandace; Alco, Gul; Nur Pilanci, Kezban; Koksal, Ulkuhan I; Elbüken, Filiz; Erdogan, Zeynep; Agacayak, Filiz; Ilgun, Serkan; Sarsenov, Dauren; Öztürk, Alper; İğdem, Şefik; Okkan, Sait; Eralp, Yeşim; Dincer, Maktav; Ozmen, Vahit

    2016-01-01

    Background Premenopausal breast cancer with a triple-negative phenotype (TNBC) has been associated with inferior locoregional recurrence free survival (LRFS) and overall survival (OS) after breast conserving surgery (BCS). The aim of this study is to analyze the association between age, subtype, and surgical treatment on survival in young women (≤40 years) with early breast cancer in a population with a high rate of breast cancer in young women. Methods Three hundred thirty-two patients ≤40 years old with stage I-II invasive breast cancer who underwent surgery at a single institution between 1998 and 2012 were identified retrospectively. Uni- and multivariate analysis evaluated predictors of LRFS, OS, and disease free survival (DFS). Results Most patients (64.2%) underwent BCS. Mean age and follow-up time were 35 (25 ± 3.61) years, and 72 months (range, 24–252), respectively. In multivariate analysis, multicentricity/multifocality and young age (<35 years) independently predicted for poorer DFS and OS. Those aged 35–40 years had higher LRFS and DFS than those <35 in the mastectomy group (p=0.007 and p=0.039, respectively). Patients with TNBC had lower OS compared with patients with luminal A subtype (p=0.042), and those who underwent BCS had higher OS than patients after mastectomy (p=0.015). Conclusion Young age (< 35 years) is an independent predictor of poorer OS and DFS as compared with ages 35–40, even in countries with a lower average age of breast cancer presentation. In addition, TNBC in the young predicts for poorer OS. BCS can be performed in young patients with TNBC, despite their poorer overall survival. PMID:27433412

  8. MALDI mass spectrometry based molecular phenotyping of CNS glial cells for prediction in mammalian brain tissue

    DEFF Research Database (Denmark)

    Hanrieder, Jørg; Wicher, Grzegorz; Bergquist, Jonas

    2011-01-01

    profiling of mammalian neural cells using direct analysis by means of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). MALDI-MS analysis is rapid, sensitive, robust, and specific for large biomolecules in complex matrices. Here, we describe a newly developed...... and straightforward methodology for direct characterization of rodent CNS glial cells using MALDI-MS-based intact cell mass spectrometry (ICMS). This molecular phenotyping approach enables monitoring of cell growth stages, (stem) cell differentiation, as well as probing cellular responses towards different....... Complementary proteomic experiments revealed the identity of these signature proteins that were predominantly expressed in the different glial cell types, including histone H4 for oligodendrocytes and S100-A10 for astrocytes. MALDI imaging MS was performed, and signature masses were employed as molecular...

  9. Human brain tumor-associated urinary high molecular weight transforming growth factor: a high molecular weight form of epidermal growth factor.

    Science.gov (United States)

    Stromberg, K; Hudgins, W R; Dorman, L S; Henderson, L E; Sowder, R C; Sherrell, B J; Mount, C D; Orth, D N

    1987-02-15

    Urinary protein obtained from a patient with a highly malignant brain tumor (astrocytoma, grade IV) was adsorbed to trimethylsilyl controlled-pore glass beads and selectively eluted with acetonitrile to yield a high molecular weight (HMW) human transforming growth factor (hTGF). This HMW hTGF promoted clonogenic cell growth in soft agar and competed for membrane receptors with mouse epidermal growth factor. After surgical resection of the tumor, no HMW hTGF was found in urine. HMW hTGF generated a human EGF (hEGF) radioimmunoassay competitive binding curve similar to that of hEGF and parallel to that of a highly purified HMW form of hEGF previously reported to be present in trace concentrations in normal human urine. Both hEGF and HMW hEGF were clonogenic in soft agar, and their clonogenic activity as well as that of HMW hTGF was inhibited by anti-hEGF serum. Both HMW hTGF and HMW hEGF had 20 to 25% of the radioreceptor binding activity of hEGF. HMW hTGF purified from the pooled urine of several patients with malignant astrocytomas and HMW hEGF purified from normal control urine comigrated at Mr 33,000. Thus, HMW hTGF was indistinguishable from HMW hEGF in terms of apparent molecular size, epidermal growth factor receptor binding activity, epidermal growth factor immunoreactivity, and clonogenic activity. Urinary HMW hEGF/hTGF may be of tumor cell origin or may represent a response of normal host tissues to the tumor or its products.

  10. Association between neuroserpin and molecular markers of brain damage in patients with acute ischemic stroke

    Directory of Open Access Journals (Sweden)

    Leira Rogelio

    2011-05-01

    Full Text Available Abstract Background Neuroserpin has shown neuroprotective effects in animal models of cerebral ischemia and has been associated with functional outcome after ischemic stroke. Our aim was to study whether neuroserpin serum levels could be associated to biomarkers of excitotoxicity, inflammation and blood brain barrier disruption. Methods We prospectively included 129 patients with ischemic stroke (58.1% male; mean age, 72.4 ± 9.6 years not treated with tPA within 12 hours (h of symptoms onset (mean time, 4.7 ± 2.1 h. Poor functional outcome at 3 months was considered as a modified Rankin scale score >2. Serum levels of neuroserpin, Interleukin 6 (IL-6, Intercellular adhesion molecule-1 (ICAM-1, active Matrix metalloproteinase 9 (MMP-9, and cellular fibronectin (cFn (determined by ELISA and glutamate (determined by HPLC were measured on admission, 24 and 72 h. The main variable was considered the decrease of neuroserpin levels within the first 24 h. ROC analysis was used to select the best predictive value for neuroserpin to predict poor functional outcome due to a lack of linearity. Results The decrease of neuroserpin levels within the first 24 h was negatively correlated with serum levels at 24 hours of glutamate (r = -0.642, IL-6 (r = -0.678, ICAM-1 (r = -0.345, MMP-9 (r = -0.554 and cFn (r = -0.703 (all P Conclusions These findings suggest that neuroprotective properties of neuroserpin may be related to the inhibition of excitotoxicity, inflammation, as well as blood brain barrier disruption that occur after acute ischemic stroke.

  11. Novel molecular pathways elicited by mutant FGFR2 may account for brain abnormalities in Apert syndrome.

    Directory of Open Access Journals (Sweden)

    Erika Yeh

    Full Text Available Apert syndrome (AS, the most severe form craniosynostosis, is characterized by premature fusion of coronal sutures. Approximately 70% of AS patients carry S252W gain-of-function mutation in FGFR2. Besides the cranial phenotype, brain dysmorphologies are present and are not seen in other FGFR2-asociated craniosynostosis, such as Crouzon syndrome (CS. Here, we hypothesized that S252W mutation leads not only to overstimulation of FGFR2 downstream pathway, but likewise induces novel pathological signaling. First, we profiled global gene expression of wild-type and S252W periosteal fibroblasts stimulated with FGF2 to activate FGFR2. The great majority (92% of the differentially expressed genes (DEGs were divergent between each group of cell populations and they were regulated by different transcription factors. We than compared gene expression profiles between AS and CS cell populations and did not observe correlations. Therefore, we show for the first time that S252W mutation in FGFR2 causes a unique cell response to FGF2 stimulation. Since our gene expression results suggested that novel signaling elicited by mutant FGFR2 might be associated with central nervous system (CNS development and maintenance, we next investigated if DEGs found in AS cells were also altered in the CNS of an AS mouse model. Strikingly, we validated Strc (stereocilin in newborn Fgfr2(S252W/+ mouse brain. Moreover, immunostaining experiments suggest a role for endothelial cells and cerebral vasculature in the establishment of characteristic CNS dysmorphologies in AS that has not been proposed by previous literature. Our approach thus led to the identification of new target genes directly or indirectly associated with FGFR2 which are contributing to the pathophysiology of AS.

  12. New neurons in aging brains: molecular control by small non-coding RNAs

    Directory of Open Access Journals (Sweden)

    Marijn eSchouten

    2012-02-01

    Full Text Available Adult neurogenesis is a process that continues in the adult and also aging brain. It generates functional neurons from neural stem cells present in specific brain regions. This phenomenon is largely confined to two main regions: the subventricular zone of the lateral ventricle, and the subgranular zone of the dentate gyrus, in the hippocampus. With age, the hippocampus and particularly the dentate gyrus are affected. For instance, adult neurogenesis is decreased with aging, in both the number of proliferating cells as well as their neuronal differentiation, while in parallel an age-associated decline in cognitive performance is often seen. Surprisingly, the synaptogenic potential of adult-born neurons appears unaffected by aging. Therefore, although proliferation, differentiation, survival and synaptogenesis of adult-born new neurons in the dentate gyrus are closely related to each other, they appear differentially regulated with aging. In this review we discuss the crucial role of a novel class of recently discovered regulators of gene expression, i.e. the small non-coding RNAs, in the development of adult neurogenesis from neural stem cells to functionally integrated neurons. In particular, a subgroup of the small non-coding RNAs, the microRNAs, fine-tune many events during adult neurogenesis progression. Moreover, multiple small non-coding RNAs are differentially expressed in the aged hippocampus. This makes small non-coding RNAs appealing candidates to orchestrate, and possibly correct or prevent, the functional alterations in adult neurogenesis and cognition associated with aging. Finally, we briefly summarize observations that link changes in circulating levels of steroid hormones with alterations in adult neurogenesis and subsequent vulnerability to psychopathology in advanced age, and discuss a possible role of microRNAs in stress-associated alterations in adult neurogenesis during aging.

  13. Efficient somatic embryogenesis and molecular marker based analysis as effective tools for conservation of red-listed plant Commiphora wightii

    Directory of Open Access Journals (Sweden)

    ASHOK KUMAR PARMAR

    2014-08-01

    Full Text Available A refined and high efficiency protocol for in vitro regeneration of Commiphora wightii, a red-listed medicinal plant of medicinal importance, has been developed through optimized somatic embryogenesis pathway. Cultures from immature fruits were induced and proliferated on B5 medium supplemented with 2.26 µM 2,4-D. Embryogenic calli were obtained and then maintained for extended periods by alternately subculturing on modified MS medium supplemented with 1.11 µM BAP, 0.57 µM IBA and with 0.5% activated charcoal or without PGR every 3-4 weeks. Cyclic embryogenesis was obtained. Late torpedo and early cotyledonary stages somatic embryos were regularly harvested from PGR-free modified MS medium. It was found that percent moisture available in culture containers play a critical role in maturation and subsequent germination of somatic embryos of C. wighti. Maximum germination of more than 80% was achieved through media recycling. Somatic embryo derived plants (emblings were acclimatized. After 5 months, acclimatized plants were out-planted in experimental field. These morphologically normal plants have been surviving for over 3 years. Molecular polymorphism was clearly evident when these plants were tested using RAPD primers, making the plants suitable for use in its species restoration program.

  14. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.

    Science.gov (United States)

    Sturm, Dominik; Orr, Brent A; Toprak, Umut H; Hovestadt, Volker; Jones, David T W; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J; Balasubramanian, Gnanaprakash; Worst, Barbara C; Pajtler, Kristian W; Brabetz, Sebastian; Johann, Pascal D; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M; Remke, Marc; Phillips, Joanna J; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C; Schniederjan, Matthew J; Santi, Mariarita; Buccoliero, Anna M; Dahiya, Sonika; Kramm, Christof M; von Bueren, André O; von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U; Shalaby, Tarek; Grotzer, Michael; van Meter, Timothy; Monoranu, Camelia-Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S; Taylor, Michael D; Jones, Chris; Jabado, Nada; Karajannis, Matthias A; Eils, Roland; Schlesner, Matthias; Lichter, Peter; von Deimling, Andreas; Pfister, Stefan M; Ellison, David W; Korshunov, Andrey; Kool, Marcel

    2016-02-25

    Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.

  15. Molecular and metabolic pattern classification for detection of brain glioma progression

    Energy Technology Data Exchange (ETDEWEB)

    Imani, Farzin, E-mail: imanif@upmc.edu [Department of Radiology, University of Pittsburgh Medical Center, PA (United States); Boada, Fernando E. [Department of Radiology, University of Pittsburgh Medical Center, PA (United States); Lieberman, Frank S. [Department of Neurology, University of Pittsburgh Medical Center, PA (United States); Davis, Denise K.; Mountz, James M. [Department of Radiology, University of Pittsburgh Medical Center, PA (United States)

    2014-02-15

    Objectives: The ability to differentiate between brain tumor progression and radiation therapy induced necrosis is critical for appropriate patient management. In order to improve the differential diagnosis, we combined fluorine-18 2-fluoro-deoxyglucose positron emission tomography ({sup 18}F-FDG PET), proton magnetic resonance spectroscopy ({sup 1}H MRS) and histological data to develop a multi-parametric machine-learning model. Methods: We enrolled twelve post-therapy patients with grade 2 and 3 gliomas that were suspicious of tumor progression. All patients underwent {sup 18}F-FDG PET and {sup 1}H MRS. Maximal standardized uptake value (SUVmax) of the tumors and reference regions were obtained. Multiple 2D maps of choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) of the tumors were generated. A support vector machine (SVM) learning model was established to take imaging biomarkers and histological data as input vectors. A combination of clinical follow-up and multiple sequential MRI studies served as the basis for assessing the clinical outcome. All vector combinations were evaluated for diagnostic accuracy and cross validation. The optimal cutoff value of individual parameters was calculated using Receiver operating characteristic (ROC) plots. Results: The SVM and ROC analyses both demonstrated that SUVmax of the lesion was the most significant single diagnostic parameter (75% accuracy) followed by Cho concentration (67% accuracy). SVM analysis of all paired parameters showed SUVmax and Cho concentration in combination could achieve 83% accuracy. SUVmax of the lesion paired with SUVmax of the white matter as well as the tumor Cho paired with the tumor Cr both showed 83% accuracy. These were the most significant paired diagnostic parameters of either modality. Combining all four parameters did not improve the results. However, addition of two more parameters, Cho and Cr of brain parenchyma contralateral to the tumor, increased the accuracy to 92

  16. Molecular and Genetic Characterization of HIV-1 Tat Exon-1 Gene from Cameroon Shows Conserved Tat HLA-Binding Epitopes: Functional Implications

    Science.gov (United States)

    Teto, Georges; Fonsah, Julius Y.; Tagny, Claude T.; Mbanya, Dora; Nchindap, Emilienne; Kenmogne, Leopoldine; Fokam, Joseph; Njamnshi, Dora M.; Kouanfack, Charles; Njamnshi, Alfred K.; Kanmogne, Georgette D.

    2016-01-01

    HIV-1 Tat plays a critical role in viral transactivation. Subtype-B Tat has potential use as a therapeutic vaccine. However, viral genetic diversity and population genetics would significantly impact the efficacy of such a vaccine. Over 70% of the 37-million HIV-infected individuals are in sub-Saharan Africa (SSA) and harbor non-subtype-B HIV-1. Using specimens from 100 HIV-infected Cameroonians, we analyzed the sequences of HIV-1 Tat exon-1, its functional domains, post-translational modifications (PTMs), and human leukocyte antigens (HLA)-binding epitopes. Molecular phylogeny revealed a high genetic diversity with nine subtypes, CRF22_01A1/CRF01_AE, and negative selection in all subtypes. Amino acid mutations in Tat functional domains included N24K (44%), N29K (58%), and N40K (30%) in CRF02_AG, and N24K in all G subtypes. Motifs and phosphorylation analyses showed conserved amidation, N-myristoylation, casein kinase-2 (CK2), serine and threonine phosphorylation sites. Analysis of HLA allelic frequencies showed that epitopes for HLAs A*0205, B*5301, Cw*0401, Cw*0602, and Cw*0702 were conserved in 58%–100% of samples, with B*5301 epitopes having binding affinity scores > 100 in all subtypes. This is the first report of N-myristoylation, amidation, and CK2 sites in Tat; these PTMs and mutations could affect Tat function. HLA epitopes identified could be useful for designing Tat-based vaccines for highly diverse HIV-1 populations, as in SSA. PMID:27438849

  17. Molecular sensing of bacteria in plants. The highly conserved RNA-binding motif RNP-1 of bacterial cold shock proteins is recognized as an elicitor signal in tobacco.

    Science.gov (United States)

    Felix, Georg; Boller, Thomas

    2003-02-21

    To detect microbial infection multicellular organisms have evolved sensing systems for pathogen-associated molecular patterns (PAMPs). Here, we identify bacterial cold shock protein (CSP) as a new such PAMP that acts as a highly active elicitor of defense responses in tobacco. Tobacco cells perceive a conserved domain of CSP and synthetic peptides representing 15 amino acids of this domain-induced responses at subnanomolar concentrations. Central to the elicitor-active domain is the RNP-1 motif KGFGFITP, a motif conserved also in many RNA- and DNA-binding proteins of eukaryotes. Csp15-Nsyl, a peptide representing the domain with highest homology to csp15 in a protein of Nicotiana sylvestris exhibited only weak activity in tobacco cells. Crystallographic and genetic data from the literature show that the RNP-1 domain of bacterial CSPs resides on a protruding loop and exposes a series of aromatic and basic side chains to the surface that are essential for the nucleotide-binding activity of CSPs. Similarly, these side chains were also essential for elicitor activity and replacement of single residues in csp15 with Ala strongly reduced or abolished activity. Most strikingly, csp15-Ala10, a peptide with the RNP-1 motif modified to KGAGFITP, lacked elicitor activity but acted as a competitive antagonist for CSP-related elicitors. Bacteria commonly have a small family of CSP-like proteins including both cold-inducible and noninducible members, and Csp-related elicitor activity was detected in extracts from all bacteria tested. Thus, the CSP domain containing the RNP-1 motif provides a structure characteristic for bacteria in general, and tobacco plants have evolved a highly sensitive chemoperception system to detect this bacterial PAMP.

  18. Current and Emerging Technologies for Probing Molecular Signatures of Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Ari Ercole

    2017-08-01

    Full Text Available Traumatic brain injury (TBI is understood as an interplay between the initial injury, subsequent secondary injuries, and a complex host response all of which are highly heterogeneous. An understanding of the underlying biology suggests a number of windows where mechanistically inspired interventions could be targeted. Unfortunately, biologically plausible therapies have to-date failed to translate into clinical practice. While a number of stereotypical pathways are now understood to be involved, current clinical characterization is too crude for it to be possible to characterize the biological phenotype in a truly mechanistically meaningful way. In this review, we examine current and emerging technologies for fuller biochemical characterization by the simultaneous measurement of multiple, diverse biomarkers. We describe how clinically available techniques such as cerebral microdialysis can be leveraged to give mechanistic insights into TBI pathobiology and how multiplex proteomic and metabolomic techniques can give a more complete description of the underlying biology. We also describe spatially resolved label-free multiplex techniques capable of probing structural differences in chemical signatures. Finally, we touch on the bioinformatics challenges that result from the acquisition of such large amounts of chemical data in the search for a more mechanistically complete description of the TBI phenotype.

  19. Early Brain Response to Low-Dose Radiation Exposure Involves Molecular Networks and Pathways Associated with Cognitive Functions, Advanced Aging and Alzheimer's Disease

    Energy Technology Data Exchange (ETDEWEB)

    Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco; Wyrobek, Andrew J.

    2008-06-06

    Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy, environmental nuclear contamination, as well as earth orbit and space missions. Analyses of transcriptome profiles of murine brain tissue after whole-body radiation showed that low-dose exposures (10 cGy) induced genes not affected by high dose (2 Gy), and low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues, and pathways that were brain tissue specific. Low-dose genes clustered into a saturated network (p < 10{sup -53}) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified 9 neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose radiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down regulated in normal human aging and Alzheimer's disease.

  20. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease.

    Science.gov (United States)

    Prinz, Marco; Priller, Josef

    2014-05-01

    Mononuclear phagocytic cells in the CNS used to be defined according to their anatomical location and surface marker expression. Recently, this concept has been challenged by the results of developmental and gene expression profiling studies that have used novel molecular biological tools to unravel the origin of microglia and to define their role as specialized tissue macrophages with long lifespans. Here, we describe how these results have redefined microglia and helped us to understand how different myeloid cell populations operate in the CNS based on their cell-specific gene expression signatures, distinct ontogeny and differential functions. Moreover, we describe the vulnerability of microglia to dysfunction and propose that myelomonocytic cells might be used in the treatment of neurological and psychiatric disorders that are characterized by primary or secondary 'microgliopathy'.

  1. Molecular Transducers from Roots Are Triggered in Arabidopsis Leaves by Root-Knot Nematodes for Successful Feeding Site Formation: A Conserved Post-Embryogenic De novo Organogenesis Program?

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    Rocío Olmo

    2017-05-01

    Full Text Available Root-knot nematodes (RKNs; Meloidogyne spp. induce feeding cells (giant cells; GCs inside a pseudo-organ (gall from still unknown root cells. Understanding GCs ontogeny is essential to the basic knowledge of RKN–plant interaction and to discover novel and effective control strategies. Hence, we report for the first time in a model plant, Arabidopsis, molecular, and cellular features concerning ectopic de novo organogenesis of RKNs GCs in leaves. RKNs induce GCs in leaves with irregular shape, a reticulated cytosol, and fragmented vacuoles as GCs from roots. Leaf cells around the nematode enter G2-M shown by ProCycB1;1:CycB1;1(NT-GUS expression, consistent to multinucleated GCs. In addition, GCs nuclei present irregular and varied sizes. All these characteristics mentioned, being equivalent to GCs in root-galls. RKNs complete their life cycle forming a gall/callus-like structure in the leaf vascular tissues resembling auxin-induced callus with an auxin-response maxima, indicated by high expression of DR5::GUS that is dependent on leaf auxin-transport. Notably, induction of leaves calli/GCs requires molecular components from roots crucial for lateral roots (LRs, auxin-induced callus and root-gall formation, i.e., LBD16. Hence, LBD16 is a xylem pole pericycle specific and local marker in LR primordia unexpectedly induced locally in the vascular tissue of leaves after RKN infection. LBD16 is also fundamental for feeding site formation as RKNs could not stablish in 35S::LBD16-SRDX leaves, and likely it is also a conserved molecular hub between biotic and developmental signals in Arabidopsis either in roots or leaves. Moreover, RKNs induce the ectopic development of roots from leaf and root-galls, also formed in mutants compromised in LR formation, arf7/arf19, slr, and alf4. Therefore, nematodes must target molecular signatures to induce post-embryogenic de novo organogenesis through the LBD16 callus formation pathway partially different from those

  2. Cellular and molecular mechanisms of immunomodulation in the brain through environmental enrichment

    Directory of Open Access Journals (Sweden)

    Gaurav eSinghal

    2014-04-01

    Full Text Available Recent studies on environmental enrichment (EE have shown cytokines, cellular immune components (e.g. T lymphocytes, NK cells and glial cells in causal relationship to EE in bringing out changes to neurobiology and behavior. The purpose of this review is to evaluate these neuroimmune mechanisms associated with neurobiological and behavioral changes in response to different EE methods. We systematically reviewed common research databases. After applying all inclusion and exclusion criteria, 328 articles remained for this review. Physical exercise, a form of EE, elicits anti-inflammatory and neuromodulatory effects through interaction with several immune pathways including IL-6 secretion from muscle fibers, reduced expression of TLR’s on monocytes and macrophages, reduced secretion of adipokines, modulation of hippocampal T cells, priming of microglia and upregulation of MKP-1 in CNS. In contrast, immunomodulatory roles of other enrichment methods are not studied extensively. Nonetheless, studies showing reduction in the expression of IL-1β and TNF-α in response to enrichment with novel objects and accessories suggest anti-inflammatory effects of novel environment. Likewise, social enrichment, though considered a necessity for healthy behavior, results in immunosuppression in socially defeated animals. This has been attributed to reduction in T lymphocytes, NK cells and IL-10 in subordinate animals. EE through sensory stimuli has been investigated to a lesser extent and the effect on immune factors has not been evaluated yet. Discovery of this multidimensional relationship between immune system, brain functioning and EE has paved a way towards formulating environ-immuno therapies for treating psychiatric illnesses with minimal use of pharmacotherapy. While the immuno-modulatory role of physical exercise has been evaluated extensively, more research is required to investigate neuroimmune changes associated with other enrichment methods.

  3. Cellular and molecular mechanisms of immunomodulation in the brain through environmental enrichment.

    Science.gov (United States)

    Singhal, Gaurav; Jaehne, Emily J; Corrigan, Frances; Baune, Bernhard T

    2014-01-01

    Recent studies on environmental enrichment (EE) have shown cytokines, cellular immune components [e.g., T lymphocytes, natural killer (NK) cells], and glial cells in causal relationship to EE in bringing out changes to neurobiology and behavior. The purpose of this review is to evaluate these neuroimmune mechanisms associated with neurobiological and behavioral changes in response to different EE methods. We systematically reviewed common research databases. After applying all inclusion and exclusion criteria, 328 articles remained for this review. Physical exercise (PE), a form of EE, elicits anti-inflammatory and neuromodulatory effects through interaction with several immune pathways including interleukin (IL)-6 secretion from muscle fibers, reduced expression of Toll-like receptors on monocytes and macrophages, reduced secretion of adipokines, modulation of hippocampal T cells, priming of microglia, and upregulation of mitogen-activated protein kinase phosphatase-1 in central nervous system. In contrast, immunomodulatory roles of other enrichment methods are not studied extensively. Nonetheless, studies showing reduction in the expression of IL-1β and tumor necrosis factor-α in response to enrichment with novel objects and accessories suggest anti-inflammatory effects of novel environment. Likewise, social enrichment, though considered a necessity for healthy behavior, results in immunosuppression in socially defeated animals. This has been attributed to reduction in T lymphocytes, NK cells and IL-10 in subordinate animals. EE through sensory stimuli has been investigated to a lesser extent and the effect on immune factors has not been evaluated yet. Discovery of this multidimensional relationship between immune system, brain functioning, and EE has paved a way toward formulating environ-immuno therapies for treating psychiatric illnesses with minimal use of pharmacotherapy. While the immunomodulatory role of PE has been evaluated extensively, more research

  4. Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain.

    Science.gov (United States)

    Trang, Tuan; Beggs, Simon; Salter, Michael W

    2011-02-01

    One of the most significant advances in pain research is the realization that neurons are not the only cell type involved in the etiology of chronic pain. This realization has caused a radical shift from the previous dogma that neuronal dysfunction alone accounts for pain pathologies to the current framework of thinking that takes into account all cell types within the central nervous system (CNS). This shift in thinking stems from growing evidence that glia can modulate the function and directly shape the cellular architecture of nociceptive networks in the CNS. Microglia, in particular, are increasingly recognized as active principal players that respond to changes in physiological homeostasis by extending their processes toward the site of neural damage, and by releasing specific factors that have profound consequences on neuronal function and that contribute to CNS pathologies caused by disease or injury. A key molecule that modulates microglia activity is ATP, an endogenous ligand of the P2 receptor family. Microglia expresses several P2 receptor subtypes, and of these the P2X4 receptor subtype has emerged as a core microglia-neuron signaling pathway: activation of this receptor drives the release of brain-derived neurotrophic factor (BDNF), a cellular substrate that causes disinhibition of pain-transmitting spinal lamina I neurons. Converging evidence points to BDNF from spinal microglia as being a critical microglia-neuron signaling molecule that gates aberrant nociceptive processing in the spinal cord. The present review highlights recent advances in our understanding of P2X4 receptor-mediated signaling and regulation of BDNF in microglia, as well as the implications for microglia-neuron interactions in the pathobiology of neuropathic pain.

