WorldWideScience

Sample records for human 9-1-1 complex

  1. ZTF-8 interacts with the 9-1-1 complex and is required for DNA damage response and double-strand break repair in the C. elegans germline.

    Directory of Open Access Journals (Sweden)

    Hyun-Min Kim

    2014-10-01

    Full Text Available Germline mutations in DNA repair genes are linked to tumor progression. Furthermore, failure in either activating a DNA damage checkpoint or repairing programmed meiotic double-strand breaks (DSBs can impair chromosome segregation. Therefore, understanding the molecular basis for DNA damage response (DDR and DSB repair (DSBR within the germline is highly important. Here we define ZTF-8, a previously uncharacterized protein conserved from worms to humans, as a novel factor involved in the repair of both mitotic and meiotic DSBs as well as in meiotic DNA damage checkpoint activation in the C. elegans germline. ztf-8 mutants exhibit specific sensitivity to γ-irradiation and hydroxyurea, mitotic nuclear arrest at S-phase accompanied by activation of the ATL-1 and CHK-1 DNA damage checkpoint kinases, as well as accumulation of both mitotic and meiotic recombination intermediates, indicating that ZTF-8 functions in DSBR. However, impaired meiotic DSBR progression partially fails to trigger the CEP-1/p53-dependent DNA damage checkpoint in late pachytene, also supporting a role for ZTF-8 in meiotic DDR. ZTF-8 partially co-localizes with the 9-1-1 DDR complex and interacts with MRT-2/Rad1, a component of this complex. The human RHINO protein rescues the phenotypes observed in ztf-8 mutants, suggesting functional conservation across species. We propose that ZTF-8 is involved in promoting repair at stalled replication forks and meiotic DSBs by transducing DNA damage checkpoint signaling via the 9-1-1 pathway. Our findings define a conserved function for ZTF-8/RHINO in promoting genomic stability in the germline.

  2. Examining the Fundamental Obstructs of Adopting Cloud Computing for 9-1-1 Dispatch Centers in the USA

    Science.gov (United States)

    Osman, Abdulaziz

    2016-01-01

    The purpose of this research study was to examine the unknown fears of embracing cloud computing which stretches across measurements like fear of change from leaders and the complexity of the technology in 9-1-1 dispatch centers in USA. The problem that was addressed in the study was that many 9-1-1 dispatch centers in USA are still using old…

  3. 78 FR 21879 - Improving 9-1-1 Reliability; Reliability and Continuity of Communications Networks, Including...

    Science.gov (United States)

    2013-04-12

    ... From the Federal Register Online via the Government Publishing Office FEDERAL COMMUNICATIONS COMMISSION 47 CFR Chapter I Improving 9-1-1 Reliability; Reliability and Continuity of Communications Networks, Including Broadband Technologies AGENCY: Federal Communications Commission. ACTION: Notice...

  4. Choreography of the 9-1-1 checkpoint complex: DDK puts a check on the checkpoints.

    Science.gov (United States)

    Paek, Andrew L; Weinert, Ted

    2010-11-24

    Checkpoint proteins respond to DNA damage by halting the cell cycle until the damage is repaired. In this issue of Molecular Cell, Furuya et al. (2010) provide evidence that checkpoint proteins need to be removed from sites of damage in order to properly repair it.

  5. Awareness of Necessity to Call 9-1-1 for Stroke Symptoms, Upstate New York

    Directory of Open Access Journals (Sweden)

    Janine M. Jurkowski, PhD, MPH

    2008-04-01

    Full Text Available IntroductionStroke is the third leading cause of death and a leading cause of disability in New York State. A New York study determined that only 19.9% of patients arrived at a designated stroke center within 3 hours of symptom onset. Yet, receiving treatment within 90 minutes of stroke symptom onset is optimal for improved outcomes. Delay in recognition of stroke symptoms and their severity contributes to treatment delay.MethodsA random-digit–dialed, list-assisted telephone survey about stroke knowledge was administered to 1789 adults aged 30 years or older in upstate New York in 2006. Bivariate and regression analysis were used to examine factors associated with intent to call 9-1-1 for symptoms of stroke.ResultsThe largest proportion of respondents (72.4%; 95% confidence interval [CI], 69.9%–74.8% reported they would call 9-1-1 if they noticed they or someone else had difficulty speaking, and the fewest (33.3%; 95% CI, 30.7%–36.0% respondents reported they would call 9-1-1 for trouble seeing or double vision. Multivariate analysis found that those who had a history of delay in getting medical care in the past 6 months had decreased odds of intending to call 9-1-1 for stroke symptoms (difficulty speaking: adjusted odds ratio [AOR], 0.76; 95% CI, 0.58–1.00; trouble seeing: AOR, 0.69; 95% CI, 0.53–0.91; facial droop: AOR, 0.85; 95% CI, 0.65–1.11; arm weakness: AOR, 0.80; 95% CI, 0.63–1.03. Age, education, and history of a stroke or heart event were not consistently associated with intent to call 9-1-1.ConclusionSurvey respondents do not interpret some stroke symptoms as urgent enough to activate the emergency medical system. History of delaying care is a behavioral pattern that influenced intent to call 9-1-1.

  6. Coordinating the Global Information Grid Initiative with the NG9-1-1 Initiative

    Energy Technology Data Exchange (ETDEWEB)

    Michael Schmitt

    2008-05-01

    As the Department of Defense develops the Global Information Grid, the Department of Transportation develops the Next Generation 9-1-1 system. Close examinations of these initiatives show that the two are similar in architectures, applications, and communications interoperability. These similarities are extracted from the lowest user level to the highest commander rank that will be involved in each network. Once the similarities are brought into perspective, efforts should be made to collaborate between the two departments.

  7. Disorder in Complex Human System

    Science.gov (United States)

    Akdeniz, K. Gediz

    2011-11-01

    Since the world of human and whose life becomes more and more complex every day because of the digital technology and under the storm of knowledge (media, internet, governmental and non-governmental organizations, etc...) the simulation is rapidly growing in the social systems and in human behaviors. The formation of the body and mutual interactions are left to digital technological, communication mechanisms and coding the techno genetics of the body. Deconstruction begins everywhere. The linear simulation mechanism with modern realities are replaced by the disorder simulation of human behaviors with awareness realities. In this paper I would like to introduce simulation theory of "Disorder Sensitive Human Behaviors". I recently proposed this theory to critique the role of disorder human behaviors in social systems. In this theory the principle of realty is the chaotic awareness of the complexity of human systems inside of principle of modern thinking in Baudrillard's simulation theory. Proper examples will be also considered to investigate the theory.

  8. The crystal structure of Cu9.1(1)TeSb3, a stuffed derivative of Cr3Si

    DEFF Research Database (Denmark)

    Søtofte, Inger; Makovicky, E.; Karup-Møller, Sven

    1998-01-01

    The intermetallic compound Cu9.1(1)TeSb3 prepared at 973 K is an ordered member of the solid solution Cu64Te31Sb5-Cu70Te8Sb22 which also exists, for more limited composition ranges, between 673 K and 1173 K. It is a stuffed derivative of the structure type A15 (Cr3Si). Te is surrounded by twelve ...

  9. MRN- and 9-1-1-Independent Activation of the ATR-Chk1 Pathway during the Induction of the Virulence Program in the Phytopathogen Ustilago maydis.

    Science.gov (United States)

    Tenorio-Gómez, María; de Sena-Tomás, Carmen; Pérez-Martín, Jose

    2015-01-01

    DNA damage response (DDR) leads to DNA repair, and depending on the extent of the damage, to further events, including cell death. Evidence suggests that cell differentiation may also be a consequence of the DDR. During the formation of the infective hypha in the phytopathogenic fungus Ustilago maydis, two DDR kinases, Atr1 and Chk1, are required to induce a G2 cell cycle arrest, which in turn is essential to display the virulence program. However, the triggering factor of DDR in this process has remained elusive. In this report we provide data suggesting that no DNA damage is associated with the activation of the DDR during the formation of the infective filament in U. maydis. We have analyzed bulk DNA replication during the formation of the infective filament, and we found no signs of impaired DNA replication. Furthermore, using RPA-GFP fusion as a surrogate marker of the presence of DNA damage, we were unable to detect any sign of DNA damage at the cellular level. In addition, neither MRN nor 9-1-1 complexes, both instrumental to transmit the DNA damage signal, are required for the induction of the above mentioned cell cycle arrest, as well as for virulence. In contrast, we have found that the claspin-like protein Mrc1, which in other systems serves as scaffold for Atr1 and Chk1, was required for both processes. We discuss possible alternative ways to trigger the DDR, independent of DNA damage, in U. maydis during virulence program activation.

  10. Approaching human language with complex networks

    Science.gov (United States)

    Cong, Jin; Liu, Haitao

    2014-12-01

    The interest in modeling and analyzing human language with complex networks is on the rise in recent years and a considerable body of research in this area has already been accumulated. We survey three major lines of linguistic research from the complex network approach: 1) characterization of human language as a multi-level system with complex network analysis; 2) linguistic typological research with the application of linguistic networks and their quantitative measures; and 3) relationships between the system-level complexity of human language (determined by the topology of linguistic networks) and microscopic linguistic (e.g., syntactic) features (as the traditional concern of linguistics). We show that the models and quantitative tools of complex networks, when exploited properly, can constitute an operational methodology for linguistic inquiry, which contributes to the understanding of human language and the development of linguistics. We conclude our review with suggestions for future linguistic research from the complex network approach: 1) relationships between the system-level complexity of human language and microscopic linguistic features; 2) expansion of research scope from the global properties to other levels of granularity of linguistic networks; and 3) combination of linguistic network analysis with other quantitative studies of language (such as quantitative linguistics).

  11. MRN- and 9-1-1-Independent Activation of the ATR-Chk1 Pathway during the Induction of the Virulence Program in the Phytopathogen Ustilago maydis.

    Directory of Open Access Journals (Sweden)

    María Tenorio-Gómez

    Full Text Available DNA damage response (DDR leads to DNA repair, and depending on the extent of the damage, to further events, including cell death. Evidence suggests that cell differentiation may also be a consequence of the DDR. During the formation of the infective hypha in the phytopathogenic fungus Ustilago maydis, two DDR kinases, Atr1 and Chk1, are required to induce a G2 cell cycle arrest, which in turn is essential to display the virulence program. However, the triggering factor of DDR in this process has remained elusive. In this report we provide data suggesting that no DNA damage is associated with the activation of the DDR during the formation of the infective filament in U. maydis. We have analyzed bulk DNA replication during the formation of the infective filament, and we found no signs of impaired DNA replication. Furthermore, using RPA-GFP fusion as a surrogate marker of the presence of DNA damage, we were unable to detect any sign of DNA damage at the cellular level. In addition, neither MRN nor 9-1-1 complexes, both instrumental to transmit the DNA damage signal, are required for the induction of the above mentioned cell cycle arrest, as well as for virulence. In contrast, we have found that the claspin-like protein Mrc1, which in other systems serves as scaffold for Atr1 and Chk1, was required for both processes. We discuss possible alternative ways to trigger the DDR, independent of DNA damage, in U. maydis during virulence program activation.

  12. Human Error Mechanisms in Complex Work Environments

    DEFF Research Database (Denmark)

    Rasmussen, Jens

    1988-01-01

    will account for most of the action errors observed. In addition, error mechanisms appear to be intimately related to the development of high skill and know-how in a complex work context. This relationship between errors and human adaptation is discussed in detail for individuals and organisations...

  13. Complex Loci in human and mouse genomes.

    Science.gov (United States)

    Engström, Pär G; Suzuki, Harukazu; Ninomiya, Noriko; Akalin, Altuna; Sessa, Luca; Lavorgna, Giovanni; Brozzi, Alessandro; Luzi, Lucilla; Tan, Sin Lam; Yang, Liang; Kunarso, Galih; Ng, Edwin Lian-Chong; Batalov, Serge; Wahlestedt, Claes; Kai, Chikatoshi; Kawai, Jun; Carninci, Piero; Hayashizaki, Yoshihide; Wells, Christine; Bajic, Vladimir B; Orlando, Valerio; Reid, James F; Lenhard, Boris; Lipovich, Leonard

    2006-04-01

    Mammalian genomes harbor a larger than expected number of complex loci, in which multiple genes are coupled by shared transcribed regions in antisense orientation and/or by bidirectional core promoters. To determine the incidence, functional significance, and evolutionary context of mammalian complex loci, we identified and characterized 5,248 cis-antisense pairs, 1,638 bidirectional promoters, and 1,153 chains of multiple cis-antisense and/or bidirectionally promoted pairs from 36,606 mouse transcriptional units (TUs), along with 6,141 cis-antisense pairs, 2,113 bidirectional promoters, and 1,480 chains from 42,887 human TUs. In both human and mouse, 25% of TUs resided in cis-antisense pairs, only 17% of which were conserved between the two organisms, indicating frequent species specificity of antisense gene arrangements. A sampling approach indicated that over 40% of all TUs might actually be in cis-antisense pairs, and that only a minority of these arrangements are likely to be conserved between human and mouse. Bidirectional promoters were characterized by variable transcriptional start sites and an identifiable midpoint at which overall sequence composition changed strand and the direction of transcriptional initiation switched. In microarray data covering a wide range of mouse tissues, genes in cis-antisense and bidirectionally promoted arrangement showed a higher probability of being coordinately expressed than random pairs of genes. In a case study on homeotic loci, we observed extensive transcription of nonconserved sequences on the noncoding strand, implying that the presence rather than the sequence of these transcripts is of functional importance. Complex loci are ubiquitous, host numerous nonconserved gene structures and lineage-specific exonification events, and may have a cis-regulatory impact on the member genes.

  14. Complex Loci in human and mouse genomes.

    Directory of Open Access Journals (Sweden)

    Pär G Engström

    2006-04-01

    Full Text Available Mammalian genomes harbor a larger than expected number of complex loci, in which multiple genes are coupled by shared transcribed regions in antisense orientation and/or by bidirectional core promoters. To determine the incidence, functional significance, and evolutionary context of mammalian complex loci, we identified and characterized 5,248 cis-antisense pairs, 1,638 bidirectional promoters, and 1,153 chains of multiple cis-antisense and/or bidirectionally promoted pairs from 36,606 mouse transcriptional units (TUs, along with 6,141 cis-antisense pairs, 2,113 bidirectional promoters, and 1,480 chains from 42,887 human TUs. In both human and mouse, 25% of TUs resided in cis-antisense pairs, only 17% of which were conserved between the two organisms, indicating frequent species specificity of antisense gene arrangements. A sampling approach indicated that over 40% of all TUs might actually be in cis-antisense pairs, and that only a minority of these arrangements are likely to be conserved between human and mouse. Bidirectional promoters were characterized by variable transcriptional start sites and an identifiable midpoint at which overall sequence composition changed strand and the direction of transcriptional initiation switched. In microarray data covering a wide range of mouse tissues, genes in cis-antisense and bidirectionally promoted arrangement showed a higher probability of being coordinately expressed than random pairs of genes. In a case study on homeotic loci, we observed extensive transcription of nonconserved sequences on the noncoding strand, implying that the presence rather than the sequence of these transcripts is of functional importance. Complex loci are ubiquitous, host numerous nonconserved gene structures and lineage-specific exonification events, and may have a cis-regulatory impact on the member genes.

  15. An evaluation of 9-1-1 calls to assess the effectiveness of dispatch-assisted cardiopulmonary resuscitation (CPR instructions: design and methodology

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    Stiell Ian G

    2008-11-01

    Full Text Available Abstract Background Cardiac arrest is the leading cause of mortality in Canada, and the overall survival rate for out-of-hospital cardiac arrest rarely exceeds 5%. Bystander cardiopulmonary resuscitation (CPR has been shown to increase survival for cardiac arrest victims. However, bystander CPR rates remain low in Canada, rarely exceeding 15%, despite various attempts to improve them. Dispatch-assisted CPR instructions have the potential to improve rates of bystander CPR and many Canadian urban communities now offer instructions to callers reporting a victim in cardiac arrest. Dispatch-assisted CPR instructions are recommended by the International Guidelines on Emergency Cardiovascular Care, but their ability to improve cardiac arrest survival remains unclear. Methods/Design The overall goal of this study is to better understand the factors leading to successful dispatch-assisted CPR instructions and to ultimately save the lives of more cardiac arrest patients. The study will utilize a before-after, prospective cohort design to specifically: 1 Determine the ability of 9-1-1 dispatchers to correctly diagnose cardiac arrest; 2 Quantify the frequency and impact of perceived agonal breathing on cardiac arrest diagnosis; 3 Measure the frequency with which dispatch-assisted CPR instructions can be successfully completed; and 4 Measure the impact of dispatch-assisted CPR instructions on bystander CPR and survival rates. The study will be conducted in 19 urban communities in Ontario, Canada. All 9-1-1 calls occurring in the study communities reporting out-of-hospital cardiac arrest in victims 16 years of age or older for which resuscitation was attempted will be eligible. Information will be obtained from 9-1-1 call recordings, paramedic patient care reports, base hospital records, fire medical records and hospital medical records. Victim, caller and system characteristics will be measured in the study communities before the introduction of dispatch

  16. Modeling the human prothrombinase complex components

    Science.gov (United States)

    Orban, Tivadar

    Thrombin generation is the culminating stage of the blood coagulation process. Thrombin is obtained from prothrombin (the substrate) in a reaction catalyzed by the prothrombinase complex (the enzyme). The prothrombinase complex is composed of factor Xa (the enzyme), factor Va (the cofactor) associated in the presence of calcium ions on a negatively charged cell membrane. Factor Xa, alone, can activate prothrombin to thrombin; however, the rate of conversion is not physiologically relevant for survival. Incorporation of factor Va into prothrombinase accelerates the rate of prothrombinase activity by 300,000-fold, and provides the physiological pathway of thrombin generation. The long-term goal of the current proposal is to provide the necessary support for the advancing of studies to design potential drug candidates that may be used to avoid development of deep venous thrombosis in high-risk patients. The short-term goals of the present proposal are to (1) to propose a model of a mixed asymmetric phospholipid bilayer, (2) expand the incomplete model of human coagulation factor Va and study its interaction with the phospholipid bilayer, (3) to create a homology model of prothrombin (4) to study the dynamics of interaction between prothrombin and the phospholipid bilayer.

  17. Further investigations on the macromolecular complex in human bile

    NARCIS (Netherlands)

    Verschure, J.C.M.; Wael, J. de; Mijnlieff, P.F.

    1956-01-01

    The formation of complexes in human bile was further studied by the preparation of various synthetic complexes and extracts. These were compared for a number of properties with the natural complex of human gall bladder bile. It appeared that protein is probably and bilirubin quite definitely a const

  18. Reducing the Complexity Gap: Expanding the Period of Human Nurturance

    Science.gov (United States)

    Kiel, L. Douglas

    2014-01-01

    Socio-techno-cultural reality, in the current historical era, evolves at a faster rate than do human brain or human institutions. This reality creates a "complexity gap" that reduces human and institutional capacities to adapt to the challenges of late modernity. New insights from the neurosciences may help to reduce the complexity gap.…

  19. Benchmarking human protein complexes to investigate drug-related systems and evaluate predicted protein complexes.

    Directory of Open Access Journals (Sweden)

    Min Wu

    Full Text Available Protein complexes are key entities to perform cellular functions. Human diseases are also revealed to associate with some specific human protein complexes. In fact, human protein complexes are widely used for protein function annotation, inference of human protein interactome, disease gene prediction, and so on. Therefore, it is highly desired to build an up-to-date catalogue of human complexes to support the research in these applications. Protein complexes from different databases are as expected to be highly redundant. In this paper, we designed a set of concise operations to compile these redundant human complexes and built a comprehensive catalogue called CHPC2012 (Catalogue of Human Protein Complexes. CHPC2012 achieves a higher coverage for proteins and protein complexes than those individual databases. It is also verified to be a set of complexes with high quality as its co-complex protein associations have a high overlap with protein-protein interactions (PPI in various existing PPI databases. We demonstrated two distinct applications of CHPC2012, that is, investigating the relationship between protein complexes and drug-related systems and evaluating the quality of predicted protein complexes. In particular, CHPC2012 provides more insights into drug development. For instance, proteins involved in multiple complexes (the overlapping proteins are potential drug targets; the drug-complex network is utilized to investigate multi-target drugs and drug-drug interactions; and the disease-specific complex-drug networks will provide new clues for drug repositioning. With this up-to-date reference set of human protein complexes, we believe that the CHPC2012 catalogue is able to enhance the studies for protein interactions, protein functions, human diseases, drugs, and related fields of research. CHPC2012 complexes can be downloaded from http://www1.i2r.a-star.edu.sg/xlli/CHPC2012/CHPC2012.htm.