  5. Molecular evolution of the human SRPX2 gene that causes brain disorders of the Rolandic and Sylvian speech areas

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    Levasseur Anthony

    2007-10-01

    Full Text Available Abstract Background The X-linked SRPX2 gene encodes a Sushi Repeat-containing Protein of unknown function and is mutated in two disorders of the Rolandic/Sylvian speech areas. Since it is linked to defects in the functioning and the development of brain areas for speech production, SRPX2 may thus have participated in the adaptive organization of such brain regions. To address this issue, we have examined the recent molecular evolution of the SRPX2 gene. Results The complete coding region was sequenced in 24 human X chromosomes from worldwide populations and in six representative nonhuman primate species. One single, fixed amino acid change (R75K has been specifically incorporated in human SRPX2 since the human-chimpanzee split. The R75K substitution occurred in the first sushi domain of SRPX2, only three amino acid residues away from a previously reported disease-causing mutation (Y72S. Three-dimensional structural modeling of the first sushi domain revealed that Y72 and K75 are both situated in the hypervariable loop that is usually implicated in protein-protein interactions. The side-chain of residue 75 is exposed, and is located within an unusual and SRPX-specific protruding extension to the hypervariable loop. The analysis of non-synonymous/synonymous substitution rate (Ka/Ks ratio in primates was performed in order to test for positive selection during recent evolution. Using the branch models, the Ka/Ks ratio for the human branch was significantly different (p = 0.027 from that of the other branches. In contrast, the branch-site tests did not reach significance. Genetic analysis was also performed by sequencing 9,908 kilobases (kb of intronic SRPX2 sequences. Despite low nucleotide diversity, neither the HKA (Hudson-Kreitman-Aguadé test nor the Tajima's D test reached significance. Conclusion The R75K human-specific variation occurred in an important functional loop of the first sushi domain of SRPX2, indicating that this evolutionary

  6. Targeting N-Glycan Cryptic Sugar Moieties for Broad-Spectrum Virus Neutralization: Progress in Identifying Conserved Molecular Targets in Viruses of Distinct Phylogenetic Origins

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    Denong Wang

    2015-03-01

    Full Text Available Identifying molecular targets for eliciting broadly virus-neutralizing antibodies is one of the key steps toward development of vaccines against emerging viral pathogens. Owing to genomic and somatic diversities among viral species, identifying protein targets for broad-spectrum virus neutralization is highly challenging even for the same virus, such as HIV-1. However, viruses rely on host glycosylation machineries to synthesize and express glycans and, thereby, may display common carbohydrate moieties. Thus, exploring glycan-binding profiles of broad-spectrum virus-neutralizing agents may provide key information to uncover the carbohydrate-based virus-neutralizing epitopes. In this study, we characterized two broadly HIV-neutralizing agents, human monoclonal antibody 2G12 and Galanthus nivalis lectin (GNA, for their viral targeting activities. Although these agents were known to be specific for oligomannosyl antigens, they differ strikingly in virus-binding activities. The former is HIV-1 specific; the latter is broadly reactive and is able to neutralize viruses of distinct phylogenetic origins, such as HIV-1, severe acute respiratory syndrome coronavirus (SARS-CoV, and human cytomegalovirus (HCMV. In carbohydrate microarray analyses, we explored the molecular basis underlying the striking differences in the spectrum of anti-virus activities of the two probes. Unlike 2G12, which is strictly specific for the high-density Man9GlcNAc2Asn (Man9-clusters, GNA recognizes a number of N-glycan cryptic sugar moieties. These include not only the known oligomannosyl antigens but also previously unrecognized tri-antennary or multi-valent GlcNAc-terminating N-glycan epitopes (Tri/m-Gn. These findings highlight the potential of N-glycan cryptic sugar moieties as conserved targets for broad-spectrum virus neutralization and suggest the GNA-model of glycan-binding warrants focused investigation.

  7. Understanding the molecular basis of stability in Kunitz (STI) family of inhibitors in terms of a conserved core tryptophan residue: A theoretical investigation.

    Science.gov (United States)

    Datta Sharma, Ravi; Goswami, Nabajyoti; Ghosh, Debasree; Majumder, Sudip

    2017-08-01

    β-trefoil is one of the superfolds among proteins. Important classes of proteins like Interleukins (ILs), FibroblastGrowth Factors (FGFs), Kunitz (STI) family of inhibitors etc. belong to this fold. Kunitz (STI) family of inhibitors of proteins possess a highly conserved and structurally important Trytophan 91 (W91) residue, which stitches the top layer of the barrel with the lid. In this article we have investigated the molecular insights of the involvement of this W91 residue in the stability and folding pathway of Kunitz (STI) family. Winged bean Chymotrypsin inhibitor (WCI), a member of Kunitz (STI) family was chosen as a model system for carrying out the work. Molecular dynamics (MD) simulations were run with a set of total six proteins, including wild type WCI (WT) & five mutants namely W91F, W91M, W91A, W91H and W91I. Among all of them the coordinates of four proteins were taken from their crystal structures deposited in the Protein Data Bank (PDB), where as the coordinates for the rest two was generated using in-silico modelling. Our results suggest that truly this W91 residue plays a determining role in stability and folding pathway of Kunitz (STI) family. The mutants are less stable and more susceptible to quicker unfolding at higher temperatures compared to the wild type WCI. These effects are most pronounced for the smallest mutants namely W91H and W91A, indicating more is the cavity created by mutation at W91 position more the proteins becomes unstable. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. From Amazonia to the Atlantic forest: molecular phylogeny of Phyzelaphryninae frogs reveals unexpected diversity and a striking biogeographic pattern emphasizing conservation challenges.

    Science.gov (United States)

    Fouquet, Antoine; Loebmann, Daniel; Castroviejo-Fisher, Santiago; Padial, José M; Orrico, Victor G D; Lyra, Mariana L; Roberto, Igor Joventino; Kok, Philippe J R; Haddad, Célio F B; Rodrigues, Miguel T

    2012-11-01

    Documenting the Neotropical amphibian diversity has become a major challenge facing the threat of global climate change and the pace of environmental alteration. Recent molecular phylogenetic studies have revealed that the actual number of species in South American tropical forests is largely underestimated, but also that many lineages are millions of years old. The genera Phyzelaphryne (1 sp.) and Adelophryne (6 spp.), which compose the subfamily Phyzelaphryninae, include poorly documented, secretive, and minute frogs with an unusual distribution pattern that encompasses the biotic disjunction between Amazonia and the Atlantic forest. We generated >5.8 kb sequence data from six markers for all seven nominal species of the subfamily as well as for newly discovered populations in order to (1) test the monophyly of Phyzelaphryninae, Adelophryne and Phyzelaphryne, (2) estimate species diversity within the subfamily, and (3) investigate their historical biogeography and diversification. Phylogenetic reconstruction confirmed the monophyly of each group and revealed deep subdivisions within Adelophryne and Phyzelaphryne, with three major clades in Adelophryne located in northern Amazonia, northern Atlantic forest and southern Atlantic forest. Our results suggest that the actual number of species in Phyzelaphryninae is, at least, twice the currently recognized species diversity, with almost every geographically isolated population representing an anciently divergent candidate species. Such results highlight the challenges for conservation, especially in the northern Atlantic forest where it is still degraded at a fast pace. Molecular dating revealed that Phyzelaphryninae originated in Amazonia and dispersed during early Miocene to the Atlantic forest. The two Atlantic forest clades of Adelophryne started to diversify some 7 Ma minimum, while the northern Amazonian Adelophryne diversified much earlier, some 13 Ma minimum. This striking biogeographic pattern coincides with

  9. Development of solid-phase microextraction coupled with liquid chromatography for analysis of tramadol in brain tissue using its molecularly imprinted polymer.

    Science.gov (United States)

    Habibi-Khorasani, Monireh; Mohammadpour, Amir Hooshang; Mohajeri, Seyed Ahmad

    2017-02-01

    In this work, performance of a molecularly imprinted polymer (MIP) as a selective solid-phase microextraction sorbent for the extraction and enrichment of tramadol in aqueous solution and rabbit brain tissue, is described. Binding properties of MIPs were studied in comparison with their nonimprinted polymer (NIP). Ten milligrams of the optimized MIP was then evaluated as a sorbent, for preconcentration, in molecularly imprinted solid-phase microextraction (MISPME) of tramadol from aqueous solution and rabbit brain tissue. The analytical method was calibrated in the range of 0.004 ppm (4 ng mL(-1) ) and 10 ppm (10 μg mL(-1) ) in aqueous media and in the ranges of 0.01 and 10 ppm in rabbit brain tissue, respectively. The results indicated significantly higher binding affinity of MIPs to tramadol, in comparison with NIP. The MISPME procedure was developed and optimized with a recovery of 81.12-107.54% in aqueous solution and 76.16-91.20% in rabbit brain tissue. The inter- and intra-day variation values were tramadol in real rabbit brain tissue samples after administration of a lethal dose. Our data demonstrated the potential of MISPME for rapid, sensitive and cost-effective sample analysis. Copyright © 2016 John Wiley & Sons, Ltd.

  10. Chronic dietary n-6 PUFA deprivation leads to conservation of arachidonic acid and more rapid loss of DHA in rat brain phospholipids.

    Science.gov (United States)

    Lin, Lauren E; Chen, Chuck T; Hildebrand, Kayla D; Liu, Zhen; Hopperton, Kathryn E; Bazinet, Richard P

    2015-02-01

    To determine how the level of dietary n-6 PUFA affects the rate of loss of arachidonic acid (ARA) and DHA in brain phospholipids, male rats were fed either a deprived or adequate n-6 PUFA diet for 15 weeks postweaning, and then subjected to an intracerebroventricular infusion of (3)H-ARA or (3)H-DHA. Brains were collected at fixed times over 128 days to determine half-lives and the rates of loss from brain phospholipids (J out). Compared with the adequate n-6 PUFA rats, the deprived n-6-PUFA rats had a 15% lower concentration of ARA and an 18% higher concentration of DHA in their brain total phospholipids. Loss half-lives of ARA in brain total phospholipids and fractions (except phosphatidylserine) were longer in the deprived n-6 PUFA rats, whereas the J out was decreased. In the deprived versus adequate n-6 PUFA rats, the J out of DHA was higher. In conclusion, chronic n-6 PUFA deprivation decreases the rate of loss of ARA and increases the rate of loss of DHA in brain phospholipids. Thus, a low n-6 PUFA diet can be used to target brain ARA and DHA metabolism.

  11. Metabolite profiles of essential oils and molecular markers analysis to explore the biodiversity of Ferula communis: Towards conservation of the endemic giant fennel.

    Science.gov (United States)

    Rahali, Fatma Zohra; Lamine, Myriam; Gargouri, Mahmoud; Rebey, Iness Bettaieb; Hammami, Majdi; Sellami, Ibtissem Hamrouni

    2016-04-01

    in situ conservation. The analysis of chemical constitution of oil of the populations from a specific region revealed predominance of specific constituents indicating possibility of their collection/selection for specific end uses like phytomedicines. Sufficient molecular and biochemical diversity detected among natural populations of this species will form the basis for the future improvement. The correlation between matrices of RAPD and essential oils was not significant. The conservation strategies of populations should be made according to their level of genetic and chemical diversity in relation to geographic location of populations. Our results give some insights into the characterization of this as yet little investigated plant.

  12. Differences in the molecular structure of the blood-brain barrier in the cerebral cortex and white matter: an in silico, in vitro, and ex vivo study.

    Science.gov (United States)

    Nyúl-Tóth, Ádám; Suciu, Maria; Molnár, Judit; Fazakas, Csilla; Haskó, János; Herman, Hildegard; Farkas, Attila E; Kaszaki, József; Hermenean, Anca; Wilhelm, Imola; Krizbai, István A

    2016-06-01

    The blood-brain barrier (BBB) is the main interface controlling molecular and cellular traffic between the central nervous system (CNS) and the periphery. It consists of cerebral endothelial cells (CECs) interconnected by continuous tight junctions, and closely associated pericytes and astrocytes. Different parts of the CNS have diverse functions and structures and may be subject of different pathologies, in which the BBB is actively involved. It is largely unknown, however, what are the cellular and molecular differences of the BBB in different regions of the brain. Using in silico, in vitro, and ex vivo techniques we compared the expression of BBB-associated genes and proteins (i.e., markers of CECs, brain pericytes, and astrocytes) in the cortical grey matter and white matter. In silico human database analysis (obtained from recalculated data of the Allen Brain Atlas), qPCR, Western blot, and immunofluorescence studies on porcine and mouse brain tissue indicated an increased expression of glial fibrillary acidic protein in astrocytes in the white matter compared with the grey matter. We have also found increased expression of genes of the junctional complex of CECs (occludin, claudin-5, and α-catenin) in the white matter compared with the cerebral cortex. Accordingly, occludin, claudin-5, and α-catenin proteins showed increased expression in CECs of the white matter compared with endothelial cells of the cortical grey matter. In parallel, barrier properties of white matter CECs were superior as well. These differences might be important in the pathogenesis of diseases differently affecting distinct regions of the brain.

  13. The enteric bacterial metabolite propionic acid alters brain and plasma phospholipid molecular species: further development of a rodent model of autism spectrum disorders

    Directory of Open Access Journals (Sweden)

    Thomas Raymond H

    2012-07-01

    Full Text Available Abstract Gastrointestinal symptoms and altered blood phospholipid profiles have been reported in patients with autism spectrum disorders (ASD. Most of the phospholipid analyses have been conducted on the fatty acid composition of isolated phospholipid classes following hydrolysis. A paucity of information exists on how the intact phospholipid molecular species are altered in ASD. We applied ESI/MS to determine how brain and blood intact phospholipid species were altered during the induction of ASD-like behaviors in rats following intraventricular infusions with the enteric bacterial metabolite propionic acid. Animals were infused daily for 8 days, locomotor activity assessed, and animals killed during the induced behaviors. Propionic acid infusions increased locomotor activity. Lipid analysis revealed treatment altered 21 brain and 30 blood phospholipid molecular species. Notable alterations were observed in the composition of brain SM, diacyl mono and polyunsaturated PC, PI, PS, PE, and plasmalogen PC and PE molecular species. These alterations suggest that the propionic acid rat model is a useful tool to study aberrations in lipid metabolism known to affect membrane fluidity, peroxisomal function, gap junction coupling capacity, signaling, and neuroinflammation, all of which may be associated with the pathogenesis of ASD.

  14. Molecular cloning of a highly conserved mouse and human integral membrane protein (Itm1) and genetic mapping to mouse chromosome 9

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Guizhu; Tylzanowski, P. [Univ. of Antwerp (Belgium); Deleersnijder, W. [N.V. Innogenetics, Ghent (Belgium)] [and others

    1996-02-01

    We have isolated and characterized a novel cDNA coding for a highly hydrophobic protein (B5) from a fetal mouse mandibular condyle cDNA library. The full-length mouse B5 cDNA is 3095 nucleotides long and contains a potential open reading frame coding for a protein of 705 amino acids with a calculated molecular weight of 80.5 kDa. The B5 mRNA is differentially polyadenylated, with the most abundant transcript having a length of 2.7 kb. The human homolog of B5 was isolated from a cDNA testis library. The predicted amino acid sequence of the human B5 is 98.5% identical to that of mouse. The most striking feature of the B5 protein is the presence of numerous (10-14) potential transmembrane domains, characteristic of an integral membrane protein. Similarity searches in public databanks reveal that B5 is 58% similar to the T12A2.2 gene of Caenorhabditis elegans and 60% similar to the STT3 gene of Saccharomyces cerevisiae. Futhermore, the report of an EST sequence (Accession No. Z13858) related to the human B5, but identical to the STT3 gene, indicates that B5 belongs to a larger gene family coding for novel putative transmembrane proteins. This family exhibits a remarkable degree of conservation in different species. The gene for B5, designated Itm1 (Integral membrane protein 1), is located on mouse chromosome 9. 28 refs., 4 figs.

  15. Insights into brain development and disease from neurogenetic analyses in Drosophila melanogaster

    Indian Academy of Sciences (India)

    Heinrich Reichert

    2014-09-01

    Groundbreaking work by Obaid Siddiqi has contributed to the powerful genetic toolkit that is now available for studying the nervous system of Drosophila. Studies carried out in this powerful neurogenetic model system during the last decade now provide insight into the molecular mechanisms that operate in neural stem cells during normal brain development and during abnormal brain tumorigenesis. These studies also provide strong support for the notion that conserved molecular genetic programs act in brain development and disease in insects and mammals including humans.

  16. Conservative management.

    Science.gov (United States)

    Kruis, W; Leifeld, L; Pfützer, R

    2012-01-01

    Treatment of diverticulitis comprises at least two options: conservative or surgical management. There is a recent trend to limit surgical treatment of acute diverticulitis and to favor conservative management. This review addresses general aspects of conservative patient care with special focus on the treatment of patients with a first attack of diverticulitis. The presentation does not include a discussion of specific drugs which is given in other sections of this issue.

  17. Comparative membrane proteomics analyses of breast cancer cell lines to understand the molecular mechanism of breast cancer brain metastasis.

    Science.gov (United States)

    Peng, Wenjing; Zhang, Yu; Zhu, Rui; Mechref, Yehia

    2017-09-01

    Breast cancer is the leading type of cancer in women. Breast cancer brain metastasis is currently considered an issue of concern among breast cancer patients. Membrane proteins play important roles in breast cancer brain metastasis, involving cell adhesion and penetration of blood-brain barrier. To understand the mechanism of breast cancer brain metastasis, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed in conjunction with enrichment of membrane proteins to analyze the proteomes from five different breast cancer and a brain cancer cell lines. Quantitative proteomic data of all cell lines were compared with MDA-MB-231BR which is a brain seeking breast cancer cell line, thus representing brain metastasis characteristics. Label-free proteomics of the six cell lines facilitates the identification of 1238 proteins and the quantification of 899 proteins of which more than 70% were membrane proteins. Unsupervised principal component analysis (PCA) of the label-free proteomics data resulted in a distinct clustering of cell lines, suggesting quantitative differences in the expression of several proteins among the different cell lines. Unique protein expressions in 231BR were observed for 28 proteins. The up-regulation of STAU1, AT1B3, NPM1, hnRNP Q, and hnRNP K and the down-regulation of TUBB4B and TUBB5 were noted in 231BR relative to 231 (precursor cell lines from which 231BR is derived). These proteins might contribute to the breast cancer brain metastasis. Ingenuity pathway analysis (IPA) supported the great brain metastatic propensity of 231BR and suggested the importance of the up-regulation of integrin proteins and down-regulation of EPHA2 in brain metastasis. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Morphogenesis and regionalization of the medaka embryonic brain.

    Science.gov (United States)

    Kage, Takahiro; Takeda, Hiroyuki; Yasuda, Takako; Maruyama, Kouichi; Yamamoto, Naoyuki; Yoshimoto, Masami; Araki, Kazuo; Inohaya, Keiji; Okamoto, Hiroyuki; Yasumasu, Shigeki; Watanabe, Kaori; Ito, Hironobu; Ishikawa, Yuji

    2004-08-23

    We examined the morphogenesis and regionalization of the embryonic brain of an acanthopterygian teleost, medaka (Oryzias latipes), by in situ hybridization using 14 gene probes. We compared our results with previous studies in other vertebrates, particularly zebrafish, an ostariophysan teleost. During the early development of the medaka neural rod, three initial brain vesicles arose: the anterior brain vesicle, which later developed into the telencephalon and rostral diencephalon; the intermediate brain vesicle, which later developed into the caudal diencephalon, mesencephalon, and metencephalon; and the posterior brain vesicle, which later developed into the myelencephalon. In the late neural rod, the rostral brain bent ventrally and the axis of the brain had a marked curvature at the diencephalon. In the final stage of the neural rod, ventricles began to develop, transforming the neural rod into the neural tube. In situ hybridization revealed that the brain can be divided into three longitudinal zones (dorsal, intermediate, and ventral) and many transverse subdivisions, on the basis of molecular expression patterns. The telencephalon was subdivided into two transverse domains. Our results support the basic concept of neuromeric models, including the prosomeric model, which suggests the existence of a conserved organization of all vertebrate neural tubes. Our results also show that brain development in medaka differs from that reported in other vertebrates, including zebrafish, in gene-expression patterns in the telencephalon, in brain vesicle formation, and in developmental speed. Developmental and genetic programs for brain development may be somewhat different even among teleosts.

  19. In silico genome wide mining of conserved and novel miRNAs in the brain and pineal gland of Danio rerio using small RNA sequencing data.

    Science.gov (United States)

    Agarwal, Suyash; Nagpure, Naresh Sahebrao; Srivastava, Prachi; Kushwaha, Basdeo; Kumar, Ravindra; Pandey, Manmohan; Srivastava, Shreya

    2016-03-01

    MicroRNAs (miRNAs) are small, non-coding RNA molecules that bind to the mRNA of the target genes and regulate the expression of the gene at the post-transcriptional level. Zebrafish is an economically important freshwater fish species globally considered as a good predictive model for studying human diseases and development. The present study focused on uncovering known as well as novel miRNAs, target prediction of the novel miRNAs and the differential expression of the known miRNA using the small RNA sequencing data of the brain and pineal gland (dark and light treatments) obtained from NCBI SRA. A total of 165, 151 and 145 known zebrafish miRNAs were found in the brain, pineal gland (dark treatment) and pineal gland (light treatment), respectively. Chromosomes 4 and 5 of zebrafish reference assembly GRCz10 were found to contain maximum number of miR genes. The miR-181a and miR-182 were found to be highly expressed in terms of number of reads in the brain and pineal gland, respectively. Other ncRNAs, such as tRNA, rRNA and snoRNA, were curated against Rfam. Using GRCz10 as reference, the subsequent bioinformatic analyses identified 25, 19 and 9 novel miRNAs from the brain, pineal gland (dark treatment) and pineal gland (light treatment), respectively. Targets of the novel miRNAs were identified, based on sequence complementarity between miRNAs and mRNA, by searching for antisense hits in the 3'-UTR of reference RNA sequences of the zebrafish. The discovery of novel miRNAs and their targets in the zebrafish genome can be a valuable scientific resource for further functional studies not only in zebrafish but also in other economically important fishes.

  20. Royal jelly-like protein localization reveals differences in hypopharyngeal glands buildup and conserved expression pattern in brains of bumblebees and honeybees

    Directory of Open Access Journals (Sweden)

    Štefan Albert

    2014-03-01

    Full Text Available Royal jelly proteins (MRJPs of the honeybee bear several open questions. One of them is their expression in tissues other than the hypopharyngeal glands (HGs, the site of royal jelly production. The sole MRJP-like gene of the bumblebee, Bombus terrestris (BtRJPL, represents a pre-diversification stage of the MRJP gene evolution in bees. Here we investigate the expression of BtRJPL in the HGs and the brain of bumblebees. Comparison of the HGs of bumblebees and honeybees revealed striking differences in their morphology with respect to sex- and caste-specific appearance, number of cells per acinus, and filamentous actin (F-actin rings. At the cellular level, we found a temporary F-actin-covered meshwork in the secretory cells, which suggests a role for actin in the biogenesis of the end apparatus in HGs. Using immunohistochemical localization, we show that BtRJPL is expressed in the bumblebee brain, predominantly in the Kenyon cells of the mushroom bodies, the site of sensory integration in insects, and in the optic lobes. Our data suggest that a dual gland-brain function preceded the multiplication of MRJPs in the honeybee lineage. In the course of the honeybee evolution, HGs dramatically changed their morphology in order to serve a food-producing function.

  1. Agonistic effect of polyunsaturated fatty acids (PUFAs and its metabolites on brain-derived neurotrophic factor (BDNF through molecular docking simulation

    Directory of Open Access Journals (Sweden)

    Vetrivel Umashankar

    2012-09-01

    Full Text Available Abstract Background Brain-derived neurotrophic factor (BDNF is a potent neurotrophic factor that is implicated in the regulation of food intake and body weight. Polyunsaturated fatty acids (PUFAs localised in cell membranes have been shown to alter the levels of BDNF in the brain, suggesting that PUFAs and BDNF could have physical interaction with each other. To decipher the molecular mechanism through which PUFAs modulates BDNF’s activity, molecular docking was performed for BDNF with PUFAs and its metabolites, with 4-Methyl Catechol as a control. Results Inferring from molecular docking studies, lipoxin A4 (LXA4, and a known anti-inflammatory bioactive metabolite derived from PUFAs, with a binding energy of −3.98 Kcal/mol and dissociation constant of 1.2mM showed highest binding affinity for BDNF in comparison to other PUFAs and metabolites considered in the study. Further, the residues Lys 18, Thr 20, Ala 21, Val 22, Phe 46, Glu 48, Lys 50, Lys 58, Thr 75, Gln 77, Arg 97 and Ile 98 form hot point motif, which on interaction enhances BDNF’s function. Conclusion These results suggest that PUFAs and their metabolites especially, LXA4, modulate insulin resistance by establishing a physical interaction with BDNF. Similar interaction(s was noted between BDNF and resolvins and protectins but were of lesser intensity compared to LXA4.

  2. Reshaping conservation

    DEFF Research Database (Denmark)

    Funder, Mikkel; Danielsen, Finn; Ngaga, Yonika

    2013-01-01

    members strengthen the monitoring practices to their advantage, and to some extent move them beyond the reach of government agencies and conservation and development practitioners. This has led to outcomes that are of greater social and strategic value to communities than the original 'planned' benefits......, although the monitoring scheme has also to some extent become dominated by local 'conservation elites' who negotiate the terrain between the state and other community members. Our findings suggest that we need to move beyond simplistic assumptions of community strategies and incentives in participatory...... conservation and allow for more adaptive and politically explicit governance spaces in protected area management....

  3. Alzheimer’s disease: relevant molecular and physiopathological events affecting amyloid-β brain balance and the putative role of PPARs

    Science.gov (United States)

    Zolezzi, Juan M.; Bastías-Candia, Sussy; Santos, Manuel J.; Inestrosa, Nibaldo C.

    2014-01-01

    Alzheimer’s disease (AD) is the most common form of age-related dementia. With the expected aging of the human population, the estimated morbidity of AD suggests a critical upcoming health problem. Several lines of research are focused on understanding AD pathophysiology, and although the etiology of the disease remains a matter of intense debate, increased brain levels of amyloid-β (Aβ) appear to be a critical event in triggering a wide range of molecular alterations leading to AD. It has become evident in recent years that an altered balance between production and clearance is responsible for the accumulation of brain Aβ. Moreover, Aβ clearance is a complex event that involves more than neurons and microglia. The status of the blood-brain barrier (BBB) and choroid plexus, along with hepatic functionality, should be considered when Aβ balance is addressed. Furthermore, it has been proposed that exposure to sub-toxic concentrations of metals, such as copper, could both directly affect these secondary structures and act as a seeding or nucleation core that facilitates Aβ aggregation. Recently, we have addressed peroxisomal proliferator-activated receptors (PPARs)-related mechanisms, including the direct modulation of mitochondrial dynamics through the PPARγ-coactivator-1α (PGC-1α) axis and the crosstalk with critical aging- and neurodegenerative-related cellular pathways. In the present review, we revise the current knowledge regarding the molecular aspects of Aβ production and clearance and provide a physiological context that gives a more complete view of this issue. Additionally, we consider the different structures involved in AD-altered Aβ brain balance, which could be directly or indirectly affected by a nuclear receptor (NR)/PPAR-related mechanism. PMID:25120477

  4. Trigeminal pathways deliver a low molecular weight drug from the nose to the brain and orofacial structures.

    Science.gov (United States)

    Johnson, Neil J; Hanson, Leah R; Frey, William H

    2010-06-07

    Intranasal delivery has been shown to noninvasively deliver drugs from the nose to the brain in minutes along the olfactory and trigeminal nerve pathways, bypassing the blood-brain barrier. However, no one has investigated whether nasally applied drugs target orofacial structures, despite high concentrations observed in the trigeminal nerve innervating these tissues. Following intranasal administration of lidocaine to rats, trigeminally innervated structures (teeth, temporomandibular joint (TMJ), and masseter muscle) were found to have up to 20-fold higher tissue concentrations of lidocaine than the brain and blood as measured by ELISA. This concentration difference could allow intranasally administered therapeutics to treat disorders of orofacial structures (i.e., teeth, TMJ, and masseter muscle) without causing unwanted side effects in the brain and the rest of the body. In this study, an intranasally administered infrared dye reached the brain within 10 minutes. Distribution of dye is consistent with dye entering the trigeminal nerve after intranasal administration through three regions with high drug concentrations in the nasal cavity: the middle concha, the maxillary sinus, and the choana. In humans the trigeminal nerve passes through the maxillary sinus to innervate the maxillary teeth. Delivering lidocaine intranasally may provide an effective anesthetic technique for a noninvasive maxillary nerve block. Intranasal delivery could be used to target vaccinations and treat disorders with fewer side effects such as tooth pain, TMJ disorder, trigeminal neuralgia, headache, and brain diseases.

  5. Molecular identification of Neospora caninum from calf/foetal brain tissue and among oocysts recovered from faeces of naturally infected dogs in southern Ethiopia.

    Science.gov (United States)

    Asmare, K; Skjerve, E; Bekele, J; Sheferaw, D; Stachurska-Hagen, T; Robertson, L J

    2014-02-01

    This study sought to confirm and investigate further recently published information regarding the occurrence of Neospora caninum in cattle in Ethiopia and investigate infection in dogs, the canine definitive host, in this region. Faecal samples from 383 dogs in Hawassa, Ethiopia were examined by microscopy for Neospora-like oocysts, and positive samples then analysed by a molecular approach (DNA isolation, PCR and sequencing at the ITS1 gene). Brain tissue samples from four late term aborted foetuses, one congenitally defective calf (hind leg arthrogryposis) and placental tissue from cattle in the same area were also examined by the same molecular approach. All foetal, calf and placental tissue were associated with Neospora seropositive dams. A high prevalence of Neospora-like oocysts (11.5 μm±1.5 μm diameter) was observed in faecal samples from dogs (37 positive samples; 9.7% prevalence), and in 17 of these the identification was confirmed by PCR, giving a prevalence of confirmed infection of 4.4%. N. caninum DNA was also detected in all foetal and calf brain tissue samples. Sequencing revealed only minor differences among all PCR products, whether from oocysts or from brain tissue samples. These data provide molecular evidence of the presence of N. caninum infection in both dog and cattle in this region of Ethiopia. Moreover these findings highlight the role of dogs in maintaining and spreading the infection horizontally in the study area. The high frequency of N. caninum infection in household dogs as well as farm dogs is worthy of further investigation.

  6. Analysis of signal transduction in brain cells using molecular signal microscope; Bunshi jiho kenbikyo wo mochiita nousaibou no joho henkan kiko no kaiseki

    Energy Technology Data Exchange (ETDEWEB)

    Kawato, Suguru [The University of Tokyo, Tokyo (Japan). Dept. of Biophysics and Life Sciences

    1999-12-16

    We analyzed the signal transduction in brain neurons by real-time imaging of Ca/NO signals using the Molecular Signal Microscope. We also analyzed synthesis and action of neurosteroids in the hippocampus. We discovered steroid synthesis machinery containing cytochrome P 450 scc in hippocampal neurons. We found that pregnenolone sulfate acutely potentiated NMDA receptor-mediated Ca conductivity in hippocampal neurons. We also found that stress steroid corticosterone acutely prolonged NMDA receptor-mediated Ca{sup 2+} influx, resulting in Ca-induced neuro-toxicity. (author)

  7. Wildlife Conservation

    OpenAIRE

    Clive L. Spash; Aldred, Jonathan

    1998-01-01

    In this paper we consider how conservation has arisen as a key aspect of the reaction to human-initiated degradation and disappearance of ecosystems, wild lands. and wildlife. Concern over species extinction is given an historical perspective which shows the way in which pressure on wild and natural aspects of global ecology have changed in recent centuries. The role of conservation in the struggle to protect the environment is then analysed using underlying ethical arguments behind the econo...

  8. Identification of a Conserved 8 aa Insert in the PIP5K Protein in the Saccharomycetaceae family of Fungi and the Molecular Dynamics Simulations and Structural Analysis to investigate its Potential Functional Role.

    Science.gov (United States)

    Khadka, Bijendra; Gupta, Radhey S

    2017-04-13

    Homologs of the phosphatidylinositol-4-phosphate-5-kinase (PIP5K), which controls a multitude of essential cellular functions, contain a 8 aa insert in a conserved region that is specific for the Saccharomycetaceae family of fungi. Using structures of human PIP4K proteins as templates, structural models were generated of the Saccharomyces cerevisiae and human PIP5K proteins. In the modeled S. cerevisiae PIP5K, the 8 aa insert forms a surface exposed loop, present on the same face of the protein as the activation loop of the kinase domain. Electrostatic potential analysis indicates that the residues from 8 aa conserved loop form a highly-positively charged surface patch, which through electrostatic interaction with the anionic portions of phospholipid head groups, is expected to play a role in the membrane interaction of the yeast PIP5K. To unravel this prediction, molecular dynamics (MD) simulations were carried out to examine the binding interaction of PIP5K, either containing or lacking the conserved signature insert (CSI), with two different membrane lipid bilayers. The results from MD studies provide insights concerning the mechanistic of interaction of PIP5K with lipid bilayer, and support the contention that the identified 8 aa conserved insert in fungal PIP5K plays an important role in the binding of this protein with membrane surface. This article is protected by copyright. All rights reserved.

  9. Molecular cloning and expression analysis of fushi tarazu factor 1 in the brain of air-breathing catfish, Clarias gariepinus.

    Directory of Open Access Journals (Sweden)

    Parikipandla Sridevi

    Full Text Available BACKGROUND: Fushi tarazu factor 1 (FTZ-F1 encodes an orphan nuclear receptor belonging to the nuclear receptor family 5A (NR5A which includes adrenal 4-binding protein or steroidogenic factor-1 (Ad4BP/SF-1 and liver receptor homologue 1 (LRH-1 and plays a pivotal role in the regulation of aromatases. METHODOLOGY/PRINCIPAL FINDINGS: Present study was aimed to understand the importance of FTZ-F1 in relation to brain aromatase (cyp19a1b during development, recrudescence and after human chorionic gonadotropin (hCG induction. Initially, we cloned FTZ-F1 from the brain of air-breathing catfish, Clarias gariepinus through degenerate primer RT-PCR and RACE. Its sequence analysis revealed high homology with other NR5A1 group members Ad4BP/SF-1 and LRH-1, and also analogous to the spatial expression pattern of the latter. In order to draw functional correlation of cyp19a1b and FTZ-F1, we analyzed the expression pattern of the latter in brain during gonadal ontogeny, which revealed early expression during gonadal differentiation. The tissue distribution both at transcript and protein levels revealed its prominent expression in brain along with liver, kidney and testis. The expression pattern of brain FTZ-F1 during reproductive cycle and after hCG induction, in vivo was analogous to that of cyp19a1b shown in our earlier study indicating its involvement in recrudescence. CONCLUSIONS/SIGNIFICANCE: Based on our previous results on cyp19a1b and the present data, it is plausible to implicate potential roles for brain FTZ-F1 in ovarian differentiation and recrudescence process probably through regulation of cyp19a1b in teleosts. Nevertheless, these interactions would require primary coordinated response from ovarian aromatase and its related transcription factors.

  10. Molecular assembly and biosynthesis of acetylcholinesterase in brain and muscle: The roles of t-peptide, FHB domain and N-linked glycosylation

    Directory of Open Access Journals (Sweden)

    Vicky P. Chen

    2011-10-01

    Full Text Available Acetylcholinesterase (AChE is responsible for the hydrolysis of the neurotransmitter, acetylcholine, in the nervous system. The functional localization and oligomerization of AChE T variant are depending primarily on the association of their anchoring partners, either collagen tail (ColQ or proline rich membrane anchor (PRiMA. Complexes with ColQ represent the asymmetric forms (A12 in muscle, while complexes with PRiMA represent tetrameric globular forms (G4 mainly found in brain and muscle. Apart from these traditional molecular forms, a ColQ-linked asymmetric form and a PRiMA-linked globular form of hybrid cholinesterases (ChEs, having both AChE and BChE catalytic subunits, were revealed in chicken brain and muscle. The similarity of various molecular forms of AChE and BChE raises interesting question regarding to their possible relationship in enzyme assembly and localization. The focus of this review is to provide current findings about the biosynthesis of different forms of ChEs together with their anchoring proteins.

  11. Tianeptine, olanzapine and fluoxetine show similar restoring effects on stress induced molecular changes in mice brain: An FT-IR study

    Science.gov (United States)

    Türker-Kaya, Sevgi; Mutlu, Oğuz; Çelikyurt, İpek K.; Akar, Furuzan; Ulak, Güner

    2016-05-01

    Chronic stress which can cause a variety of disorders and illness ranging from metabolic and cardiovascular to mental leads to alterations in content, structure and dynamics of biomolecules in brain. The determination of stress-induced changes along with the effects of antidepressant treatment on these parameters might bring about more effective therapeutic strategies. In the present study, we investigated unpredictable chronic mild stress (UCMS)-induced changes in biomolecules in mouse brain and the restoring effects of tianeptine (TIA), olanzapine (OLZ) and fluoxetine (FLX) on these variations, by Fourier transform infrared (FT-IR) spectroscopy. The results revealed that chronic stress causes different membrane packing and an increase in lipid peroxidation, membrane fluidity. A significant increment for lipid/protein, Cdbnd O/lipid, CH3/lipid, CH2/lipid, PO-2/lipid, COO-/lipid and RNA/protein ratios but a significant decrease for lipid/protein ratios were also obtained. Additionally, altered protein secondary structure components were estimated, such as increment in random coils and beta structures. The administration of TIA, OLZ and FLX drugs restored these stress-induced variations except for alterations in protein structure and RNA/protein ratio. This may suggest that these drugs have similar restoring effects on the consequences of stress activity in brain, in spite of the differences in their action mechanisms. All findings might have importance in understanding molecular mechanisms underlying chronic stress and contribute to studies aimed for drug development.

  12. Molecular structures of quiescently grown and brain-derived polymorphic fibrils of the Alzheimer amyloid abeta9-40 peptide: a comparison to agitated fibrils.

    Directory of Open Access Journals (Sweden)

    Chun Wu

    2010-03-01

    Full Text Available The presence of amyloid deposits consisting primarily of Amyloid-beta (Abeta fibril in the brain is a hallmark of Alzheimer's disease (AD. The morphologies of these fibrils are exquisitely sensitive to environmental conditions. Using molecular dynamics simulations combined with data from previously published solid-state NMR experiments, we propose the first atomically detailed structures of two asymmetric polymorphs of the Abeta(9-40 peptide fibril. The first corresponds to synthetic fibrils grown under quiescent conditions and the second to fibrils derived from AD patients' brain-extracts. Our core structure in both fibril structures consists of a layered structure in which three cross-beta subunits are arranged in six tightly stacked beta-sheet layers with an antiparallel hydrophobic-hydrophobic and an antiparallel polar-polar interface. The synthetic and brain-derived structures differ primarily in the side-chain orientation of one beta-strand. The presence of a large and continually exposed hydrophobic surface (buried in the symmetric agitated Abeta fibrils may account for the higher toxicity of the asymmetric fibrils. Our model explains the effects of external perturbations on the fibril lateral architecture as well as the fibrillogenesis inhibiting action of amphiphilic molecules.

  13. Conservation endocrinology

    Science.gov (United States)

    McCormick, Stephen; Romero, Michael

    2017-01-01

    Endocrinologists can make significant contributions to conservation biology by helping to understand the mechanisms by which organisms cope with changing environments. Field endocrine techniques have advanced rapidly in recent years and can provide substantial information on the growth, stress, and reproductive status of individual animals, thereby providing insight into current and future responses of populations to changes in the environment. Environmental stressors and reproductive status can be detected nonlethally by measuring a number of endocrine-related endpoints, including steroids in plasma, living and nonliving tissue, urine, and feces. Information on the environmental or endocrine requirements of individual species for normal growth, development, and reproduction will provide critical information for species and ecosystem conservation. For many taxa, basic information on endocrinology is lacking, and advances in conservation endocrinology will require approaches that are both “basic” and “applied” and include integration of laboratory and field approaches.

  14. Amplification of neural stem cell proliferation by intermediate progenitor cells in Drosophila brain development

    Directory of Open Access Journals (Sweden)

    Bello Bruno C

    2008-02-01

    Full Text Available Abstract Background In the mammalian brain, neural stem cells divide asymmetrically and often amplify the number of progeny they generate via symmetrically dividing intermediate progenitors. Here we investigate whether specific neural stem cell-like neuroblasts in the brain of Drosophila might also amplify neuronal proliferation by generating symmetrically dividing intermediate progenitors. Results Cell lineage-tracing and genetic marker analysis show that remarkably large neuroblast lineages exist in the dorsomedial larval brain of Drosophila. These lineages are generated by brain neuroblasts that divide asymmetrically to self renew but, unlike other brain neuroblasts, do not segregate the differentiating cell fate determinant Prospero to their smaller daughter cells. These daughter cells continue to express neuroblast-specific molecular markers and divide repeatedly to produce neural progeny, demonstrating that they are proliferating intermediate progenitors. The proliferative divisions of these intermediate progenitors have novel cellular and molecular features; they are morphologically symmetrical, but molecularly asymmetrical in that key differentiating cell fate determinants are segregated into only one of the two daughter cells. Conclusion Our findings provide cellular and molecular evidence for a new mode of neurogenesis in the larval brain of Drosophila that involves the amplification of neuroblast proliferation through intermediate progenitors. This type of neurogenesis bears remarkable similarities to neurogenesis in the mammalian brain, where neural stem cells as primary progenitors amplify the number of progeny they generate through generation of secondary progenitors. This suggests that key aspects of neural stem cell biology might be conserved in brain development of insects and mammals.

  15. Conserved signature indels and signature proteins as novel tools for understanding microbial phylogeny and systematics: identification of molecular signatures that are specific for the phytopathogenic genera Dickeya, Pectobacterium and Brenneria.

    Science.gov (United States)

    Naushad, Hafiz Sohail; Lee, Brian; Gupta, Radhey S

    2014-02-01

    Genome sequences are enabling applications of different approaches to more clearly understand microbial phylogeny and systematics. Two of these approaches involve identification of conserved signature indels (CSIs) and conserved signature proteins (CSPs) that are specific for different lineages. These molecular markers provide novel and more definitive means for demarcation of prokaryotic taxa and for identification of species from these groups. Genome sequences are also enabling determination of phylogenetic relationships among species based upon sequences for multiple proteins. In this work, we have used all of these approaches for studying the phytopathogenic bacteria belonging to the genera Dickeya, Pectobacterium and Brenneria. Members of these genera, which cause numerous diseases in important food crops and ornamental plants, are presently distinguished mainly on the basis of their branching in phylogenetic trees. No biochemical or molecular characteristic is known that is uniquely shared by species from these genera. Hence, detailed studies using the above approaches were carried out on proteins from the genomes of these bacteria to identify molecular markers that are specific for them. In phylogenetic trees based upon concatenated sequences for 23 conserved proteins, members of the genera Dickeya, Pectobacterium and Brenneria formed a strongly supported clade within the other Enterobacteriales. Comparative analysis of protein sequences from the Dickeya, Pectobacterium and Brenneria genomes has identified 10 CSIs and five CSPs that are either uniquely or largely found in all genome-sequenced species from these genera, but not present in any other bacteria in the database. In addition, our analyses have identified 10 CSIs and 17 CSPs that are specifically present in either all or most sequenced Dickeya species/strains, and six CSIs and 19 CSPs that are uniquely found in the sequenced Pectobacterium genomes. Finally, our analysis also identified three CSIs

  16. Colorful Conservation

    Science.gov (United States)

    Skophammer, Karen

    2011-01-01

    Some people only think about conservation on Earth Day. Being in the "art business" however, this author is always conscious of the many products she thinks get wasted when they could be reused, recycled, and restored--especially in a school building and art room. In this article, she describes an art lesson that allows students to paint…

  17. [Conservation Units.

    Science.gov (United States)

    Texas Education Agency, Austin.

    Each of the six instructional units deals with one aspect of conservation: forests, water, rangeland, minerals (petroleum), and soil. The area of the elementary school curriculum with which each correlates is indicated. Lists of general and specific objectives are followed by suggested teaching procedures, including ideas for introducing the…

  18. [Conservation Units.

    Science.gov (United States)

    Texas Education Agency, Austin.

    Instructional units deal with each aspect of conservation: forests, wildlife, rangelands, water, minerals, and soil. The area of the secondary school curriculum with which each is correlated is indicated. Lists of general and specific objectives are followed by suggested teaching procedures, including ideas for introducing the topic, questions to…

  19. Genomics: A Hallmark to Monitor Molecular and Biochemical Processes Leading Toward a Better Perceptive of Seed Aging and ex-situ Conservation.

    Science.gov (United States)

    Ahmed, Zaheer; Shah, Zahid Hussain; Rehman, Hafiz Mamoon; Shahzad, Khurram; Daur, Ihsanullah; Elfeel, Abdalla; Hassan, Mahmood Ul; Elsafori, Ali Khalid; Yang, Seung Hwan; Chung, Gyuhwa

    2017-01-01

    For human food security, the preservation of 7.4 million ex-situ germplasm is a global priority. However, ex-situ-conserved seeds are subject to aging, which reduces their viability and ultimately results in the loss of valuable genetic material over long periods. Recent progress in seed biology and genomics has revealed new opportunities to improve the long-term storage of ex-situ seed germplasm. This review summarizes the recent improvements in seed physiology and genomics, with the intention of developing genomic tools for evaluating seed aging. Several lines of seed biology research have shown promise in retrieving viability signal from various stages of seed germination. We conclude that seed aging is associated with mitochondrial alteration and programmed cell death, DNA and enzyme repair, anti-oxidative genes, telomere length, and epigenetic regulation. Clearly, opportunities exist for observing seed aging for developing genomic tools to increment the traditional germination test for effective conservation of ex-situ germplasm.

  20. Linking ATM Promoter Methylation to Cell Cycle Protein Expression in Brain Tumor Patients: Cellular Molecular Triangle Correlation in ATM Territory.

    Science.gov (United States)

    Mehdipour, P; Karami, F; Javan, Firouzeh; Mehrazin, M

    2015-08-01

    Ataxia telangiectasia mutated (ATM) is a key gene in DNA double-strand break (DSB), and therefore, most of its disabling genetic alterations play an important initiative role in many types of cancer. However, the exact role of ATM gene and its epigenetic alterations, especially promoter methylation in different grades of brain tumors, remains elusive. The current study was conducted to query possible correlations among methylation statue of ATM gene, ATM/ retinoblastoma (RB) protein expression, D1853N ATM polymorphism, telomere length (TL), and clinicopathological characteristics of various types of brain tumors. Isolated DNA from 30 fresh tissues was extracted from different types of brain tumors and two brain tissues from deceased normal healthy individuals. DNAs were treated with bisulfate sodium using DNA modification kit (Qiagen). Methylation-specific polymerase chain reaction (MSP-PCR) was implicated to determine the methylation status of treated DNA templates confirmed by promoter sequencing. Besides, the ATM and RB protein levels were determined by immunofluorescence (IF) assay using monoclonal mouse antihuman against ATM, P53, and RB proteins. To achieve an interactive correlation, the methylation data were statistically analyzed by considering TL and D1853N ATM polymorphism. More than 73% of the brain tumors were methylated in ATM gene promoter. There was strong correlation between ATM promoter methylation and its protein expression (p ATM promoter and ATM protein expression with D1853N ATM polymorphism (p = 0.01). ATM protein expression was not in line with RB protein expression while it was found to be significantly correlated with ATM promoter methylation (p = 0.01). There was significant correlation between TL neither with ATM promoter methylation nor with ATM protein expression nor with D1853N polymorphism. However, TL has shown strong correlation with patient's age and tumor grade (p = 0.01). Given the important role of cell cycle checkpoint

  1. Molecular characterization of flavanone 3 beta-hydroxylases. Consensus sequence, comparison with related enzymes and the role of conserved histidine residues.

    Science.gov (United States)

    Britsch, L; Dedio, J; Saedler, H; Forkmann, G

    1993-10-15

    A heterologous cDNA probe from Petunia hybrida was used to isolate flavanone-3 beta-hydroxylase-encoding cDNA clones from carnation (Dianthus caryophyllus), china aster (Callistephus chinensis) and stock (Matthiola incana). The deduced protein sequences together with the known sequences of the enzyme from P. hybrida, barley (Hordeum vulgare) and snapdragon (Antirrhinum majus) enabled the determination of a consensus sequence which revealed an overall 84% similarity (53% identity) of flavanone 3 beta-hydroxylases from the different sources. Alignment with the sequences of other known enzymes of the same class and to related non-heme iron-(II) enzymes demonstrated the strict genetic conservation of 14 amino acids, in particular, of three histidines and an aspartic acid. The conservation of the histidine motifs provides strong support for the possible conservation of structurally similar iron-binding sites in these enzymes. The putative role of histidines as chelators of ferrous ions in the active site of flavanone 3 beta-hydroxylases was corroborated by diethyl-pyrocarbonate modification of the partially purified recombinant Petunia enzyme.

  2. 微生物分子生态学技术在文物保护中应用的进展%Application of microbial molecular ecology in conservation of cultural heritage

    Institute of Scientific and Technical Information of China (English)

    王亚丽

    2012-01-01

    微生物分子生态学技术近年来在文物保护研究中得到了广泛的应用,已经成为控制文物被微生物侵害的一个不可或缺的工具。本研究较系统地总结了国内外利用微生物分子生态学技术进行文物保护研究的进展,为更有效防治微生物危害侵蚀文物,进而长久的保存文物提供理论支持。%In recent years, microbial molecular ecology has been widely applied in the field of conservation. This article reviews the domestic and international application of microbial ecology technology for conservation of cultural heritage objects, so as to effectively prevent microbiological damage to them. This review provides theoretical foun- dations for long - term conservation of cultural heritage objects.

  3. Quantum Brain?

    CERN Document Server

    Mershin, A; Skoulakis, E M C

    2000-01-01

    In order to create a novel model of memory and brain function, we focus our approach on the sub-molecular (electron), molecular (tubulin) and macromolecular (microtubule) components of the neural cytoskeleton. Due to their size and geometry, these systems may be approached using the principles of quantum physics. We identify quantum-physics derived mechanisms conceivably underlying the integrated yet differentiated aspects of memory encoding/recall as well as the molecular basis of the engram. We treat the tubulin molecule as the fundamental computation unit (qubit) in a quantum-computational network that consists of microtubules (MTs), networks of MTs and ultimately entire neurons and neural networks. We derive experimentally testable predictions of our quantum brain hypothesis and perform experiments on these.

  4. Molecular cloning and chromosomal assignment of the human brain-type phosphodiesterase I/nucleotide pyrophosphatase gene (PDNP2)

    Energy Technology Data Exchange (ETDEWEB)

    Kawagoe, Hiroyuki; Soma, Osamu; Goji, Junko [Kobe Univ. School of Medicine (Japan)] [and others

    1995-11-20

    Phosphodiesterase I/nucleotide pyrophosphatase is a widely expressed membrane-bound enzyme that cleaves diester bonds of a variety of substrates. We have cloned brain-type cDNA for this enzyme from rat brain and designated it PD-I{alpha}. In this study we have isolated cDNA and genomic DNA encoding human PD-I{alpha}. Human PD-I{alpha} cDNA, designated PDNP2 in HGMW nomenclature, has a 2589-nucleotide open reading frame encoding a polypeptide of 863 amino acids with a calculated M{sub r} of 99,034. Northern blot analysis revealed that human PD-I{alpha} transcript was present in brain, lung, placenta, and kidney. The database analysis showed that human PD-I{alpha} was identical with human autotaxin (ATX), a novel tumor motility-stimulating factor, except that human PD-I{alpha} lacks 156 nucleotides and 52 amino acids of human ATX. Human PD-I{alpha} and human ATX are likely to be alternative splicing products from the same gene. The 5{prime} region of the human PDNP2 gene contains four putative binding sites of transcription factor Sp1 without typical TATA or CAAT boxes, and there is a potential octamer binding motif in intron 2. From the results of fluorescence in situ hybridization, the human PDNP2 gene is located at chromosome 8q24.1. 17 refs., 3 figs.

  5. Intracellular uptake of macromolecules by brain lymphatic endothelial cells during zebrafish embryonic development.

    Science.gov (United States)

    van Lessen, Max; Shibata-Germanos, Shannon; van Impel, Andreas; Hawkins, Thomas A; Rihel, Jason; Schulte-Merker, Stefan

    2017-05-12

    The lymphatic system controls fluid homeostasis and the clearance of macromolecules from interstitial compartments. In mammals brain lymphatics were only recently discovered, with significant implications for physiology and disease. We examined zebrafish for the presence of brain lymphatics and found loosely connected endothelial cells with lymphatic molecular signature covering parts of the brain without forming endothelial tubular structures. These brain lymphatic endothelial cells (BLECs) derive from venous endothelium, are distinct from macrophages, and are sensitive to loss of Vegfc. BLECs endocytose macromolecules in a selective manner, which can be blocked by injection of mannose receptor ligands. This first report on brain lymphatic endothelial cells in a vertebrate embryo identifies cells with unique features, including the uptake of macromolecules at a single cell level. Future studies will address whether this represents an uptake mechanism that is conserved in mammals and how these cells affect functions of the embryonic and adult brain.

  6. Spintronic characteristics of self-assembled neurotransmitter acetylcholine molecular complexes enable quantum information processing in neural networks and brain

    Science.gov (United States)

    Tamulis, Arvydas; Majauskaite, Kristina; Kairys, Visvaldas; Zborowski, Krzysztof; Adhikari, Kapil; Krisciukaitis, Sarunas

    2016-09-01

    Implementation of liquid state quantum information processing based on spatially localized electronic spin in the neurotransmitter stable acetylcholine (ACh) neutral molecular radical is discussed. Using DFT quantum calculations we proved that this molecule possesses stable localized electron spin, which may represent a qubit in quantum information processing. The necessary operating conditions for ACh molecule are formulated in self-assembled dimer and more complex systems. The main quantum mechanical research result of this paper is that the neurotransmitter ACh systems, which were proposed, include the use of quantum molecular spintronics arrays to control the neurotransmission in neural networks.

  7. Heron conservation

    Science.gov (United States)

    Kushlan, J.A.; Hafner, H.

    2000-01-01

    Herons are large, popular and, in many cases, spectacular birds found in wetlands world-wide, both tropical and temperate, natural and man-made. Some populations are very small and localized, some have decreased, some have expanded their ranges, and a few are pests of human activities. In the fifteen years since the publication of the latest monographic treatment of the family, The Herons Handbook, there has been a tremendous increase in our knowledge of heron status and conservation requirements, set against a backdrop of increasing concern about the future of the world?s wetland habitats. This book provides a comprehensive update following two distinct threads. The status and conservation needs of herons are first presented on a regional basis, in a series of chapters set at a continental or subcontinental scale. Over 200 biologists and heron conservationists have contributed to the data summarized here, and the very latest census and survey results provide the most up-to-date and detailed picture of heron populations currently available. Chapters discussing several critical issues in heron conservation follow, tending to focus on the international nature of the problems.

  8. Comparison of molecular signatures in large scale protein interaction networks in normal and cancer conditions of brain, cervix, lung, ovary and prostate

    Directory of Open Access Journals (Sweden)

    Rajat Suvra Banik

    2016-04-01

    Full Text Available Background Cancer, the disease of intricateness, has remained beyond our complete perception so far. Network systems biology (termed NSB is one of the most recent approaches to understand the unsolved problems of cancer development. From this perspective, differential protein networks (PINs have been developed based on the expression and interaction data of brain, cervix, lung, ovary and prostate for normal and cancer conditions. Methods Differential expression database GeneHub-GEPIS and interaction database STRING were applied for primary data retrieval. Cytoscape platform and related plugins named network analyzer; MCODE and ModuLand were used for visualization of complex networks and subsequent analysis. Results Significant differences were observedamong different common network parameters between normal and cancer states. Moreover, molecular complex numbers and overlapping modularization found to be varying significantly between normal and cancerous tissues. The number of the ranked molecular complex and the nodes involved in the overlapping modules were meaningfully higher in cancer condition.We identified79 commonly up regulated and 6 down regulated proteins in all five tissues. Number of nodes, edges; multi edge node pair, and average number of neighbor are found with significant fluctuations in case of cervix and ovarian tissues.Cluster analysis showed that the association of Myc and Cdk4 proteins is very close with other proteins within the network.Cervix and ovarian tissue showed higher increment of the molecular complex number and overlapping module network during cancer in comparison to normal state. Conclusions The differential molecular signatures identified from the work can be studied further to understand the cancer signaling process, and potential therapeutic and detection approach. [Biomed Res Ther 2016; 3(4.000: 605-615

  9. A multimodal Pepstatin A peptide-based nanoagent for the molecular imaging of P-glycoprotein in the brains of epilepsy rats.

    Science.gov (United States)

    Yu, Xiangrong; Wang, Jianhong; Liu, Jiansheng; Shen, Shun; Cao, Zhonglian; Pan, Jiawei; Zhou, Shuyi; Pang, Zhiqing; Geng, Daoying; Zhang, Jun

    2016-01-01

    Regional overexpression of the multidrug transporter P-glycoprotein (P-gp) in epileptic brain tissues may lower antiepileptic drugs concentrations at the target site and contribute to pharmacoresistance in refractory epilepsy. However, few techniques are available to quantitate the level of P-gp expression noninvasively in vivo. In this study, we developed a nanoagent by conjugating superparamagnetic iron oxide nanoparticles with a near infrared probe and the targeting element Pepstatin A, a peptide with specific affinity for P-gp. In a rat model of epilepsy, the nanoagent was readily and selectively accumulated within epileptogenic cerebral regions, which were detectable by both magnetic resonance imaging and optical imaging modalities. This P-gp-targeted nanoagent could be used not only in the molecular imaging of P-gp expression changes in seizure-induced regional, understanding the mechanisms of P-gp disorders, and the prediction of refractory epilepsy, but also in targeted therapies with P-gp modulators.

  10. Development of microsatellite markers as a molecular tool for conservation studies of the Mediterranean reef builder coral Cladocora caespitosa (Anthozoa, Scleractinia).