  20. Complex Human Dynamics From Mind to Societies

    CERN Document Server

    Winkowska-Nowak, Katarzyna; Brée, David

    2013-01-01

    This book, edited and authored by a closely collaborating network of social scientists and psychologists, recasts typical research topics in these fields into the language of nonlinear, dynamic and complex systems. The aim is to provide scientists with different backgrounds - physics, applied mathematics and computer sciences - with the opportunity to apply the tools of their trade to an altogether new range of possible applications. At the same time, this book will serve as a first reference for a new generation of social scientists and psychologists wishing to familiarize themselves with the new methodology and the "thinking in complexity".

  1. Complex Systems and Human Performance Modeling

    Science.gov (United States)

    2013-12-01

    constitute a cognitive architecture or decomposing the work flows and resource constraints that characterize human-system interactions, the modeler...also explored the generation of so-called “ fractal ” series from simple task network models where task times are the calculated by way of a moving

  2. Understanding complexity in the human brain.

    Science.gov (United States)

    Bassett, Danielle S; Gazzaniga, Michael S

    2011-05-01

    Although the ultimate aim of neuroscientific enquiry is to gain an understanding of the brain and how its workings relate to the mind, the majority of current efforts are largely focused on small questions using increasingly detailed data. However, it might be possible to successfully address the larger question of mind-brain mechanisms if the cumulative findings from these neuroscientific studies are coupled with complementary approaches from physics and philosophy. The brain, we argue, can be understood as a complex system or network, in which mental states emerge from the interaction between multiple physical and functional levels. Achieving further conceptual progress will crucially depend on broad-scale discussions regarding the properties of cognition and the tools that are currently available or must be developed in order to study mind-brain mechanisms.

  3. Interaction profiling identifies the human nuclear exosome targeting complex

    DEFF Research Database (Denmark)

    Lubas, Michal Szymon; Christensen, Marianne Spangsberg; Kristiansen, Maiken Søndergaard

    2011-01-01

    of a similar activator(s) in humans remains elusive. By establishing an interaction network of the human nuclear exosome, we identify the trimeric Nuclear Exosome Targeting (NEXT) complex, containing hMTR4, the Zn-knuckle protein ZCCHC8, and the putative RNA binding protein RBM7. ZCCHC8 and RBM7 are excluded...... to nucleoli. Our results suggest that human nuclear exosome degradation pathways comprise modules of spatially organized cofactors that diverge from the yeast model....

  4. Systematic analysis of human protein complexes identifies chromosome segregation proteins.

    Science.gov (United States)

    Hutchins, James R A; Toyoda, Yusuke; Hegemann, Björn; Poser, Ina; Hériché, Jean-Karim; Sykora, Martina M; Augsburg, Martina; Hudecz, Otto; Buschhorn, Bettina A; Bulkescher, Jutta; Conrad, Christian; Comartin, David; Schleiffer, Alexander; Sarov, Mihail; Pozniakovsky, Andrei; Slabicki, Mikolaj Michal; Schloissnig, Siegfried; Steinmacher, Ines; Leuschner, Marit; Ssykor, Andrea; Lawo, Steffen; Pelletier, Laurence; Stark, Holger; Nasmyth, Kim; Ellenberg, Jan; Durbin, Richard; Buchholz, Frank; Mechtler, Karl; Hyman, Anthony A; Peters, Jan-Michael

    2010-04-30

    Chromosome segregation and cell division are essential, highly ordered processes that depend on numerous protein complexes. Results from recent RNA interference screens indicate that the identity and composition of these protein complexes is incompletely understood. Using gene tagging on bacterial artificial chromosomes, protein localization, and tandem-affinity purification-mass spectrometry, the MitoCheck consortium has analyzed about 100 human protein complexes, many of which had not or had only incompletely been characterized. This work has led to the discovery of previously unknown, evolutionarily conserved subunits of the anaphase-promoting complex and the gamma-tubulin ring complex--large complexes that are essential for spindle assembly and chromosome segregation. The approaches we describe here are generally applicable to high-throughput follow-up analyses of phenotypic screens in mammalian cells.

  5. Prehospital Trauma Triage Decision-making: A Model of What Happens between the 9-1-1 Call and the Hospital.

    Science.gov (United States)

    Jones, Courtney Marie Cora; Cushman, Jeremy T; Lerner, E Brooke; Fisher, Susan G; Seplaki, Christopher L; Veazie, Peter J; Wasserman, Erin B; Dozier, Ann; Shah, Manish N

    2016-01-01

    We describe the decision-making process used by emergency medical services (EMS) providers in order to understand how 1) injured patients are evaluated in the prehospital setting; 2) field triage criteria are applied in-practice; and 3) selection of a destination hospital is determined. We conducted separate focus groups with advanced and basic life support providers from rural and urban/suburban regions. Four exploratory focus groups were conducted to identify overarching themes and five additional confirmatory focus groups were conducted to verify initial focus group findings and provide additional detail regarding trauma triage decision-making and application of field triage criteria. All focus groups were conducted by a public health researcher with formal training in qualitative research. A standardized question guide was used to facilitate discussion at all focus groups. All focus groups were audio-recorded and transcribed. Responses were coded and categorized into larger domains to describe how EMS providers approach trauma triage and apply the Field Triage Decision Scheme. We conducted 9 focus groups with 50 EMS providers. Participants highlighted that trauma triage is complex and there is often limited time to make destination decisions. Four overarching domains were identified within the context of trauma triage decision-making: 1) initial assessment; 2) importance of speed versus accuracy; 3) usability of current field triage criteria; and 4) consideration of patient and emergency care system-level factors. Field triage is a complex decision-making process which involves consideration of many patient and system-level factors. The decision model presented in this study suggests that EMS providers place significant emphasis on speed of decisions, relying on initial impressions and immediately observable information, rather than precise measurement of vital signs or systematic application of field triage criteria.

  6. Structure of a human rhinovirus complexed with its receptor molecule.

    OpenAIRE

    1993-01-01

    Cryoelectron microscopy has been used to determine the structure of a virus when complexed with its glycoprotein cellular receptor. Human rhinovirus 16 complexed with the two amino-terminal, immunoglobulin-like domains of the intercellular adhesion molecule 1 shows that the intercellular adhesion molecule 1 binds into the 12-A deep "canyon" on the viral surface. This result confirms the prediction that the viral-receptor attachment site lies in a cavity inaccessible to the host's antibodies. ...

  7. Copper(II) complexes encapsulated in human red blood cells.

    Science.gov (United States)

    Bonomo, R P; De Flora, A; Rizzarelli, E; Santoro, A M; Tabbí, G; Tonetti, M

    1995-09-01

    Copper(II) complexes were encapsulated in human red blood cells in order to test their possible use as antioxidant drugs by virtue of their labile character. ESR spectroscopy was used to verify whether encapsulation in red blood cells leads to the modification of such complexes. With copper(II) complexes bound to dipeptides or tripeptides, an interaction with hemoglobin was found to be present, the hemoglobin having a strong coordinative site formed by four nitrogen donor atoms. Instead, with copper(II) complexes with TAD or PheANN3, which have the greatest stability. ESR spectra always showed the original species. Only the copper(II) complex with GHL gave rise to a complicated behavior, which contained signals from iron(III) species probably coming from oxidative processes. Encapsulation of all copper(II) complexes in erythrocytes caused a slight oxidative stress, compared to the unloaded and to the native cells. However, no significant differences were observed in the major metabolic properties (GSH, glycolytic rate, hexose monophosphate shunt, Ca(2+)-ATPase) of erythrocytes loaded with different copper(II) complexes, with the exception of methemoglobin levels, which were markedly increased in the case of [Cu(GHL)H-1] compared to [Cu(TAD)]. This latter finding suggests that methemoglobin formation can be affected by the type of complex used for encapsulation, depending on the direct interaction of the copper(II) complex with hemoglobin.

  8. Peak Oil and the Everyday Complexity of Human Progress Narratives

    Directory of Open Access Journals (Sweden)

    John C. Pruit

    2012-11-01

    Full Text Available The “big” story of human progress has polarizing tendencies featuring the binary options of progress or decline. I consider human progress narratives in the context of everyday life. Analysis of the “little” stories from two narrative environments focusing on peak oil offers a more complex picture of the meaning and contours of the narrative. I consider the impact of differential blog site commitments to peak oil perspectives and identify five narrative types culled from two narrative dimensions. I argue that the lived experience complicates human progress narratives, which is no longer an either/or proposition.

  9. In situ structural analysis of the human nuclear pore complex.

    Science.gov (United States)

    von Appen, Alexander; Kosinski, Jan; Sparks, Lenore; Ori, Alessandro; DiGuilio, Amanda L; Vollmer, Benjamin; Mackmull, Marie-Therese; Banterle, Niccolo; Parca, Luca; Kastritis, Panagiotis; Buczak, Katarzyna; Mosalaganti, Shyamal; Hagen, Wim; Andres-Pons, Amparo; Lemke, Edward A; Bork, Peer; Antonin, Wolfram; Glavy, Joseph S; Bui, Khanh Huy; Beck, Martin

    2015-10-01

    Nuclear pore complexes are fundamental components of all eukaryotic cells that mediate nucleocytoplasmic exchange. Determining their 110-megadalton structure imposes a formidable challenge and requires in situ structural biology approaches. Of approximately 30 nucleoporins (Nups), 15 are structured and form the Y and inner-ring complexes. These two major scaffolding modules assemble in multiple copies into an eight-fold rotationally symmetric structure that fuses the inner and outer nuclear membranes to form a central channel of ~60 nm in diameter. The scaffold is decorated with transport-channel Nups that often contain phenylalanine-repeat sequences and mediate the interaction with cargo complexes. Although the architectural arrangement of parts of the Y complex has been elucidated, it is unclear how exactly it oligomerizes in situ. Here we combine cryo-electron tomography with mass spectrometry, biochemical analysis, perturbation experiments and structural modelling to generate, to our knowledge, the most comprehensive architectural model of the human nuclear pore complex to date. Our data suggest previously unknown protein interfaces across Y complexes and to inner-ring complex members. We show that the transport-channel Nup358 (also known as Ranbp2) has a previously unanticipated role in Y-complex oligomerization. Our findings blur the established boundaries between scaffold and transport-channel Nups. We conclude that, similar to coated vesicles, several copies of the same structural building block--although compositionally identical--engage in different local sets of interactions and conformations.

  10. Complex human activities recognition using interval temporal syntactic model

    Institute of Scientific and Technical Information of China (English)

    夏利民; 韩芬; 王军

    2016-01-01

    A novel method based on interval temporal syntactic model was proposed to recognize human activities in video flow. The method is composed of two parts: feature extract and activities recognition. Trajectory shape descriptor, speeded up robust features (SURF) and histograms of optical flow (HOF) were proposed to represent human activities, which provide more exhaustive information to describe human activities on shape, structure and motion. In the process of recognition, a probabilistic latent semantic analysis model (PLSA) was used to recognize sample activities at the first step. Then, an interval temporal syntactic model, which combines the syntactic model with the interval algebra to model the temporal dependencies of activities explicitly, was introduced to recognize the complex activities with a time relationship. Experiments results show the effectiveness of the proposed method in comparison with other state-of-the-art methods on the public databases for the recognition of complex activities.

  11. Emergence of dynamical complexity related to human heart rate variability

    Science.gov (United States)

    Chang, Mei-Chu; Peng, C.-K.; Stanley, H. Eugene

    2014-12-01

    We apply the refined composite multiscale entropy (MSE) method to a one-dimensional directed small-world network composed of nodes whose states are binary and whose dynamics obey the majority rule. We find that the resulting fluctuating signal becomes dynamically complex. This dynamical complexity is caused (i) by the presence of both short-range connections and long-range shortcuts and (ii) by how well the system can adapt to the noisy environment. By tuning the adaptability of the environment and the long-range shortcuts we can increase or decrease the dynamical complexity, thereby modeling trends found in the MSE of a healthy human heart rate in different physiological states. When the shortcut and adaptability values increase, the complexity in the system dynamics becomes uncorrelated.

  12. Dynamic analysis of the human brain with complex cerebral sulci.

    Science.gov (United States)

    Tseng, Jung-Ge; Huang, Bo-Wun; Ou, Yi-Wen; Yen, Ke-Tien; Wu, Yi-Te

    2016-07-03

    The brain is one of the most vulnerable organs inside the human body. Head accidents often appear in daily life and are easy to cause different level of brain damage inside the skull. Once the brain suffered intense locomotive impact, external injuries, falls, or other accidents, it will result in different degrees of concussion. This study employs finite element analysis to compare the dynamic characteristics between the geometric models of an assumed simple brain tissue and a brain tissue with complex cerebral sulci. It is aimed to understand the free vibration of the internal brain tissue and then to protect the brain from injury caused by external influences. Reverse engineering method is used for a Classic 5-Part Brain (C18) model produced by 3B Scientific Corporation. 3D optical scanner is employed to scan the human brain structure model with complex cerebral sulci and imported into 3D graphics software to construct a solid brain model to simulate the real complex brain tissue. Obtaining the normal mode analysis by inputting the material properties of the true human brain into finite element analysis software, and then to compare the simplified and the complex of brain models.

  13. Converging Strategies in Expression of Human Complex Retroviruses

    Directory of Open Access Journals (Sweden)

    Ilaria Cavallari

    2011-08-01

    Full Text Available The discovery of human retroviruses in the early 1980s revealed the existence of viral-encoded non-structural genes that were not evident in previously described animal retroviruses. Based on the absence or presence of these additional genes retroviruses were classified as ‘simple’ and ‘complex’, respectively. Expression of most of these extra genes is achieved through the generation of alternatively spliced mRNAs. The present review summarizes the genetic organization and expression strategies of human complex retroviruses and highlights the converging mechanisms controlling their life cycles.

  14. Human mitochondrial complex I assembles through the combination of evolutionary conserved modules: a framework to interpret complex I deficiencies.

    NARCIS (Netherlands)

    Ugalde, C.; Vogel, R.O.; Huijbens, R.J.F.; Heuvel, L.P.W.J. van den; Smeitink, J.A.M.; Nijtmans, L.G.J.

    2004-01-01

    With 46 subunits, human mitochondrial complex I is the largest enzyme of the oxidative phosphorylation system. We have studied the assembly of complex I in cultured human cells. This will provide essential information about the nature of complex I deficiencies and will enhance our understanding of

  15. Long Non-Coding RNAs and Complex Human Diseases

    Directory of Open Access Journals (Sweden)

    Changning Liu

    2013-09-01

    Full Text Available Long non-coding RNAs (lncRNAs are a heterogeneous class of RNAs that are generally defined as non-protein-coding transcripts longer than 200 nucleotides. Recently, an increasing number of studies have shown that lncRNAs can be involved in various critical biological processes, such as chromatin remodeling, gene transcription, and protein transport and trafficking. Moreover, lncRNAs are dysregulated in a number of complex human diseases, including coronary artery diseases, autoimmune diseases, neurological disorders, and various cancers, which indicates their important roles in these diseases. Here, we reviewed the current understanding of lncRNAs, including their definition and subclassification, regulatory functions, and potential roles in different types of complex human diseases.

  16. Mitochondrial network complexity and pathological decrease in complex I activity are tightly correlated in isolated human complex I deficiency.

    Science.gov (United States)

    Koopman, Werner J H; Visch, Henk-Jan; Verkaart, Sjoerd; van den Heuvel, Lambertus W P J; Smeitink, Jan A M; Willems, Peter H G M

    2005-10-01

    Complex I (NADH:ubiquinone oxidoreductase) is the largest multisubunit assembly of the oxidative phosphorylation system, and its malfunction is associated with a wide variety of clinical syndromes ranging from highly progressive, often early lethal, encephalopathies to neurodegenerative disorders in adult life. The changes in mitochondrial structure and function that are at the basis of the clinical symptoms are poorly understood. Video-rate confocal microscopy of cells pulse-loaded with mitochondria-specific rhodamine 123 followed by automated analysis of form factor (combined measure of length and degree of branching), aspect ratio (measure of length), and number of revealed marked differences between primary cultures of skin fibroblasts from 13 patients with an isolated complex I deficiency. These differences were independent of the affected subunit, but plotting of the activity of complex I, normalized to that of complex IV, against the ratio of either form factor or aspect ratio to number revealed a linear relationship. Relatively small reductions in activity appeared to be associated with an increase in form factor and never with a decrease in number, whereas relatively large reductions occurred in association with a decrease in form factor and/or an increase in number. These results demonstrate that complex I activity and mitochondrial structure are tightly coupled in human isolated complex I deficiency. To further prove the relationship between aberrations in mitochondrial morphology and pathological condition, fibroblasts from two patients with a different mutation but a highly fragmented mitochondrial phenotype were fused. Full restoration of the mitochondrial network demonstrated that this change in mitochondrial morphology was indeed associated with human complex I deficiency.

  17. Complex-tone pitch representations in the human auditory system

    DEFF Research Database (Denmark)

    Bianchi, Federica

    ) listeners and the effect of musical training for pitch discrimination of complex tones with resolved and unresolved harmonics. Concerning the first topic, behavioral and modeling results in listeners with sensorineural hearing loss (SNHL) indicated that temporal envelope cues of complex tones...... for the individual pitch-discrimination abilities, the musically trained listeners still allocated lower processing effort than did the non-musicians to perform the task at the same performance level. This finding suggests an enhanced pitch representation along the auditory system in musicians, possibly as a result......Understanding how the human auditory system processes the physical properties of an acoustical stimulus to give rise to a pitch percept is a fascinating aspect of hearing research. Since most natural sounds are harmonic complex tones, this work focused on the nature of pitch-relevant cues...

  18. How to Save Human Lives with Complexity Science

    CERN Document Server

    Helbing, Dirk; Chadefaux, Thomas; Donnay, Karsten; Blanke, Ulf; Woolley-Meza, Olivia; Moussaid, Mehdi; Johansson, Anders; Krause, Jens; Schutte, Sebastian; Perc, Matjaz

    2014-01-01

    We discuss models and data of crowd disasters, crime, terrorism, war and disease spreading to show that conventional recipes, such as deterrence strategies, are not effective and sufficient to contain them. The failure of many conventional approaches results from their neglection of feedback loops, instabilities and/or cascade effects, due to which equilibrium models do often not provide a good picture of the actual system behavior. However, the complex and often counter-intuitive behavior of social systems and their macro-level collective dynamics can be understood by means of complexity science, which enables one to address the aforementioned problems more successfully. We highlight that a suitable system design and management can help to stop undesirable cascade effects and to enable favorable kinds of self-organization in the system. In such a way, complexity science can help to save human lives.

  19. Pedigree models for complex human traits involving the mitochrondrial genome

    Energy Technology Data Exchange (ETDEWEB)

    Schork, N.J.; Guo, S.W. (Univ. of Michigan, Ann Arbor, MI (United States))

    1993-12-01

    Recent biochemical and molecular-genetic discoveries concerning variations in human mtDNA have suggested a role for mtDNA mutations in a number of human traits and disorders. Although the importance of these discoveries cannot be emphasized enough, the complex natures of mitochondrial biogenesis, mutant mtDNA phenotype expression, and the maternal inheritance pattern exhibited by mtDNA transmission make it difficult to develop models that can be used routinely in pedigree analyses to quantify and test hypotheses about the role of mtDNA in the expression of a trait. In the present paper, the authors describe complexities inherent in mitochondrial biogenesis and genetic transmission and show how these complexities can be incorporated into appropriate mathematical models. The authors offer a variety of likelihood-based models which account for the complexities discussed. The derivation of the models is meant to stimulate the construction of statistical tests for putative mtDNA contribution to a trait. Results of simulation studies which make use of the proposed models are described. The results of the simulation studies suggest that, although pedigree models of mtDNA effects can be reliable, success in mapping chromosomal determinants of a trait does not preclude the possibility that mtDNA determinants exist for the trait as well. Shortcomings inherent in the proposed models are described in an effort to expose areas in need of additional research. 58 refs., 5 figs., 2 tabs.

  20. Human copy number variation and complex genetic disease.

    Science.gov (United States)

    Girirajan, Santhosh; Campbell, Catarina D; Eichler, Evan E

    2011-01-01

    Copy number variants (CNVs) play an important role in human disease and population diversity. Advancements in technology have allowed for the analysis of CNVs in thousands of individuals with disease in addition to thousands of controls. These studies have identified rare CNVs associated with neuropsychiatric diseases such as autism, schizophrenia, and intellectual disability. In addition, copy number polymorphisms (CNPs) are present at higher frequencies in the population, show high diversity in copy number, sequence, and structure, and have been associated with multiple phenotypes, primarily related to immune or environmental response. However, the landscape of copy number variation still remains largely unexplored, especially for smaller CNVs and those embedded within complex regions of the human genome. An integrated approach including characterization of single nucleotide variants and CNVs in a large number of individuals with disease and normal genomes holds the promise of thoroughly elucidating the genetic basis of human disease and diversity.

  1. Environmental layout complexity affects neural activity during navigation in humans.

    Science.gov (United States)

    Slone, Edward; Burles, Ford; Iaria, Giuseppe

    2016-05-01

    Navigating large-scale surroundings is a fundamental ability. In humans, it is commonly assumed that navigational performance is affected by individual differences, such as age, sex, and cognitive strategies adopted for orientation. We recently showed that the layout of the environment itself also influences how well people are able to find their way within it, yet it remains unclear whether differences in environmental complexity are associated with changes in brain activity during navigation. We used functional magnetic resonance imaging to investigate how the brain responds to a change in environmental complexity by asking participants to perform a navigation task in two large-scale virtual environments that differed solely in interconnection density, a measure of complexity defined as the average number of directional choices at decision points. The results showed that navigation in the simpler, less interconnected environment was faster and more accurate relative to the complex environment, and such performance was associated with increased activity in a number of brain areas (i.e. precuneus, retrosplenial cortex, and hippocampus) known to be involved in mental imagery, navigation, and memory. These findings provide novel evidence that environmental complexity not only affects navigational behaviour, but also modulates activity in brain regions that are important for successful orientation and navigation.

  2. Human Serum Albumin Complexed with Myristate and AZT

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Lili; Yang, Feng; Chen, Liqing; Meehan, Edward J.; Huang, Mingdong (UGA); (UAH)

    2008-06-16

    3'-Azido-3'-deoxythymidine (AZT) is the first clinically effective drug for the treatment of human immunodeficiency virus infection. The drug interaction with human serum albumin (HSA) has been an important component in understanding its mechanism of action, especially in drug distribution and in drug-drug interaction on HSA in the case of multi-drug therapy. We present here crystal structures of a ternary HSA-Myr-AZT complex and a quaternary HSA-Myr-AZT-SAL complex (Myr, myristate; SAL, salicylic acid). From this study, a new drug binding subsite on HSA Sudlow site 1 was identified. The presence of fatty acid is needed for the creation of this subsite due to fatty acid induced conformational changes of HSA. Thus, the Sudlow site 1 of HSA can be divided into three non-overlapped subsites: a SAL subsite, an indomethacin subsite and an AZT subsite. Binding of a drug to HSA often influences simultaneous binding of other drugs. From the HSA-Myr-AZT-SAL complex structure, we observed the coexistence of two drugs (AZT and SAL) in Sudlow site 1 and the competition between these two drugs in subdomain IB. These results provide new structural information on HSA-drug interaction and drug-drug interaction on HSA.

  3. Proposal for analysis of human talent from complex thought

    Directory of Open Access Journals (Sweden)

    Abel Del Río Cortina

    2015-12-01

    Full Text Available In this paper, it is expose a displaying scheme of the actions of the individual in the context of the productive world*, considering a series of demonstrations framed in the learning process, this, with respect to the complexity of the human development derived from the interactions of the individual, the family, the community, the labor environment, and society in general from the perspective of volitional, cognitive, and procedural dimensions. The proposed visualization, is conceived as a relational map that includes six pillars of human interaction immersed in the above dimensions, being them, know-to be, know-to know, Know-to live, Know-to create, know-to manage, and know-to communicate, being all these reflected as a synergic structure made manifest in the know-how, from the interplay of values, emotional skills or soft skills, attitudes, knowledge, and finally, ways of proceeding. All of the above, in order to generate an approach to the relational complexity of the human talent development in society. * The productive world, in this document, is conceived as the one in which people get articulated in order to live in family, community, entrepreneurial organization, a diverse kind of institutions, and society in general.

  4. Rendezvous Integration Complexities of NASA Human Flight Vehicles

    Science.gov (United States)

    Brazzel, Jack P.; Goodman, John L.

    2009-01-01

    Propellant-optimal trajectories, relative sensors and navigation, and docking/capture mechanisms are rendezvous disciplines that receive much attention in the technical literature. However, other areas must be considered. These include absolute navigation, maneuver targeting, attitude control, power generation, software development and verification, redundancy management, thermal control, avionics integration, robotics, communications, lighting, human factors, crew timeline, procedure development, orbital debris risk mitigation, structures, plume impingement, logistics, and in some cases extravehicular activity. While current and future spaceflight programs will introduce new technologies and operations concepts, the complexity of integrating multiple systems on multiple spacecraft will remain. The systems integration task may become more difficult as increasingly complex software is used to meet current and future automation, autonomy, and robotic operation requirements.

  5. Genetics of human episodic memory: dealing with complexity.

    Science.gov (United States)

    Papassotiropoulos, Andreas; de Quervain, Dominique J-F

    2011-09-01

    Episodic memory is a polygenic behavioral trait with substantial heritability estimates. Despite its complexity, recent empirical evidence supports the notion that behavioral genetic studies of episodic memory might successfully identify trait-associated molecules and pathways. The development of high-throughput genotyping methods, of elaborated statistical analyses and of phenotypic assessment methods at the neural systems level will facilitate the reliable identification of novel memory-related genes. Importantly, a necessary crosstalk between behavioral genetic studies and investigation of causality by molecular genetic studies will ultimately pave the way towards the identification of biologically important, and hopefully druggable, genes and molecular pathways related to human episodic memory.

  6. Preeclampsia (PE is a complex illness of the human gestation

    Directory of Open Access Journals (Sweden)

    Laura Gil Urbano

    2002-12-01

    Full Text Available Preeclampsia (PE is a complex illness of the human gestation. It is responsible for a high perinatal morbimortality.It is the illness of the multiple theories; in one environmentaland genetic factors are associated to explain it. To find genes candidates to be associated with PE, two methodology types are used: association and binding studies. In this paper we presented the foundation of both studies that explain the main genes candidates to involve in the genesis of this illness,like that ones that code for the methylenetetrahydrofolatereductase, lipoprotein lipase and endothelial nitric oxidesintase, Leiden‘s V factor, angiotensinogen, HLA-G, alphatumoral necrosis factor.

  7. Understanding Complex Human Ecosystems: The Case of Ecotourism on Bonaire

    Directory of Open Access Journals (Sweden)

    Thomas Abel

    2003-12-01

    Full Text Available It is suggested that ecotourism development on the island of Bonaire can be productively understood as a perturbation of a complex human ecosystem. Inputs associated with ecotourism have fueled transformations of the island ecology and sociocultural system. The results of this study indicate that Bonaire's social and economic hierarchy is approaching a new, stable systems state following a 50-yr transition begun by government and industry that stabilized with the appearance of ecotourism development and population growth. Ecotourism can be understood to have "filled in" the middle of the production hierarchy of Bonaire. Interpreted from this perspective, population growth has completed the transformation by expanding into production niches at smaller scales in the production hierarchy. Both a consequence and a cause, ecotourism has transformed the island's social structure and demography. The theory and methods applied in this case study of interdisciplinary research in the field of human ecosystems are also presented.

  8. Human more complex than mouse at cellular level.

    Directory of Open Access Journals (Sweden)

    Alexander E Vinogradov

    Full Text Available The family of transcription factors with the C2H2 zinc finger domain is expanding in the evolution of vertebrates, reaching its highest numbers in the mammals. The question arises: whether an increased amount of these transcription factors is related to embryogenesis, nervous system, pathology or more of them are expressed in individual cells? Among mammals, the primates have a more complex anatomical structure than the rodents (e.g., brain. In this work, I show that a greater number of C2H2-ZF genes are expressed in the human cells than in the mouse cells. The effect is especially pronounced for C2H2-ZF genes accompanied with the KRAB domain. The relative difference between the numbers of C2H2-ZF(-KRAB genes in the human and mouse cellular transcriptomes even exceeds their difference in the genomes (i.e. a greater subset of existing in the genome genes is expressed in the human cellular transcriptomes compared to the mouse transcriptomes. The evolutionary turnover of C2H2-ZF(-KRAB genes acts in the direction of the revealed phenomenon, i.e. gene duplication and loss enhances the difference in the relative number of C2H2-ZF(-KRAB genes between human and mouse cellular transcriptomes. A higher amount of these genes is expressed in the brain and embryonic cells (compared with other tissues, whereas a lower amount--in the cancer cells. It is specifically the C2H2-ZF transcription factors whose repertoire is poorer in the cancer and richer in the brain (other transcription factors taken together do not show this trend. These facts suggest that increase of anatomical complexity is accompanied by a more complex intracellular regulation involving these transcription factors. Malignization is associated with simplification of this regulation. These results agree with the known fact that human cells are more resistant to oncogenic transformation than mouse cells. The list of C2H2-ZF genes whose suppression might be involved in malignization is provided.

  9. Complexity of serrated sutures of a human skull

    Directory of Open Access Journals (Sweden)

    Kochenkova О.V.

    2011-09-01

    Full Text Available Objective: to reveal the variability mechanism of complexity of serrated sutures of a human skull in the correlation with cranial form. Materials and methods. Researches of 253 arches of male and female skulls of patients at the age of 1 day-105 years without signs of cranial trauma or skeletal systemic diseases with absence of morphological signs of increase of intracranial pressure. Minimal (Min and maximal (Max values, average arithmetic (M, a mistake of average arithmetic (m have been studied. For definition of reliability of average size difference parametrical and non-parametric statistical criteria were used: parametrical criterion (t-criterion of Student applied for parameters submitting to the law of normal distribution (Lakin G. R, 1990. Distinctions of average arithmetic size were considered statistically authentic from 95% (p<0,05 a level of correct judgement (Plokhinskiy N.A., 1970. Results. On the surface of the arch lambdoid and coronal sutures in male skulls and lambdoid and sagittal sutures in female were found out to be of the greatest degree of complexity. Conclusion. The increase of complexity of sutures has been observed in children and adolescents; the directed asymmetry of sutures form is absent

  10. Synchronization in human musical rhythms and mutually interacting complex systems.

    Science.gov (United States)

    Hennig, Holger

    2014-09-09

    Though the music produced by an ensemble is influenced by multiple factors, including musical genre, musician skill, and individual interpretation, rhythmic synchronization is at the foundation of musical interaction. Here, we study the statistical nature of the mutual interaction between two humans synchronizing rhythms. We find that the interbeat intervals of both laypeople and professional musicians exhibit scale-free (power law) cross-correlations. Surprisingly, the next beat to be played by one person is dependent on the entire history of the other person's interbeat intervals on timescales up to several minutes. To understand this finding, we propose a general stochastic model for mutually interacting complex systems, which suggests a physiologically motivated explanation for the occurrence of scale-free cross-correlations. We show that the observed long-term memory phenomenon in rhythmic synchronization can be imitated by fractal coupling of separately recorded or synthesized audio tracks and thus applied in electronic music. Though this study provides an understanding of fundamental characteristics of timing and synchronization at the interbrain level, the mutually interacting complex systems model may also be applied to study the dynamics of other complex systems where scale-free cross-correlations have been observed, including econophysics, physiological time series, and collective behavior of animal flocks.

  11. Human serum albumin complexes with chlorophyll and chlorophyllin.

    Science.gov (United States)

    Ouameur, A Ahmed; Marty, R; Tajmir-Riahi, H A

    2005-02-15

    Porphyrins and their metal derivatives are strong protein binders. Some of these compounds have been used for radiation sensitization therapy of cancer and are targeted to interact with cellular DNA and protein. The presence of several high-affinity binding sites on human serum albumin (HSA) makes it possible target for many organic and inorganic molecules. Chlorophyll a and chlorophyllin (a food-grade derivative of chlorophyll), the ubiquitous green plant pigment widely consumed by humans, are potent inhibitors of experimental carcinogenesis and interact with protein and DNA in many ways. This study was designed to examine the interaction of HSA with chlorophyll (Chl) and chlorophyllin (Chln) in aqueous solution at physiological conditions. Fourier transform infrared, UV-visible, and CD spectroscopic methods were used to determine the pigment binding mode, the binding constant, and the effects of porphyrin complexation on protein secondary structure. Spectroscopic results showed that chlorophyll and chlorophyllin are located along the polypeptide chains with no specific interaction. Stronger protein association was observed for Chl than for Chln, with overall binding constants of K(Chl) = 2.9 x 10(4)M(-1) and K(Chln) = 7.0 x 10(3)M(-1). The protein conformation was altered (infrared data) with reduction of alpha-helix from 55% (free HSA) to 41-40% and increase of beta-structure from 22% (free HSA) to 29-35% in the pigment-protein complexes. Using the CDSSTR program (CD data) also showed major reduction of alpha-helix from 66% (free HSA) to 58 and 55% upon complexation with Chl and Chln, respectively.

  12. The complexity of human walking: a knee osteoarthritis study.

    Directory of Open Access Journals (Sweden)

    Margarita Kotti

    Full Text Available This study proposes a framework for deconstructing complex walking patterns to create a simple principal component space before checking whether the projection to this space is suitable for identifying changes from the normality. We focus on knee osteoarthritis, the most common knee joint disease and the second leading cause of disability. Knee osteoarthritis affects over 250 million people worldwide. The motivation for projecting the highly dimensional movements to a lower dimensional and simpler space is our belief that motor behaviour can be understood by identifying a simplicity via projection to a low principal component space, which may reflect upon the underlying mechanism. To study this, we recruited 180 subjects, 47 of which reported that they had knee osteoarthritis. They were asked to walk several times along a walkway equipped with two force plates that capture their ground reaction forces along 3 axes, namely vertical, anterior-posterior, and medio-lateral, at 1000 Hz. Data when the subject does not clearly strike the force plate were excluded, leaving 1-3 gait cycles per subject. To examine the complexity of human walking, we applied dimensionality reduction via Probabilistic Principal Component Analysis. The first principal component explains 34% of the variance in the data, whereas over 80% of the variance is explained by 8 principal components or more. This proves the complexity of the underlying structure of the ground reaction forces. To examine if our musculoskeletal system generates movements that are distinguishable between normal and pathological subjects in a low dimensional principal component space, we applied a Bayes classifier. For the tested cross-validated, subject-independent experimental protocol, the classification accuracy equals 82.62%. Also, a novel complexity measure is proposed, which can be used as an objective index to facilitate clinical decision making. This measure proves that knee osteoarthritis

  13. The complexity of human walking: a knee osteoarthritis study.

    Science.gov (United States)

    Kotti, Margarita; Duffell, Lynsey D; Faisal, Aldo A; McGregor, Alison H

    2014-01-01

    This study proposes a framework for deconstructing complex walking patterns to create a simple principal component space before checking whether the projection to this space is suitable for identifying changes from the normality. We focus on knee osteoarthritis, the most common knee joint disease and the second leading cause of disability. Knee osteoarthritis affects over 250 million people worldwide. The motivation for projecting the highly dimensional movements to a lower dimensional and simpler space is our belief that motor behaviour can be understood by identifying a simplicity via projection to a low principal component space, which may reflect upon the underlying mechanism. To study this, we recruited 180 subjects, 47 of which reported that they had knee osteoarthritis. They were asked to walk several times along a walkway equipped with two force plates that capture their ground reaction forces along 3 axes, namely vertical, anterior-posterior, and medio-lateral, at 1000 Hz. Data when the subject does not clearly strike the force plate were excluded, leaving 1-3 gait cycles per subject. To examine the complexity of human walking, we applied dimensionality reduction via Probabilistic Principal Component Analysis. The first principal component explains 34% of the variance in the data, whereas over 80% of the variance is explained by 8 principal components or more. This proves the complexity of the underlying structure of the ground reaction forces. To examine if our musculoskeletal system generates movements that are distinguishable between normal and pathological subjects in a low dimensional principal component space, we applied a Bayes classifier. For the tested cross-validated, subject-independent experimental protocol, the classification accuracy equals 82.62%. Also, a novel complexity measure is proposed, which can be used as an objective index to facilitate clinical decision making. This measure proves that knee osteoarthritis subjects exhibit more

  14. The emergence of complex patterns in online human communication

    CERN Document Server

    Mathiesen, Joachim; Jensen, Mogens H

    2012-01-01

    Social media have become essential conduits in the worldwide exchange of ideas, opinions and consumer marketing. Complex networks are important tools for analyzing the information flow in many aspects of nature and human society. Here, we introduce a method based on networks and social media to gauge how ideas, opinions and new trends impact society. We show that correlations between different international brands, nouns or US major cities follow a universal scale free distribution. The correlations indicate a self-organizing dynamics in large social organizations where the exchange of information between individuals is highly volatile. Our method provides new fundamental insight on the propagation of opinions and the emergence of trends in online communities.

  15. Forward-time simulations of human populations with complex diseases.

    Directory of Open Access Journals (Sweden)

    Bo Peng

    2007-03-01

    Full Text Available Due to the increasing power of personal computers, as well as the availability of flexible forward-time simulation programs like simuPOP, it is now possible to simulate the evolution of complex human diseases using a forward-time approach. This approach is potentially more powerful than the coalescent approach since it allows simulations of more than one disease susceptibility locus using almost arbitrary genetic and demographic models. However, the application of such simulations has been deterred by the lack of a suitable simulation framework. For example, it is not clear when and how to introduce disease mutants-especially those under purifying selection-to an evolving population, and how to control the disease allele frequencies at the last generation. In this paper, we introduce a forward-time simulation framework that allows us to generate large multi-generation populations with complex diseases caused by unlinked disease susceptibility loci, according to specified demographic and evolutionary properties. Unrelated individuals, small or large pedigrees can be drawn from the resulting population and provide samples for a wide range of study designs and ascertainment methods. We demonstrate our simulation framework using three examples that map genes associated with affection status, a quantitative trait, and the age of onset of a hypothetical cancer, respectively. Nonadditive fitness models, population structure, and gene-gene interactions are simulated. Case-control, sibpair, and large pedigree samples are drawn from the simulated populations and are examined by a variety of gene-mapping methods.

  16. Algorithmic complexity of growth hormone release in humans.

    Science.gov (United States)

    Prank, K; Wagner, M; Brabant, G

    1997-01-01

    Most hormones are secreted in an pulsatile rather than in a constant manner. This temporal pattern of pulsatile hormone release plays an important role in the regulation of cellular function and structure. In healthy humans growth hormone (GH) secretion is characterized by distinct pulses whereas patients bearing a GH producing tumor accompanied with excessive secretion (acromegaly) exhibit a highly irregular pattern of GH release. It has been hypothesized that this highly disorderly pattern of GH release in acromegaly arises from random events in the GH-producing tumor under decreased normal control of GH secretion. Using a context-free grammar complexity measure (algorithmic complexity) in conjunction with random surrogate data sets we demonstrate that the temporal pattern of GH release in acromegaly is not significantly different from a variety of stochastic processes. In contrast, normal subjects clearly exhibit deterministic structure in their temporal patterns of GH secretion. Our results support the hypothesis that GH release in acromegaly is due to random events in the GH-producing tumorous cells which might become independent from hypothalamic regulation.

  17. Algorithmic complexity of growth hormone release in humans

    Energy Technology Data Exchange (ETDEWEB)

    Prank, K.; Wagner, M.; Brabant, G. [Medical School Hannover (Germany)

    1996-12-31

    Most hormones are secreted in an pulsatile rather than in a constant manner. This temporal pattern of pulsatile hormone release plays an important role in the regulation of cellular function and structure. In healthy humans growth hormone (GH) secretion is characterized by distinct pulses whereas patients bearing a GH producing tumor accompanied with excessive secretion (acromegaly) exhibit a highly irregular pattern of GH release. It has been hypothesized that this highly disorderly pattern of GH release in acromegaly arises from random events in the GH-producing tumor under decreased normal control of GH secretion. Using a context-free grammar complexity measure (algorithmic complexity) in conjunction with random surrogate data sets we demonstrate that the temporal pattern of GH release in acromegaly is not significantly different from a variety of stochastic processes. In contrast, normal subjects clearly exhibit deterministic structure in their temporal patterns of GH secretion. Our results support the hypothesis that GH release in acromegaly is due to random events in the GH-producing tumorous cells which might become independent from hypothalamic regulation. 17 refs., 1 fig., 2 tabs.