    Science.gov (United States)

    Casado-Amezúa, Pilar; García-Jiménez, Ricardo; Kersting, Diego K; Templado, José; Coffroth, Mary Alice; Merino, Paula; Acevedo, Iván; Machordom, Annie

    2011-01-01

    Cladocora caespitosa is a reef-building zooxanthellate scleractinian coral in the Mediterranean Sea. Mortality events have recurrently affected this species during the last decade. Thus, knowledge of its genetic structure, population diversity, and connectivity is needed to accomplish suitable conservation plans. In order to obtain a better understanding of the population genetics of this species, 13 highly variable microsatellites markers were developed from a naturally bleached colony. The developed primers failed to amplify zooxanthella DNA, isolated from C. caespitosa, verifying that these markers were of the coral and not algal symbiont origin. The degree of polymorphism of these loci was tested on tissue samples from 28 colonies. The allele number for each loci ranged from 2 to 13 (mean N(a) = 5.4), with an average observed heterozygosity of 0.42 (H(e) = 0.43) and all loci were in Hardy-Weinberg equilibrium. These new markers should be useful in future conservation genetic studies and will help to improve the resolution of the individual identification within this coral species. Primers were also tested in Oculina patagonica, with successful amplifications of several loci.

  11. Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans.

    Science.gov (United States)

    Rabiner, E A; Beaver, J; Makwana, A; Searle, G; Long, C; Nathan, P J; Newbould, R D; Howard, J; Miller, S R; Bush, M A; Hill, S; Reiley, R; Passchier, J; Gunn, R N; Matthews, P M; Bullmore, E T

    2011-08-01

    Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the μ-OR sub-type. In a sample of healthy volunteers, we used [(11)C]-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100 mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50 = 7.10 ng ml(-1)) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-β-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration-RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption.

  12. Recapitulation of tumor heterogeneity and molecular signatures in a 3D brain cancer model with decreased sensitivity to histone deacetylase inhibition.

    Directory of Open Access Journals (Sweden)

    Stuart J Smith

    Full Text Available INTRODUCTION: Physiologically relevant pre-clinical ex vivo models recapitulating CNS tumor micro-environmental complexity will aid development of biologically-targeted agents. We present comprehensive characterization of tumor aggregates generated using the 3D Rotary Cell Culture System (RCCS. METHODS: CNS cancer cell lines were grown in conventional 2D cultures and the RCCS and comparison with a cohort of 53 pediatric high grade gliomas conducted by genome wide gene expression and microRNA arrays, coupled with immunohistochemistry, ex vivo magnetic resonance spectroscopy and drug sensitivity evaluation using the histone deacetylase inhibitor, Vorinostat. RESULTS: Macroscopic RCCS aggregates recapitulated the heterogeneous morphology of brain tumors with a distinct proliferating rim, necrotic core and oxygen tension gradient. Gene expression and microRNA analyses revealed significant differences with 3D expression intermediate to 2D cultures and primary brain tumors. Metabolic profiling revealed differential profiles, with an increase in tumor specific metabolites in 3D. To evaluate the potential of the RCCS as a drug testing tool, we determined the efficacy of Vorinostat against aggregates of U87 and KNS42 glioblastoma cells. Both lines demonstrated markedly reduced sensitivity when assaying in 3D culture conditions compared to classical 2D drug screen approaches. CONCLUSIONS: Our comprehensive characterization demonstrates that 3D RCCS culture of high grade brain tumor cells has profound effects on the genetic, epigenetic and metabolic profiles of cultured cells, with these cells residing as an intermediate phenotype between that of 2D cultures and primary tumors. There is a discrepancy between 2D culture and tumor molecular profiles, and RCCS partially re-capitulates tissue specific features, allowing drug testing in a more relevant ex vivo system.

  13. Combined computational-experimental approach to predict blood-brain barrier (BBB) permeation based on "green" salting-out thin layer chromatography supported by simple molecular descriptors.

    Science.gov (United States)

    Ciura, Krzesimir; Belka, Mariusz; Kawczak, Piotr; Bączek, Tomasz; Markuszewski, Michał J; Nowakowska, Joanna

    2017-09-05

    The objective of this paper is to build QSRR/QSAR model for predicting the blood-brain barrier (BBB) permeability. The obtained models are based on salting-out thin layer chromatography (SOTLC) constants and calculated molecular descriptors. Among chromatographic methods SOTLC was chosen, since the mobile phases are free of organic solvent. As consequences, there are less toxic, and have lower environmental impact compared to classical reserved phases liquid chromatography (RPLC). During the study three stationary phase silica gel, cellulose plates and neutral aluminum oxide were examined. The model set of solutes presents a wide range of log BB values, containing compounds which cross the BBB readily and molecules poorly distributed to the brain including drugs acting on the nervous system as well as peripheral acting drugs. Additionally, the comparison of three regression models: multiple linear regression (MLR), partial least-squares (PLS) and orthogonal partial least squares (OPLS) were performed. The designed QSRR/QSAR models could be useful to predict BBB of systematically synthesized newly compounds in the drug development pipeline and are attractive alternatives of time-consuming and demanding directed methods for log BB measurement. The study also shown that among several regression techniques, significant differences can be obtained in models performance, measured by R(2) and Q(2), hence it is strongly suggested to evaluate all available options as MLR, PLS and OPLS. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Molecular insights and therapeutic targets for blood-brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator

    Science.gov (United States)

    Jin, Rong; Yang, Guojun; Li, Guohong

    2010-01-01

    Blood-brain barrier (BBB) disruption, mediated through matrix metalloproteinases (MMPs) and other mechanisms, is a critical event during ischemic stroke. Tissue plasminogen activator (tPA) is the only FDA-approved thrombolytic therapy for acute ischemic stroke, but the efficacy and safety of its therapeutic application is limited by narrow treatment time windows and side effects. Thus, there is a pressing need to develop combinational therapy that could offset tPA side effects and improve efficacy in clinical practice. Recent experimental studies indicate that tPA has previously unidentified functions in the brain beyond its well established thrombolytic activity, which might contribute to tPA-related side effects through MMPs (mainly MMP-9) and several signaling pathways involved in LDL receptor-related protein (LRP), activated protein C (APC) and protease-activated receptor 1 (PAR-1), platelet-derived growth factor C (PDGF-C), and N-methyl-D-aspartate (NMDA) receptor. Therapeutic targeting of MMPs and/or tPA-related signaling pathways might offer promising new approaches to combination therapies for ischemic stroke. This review provides an overview of the relationship between structural components and function of the BBB/neurovascular unit with respect to ischemic stroke. We discuss how MMPs and tPA contribute to BBB disruption during ischemic stroke and highlight recent findings of molecular signaling pathways involved in neurotoxicity of tPA therapy. PMID:20302940

  15. Systemic Inflammation and the Brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Roman eSankowski

    2015-02-01

    Full Text Available The nervous and immune systems have evolved in parallel from the early bilaterians, in which innate immunity and a central nervous system coexisted for the first time, to jawed vertebrates and the appearance of adaptive immunity. The central nervous system (CNS feeds from, and integrates efferent signals in response to, somatic and autonomic sensory information. The CNS receives input also from the periphery about inflammation and infection. Cytokines, chemokines, damage-associated soluble mediators of systemic inflammation can also gain access to the CNS via blood flow. In response to systemic inflammation, those soluble mediators can access directly through the circumventricular organs, as well as open the blood-brain barrier (BBB. The resulting translocation of inflammatory mediators can interfere with neuronal and glial well-being, leading to a break of balance in brain homeostasis. This in turn results in cognitive and behavioral manifestations commonly present during acute infections -including anorexia, malaise, depression, and decreased physical activity- collectively known as the sickness behavior (SB. While SB manifestations are transient and self-limited, under states of persistent systemic inflammatory response the cognitive and behavioral changes can become permanent. For example, cognitive decline is almost universal in sepsis survivors, and a common finding in patients with systemic lupus erythematosus (SLE. Here, we review recent genetic evidence suggesting an association between neurodegenerative disorders and persistent immune activation; clinical and experimental evidence indicating previously unidentified immune-mediated pathways of neurodegeneration; and novel immunomodulatory targets and their potential relevance for neurodegenerative disorders.

  16. Methionine restriction decreases endogenous oxidative molecular damage and increases mitochondrial biogenesis and uncoupling protein 4 in rat brain.

    Science.gov (United States)

    Naudí, Alba; Caro, Pilar; Jové, Mariona; Gómez, José; Boada, Jordi; Ayala, Victoria; Portero-Otín, Manuel; Barja, Gustavo; Pamplona, Reinald

    2007-12-01

    Aging plays a central role in the occurrence of neurodegenerative diseases. Caloric restriction (CR) mitigates oxidative stress by decreasing the rate of generation of endogenous damage, a mechanism that can contribute to the slowing of the aging rate induced by this intervention. Various reports have recently linked methionine to aging, and methionine restriction (MetR) without energy restriction also increases life span. We have thus hypothesized that MetR can be responsible, at least in part, for the decrease in endogenous oxidative damage in CR. In this investigation we subjected male rats to exactly the same dietary protocol of MetR that is known to increase their life span. We have found that MetR: (1) decreases the mitochondrial complex I content and activity, as well as complex III content, while the complex II and IV, the mitochondrial flavoprotein apoptosis-inducing factor (AIF) and ATP content are unchanged; (2) increases the mitochondrial biogenesis factor PGC-1alpha; (3) increases the resistance of brain to metabolic and oxidative stress by increasing mitochondrial uncoupling protein 4 uncoupling protein 4 (UCP4); and (4) decreases mitochondrial oxidative DNA damage and all five different markers of protein oxidation measured and lowers membrane unsaturation in rat brain. No changes were detected for protein amino acid composition. These beneficial MetR-induced changes likely derived from metabolic reprogramming at the cellular and tissue level can play a key role in the protection against aging-associated neurodegenerative disorders.

  17. Chemical Reaction Rates from Ring Polymer Molecular Dynamics: Zero Point Energy Conservation in Mu + H2 → MuH + H.

    Science.gov (United States)

    Pérez de Tudela, Ricardo; Aoiz, F J; Suleimanov, Yury V; Manolopoulos, David E

    2012-02-16

    A fundamental issue in the field of reaction dynamics is the inclusion of the quantum mechanical (QM) effects such as zero point energy (ZPE) and tunneling in molecular dynamics simulations, and in particular in the calculation of chemical reaction rates. In this work we study the chemical reaction between a muonium atom and a hydrogen molecule. The recently developed ring polymer molecular dynamics (RPMD) technique is used, and the results are compared with those of other methods. For this reaction, the thermal rate coefficients calculated with RPMD are found to be in excellent agreement with the results of an accurate QM calculation. The very minor discrepancies are within the convergence error even at very low temperatures. This exceptionally good agreement can be attributed to the dominant role of ZPE in the reaction, which is accounted for extremely well by RPMD. Tunneling only plays a minor role in the reaction.

  18. Molecular footprinting of skeletal tissues in the catshark Scyliorhinus canicula and the clawed frog Xenopus tropicalis identifies conserved and derived features of vertebrate calcification

    Directory of Open Access Journals (Sweden)

    Sebastien eEnault

    2015-09-01

    Full Text Available Understanding the evolutionary emergence and subsequent diversification of the vertebrate skeleton requires a comprehensive view of the diverse skeletal cell types found in distinct developmental contexts, tissues and species. To date, our knowledge of the molecular nature of the shark calcified extracellular matrix, and its relationships with osteichthyan skeletal tissues, remain scarce. Here, based on specific combinations of expression patterns of the Col1a1, Col1a2 and Col2a1 fibrillar collagen genes, we compare the molecular footprint of endoskeletal elements from the chondrichthyan Scyliorhinus canicula and the tetrapod Xenopus tropicalis. We find that, depending on the anatomical location, Scyliorhinus skeletal calcification is associated to cell types expressing different subsets of fibrillar collagen genes, such as high levels of Col1a1 and Col1a2 in the neural arches, high levels of Col2a1 in the tesserae, or associated to a drastic Col2a1 downregulation in the centrum. We detect low Col2a1 levels in Xenopus osteoblasts, thereby revealing that the osteoblastic expression of this gene was significantly reduced in the tetrapod lineage. Finally, we uncover a striking parallel, from a molecular and histological perspective, between the vertebral cartilage calcification of both species and discuss the evolutionary origin of endochondral ossification.

  19. From Molecular to Nanotechnology Strategies for Delivery of Neurotrophins: Emphasis on Brain-Derived Neurotrophic Factor (BDNF

    Directory of Open Access Journals (Sweden)

    Claire Géral

    2013-02-01

    Full Text Available Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe the existing approaches for delivery of brain-derived neurotrophic factor (BDNF, which is the most abundant neurotrophin in the mammalian central nervous system (CNS. Biomimetic peptides of BDNF have emerged as a promising therapy against neurodegenerative disorders. Polymer-based carriers have provided sustained neurotrophin delivery, whereas lipid-based particles have contributed also to potentiation of the BDNF action. Nanotechnology offers new possibilities for the design of vehicles for neuroprotection and neuroregeneration. Recent developments in nanoscale carriers for encapsulation and transport of BDNF are highlighted.

  20. From molecular to nanotechnology strategies for delivery of neurotrophins: emphasis on brain-derived neurotrophic factor (BDNF).

    Science.gov (United States)

    Géral, Claire; Angelova, Angelina; Lesieur, Sylviane

    2013-02-08

    Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe the existing approaches for delivery of brain-derived neurotrophic factor (BDNF), which is the most abundant neurotrophin in the mammalian central nervous system (CNS). Biomimetic peptides of BDNF have emerged as a promising therapy against neurodegenerative disorders. Polymer-based carriers have provided sustained neurotrophin delivery, whereas lipid-based particles have contributed also to potentiation of the BDNF action. Nanotechnology offers new possibilities for the design of vehicles for neuroprotection and neuroregeneration. Recent developments in nanoscale carriers for encapsulation and transport of BDNF are highlighted.

  1. Molecular and mass spectral identification of the broadly conserved decapod crustacean neuropeptide pQIRYHQCYFNPISCF: the first PISCF-allatostatin (Manduca sexta- or C-type allatostatin) from a non-insect

    Science.gov (United States)

    Stemmler, Elizabeth A.; Bruns, Emily A.; Cashman, Christopher R.; Dickinson, Patsy S.; Christie, Andrew E.

    2009-01-01

    The PISCF-allatostatins (Manduca sexta- or C-type allatostatins) are a family of pentadecapeptides characterized by a pyroglutamine blocked N-terminus, an unamidated –PISCF C-terminus, and a disulfide bridge between two internal Cys residues. Several isoforms of PISCF-AST are known, all from holometabolous insects. Using a combination of transcriptomics and mass spectrometry, we have identified the first PISCF-type peptides from a non-insect species. In silico analysis of crustacean ESTs identified several Litopenaeus vannamei (infraorder Penaeidea) transcripts encoding putative PISCF-AST precursors. Translation of these ESTs, with subsequent prediction of their putative post-translational processing, revealed the existence of as many as three PISCF-type peptides, including pQIRYHQCYFNPISCF (disulfide bridging between Cys7 and Cys14). Although none of the predicted isoforms was detected by mass spectrometry in L. vannamei, MALDI-FTMS mass profiling identified an m/z signal corresponding to pQIRYHQCYFNPISCF (disulfide bridge present) in neural tissue from 28 other decapods, which included members of six infraorders (Stenopodidea, Astacidea, Thalassinidea, Achelata, Anomura and Brachyura). Further characterization of the peptide using SORI-CID and chemical derivatization/enzymatic digestion supported the theorized structure. In both the crab Cancer borealis and the lobster Homarus americanus, MALDI-based tissue surveys suggest that pQIRYHQCYFNPISCF is broadly distributed in the nervous system; it was also detected in the posterior midgut caecum. Collectively, our data show that members of the PISCF-AST family are not restricted to the holometabolous insects, but instead may be broadly conserved within the Pancrustacea. Moreover, our data suggest that one highly conserved PISCF-type peptide, pQIRYHQCYFNPISCF, is present in decapod crustaceans, functioning as a brain-gut paracrine/hormone. PMID:19467234

  2. Functional and Developmental Identification of a Molecular Subtype of Brain Serotonergic Neuron Specialized to Regulate Breathing Dynamics

    Directory of Open Access Journals (Sweden)

    Rachael D. Brust

    2014-12-01

    Full Text Available Serotonergic neurons modulate behavioral and physiological responses from aggression and anxiety to breathing and thermoregulation. Disorders involving serotonin (5HT dysregulation are commensurately heterogeneous and numerous. We hypothesized that this breadth in functionality derives in part from a developmentally determined substructure of distinct subtypes of 5HT neurons each specialized to modulate specific behaviors. By manipulating developmentally defined subgroups one by one chemogenetically, we find that the Egr2-Pet1 subgroup is specialized to drive increased ventilation in response to carbon dioxide elevation and acidosis. Furthermore, this subtype exhibits intrinsic chemosensitivity and modality-specific projections—increasing firing during hypercapnic acidosis and selectively projecting to respiratory chemosensory but not motor centers, respectively. These findings show that serotonergic regulation of the respiratory chemoreflex is mediated by a specialized molecular subtype of 5HT neuron harboring unique physiological, biophysical, and hodological properties specified developmentally and demonstrate that the serotonergic system contains specialized modules contributing to its collective functional breadth.

  3. Laser conservation paleontology

    Science.gov (United States)

    Asmus, John F.

    2001-10-01

    Just as lasers have found countless applications in science, industry, medicine, and entertainment, an array of real and potential uses for lasers in art-conservation analytes and practice have been investigated over the past thirty years. These include holographic recording, holographic recording, holographic nondestructive testing, laser-induced ultrasonic imaging, laser-scattering surface characterization, atomic and molecular analyses, photoacoustic spectroscopy, surface modification, as well as surface divestment and cleaning. The initial endeavors in exploring and assessing the utility of these tools for art conservation are recounted for investigations involving ruby, glass, ion, YAG, carbon dioxide, dye, and excimer lasers as well as high-intensity nonlaser light generators such as xenon flashlamps and argon pinchlamps. Initially, laser divestment/cleaning was, by general consensus, the least plausible laser application in art conservation. In the past ten years it has emerged to dominate all the other applications noted above. Today, at least a dozen firms supply user-friendly laser systems optimized for a range of art-conservation divestment applications. The first-generation laser-cleaning tools are essentially a laser, a beam-delivery device, and a debris- collection accessory. Advanced developmental work has turned in large measure to ancillary subsystems for more sophisticated process control. Of particular importance are acoustic, optical, spectral, EMP, and electronic-vision process control. Beam direction may be via manual, translational-scanner, or robotic beam positioning implemented by means of fiber optics, minors, or prisms and computer control. Substrate thermal alteration and debris redeposition may be minimized or avoided through the incorporation of a gas jet, fluid or fluid jet, or dry-ice blast.

  4. Application of multiplex PCR approaches for shark molecular identification: feasibility and applications for fisheries management and conservation in the Eastern Tropical Pacific.

    Science.gov (United States)

    Caballero, S; Cardeñosa, D; Soler, G; Hyde, J

    2012-03-01

    Here we describe the application of new and existing multiplex PCR methodologies for shark species molecular identification. Four multiplex systems (group ID, thresher sharks, hammerhead sharks and miscellaneous shark) were employed with primers previously described and some designed in this study, which allow for species identification after running PCR products through an agarose gel. This system was implemented for samples (bodies and fins) collected from unidentified sharks landed in the port of Buenaventura and from confiscated tissues obtained from illegal fishing around the Malpelo Island Marine Protected Area, Pacific Coast of Colombia. This method has allowed reliable identification, to date, of 407 samples to the genus and/or species levels, most of them (380) identified as the pelagic thresher shark (Alopias pelagicus). Another seven samples were identified as scalloped hammerhead sharks (Sphyrna lewini). This is an easy-to-implement and reliable identification method that could even be used locally to monitor shark captures in the main fishing ports of developed and developing countries.

  5. Barrier mechanisms in the Drosophila blood-brain barrier

    Directory of Open Access Journals (Sweden)

    Samantha Jane Hindle

    2014-12-01

    Full Text Available The invertebrate blood-brain barrier field is growing at a rapid pace and, in recent years, studies have shown a physiologic and molecular complexity that has begun to rival its vertebrate counterpart. Novel mechanisms of paracellular barrier maintenance through GPCR signaling were the first demonstrations of the complex adaptive mechanisms of barrier physiology. Building upon this work, the integrity of the invertebrate blood-brain barrier has recently been shown to require coordinated function of all layers of the compound barrier structure, analogous to signaling between the layers of the vertebrate neurovascular unit. These findings strengthen the notion that many blood-brain barrier mechanisms are conserved between vertebrates and invertebrates, and suggest that novel findings in invertebrate model organisms will have a significant impact on the understanding of vertebrate BBB functions. In this vein, important roles in coordinating localized and systemic signaling to dictate organism development and growth are beginning to show how the blood-brain barrier can govern whole animal physiologies. This includes novel functions of blood-brain barrier gap junctions in orchestrating synchronized neuroblast proliferation, and of blood-brain barrier secreted antagonists of insulin receptor signaling. These advancements and others are pushing the field forward in exciting new directions. In this review, we provide a synopsis of invertebrate blood-brain barrier anatomy and physiology, with a focus on insights from the past 5 years, and highlight important areas for future study.

  6. Brain Basics

    Medline Plus

    Full Text Available ... News About Us Home > Health & Education > Educational Resources Brain Basics Introduction The Growing Brain The Working Brain ... to mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are ...

  7. Brain Basics

    Science.gov (United States)

    ... News About Us Home > Health & Education > Educational Resources Brain Basics Introduction The Growing Brain The Working Brain ... to mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are ...

  8. Brain Basics

    Medline Plus

    Full Text Available ... Events About Us Home > Health & Education > Educational Resources Brain Basics Introduction The Growing Brain The Working Brain ... to mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are ...

  9. Brain Basics

    Medline Plus

    Full Text Available ... Brain Research Glossary Brain Basics (PDF, 10 pages) Introduction Watch the Brain Basics video Welcome. Brain Basics ... brain may play a role in disorders like schizophrenia or attention deficit hyperactivity disorder (ADHD) . Glutamate —the ...

  10. A computational study on the N-heterocyclic carbene-catalyzed Csp(2)-Csp(3) bond activation/[4+2] cycloaddition cascade reaction of cyclobutenones with imines: a new application of the conservation principle of molecular orbital symmetry.

    Science.gov (United States)

    Wang, Yang; Wu, Bohua; Zhang, Haoyang; Wei, Donghui; Tang, Mingsheng

    2016-07-20

    A comprehensive density functional theory (DFT) investigation has been performed to interrogate the mechanisms and stereoselectivities of the Csp(2)-Csp(3) single bond activation of cyclobutenones and their [4+2] cycloaddition reaction with imines via N-heterocyclic carbene (NHC) organocatalysis. According to our calculated results, the fundamental reaction pathway contains four steps: nucleophilic addition of NHC to cyclobutenone, C-C bond cleavage for the formation of an enolate intermediate, [4+2] cycloaddition of the enolate intermediate with isatin imine, and the elimination of the NHC catalyst. In addition, the calculated results also reveal that the second reaction step is the rate-determining step, whereas the third step is the regio- and stereo-selectivity determining step. For the regio- and stereo-selectivity determining step, all four possible attack modes were considered. The addition of the C[double bond, length as m-dash]N bond in isatin imine to the dienolate intermediate is more energy favorable than the addition of the C[double bond, length as m-dash]O bond to a dienolate intermediate. Moreover, the Re face addition of the C[double bond, length as m-dash]N bond in isatin imine to the Re face of the dienolate intermediate leading to the SS configuration N-containing product was demonstrated to be most energy favorable, which is mainly due to the stronger second-order perturbation energy value in the corresponding transition state. Furthermore, by tracking the frontier molecular orbital (FMO) changes in the rate-determining C-C bond cleavage step, we found that the reaction obeys the conservation principle of molecular orbital symmetry. We believe that the present work would provide valuable insights into this kind of reaction.

  11. Hemangiosarcoma after breast-conserving therapy of breast cancer. Report of four cases with molecular genetic diagnosis and literature review; Haemangiosarkom nach brusterhaltender Therapie beim Mammakarzinom. Vier Fallbeispiele mit molekulargenetischer Diagnostik und Literaturuebersicht

    Energy Technology Data Exchange (ETDEWEB)

    Nestle-Kraemling, Carolin [Universitaetsklinikum, Duesseldorf (Germany). Frauenklinik; Boelke, Edwin; Budach, Wilfried [Universitaetsklinikum Duesseldorf (DE). Klinik und Poliklinik fuer Strahlentherapie und radiologische Onkologie] (and others)

    2011-10-15

    Hemangiosarcomas of the breast represent a rare disease of the breast mainly occurring as secondary neoplasias with a latency of 5-10 years after primary treatment of breast cancer and are associated with an unfavourable prognosis. Radiation therapy, which is integrated within the concept of breast conserving therapy ranks as the main risk factor. In this report we describe the clinical course of 4 patients including their molecular genetic pattern and give a summary of the actual literature. Hemangiosarcomas occur as a secondary neoplasm with a latency of 5-10 years after primary treatment of breast cancer and have an unfavorable prognosis. A genetic predisposition is assumed, but we could not find a significant role of tumor suppressor genes BRCA1, BRCA2 or p53 in our patients. Due to limited data available for these tumors, recommendations for therapy include radical tumor resection achieving wide free margins and inconsistent regimens of chemo- and/or immunetherapy modalities. In the majority these are based on systemic therapy regimens for other cutaneous sarcomas, such as Kaposi's sarcoma. Efforts should be taken for a nation-wide systematic registration of all cases of post-irradiation hemangiosarcomas.

  12. The Use of Multiscale Molecular Simulations in Understanding a Relationship between the Structure and Function of Biological Systems of the Brain: The Application to Monoamine Oxidase Enzymes.

    Science.gov (United States)

    Vianello, Robert; Domene, Carmen; Mavri, Janez

    2016-01-01

    HIGHLIGHTS Computational techniques provide accurate descriptions of the structure and dynamics of biological systems, contributing to their understanding at an atomic level.Classical MD simulations are a precious computational tool for the processes where no chemical reactions take place.QM calculations provide valuable information about the enzyme activity, being able to distinguish among several mechanistic pathways, provided a carefully selected cluster model of the enzyme is considered.Multiscale QM/MM simulation is the method of choice for the computational treatment of enzyme reactions offering quantitative agreement with experimentally determined reaction parameters.Molecular simulation provide insight into the mechanism of both the catalytic activity and inhibition of monoamine oxidases, thus aiding in the rational design of their inhibitors that are all employed and antidepressants and antiparkinsonian drugs. Aging society and therewith associated neurodegenerative and neuropsychiatric diseases, including depression, Alzheimer's disease, obsessive disorders, and Parkinson's disease, urgently require novel drug candidates. Targets include monoamine oxidases A and B (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and various receptors and transporters. For rational drug design it is particularly important to combine experimental synthetic, kinetic, toxicological, and pharmacological information with structural and computational work. This paper describes the application of various modern computational biochemistry methods in order to improve the understanding of a relationship between the structure and function of large biological systems including ion channels, transporters, receptors, and metabolic enzymes. The methods covered stem from classical molecular dynamics simulations to understand the physical basis and the time evolution of the structures, to combined QM, and QM/MM approaches to probe the chemical mechanisms of enzymatic

  13. Brain glycogen

    DEFF Research Database (Denmark)

    Obel, Linea Lykke Frimodt; Müller, Margit S; Walls, Anne B

    2012-01-01

    activity and memory formation. In line with the great spatiotemporal complexity of the brain and thereof derived focus on the basis for ensuring the availability of the right amount of energy at the right time and place, we here encourage a closer look into the molecular and subcellular mechanisms...... underlying glycogen metabolism. Based on (1) the compartmentation of the interconnected second messenger pathways controlling glycogen metabolism (calcium and cAMP), (2) alterations in the subcellular location of glycogen-associated enzymes and proteins induced by the metabolic status and (3) a sequential...

  14. Acute brain hemorrhage in dengue

    Institute of Scientific and Technical Information of China (English)

    Somsri Wiwanitkit; Viroj Wiwanitkit

    2014-01-01

    Dengue is a tropical arboviral infection that can have severe hemorrhagic complication.Acute brain hemorrhage in dengue is rare and is a big challenge in neurosurgery.To perform surgery for management of acute brain hemorrhage in dengue is a controversial issue.Here, the authors try to summarize the previous reports on this topic and compare neurosurgery versus conservative management.

  15. Molecular abnormalities in pediatric embryonal brain tumors--analysis of loss of heterozygosity on chromosomes 1, 5, 9, 10, 11, 16, 17 and 22.