  18. Complexity of human and ecosystem interactions in an agricultural landscape

    Science.gov (United States)

    Coupe, Richard H.; Barlow, Jeannie R.; Capel, Paul D.

    2012-01-01

    The complexity of human interaction in the commercial agricultural landscape and the resulting impacts on the ecosystem services of water quality and quantity is largely ignored by the current agricultural paradigm that maximizes crop production over other ecosystem services. Three examples at different spatial scales (local, regional, and global) are presented where human and ecosystem interactions in a commercial agricultural landscape adversely affect water quality and quantity in unintended ways in the Delta of northwestern Mississippi. In the first example, little to no regulation of groundwater use for irrigation has caused declines in groundwater levels resulting in loss of baseflow to streams and threatening future water supply. In the second example, federal policy which subsidizes corn for biofuel production has encouraged many producers to switch from cotton to corn, which requires more nutrients and water, counter to national efforts to reduce nutrient loads to the Gulf of Mexico and exacerbating groundwater level declines. The third example is the wholesale adoption of a system for weed control that relies on a single chemical, initially providing many benefits and ultimately leading to the widespread occurrence of glyphosate and its degradates in Delta streams and necessitating higher application rates of glyphosate as well as the use of other herbicides due to increasing weed resistance. Although these examples are specific to the Mississippi Delta, analogous situations exist throughout the world and point to the need for change in how we grow our food, fuel, and fiber, and manage our soil and water resources.

  19. Perception of complex motion in humans and pigeons (Columba livia).

    Science.gov (United States)

    Nankoo, Jean-François; Madan, Christopher R; Spetch, Marcia L; Wylie, Douglas R

    2014-06-01

    In the primate visual system, local motion signals are pooled to create a global motion percept. Like primates, many birds are highly dependent on vision for their survival, yet relatively little is known about motion perception in birds. We used random-dot stimuli to investigate pigeons' ability to detect complex motion (radial, rotation, and spiral) compared to humans. Our human participants had a significantly lower threshold for rotational and radial motion when compared to spiral motion. The data from the pigeons, however, showed that the pigeons were most sensitive to rotational motion and least sensitive to radial motion, while sensitivity for spiral motion was intermediate. We followed up the pigeon results with an investigation of the effect of display aperture shape for rotational motion and velocity gradient for radial motion. We found no effect of shape of the aperture on thresholds, but did observe that radial motion containing accelerating dots improved thresholds. However, this improvement did not reach the thresholds levels observed for rotational motion. In sum, our experiments demonstrate that the pooling mechanism in the pigeon motion system is most efficient for rotation.

  20. Discrimination of complex human behavior by pigeons (Columba livia and humans.

    Directory of Open Access Journals (Sweden)

    Muhammad A J Qadri

    Full Text Available The cognitive and neural mechanisms for recognizing and categorizing behavior are not well understood in non-human animals. In the current experiments, pigeons and humans learned to categorize two non-repeating, complex human behaviors ("martial arts" vs. "Indian dance". Using multiple video exemplars of a digital human model, pigeons discriminated these behaviors in a go/no-go task and humans in a choice task. Experiment 1 found that pigeons already experienced with discriminating the locomotive actions of digital animals acquired the discrimination more rapidly when action information was available than when only pose information was available. Experiments 2 and 3 found this same dynamic superiority effect with naïve pigeons and human participants. Both species used the same combination of immediately available static pose information and more slowly perceived dynamic action cues to discriminate the behavioral categories. Theories based on generalized visual mechanisms, as opposed to embodied, species-specific action networks, offer a parsimonious account of how these different animals recognize behavior across and within species.

  1. Reducing sample complexity of polyclonal human autoantibodies by chromatofocusing.

    Science.gov (United States)

    Hagemann, Sascha; Faude, Alexander; Rabenstein, Monika; Balzer-Geldsetzer, Monika; Nölker, Carmen; Bacher, Michael; Dodel, Richard

    2010-08-15

    Chromatofocusing was performed in order to separate a polyclonal antigen-specific mixture of human immunoglobulins (IgGs) that would then allow for further analyses of as few different IgGs as possible. Because polyclonal IgGs only differ by amino acid sequence and possible post-translational modifications but not by molecular weight, we chose chromatofocusing for protein separation by different isoelectric points. We isolated antigen-specific IgGs from commercially available intravenous immunoglobulins (IVIG) using a combination of affinity- and size exclusion-chromatography and in order to reduce the complexity of the starting material IVIG was then replaced by single-donor plasmapheresis material. Using two-dimensional gel electrophoresis (2-DE), we observed a clear decrease in the number of different light and heavy chains in the chromatofocusing peak as compared to the starting material. In parallel, we monitored slight problems with the selected peak in isoelectric focusing as the first dimension of 2-DE, displayed in by the less proper focusing of the spots. When we tested whether IgGs were binding to their specific antigen after chromatofocusing, we were able to show that they were still in native conformation. In conclusion, we showed that chromatofocusing can be used as a first step in the analysis of mixtures of very similar proteins, e.g. polyclonal IgG preparations, in order to minimize the amount of different proteins in separated fractions in a reproducible way. Copyright 2010 Elsevier B.V. All rights reserved.

  2. Model of human collective decision-making in complex environments

    Science.gov (United States)

    Carbone, Giuseppe; Giannoccaro, Ilaria

    2015-12-01

    A continuous-time Markov process is proposed to analyze how a group of humans solves a complex task, consisting in the search of the optimal set of decisions on a fitness landscape. Individuals change their opinions driven by two different forces: (i) the self-interest, which pushes them to increase their own fitness values, and (ii) the social interactions, which push individuals to reduce the diversity of their opinions in order to reach consensus. Results show that the performance of the group is strongly affected by the strength of social interactions and by the level of knowledge of the individuals. Increasing the strength of social interactions improves the performance of the team. However, too strong social interactions slow down the search of the optimal solution and worsen the performance of the group. In particular, we find that the threshold value of the social interaction strength, which leads to the emergence of a superior intelligence of the group, is just the critical threshold at which the consensus among the members sets in. We also prove that a moderate level of knowledge is already enough to guarantee high performance of the group in making decisions.

  3. Complexation of insecticide chlorantraniliprole with human serum albumin: Biophysical aspects

    Energy Technology Data Exchange (ETDEWEB)

    Ding Fei [Department of Chemistry, China Agricultural University, No. 2 Yuanmingyuan Xi Road, Haidian District, Beijing 100193 (China); Liu Wei [College of Economics and Management, China Agricultural University, Beijing 100083 (China); Diao Jianxiong [Department of Chemistry, China Agricultural University, No. 2 Yuanmingyuan Xi Road, Haidian District, Beijing 100193 (China); Yin Bin [Key Laboratory of Pesticide Chemistry and Application Technology, Ministry of Agriculture, Department of Applied Chemistry, China Agricultural University, Beijing 100193 (China); Zhang Li, E-mail: zhli.work@gmail.co [Key Laboratory of Pesticide Chemistry and Application Technology, Ministry of Agriculture, Department of Applied Chemistry, China Agricultural University, Beijing 100193 (China); Sun Ying, E-mail: sunying@cau.edu.c [Department of Chemistry, China Agricultural University, No. 2 Yuanmingyuan Xi Road, Haidian District, Beijing 100193 (China)

    2011-07-15

    Chlorantraniliprole is a novel insecticide belonging to the diamide class of selective ryanodine receptor agonists. A biophysical study on the binding interaction of a novel diamide insecticide, chlorantraniliprole, with staple in vivo transporter, human serum albumin (HSA) has been investigated utilizing a combination of steady-state and time-resolved fluorescence, circular dichroism (CD), and molecular modeling methods. The interaction of chlorantraniliprole with HSA gives rise to fluorescence quenching through static mechanism, this corroborates the fluorescence lifetime outcomes that the ground state complex formation and the predominant forces in the HSA-chlorantraniliprole conjugate are van der Waals forces and hydrogen bonds, as derived from thermodynamic analysis. The definite binding site of chlorantraniliprole in HSA has been identified from the denaturation of protein, competitive ligand binding, and molecular modeling, subdomain IIIA (Sudlow's site II) was designated to possess high-affinity binding site for chlorantraniliprole. Moreover, using synchronous fluorescence, CD, and three-dimensional fluorescence we testified some degree of HSA structure unfolding upon chlorantraniliprole binding. - Highlights: {yields} Our study highlights for the first time how binding dynamics can predominate for the new diamide insecticide, chlorantraniliprole. {yields} Chlorantraniliprole is situated within subdomain IIIA, Sudlow's site II, which is the same as that of indole-benzodiazepine site. {yields} Biophysical and molecular modeling approaches are useful to resolve the ligand interaction with biomacromolecule. {yields} It serves as a protective device in binding and in inactivating potential toxic compounds to which the body is exposed.

  4. Similarities between GCS and human motor cortex: complex movement coordination

    Science.gov (United States)

    Rodríguez, Jose A.; Macias, Rosa; Molgo, Jordi; Guerra, Dailos

    2014-07-01

    The "Gran Telescopio de Canarias" (GTC1) is an optical-infrared 10-meter segmented mirror telescope at the ORM observatory in Canary Islands (Spain). The GTC control system (GCS), the brain of the telescope, is is a distributed object & component oriented system based on RT-CORBA and it is responsible for the management and operation of the telescope, including its instrumentation. On the other hand, the Human motor cortex (HMC) is a region of the cerebrum responsible for the coordination of planning, control, and executing voluntary movements. If we analyze both systems, as far as the movement control of their mechanisms and body parts is concerned, we can find extraordinary similarities in their architectures. Both are structured in layers, and their functionalities are comparable from the movement conception until the movement action itself: In the GCS we can enumerate the Sequencer high level components, the Coordination libraries, the Control Kit library and the Device Driver library as the subsystems involved in the telescope movement control. If we look at the motor cortex, we can also enumerate the primary motor cortex, the secondary motor cortices, which include the posterior parietal cortex, the premotor cortex, and the supplementary motor area (SMA), the motor units, the sensory organs and the basal ganglia. From all these components/areas we will analyze in depth the several subcortical regions, of the the motor cortex, that are involved in organizing motor programs for complex movements and the GCS coordination framework, which is composed by a set of classes that allow to the high level components to transparently control a group of mechanisms simultaneously.

  5. Exploring the potential relevance of human-specific genes to complex disease

    Directory of Open Access Journals (Sweden)

    Cooper David N

    2011-01-01

    Full Text Available Abstract Although human disease genes generally tend to be evolutionarily more ancient than non-disease genes, complex disease genes appear to be represented more frequently than Mendelian disease genes among genes of more recent evolutionary origin. It is therefore proposed that the analysis of human-specific genes might provide new insights into the genetics of complex disease. Cross-comparison with the Human Gene Mutation Database (http://www.hgmd.org revealed a number of examples of disease-causing and disease-associated mutations in putatively human-specific genes. A sizeable proportion of these were missense polymorphisms associated with complex disease. Since both human-specific genes and genes associated with complex disease have often experienced particularly rapid rates of evolutionary change, either due to weaker purifying selection or positive selection, it is proposed that a significant number of human-specific genes may play a role in complex disease.

  6. Information-Theoretic Measures Predict the Human Judgment of Rhythm Complexity.

    Science.gov (United States)

    de Fleurian, Remi; Blackwell, Tim; Ben-Tal, Oded; Müllensiefen, Daniel

    2017-04-01

    To formalize the human judgment of rhythm complexity, we used five measures from information theory and algorithmic complexity to measure the complexity of 48 artificially generated rhythmic sequences. We compared these measurements to human prediction accuracy and easiness judgments obtained from a listening experiment, in which 32 participants guessed the last beat of each sequence. We also investigated the modulating effects of musical expertise and general pattern identification ability. Entropy rate and Kolmogorov complexity were correlated with prediction accuracy, and highly correlated with easiness judgments. A logistic regression showed main effects of musical training, entropy rate, and Kolmogorov complexity, and an interaction between musical training and both entropy rate and Kolmogorov complexity. These results indicate that information-theoretic concepts capture some salient features of the human judgment of rhythm complexity, and they confirm the influence of musical expertise on complexity judgments. Copyright © 2016 Cognitive Science Society, Inc.

  7. Worms under stress: C. elegans stress response and its relevance to complex human disease and aging

    NARCIS (Netherlands)

    Rodriguez Sanchez, M.; Snoek, L.B.; Bono, de M.; Kammenga, J.E.

    2013-01-01

    Many organisms have stress response pathways, components of which share homology with players in complex human disease pathways. Research on stress response in the nematode worm Caenorhabditis elegans has provided detailed insights into the genetic and molecular mechanisms underlying complex human d

  8. Formation mechanism and biological activity of novel thiolated human-like collagen iron complex.

    Science.gov (United States)

    Zhu, Chenhui; Liu, Lingyun; Deng, Jianjun; Ma, Xiaoxuan; Hui, Junfeng; Fan, Daidi

    2016-03-01

    To develop an iron supplement that is effectively absorbed and utilized, thiolated human-like collagen was created to improve the iron binding capacity of human-like collagen. A thiolated human-like collagen-iron complex was prepared in a phosphate buffer, and one mole of thiolated human-like collagen-iron possessed approximately 28.83 moles of iron. The characteristics of thiolated human-like collagen-iron were investigated by ultraviolet-visible absorption spectroscopy, Fourier transform infrared spectroscopy, circular dichroism, and differential scanning calorimetry. The results showed that the thiolated human-like collagen-iron complex retained the secondary structure of human-like collagen and had greater thermodynamic stability than human-like collagen, although interactions between iron ions and human-like collagen occurred during the formation of the complex. In addition, to evaluate the bioavailability of thiolated human-like collagen-iron, an in vitro Caco-2 cell model and an in vivo iron deficiency anemia mouse model were employed. The data demonstrated that the thiolated human-like collagen-iron complex exhibited greater bioavailability and was more easily utilized than FeSO4, ferric ammonium citrate, or ferrous glycinate. These results indicated that the thiolated human-like collagen-iron complex is a potential iron supplement in the biomedical field.

  9. Enhanced dynamic complexity in the human EEG during creative thinking.

    Science.gov (United States)

    Mölle, M; Marshall, L; Lutzenberger, W; Pietrowsky, R; Fehm, H L; Born, J

    1996-04-12

    This study shows that divergent thinking, considered the general process underlying creative production, can be distinguished from convergent, analytical thought based on the dimensional complexity of ongoing electroencephalographic (EEG) activity. EEG complexity over the central and posterior cortex was higher while subjects solved tasks of divergent than convergent thinking, and also higher than during mental relaxation. Over the frontal cortex, EEG complexity was comparable during divergent thinking and mental relaxation, but reduced during convergent thinking. Results indicate that the basic process underlying the generation of novel ideas expresses itself in a strong increase in the EEG's complexity, reflecting higher degrees of freedom in the competitive interactions among cortical neuron assemblies. Frontocortical EEG complexity being comparable with that during mental relaxation, speaks for a loosened attentional control during creative thinking.

  10. Human Navigational Performance in a Complex Network with Progressive Disruptions

    CERN Document Server

    Ramesh, Amitash; Iyengar, Sudarshan; Sekhar, Vinod

    2012-01-01

    The current paper is an investigation towards understanding the navigational performance of humans on a network when the "landmark" nodes are blocked. We observe that humans learn to cope up, despite the continued introduction of blockages in the network. The experiment proposed involves the task of navigating on a word network based on a puzzle called the wordmorph. We introduce blockages in the network and report an incremental improvement in performance with respect to time. We explain this phenomenon by analyzing the evolution of the knowledge in the human participants of the underlying network as more and more landmarks are removed. We hypothesize that humans learn the bare essentials to navigate unless we introduce blockages in the network which would whence enforce upon them the need to explore newer ways of navigating. We draw a parallel to human problem solving and postulate that obstacles are catalysts for humans to innovate techniques to solve a restricted variant of a familiar problem.

  11. The Impact of Evolutionary Driving Forces on Human Complex Diseases: A Population Genetics Approach

    Directory of Open Access Journals (Sweden)

    Amr T. M. Saeb

    2016-01-01

    Full Text Available Investigating the molecular evolution of human genome has paved the way to understand genetic adaptation of humans to the environmental changes and corresponding complex diseases. In this review, we discussed the historical origin of genetic diversity among human populations, the evolutionary driving forces that can affect genetic diversity among populations, and the effects of human movement into new environments and gene flow on population genetic diversity. Furthermore, we presented the role of natural selection on genetic diversity and complex diseases. Then we reviewed the disadvantageous consequences of historical selection events in modern time and their relation to the development of complex diseases. In addition, we discussed the effect of consanguinity on the incidence of complex diseases in human populations. Finally, we presented the latest information about the role of ancient genes acquired from interbreeding with ancient hominids in the development of complex diseases.

  12. Matriptase Complexes and Prostasin Complexes with HAI-1 and HAI-2 in Human Milk: Significant Proteolysis in Lactation.

    Science.gov (United States)

    Lai, Chih-Hsin; Lai, Ying-Jung J; Chou, Feng-Pai; Chang, Hsiang-Hua D; Tseng, Chun-Che; Johnson, Michael D; Wang, Jehng-Kang; Lin, Chen-Yong

    2016-01-01

    Significant proteolysis may occur during milk synthesis and secretion, as evidenced by the presence of protease-protease inhibitor complex containing the activated form of the type 2 transmembrane serine protease matriptase and the transmembrane Kunitz-type serine protease inhibitor HAI-1. In order to identify other proteolysis events that may occur during lactation, human milk was analyzed for species containing HAI-1 and HAI-2 which is closely related to HAI-1. In addition to the previously demonstrated matriptase-HAI-1 complex, HAI-1 was also detected in complex with prostasin, a glycosylphosphatidylinositol (GPI)-anchored serine protease. HAI-2 was also detected in complexes, the majority of which appear to be part of higher-order complexes, which do not bind to ionic exchange columns or immunoaffinity columns, suggesting that HAI-2 and its target proteases may be incorporated into special protein structures during lactation. The small proportion HAI-2 species that could be purified contain matriptase or prostasin. Human mammary epithelial cells are the likely cellular sources for these HAI-1 and HAI-2 complexes with matriptase and prostasin given that these protease-inhibitor complexes with the exception of prostasin-HAI-2 complex were detected in milk-derived mammary epithelial cells. The presence of these protease-inhibitor complexes in human milk provides in vivo evidence that the proteolytic activity of matriptase and prostasin are significantly elevated at least during lactation, and possibly contribute to the process of lactation, and that they are under tight control by HAI-1 and HAI-2.

  13. Matriptase Complexes and Prostasin Complexes with HAI-1 and HAI-2 in Human Milk: Significant Proteolysis in Lactation.

    Directory of Open Access Journals (Sweden)

    Chih-Hsin Lai

    Full Text Available Significant proteolysis may occur during milk synthesis and secretion, as evidenced by the presence of protease-protease inhibitor complex containing the activated form of the type 2 transmembrane serine protease matriptase and the transmembrane Kunitz-type serine protease inhibitor HAI-1. In order to identify other proteolysis events that may occur during lactation, human milk was analyzed for species containing HAI-1 and HAI-2 which is closely related to HAI-1. In addition to the previously demonstrated matriptase-HAI-1 complex, HAI-1 was also detected in complex with prostasin, a glycosylphosphatidylinositol (GPI-anchored serine protease. HAI-2 was also detected in complexes, the majority of which appear to be part of higher-order complexes, which do not bind to ionic exchange columns or immunoaffinity columns, suggesting that HAI-2 and its target proteases may be incorporated into special protein structures during lactation. The small proportion HAI-2 species that could be purified contain matriptase or prostasin. Human mammary epithelial cells are the likely cellular sources for these HAI-1 and HAI-2 complexes with matriptase and prostasin given that these protease-inhibitor complexes with the exception of prostasin-HAI-2 complex were detected in milk-derived mammary epithelial cells. The presence of these protease-inhibitor complexes in human milk provides in vivo evidence that the proteolytic activity of matriptase and prostasin are significantly elevated at least during lactation, and possibly contribute to the process of lactation, and that they are under tight control by HAI-1 and HAI-2.