    Science.gov (United States)

    Zakrzewska, M; Rieske, P; Debiec-Rychter, M; Zakrzewski, K; Polis, L; Fiks, T; Liberski, P P

    2004-01-01

    Embryonal tumors, the most common group of malignant brain tumors in childhood, are heterogeneous and have been associated with a large number of genetic abnormalities. The aim of this study was to comprehensively analyze loss of heterozygosity (LOH) on regions harboring suppressor genes (PTCH2, PTCH1, APC, PTEN, DMBT1, SUFU, AXIN1, hSNF5/INI1) and to study chromosomal regions in which deletions have been described most frequently (1p, 1q, 11p, 16p, 17p). Twenty-nine children (17 male and 12 female), aged from 1 year 13 years were included in this study. There were 24 medulloblastomas (MB) and 5 supratentorial primitive neuroectodermal tumors (sPNET). Tissue samples from 29 primary and 11 recurrent tumors were analyzed according to the LOH standard procedures, which were extended to include fluorescence in situ hybridization for detection of isochromosome 17q (i(17q)) and direct sequencing ofTP53 exon 4. LOH on 17p was found in 15 out of 29 tumors. FISH analysis identified the presence of i(17q) in 16 tumors. Comparison of LOH analysis and the FISH data indicated that alterations of 17p were related to be the introduction of an i(17q) formation. LOH on 10q and 9q was observed in 4 and 2 cases, respectively, and was associated with alterations of chromosome 17. These results indicated a connection between alterations of PTCH/SHH genes and abnormalities of chromosome 17. A deleted region on 22q, covering the hSNF5/INI1 locus, was observed in 3 tumors. Progression of the molecular changes occurred in 1 case of recurrent medulloblastoma. LOH on 10q and 17p was found in both primary and recurrent tumor, while losses on 11p, 16p, and 16q occurred only in the recurrent tumor. No evidence of alteration in TP53 exon 4 was identified.

  16. The use of multiscale molecular simulations in understanding a relationship between the structure and function of biological systems of the brain: the application to monoamine oxidase enzymes

    Directory of Open Access Journals (Sweden)

    Robert Vianello

    2016-07-01

    Full Text Available Aging society and therewith associated neurodegenerative and neuropsychiatric diseases, including depression, Alzheimer’s disease, obsessive disorders, and Parkinson’s disease, urgently require novel drug candidates. Targets include monoamine oxidases A and B (MAOs, acetylcholinesterase (AChE and butyrylcholinesterase (BChE, and various receptors and transporters. For rational drug design it is particularly important to combine experimental synthetic, kinetic, toxicological and pharmacological information with structural and computational work. This paper describes the application of various modern computational biochemistry methods in order to improve the understanding of a relationship between the structure and function of large biological systems including ion channels, transporters, receptors and metabolic enzymes. The methods covered stem from classical molecular dynamics simulations to understand the physical basis and the time evolution of the structures, to combined QM and QM/MM approaches to probe the chemical mechanisms of enzymatic activities and their inhibition. As an illustrative example, the later will focus on the monoamine oxidase family of enzymes, which catalyze the degradation of amine neurotransmitters in various parts of the brain, the imbalance of which is associated with the development and progression of a range of neurodegenerative disorders. Inhibitors that act mainly on MAO A are used in the treatment of depression, due to their ability to raise serotonin concentrations, while MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Our results give strong support that both MAO isoforms, A and B, operate through the hydride transfer mechanism. Relevance of MAO catalyzed reactions and MAO inhibition in the context of neurodegeneration will be discussed.

  17. Brain herniation

    Science.gov (United States)

    ... herniation; Uncal herniation; Subfalcine herniation; Tonsillar herniation; Herniation - brain ... Brain herniation occurs when something inside the skull produces pressure that moves brain tissues. This is most ...

  18. Conserved nematode signalling molecules elicit plant defenses and pathogen resistance

    OpenAIRE

    Manosalva, P; Manohar, M; von Reuss, S.; Chen, S.; Koch, A; Kaplan, F; Choe, A.; Micikas, R.; X. Wang; Kogel, K.; Sternberg, P.; Williamson, V; Schroeder, D; Klessig, F.

    2015-01-01

    Plant-defense responses are triggered by perception of conserved microbe-associated molecular patterns (MAMPs), for example, flagellin or peptidoglycan. However, it remained unknown whether plants can detect conserved molecular patterns derived from plant-parasitic animals, including nematodes. Here we show that several genera of plant-parasitic nematodes produce small molecules called ascarosides, an evolutionarily conserved family of nematode pheromones. Picomolar to micromolar concentratio...

  19. Influence of the conserved disulphide bond, exposed to the putative binding pocket, on the structure and function of the immunoglobulin-like molecular chaperone Caf1M of Yersinia pestis.

    Science.gov (United States)

    Zav'yalov, V P; Chernovskaya, T V; Chapman, D A; Karlyshev, A V; MacIntyre, S; Zavialov, A V; Vasiliev, A M; Denesyuk, A I; Zav'yalova, G A; Dudich, I V; Korpela, T; Abramov, V M

    1997-06-01

    The Yersinia pestis protein Caf1M is a typical representative of a subfamily of periplasmic molecular chaperones with characteristic structural and functional features, one of which is the location of two conserved cysteine residues close to the putative binding pocket. We show that these residues form a disulphide bond, the reduction and alkylation of which significantly increases the dissociation constant of the Caf1M-Caf1 (where Caf 1 is a polypeptide subunit of the capsule) complex [from a Kd of (4.77+/-0.50)x10(-9) M for the intact protein to one of (3.68+/-0.68)x10(-8) M for the modified protein]. The importance of the disulphide bond for the formation of functional Caf1M in vivo was demonstrated using an Escherichia coli dsbA mutant carrying the Y. pestis f1 operon. In accordance with the CD and fluorescence measurements, the disulphide bond is not important for maintenance of the overall structure of the Caf1M molecule, but would appear to affect the fine structural properties of the subunit binding site. A three-dimensional model of the Caf1M-Caf1 complex was designed based on the published crystal structure of PapD (a chaperone required for Pap pili assembly) complexed with a peptide corresponding to the C-terminus of the papG subunit. In the model the disulphide bond is in close proximity to the invariant Caf1M Arg-23 and Lys-142 residues that are assumed to anchor the C-terminal group of the subunit. The importance of this characteristic disulphide bond for the orchestration of the binding site and subunit binding, as well as for the folding of the protein in vivo, is likely to be a common feature of this subfamily of Caf1M-like chaperones. A possible model for the role of the disulphide bond in Caf1 assembly is discussed.

  20. A conservative region of the mercuric reductase gene (merA as a molecular marker of bacterial mercury resistance Região conservada do gene da mercúrio redutase (merA como marcador molecular da resistência bacteriana ao mercúrio

    Directory of Open Access Journals (Sweden)

    Adriana Sotero-Martins

    2008-06-01

    Full Text Available The most common bacterial mercury resistance mechanism is based on the reduction of Hg(II to Hg0, which is dependent of the mercuric reductase enzyme (MerA activity. The use of a 431 bp fragment of a conservative region of the mercuric reductase (merA gene was applied as a molecular marker of this mechanism, allowing the identification of mercury resistant bacterial strains.O mecanismo de resistência bacteriana ao mercúrio mais comum é baseada na redução do Hg(II a Hg0, através da atividade da enzima mercúrio redutase (MerA. O uso do fragmento de 431 pb amplificado de uma região conservada do gene merA, que codifica a enzima MerA,foi utilizado como marcador molecular deste mecanismo, permitindo a identificação de bactérias resistentes ao mercúrio.

  1. Effects of special brain area regional cerebral blood flow abnormal perfusion on learning and memory function and its molecular mechanism in rats

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    s To study the effect of special brain area regional cerebral blood flow (rCBF) abnormal perfusion on learning and memory function and its molecular mechanism,64 adult male healthy Spragne-Dawley (SD) rats were randomly divided into two groups,the false operation group (control group) and the operation group (model group).After surgical operation,the operation group undertook bilateral common carotid artery permanent ligation,while the other group did not.Learning and memory function were measured by Y-maze at 4 h,8 h,24 h and 3 d after surgical operation,respectively.The rCBF of the right frontal lobe and hippocampus was also detected by the PerifluxPF model laser Doppler flowmetry,and the expressions of c-fos or c-jun or Bcl-2 and Bax were also measured by immune histochemistry S-P method accordingly.Results showed that the rCBF of the right frontal lobe and hippocampus in the operation group was significantly lower than that in the false operation group (P < 0.05).The learning indexes,error number (EN),day of reach standard and total reaction time (TRT) in the operation group,were significantly higher than that in the false operation group (P< 0.05).However,the initiative evasion rate in the operation group was significantly lower than that in the false operation group.The study also found that the rCBF was relatively more,the indexes (EN,the day of reach standard and TRT) relatively fewer,but the initiative evasion rate and the memory keeping rate were relatively more.The positive expression and the average absorbency of Fos and Jun in the operation group were significantly higher than that in the false operation group (P< 0.05).Furthermore,Bax and Bcl-2 positive cells were all increased over time in the operation group,and the expression ratio of Bax/Bcl-2 in the operation group was significantly higher than that in the false operation group (P<0.01).In conclusion,rCBF decrease can impair the learning and memory function in rats,which may be related to

  2. The Conservation Status and Conservation Strategy of Picea neoveitchii

    Institute of Scientific and Technical Information of China (English)

    Zhang Deshun; Kim Yongshik; Mike Maunder; Li Xiufen

    2006-01-01

    Picea neoveitchii is an endemic species in China. It had been listed as an endangered species in red data books. It scatters in several locations of south slope of the Qinling Mountain of China. Upon reviewing the related literature, discussing with leading scholars on gymnosperm, ecology and plant conservation, the field survey was carried out in four locations. There are eleven mature individuals and two seedlings surviving in its natural habitats. With the survey of quadrat method in four locations, related community index were calculated such as relative important value (RIV), species richness,similarity index, diversity index and evenness index etc.The community could be sorted and characterized as three groups based on the community parameters. The analysis of vegetation table elucidates that Picea neoveitchii is a dominant species with low grouping rate in most surveyed sites.The RAPD analysis shows target species has intraspecific genetic variability. The estimation of Shannon's phenotypic diversity index (Ho) also explains the difference of genetic variations of different locations.Due to the lack of enough knowledge and professional guide of conservation biological perspective,Picea neoveitchii had been clear-cut for timber production. The extent of occurrence and area of occupancy declined rapidly from 1950s to 1990s.According to the Conservation Category guideline proposed by the World Conservation Union, the conservation status of Picea neoveitchii was reevaluated as Critically Endangered (CR) B2b C2a D. Upon research in areas of ecology, molecular biology, cluster analysis of environmental parameters, a practical conservation strategy is recommended in this research.

  3. Multispecies genetic objectives in spatial conservation planning.

    Science.gov (United States)

    Nielsen, Erica S; Beger, Maria; Henriques, Romina; Selkoe, Kimberly A; von der Heyden, Sophie

    2016-12-07

    The growing threats to biodiversity and global alteration of habitats and species distributions make it increasingly necessary to consider evolutionary patterns in conservation decision-making. Yet there is no clear-cut guidance on how genetic features can be incorporated into conservation planning processes, with multiple molecular markers and several genetic metrics for each marker type to choose from. Genetic patterns also differ between species, but the potential trade-offs amongst genetic objectives for multiple species in conservation planning are currently understudied. This study compares spatial conservation prioritizations derived from two metrics of both genetic diversity (nucleotide and haplotype diversity) and genetic isolation (private haplotypes and local genetic differentiation) for mitochondrial DNA for five marine species. The findings show that conservation plans based solely on habitat representation noticeably differ from those additionally including genetic data, with habitat-based conservation plans selecting fewer conservation priority areas. Furthermore, all four genetic metrics selected approximately similar conservation priority areas, which is likely a result of prioritizing genetic patterns across a genetically diverse array of species. Largely, the results suggest that multi-species genetic conservation objectives are vital to create protected area networks that appropriately preserve community-level evolutionary patterns. This article is protected by copyright. All rights reserved.

  4. Pediatric brain tumors

    Energy Technology Data Exchange (ETDEWEB)

    Poussaint, Tina Y. [Department of Radiology, Boston, MA (United States); Panigrahy, Ashok [Children' s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Department of Radiology, Pittsburgh, PA (United States); Huisman, Thierry A.G.M. [Charlotte R. Bloomberg Children' s Center, Johns Hopkins Hospital, Division of Pediatric Radiology and Pediatric Neuroradiology, Baltimore, MD (United States)

    2015-09-15

    Among all causes of death in children from solid tumors, pediatric brain tumors are the most common. This article includes an overview of a subset of infratentorial and supratentorial tumors with a focus on tumor imaging features and molecular advances and treatments of these tumors. Key to understanding the imaging features of brain tumors is a firm grasp of other disease processes that can mimic tumor on imaging. We also review imaging features of a common subset of tumor mimics. (orig.)

  5. Meeting global conservation challenges

    Science.gov (United States)

    2016-10-01

    Hot on the heels of last year's Sustainable Development Goals and the Paris Agreement, representatives from the global conservation community met to set the conservation agenda that will help to implement these targets.

  6. Conservation: Threatened by Luxury.

    Science.gov (United States)

    Webb, Thomas J

    2016-06-20

    When animals are traded in lucrative international luxury markets, individuals really do matter to conservation. Identifying the intrinsic and extrinsic factors that make some species especially vulnerable to this kind of threat helps set guidelines for more effective conservation.

  7. Early, nonciliary role for microtubule proteins in left-right patterning is conserved across kingdoms.

    Science.gov (United States)

    Lobikin, Maria; Wang, Gang; Xu, Jingsong; Hsieh, Yi-Wen; Chuang, Chiou-Fen; Lemire, Joan M; Levin, Michael

    2012-07-31

    Many types of embryos' bodyplans exhibit consistently oriented laterality of the heart, viscera, and brain. Errors of left-right patterning present an important class of human birth defects, and considerable controversy exists about the nature and evolutionary conservation of the molecular mechanisms that allow embryos to reliably orient the left-right axis. Here we show that the same mutations in the cytoskeletal protein tubulin that alter asymmetry in plants also affect very early steps of left-right patterning in nematode and frog embryos, as well as chirality of human cells in culture. In the frog embryo, tubulin α and tubulin γ-associated proteins are required for the differential distribution of maternal proteins to the left or right blastomere at the first cell division. Our data reveal a remarkable molecular conservation of mechanisms initiating left-right asymmetry. The origin of laterality is cytoplasmic, ancient, and highly conserved across kingdoms, a fundamental feature of the cytoskeleton that underlies chirality in cells and multicellular organisms.

  8. The primary brain vesicles revisited: are the three primary vesicles (forebrain/midbrain/hindbrain) universal in vertebrates?

    Science.gov (United States)

    Ishikawa, Yuji; Yamamoto, Naoyuki; Yoshimoto, Masami; Ito, Hironobu

    2012-01-01

    It is widely held that three primary brain vesicles (forebrain, midbrain, and hindbrain vesicles) develop into five secondary brain vesicles in all vertebrates (von Baer's scheme). We reviewed previous studies in various vertebrates to see if this currently accepted scheme of brain morphogenesis is a rule applicable to vertebrates in general. Classical morphological studies on lamprey, shark, zebrafish, frog, chick, Chinese hamster, and human embryos provide only partial evidence to support the existence of von Baer's primary vesicles at early stages. Rather, they suggest that early brain morphogenesis is diverse among vertebrates. Gene expression and fate map studies on medaka, chick, and mouse embryos show that the fates of initial brain vesicles do not accord with von Baer's scheme, at least in medaka and chick brains. The currently accepted von Baer's scheme of brain morphogenesis, therefore, is not a universal rule throughout vertebrates. We propose here a developmental hourglass model as an alternative general rule: Brain morphogenesis is highly conserved at the five-brain vesicle stage but diverges more extensively at earlier and later stages. This hypothesis does not preclude the existence of deep similarities in molecular prepatterns at early stages.

  9. Conservation Action Handbook.

    Science.gov (United States)

    National Rifle Association, Washington, DC.

    Conservation problems are identified, with some suggestions for action. General areas covered are: Wildlife Conservation, Soil Conservation, Clean Water, Air Pollution Action, and Outdoor Recreation Action. Appendices list private organizations or agencies concerned with natural resource use and/or management, congressional committees considering…

  10. Brain Fingerprinting

    Directory of Open Access Journals (Sweden)

    Ravi Kumar

    2012-12-01

    Full Text Available Brain Fingerprinting is a scientific technique to determine whether or not specific information is stored in an individual's brain by measuring a electrical brain wave response to Word, phrases, or picture that are presented on computer screen. Brain Fingerprinting is a controversial forensic science technique that uses electroencephalography (EEG to determine whether specific information is stored in a subject's brain.

  11. Brain Fingerprinting

    Directory of Open Access Journals (Sweden)

    ravi kumar

    2012-12-01

    Full Text Available Brain Fingerprinting is a scientific technique to determine whether or not specific information is stored in an individual's brain by measuring a electrical brain wave response to Word, phrases, or picture that are presented on computer screen. Brain Fingerprinting is a controversial forensic science technique that uses electroencephalograph y (EEG to determine whether specific information is stored in a subject's brain

  12. Brain Basics

    Medline Plus

    Full Text Available ... Basics will introduce you to some of this science, such as: How the brain develops How genes and the environment affect the brain The basic structure of the brain How different parts of the brain communicate and work with each other How changes in the brain ...

  13. Brain Tumors

    Science.gov (United States)

    A brain tumor is a growth of abnormal cells in the tissues of the brain. Brain tumors can be benign, with no cancer cells, ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are ...

  14. Importance of a Conserved Lys/Arg Residue for Ligand/PDZ Domain Interactions as Examined by Protein Semisynthesis

    DEFF Research Database (Denmark)

    Pedersen, Søren W; Moran, Griffin E; Sereikaité, Vita

    2016-01-01

    drug targets for diseases (in the brain in particular), so understanding the molecular details of PDZ domain interactions is of fundamental importance. PDZ domains bind to a protein partner at either a C-terminal peptide or internal peptide motifs. Here, we examined the importance of a conserved Lys......PDZ domains are ubiquitous small protein domains that are mediators of numerous protein-protein interactions, and play a pivotal role in protein trafficking, synaptic transmission, and the assembly of signaling-transduction complexes. In recent years, PDZ domains have emerged as novel and exciting...

  15. Development of the hypothalamus: conservation, modification and innovation.

    Science.gov (United States)

    Xie, Yuanyuan; Dorsky, Richard I

    2017-05-01

    The hypothalamus, which regulates fundamental aspects of physiological homeostasis and behavior, is a brain region that exhibits highly conserved anatomy across vertebrate species. Its development involves conserved basic mechanisms of induction and patterning, combined with a more plastic process of neuronal fate specification, to produce brain circuits that mediate physiology and behavior according to the needs of each species. Here, we review the factors involved in the induction, patterning and neuronal differentiation of the hypothalamus, highlighting recent evidence that illustrates how changes in Wnt/β-catenin signaling during development may lead to species-specific form and function of this important brain structure. © 2017. Published by The Company of Biologists Ltd.

  16. N-terminal pro-brain natriuretic peptide for additional risk stratification in patients with non-ST-elevation acute coronary syndrome and an elevated troponin T: an Invasive versus Conservative Treatment in Unstable coronary Syndromes (ICTUS) substudy.

    NARCIS (Netherlands)

    Windhausen, F.; Hirsch, A.; Sanders, G.T.B.; Cornel, J.H.; Fischer, J.; Straalen, J.P. van; Tijssen, J.G.P.; Verheugt, F.W.A.; Winter, R.J. de

    2007-01-01

    BACKGROUND: New evidence has emerged that the assessment of multiple biomarkers such as cardiac troponin T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with non-ST-elevation acute coronary syndrome (nSTE-ACS) provides unique prognostic information. The purpose of this

  17. Exactly conservation integrators

    Energy Technology Data Exchange (ETDEWEB)

    Shadwick, B.A.; Bowman, J.C.; Morrison, P.J. [Univ. of Texas, Austin, TX (United States)

    1999-03-01

    Traditional explicit numerical discretizations of conservative systems generically predict artificial secular drifts of any nonlinear invariants. In this work the authors present a general approach for developing explicit nontraditional algorithms that conserve such invariants exactly. They illustrate the method by applying it to the three-wave truncation of the Euler equations, the Lotka-Volterra predator-prey model, and the Kepler problem. The ideas are discussed in the context of symplectic (phase-space-conserving) integration methods as well as nonsymplectic conservative methods. They comment on the application of the method to general conservative systems.

  18. Exactly conservative integrators

    Energy Technology Data Exchange (ETDEWEB)

    Shadwick, B.A.; Bowman, J.C.; Morrison, P.J.

    1995-07-19

    Traditional numerical discretizations of conservative systems generically yield an artificial secular drift of any nonlinear invariants. In this work we present an explicit nontraditional algorithm that exactly conserves invariants. We illustrate the general method by applying it to the Three-Wave truncation of the Euler equations, the Volterra-Lotka predator-prey model, and the Kepler problem. We discuss our method in the context of symplectic (phase space conserving) integration methods as well as nonsymplectic conservative methods. We comment on the application of our method to general conservative systems.

  19. Exactly conservative integrators

    CERN Document Server

    Shadwick, B A; Morrison, P J; Bowman, John C

    1995-01-01

    Traditional numerical discretizations of conservative systems generically yield an artificial secular drift of any nonlinear invariants. In this work we present an explicit nontraditional algorithm that exactly conserves these invariants. We illustrate the general method by applying it to the three-wave truncation of the Euler equations, the Lotka--Volterra predator--prey model, and the Kepler problem. This method is discussed in the context of symplectic (phase space conserving) integration methods as well as nonsymplectic conservative methods. We comment on the application of our method to general conservative systems.

  20. Exactly conservative integrators

    Energy Technology Data Exchange (ETDEWEB)

    Shadwick, B.A.; Bowman, J.C.; Morrison, P.J.

    1995-07-19

    Traditional numerical discretizations of conservative systems generically yield an artificial secular drift of any nonlinear invariants. In this work we present an explicit nontraditional algorithm that exactly conserves invariants. We illustrate the general method by applying it to the Three-Wave truncation of the Euler equations, the Volterra-Lotka predator-prey model, and the Kepler problem. We discuss our method in the context of symplectic (phase space conserving) integration methods as well as nonsymplectic conservative methods. We comment on the application of our method to general conservative systems.

  1. Brain Basics

    Medline Plus

    Full Text Available ... science, such as: How the brain develops How genes and the environment affect the brain The basic ... that with brain development in people mental disorders. Genes and environmental cues both help to direct this ...

  2. Brain Basics

    Medline Plus

    Full Text Available ... can lead to mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits ... tailored treatments, and possibly prevention of such illnesses. The Working Brain Neurotransmitters Everything we do relies on ...

  3. Brain Basics

    Medline Plus

    Full Text Available ... brain's structure, studies show that brain growth in children with autism appears to peak early. And as ... grow there are differences in brain development in children who develop bipolar disorder than children who do ...

  4. Brain Basics

    Medline Plus

    Full Text Available ... science, such as: How the brain develops How genes and the environment affect the brain The basic ... that with brain development in people mental disorders. Genes and environmental cues both help to direct this ...

  5. Brain Basics

    Medline Plus

    Full Text Available ... lead to mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons ... affects the Brain Meet Sarah Sarah is a middle-aged woman who seemed to have it all. ...

  6. Brain surgery

    Science.gov (United States)

    Craniotomy; Surgery - brain; Neurosurgery; Craniectomy; Stereotactic craniotomy; Stereotactic brain biopsy; Endoscopic craniotomy ... cut depends on where the problem in the brain is located. The surgeon creates a hole in ...

  7. Brain Malformations

    Science.gov (United States)

    Most brain malformations begin long before a baby is born. Something damages the developing nervous system or causes it ... medicines, infections, or radiation during pregnancy interferes with brain development. Parts of the brain may be missing, ...

  8. Brain Basics

    Medline Plus

    Full Text Available ... related to changes in the anatomy, physiology, and chemistry of the nervous system. When the brain cannot ... How the brain develops How genes and the environment affect the brain The basic structure of the ...

  9. Brain Basics

    Medline Plus

    Full Text Available ... can lead to mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits ... tailored treatments, and possibly prevention of such illnesses. The Working Brain Neurotransmitters Everything we do relies on ...

  10. Brain Basics

    Medline Plus

    Full Text Available ... as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are the basic working unit of the brain ... specialized for the function of conducting messages. A neuron has three basic parts: Cell body which includes ...

  11. Canonical Genetic Signatures of the Adult Human Brain

    Science.gov (United States)

    Hawrylycz, Michael; Miller, Jeremy A.; Menon, Vilas; Feng, David; Dolbeare, Tim; Guillozet-Bongaarts, Angela L.; Jegga, Anil G.; Aronow, Bruce J.; Lee, Chang-Kyu; Bernard, Amy; Glasser, Matthew F.; Dierker, Donna L.; Menche, Jörge; Szafer, Aaron; Collman, Forrest; Grange, Pascal; Berman, Kenneth A.; Mihalas, Stefan; Yao, Zizhen; Stewart, Lance; Barabási, Albert-László; Schulkin, Jay; Phillips, John; Ng, Lydia; Dang, Chinh; Haynor, David R.; Jones, Allan; Van Essen, David C.; Koch, Christof; Lein, Ed

    2015-01-01

    The structure and function of the human brain are highly stereotyped, implying a conserved molecular program responsible for its development, cellular structure, and function. We applied a correlation-based metric of “differential stability” (DS) to assess reproducibility of gene expression patterning across 132 structures in six individual brains, revealing meso-scale genetic organization. The highest DS genes are highly biologically relevant, with enrichment for brain-related biological annotations, disease associations, drug targets, and literature citations. Using high DS genes we identified 32 anatomically diverse and reproducible gene expression signatures, which represent distinct cell types, intracellular components, and/or associations with neurodevelopmental and neurodegenerative disorders. Genes in neuron-associated compared to non-neuronal networks showed higher preservation between human and mouse; however, many diversely-patterned genes displayed dramatic shifts in regulation between species. Finally, highly consistent transcriptional architecture in neocortex is correlated with resting state functional connectivity, suggesting a link between conserved gene expression and functionally relevant circuitry. PMID:26571460

  12. Identification of evolutionarily conserved, functional noncoding elements in the promoter region of the sodium channel gene SCN8A.

    Science.gov (United States)

    Drews, Valerie L; Shi, Kehui; de Haan, Georgius; Meisler, Miriam H

    2007-10-01

    SCN8A is a major neuronal sodium channel gene expressed throughout the central and peripheral nervous systems. Mutations of SCN8A result in movement disorders and impaired cognition. To investigate the basis for the tissue-specific expression of SCN8A, we located conserved, potentially regulatory sequences in the human, mouse, chicken, and fish genes by 5' RACE of brain RNA and genomic sequence comparison. A highly conserved 5' noncoding exon, exon 1c, is present in vertebrates from fish to mammals and appears to define the ancestral promoter region. The distance from exon 1c to the first coding exon increased tenfold during vertebrate evolution, largely by insertion of repetitive elements. The mammalian gene acquired three novel, mutually exclusive noncoding exons that are not represented in the lower vertebrates. Within the shared exon 1c, we identified four short sequence elements of 10-20 bp with an unusually high level of evolutionary conservation. The conserved elements are most similar to consensus sites for the transcription factors Pou6f1/Brn5, YY1, and REST/NRSF. Introduction of mutations into the predicted Pou6f1 and REST sites reduced promoter activity in transfected neuronal cells. A 470-bp promoter fragment containing all of the conserved elements directed brain-specific expression of the LacZ reporter in transgenic mice. Transgene expression was highest in hippocampal neurons and cerebellar Purkinje cells, consistent with the expression of the endogenous gene. The compact cluster of conserved regulatory elements in SCN8A provides a useful target for molecular analysis of neuronal gene expression.

  13. 人类大脑容量及语言进化的分子生物学证据与质疑%Controversial Researches on Molecular Evolution of Language and Brain Size

    Institute of Scientific and Technical Information of China (English)

    俞建梁

    2015-01-01

    Language and larger brain size than other primates are the deifning features of human beings. The evolution of language and brain size has been the research hotspot all the time. Over the past 20 years the research in the evolution of language and brain size through molecular biology, which transcends the disputes between nature and nurture in language aquisition, has made great achievement. But many test results are incongruous or even controversial over the questions whether the evolution of FOXP2 might underlie linguistic behavior and whether the evolution of genes such as MCPH1, ASPM and etc. has undergone positive selection or implicated in the brain size and intelligence. The discussion of these questions allows us to understand the current situation of the molecular evolution of language and brain size, and the developmental trend of biolinguistics.%语言和拥有比其他灵长类动物更大的脑容量是人类的显著特征。语言与大脑的进化一直是人们研究的热点。过去近20年有关人类语言与脑容量进化的分子生物学研究超越了思辨层面的先天论和后天论之争,取得了许多重要的发现。但许多研究结果相左,有的甚至相互矛盾:FOXP2基因的进化是否与语言相关;MCPH1、ASPM等基因的进化是否受到正向选择、是否影响大脑容量以及是否与智力有关等等。这些问题在分子生物学领域引起了诸多争论和质疑。对这些问题的了解有助于认识当前有关语言与大脑容量进化的研究现状和生物语言学的发展动态。

  14. 7 CFR 12.23 - Conservation plans and conservation systems.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Conservation plans and conservation systems. 12.23 Section 12.23 Agriculture Office of the Secretary of Agriculture HIGHLY ERODIBLE LAND AND WETLAND CONSERVATION Highly Erodible Land Conservation § 12.23 Conservation plans and conservation systems. (a) Use...

  15. Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: A report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial

    NARCIS (Netherlands)

    H.J. Dubbink (Erik Jan); P.N. Atmodimedjo; J.M. Kros (Johan); P.J. French (Pim); M. Sanson (Marc); A. Idbaih (Ahmed); P. Wesseling (Pieter); R. Enting (Roelien); W.G.M. Spliet (Wim); C.C. Tijssen (Cees); W.N.M. Dinjens (Winand); T.S. Gorlia (Thierry); M.J. van den Bent (Martin)

    2016-01-01

    textabstractBackground Histopathological diagnosis of diffuse gliomas is subject to interobserver variation and correlates modestly with major prognostic and predictive molecular abnormalities. We investigated a series of patients with locally diagnosed anaplastic oligodendroglial tumors included in

  16. Transcriptome analysis of the brain of the silkworm Bombyx mori infected with Bombyx mori nucleopolyhedrovirus: A new insight into the molecular mechanism of enhanced locomotor activity induced by viral infection.

    Science.gov (United States)

    Wang, Guobao; Zhang, Jianjia; Shen, Yunwang; Zheng, Qin; Feng, Min; Xiang, Xingwei; Wu, Xiaofeng

    2015-06-01

    Baculoviruses have been known to induce hyperactive behavior in their lepidopteran hosts for over a century. As a typical lepidopteran insect, the silkworm Bombyx mori displays enhanced locomotor activity (ELA) following infection with B. mori nucleopolyhedrovirus (BmNPV). Some investigations have focused on the molecular mechanisms underlying this abnormal hyperactive wandering behavior due to the virus; however, there are currently no reports about B. mori. Based on previous studies that have revealed that behavior is controlled by the central nervous system, the transcriptome profiles of the brains of BmNPV-infected and non-infected silkworm larvae were analyzed with the RNA-Seq technique to reveal the changes in the BmNPV-infected brain on the transcriptional level and to provide new clues regarding the molecular mechanisms that underlies BmNPV-induced ELA. Compared with the controls, a total of 742 differentially expressed genes (DEGs), including 218 up-regulated and 524 down-regulated candidates, were identified, of which 499, 117 and 144 DEGs could be classified into GO categories, KEGG pathways and COG annotations by GO, KEGG and COG analyses, respectively. We focused our attention on the DEGs that are involved in circadian rhythms, synaptic transmission and the serotonin receptor signaling pathway of B. mori. Our analyses suggested that these genes were related to the locomotor activity of B. mori via their essential roles in the regulations of a variety of behaviors and the down-regulation of their expressions following BmNPV infection. These results provide new insight into the molecular mechanisms of BmNPV-induced ELA.

  17. Conservation: Toward firmer ground

    Science.gov (United States)

    1975-01-01

    The following aspects of energy conservation were discussed: conservation history and goals, conservation modes, conservation accounting-criteria, and a method to overcome obstacles. The conservation modes tested fall into one of the following categories: reduced energy consumption, increased efficiency of energy utilization, or substitution of one or more forms of energy for another which is in shorter supply or in some sense thought to be of more value. The conservation accounting criteria include net energy reduction, economic, and technical criteria. A method to overcome obstacles includes (approaches such as: direct personal impact (life style, income, security, aspiration), an element of crisis, large scale involvement of environmental, safety, and health issues, connections to big government, big business, big politics, involvement of known and speculative science and technology, appeal to moral and ethical standards, the transient nature of opportunities to correct the system.

  18. Large-scale cellular-resolution gene profiling in human neocortex reveals species-specific molecular signatures

    Science.gov (United States)

    Zeng, Hongkui; Shen, Elaine H.; Hohmann, John G.; Oh, Wook Seung; Bernard, Amy; Royall, Joshua J.; Glattfelder, Katie J.; Sunkin, Susan M.; Morris, John A.; Guillozet-Bongaarts, Angela L.; Smith, Kimberly A.; Ebbert, Amanda J.; Swanson, Beryl; Kuan, Leonard; Page, Damon T.; Overly, Caroline C.; Lein, Ed S.; Hawrylycz, Michael J.; Hof, Patrick R.; Hyde, Thomas M.; Kleinman, Joel E.; Jones, Allan R.

    2012-01-01

    Summary Although there have been major advances in elucidating the functional biology of the human brain, relatively little is known of its cellular and molecular organization. Here we report a large-scale characterization of the expression of ~1,000 genes important for neural functions, by in situ hybridization with cellular resolution in visual and temporal cortices of adult human brains. These data reveal diverse gene expression patterns and remarkable conservation of each individual gene’s expression among individuals (95%), cortical areas (84%), and between human and mouse (79%). A small but substantial number of genes (21%) exhibited species-differential expression. Distinct molecular signatures, comprised of genes both common between species and unique to each, were identified for each major cortical cell type. The data suggest that gene expression profile changes may contribute to differential cortical function across species, in particular, a shift from corticosubcortical to more predominant corticocortical communications in the human brain. PMID:22500809

  19. Brain Basics

    Medline Plus

    Full Text Available ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures of the brain's structure, studies show that brain growth in children with autism appears to peak early. And as ...

  20. Anatomy of the Brain

    Science.gov (United States)

    ... Menu Brain Tumor Information Brain Anatomy Brain Structure Neuron Anatomy Brain Tumor Symptoms Diagnosis Types of Tumors Risk Factors ... form Brain Tumor Information Brain Anatomy Brain Structure Neuron Anatomy Brain Tumor Symptoms Diagnosis Types of Tumors Risk Factors ...

  1. Molecular evolution of the vertebrate mechanosensory cell and ear

    Science.gov (United States)

    Fritzsch, Bernd; Beisel, Kirk W.; Pauley, Sarah; Soukup, Garrett

    2014-01-01

    The molecular basis of mechanosensation, mechanosensory cell development and mechanosensory organ development is reviewed with an emphasis on its evolution. In contrast to eye evolution and development, which apparently modified a genetic program through intercalation of genes between the master control genes on the top (Pax6, Eya1, Six1) of the hierarchy and the structural genes (rhodopsin) at the bottom, the as yet molecularly unknown mechanosensory channel precludes such a firm conclusion for mechanosensors. However, recent years have seen the identification of several structural genes which are involved in mechanosensory tethering and several transcription factors controlling mechanosensory cell and organ development; these warrant the interpretation of available data in very much the same fashion as for eye evolution: molecular homology combined with potential morphological parallelism. This assertion of molecular homology is strongly supported by recent findings of a highly conserved set of microRNAs that appear to be associated with mechanosensory cell development across phyla. The conservation of transcription factors and their regulators fits very well to the known or presumed mechanosensory specializations which can be mostly grouped as variations of a common cellular theme. Given the widespread distribution of the molecular ability to form mechanosensory cells, it comes as no surprise that structurally different mechanosensory organs evolved in different phyla, presenting a variation of a common theme specified by a conserved set of transcription factors in their cellular development. Within vertebrates and arthropods, some mechanosensory organs evolved into auditory organs, greatly increasing sensitivity to sound through modifications of accessory structures to direct sound to the specific sensory epithelia. However, while great attention has been paid to the evolution of these accessory structures in vertebrate fossils, comparatively less attention has

  2. Characterization of Behavioral, Neuropathological, Brain Metabolic and Key Molecular Changes in zQ175 Knock-In Mouse Model of Huntington's Disease.

    Directory of Open Access Journals (Sweden)

    Qi Peng

    Full Text Available Huntington's disease (HD is caused by an expansion of the trinucleotide poly (CAG tract located in exon 1 of the huntingtin (Htt gene leading to progressive neurodegeneration in selected brain regions, and associated functional impairments in motor, cognitive, and psychiatric domains. Since the discovery of the gene mutation that causes the disease, mouse models have been developed by different strategies. Recently, a new model, the zQ175 knock-in (KI line, was developed in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. The behavioral phenotype was characterized across the independent laboratories and important features reminiscent of human HD are observed in zQ175 mice. In the current study, we characterized the zQ175 model housed in an academic laboratory under reversed dark-light cycle, including motor function, in vivo longitudinal structural MRI imaging for brain volume, MRS for striatal metabolites, neuropathology, as well as a panel of key disease marker proteins in the striatum at different ages. Our results suggest that homozygous zQ175 mice exhibited significant brain atrophy before the motor deficits and brain metabolite changes. Altered striatal medium spiny neuronal marker, postsynaptic marker protein and complement component C1qC also characterized zQ175 mice. Our results confirmed that the zQ175 KI model is valuable in understanding of HD-like pathophysiology and evaluation of potential therapeutics. Our data also provide suggestions to select appropriate outcome measurements in preclinical studies using the zQ175 mice.

  3. Combining magnetic resonance spectroscopy and molecular genomics offers better accuracy in brain tumor typing and prediction of survival than either methodology alone.

    Science.gov (United States)

    Astrakas, Loukas; Blekas, Konstantinos D; Constantinou, Caterina; Andronesi, Ovidiu C; Mindrinos, Michael N; Likas, Aristidis C; Rahme, Laurence G; Black, Peter M; Marcus, Karen J; Tzika, A Aria

    2011-04-01

    Recent advents in magnetic resonance spectroscopy (MRS) techniques permit subsequent microarray analysis over the entire human transcriptome in the same tissue biopsies. However, extracting information from such immense quantities of data is limited by difficulties in recognizing and evaluating the relevant patterns of apparent gene expression in the context of the existing knowledge of phenotypes by histopathology. Using a quantitative approach derived from a knowledge base of pathology findings, we present a novel methodology used to process genome-wide transcription and MRS data. This methodology was tested to examine metabolite and genome-wide profiles in MRS and RNA in 55 biopsies from human subjects with brain tumors with ~100% certainty. With the guidance of histopathology and clinical outcome, 15 genes with the assistance of 15 MRS metabolites were able to be distinguished by tumor categories and the prediction of survival was better than when either method was used alone. This new method, combining MRS, genomics, statistics and biological content, improves the typing and understanding of the complexity of human brain tumors, and assists in the search for novel tumor biomarkers. It is an important step for novel drug development, it generates testable hypotheses regarding neoplasia and promises to guide human brain tumor therapy provided improved in vivo methods for monitoring response to therapy are developed.

  4. Molecular modifications by regulating cAMP signaling and oxidant-antioxidant defence mechanisms, produce antidepressant-like effect: A possible mechanism of etazolate aftermaths of impact accelerated traumatic brain injury in rat model.

    Science.gov (United States)

    Jindal, Ankur; Mahesh, Radhakrishnan; Bhatt, Shvetank; Pandey, Dilip

    2016-12-14

    Traumatic brain injury (TBI) is one of the leading cause of psychiatric conditions in patients, amongst which, depression and anxiety are more frequent. Despite the preclinical antidepressant-like effects, clinical development of Phospodiesterase-4 (PDE4) enzyme inhibitors has been hampered due to serious side effect profiles, such as nausea and vomiting. Etazolate (ETZ) is a new generation PDE4 inhibitor with encouraging safety and tolerance profiles. In our previous studies we have addressed that ETZ produces antidepressant-like effects in animal models of depression, however, the underlying mechanism(s) following TBI have not been completely explored. Impact accelerated TBI by weight drop method causes depression-like behavioral deficits in modified open field exploration, hyper-emotionality and sucrose consumption paradigms. TBI not only causes immediate mechanical damage to the brain, but also induces biochemical changes that lead to delayed neural cell loss leading to a secondary injury. The present study examines the antidepressant effects of ETZ on the TBI-induced depression-like behavior deficits and attempts to explore the underlying mechanism. In order to understand the underlying pathology of TBI and mechanism(s) of ETZ in TBI molecular markers namely, brain cAMP, cAMP response element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) were estimated. Additionally, the level of oxidative (lipid peroxidation) & nitrosative (nitrite) stress markers, along with antioxidant enzymes markers, such as, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were measured. Furthermore, the involvement of hypothalamic-pituitary adrenal (HPA) axis activity in underlying mechanism was also investigated by measuring serum corticosterone (CORT) level. The results revealed that TBI significantly altered cAMP, pCREB and BDNF levels. Moreover, a significant increase in oxidative-nitrosative stress markers levels, while, significant

  5. Paradigms for parasite conservation.

    Science.gov (United States)

    Dougherty, Eric R; Carlson, Colin J; Bueno, Veronica M; Burgio, Kevin R; Cizauskas, Carrie A; Clements, Christopher F; Seidel, Dana P; Harris, Nyeema C

    2016-08-01

    Parasitic species, which depend directly on host species for their survival, represent a major regulatory force in ecosystems and a significant component of Earth's biodiversity. Yet the negative impacts of parasites observed at the host level have motivated a conservation paradigm of eradication, moving us farther from attainment of taxonomically unbiased conservation goals. Despite a growing body of literature highlighting the importance of parasite-inclusive conservation, most parasite species remain understudied, underfunded, and underappreciated. We argue the protection of parasitic biodiversity requires a paradigm shift in the perception and valuation of their role as consumer species, similar to that of apex predators in the mid-20th century. Beyond recognizing parasites as vital trophic regulators, existing tools available to conservation practitioners should explicitly account for the unique threats facing dependent species. We built upon concepts from epidemiology and economics (e.g., host-density threshold and cost-benefit analysis) to devise novel metrics of margin of error and minimum investment for parasite conservation. We define margin of error as the risk of accidental host extinction from misestimating equilibrium population sizes and predicted oscillations, while minimum investment represents the cost associated with conserving the additional hosts required to maintain viable parasite populations. This framework will aid in the identification of readily conserved parasites that present minimal health risks. To establish parasite conservation, we propose an extension of population viability analysis for host-parasite assemblages to assess extinction risk. In the direst cases, ex situ breeding programs for parasites should be evaluated to maximize success without undermining host protection. Though parasitic species pose a considerable conservation challenge, adaptations to conservation tools will help protect parasite biodiversity in the face of

  6. Neuroprotective profile of enoxaparin, a low molecular weight heparin, in in vivo models of cerebral ischemia or traumatic brain injury in rats: a review.

    Science.gov (United States)

    Stutzmann, Jean-Marie; Mary, Veronique; Wahl, Florence; Grosjean-Piot, Odile; Uzan, André; Pratt, Jeremy

    2002-01-01

    The development of treatments for acute neurodegenerative diseases (stroke and brain trauma) has focused on (i) reestablishing blood flow to ischemic areas as quickly as possible (i.e. mainly antithrombotics or thrombolytics for stroke therapy) and (ii) on protecting neurons from cytotoxic events (i.e. neuroprotective therapies such as anti-excitotoxic or anti-inflammatory agents for stroke and neurotrauma therapies). This paper reviews the preclinical data for enoxaparin in in vivo models of ischemia and brain trauma in rats. Following a photothrombotic lesion in the rat, enoxaparin significantly reduced edema at 24 h after lesion when the treatment was started up to 18 h after insult. Enoxaparin was also tested after an ischemic insult using the transient middle cerebral artery occlusion (tMCAO) model in the rat. Enoxaparin, 2 x 1.5 mg/kg i.v., significantly reduced the lesion size and improved the neuroscore when the treatment was started up to 5 h after ischemia. Enoxaparin, administered at 5 h after insult, reduced cortical lesion size in a dose-dependent manner. In permanent MCAO, enoxaparin (5 and 24 h after insult) significantly reduced lesion size and improved neuroscore. A slight and reversible elevation of activated partial thromboplastin time (APTT) suggests that enoxaparin is neuroprotective at a non-hemorrhagic dose. Traumatic brain injury (TBI) is often accompanied by secondary ischemia due in part to edema-induced compression of blood vessels. When enoxaparin, at 0.5 mg/kg i.v. + 4 x 1 mg/kg s.c., was administered later than 30 h after TBI, it significantly reduced edema in hippocampus and parietal cortex. At one week after TBI the lesion size was significantly reduced and the neurological deficit significantly improved in enoxaparin treated animals. Finally, the cognitive impairment was significantly improved by enoxaparin at 48 h to 2 weeks after TBI. The anticoagulant properties of unfractionated heparin and specifically enoxaparin can explain

  7. BrainBank Metadata Specification for the Human Brain Project and Neuroinformatics

    Directory of Open Access Journals (Sweden)

    Hu Lianglin

    2007-07-01

    Full Text Available Many databases and platforms for human brain data have been established in China over the years, and metadata plays an important role in understanding and using them. The BrainBank Metadata Specification for the Human Brain Project and Neuroinformatics provides a structure for describing the context and content information of BrainBank databases and services. It includes six parts: identification, method, data schema, distribution of the database, metadata extension, and metadata reference The application of the BrainBank Metadata Specification will promote conservation and management of BrainBank databases and platforms. it will also greatly facilitate the retrieval, evaluation, acquisition, and application of the data.

  8. Conservation in transportation

    Energy Technology Data Exchange (ETDEWEB)

    None

    1980-05-30

    A nationwide examination was made of grassroots energy conservation programs related to transportation. Information compiled from civic groups, trade associations, and corporations is included on driver awareness/mass transit; travel; and ride sharing. It is concluded that a willingness by the public to cooperate in transportation energy conservation exists and should be exploited. (LCL)

  9. Creative Soil Conservation

    Science.gov (United States)

    Smith, Martha

    2010-01-01

    Take plant lessons outdoors with this engaging and inquiry-based activity in which third-grade students learn how to apply soil conservation methods to growing plants. They also collect data and draw conclusions about the effectiveness of their method of soil conservation. An added benefit to this activity is that the third-grade students played…

  10. Biodiversity Conservation in Asia

    OpenAIRE

    Dale Squires

    2014-01-01

    Asian's remarkable economic growth brought many benefits but also fuelled threats to its ecosystems and biodiversity. Economic growth brings biodiversity threats but also conservation opportunities. Continued biodiversity loss is inevitable, but the types, areas and rates of biodiversity loss are not. Prioritising biodiversity conservation, tempered by what is tractable, remains a high priority. Policy and market distortions and failures significantly underprice biodiversity, undermine ecosys...

  11. Fixism and conservation science.

    Science.gov (United States)

    Robert, Alexandre; Fontaine, Colin; Veron, Simon; Monnet, Anne-Christine; Legrand, Marine; Clavel, Joanne; Chantepie, Stéphane; Couvet, Denis; Ducarme, Frédéric; Fontaine, Benoît; Jiguet, Frédéric; le Viol, Isabelle; Rolland, Jonathan; Sarrazin, François; Teplitsky, Céline; Mouchet, Maud

    2017-08-01

    The field of biodiversity conservation has recently been criticized as relying on a fixist view of the living world in which existing species constitute at the same time targets of conservation efforts and static states of reference, which is in apparent disagreement with evolutionary dynamics. We reviewed the prominent role of species as conservation units and the common benchmark approach to conservation that aims to use past biodiversity as a reference to conserve current biodiversity. We found that the species approach is justified by the discrepancy between the time scales of macroevolution and human influence and that biodiversity benchmarks are based on reference processes rather than fixed reference states. Overall, we argue that the ethical and theoretical frameworks underlying conservation research are based on macroevolutionary processes, such as extinction dynamics. Current species, phylogenetic, community, and functional conservation approaches constitute short-term responses to short-term human effects on these reference processes, and these approaches are consistent with evolutionary principles. © 2016 Society for Conservation Biology.

  12. Water Conservation Resource List.

    Science.gov (United States)

    NJEA Review, 1981

    1981-01-01

    Alarmed by the growing water shortage, the New Jersey State Office of Dissemination has prepared this annotated list of free or inexpensive instructional materials for teaching about water conservation, K-l2. A tipsheet for home water conservation is appended. (Editor/SJL)

  13. Conservation Science Fair Projects.

    Science.gov (United States)

    Soil Conservation Society of America, Ankeny, IA.

    Included are ideas, suggestions, and examples for selecting and designing conservation science projects. Over 70 possible conservation subject areas are presented with suggested projects. References are cited with each of these subject areas, and a separate list of annotated references is included. The references pertain to general subject…

  14. Resource Conservation Glossary.

    Science.gov (United States)

    Soil Conservation Society of America, Ankeny, IA.

    This glossary is a composite of terms selected from 13 technologies, and is the expanded revision of the original 1952 edition of "The Soil and Water Conservation Glossary." The terms were selected from these areas: agronomy, biology, conservation, ecology, economics, engineering, forestry, geology, hydrology, range, recreation, soils, and…

  15. Otter Conservation In Pakistan

    Directory of Open Access Journals (Sweden)

    Waseem Ahmad Khan

    2010-04-01

    Full Text Available This note describes the conservation status and threats of the two otter species described in Pakistan; Smooth coated otter (Lutrogale perspicillata sindica and the Eurasian or common otter (Lutra lutra. It also briefly describes the actors involved as well as the efforts made for its conservation.

  16. Introducing Conservation of Momentum

    Science.gov (United States)

    Brunt, Marjorie; Brunt, Geoff

    2013-01-01

    The teaching of the principle of conservation of linear momentum is considered (ages 15 + ). From the principle, the momenta of two masses in an isolated system are considered. Sketch graphs of the momenta make Newton's laws appear obvious. Examples using different collision conditions are considered. Conservation of momentum is considered…

  17. On exactly conservative integrators

    Energy Technology Data Exchange (ETDEWEB)

    Bowman, J.C. [Max-Planck-Inst. fuer Plasmaphysik, Garching (Germany); Shadwick, B.A. [Univ. of California, Berkeley, CA (United States). Dept. of Physics; Morrison, P.J. [Texas Univ., Austin, TX (United States). Inst. for Fusion Studies

    1997-06-01

    Traditional explicit numerical discretizations of conservative systems generically predict artificial secular drifts of nonlinear invariants. These algorithms are based on polynomial functions of the time step. The authors discuss a general approach for developing explicit algorithms that conserve such invariants exactly. They illustrate the method by applying it to the truncated two-dimensional Euler equations.

  18. On exactly conservative integrators

    Energy Technology Data Exchange (ETDEWEB)

    Bowman, J.C. [Max-Planck-Inst. fuer Plasmaphysik, Garching (Germany); Shadwick, B.A. [Univ. of California, Berkeley, CA (United States). Dept. of Physics; Morrison, P.J. [Texas Univ., Austin, TX (United States). Inst. for Fusion Studies

    1997-06-01

    Traditional explicit numerical discretizations of conservative systems generically predict artificial secular drifts of nonlinear invariants. These algorithms are based on polynomial functions of the time step. The authors discuss a general approach for developing explicit algorithms that conserve such invariants exactly. They illustrate the method by applying it to the truncated two-dimensional Euler equations.

  19. Cultivating creativity in conservation science.

    Science.gov (United States)

    Aslan, Clare E; Pinsky, Malin L; Ryan, Maureen E; Souther, Sara; Terrell, Kimberly A

    2014-04-01

    Conservation practitioners and scientists are often faced with seemingly intractable problems in which traditional approaches fail. While other sectors (e.g., business) frequently emphasize creative thinking to overcome complex challenges, creativity is rarely identified as an essential skill for conservationists. Yet more creative approaches are urgently needed in the effort to sustain Earth's biodiversity. We identified 4 strategies to develop skills in creative thinking and discuss underlying research and examples supporting each strategy. First, by breaking down barriers between disciplines and surrounding oneself with unfamiliar people, concepts, and perspectives, one can expand base knowledge and experiences and increase the potential for new combinations of ideas. Second, by meeting people where they are (both literally and figuratively), one exposes oneself to new environments and perspectives, which again broadens experiences and increases ability to communicate effectively with stakeholders. Third, by embracing risk responsibly, one is more likely to develop new, nontraditional solutions and be open to high-impact outcomes. Finally, by following a cycle of learning, struggle, and reflection, one can trigger neurophysiological changes that allow the brain to become more creative. Creativity is a learned trait, rather than an innate skill. It can be actively developed at both the individual and institutional levels, and learning to navigate the relevant social and practical barriers is key to the process. To maximize the success of conservation in the face of escalating challenges, one must take advantage of what has been learned from other disciplines and foster creativity as both a professional skill and an essential component of career training and individual development. © 2013 Society for Conservation Biology.

  20. Antimicrobial peptides in the brain.

    Science.gov (United States)

    Su, Yanhua; Zhang, Kai; Schluesener, Hermann J

    2010-10-01

    Antimicrobial peptides (AMPs) are an evolutionarily conserved component of the innate immune system of many species. The brain is an immunologically privileged organ but can produce a robust immune response against pathogens and cell debris, promoting rapid and efficient clearance. AMPs may be critically involved in the innate immune system of the brain. Though the mechanisms of AMPs' action in the brain still need further elucidation, many studies have shown that AMPs are multifunctional molecules in the brain. In addition to antimicrobial action, they take part in congenital and adaptive immune reactions (immunoregulation), function as signaling molecules in tissue repair, inflammation and other important processes through different mechanisms, and they might, in addition, become diagnostic markers of brain disease.

  1. Transporter-Mediated Drug Interaction Strategy for 5-Aminolevulinic Acid (ALA-Based Photodynamic Diagnosis of Malignant Brain Tumor: Molecular Design of ABCG2 Inhibitors

    Directory of Open Access Journals (Sweden)

    Toshihisa Ishikawa

    2011-09-01

    Full Text Available Photodynamic diagnosis (PDD is a practical tool currently used in surgical operation of aggressive brain tumors, such as glioblastoma. PDD is achieved by a photon-induced physicochemical reaction which is induced by excitation of protoporphyrin IX (PpIX exposed to light. Fluorescence-guided gross-total resection has recently been developed in PDD, where 5-aminolevulinic acid (ALA or its ester is administered as the precursor of PpIX. ALA induces the accumulation of PpIX, a natural photo-sensitizer, in cancer cells. Recent studies provide evidence that adenosine triphosphate (ATP-binding cassette (ABC transporter ABCG2 plays a pivotal role in regulating the cellular accumulation of porphyrins in cancer cells and thereby affects the efficacy of PDD. Protein kinase inhibitors are suggested to potentially enhance the PDD efficacy by blocking ABCG2-mediated porphyrin efflux from cancer cells. It is of great interest to develop potent ABCG2-inhibitors that can be applied to PDD for brain tumor therapy. This review article addresses a pivotal role of human ABC transporter ABCG2 in PDD as well as a new approach of quantitative structure-activity relationship (QSAR analysis to design potent ABCG2-inhibitors.

  2. Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia.

    Science.gov (United States)

    Takao, Keizo; Kobayashi, Katsunori; Hagihara, Hideo; Ohira, Koji; Shoji, Hirotaka; Hattori, Satoko; Koshimizu, Hisatsugu; Umemori, Juzoh; Toyama, Keiko; Nakamura, Hironori K; Kuroiwa, Mahomi; Maeda, Jun; Atsuzawa, Kimie; Esaki, Kayoko; Yamaguchi, Shun; Furuya, Shigeki; Takagi, Tsuyoshi; Walton, Noah M; Hayashi, Nobuhiro; Suzuki, Hidenori; Higuchi, Makoto; Usuda, Nobuteru; Suhara, Tetsuya; Nishi, Akinori; Matsumoto, Mitsuyuki; Ishii, Shunsuke; Miyakawa, Tsuyoshi

    2013-07-01

    Schnurri-2 (Shn-2), an nuclear factor-κB site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes and inflammatory cytokines, which have been shown to harbor common variant single-nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout (KO) results in schizophrenia. Here, we show that Shn-2 KO mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 KO mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest-building behaviors in Shn-2 KO mice. These results suggest that genetically induced changes in immune system can be a predisposing factor in schizophrenia.

  3. Brain Basics

    Medline Plus

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  4. Brain Basics

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  5. Brain Basics

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  6. Brain Basics

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    Full Text Available ... works in healthy people, and how normal brain development and function can go awry, leading to mental ... and are working to compare that with brain development in people mental disorders. Genes and environmental cues ...

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    Full Text Available ... Life Brain Basics in Real Life—How Depression affects the Brain Meet Sarah Sarah is a middle- ... harder for Sarah to recover normally from her low mood. It's important to remember that everyone gets " ...

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    Full Text Available ... in the anatomy, physiology, and chemistry of the nervous system. When the brain cannot effectively coordinate the billions ... the basic working unit of the brain and nervous system. These cells are highly specialized for the function ...

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    Full Text Available ... and her husband questions about Sarah's symptoms and family medical history. Epigenetic changes from stress or early- ... and techniques are giving scientists a more detailed understanding of the brain than ever before. Brain Imaging ...

  12. Brain Basics

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    Full Text Available ... mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are the ... enclosed by a cell membrane, which separates the inside contents of the cell from its surrounding environment ...