  14. Mitochondrial Complex I plays an Essential Role in Human Respirasome Assembly

    OpenAIRE

    Moreno Lastres, David; Fontanesi, Flavia; García Consuegra, Inés; Martín, Miguel A.; Arenas, Joaquín; Barrientos, Antoni; Ugalde, Cristina

    2012-01-01

    The assembly and function of the mitochondrial respiratory chain (RC) involve the organization of RC enzyme complexes in supercomplexes or respirasomes through an unknown biosynthetic process. This leads to structural interdependences between RC complexes, which are highly relevant from biological and biomedical perspectives, because RC defects lead to severe human disorders. We show that in human cells, respirasome biogenesis involves a complex I assembly intermediate acting as a scaffold fo...

  15. Linguistic complex networks: Rationale, application, interpretation, and directions. Reply to comments on "Approaching human language with complex networks"

    Science.gov (United States)

    Cong, Jin; Liu, Haitao

    2014-12-01

    Amid the enthusiasm for real-world networks of the new millennium, the enquiry into linguistic networks is flourishing not only as a productive branch of the new networks science but also as a promising approach to linguistic research. Although the complex network approach constitutes a potential opportunity to make linguistics a science, the world of linguistics seems unprepared to embrace it. For one thing, linguistics has been largely unaffected by quantitative methods. Those who are accustomed to qualitative linguistic methods may find it hard to appreciate the application of quantitative properties of language such as frequency and length, not to mention quantitative properties of language modeled as networks. With this in mind, in our review [1] we restrict ourselves to the basics of complex networks and the new insights into human language with the application of complex networks. For another, while breaking new grounds and posing new challenges for linguistics, the complex network approach to human language as a new tradition of linguistic research is faced with challenges and unsolved issues of its own. It is no surprise that the comments on our review, especially their skepticism and suggestions, focus on various different aspects of the complex network approach to human language. We are grateful to all the insightful and penetrating comments, which, together with our review, mark a significant impetus to linguistic research from the complex network approach. In this reply, we would like to address four major issues of the complex network approach to human language, namely, a) its theoretical rationale, b) its application in linguistic research, c) interpretation of the results, and d) directions of future research.

  16. A complex genome-microRNA interplay in human mitochondria.

    Science.gov (United States)

    Shinde, Santosh; Bhadra, Utpal

    2015-01-01

    Small noncoding regulatory RNA exist in wide spectrum of organisms ranging from prokaryote bacteria to humans. In human, a systematic search for noncoding RNA is mainly limited to the nuclear and cytosolic compartments. To investigate whether endogenous small regulatory RNA are present in cell organelles, human mitochondrial genome was also explored for prediction of precursor microRNA (pre-miRNA) and mature miRNA (miRNA) sequences. Six novel miRNA were predicted from the organelle genome by bioinformatics analysis. The structures are conserved in other five mammals including chimp, orangutan, mouse, rat, and rhesus genome. Experimentally, six human miRNA are well accumulated or deposited in human mitochondria. Three of them are expressed less prominently in Northern analysis. To ascertain their presence in human skeletal muscles, total RNA was extracted from enriched mitochondria by an immunomagnetic method. The expression of six novel pre-miRNA and miRNA was confirmed by Northern blot analysis; however, low level of remaining miRNA was found by sensitive Northern analysis. Their presence is further confirmed by real time RT-PCR. The six miRNA find their multiple targets throughout the human genome in three different types of software. The luciferase assay was used to confirm that MT-RNR2 gene was the potential target of hsa-miR-mit3 and hsa-miR-mit4.

  17. Significance of respirasomes for the assembly/stability of human respiratory chain complex I.

    Science.gov (United States)

    Schägger, Hermann; de Coo, René; Bauer, Matthias F; Hofmann, Sabine; Godinot, Catherine; Brandt, Ulrich

    2004-08-27

    We showed that the human respiratory chain is organized in supramolecular assemblies of respiratory chain complexes, the respirasomes. The mitochondrial complexes I (NADH dehydrogenase) and III (cytochrome c reductase) form a stable core respirasome to which complex IV (cytochrome c oxidase) can also bind. An analysis of the state of respirasomes in patients with an isolated deficiency of single complexes provided evidence that the formation of respirasomes is essential for the assembly/stability of complex I, the major entry point of respiratory chain substrates. Genetic alterations leading to a loss of complex III prevented respirasome formation and led to the secondary loss of complex I. Therefore, primary complex III assembly deficiencies presented as combined complex III/I defects. This dependence of complex I assembly/stability on respirasome formation has important implications for the diagnosis of mitochondrial respiratory chain disorders.

  18. Mitochondrial network complexity and pathological decrease in complex I activity are tightly correlated in isolated human complex I deficiency

    NARCIS (Netherlands)

    Koopman, W.J.H.; Visch, H.J.; Verkaart, S.A.J.; Heuvel, L.W. van den; Smeitink, J.A.M.; Willems, P.H.G.M.

    2005-01-01

    Complex I (NADH:ubiquinone oxidoreductase) is the largest multisubunit assembly of the oxidative phosphorylation system, and its malfunction is associated with a wide variety of clinical syndromes ranging from highly progressive, often early lethal, encephalopathies to neurodegenerative disorders in

  19. Complex assembly, crystallization and preliminary X-ray crystallographic analysis of the human Rod–Zwilch–ZW10 (RZZ) complex

    Energy Technology Data Exchange (ETDEWEB)

    Altenfeld, Anika; Wohlgemuth, Sabine [Max Planck Institute of Molecular Physiology, Otto Hahn Strasse 11, 44227 Dortmund (Germany); Wehenkel, Annemarie [Institut Curie, CNRS UMR 3348/INSERM U1005, Bâtiment 110, Centre Universitaire, 91405 Orsay CEDEX (France); Vetter, Ingrid R. [Max Planck Institute of Molecular Physiology, Otto Hahn Strasse 11, 44227 Dortmund (Germany); Musacchio, Andrea, E-mail: andrea.musacchio@mpi-dortmund.mpg.de [Max Planck Institute of Molecular Physiology, Otto Hahn Strasse 11, 44227 Dortmund (Germany); University of Duisburg-Essen, Universitätstrasse 1, 45141 Essen (Germany)

    2015-03-20

    The 800 kDa complex of the human Rod, Zwilch and ZW10 proteins (the RZZ complex) was reconstituted in insect cells, purified, crystallized and subjected to preliminary X-ray diffraction analysis. The spindle-assembly checkpoint (SAC) monitors kinetochore–microtubule attachment during mitosis. In metazoans, the three-subunit Rod–Zwilch–ZW10 (RZZ) complex is a crucial SAC component that interacts with additional SAC-activating and SAC-silencing components, including the Mad1–Mad2 complex and cytoplasmic dynein. The RZZ complex contains two copies of each subunit and has a predicted molecular mass of ∼800 kDa. Given the low abundance of the RZZ complex in natural sources, its recombinant reconstitution was attempted by co-expression of its subunits in insect cells. The RZZ complex was purified to homogeneity and subjected to systematic crystallization attempts. Initial crystals containing the entire RZZ complex were obtained using the sitting-drop method and were subjected to optimization to improve the diffraction resolution limit. The crystals belonged to space group P3{sub 1} (No. 144) or P3{sub 2} (No. 145), with unit-cell parameters a = b = 215.45, c = 458.7 Å, α = β = 90.0, γ = 120.0°.

  20. Colloque S&T Symposium 2008: Understanding the Human Dimension in 21st Century Conflict/Warfare: The Complexities of Human-with-Human Relationships

    Science.gov (United States)

    2008-08-01

    Colloque S&T Symposium 2008 Undestanding the Human Dimension in 21st Century Conflict/Warfare: The Complexities of Human-with-Human Relationships ...conditions for self-sustaining stability. By working towards the development of models and concepts to better understand and influence the human in...This page intentionally left blank. Colloque S&T Symposium 2008 Undestanding the Human Dimension in 21st Century Conflict

  1. Expression, purification and characterization of the human MTA2-RBBP7 complex.

    Science.gov (United States)

    Brasen, Christoffer; Dorosz, Jerzy; Wiuf, Anders; Boesen, Thomas; Mirza, Osman; Gajhede, Michael

    2017-02-04

    The repressive Nucleosome Remodeling and histone Deacetylation (NuRD) complex remodels the chromatin structure by coupling ATP-dependent remodeling activity with histone deacetylase function and plays important roles in regulating gene transcription, DNA damage repair and chromatin assembly. The complex is composed of six subunits: Metastasis Associated proteins MTA1/2/3 initially recruit histone chaperones RBBP4/7 followed by the histone deacetylases HDAC1/2 forming a core complex. Further association of the CpG-binding protein MBD2/3, p66α/β and the ATP-dependent helicase CDH3/4 constitutes the NuRD complex. Recent structural studies on truncated human proteins or orthologous have revealed that the stoichiometry of the MTA1-RBBP4 complex is 2:4. This study reports expression and purification of the intact human MTA2-RBBP7 complex using HEK293F cells as expression system. In analogy with findings on the Drosophila NuRD complex, we find that also the human MTA-RBBP can be isolated in vitro. Taken together with previous findings this suggests, that MTA-RBBP is a stable complex, with a central role in the initial assembly of the human NuRD complex. Refined 3D volumes of the complex generated from negative stain electron microscopy (EM) data reveals an elongated architecture that is capable of hinge like motion around the center of the particle.

  2. Engineering Complex Human-Technological Work Systems: A Sensemaking Approach

    Science.gov (United States)

    2007-06-01

    by Rene Descartes , Immanuel Kant, and Ludwig Wittgenstein, and mathematically by Alfred North Whitehead and Bertrand Russell. Logical rationalism...reductionism—originally introduced by Descartes in 1673)— asserts that complex objects, phenomena, theories, and meanings can always be reduced to a...Positivism Essentialism Analytic Philosophy Social Constructivism Nominalism Autopoiesis Descartes Plato Aristotle Aquinas Bacon Locke Wittgenstein

  3. Complexity of Human Circulation Design: Tips for Students

    Science.gov (United States)

    Kurbel, Sven; Gros, Mario; Maric, Svjetlana

    2009-01-01

    Medical students are faced with a challenge to comprehend the enormous complexity of the circulatory systems. There is a gap between courses of anatomy, with detailed description of all normally present macroscopic vessels, and histology, which is focused on microscopic tissue architecture. Both courses leave arterioles, capillaries, and venules…

  4. Accessory subunits are integral for assembly and function of human mitochondrial complex I.

    Science.gov (United States)

    Stroud, David A; Surgenor, Elliot E; Formosa, Luke E; Reljic, Boris; Frazier, Ann E; Dibley, Marris G; Osellame, Laura D; Stait, Tegan; Beilharz, Traude H; Thorburn, David R; Salim, Agus; Ryan, Michael T

    2016-10-06

    Complex I (NADH:ubiquinone oxidoreductase) is the first enzyme of the mitochondrial respiratory chain and is composed of 45 subunits in humans, making it one of the largest known multi-subunit membrane protein complexes. Complex I exists in supercomplex forms with respiratory chain complexes III and IV, which are together required for the generation of a transmembrane proton gradient used for the synthesis of ATP. Complex I is also a major source of damaging reactive oxygen species and its dysfunction is associated with mitochondrial disease, Parkinson's disease and ageing. Bacterial and human complex I share 14 core subunits that are essential for enzymatic function; however, the role and necessity of the remaining 31 human accessory subunits is unclear. The incorporation of accessory subunits into the complex increases the cellular energetic cost and has necessitated the involvement of numerous assembly factors for complex I biogenesis. Here we use gene editing to generate human knockout cell lines for each accessory subunit. We show that 25 subunits are strictly required for assembly of a functional complex and 1 subunit is essential for cell viability. Quantitative proteomic analysis of cell lines revealed that loss of each subunit affects the stability of other subunits residing in the same structural module. Analysis of proteomic changes after the loss of specific modules revealed that ATP5SL and DMAC1 are required for assembly of the distal portion of the complex I membrane arm. Our results demonstrate the broad importance of accessory subunits in the structure and function of human complex I. Coupling gene-editing technology with proteomics represents a powerful tool for dissecting large multi-subunit complexes and enables the study of complex dysfunction at a cellular level.

  5. Accommodating complexity and human behaviors in decision analysis.

    Energy Technology Data Exchange (ETDEWEB)

    Backus, George A.; Siirola, John Daniel; Schoenwald, David Alan; Strip, David R.; Hirsch, Gary B.; Bastian, Mark S.; Braithwaite, Karl R.; Homer, Jack [Homer Consulting

    2007-11-01

    This is the final report for a LDRD effort to address human behavior in decision support systems. One sister LDRD effort reports the extension of this work to include actual human choices and additional simulation analyses. Another provides the background for this effort and the programmatic directions for future work. This specific effort considered the feasibility of five aspects of model development required for analysis viability. To avoid the use of classified information, healthcare decisions and the system embedding them became the illustrative example for assessment.

  6. Beyond membrane channelopathies: alternative mechanisms underlying complex human disease

    Institute of Scientific and Technical Information of China (English)

    Konstantinos Dean BOUDOULAS; Peter J MOHLER

    2011-01-01

    Over the past fifteen years, our understanding of the molecular mechanisms underlying human disease has flourished in large part due to the discovery of gene mutations linked with membrane ion channels and transporters. In fact, ion channel defects ("channelopathies" - the focus of this review series) have been associated with a spectrum of serious human disease phenotypes including cystic fibrosis, cardiac arrhythmia, diabetes, skeletal muscle defects, and neurological disorders. However, we now know that human disease, particularly excitable cell disease, may be caused by defects in non-ion channel polypeptides including in cellular components residing well beneath the plasma membrane. For example, over the past few years, a new class of potentially fatal cardiac arrhythmias has been linked with cytoplasmic proteins that include sub-membrane adapters such as ankyrin-B (ANK2),ankyrin-G (ANK3), and alpha-1 syntrophin, membrane coat proteins including caveolin-3 (CAV3), signaling platforms including yotiao (AKAPg), and cardiac enzymes (GPD1L). The focus of this review is to detail the exciting role of lamins, yet another class of gene products that have provided elegant new insight into human disease.

  7. Alteration to the SWI/SNF complex in human cancers

    Directory of Open Access Journals (Sweden)

    Vanessa S. Gordon

    2011-12-01

    Full Text Available The SWI/SNF complex is a key catalyst for gene expression and regulates a variety of pathways, many of which have anticancer roles. Its central roles in cellular growth control, DNA repair, differentiation, cell adhesion and development are often targeted, and inactivated, during cancer development and progression. In this review, we will discuss what is known about how SWI/SNF is inactivated, and describe the potential impact of abrogating this complex. BRG1 and BRM are the catalytic subunits which are essential for SWI/SNF function, and thus, it is not surprising that they are lost in a variety of cancer types. As neither gene is mutated when lost, the mechanism of suppression, as well as the impact of potential gene activity restoration, are reviewed.

  8. Complex-tone pitch representations in the human auditory system

    DEFF Research Database (Denmark)

    Bianchi, Federica; Dau, Torsten; Santurette, Sébastien;

    , specifically those showing enhanced pitch cues (i.e., musicians) and those typically having disrupted pitch cues (i.e., hearing-impaired listeners). In particular, two main topics were addressed: the relative importance of resolved and unresolved harmonics for normal-hearing (NH) and hearing-impaired (HI......) listeners and the effect of musical training for pitch discrimination of complex tones with resolved and unresolved harmonics. Concerning the first topic, behavioral and modeling results in listeners with sensorineural hearing loss (SNHL) indicated that temporal envelope cues of complex tones...... discrimination to that of NH listeners. In the second part of this work, behavioral and objective measures of pitch discrimination were carried out in musicians and non-musicians. Musicians showed an increased pitch-discrimination performance relative to non-musicians for both resolved and unresolved harmonics...

  9. Modeling Reduced Human Performance as a Complex Adaptive System

    Science.gov (United States)

    2003-09-01

    fittingly, the latest research paper describes these types of components as LEGOs (listener event graph objects). “The name is also a metaphor for how...Buss, A. H. and P. J. Sanchez (2002). Building Complex Models With LEGOs (Listener Event Graph Objects). Winter Simulation Conference. Buss, D. (1999...Kaarlela, C. (1997). New Gene Therapy Technique Could Eliminate Insulin Injections for many Diabetics, Jeffrey Norris and Jennifer O’Brien (415) 476-481

  10. Improved methodology for the affinity isolation of human protein complexes expressed at near endogenous levels

    DEFF Research Database (Denmark)

    Domanski, Michal; Molloy, Kelly; Jiang, Hua;

    2012-01-01

    An efficient and reliable procedure for the capture of affinity-tagged proteins and associated complexes from human cell lines is reported. Through multiple optimizations, high yield and low background affinity-purifications are achieved from modest quantities of human cells expressing endogenous......-level tagged proteins. Isolations of triple-FLAG and GFP-tagged fusion proteins involved in RNA metabolism are presented.......An efficient and reliable procedure for the capture of affinity-tagged proteins and associated complexes from human cell lines is reported. Through multiple optimizations, high yield and low background affinity-purifications are achieved from modest quantities of human cells expressing endogenous...

  11. Expression, purification and characterization of the human MTA2-RBBP7 complex

    DEFF Research Database (Denmark)

    Brasen, Christoffer; Dorosz, Jerzy; Wiuf, Anders

    2017-01-01

    . The complex is composed of six subunits: Metastasis Associated proteins MTA1/2/3 initially recruit histone chaperones RBBP4/7 followed by the histone deacetylases HDAC1/2 forming a core complex. Further association of the CpG-binding protein MBD2/3, p66α/β and the ATP-dependent helicase CDH3/4 constitutes...... the NuRD complex. Recent structural studies on truncated human proteins or orthologous have revealed that the stoichiometry of the MTA1-RBBP4 complex is 2:4. This study reports expression and purification of the intact human MTA2-RBBP7 complex using HEK293F cells as expression system. In analogy...... with findings on the Drosophila NuRD complex, we find that also the human MTA-RBBP can be isolated in vitro. Taken together with previous findings this suggests, that MTA-RBBP is a stable complex, with a central role in the initial assembly of the human NuRD complex. Refined 3D volumes of the complex generated...

  12. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells

    National Research Council Canada - National Science Library

    Tchasovnikarova, I. A; Timms, R. T; Matheson, N. J; Wals, K; Antrobus, R; Gottgens, B; Dougan, G; Dawson, M. A; Lehner, P. J

    2015-01-01

    ... (see the Perspective by Brummelkamp). They identified a complex of proteins in human cells they called HUSH that kept particular parts of the genome silent by changing associated histone methylation marks...

  13. Structural Biology of Proteins of the Multi-enzyme Assembly Human Pyruvate Dehydrogenase Complex

    Science.gov (United States)

    2003-01-01

    Objectives and research challenges of this effort include: 1. Need to establish Human Pyruvate Dehydrogenase Complex protein crystals; 2. Need to test value of microgravity for improving crystal quality of Human Pyruvate Dehydrogenase Complex protein crystals; 3. Need to improve flight hardware in order to control and understand the effects of microgravity on crystallization of Human Pyruvate Dehydrogenase Complex proteins; 4. Need to integrate sets of national collaborations with the restricted and specific requirements of flight experiments; 5. Need to establish a highly controlled experiment in microgravity with a rigor not yet obtained; 6. Need to communicate both the rigor of microgravity experiments and the scientific value of results obtained from microgravity experiments to the national community; and 7. Need to advance the understanding of Human Pyruvate Dehydrogenase Complex structures so that scientific and commercial advance is identified for these proteins.

  14. Concordance of gene expression in human protein complexes reveals tissue specificity and pathology

    DEFF Research Database (Denmark)

    Börnigen, Daniela; Pers, Tune Hannes; Thorrez, Lieven

    2013-01-01

    Disease-causing variants in human genes usually lead to phenotypes specific to only a few tissues. Here, we present a method for predicting tissue specificity based on quantitative deregulation of protein complexes. The underlying assumption is that the degree of coordinated expression among...... proteins in a complex within a given tissue may pinpoint tissues that will be affected by a mutation in the complex and coordinated expression may reveal the complex to be active in the tissue. We identified known disease genes and their protein complex partners in a high-quality human interactome. Each...... susceptibility gene's tissue involvement was ranked based on coordinated expression with its interaction partners in a non-disease global map of human tissue-specific expression. The approach demonstrated high overall area under the curve (0.78) and was very successfully benchmarked against a random model...

  15. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Halling-Sørensen, Bent; Birkved, Franziska Maria A Kramer

    2008-01-01

    transfected insect cells using dibenzylfluorescein as substrate. The drugs inhibiting CYP19 were: lamotrigine, oxcarbazepine, tiagabine, phenobarbital, phenytoin, ethosuximide, and valproate. The inhibitory effects (50% reduction in activity compared to enzymes without inhibitor present) were in the range...... with valproate and phenobarbital. When adding carbamazepine to a range of valproate concentrations no additional inhibition was seen. The data for some of the AEDs show that side effects on steroid synthesis in humans due to inhibition of aromatase should be considered....

  16. DTPA complexation of bismuth in human blood serum.

    Science.gov (United States)

    Montavon, G; Le Du, A; Champion, J; Rabung, T; Morgenstern, A

    2012-07-28

    The in vivo(212)Pb/(212)Bi generator is promising for application in targeted alpha therapy (TAT) of cancer. One main limitation of its therapeutic application is due to potential release of (212)Bi from the radioconjugate upon radioactive decay of the mother nuclide (212)Pb, potentially leading to irradiation of healthy tissue. The objective of the present work is to assess whether the chelate CHX-A''-DTPA (N-(2-aminoethyl)-trans-1,2-diaminocyclohexane-N,N',N''-pentaacetic acid) bound to a biological carrier molecule may be able to re-complex released (212)Bi under in vivo conditions to limit its translocation from the target site. CHX-A''-DTPA was bound to bovine gamma globulin (BGG) to mimic a model conjugate and the stability of the Bi-CHX-A''-DTPA-BGG conjugate was studied in blood serum by ultrafiltration. TRLFS experiments using Cm(III) as a fluorescent probe demonstrated that linking CHX-A''-DTPA to BGG does not affect the coordination properties of the ligand. Furthermore, comparable stability constants were observed between Bi(III) and free CHX-A''-DTPA, BGG-bound CHX-A''-DTPA and DTPA. The complexation constants determined between Bi(III) and the chelate molecules are sufficiently high to allow ultra trace amounts of the ligand to efficiently compete with serum transferrin controlling Bi(III) speciation in blood plasma conditions. Nevertheless, CHX-A''-DTPA is not able to complex Bi(III) generated in blood serum because of the strong competition between Bi(III) and Fe(II) for the ligand. In other words, CHX-A''-DTPA is not "selective" enough to limit Bi(iii) release in the body when applying the (212)Pb/(212)Bi in vivo generator.

  17. Genetic mapping of complex discrete human diseases by discriminant analysis

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The objective of the present study is to propose and evaluate a novel multivariate approach for genetic mapping of complex categorical diseases. This approach results from an application of standard stepwise discriminant analysis to detect linkage based on the differential marker identity-by-descent (IBD) distributions among the different groups of sib pairs. Two major advantages of this method are that it allows for simultaneously testing all markers, together with other genetic and environmental factors in a single multivariate setting and it avoids explicitly modeling the complex relationship between the affection status of sib pairs and the underlying genetic determinants. The efficiency and properties of the method are demonstrated via simulations. The proposed multivariate approach has successfully located the true position(s) under various genetic scenarios. The more important finding is that using highly densely spaced markers (1~2 cM) leads to only a marginal loss of statistical efficiency of the proposed methods in terms of gene localization and statistical power. These results have well established its utility and advantages as a fine-mapping tool. A unique property of the proposed method is the ability to map multiple linked trait loci to their precise positions due to its sequential nature, as demonstrated via simulations.

  18. Random mutagenesis and screening of complex glycoproteins : expression of human gonadotropins in Dictyostelium discoideum

    NARCIS (Netherlands)

    Linskens, Maarten H.K.; Grootenhuis, Peter D.J.; Blaauw, Mieke; Huisman-de Winkel, Bianca; Ravestein, Arno van; Haastert, Peter J.M. van; Heikoop, Judith C.

    1999-01-01

    The soil amoeba Dictyostelium discoideum is a host cell that provides simple genetics in combination with complex protein synthesis. We show that the complex human heterodimeric gonadotropins can be produced and secreted by this organism, Furthermore, both follicle stimulation hormone and choriogona

  19. Global properties and functional complexity of human gene regulatory variation.

    Directory of Open Access Journals (Sweden)

    Daniel J Gaffney

    2013-05-01

    Full Text Available Identification and functional interpretation of gene regulatory variants is a major focus of modern genomics. The application of genetic mapping to molecular and cellular traits has enabled the detection of regulatory variation on genome-wide scales and revealed an enormous diversity of regulatory architecture in humans and other species. In this review I summarise the insights gained and questions raised by a decade of genetic mapping of gene expression variation. I discuss recent extensions of this approach using alternative molecular phenotypes that have revealed some of the biological mechanisms that drive gene expression variation between individuals. Finally, I highlight outstanding problems and future directions for development.

  20. Unraveling the complexity of lipid body organelles in human eosinophils.

    Science.gov (United States)

    Melo, Rossana C N; Weller, Peter F

    2014-11-01

    Lipid-rich organelles are common in many cell types. In cells, such as adipocytes, these organelles are termed LDs, whereas in other cells, such as leukocytes, they are called LBs. The study of leukocyte LBs has attracted attention as a result of their association with human diseases. In leukocytes, such as eosinophils, LB accumulation has been documented extensively during inflammatory conditions. In these cells, LBs are linked to the regulation of immune responses by compartmentalization of several proteins and lipids involved in the control and biosynthesis of inflammatory mediators (eicosanoids). However, it has been unclear how diverse proteins, including membrane-associated enzymes involved in eicosanoid formation, incorporate into LBs, especially if the internal content of LBs is assumed to consist solely of stores of neutral lipids, as present within adipocyte LDs. Studies of the formation, function, and ultrastructure of LBs in eosinophils have been providing insights pertinent to LBs in other leukocytes. Here, we review current knowledge of the composition and function of leukocyte LBs as provided by studies of human eosinophil LBs, including recognitions of the internal architecture of eosinophil LBs based on 3D electron tomographic analyses.

  1. EFECT OF ERYTHROMYCIN ON INTERDIGESTIVE MIGRATING MOTOR COMPLEX IN HUMANS

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Objective To investigate the effect of erythromycin (EM) on interdigestive migrating motor complex (MMC) in healthy volunteers. Methods 20 healthy volunteers were randomly divided into 2 groups: EM group (n=11) and placebo group (n=9). The changes of MMC were observed by gastrointestinal manometry before and after oral administration of EM or placebo. Results Gastric antral MMCs that evoked by EM were similar to spontaneous MMCs. EM orally intaking decreased MMC cycle duration significantly (P<0.05). EM orally intaking decreased the percentage of phase Ⅱ duration to MMC cycle duration significantly (P<0.05). But EM orally intaking increased the percentage of phase Ⅲ duration to MMC cycle duration significantly (P<0.05). The amplitude of antral waves of phase Ⅲ increased significantly after EM orally intaking (P<0.05). Placebo orally and percentages of phase Ⅰ, phase Ⅱ, phase Ⅲ duration to MMC cycle duration. Conclusion EM has stimulating effect on gastrointestinal motor activity.

  2. The Cultural Historical Complexity of Human Personality Adaptation

    Directory of Open Access Journals (Sweden)

    Melissa E. Wynn

    2012-10-01

    Full Text Available Research on implicit intelligence has conceptualized students’ beliefs about the nature of intelligence as either fixed or malleable. This research has largely not included African American adolescents, a group for whom beliefs about intelligence have a cultural historical complexity related to both scientific racism and master narratives of race and intelligence. The purpose of this study was to investigate the nature of implicit theories of intelligence for 63 African American adolescents who are seventh and eighth graders in a public charter school. The two-way ANOVA revealed that these adolescents held a malleable view of intelligence, which did not vary by gender or grade. Exploratory correlation analysis showed some consistent relationships with achievement motivation variables found in other studies. These findings may be explained by African American cultural values and the personality characteristic adaptations that they make living within a racialized society.

  3. Network properties of complex human disease genes identified through genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Fredrik Barrenas

    Full Text Available BACKGROUND: Previous studies of network properties of human disease genes have mainly focused on monogenic diseases or cancers and have suffered from discovery bias. Here we investigated the network properties of complex disease genes identified by genome-wide association studies (GWAs, thereby eliminating discovery bias. PRINCIPAL FINDINGS: We derived a network of complex diseases (n = 54 and complex disease genes (n = 349 to explore the shared genetic architecture of complex diseases. We evaluated the centrality measures of complex disease genes in comparison with essential and monogenic disease genes in the human interactome. The complex disease network showed that diseases belonging to the same disease class do not always share common disease genes. A possible explanation could be that the variants with higher minor allele frequency and larger effect size identified using GWAs constitute disjoint parts of the allelic spectra of similar complex diseases. The complex disease gene network showed high modularity with the size of the largest component being smaller than expected from a randomized null-model. This is consistent with limited sharing of genes between diseases. Complex disease genes are less central than the essential and monogenic disease genes in the human interactome. Genes associated with the same disease, compared to genes associated with different diseases, more often tend to share a protein-protein interaction and a Gene Ontology Biological Process. CONCLUSIONS: This indicates that network neighbors of known disease genes form an important class of candidates for identifying novel genes for the same disease.

  4. Network properties of complex human disease genes identified through genome-wide association studies.

    Science.gov (United States)

    Barrenas, Fredrik; Chavali, Sreenivas; Holme, Petter; Mobini, Reza; Benson, Mikael

    2009-11-30

    Previous studies of network properties of human disease genes have mainly focused on monogenic diseases or cancers and have suffered from discovery bias. Here we investigated the network properties of complex disease genes identified by genome-wide association studies (GWAs), thereby eliminating discovery bias. We derived a network of complex diseases (n = 54) and complex disease genes (n = 349) to explore the shared genetic architecture of complex diseases. We evaluated the centrality measures of complex disease genes in comparison with essential and monogenic disease genes in the human interactome. The complex disease network showed that diseases belonging to the same disease class do not always share common disease genes. A possible explanation could be that the variants with higher minor allele frequency and larger effect size identified using GWAs constitute disjoint parts of the allelic spectra of similar complex diseases. The complex disease gene network showed high modularity with the size of the largest component being smaller than expected from a randomized null-model. This is consistent with limited sharing of genes between diseases. Complex disease genes are less central than the essential and monogenic disease genes in the human interactome. Genes associated with the same disease, compared to genes associated with different diseases, more often tend to share a protein-protein interaction and a Gene Ontology Biological Process. This indicates that network neighbors of known disease genes form an important class of candidates for identifying novel genes for the same disease.

  5. EEG correlates of spatial orientation in the human retrosplenial complex.

    Science.gov (United States)

    Lin, C-T; Chiu, T-C; Gramann, K

    2015-10-15

    Studies on spatial navigation reliably demonstrate that the retrosplenial complex (RSC) plays a pivotal role for allocentric spatial information processing by transforming egocentric and allocentric spatial information into the respective other spatial reference frame (SRF). While more and more imaging studies investigate the role of the RSC in spatial tasks, high temporal resolution measures such as electroencephalography (EEG) are missing. To investigate the function of the RSC in spatial navigation with high temporal resolution we used EEG to analyze spectral perturbations during navigation based on allocentric and egocentric SRF. Participants performed a path integration task in a clearly structured virtual environment providing allothetic information. Continuous EEG recordings were decomposed by independent component analysis (ICA) with subsequent source reconstruction of independent time source series using equivalent dipole modeling. Time-frequency transformation was used to investigate reference frame-specific orientation processes during navigation as compared to a control condition with identical visual input but no orientation task. Our results demonstrate that navigation based on an egocentric reference frame recruited a network including the parietal, motor, and occipital cortices with dominant perturbations in the alpha band and theta modulation in frontal cortex. Allocentric navigation was accompanied by performance-related desynchronization of the 8-13 Hz frequency band and synchronization in the 12-14 Hz band in the RSC. The results support the claim that the retrosplenial complex is central to translating egocentric spatial information into allocentric reference frames. Modulations in different frequencies with different time courses in the RSC further provide first evidence of two distinct neural processes reflecting translation of spatial information based on distinct reference frames and the computation of heading changes.

  6. A role for Aurora C in the chromosomal passenger complex during human preimplantation embryo development

    NARCIS (Netherlands)

    Santos, Margarida Avo; van de Werken, Christine; de Vries, Marieke; Jahr, Holger; Vromans, Martijn J. M.; Laven, Joop S. E.; Fauser, Bart C.; Kops, Geert J.; Lens, Susanne M.; Baart, Esther B.

    2011-01-01

    BACKGROUND: Human embryos generated by IVF demonstrate a high incidence of chromosomal segregation errors during the cleavage divisions. To analyse underlying molecular mechanisms, we investigated the behaviour of the chromosomal passenger complex (CPC) in human oocytes and embryos. This important m

  7. A Scale and Pose Invariant Algorithm for Fast Detecting Human Faces in a Complex Background

    Institute of Scientific and Technical Information of China (English)

    XING Xin; SHEN Lansun; JIA Kebin

    2001-01-01

    Human face detection is an interesting and challenging task in computer vision. A scale and pose invariant algorithm is proposed in this paper.The algorithm is able to detect human faces in a complex background in about 400ms with a detection rate of 92%. The algorithm can be used in a wide range of applications such as human-computer interface, video coding, etc.

  8. Recognition of complex human behaviours using 3D imaging for intelligent surveillance applications

    Science.gov (United States)

    Yao, Bo; Lepley, Jason J.; Peall, Robert; Butler, Michael; Hagras, Hani

    2016-10-01

    We introduce a system that exploits 3-D imaging technology as an enabler for the robust recognition of the human form. We combine this with pose and feature recognition capabilities from which we can recognise high-level human behaviours. We propose a hierarchical methodology for the recognition of complex human behaviours, based on the identification of a set of atomic behaviours, individual and sequential poses (e.g. standing, sitting, walking, drinking and eating) that provides a framework from which we adopt time-based machine learning techniques to recognise complex behaviour patterns.

  9. Invited commentary: Positive youth development and human complexity.

    Science.gov (United States)

    Larson, Reed W; Tran, Steve P

    2014-06-01

    The process of positive development for adolescents includes struggling to address a wide variety of complex, often unstated bio-psycho-social-cultural challenges. These include formulating workable values, learning self-regulation, preparation for adult work roles-and innumerable other un-tidy puzzles. Variable-based research can only scratch the surface of how youth go about these processes; nonetheless, systematic longitudinal research like this can provide valuable information about developmental pathways and directions of change. Highlights from these papers include the finding that older youth report more goals aimed at meaningful connection with others and contributing to society; yet also that moral character did not differ by age. The papers suggest that relationships adults, hope, school engagement, participation in out-of-school programs, and intentional self-regulation can serve as mediators of positive development. Yet, a striking finding was that comparatively few youth in the study manifest a pattern of change marked by the coupling of increases in positive youth development and decreases in risk/problem behavior. We believe there is much beneath the surface to be uncovered.

  10. Complex posttraumatic stress disorder and survivors of human rights violations.

    Science.gov (United States)

    McDonnell, Matthew; Robjant, Katy; Katona, Cornelius

    2013-01-01

    This article reviews recent findings on Complex Posttraumatic Stress Disorder (CPTSD) and proposes future research which would help to establish the nature of CPTSD in relation to Posttraumatic Stress Disorder (PTSD). Research on survivors of torture and war has found that CPTSD can occur when there is no history of childhood abuse. fMRI studies appear to highlight differences in neural activity in individuals exhibiting primary dissociation compared with individuals exhibiting secondary dissociation. Research has begun to show that, when symptoms of secondary dissociation are appropriately managed, exposure-based therapies are an effective treatment for individuals with CPTSD. Much research on CPTSD has emphasized its developmental basis and the disruptive effects of trauma in childhood and adolescence on subsequent emotional development. However, some studies on survivors of torture in adult life identify similar symptom patterns, despite there being no history of childhood trauma. It is argued that comparative research is required between victims of developmental trauma (such as childhood sexual abuse) and victims who experienced prolonged interpersonal trauma in adulthood (such as torture), as this could be useful in establishing the cause of CPTSD and in delineating clinically and therapeutically meaningful subtypes. It is also proposed that a focus on underlying neurobiological processes would help in developing and refining CPTSD as a construct and informing treatment.

  11. Complex formation between human prostate-specific antigen and protease inhibitors in mouse plasma.

    Science.gov (United States)

    Hekim, Can; Riipi, Tero; Zhu, Lei; Laakkonen, Pirjo; Stenman, Ulf-Håkan; Koistinen, Hannu

    2010-04-01

    When secreted from the prostate, most of prostate-specific antigen (PSA) is free and enzymatically active. Upon reaching circulation, active PSA is inactivated by complex formation with protease inhibitors. To justify the use of mouse models for evaluation of the function of PSA and for studies on therapeutic modalities based on modulation of PSA activity, it is important to know whether PSA complexation is similar in mouse and man. To characterize the circulating forms of PSA in mouse, we used subcutaneous LNCaP and 22RV1 human prostate cancer cell xenograft tumor models. We also added PSA directly to mouse serum. Free and total PSA were measured by immunoassay, and PSA complexes were extracted by immunopurification followed by SDS-PAGE, in-gel trypsin digestion and identification of signature peptides by mass spectrometry. In mice bearing xenograft tumors, 68% of the immunoreactive PSA occurred in complex, and when added to mouse serum, over 70% of PSA forms complexes that comprises alpha(2)-macroglobulin and members of the alpha(1)-antitrypsin (AAT) family. In mouse plasma, PSA forms complexes similar to those in man, but the major immunoreactive complex contains AAT rather than alpha(1)-antichymotrypsin, which is the main complex forming serpin in man. The complex formation of PSA produced by xenograft tumor models in mice is similar to that of human prostate tumors with respect to the complexation of PSA. (c) 2009 Wiley-Liss, Inc.

  12. Connectivity in the human brain dissociates entropy and complexity of auditory inputs.

    Science.gov (United States)

    Nastase, Samuel A; Iacovella, Vittorio; Davis, Ben; Hasson, Uri

    2015-03-01

    Complex systems are described according to two central dimensions: (a) the randomness of their output, quantified via entropy; and (b) their complexity, which reflects the organization of a system's generators. Whereas some approaches hold that complexity can be reduced to uncertainty or entropy, an axiom of complexity science is that signals with very high or very low entropy are generated by relatively non-complex systems, while complex systems typically generate outputs with entropy peaking between these two extremes. In understanding their environment, individuals would benefit from coding for both input entropy and complexity; entropy indexes uncertainty and can inform probabilistic coding strategies, whereas complexity reflects a concise and abstract representation of the underlying environmental configuration, which can serve independent purposes, e.g., as a template for generalization and rapid comparisons between environments. Using functional neuroimaging, we demonstrate that, in response to passively processed auditory inputs, functional integration patterns in the human brain track both the entropy and complexity of the auditory signal. Connectivity between several brain regions scaled monotonically with input entropy, suggesting sensitivity to uncertainty, whereas connectivity between other regions tracked entropy in a convex manner consistent with sensitivity to input complexity. These findings suggest that the human brain simultaneously tracks the uncertainty of sensory data and effectively models their environmental generators.

  13. Mitochondrial complex I plays an essential role in human respirasome assembly.

    Science.gov (United States)

    Moreno-Lastres, David; Fontanesi, Flavia; García-Consuegra, Inés; Martín, Miguel A; Arenas, Joaquín; Barrientos, Antoni; Ugalde, Cristina

    2012-03-01

    The biogenesis and function of the mitochondrial respiratory chain (RC) involve the organization of RC enzyme complexes in supercomplexes or respirasomes through an unknown biosynthetic process. This leads to structural interdependences between RC complexes, which are highly relevant from biological and biomedical perspectives, because RC defects often lead to severe neuromuscular disorders. We show that in human cells, respirasome biogenesis involves a complex I assembly intermediate acting as a scaffold for the combined incorporation of complexes III and IV subunits, rather than originating from the association of preassembled individual holoenzymes. The process ends with the incorporation of complex I NADH dehydrogenase catalytic module, which leads to the respirasome activation. While complexes III and IV assemble either as free holoenzymes or by incorporation of free subunits into supercomplexes, the respirasomes constitute the structural units where complex I is assembled and activated, thus explaining the significance of the respirasomes for RC function.