  13. Brain Basics

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    Full Text Available ... affect many aspects of life. Scientists are continually learning more about how the brain grows and works ... early brain development. It may also assist in learning and memory. Problems in making or using glutamate ...

  14. Brain Basics

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    Full Text Available ... Real Life Brain Basics in Real Life—How Depression affects the Brain Meet Sarah Sarah is a ... blues" from time to time. In contrast, major depression is a serious disorder that lasts for weeks. ...

  15. Brain Basics

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    Full Text Available ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses ... depression experience when starting treatment. Gene Studies Advanced technologies are also making it faster, easier, and more ...

  16. Brain Basics

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    Full Text Available ... lead to mental disorders, such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons ... However, recent research points to a possible new class of antidepressants that can relieve symptoms of the ...

  17. Brain Basics

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    Full Text Available ... Functional magnetic resonance imaging (fMRI) is another important research tool in understanding how the brain functions. Another type of brain scan called magnetoencephalography, or MEG, can ...

  18. Brain Basics

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    Full Text Available ... normal brain development and function can go awry, leading to mental illnesses. Brain Basics will introduce you ... of DNA. Sometimes this copying process is imperfect, leading to a gene mutation that causes the gene ...

  19. Brain Diseases

    Science.gov (United States)

    The brain is the control center of the body. It controls thoughts, memory, speech, and movement. It regulates the function of many organs. When the brain is healthy, it works quickly and automatically. However, ...

  20. Brain Basics

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    Full Text Available ... body, the results can affect many aspects of life. Scientists are continually learning more about how the brain grows and works in healthy people, and how normal brain development ...

  1. Brain Basics

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    Full Text Available ... have been linked to many mental disorders, including autism , obsessive compulsive disorder (OCD) , schizophrenia , and depression . Brain ... studies show that brain growth in children with autism appears to peak early. And as they grow ...

  2. Brain Basics

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    Full Text Available ... experienced long periods of deep sadness throughout her teenage years, but had never seen a doctor about ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses ...

  3. Brain Basics

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    Full Text Available ... Real Life Brain Basics in Real Life—How Depression affects the Brain Meet Sarah Sarah is a ... blues" from time to time. In contrast, major depression is a serious disorder that lasts for weeks. ...

  4. Brain Basics

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    Full Text Available ... the brain cannot effectively coordinate the billions of cells in the body, the results can affect many ... unit of the brain and nervous system. These cells are highly specialized for the function of conducting ...

  5. Brain Basics

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    Full Text Available ... affect many aspects of life. Scientists are continually learning more about how the brain grows and works ... early brain development. It may also assist in learning and memory. Problems in making or using glutamate ...

  6. Brain Basics

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    Full Text Available ... works in healthy people, and how normal brain development and function can go awry, leading to mental ... and are working to compare that with brain development in people mental disorders. Genes and environmental cues ...

  7. Brain Basics

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    Full Text Available ... than ever before. Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses ... depression experience when starting treatment. Gene Studies Advanced technologies are also making it faster, easier, and more ...

  8. Brain Basics

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    Full Text Available ... the brain cannot effectively coordinate the billions of cells in the body, the results can affect many ... unit of the brain and nervous system. These cells are highly specialized for the function of conducting ...

  9. Brain Basics

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    Full Text Available ... treatments, and possibly prevention of such illnesses. The Working Brain Neurotransmitters Everything we do relies on neurons ... Using MEG, some scientists have found a specific pattern of brain activity that may help predict who ...

  10. Brain Basics

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    Full Text Available ... all. She was happily married and successful in business. Then, after a serious setback at work, she ... of the brain's structure, studies show that brain growth in children with autism appears to peak early. ...

  11. Brain Basics

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    Full Text Available ... depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are the basic working unit of ... but sometimes give rise to disabilities or diseases. neural circuit —A network of neurons and their interconnections. ...

  12. Brain Basics

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    Full Text Available ... healthy people, and how normal brain development and function can go awry, leading to mental illnesses. Brain ... system. These cells are highly specialized for the function of conducting messages. A neuron has three basic ...

  13. Brain Basics

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    Full Text Available ... brain may play a role in disorders like schizophrenia or attention deficit hyperactivity disorder (ADHD) . Glutamate —the ... mental disorders, including autism , obsessive compulsive disorder (OCD) , schizophrenia , and depression . Brain Regions Just as many neurons ...

  14. Brain Basics

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    Full Text Available ... the anatomy, physiology, and chemistry of the nervous system. When the brain cannot effectively coordinate the billions ... basic working unit of the brain and nervous system. These cells are highly specialized for the function ...

  15. Brain Basics

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    Full Text Available ... as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures of the brain's structure, studies ... MRI) mdash;An imaging technique that uses magnetic fields to take pictures of the brain's structure. mutation — ...

  16. Brain Basics

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    Full Text Available ... How the brain develops How genes and the environment affect the brain The basic structure of the ... inside contents of the cell from its surrounding environment and controls what enters and leaves the cell, ...

  17. Development of a New Reporter Gene System-dsRed/Xanthine Phosphoribosyltransferase-Xanthine for Molecular Imaging of Processes Behind the Intact Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    Mikhail Doubrovin

    2003-04-01

    Full Text Available We report the development of a novel dual-modality fusion reporter gene system consisting of Escherichia coli xanthine phosphoribosyltransferase (XPRT for nuclear imaging with radiolabeled xanthine and Discosoma red fluorescent protein for optical fluorescent imaging applications. The dsRed/XPRT fusion gene was successfully created and stably transduced into RG2 glioma cells, and both reporters were shown to be functional. The level of dsRed fluorescence directly correlated with XPRT enzymatic activity as measured by ribophosphorylation of [14C]-xanthine was in vitro (Ki = 0.124 ± 0.008 vs. 0.00031 ± 0.00005 mL/min/g in parental cell line, and [*]-xanthine octanol/water partition coefficient was 0.20 at pH = 7.4 (logP = 0.69, meeting requirements for the blood-brain barrier (BBB penetrating tracer. In the in vivo experiment, the concentration of [* C]-xanthine in the normal brain varied from 0.20 to 0.16 + 0.05% dose/g under 0.87 + 0.24% dose/g plasma radiotracer concentration. The accumulation in vivo in the transfected flank tumor was to 2.4 ± 0.3% dose/g, compared to 0.78 ± 0.02% dose/g and 0.64 ± 0.05% dose/g in the control flank tumors and intact muscle, respectively. [14C]-Xanthine appeared to be capable of specific accumulation in the transfected infiltrative brain tumor (RG2-dsRed/XPRT, which corresponded to the 585 nm fluorescent signal obtained from the adjacent cryosections. The images of endogenous gene expression with the “sensory system” have to be normalized for the transfection efficiency based on the “beacon system” image data. Such an approach requires two different “reporter genes” and two different “reporter substrates.” Therefore, the novel dsRed/XPRT fusion gene can be used as a multimodality reporter system in the biological applications requiring two independent reporter genes, including the cells located behind the BBB.

  18. The Brain.

    Science.gov (United States)

    Hubel, David H.

    1979-01-01

    This article on the brain is part of an entire issue about neurobiology and the question of how the human brain works. The brain as an intricate tissue composed of cells is discussed based on the current knowledge and understanding of its composition and structure. (SA)

  19. Brain Basics

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    Full Text Available ... and plays an important role during early brain development. It may also assist in learning and memory. Problems in making or using glutamate ... increases neuronal activity, is involved in early brain development, and may also assist in learning and memory. hippocampus —A portion of the brain ...

  20. Brain Aneurysm

    Science.gov (United States)

    A brain aneurysm is an abnormal bulge or "ballooning" in the wall of an artery in the brain. They are sometimes called berry aneurysms because they ... often the size of a small berry. Most brain aneurysms produce no symptoms until they become large, ...

  1. Brain Basics

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    Full Text Available ... such as depression. The Growing Brain Inside the Brain: Neurons & Neural Circuits Neurons are the basic working unit ... final destination. Chemical signals from other cells guide neurons in forming various brain structures. Neighboring neurons make connections with each other ...

  2. Brain Basics

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    Full Text Available ... pituitary-adrenal (HPA) axis. Brain Basics in Real Life Brain Basics in Real Life—How Depression affects the Brain Meet Sarah Sarah ... having trouble coping with the stresses in her life. She began to think of suicide because she ...

  3. Hearing Conservation Team

    Data.gov (United States)

    Federal Laboratory Consortium — The Hearing Conservation Team focuses on ways to identify the early stages of noise-induced damage to the human ear.Our current research involves the evaluation of...

  4. Hearing Conservation Team

    Data.gov (United States)

    Federal Laboratory Consortium — The Hearing Conservation Team focuses on ways to identify the early stages of noise-induced damage to the human ear. Our current research involves the evaluation of...

  5. Conservation of Beclardia macrostachya

    African Journals Online (AJOL)

    admpather

    Department of Agriculture and Food Science ... Tissue culture is an essential tool for ex situ conservation. ... In vitro culture also provides plausible solutions to ..... Cryopreservation of zygotic embryos of a Japanese terrestrial orchid (Bletilla.

  6. Metro Conservation Corridors

    Data.gov (United States)

    Minnesota Department of Natural Resources — The Metro Conservation Corridors (MeCC) grow out of the natural resource analysis work done by the DNR in the late '90's, documented in the Metro Greenprint...

  7. Conservation among Elderly Women.

    Science.gov (United States)

    Hughston, George A.; Protinsky, Howard O.

    1979-01-01

    The majority of 63 elderly women were able to pass tests in the conservation of mass (98 percent), volume (100 percent), and surface area (65 percent). These results conflict with previous research about Piagetian abilities of elderly people. (RL)

  8. Landscape Conservation Cooperatives

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Landscape Conservation Cooperatives (LCCs) are public-private partnerships composed of states, tribes, federal agencies, non-governmental organizations,...

  9. Policy: Palatable forest conservation

    Science.gov (United States)

    Tacconi, Luca

    2011-06-01

    Current policies to reduce emissions from forest loss could mean that rising demand for food is not met. A new approach to forest conservation that reduces emissions while meeting demand for agricultural products may be feasible, but more expensive.

  10. Monitoring for conservation

    Science.gov (United States)

    Nichols, J.D.; Williams, B.K.

    2006-01-01

    Human-mediated environmental changes have resulted in appropriate concern for the conservation of ecological systems and have led to the development of many ecological monitoring programs worldwide. Many programs that are identified with the purpose of `surveillance? represent an inefficient use of conservation funds and effort. Here, we revisit the 1964 paper by Platt and argue that his recommendations about the conduct of science are equally relevant to the conduct of ecological monitoring programs. In particular, we argue that monitoring should not be viewed as a stand-alone activity, but instead as a component of a larger process of either conservation-oriented science or management. Corresponding changes in monitoring focus and design would lead to substantial increases in the efficiency and usefulness of monitoring results in conservation.

  11. Energy Conservation Behaviour Toolkit

    NARCIS (Netherlands)

    Kalz, Marco; Börner, Dirk; Ternier, Stefaan; Specht, Marcus

    2013-01-01

    Kalz, M., Börner, D., Ternier, S., & Specht, M. (2013, 31 January). Energy Conservation Behaviour Toolkit. Presentation given at the symposium "Groene ICT en Duurzame ontwikkeling: Meters maken in het Hoger Onderwijs", Driebergen, The Netherlands.

  12. Adaptive evolution of four microcephaly genes and the evolution of brain size in anthropoid primates.

    Science.gov (United States)

    Montgomery, Stephen H; Capellini, Isabella; Venditti, Chris; Barton, Robert A; Mundy, Nicholas I

    2011-01-01

    The anatomical basis and adaptive function of the expansion in primate brain size have long been studied; however, we are only beginning to understand the genetic basis of these evolutionary changes. Genes linked to human primary microcephaly have received much attention as they have accelerated evolutionary rates along lineages leading to humans. However, these studies focus narrowly on apes, and the link between microcephaly gene evolution and brain evolution is disputed. We analyzed the molecular evolution of four genes associated with microcephaly (ASPM, CDK5RAP2, CENPJ, MCPH1) across 21 species representing all major clades of anthropoid primates. Contrary to prevailing assumptions, positive selection was not limited to or intensified along the lineage leading to humans. In fact we show that all four loci were subject to positive selection across the anthropoid primate phylogeny. We developed clearly defined hypotheses to explicitly test if selection on these loci was associated with the evolution of brain size. We found positive relationships between both CDK5RAP2 and ASPM and neonatal brain mass and somewhat weaker relationships between these genes and adult brain size. In contrast, there is no evidence linking CENPJ and MCPH1 to brain size evolution. The stronger association of ASPM and CDK5RAP2 evolution with neonatal brain size than with adult brain size is consistent with these loci having a direct effect on prenatal neuronal proliferation. These results suggest that primate brain size may have at least a partially conserved genetic basis. Our results contradict a previous study that linked adaptive evolution of ASPM to changes in relative cortex size; however, our analysis indicates that this conclusion is not robust. Our finding that the coding regions of two widely expressed loci has experienced pervasive positive selection in relation to a complex, quantitative developmental phenotype provides a notable counterexample to the commonly asserted

  13. 创伤性脑损伤的分子机制和治疗策略%Molecular mechanisms and therapeutic strategy of traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    周旺宁; 陈忠平

    2005-01-01

    创伤性脑损伤(traumatic brain injury,TBI)的病理生理过程相当复杂,除原发创伤产生的剪切力对细胞膜、神经元胞体、白质结构和血管床的损伤外,伤后脑缺血、脑水肿/脑肿胀和颅内K增高是加重损伤程度的重要因。在脑损伤后积极纠正缺血、低氧、低血糖、脑水肿、癫痫,感染和电解质紊乱,

  14. Energy conservation in infants.

    Science.gov (United States)

    Blass, Elliott

    2015-08-01

    Energy acquisition through suckling has been widely studied in rat and human infants. Processes mediating energy conservation, however, have not received the attention that they deserve. This essay, in honor of Professor Jerry Hogan, discusses parallel behaviors used by rat and human mothers to minimize energy loss in their offspring. Parallel mechanisms underlying energy preservation have been identified in rats and humans, suggesting phylogenetic conservation and possibly continuity. This article is part of a Special Issue entitled: In Honor of Jerry Hogan.

  15. Molecular effects of lithium are partially mimicked by inositol-monophosphatase (IMPA)1 knockout mice in a brain region-dependent manner.

    Science.gov (United States)

    Damri, O; Sade, Y; Toker, L; Bersudsky, Y; Belmaker, R H; Agam, G; Azab, A N

    2015-03-01

    We have previously shown that homozygote knockout (KO) of inositol-monophosphatase1 (IMPA1) results in lithium (Li)-like behavior. We now aimed to find out whether Li-treated mice and IMPA1 KO mice exhibit neurochemical similarity at the gene- and protein-expression level. Hippocampal and frontal cortex B-cell lymphoma (Bcl-2), Bcl-2-associated X protein (BAX), P53, Perodoxin2 (PRDX2), myristoylated alanine-rich C kinase substrate (MARCKS) and neuropeptide Y (NPY) mRNA levels, and hippocampal, frontal cortex and hypothalamic cytokine levels, all previously reported to be affected by lithium treatment, were measured in three groups of mice: wildtype (WT) on regular-food (RF), WT on Li-supplemented food (Li-treated) and IMPA1-KOs. Hippocampal and frontal cortex Bcl-2 and MARCKS were the only genes commonly affected (downregulated) by Li and IMPA1 KO; Bcl-2 - by 28% and 19%, respectively; MARCKS - by about 20% in both regions. The effect of Li and of IMPA1 KO on cytokine levels differed among the three brain areas studied. Only in the hippocampus both interventions exerted similar effects. Frontal cortex cytokine levels were unaffected neither by Li nor by IMPA1 KO. Similar changes in Bcl-2 and MARCKS but not in PRDX2 and NPY following both Li-treatment and IMPA1 KO suggest a mechanism different than inositol-monophosphatase1 inhibition for Li׳s effect on the latter genes. The cytokine levels results suggest that the mechanism mediating Li׳s effect on the inflammatory system differs among brain regions. Only in the hippocampus the results favor the involvement of the phosphatidylinositol (PI) cycle. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  16. Conservation Kickstart- Catalyzing Conservation Initiatives Worldwide

    Science.gov (United States)

    Treinish, G.

    2014-12-01

    Adventurers and Scientists for Conservation (ASC) is a nonprofit organization that collects environmental data to catalyze conservation initiatives worldwide. Adventure athletes have the skills and motivation to reach the most remote corners of the world. ASC utilizes those skills to provide the scientific community with data while providing the outdoor community with purpose beyond the personal high of reaching a summit or rowing across an ocean. We carefully select projects, choosing partnerships that will maximize the impact of ASC volunteers. Each project must have a clear path to a tangible conservation outcome and demonstrate a clear need for our brand of volunteers. We partner with government agencies, universities, and independant reseachers to kickstart data collection efforts around the world. Last year, through a partnership with the Olympic National Forest, 20 volunteers from the Seattle area set up and monitored camera traps in an effort to survey for costal Pacific marten. Our work led to the species' listing as "critically imperiled" with NatureServe. A partnership with the inaugural Great Pacific Race, engaging trans-Pacific rowing teams, searched for microplastics in the Pacific Ocean as part of our ongoing microplastics campaign. In a multi-year partnership with the American Prairie Reserve (APR), ASC volunteer crews live and work on the Reserve collecting wildlife data year round. The data we obtain directly informs the Reserve's wildlife management decisions. On this project, our crews have safely and effectively navigated temperature extremes from -30 degrees to 100+ degrees while traveling in a remote location. We are currently scouting projects in the Okavango Delta of Botswana and the rainforest of Suriname where we will be able to cover large amounts of area in a short periord of time. ASC is at the crossroads of the adventure and coservation science communities. Our approach of answering specific questions by using highly skilled and

  17. Improving and Conserving Sahelian Fruits Trees

    DEFF Research Database (Denmark)

    Ouedraogo, Moussa

    traits and careful choice has to be made when selecting the provenances for seed orchards. The PhD project leads to the initiation of a programme for conservation and use of genetic resources of P. biglobosa in Burkina Faso through germplasm collection and breeding seed orchard establishment...... is among the top five priority indigenous tree species in the Sahel and one of the priority research species in Burkina Faso. Several studies have been made since the 1980’s. The present thesis is about breeding and conservation of this species and addresses four specific aspects: •Performance...... of provenances in field trials; •Genetic structure of P. biglobosa in its natural range in West and Central Africa based on leaf morphology and molecular markers; •Variation between provenances in phenology; •An approach for utilisation of P. biglobosa genetic resources and a conservation strategy in Burkina...

  18. Breast Cancer Cells May Change When They Spread to Brain

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_162415.html Breast Cancer Cells May Change When They Spread to Brain: ... 2016 WEDNESDAY, Dec. 7, 2016 (HealthDay News) -- When breast cancer spreads to the brain, important molecular changes may ...

  19. Linoleic acid: Is this the key that unlocks the quantum brain? Insights linking broken symmetries in molecular biology, mood disorders and personalistic emergentism.

    Science.gov (United States)

    Cocchi, Massimo; Minuto, Chiara; Tonello, Lucio; Gabrielli, Fabio; Bernroider, Gustav; Tuszynski, Jack A; Cappello, Francesco; Rasenick, Mark

    2017-04-19

    In this paper we present a mechanistic model that integrates subneuronal structures, namely ion channels, membrane fatty acids, lipid rafts, G proteins and the cytoskeleton in a dynamic system that is finely tuned in a healthy brain. We also argue that subtle changes in the composition of the membrane's fatty acids may lead to down-stream effects causing dysregulation of the membrane, cytoskeleton and their interface. Such exquisite sensitivity to minor changes is known to occur in physical systems undergoing phase transitions, the simplest and most studied of them is the so-called Ising model, which exhibits a phase transition at a finite temperature between an ordered and disordered state in 2- or 3-dimensional space. We propose this model in the context of neuronal dynamics and further hypothesize that it may involve quantum degrees of freedom dependent upon variation in membrane domains associated with ion channels or microtubules. Finally, we provide a link between these physical characteristics of the dynamical mechanism to psychiatric disorders such as major depression and antidepressant action.

  20. The Data Conservancy

    Science.gov (United States)

    Choudhury, S.; Duerr, R. E.

    2009-12-01

    NSF's Sustainable Digital Data Preservation and Access Network Partners program is an ambitious attempt to integrate a wide variety of expertise and infrastructure into a network for providing "reliable digital preservation, access, integration, and analysis capabilities for science." One of the first two DataNet award recipients, the Data Conservancy, is itself a network of widely diverse partners led by the libraries at the Johns Hopkins University. The Data Conservancy is built on existing exemplar scientific projects, communities, and virtual organizations that have deep engagement with their user communities, and extensive experience with large-scale distributed system development. Data Conservancy members embrace a shared vision that data curation is not an end, but rather a means to collect, organize, validate, and preserve data needed to address the grand research challenges that face society. Data Conservancy members holdings encompass the entire range of earth, life, and space science data. New to the Data Conservancy is the concept that University libraries will be part of the distributed network of data centers and that data science will become a path in the library and information science curricula. As noted by Winston Tabb (JHU Dean of Libraries) "Data Centers are the new library stacks."

  1. Creative Conservation Communication

    Science.gov (United States)

    Houston, Jason

    2015-04-01

    I am a fellow with the International League of Conservation photographers (iLCP) and have been focused on photographing conservation dynamics at the intersection of social and environmental issues for a decade. Subjects have included traditional concerns such as deforestation, water conservation, endangered species, and fisheries. However, I rarely make photographs of the traditional nature, wildlife, landscapes, or environmental atrocities that most people think of when they think about environmentalism. Instead, I photograph people and how they live on the planet, as I believe passionately that without also considering social and cultural concerns, we will not be able to effectively and sustainably do conservation work or achieve positive environmental change. My presentation will share recent photography projects on forest conservation in Indonesian Borneo and fisheries management in Central America where I used a 'stakeholder profile-based' process to broadly survey the complexity of the issues while also making personal connections for these projects' diverse audiences. Through these case studies I will explore the opportunities and challenges of combining the authenticity, accuracy, and scientific validity of journalistic and documentary work with the emotional impact of the conventions of art and storytelling.

  2. Brain gene expression profiles of Cln1 and Cln5 deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases

    Directory of Open Access Journals (Sweden)

    Gentile Massimiliano

    2008-03-01

    Full Text Available Abstract Background The neuronal ceroid lipofuscinoses (NCL are a group of children's inherited neurodegenerative disorders, characterized by blindness, early dementia and pronounced cortical atrophy. The similar pathological and clinical profiles of the different forms of NCL suggest that common disease mechanisms may be involved. To explore the NCL-associated disease pathology and molecular pathways, we have previously produced targeted knock-out mice for Cln1 and Cln5. Both mouse-models replicate the NCL phenotype and neuropathology; the Cln1-/- model presents with early onset, severe neurodegenerative disease, whereas the Cln5-/- model produces a milder disease with a later onset. Results Here we have performed quantitative gene expression profiling of the cortex from 1 and 4 month old Cln1-/- and Cln5-/- mice. Combined microarray datasets from both mouse models exposed a common affected pathway: genes regulating neuronal growth cone stabilization display similar aberrations in both models. We analyzed locus specific gene expression and showed regional clustering of Cln1 and three major genes of this pathway, further supporting a close functional relationship between the corresponding gene products; adenylate cyclase-associated protein 1 (Cap1, protein tyrosine phosphatase receptor type F (Ptprf and protein tyrosine phosphatase 4a2 (Ptp4a2. The evidence from the gene expression data, indicating changes in the growth cone assembly, was substantiated by the immunofluorescence staining patterns of Cln1-/- and Cln5-/- cortical neurons. These primary neurons displayed abnormalities in cytoskeleton-associated proteins actin and β-tubulin as well as abnormal intracellular distribution of growth cone associated proteins GAP-43, synapsin and Rab3. Conclusion Our data provide the first evidence for a common molecular pathogenesis behind neuronal degeneration in INCL and vLINCL. Since CLN1 and CLN5 code for proteins with distinct functional roles

  3. Minireview of Stereoselective Brain Imaging

    DEFF Research Database (Denmark)

    Smith, Donald F.; Jakobsen, Steen

    2014-01-01

    Stereoselectivity is a fundamental principle in living systems. Stereoselectivity reflects the dependence of molecular processes on the spatial orientation of constituent atoms. Stereoselective processes govern many aspects of brain function and direct the course of many psychotropic drugs. Today......, modern imaging techniques such as SPECT and PET provide a means for studying stereoselective processes in the living brain. Chemists have prepared numerous radiolabelled stereoisomers for use in SPECT and PET in order to explore various molecular processes in the living brain of anesthetized laboratory...... animals and awake humans. The studies have demonstrated how many aspects of neurotransmission consist of crucial stereoselective events that can affect brain function in health and disease. Here, we present a brief account of those findings in hope of stimulating further interest in the vital topic....

  4. Conservation reaches new heights.

    Science.gov (United States)

    Pepall, J; Khanal, P

    1992-10-01

    The conservation program with the management assistance of the Woodlands Mountain Institute in 2 contiguous parks, the Mount Everest National Park in Nepal and the Qomolangma Nature Reserve in China, in 2 countries is described. The focus is on conservation of the complex ecosystem with sustainable development by showing local people how to benefit from the park without environmental damage. Cultural diversity is as important as biological diversity. The area has been designated by UNESCO as a World Heritage Site with the "last pure ecological seed" of the Himalayas. The regional geography and culture are presented. Population growth has impacted natural resources through overgrazing, cultivation of marginal land, and deforestation; future plans to build a dam and road bordering the nature reserve pose other threats. Proposed management plans for the Makalu-Barun Nature Park (established in November 1991) and Conservation Area include a division of the park into nature reserve areas free of human activity, protected areas which permit traditional land use, and special sites and trail for tourists and religious pilgrims. The conservation area will act as a buffer for the park and provide economic opportunities; further subdivisions include land use for biodiversity protection, community forest and pasture, agroforestry, and agriculture and settlement. Efforts will be made to increase the welfare of women and local people; proposed projects include the introduction of higher milk-producing animals for stall feeding. Also proposed is a cultural and natural history museum. 70% of the project's resources will be directed to local community participation in consultation and park maintenance. The project is a model of how conservation and protection of natural resources can coexist with local economic development and participation; an integration of preservation of biological diversity, mountain wisdom, and the value of local people as resources for conservation.

  5. Information, conservation and retrieval

    Energy Technology Data Exchange (ETDEWEB)

    Eng, T. [Swedish Nuclear Fuel and Waste Management Co., Stockholm (Sweden); Norberg, E. [National Swedish Archives, Stockholm (Sweden); Torbacke, J. [Stockholm Univ. (Sweden). Dept. of History; Jensen, M. [Swedish Radiation Protection Inst., Stockholm (Sweden)

    1996-12-01

    The seminar took place on the Swedish ship for transportation of radioactive wastes, M/S Sigyn, which at summer time is used for exhibitions. The seminar treated items related to general information needs in society and questions related to radioactive waste, i.e. how knowledge about a waste repository should be passed on to future generations. Three contributions are contained in the report from the seminar and are indexed separately: `Active preservation - otherwise no achieves`; `The conservation and dissemination of information - A democratic issue`; and, `Conservation and retrieval of information - Elements of a strategy to inform future societies about nuclear waste repositories`.

  6. General vorticity conservation

    CERN Document Server

    Gümral, H

    1998-01-01

    The motion of an incompressible fluid in Lagrangian coordinates involves infinitely many symmetries generated by the left Lie algebra of group of volume preserving diffeomorphisms of the three dimensional domain occupied by the fluid. Utilizing a 1+3-dimensional Hamiltonian setting an explicit realization of this symmetry algebra and the related Lagrangian and Eulerian conservation laws are constructed recursively. Their Lie algebraic structures are inherited from the same construction. The laws of general vorticity and helicity conservations are formulated globally in terms of invariant differential forms of the velocity field.

  7. 14 Conservation of Energy

    OpenAIRE

    Torre, Charles G.

    2014-01-01

    After all of these developments it is nice to keep in mind the idea that the wave equation describes (a continuum limit of) a network of coupled oscillators. This raises an interesting question. Certainly you have seen by now how important energy and momentum — and their conservation — are for understanding the behavior of dynamical systems such as an oscillator. If a wave is essentially the collective motion of many oscillators, might not there be a notion of conserved energy and momentum fo...

  8. Two Centuries of Soil Conservation.

    Science.gov (United States)

    Helms, Douglas

    1991-01-01

    Narrates U.S. soil conservation history since the late eighteenth century. Discusses early practices such as contour plowing. Profiles individuals who promoted soil conservation and were largely responsible for the creation of the Soil Conservation Service. Explains the causes of erosion and how soil conservation districts help farmers prevent…

  9. Sex, stress and the brain: interactive actions of hormones on the developing and adult brain.

    Science.gov (United States)

    McEwen, B S

    2014-12-01

    The brain is a target of steroid hormone actions that affect brain architecture, molecular and neurochemical processes, behavior and neuroprotection via both genomic and non-genomic actions. Estrogens have such effects throughout the brain and this article provides an historical and current view of how this new view has come about and how it has affected the study of sex differences, as well as other areas of neuroscience, including the effects of stress on the brain.