  14. The N2-P3 complex of the evoked potential and human performance

    Science.gov (United States)

    Odonnell, Brian F.; Cohen, Ronald A.

    1988-01-01

    The N2-P3 complex and other endogenous components of human evoked potential provide a set of tools for the investigation of human perceptual and cognitive processes. These multidimensional measures of central nervous system bioelectrical activity respond to a variety of environmental and internal factors which have been experimentally characterized. Their application to the analysis of human performance in naturalistic task environments is just beginning. Converging evidence suggests that the N2-P3 complex reflects processes of stimulus evaluation, perceptual resource allocation, and decision making that proceed in parallel, rather than in series, with response generation. Utilization of these EP components may provide insights into the central nervous system mechanisms modulating task performance unavailable from behavioral measures alone. The sensitivity of the N2-P3 complex to neuropathology, psychopathology, and pharmacological manipulation suggests that these components might provide sensitive markers for the effects of environmental stressors on the human central nervous system.

  15. Microtomography of the human tooth-alveolar bone complex

    Science.gov (United States)

    Dalstra, Michel; Cattaneo, Paolo M.; Beckmann, Felix; Sakima, Maurício T.; Lemor, Carsten; Laursen, Morten G.; Melsen, Birte

    2006-08-01

    In this study the structure of the adult human dentoalveolar process is examined using conventional and synchrotron radiation-based microtomography (SRμCT). Mandibular and maxillary segments containing two to five adjacent teeth were harvested at autopsy from 49 adult donors. These segments were embedded in blocks of methylmetacrylate and scanned using a conventional table-top μCT-scanner at a pixel size and slice thickness of 35 μm. A few segments were also scanned at a synchrotron facility at an initial pixel size of 16.4 μm, which was binned by a factor 2 to result in an effective voxel size of almost 32.8 μm. The three-dimensional reconstructions revealed how intricately the teeth are supported by the alveolar bone. Furthermore, this support is highly inhomogeneous with respect to the buccal, mesial, lingual and distal quadrants. Reflecting their various degrees of mineralization, tissues like bone, dentine, enamel and cementum, could well be identified, especially in the scans made with SRμCT. Despite comparable voxel sizes, the reconstructed data-sets obtained with conventional μCT were less detailed and somewhat fuzzy in appearance compared to the data-sets of SRμCT. However, for quantification of macroscopical features like the thickness of the alveolar wall or the presence of dehiscences/fenestrations this seemed sufficient.

  16. Complex relationship between meiotic recombination frequency and autosomal synaptonemal complex length per cell in normal human males.

    Science.gov (United States)

    Pan, Zhenzhen; Yang, Qingling; Ye, Nan; Wang, Liu; Li, Jianhua; Yu, Dexin; Cooke, Howard J; Shi, Qinghua

    2012-03-01

    Although the relationship between meiotic recombination frequency and synaptonemal complex (SC) length has been of interest for a long time, how recombination frequency is related to SC length has not been carefully explored. To address this question, we have measured the meiotic recombination frequency as represented by MLH1 foci in 889 pachytene spermatocytes and measured the length of 19,558 autosomal SCs from 10 human males. A complex relationship between the number of MLH1 foci and total autosomal SC length per cell was observed. A positive correlation with significant correlation coefficients between the two variables was found in eight of the ten donors examined, with three donors showing weak correlation, and five showing moderate correlation. Two donors who did not show any correlation between the two variables were identified for the first time. Moreover, most cells with similar total autosomal SC length showed very different numbers of MLH1 foci both between individuals and even within an individual, and vice versa. Our data provide the first evidence for a complex relationship between the recombination frequency and total length of autosomal SCs per cell in human males.

  17. [Elderly human being with ostomy and environments of care: reflection on the perspective of complexity].

    Science.gov (United States)

    Barros, Edaiane Joana Lima; Santos, Silvana Sidney Costa; Lunardi, Valéria Lerch; Lunardi Filho, Wilson Danilo

    2012-01-01

    This is discussion about the relationship between elderly human beings with ostomy and their environments care, under the perspective of Complexity Edgar Morin. An axis holds the reflection: environments of care for elderly humans with ostomy. In this sense, we present three types of environment that surround the context of elderly humans with ostomy: home environment, group environment and hospital environment. This brings, as a social contribution, a new look about resizing caring of elderly humans with ostomy in their environment. It is considered that the environment hosting this human being contains a diversity of feelings, emotions, experiences; it binds multiple meanings, from the Complexity perspective, about the relationship between the environment and the caring process.

  18. Structural analysis of the human SYCE2-TEX12 complex provides molecular insights into synaptonemal complex assembly.

    Science.gov (United States)

    Davies, Owen R; Maman, Joseph D; Pellegrini, Luca

    2012-07-01

    The successful completion of meiosis is essential for all sexually reproducing organisms. The synaptonemal complex (SC) is a large proteinaceous structure that holds together homologous chromosomes during meiosis, providing the structural framework for meiotic recombination and crossover formation. Errors in SC formation are associated with infertility, recurrent miscarriage and aneuploidy. The current lack of molecular information about the dynamic process of SC assembly severely restricts our understanding of its function in meiosis. Here, we provide the first biochemical and structural analysis of an SC protein component and propose a structural basis for its function in SC assembly. We show that human SC proteins SYCE2 and TEX12 form a highly stable, constitutive complex, and define the regions responsible for their homotypic and heterotypic interactions. Biophysical analysis reveals that the SYCE2-TEX12 complex is an equimolar hetero-octamer, formed from the association of an SYCE2 tetramer and two TEX12 dimers. Electron microscopy shows that biochemically reconstituted SYCE2-TEX12 complexes assemble spontaneously into filamentous structures that resemble the known physical features of the SC central element (CE). Our findings can be combined with existing biological data in a model of chromosome synapsis driven by growth of SYCE2-TEX12 higher-order structures within the CE of the SC.

  19. Human guidance of mobile robots in complex 3D environments using smart glasses

    Science.gov (United States)

    Kopinsky, Ryan; Sharma, Aneesh; Gupta, Nikhil; Ordonez, Camilo; Collins, Emmanuel; Barber, Daniel

    2016-05-01

    In order for humans to safely work alongside robots in the field, the human-robot (HR) interface, which enables bi-directional communication between human and robot, should be able to quickly and concisely express the robot's intentions and needs. While the robot operates mostly in autonomous mode, the human should be able to intervene to effectively guide the robot in complex, risky and/or highly uncertain scenarios. Using smart glasses such as Google Glass∗, we seek to develop an HR interface that aids in reducing interaction time and distractions during interaction with the robot.

  20. Cellular and biomolecular responses of human ovarian cancer cells to cytostatic dinuclear platinum(II) complexes.

    Science.gov (United States)

    Lin, Miaoxin; Wang, Xiaoyong; Zhu, Jianhui; Fan, Damin; Zhang, Yangmiao; Zhang, Junfeng; Guo, Zijian

    2011-03-01

    Polynuclear platinum(II) complexes represent a class of potential anticancer agents that have shown promising pharmacological properties in preclinical studies. The nature of cellular responses induced by these complexes, however, is poorly understood. In this research, the cellular responses of human ovarian cancer COC1 cells to dinuclear platinum(II) complexes {[cis-Pt(NH₃)₂Cl]₂L¹}(NO₃)₂ (1) and {[cis-Pt(NH₃)₂Cl]₂L²}(NO₃)₂ (2) (L¹ = α,α'-diamino-p-xylene, L² = 4,4'-methylenedianiline) has been studied using cisplatin as a reference. The effect of platinum complexes on the proliferation, death mode, mitochondrial membrane potential, and cell cycle progression has been examined by MTT assay and flow cytometry. The activation of cell cycle checkpoint kinases (CHK1/2), extracellular signal-regulated kinases (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) of the cells by the complexes has also been analyzed using phospho-specific flow cytometry. Complex 1 is more cytotoxic than complex 2 and cisplatin at most concentrations; complex 2 and cisplatin are comparably cytotoxic. These complexes kill the cells through an apoptotic or apoptosis-like pathway characterized by exposure of phosphatidylserine and dissipation of mitochondrial membrane potential. Complex 1 shows the strongest inductive effect on the morphological changes of the cells, followed by cisplatin and complex 2. Complexes 1 and 2 arrest the cell cycle in G2 or M phase, while cisplatin arrests the cell cycle in S phase. The influence of these complexes on CHK1/2, ERK1/2, and p38 MAPK varies with the dose of the drugs or reaction time. Activation of phospho-ERK1/2 and phospho-p38 MAPK by these complexes is closely related to the cytostatic activity. The results demonstrate that dinuclear platinum(II) complexes can induce some cellular responses different from those caused by cisplatin.

  1. A Phase-Dependent Hypothesis for Locomotor Functions of Human Foot Complex

    Institute of Scientific and Technical Information of China (English)

    Lei Ren; David Howard; Lu-quan Ren; Chris Nester; Li-mei Tian

    2008-01-01

    The human foot is a very complex structure comprising numerous bones, muscles, ligaments and synovial joints. As the only component in contact with the ground, the foot complex delivers a variety of biomechanical functions during human locomotion, e.g. body support and propulsion, stability maintenance and impact absorption. These need the human foot to be rigid and damped to transmit ground reaction forces to the upper body and maintain body stability, and also to be compliant and resilient to moderate risky impacts and save energy. How does the human foot achieve these apparent conflicting functions? In this study, we propose a phase-dependent hypothesis for the overall locomotor functions of the human foot complex based on in-vivo measurements of human natural gait and simulation results of a mathematical foot model. We propse that foot functions are highly dependent on gait phase, which is a major characteristics of human locomotion. In early stance just after heel strike,the foot mainly works as a shock absorber by moderating high impacts using the viscouselastic heel pad in both. vertical and horizontal directions. In mid-stance phase(~80% of stance phase), the foot complex can be considered as a springy rocker,reserving external mechanical work using the foot arch whilst moving ground contact point forward along a curved path to maintain body stability. In late stance after heel off, the foot complex mainly serves as a force modulator like a gear box,modulating effective mechanical advantages of ankle plantiflexor muscles using metatarsal-phalangeal joints. A sound understanding of how diverse functions are implemented in a simple foot segment during human locomotion might be useful to gain insight into the overall foot locomotor functions and hence to facilitate clinical diagnosis, rehabilitation product design and humanoid robot development.

  2. GENE SILENCING. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells.

    Science.gov (United States)

    Tchasovnikarova, Iva A; Timms, Richard T; Matheson, Nicholas J; Wals, Kim; Antrobus, Robin; Göttgens, Berthold; Dougan, Gordon; Dawson, Mark A; Lehner, Paul J

    2015-06-26

    Forward genetic screens in Drosophila melanogaster for modifiers of position-effect variegation have revealed the basis of much of our understanding of heterochromatin. We took an analogous approach to identify genes required for epigenetic repression in human cells. A nonlethal forward genetic screen in near-haploid KBM7 cells identified the HUSH (human silencing hub) complex, comprising three poorly characterized proteins, TASOR, MPP8, and periphilin; this complex is absent from Drosophila but is conserved from fish to humans. Loss of HUSH components resulted in decreased H3K9me3 both at endogenous genomic loci and at retroviruses integrated into heterochromatin. Our results suggest that the HUSH complex is recruited to genomic loci rich in H3K9me3, where subsequent recruitment of the methyltransferase SETDB1 is required for further H3K9me3 deposition to maintain transcriptional silencing.

  3. Detailed analysis of the human mitochondrial contact site complex indicate a hierarchy of subunits.

    Science.gov (United States)

    Ott, Christine; Dorsch, Eva; Fraunholz, Martin; Straub, Sebastian; Kozjak-Pavlovic, Vera

    2015-01-01

    Mitochondrial inner membrane folds into cristae, which significantly increase its surface and are important for mitochondrial function. The stability of cristae depends on the mitochondrial contact site (MICOS) complex. In human mitochondria, the inner membrane MICOS complex interacts with the outer membrane sorting and assembly machinery (SAM) complex, to form the mitochondrial intermembrane space bridging complex (MIB). We have created knockdown cell lines of most of the MICOS and MIB components and have used them to study the importance of the individual subunits for the cristae formation and complex stability. We show that the most important subunits of the MIB complex in human mitochondria are Mic60/Mitofilin, Mic19/CHCHD3 and an outer membrane component Sam50. We provide additional proof that ApoO indeed is a subunit of the MICOS and MIB complexes and propose the name Mic23 for this protein. According to our results, Mic25/CHCHD6, Mic27/ApoOL and Mic23/ApoO appear to be periphery subunits of the MICOS complex, because their depletion does not affect cristae morphology or stability of other components.

  4. Social-network complexity in humans is associated with the neural response to social information.

    Science.gov (United States)

    Dziura, Sarah L; Thompson, James C

    2014-11-01

    Humans have evolved to thrive in large and complex social groups, and it is likely that this increase in group complexity has come with a greater need to decode and respond to complex and uncertain communicatory signals. In this functional MRI study, we examined whether complexity of social networks in humans is related to the functioning of brain regions key to the perception of basic, nonverbal social stimuli. Greater activation to biological than to scrambled motion in the right posterior superior temporal sulcus (pSTS) and right amygdala were positively correlated with the diversity of social-network roles. In the pSTS, in particular, this association was not due to a relationship between network diversity and network size. These findings suggest that increased functioning of brain regions involved in decoding social signals might facilitate the detection and decoding of subtle signals encountered in varied social settings.

  5. Vitamin B-complex initiates growth and development of human embryonic brain cells in vitro.

    Science.gov (United States)

    Danielyan, K E; Abramyan, R A; Galoyan, A A; Kevorkian, G A

    2011-09-01

    We studied a combined effect of subcomponents of vitamin B complex on the growth, development, and death of human embryonic brain-derived cells (E90) cultured using a modified method of Matson. Cell death was detected by trypan blue staining. According to our results, vitamin B-complex in low-doses promote the development, maturation, and enlargement of human embryonic brain cells, on the one hand, and increases the percent of cell death, which attests to accelerated maturation and metabolism, on the other.

  6. Resolving the complexity of the human genome using single-molecule sequencing.

    Science.gov (United States)

    Chaisson, Mark J P; Huddleston, John; Dennis, Megan Y; Sudmant, Peter H; Malig, Maika; Hormozdiari, Fereydoun; Antonacci, Francesca; Surti, Urvashi; Sandstrom, Richard; Boitano, Matthew; Landolin, Jane M; Stamatoyannopoulos, John A; Hunkapiller, Michael W; Korlach, Jonas; Eichler, Evan E

    2015-01-29

    The human genome is arguably the most complete mammalian reference assembly, yet more than 160 euchromatic gaps remain and aspects of its structural variation remain poorly understood ten years after its completion. To identify missing sequence and genetic variation, here we sequence and analyse a haploid human genome (CHM1) using single-molecule, real-time DNA sequencing. We close or extend 55% of the remaining interstitial gaps in the human GRCh37 reference genome--78% of which carried long runs of degenerate short tandem repeats, often several kilobases in length, embedded within (G+C)-rich genomic regions. We resolve the complete sequence of 26,079 euchromatic structural variants at the base-pair level, including inversions, complex insertions and long tracts of tandem repeats. Most have not been previously reported, with the greatest increases in sensitivity occurring for events less than 5 kilobases in size. Compared to the human reference, we find a significant insertional bias (3:1) in regions corresponding to complex insertions and long short tandem repeats. Our results suggest a greater complexity of the human genome in the form of variation of longer and more complex repetitive DNA that can now be largely resolved with the application of this longer-read sequencing technology.

  7. The SMC5/6 complex is involved in crucial processes during human spermatogenesis.

    Science.gov (United States)

    Verver, Dideke E; Langedijk, Nathalia S M; Jordan, Philip W; Repping, Sjoerd; Hamer, Geert

    2014-07-01

    Genome integrity is crucial for safe reproduction. Therefore, chromatin structure and dynamics should be tightly regulated during germ cell development. Chromatin structure and function are in large part determined by the structural maintenance of chromosomes (SMC) protein complexes, of which SMC5/6 recently has been shown to be involved in both spermatogonial differentiation and meiosis during mouse spermatogenesis. We therefore investigated the role of this complex in human spermatogenesis. We found SMC6 to be expressed in the human testis and present in a subset of type Adark and type Apale spermatogonia, all spermatocytes, and round spermatids. During human meiosis, SMC5/6 is located at the synaptonemal complex (SC), the XY body, and at the centromeres during meiotic metaphases. However, in contrast to mouse spermatogenesis, SMC6 is not located at pericentromeric heterochromatin in human spermatogenic cells, indicating subtle but perhaps important differences in not only SMC5/6 function but maybe also in maintenance of genomic integrity at the repetitive pericentromeric regions. Nonetheless, our data clearly indicate that the SMC5/6 complex, as shown in mice, is involved in numerous crucial processes during human spermatogenesis, such as in spermatogonial development, on the SC between synapsed chromosomes, and in DNA double-strand break repair on unsynapsed chromosomes during pachynema.

  8. In vivo formation of complex microvessels lined by human endothelial cells in an immunodeficient mouse

    OpenAIRE

    2000-01-01

    We have identified conditions for forming cultured human umbilical vein endothelial cells (HUVEC) into tubes within a three-dimensional gel that on implantation into immunoincompetent mice undergo remodeling into complex microvessels lined by human endothelium. HUVEC suspended in mixed collagen/fibronectin gels organize into cords with early lumena by 24 h and then apoptose. Twenty-hour constructs, s.c. implanted in immunodeficient mice, display HUVEC-lined thin-walled microvessels within the...

  9. How do precision medicine and system biology response to human body's complex adaptability?

    Science.gov (United States)

    Yuan, Bing

    2016-12-01

    In the field of life sciences, although system biology and "precision medicine" introduce some complex scientifific methods and techniques, it is still based on the "analysis-reconstruction" of reductionist theory as a whole. Adaptability of complex system increase system behaviour uncertainty as well as the difficulties of precise identifification and control. It also put systems biology research into trouble. To grasp the behaviour and characteristics of organism fundamentally, systems biology has to abandon the "analysis-reconstruction" concept. In accordance with the guidelines of complexity science, systems biology should build organism model from holistic level, just like the Chinese medicine did in dealing with human body and disease. When we study the living body from the holistic level, we will fifind the adaptability of complex system is not the obstacle that increases the diffificulty of problem solving. It is the "exceptional", "right-hand man" that helping us to deal with the complexity of life more effectively.

  10. Effects of human serun albumin in some biological properties of rhodium(II complexes

    Directory of Open Access Journals (Sweden)

    Espósito Breno P.

    2000-01-01

    Full Text Available The affinities for human albumin (HSA of five rhodium(II complexes of general formula [Rh2(bridge4] (bridge = acetate, propionate, butyrate, trifluoroacetate and trifluoroacetamidate were determined by spectrophotometry. In the case of the alkylcarboxylates, an inverse correlation of affinity with their liposolubilities was observed. Diffusion of the free or protein-bound complexes into Ehrlich cells in vitro seems to be primarily governed by the hydrophobic character of the complex. The complex [Rh2(tfc4] exhibited affinity towards the protein (K = 214.1 as well as cell partition both in the absence (32.1% and presence (48.6% of HSA. The compound HSA: [Rh2(tfc4] has had its antitumoral action in tumor-bearing Balb-c mice investigated, showing that HSA can be a drug reservoir for the rhodium complex.