  10. Blood/Brain Biomarkers of Inflammation After Stroke and Their Association With Outcome: From C-Reactive Protein to Damage-Associated Molecular Patterns.

    Science.gov (United States)

    Bustamante, Alejandro; Simats, Alba; Vilar-Bergua, Andrea; García-Berrocoso, Teresa; Montaner, Joan

    2016-10-01

    Stroke represents one of the most important causes of disability and death in developed countries. However, there is a lack of prognostic tools in clinical practice to monitor the neurological condition and predict the final outcome. Blood biomarkers have been proposed and studied in this indication; however, no biomarker is currently used in clinical practice. The stroke-related neuroinflammatory processes have been associated with a poor outcome in stroke, as well as with poststroke complications. In this review, we focus on the most studied blood biomarkers of this inflammatory processes, cytokines, and C-reactive protein, evaluating its association with outcome and complications in stroke through the literature, and performing a systematic review on the association of C-reactive protein and functional outcome after stroke. Globally, we identified uncertainty with regard to the association of the evaluated biomarkers with stroke outcome, with little added value on top of clinical predictors such as age or stroke severity, which makes its implementation unlikely in clinical practice for global outcome prediction. Regarding poststroke complications, despite being more practical scenarios in which to make medical decisions following a biomarker prediction, not many studies have been performed, although there are now some candidates for prediction of poststroke infections. Finally, as potential new candidates, we reviewed the pathophysiological actions of damage-associated molecular patterns as triggers of the neuroinflammatory cascade of stroke, and their possible use as biomarkers.

  11. Running from Disease: Molecular Mechanisms Associating Dopamine and Leptin Signaling in the Brain with Physical Inactivity, Obesity, and Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Gregory N. Ruegsegger

    2017-05-01

    Full Text Available Physical inactivity is a primary contributor to diseases such as obesity, cardiovascular disease, and type 2 diabetes. Accelerometry data suggest that a majority of US adults fail to perform substantial levels of physical activity needed to improve health. Thus, understanding the molecular factors that stimulate physical activity, and physical inactivity, is imperative for the development of strategies to reduce sedentary behavior and in turn prevent chronic disease. Despite many of the well-known health benefits of physical activity being described, little is known about genetic and biological factors that may influence this complex behavior. The mesolimbic dopamine system regulates motivating and rewarding behavior as well as motor movement. Here, we present data supporting the hypothesis that obesity may mechanistically lower voluntary physical activity levels via dopamine dysregulation. In doing so, we review data that suggest mesolimbic dopamine activity is a strong contributor to voluntary physical activity behavior. We also summarize findings suggesting that obesity leads to central dopaminergic dysfunction, which in turn contributes to reductions in physical activity that often accompany obesity. Additionally, we highlight examples in which central leptin activity influences physical activity levels in a dopamine-dependent manner. Future elucidation of these mechanisms will help support strategies to increase physical activity levels in obese patients and prevent diseases caused by physical inactivity.

  12. Foundry energy conservation workbook

    Energy Technology Data Exchange (ETDEWEB)

    1990-12-31

    This report discusses methods for promoting energy conservation in foundries. Use of electric power, natural gas, and coke are evaluated. Waste heat recovery systems are considered. Energy consumption in the specific processes of electric melting, natural gas melting, heat treatments, ladle melting, and coke fuel melting is described. An example energy analysis is included. (GHH)

  13. Supersymmetric non conservative systems

    CERN Document Server

    Martínez-Pérez, N E

    2015-01-01

    We give the generalization of a recent variational formulation for nonconservative classical mechanics, for fermionic and sypersymmetric systems. Both cases require slightly modified boundary conditions. The supersymmetric version is given in the superfield formalism. The corresponding Noether theorem is formulated. As expected, like the energy, the supersymmetric charges are not conserved. Examples are discussed.

  14. Communities, Cameras, and Conservation

    Science.gov (United States)

    Patterson, Barbara

    2012-01-01

    Communities, Cameras, and Conservation (CCC) is the most exciting and valuable program the author has seen in her 30 years of teaching field science courses. In this citizen science project, students and community volunteers collect data on mountain lions ("Puma concolor") at four natural areas and public parks along the Front Range of Colorado.…

  15. Conservation of fern spores

    Science.gov (United States)

    Ferns are a diverse and important group of plants, but diversity of species and populations are at risk from increasing social pressures, loss of habitat and climate change. Ex situ conservation is a useful strategy to limit decline in genetic diversity and requires technologies to preserve fern ger...

  16. Deficiencies in Water Conservancy

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    Recent droughts and floods show the fragility of China’s water conservancy capabilities Be it extreme flooding or severe droughts,China has yet to find a stable middle ground concerning its water supply.These disasters,primarily in the Yangtze

  17. Energy Conservation Simplified

    Science.gov (United States)

    Hecht, Eugene

    2008-01-01

    The standard formulation of energy conservation involves the subsidiary ideas of kinetic energy ("KE"), work ("W"), thermal energy, internal energy, and a half-dozen different kinds of potential energy ("PE"): elastic, chemical, nuclear, gravitational, and so forth. These quantities came to be recognized during the centuries over which the…

  18. Beyond conservation agriculture

    NARCIS (Netherlands)

    Giller, K.E.; Andersson, J.A.; Corbeels, Marc; Kirkegaard, John; Mortensen, David; Erenstein, Olaf; Vanlauwe, Bernard

    2015-01-01

    Global support for Conservation Agriculture (CA) as a pathway to Sustainable Intensification is strong. CA revolves around three principles: no-till (or minimal soil disturbance), soil cover, and crop rotation. The benefits arising from the ease of crop management, energy/cost/time savings, and

  19. Conservative Public Interest Litigation

    Science.gov (United States)

    Pell, Terence J.

    2007-01-01

    The idea that lawsuits can move a public as well as a legal agenda is not new. In recent years, conservatives have brought high profile lawsuits designed both to vindicate the rights of an individual plaintiff and to educate the public about an important issue. For example, lawsuits filed nearly 10 years ago against the University of Michigan's…

  20. Conservation and gene banking

    Science.gov (United States)

    Plant conservation has several objectives the main ones include safeguarding our food supply, preserving crop wild relatives for breeding and selection of new cultivars, providing material for industrial and pharmaceutical uses and preserving the beauty and diversity of our flora for generations to ...

  1. The Conservation Fund

    Science.gov (United States)

    2004-08-01

    Create Walkable Neighborhoods 3. Encourage Community and Stakeholder Collaboration 4. Foster Distinctive, Attractive Communities with a Strong Sense of...Network www.smartgrowth.org Smart Growth America www.smartgrowthamerica.net The International City /County Management Assn. www.icma.org The Conservation

  2. Beyond conservation agriculture

    NARCIS (Netherlands)

    Giller, K.E.; Andersson, J.A.; Corbeels, Marc; Kirkegaard, John; Mortensen, David; Erenstein, Olaf; Vanlauwe, Bernard

    2015-01-01

    Global support for Conservation Agriculture (CA) as a pathway to Sustainable Intensification is strong. CA revolves around three principles: no-till (or minimal soil disturbance), soil cover, and crop rotation. The benefits arising from the ease of crop management, energy/cost/time savings, and s

  3. Urban bird conservation

    NARCIS (Netherlands)

    Snep, Robbert P.H.; Kooijmans, Jip Louwe; Kwak, Robert G.M.; Foppen, Ruud P.B.; Parsons, Holly; Awasthy, Monica; Sierdsema, Henk L.K.; Marzluff, John M.; Fernandez-Juricic, Esteban; Laet, de Jenny

    2016-01-01

    Following the call from the United Nations Convention on Biological Diversity “Cities & Biodiversity Outlook” project to better preserve urban biodiversity, this paper presents stakeholder-specific statements for bird conservation in city environments. Based upon the current urban bird

  4. Conservative Pressures on Curriculum.

    Science.gov (United States)

    Bryson, Joseph E.

    Pressure on the public schools is coming from conservative New Right religious-political groups. Their concerns focus on: (1) secular humanism--a Godless form of religion that the public schools are alleged to be teaching; (2) scientific evolution versus creationism--the balanced treatment statute; (3) Bible clubs and prayer in the classroom; and…

  5. A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study.

    Science.gov (United States)

    Salloum, Ralph; Hummel, Trent R; Kumar, Shiva Senthil; Dorris, Kathleen; Li, Shaoyu; Lin, Tong; Daryani, Vinay M; Stewart, Clinton F; Miles, Lili; Poussaint, Tina Young; Stevenson, Charles; Goldman, Stewart; Dhall, Girish; Packer, Roger; Fisher, Paul; Pollack, Ian F; Fouladi, Maryam; Boyett, James; Drissi, Rachid

    2016-09-01

    Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m(2), 12-24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m(2). Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.

  6. A molecularly cloned, live-attenuated japanese encephalitis vaccine SA14-14-2 virus: a conserved single amino acid in the ij Hairpin of the Viral E glycoprotein determines neurovirulence in mice.

    Science.gov (United States)

    Yun, Sang-Im; Song, Byung-Hak; Kim, Jin-Kyoung; Yun, Gil-Nam; Lee, Eun-Young; Li, Long; Kuhn, Richard J; Rossmann, Michael G; Morrey, John D; Lee, Young-Min

    2014-07-01

    Japanese encephalitis virus (JEV), a mosquito-borne flavivirus that causes fatal neurological disease in humans, is one of the most important emerging pathogens of public health significance. JEV represents the JE serogroup, which also includes West Nile, Murray Valley encephalitis, and St. Louis encephalitis viruses. Within this serogroup, JEV is a vaccine-preventable pathogen, but the molecular basis of its neurovirulence remains unknown. Here, we constructed an infectious cDNA of the most widely used live-attenuated JE vaccine, SA14-14-2, and rescued from the cDNA a molecularly cloned virus, SA14-14-2MCV, which displayed in vitro growth properties and in vivo attenuation phenotypes identical to those of its parent, SA14-14-2. To elucidate the molecular mechanism of neurovirulence, we selected three independent, highly neurovirulent variants (LD50, 1.5×105 PFU) by serial intracerebral passage in mice. Complete genome sequence comparison revealed a total of eight point mutations, with a common single G1708→A substitution replacing a Gly with Glu at position 244 of the viral E glycoprotein. Using our infectious SA14-14-2 cDNA technology, we showed that this single Gly-to-Glu change at E-244 is sufficient to confer lethal neurovirulence in mice, including rapid development of viral spread and tissue inflammation in the central nervous system. Comprehensive site-directed mutagenesis of E-244, coupled with homology-based structure modeling, demonstrated a novel essential regulatory role in JEV neurovirulence for E-244, within the ij hairpin of the E dimerization domain. In both mouse and human neuronal cells, we further showed that the E-244 mutation altered JEV infectivity in vitro, in direct correlation with the level of neurovirulence in vivo, but had no significant impact on viral RNA replication. Our results provide a crucial step toward developing novel therapeutic and preventive strategies against JEV and possibly other encephalitic flaviviruses.

  7. Brain Basics

    Medline Plus

    Full Text Available ... Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures of ... to slow or stop them from progressing. Functional magnetic resonance imaging (fMRI) is another important research tool in understanding ...

  8. Brain Basics

    Medline Plus

    Full Text Available ... as they grow there are differences in brain development in children who develop bipolar disorder than children who do not. Studies comparing such children to those with normal brain development may help scientists to pinpoint when and where ...

  9. Brain Basics

    Medline Plus

    Full Text Available ... Brain Imaging Using brain imaging technologies such as magnetic resonance imaging (MRI), which uses magnetic fields to take pictures ... to slow or stop them from progressing. Functional magnetic resonance imaging (fMRI) is another important research tool in understanding ...

  10. Brain Basics

    Medline Plus

    Full Text Available ... chemicals. glutamate —The most common neurotransmitter in a person's body, which increases neuronal activity, is involved in early brain development, and may also assist in learning and memory. hippocampus —A portion of the brain ...

  11. Brain Autopsy

    Science.gov (United States)

    ... why a family should consider arranging for a brain autopsy upon the death of their loved one. To get a definitive ... study of tissue removed from the body after death. Examination of the whole brain is important in understanding FTD because the patterns ...

  12. Brain Basics

    Medline Plus

    Full Text Available ... Join A Study News & Events News & Events Home Science News Events Multimedia Social Media Press Resources Newsletters NIMH News Feeds About ... on how the brain works, how mental illnesses are disorders of the brain, and ongoing research that ...

  13. Brain Basics

    Medline Plus

    Full Text Available ... PTSD) . Prefrontal cortex (PFC) —Seat of the brain's executive functions, such as judgment, decision making, and problem solving. ... brain that, in humans, plays a role in executive functions such as judgment, decision making and problem solving, ...

  14. Brain Basics

    Medline Plus

    Full Text Available ... as they grow there are differences in brain development in children who develop bipolar disorder than children who do not. Studies comparing such children to those with normal brain development may help scientists to pinpoint when and where ...

  15. Brain Basics

    Medline Plus

    Full Text Available ... and are working to compare that with brain development in people mental disorders. Genes and environmental cues both help to direct ... comparing such children to those with normal brain development may help scientists to pinpoint when and where mental disorders begin and perhaps how to slow or stop ...

  16. Brain peroxisomes.

    Science.gov (United States)

    Trompier, D; Vejux, A; Zarrouk, A; Gondcaille, C; Geillon, F; Nury, T; Savary, S; Lizard, G

    2014-03-01

    Peroxisomes are essential organelles in higher eukaryotes as they play a major role in numerous metabolic pathways and redox homeostasis. Some peroxisomal abnormalities, which are often not compatible with life or normal development, were identified in severe demyelinating and neurodegenerative brain diseases. The metabolic roles of peroxisomes, especially in the brain, are described and human brain peroxisomal disorders resulting from a peroxisome biogenesis or a single peroxisomal enzyme defect are listed. The brain abnormalities encountered in these disorders (demyelination, oxidative stress, inflammation, cell death, neuronal migration, differentiation) are described and their pathogenesis are discussed. Finally, the contribution of peroxisomal dysfunctions to the alterations of brain functions during aging and to the development of Alzheimer's disease is considered.

  17. Conservation businesses and conservation planning in a biological diversity hotspot.

    Science.gov (United States)

    Di Minin, Enrico; Macmillan, Douglas Craig; Goodman, Peter Styan; Escott, Boyd; Slotow, Rob; Moilanen, Atte

    2013-08-01

    The allocation of land to biological diversity conservation competes with other land uses and the needs of society for development, food, and extraction of natural resources. Trade-offs between biological diversity conservation and alternative land uses are unavoidable, given the realities of limited conservation resources and the competing demands of society. We developed a conservation-planning assessment for the South African province of KwaZulu-Natal, which forms the central component of the Maputaland-Pondoland-Albany biological diversity hotspot. Our objective was to enhance biological diversity protection while promoting sustainable development and providing spatial guidance in the resolution of potential policy conflicts over priority areas for conservation at risk of transformation. The conservation-planning assessment combined spatial-distribution models for 646 conservation features, spatial economic-return models for 28 alternative land uses, and spatial maps for 4 threats. Nature-based tourism businesses were competitive with other land uses and could provide revenues of >US$60 million/year to local stakeholders and simultaneously help meeting conservation goals for almost half the conservation features in the planning region. Accounting for opportunity costs substantially decreased conflicts between biological diversity, agricultural use, commercial forestry, and mining. Accounting for economic benefits arising from conservation and reducing potential policy conflicts with alternative plans for development can provide opportunities for successful strategies that combine conservation and sustainable development and facilitate conservation action. © 2013 Society for Conservation Biology.

  18. Conservation genetics of the protected moth "Graellsia isabellae" (Lepidoptera, Saturniidae)

    OpenAIRE

    2013-01-01

    [Abstract] Evolutionary and molecular genetics provides valuable information for the efficient conservation of endangered species. In this thesis, I have used a combination of newly generated genetic and ecological data to assess the conservation status of the protected moth Graellsia isabellae. Firstly, I reconstructed the evolutionary history of this iconic insect by using genetic data obtained from samples obtained across the whole known distribution area: Iberia Peninsula and French Alps....

  19. DNA in the conservation and management of African antelope

    DEFF Research Database (Denmark)

    Lorenzen, Eline

    2016-01-01

    tool in informed species conservation and sustainable wildlife management. The movement of antelope through translocations, reintroductions, and population augmentations is common practice in wildlife management. DNA-led species identification using genetic barcoding is an effective use of genetic data......This chapter addresses species conservation using population genetics, including delimiting species and subspecies, revealing cryptic diversity, and assessing hybridization between distinct populations. The molecular information from these studies is publicly available and can be found in online...

  20. BIOLOGIE DE LA CONSERVATION APPLIQUEE AUX PLANTES MENACEES DES ALPES

    OpenAIRE

    Nicolè, Florence

    2005-01-01

    Through concrete examples of endangered plants chosen in the flora of the French Alps, this work presents the application of three main aspects classically used in conservation biology: the study of genetic variation, the study of reproductive performance and reproductive system and the study of population dynamics.First, we show that molecular markers are a useful tool to resolve taxonomic ambiguities and verify the status of conservation unit in the case of Potentilla delphinensis Gren. and...

  1. Metrology and Energy Conservation

    Institute of Scientific and Technical Information of China (English)

    Xuan Xiang

    2006-01-01

    @@ May 20 is World Metrology Day and the theme of this year is "Metrology and Energy Conservation." Energy is not only a vital issue for China, but also for the world. In order to implement Proposal of the CPC Central Committee on the 11th Five-Year Program for National Economic and Social Development, the government bulletin of 5th Plenary Session of the 16th CPC Central Committee announced that "there shall be marked improvement on resource utilization; the energy consumption for unit GDP shall cut 20%, water consumption of unit industrial added value drop 30%... and the recycle ratio of industrial solid wastes shall raise by 60%." These are key targets of economic development during the 11th five-year program. To make full use of metrology for energy conservation and energy utilization, the competent metrology department of Chinese Goyernment advanced metrology program in light of China's energy status.

  2. Bison Conservation Initiative : Bison Conservation Genetics Workshop : Reports and Recommendations

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — One of the first outcomes of the Department of the Interior (DOI) Bison Conservation Initiative was the Bison Conservation Genetics Workshop held in Nebraska in...

  3. Selling Conservation? Scientific Legitimacy and the Commodification of Conservation Tourism

    Directory of Open Access Journals (Sweden)

    Jenny A. Cousins

    2009-06-01

    Full Text Available Conservation tourism is a rapidly growing subsector of ecotourism that engages paying volunteers as active participants in conservation projects. Once the preserve of charities, the sector now hosts a proliferation of private companies seeking to make money by selling international conservation work to tourists as a commodity. The commodification of conservation depends upon balancing the scientific legitimacy of projects against the need to offer desirable tourist experiences. Drawing on interviews with UK tour operators and their counterparts in South Africa who run the conservation projects, we explore the transnational geography of commercial conservation tourism, charting how scientific legitimacy is constructed and negotiated within the industry. Although conservation tourism makes trade-offs between scientific rigor and neoliberal market logic, it is a partial and plural process that resists simple categorization. We conclude by considering the difference that commodification makes to conservation science, and vice versa.

  4. A Hypothesis for the Composition of the Tardigrade Brain and its Implications for Panarthropod Brain Evolution.

    Science.gov (United States)

    Smith, Frank W; Bartels, Paul J; Goldstein, Bob

    2017-09-01

    Incredibly disparate brain types are found in Metazoa, which raises the question of how this disparity evolved. Ecdysozoa includes representatives that exhibit ring-like brains-the Cycloneuralia-and representatives that exhibit ganglionic brains-the Panarthropoda (Euarthropoda, Onychophora, and Tardigrada). The evolutionary steps leading to these distinct brain types are unclear. Phylogenomic analyses suggest that the enigmatic Tardigrada is a closely related outgroup of a Euarthropoda + Onychophora clade; as such, the brains of tardigrades may provide insight into the evolution of ecdysozoan brains. Recently, evolutionarily salient questions have arisen regarding the composition of the tardigrade brain. To address these questions, we investigated brain anatomy in four tardigrade species-Hypsibius dujardini, Milnesium n. sp., Echiniscus n. sp., and Batillipes n. sp.-that together span Tardigrada. Our results suggest that general brain morphology is conserved across Tardigrada. Based on our results we present a hypothesis that proposes direct parallels between the tardigrade brain and the segmental trunk ganglia of the tardigrade ventral nervous system. In this hypothesis, brain neuropil nearly circumscribes the tardigrade foregut. We suggest that the tardigrade brain retains aspects of an ancestral cycloneuralian brain, while exhibiting ganglionic structure characteristic of euarthropods and onychophorans. © The Author 2017. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology.All rights reserved. For permissions please email: journals.permissions@oup.com.

  5. Molecular psychiatry of zebrafish.

    Science.gov (United States)

    Stewart, A M; Ullmann, J F P; Norton, W H J; Parker, M O; Brennan, C H; Gerlai, R; Kalueff, A V

    2015-02-01

    Due to their well-characterized neural development and high genetic homology to mammals, zebrafish (Danio rerio) have emerged as a powerful model organism in the field of biological psychiatry. Here, we discuss the molecular psychiatry of zebrafish, and its implications for translational neuroscience research and modeling central nervous system (CNS) disorders. In particular, we outline recent genetic and technological developments allowing for in vivo examinations, high-throughput screening and whole-brain analyses in larval and adult zebrafish. We also summarize the application of these molecular techniques to the understanding of neuropsychiatric disease, outlining the potential of zebrafish for modeling complex brain disorders, including attention-deficit/hyperactivity disorder (ADHD), aggression, post-traumatic stress and substance abuse. Critically evaluating the advantages and limitations of larval and adult fish tests, we suggest that zebrafish models become a rapidly emerging new field in modern molecular psychiatry research.

  6. [Brain concussion].

    Science.gov (United States)

    Pälvimäki, Esa-Pekka; Siironen, Jari; Pohjola, Juha; Hernesniemi, Juha

    2011-01-01

    Brain concussion is a common disturbance caused by external forces or acceleration affecting the head. It may be accompanied by transient loss of consciousness and amnesia. Typical symptoms include headache, nausea and dizziness; these may remain for a week or two. Some patients may experience transient loss of inability to create new memories or other brief impairment of mental functioning. Treatment is symptomatic. Some patients may suffer from prolonged symptoms, the connection of which with brain concession is difficult to show. Almost invariably the prognosis of brain concussion is good.

  7. Role of highly conserved pyrimidine-rich sequences in the 3' untranslated region of the GAP-43 mRNA in mRNA stability and RNA-protein interactions.

    Science.gov (United States)

    Kohn, D T; Tsai, K C; Cansino, V V; Neve, R L; Perrone-Bizzozero, N I

    1996-03-01

    We have shown previously that the mRNA for the growth-associated protein GAP-43 is selectively stabilized during neuronal differentiation. In this study, we explored the role of its highly conserved 3' untranslated region (3'UTR) in mRNA stability and RNA-protein interactions. The 3'UTRs of the rat and chicken GAP-43 mRNAs show 78% sequence identity, which is equivalent to the conservation of their coding regions. In rat PC12 cells stably transfected with the full-length rat or chicken GAP-43 cDNAs, the transgene mRNAs decayed with same half-life of about 3 h. The GAP-43 3'UTR also caused the rabbit beta-globin mRNA to decay with a half-life of 4 h, indicating that the major determinants for GAP-43 mRNA stability are localized in its highly conserved 3'UTR. Three brain cytosolic RNA-binding proteins (molecular mass 40, 65 and 95 kDa) were found to interact with both the rat and chicken GAP-43 mRNAs. These RNA-protein interactions were specific and involved pyrimidine-rich sequences in the 3'UTR. Like the GAP-43 mRNA, the activity of these proteins was enriched in brain and increased during development. We propose that highly conserved pyrimidine-rich sequences in the 3'UTR of this mRNA regulate GAP-43 gene expression via interactions with specific RNA-binding proteins.

  8. 75 FR 59469 - Energy Conservation Program: Energy Conservation Standards for Residential Refrigerators...

    Science.gov (United States)

    2010-09-27

    ... Energy 10 CFR Part 430 Energy Conservation Program: Energy Conservation Standards for Residential... Energy Conservation Program: Energy Conservation Standards for Residential Refrigerators, Refrigerator... Conservation Act (EPCA) prescribes energy conservation standards for various consumer products and......

  9. Drosophila glia use a conserved cotransporter mechanism to regulate extracellular volume.

    Science.gov (United States)

    Leiserson, William M; Forbush, Biff; Keshishian, Haig

    2011-02-01

    The nervous system is protected by blood barriers that use multiple systems to control extracellular solute composition, osmotic pressure, and fluid volume. In the human nervous system, misregulation of the extracellular volume poses serious health threats. Here, we show that the glial cells that form the Drosophila blood-nerve barrier have a conserved molecular mechanism that regulates extracellular volume: the Serine/Threonine kinase Fray, which we previously showed is an ortholog of mammalian PASK/SPAK; and the Na-K-Cl cotransporter Ncc69, which we show is an ortholog of human NKCC1. In mammals, PASK/SPAK binds to NKCC1 and regulates its activity. In Drosophila, larvae mutant for Ncc69 develop a peripheral neuropathy, where fluid accumulates between glia and axons. The accumulation of fluid has no detectable impact on action potential conduction, suggesting that the role of Ncc69 is to maintain volume or osmotic homeostasis. Drosophila Ncc69 has kinetics similar to human NKCC1, and NKCC1 can rescue Ncc69, suggesting that they function in a conserved physiological mechanism. We show that fray and Ncc69 are coexpressed in nerve glia, interact in a yeast-two-hybrid assay, and have an essentially identical bulging nerve phenotype. We propose that normally functioning nerves generate extracellular solutes that are removed by Ncc69 under the control of Fray. This mechanism may perform a similar role in humans, given that NKCC1 is expressed at the blood-brain barrier.

  10. Brain radiation - discharge

    Science.gov (United States)

    Radiation - brain - discharge; Cancer-brain radiation; Lymphoma - brain radiation; Leukemia - brain radiation ... Decadron) while you are getting radiation to the brain. It may make you hungrier, cause leg swelling ...

  11. Brain tumor - primary - adults

    Science.gov (United States)

    ... Vestibular schwannoma (acoustic neuroma) - adults; Meningioma - adults; Cancer - brain tumor (adults) ... Primary brain tumors include any tumor that starts in the brain. Primary brain tumors can start from brain cells, ...

  12. Brain Basics

    Medline Plus

    Full Text Available ... control specific body functions such as sleep and speech. The brain continues maturing well into a person's ... as sleep, diet, or stress. These factors may act alone or together in complex ways, to change ...

  13. Brain Basics

    Medline Plus

    Full Text Available ... can be related to changes in the anatomy, physiology, and chemistry of the nervous system. When the brain cannot effectively coordinate the billions of cells in the body, the results can affect many ...

  14. Brain Basics

    Medline Plus

    Full Text Available ... of the cell from its surrounding environment and controls what enters and leaves the cell, and responds ... via axons) to form brain circuits. These circuits control specific body functions such as sleep and speech. ...

  15. Brain Basics

    Medline Plus

    Full Text Available ... sends impulses and extends from cell bodies to meet and deliver impulses to another nerve cell. Axons ... in Real Life—How Depression affects the Brain Meet Sarah Sarah is a middle-aged woman who ...

  16. Brain Basics

    Medline Plus

    Full Text Available ... Amygdala —The brain's "fear hub," which activates our natural "fight-or-flight" response to confront or escape ... identify unknown pills from the National Library of Medicine Contact Us Staff Directories Privacy Notice Policies FOIA ...

  17. Brain Basics

    Medline Plus

    Full Text Available ... in early detection, more tailored treatments, and possibly prevention of such illnesses. The Working Brain Neurotransmitters Everything ... can cause tremors or symptoms found in Parkinson's disease. Serotonin —helps control many functions, such as mood, ...

  18. Brain Basics

    Medline Plus

    Full Text Available ... Offices and Divisions Careers@NIMH Advisory Boards and Groups Staff Directories Getting to NIMH National Institutes of ... electrical signals. The brain begins as a small group of cells in the outer layer of a ...

  19. Brain Basics

    Medline Plus

    Full Text Available ... the brain, which is linked to thought and emotion. It is also linked to reward systems in ... or-flight response and is also involved in emotions and memory. anterior cingulate cortex —Is involved in ...

  20. Brain Basics

    Medline Plus

    Full Text Available ... they can cause tremors or symptoms found in Parkinson's disease. Serotonin —helps control many functions, such as ... brain. Problems in producing dopamine can result in Parkinson's disease, a disorder that affects a person's ability ...