  11. Interactions of the human MCM-BP protein with MCM complex components and Dbf4.

    Directory of Open Access Journals (Sweden)

    Tin Nguyen

    Full Text Available MCM-BP was discovered as a protein that co-purified from human cells with MCM proteins 3 through 7; results which were recapitulated in frogs, yeast and plants. Evidence in all of these organisms supports an important role for MCM-BP in DNA replication, including contributions to MCM complex unloading. However the mechanisms by which MCM-BP functions and associates with MCM complexes are not well understood. Here we show that human MCM-BP is capable of interacting with individual MCM proteins 2 through 7 when co-expressed in insect cells and can greatly increase the recovery of some recombinant MCM proteins. Glycerol gradient sedimentation analysis indicated that MCM-BP interacts most strongly with MCM4 and MCM7. Similar gradient analyses of human cell lysates showed that only a small amount of MCM-BP overlapped with the migration of MCM complexes and that MCM complexes were disrupted by exogenous MCM-BP. In addition, large complexes containing MCM-BP and MCM proteins were detected at mid to late S phase, suggesting that the formation of specific MCM-BP complexes is cell cycle regulated. We also identified an interaction between MCM-BP and the Dbf4 regulatory component of the DDK kinase in both yeast 2-hybrid and insect cell co-expression assays, and this interaction was verified by co-immunoprecipitation of endogenous proteins from human cells. In vitro kinase assays showed that MCM-BP was not a substrate for DDK but could inhibit DDK phosphorylation of MCM4,6,7 within MCM4,6,7 or MCM2-7 complexes, with little effect on DDK phosphorylation of MCM2. Since DDK is known to activate DNA replication through phosphorylation of these MCM proteins, our results suggest that MCM-BP may affect DNA replication in part by regulating MCM phosphorylation by DDK.

  12. Immunolocalisation pattern of complex I-V in ageing human retina: Correlation with mitochondrial ultrastructure.

    Science.gov (United States)

    Nag, Tapas Chandra; Wadhwa, Shashi

    2016-11-01

    Earlier studies reported accumulation of mitochondrial DNA mutations in ageing and age-related macular degeneration. To know about the mitochondrial status with age, we examined immunoreactivity (IR) to markers of mitochondria (anti-mitochondrial antibody and voltage-dependent anion channel-1) and complex I-V (that mediate oxidative phosphorylation, OXPHOS) in donor human retinas (age: 19-94years; N=26; right eyes). In all samples, at all ages, IR to anti-mitochondrial antibody and voltage-dependent anion channel-1 was prominent in photoreceptor cells. Between second and seventh decade of life, strong IR to complex I-V was present in photoreceptors over macular to peripheral retina. With progressive ageing, the photoreceptors showed a decrease in complex I-IR (subunit NDUFB4) at eighth decade, and a weak or absence of IR in 10 retinas between ninth and tenth decade. Patchy IR to complex III and complex IV was detected at different ages. IR to ND1 (complex I) and complex II and V remained unaltered with ageing. Nitrosative stress (evaluated by IR to a nitro-tyrosine antibody) was found in photoreceptors. Superoxide dismutase-2 was found upregulated in photoreceptors with ageing. Mitochondrial ultrastructure was examined in two young retinas with intact complex IR and six aged retinas whose counterparts showed weak to absence of IR. Observations revealed irregular, photoreceptor inner segment mitochondria in aged maculae and mid-peripheral retina between eighth and ninth decade; many cones possessed autophagosomes with damaged mitochondria, indicating age-related alterations. A trend in age-dependent reduction of complex I-IR was evident in aged photoreceptors, whereas patchy complex IV-IR (subunits I and II) was age-independent, suggesting that the former is prone to damage with ageing perhaps due to oxidative stress. These changes in OXPHOS system may influence the energy budget of human photoreceptors, affecting their viability. Copyright © 2016 Elsevier B.V. and

  13. Very stable high molecular mass multiprotein complex with DNase and amylase activities in human milk.

    Science.gov (United States)

    Soboleva, Svetlana E; Dmitrenok, Pavel S; Verkhovod, Timofey D; Buneva, Valentina N; Sedykh, Sergey E; Nevinsky, Georgy A

    2015-01-01

    For breastfed infants, human milk is more than a source of nutrients; it furnishes a wide array of proteins, peptides, antibodies, and other components promoting neonatal growth and protecting infants from viral and bacterial infection. It has been proposed that most biological processes are performed by protein complexes. Therefore, identification and characterization of human milk components including protein complexes is important for understanding the function of milk. Using gel filtration, we have purified a stable high molecular mass (~1000 kDa) multiprotein complex (SPC) from 15 preparations of human milk. Light scattering and gel filtration showed that the SPC was stable in the presence of high concentrations of NaCl and MgCl2 but dissociated efficiently under the conditions that destroy immunocomplexes (2 M MgCl2 , 0.5 M NaCl, and 10 mM DTT). Such a stable complex is unlikely to be a casual associate of different proteins. The relative content of the individual SPCs varied from 6% to 25% of the total milk protein. According to electrophoretic and mass spectrometry analysis, all 15 SPCs contained lactoferrin (LF) and α-lactalbumin as major proteins, whereas human milk albumin and β-casein were present in moderate or minor amounts; a different content of IgGs and sIgAs was observed. All SPCs efficiently hydrolyzed Plasmid supercoiled DNA and maltoheptaose. Some freshly prepared SPC preparations contained not only intact LF but also small amounts of its fragments, which appeared in all SPCs during their prolonged storage; the fragments, similar to intact LF, possessed DNase and amylase activities. LF is found in human epithelial secretions, barrier body fluids, and in the secondary granules of leukocytes. LF is a protein of the acute phase response and nonspecific defense against different types of microbial and viral infections. Therefore, LF complexes with other proteins may be important for its functions not only in human milk.

  14. Mixed-complexity artificial grammar learning in humans and macaque monkeys: evaluating learning strategies.

    Science.gov (United States)

    Wilson, Benjamin; Smith, Kenny; Petkov, Christopher I

    2015-03-01

    Artificial grammars (AG) can be used to generate rule-based sequences of stimuli. Some of these can be used to investigate sequence-processing computations in non-human animals that might be related to, but not unique to, human language. Previous AG learning studies in non-human animals have used different AGs to separately test for specific sequence-processing abilities. However, given that natural language and certain animal communication systems (in particular, song) have multiple levels of complexity, mixed-complexity AGs are needed to simultaneously evaluate sensitivity to the different features of the AG. Here, we tested humans and Rhesus macaques using a mixed-complexity auditory AG, containing both adjacent (local) and non-adjacent (longer-distance) relationships. Following exposure to exemplary sequences generated by the AG, humans and macaques were individually tested with sequences that were either consistent with the AG or violated specific adjacent or non-adjacent relationships. We observed a considerable level of cross-species correspondence in the sensitivity of both humans and macaques to the adjacent AG relationships and to the statistical properties of the sequences. We found no significant sensitivity to the non-adjacent AG relationships in the macaques. A subset of humans was sensitive to this non-adjacent relationship, revealing interesting between- and within-species differences in AG learning strategies. The results suggest that humans and macaques are largely comparably sensitive to the adjacent AG relationships and their statistical properties. However, in the presence of multiple cues to grammaticality, the non-adjacent relationships are less salient to the macaques and many of the humans.

  15. Complexity

    CERN Document Server

    Gershenson, Carlos

    2011-01-01

    The term complexity derives etymologically from the Latin plexus, which means interwoven. Intuitively, this implies that something complex is composed by elements that are difficult to separate. This difficulty arises from the relevant interactions that take place between components. This lack of separability is at odds with the classical scientific method - which has been used since the times of Galileo, Newton, Descartes, and Laplace - and has also influenced philosophy and engineering. In recent decades, the scientific study of complexity and complex systems has proposed a paradigm shift in science and philosophy, proposing novel methods that take into account relevant interactions.

  16. Temporal coherence for complex signals in budgerigars (Melopsittacus undulatus) and humans (Homo sapiens).

    Science.gov (United States)

    Neilans, Erikson G; Dent, Micheal L

    2015-05-01

    The auditory scene is filled with an array of overlapping acoustic signals, yet relatively little work has focused on how animals are able to perceptually isolate different sound sources necessary for survival. Much of the previous work on auditory scene analysis has investigated how sequential pure tone stimuli are perceived, but how temporally overlapping complex communication signals are segregated has been largely ignored. In this study, budgerigars and humans were tested using psychophysical procedures to measure their perception of synchronous, asynchronous, and partially overlapping complex signals, including bird calls and human vowels. Segregation thresholds for complex stimuli were significantly lower than those for pure tone stimuli in both humans and birds. Additionally, a species effect was discovered such that relative to humans, budgerigars required significantly less temporal separation between 2 sounds in order to segregate them. Overall, and similar to previous behavioral results investigating temporal coherence, the results from this experiment illustrate that temporal cues are particularly important for auditory scene analysis across multiple species and for both simple and complex acoustic signals.

  17. Localising versus standardising electronic human resource management: complexities and tensions between HRM and IT departments

    NARCIS (Netherlands)

    Tate, Mary; Furtmueller, E.; Wilderom, C.P.M.

    2013-01-01

    In this paper, we provide an analysis of the complexities involved during global e-HRM (Electronic Human Resource Management) implementation. We present findings from a case study on the challenge of global integration versus local responsiveness of e-HRM systems. We take a local site lens, analysin

  18. The genetics of complex human behaviour: Cannabis use, personality, sexuality and mating

    NARCIS (Netherlands)

    Verweij, K.J.H.

    2012-01-01

    I investigated the genetic and environmental etiology of individual differences in a variety of complex human behaviours, broadly captured within three domains - 1) cannabis use, 2) personality, and 3) sexuality and mating. Research questions and hypotheses are addressed with large community-based,

  19. Training Social Workers and Human Service Professionals to Address the Complex Financial Needs of Clients

    Science.gov (United States)

    Frey, Jodi Jacobson; Hopkins, Karen; Osteen, Philip; Callahan, Christine; Hageman, Sally; Ko, Jungyai

    2017-01-01

    In social work and other community-based human services settings, clients often present with complex financial problems. As a need for more formal training is beginning to be addressed, evaluation of existing training is important, and this study evaluates outcomes from the Financial Stability Pathway (FSP) project. Designed to prepare…

  20. MOLECULAR CHARACTERIZATION OF A RECURRING COMPLEX CHROMOSOMAL TRANSLOCATION IN 2 HUMAN EXTRAGONADAL GERM-CELL TUMORS

    NARCIS (Netherlands)

    SINKE, RJ; WEGHUIS, DO; SUIJKERBUIJK, RF; TANIGAMI, A; NAKAMURA, Y; LARSSON, C; WEBER, G; DEJONG, B; OOSTERHUIS, JW; MOLENAAR, WM; VANKESSEL, AG

    1994-01-01

    The molecular characterization of a recurring complex chromosomal translocation involving 6p21, 6p22, 6p23, and 11q13 in two independent bur similar extragonadal human germ cell rumors was initiated using fluorescence in situ hybridization (FISH) and pulse field gel electrophoresis (PFGE) techniques

  1. Molecular characterization of a recurring complex chromosomal translocation in two human extragonadal germ cell tumors.

    NARCIS (Netherlands)

    Sinke, R J; Weghuis, D O; Suijkerbuijk, R F; Tanigami, A; Nakamura, Y; Larsson, C; Weber, G; Jong, B de; Oosterhuis, J W; Molenaar, W M

    1994-01-01

    The molecular characterization of a recurring complex chromosomal translocation involving 6p21, 6p22, 6q23, and 11q13 in two independent but similar extragonadal human germ cell tumors was initiated using fluorescence in situ hybridization (FISH) and pulse field gel electrophoresis (PFGE) techniques

  2. Plasticity in Single Axon Glutamatergic Connection to GABAergic Interneurons Regulates Complex Events in the Human Neocortex.

    Science.gov (United States)

    Szegedi, Viktor; Paizs, Melinda; Csakvari, Eszter; Molnar, Gabor; Barzo, Pal; Tamas, Gabor; Lamsa, Karri

    2016-11-01

    In the human neocortex, single excitatory pyramidal cells can elicit very large glutamatergic EPSPs (VLEs) in inhibitory GABAergic interneurons capable of triggering their firing with short (3-5 ms) delay. Similar strong excitatory connections between two individual neurons have not been found in nonhuman cortices, suggesting that these synapses are specific to human interneurons. The VLEs are crucial for generating neocortical complex events, observed as single pyramidal cell spike-evoked discharge of cell assemblies in the frontal and temporal cortices. However, long-term plasticity of the VLE connections and how the plasticity modulates neocortical complex events has not been studied. Using triple and dual whole-cell recordings from synaptically connected human neocortical layers 2-3 neurons, we show that VLEs in fast-spiking GABAergic interneurons exhibit robust activity-induced long-term depression (LTD). The LTD by single pyramidal cell 40 Hz spike bursts is specific to connections with VLEs, requires group I metabotropic glutamate receptors, and has a presynaptic mechanism. The LTD of VLE connections alters suprathreshold activation of interneurons in the complex events suppressing the discharge of fast-spiking GABAergic cells. The VLEs triggering the complex events may contribute to cognitive processes in the human neocortex, and their long-term plasticity can alter the discharging cortical cell assemblies by learning.

  3. MOLECULAR CHARACTERIZATION OF A RECURRING COMPLEX CHROMOSOMAL TRANSLOCATION IN 2 HUMAN EXTRAGONADAL GERM-CELL TUMORS

    NARCIS (Netherlands)

    SINKE, RJ; WEGHUIS, DO; SUIJKERBUIJK, RF; TANIGAMI, A; NAKAMURA, Y; LARSSON, C; WEBER, G; DEJONG, B; OOSTERHUIS, JW; MOLENAAR, WM; VANKESSEL, AG

    1994-01-01

    The molecular characterization of a recurring complex chromosomal translocation involving 6p21, 6p22, 6p23, and 11q13 in two independent bur similar extragonadal human germ cell rumors was initiated using fluorescence in situ hybridization (FISH) and pulse field gel electrophoresis (PFGE) techniques

  4. Recent Emergence of Staphylococcus aureus Clonal Complex 398 in Human Blood Cultures

    NARCIS (Netherlands)

    E. Verkade (Erwin); A.M.C. Bergmans (Anneke); A.E. Budding (Andries); A.F. van Belkum (Alex); P.H.M. Savelkoul (Paul); A.G.M. Buiting (Anton); J.A.J.W. Kluytmans (Jan)

    2012-01-01

    textabstractBackground: Recently, a clone of MRSA with clonal complex 398 (CC398) has emerged that is related to an extensive reservoir in animals, especially pigs and veal calves. It has been reported previously that methicillin-susceptible variants of CC398 circulate among humans at low frequency,

  5. Using Complexity Measure to Characterize Information Transmission of Human Brain Cortex

    Institute of Scientific and Technical Information of China (English)

    徐京华; 吴祥宝

    1994-01-01

    The information transmission among various parts of the cortex are computed with the the-ory of mutual information from the data of the electroencephalogram(EEG)time series of normal humansubjects.The intensities of these transmissions are characterized by the"complexity"measures.These mea-sures have revealed to be sensitively related to the functional conditions of human beings.

  6. Multi-view 3D human pose estimation in complex environment

    NARCIS (Netherlands)

    M. Hofmann; D.M. Gavrila

    2012-01-01

    We introduce a framework for unconstrained 3D human upper body pose estimation from multiple camera views in complex environment. Its main novelty lies in the integration of three components: single-frame pose recovery, temporal integration and model texture adaptation. Single-frame pose recovery co

  7. Multi-view 3D Human Pose Estimation in Complex Environment

    NARCIS (Netherlands)

    Hofmann, K.M.; Gavrila, D.M.

    2012-01-01

    We introduce a framework for unconstrained 3D human upper body pose estimation from multiple camera views in complex environment. Its main novelty lies in the integration of three components: single-frame pose recovery, temporal integration and model texture adaptation. Single-frame pose recovery co

  8. Impact of familiarity on information complexity in human-computer interfaces

    Directory of Open Access Journals (Sweden)

    Bakaev Maxim

    2016-01-01

    Full Text Available A quantitative measure of information complexity remains very much desirable in HCI field, since it may aid in optimization of user interfaces, especially in human-computer systems for controlling complex objects. Our paper is dedicated to exploration of subjective (subject-depended aspect of the complexity, conceptualized as information familiarity. Although research of familiarity in human cognition and behaviour is done in several fields, the accepted models in HCI, such as Human Processor or Hick-Hyman’s law do not generally consider this issue. In our experimental study the subjects performed search and selection of digits and letters, whose familiarity was conceptualized as frequency of occurrence in numbers and texts. The analysis showed significant effect of information familiarity on selection time and throughput in regression models, although the R2 values were somehow low. Still, we hope that our results might aid in quantification of information complexity and its further application for optimizing interaction in human-machine systems.

  9. The genetics of complex human behaviour: Cannabis use, personality, sexuality and mating

    NARCIS (Netherlands)

    Verweij, K.J.H.

    2012-01-01

    I investigated the genetic and environmental etiology of individual differences in a variety of complex human behaviours, broadly captured within three domains - 1) cannabis use, 2) personality, and 3) sexuality and mating. Research questions and hypotheses are addressed with large community-based,

  10. DNA induces conformational changes in a recombinant human minichromosome maintenance complex.

    Science.gov (United States)

    Hesketh, Emma L; Parker-Manuel, Richard P; Chaban, Yuriy; Satti, Rabab; Coverley, Dawn; Orlova, Elena V; Chong, James P J

    2015-03-20

    ATP-dependent DNA unwinding activity has been demonstrated for recombinant archaeal homohexameric minichromosome maintenance (MCM) complexes and their yeast heterohexameric counterparts, but in higher eukaryotes such as Drosophila, MCM-associated DNA helicase activity has been observed only in the context of a co-purified Cdc45-MCM-GINS complex. Here, we describe the production of the recombinant human MCM (hMCM) complex in Escherichia coli. This protein displays ATP hydrolysis activity and is capable of unwinding duplex DNA. Using single-particle asymmetric EM reconstruction, we demonstrate that recombinant hMCM forms a hexamer that undergoes a conformational change when bound to DNA. Recombinant hMCM produced without post-translational modifications is functional in vitro and provides an important tool for biochemical reconstitution of the human replicative helicase.

  11. Human factors issues for resolving adverse effects of human work underload and workload transitions in complex human-machine systems

    Energy Technology Data Exchange (ETDEWEB)

    Ryan, T.G.

    1995-10-01

    A workshop was conducted whose specific purpose was to build on earlier work of the United States National Research Council, United States Federal government agencies, and the larger human factors community to: (1) clarify human factors issues pertaining to degraded performance in advanced human-machine systems (e.g., nuclear production, transportation, aerospace) due to human work underload and workload transition, and (2) develop strategies for resolving these issues. Recent history demonstrates that: (1) humans often react adversely to their diminishing roles in advanced human-machine systems, and therefore (2) new allocation models and strategies are required if humans are to be willing and able to assume diminishing and shifting roles assigned to them in these systems, and are to accept new technologies making up these systems. Problems associated with theses diminishing and shifting human roles are characterized as work underload and workload transitions. The workshop affirmed that: (1) work underload and workload transition are issues that will have to be addressed by designers of advanced human-machine systems, especially those relying on automation, if cost, performance, safety, and operator acceptability are to be optimized, (2) human machine allocation models, standards, and guidelines which go beyond simple capability approaches will be needed to preclude or seriously diminish the work underload and workload transition problems, and (3) the 16 workload definition, measurement, situational awareness, and trust issues identified during the workshop, need resolution if these models, standards, and guidelines are to be achieved.

  12. Synergy and antagonism in regulation of recombinant human INO80 chromatin remodeling complex

    Science.gov (United States)

    Willhoft, Oliver; Bythell-Douglas, Rohan; McCormack, Elizabeth A.; Wigley, Dale B.

    2016-01-01

    We have purified a minimal core human Ino80 complex from recombinant protein expressed in insect cells. The complex comprises one subunit each of an N-terminally truncated Ino80, actin, Arp4, Arp5, Arp8, Ies2 and Ies6, together with a single heterohexamer of the Tip49a and Tip49b proteins. This core complex has nucleosome sliding activity that is similar to that of endogenous human and yeast Ino80 complexes and is also inhibited by inositol hexaphosphate (IP6). We show that IP6 is a non-competitive inhibitor that acts by blocking the stimulatory effect of nucleosomes on the ATPase activity. The IP6 binding site is located within the C-terminal region of the Ino80 subunit. We have also prepared complexes lacking combinations of Ies2 and Arp5/Ies6 subunits that reveal regulation imposed by each of them individually and synergistically that couples ATP hydrolysis to nucleosome sliding. This coupling between Ies2 and Arp5/Ies6 can be overcome in a bypass mutation of the Arp5 subunit that is active in the absence of Ies2. These studies reveal several underlying mechanisms for regulation of ATPase activity involving a complex interplay between these protein subunits and IP6 that in turn controls nucleosome sliding. PMID:27257055

  13. Does human migration affect international trade? A complex-network perspective.

    Directory of Open Access Journals (Sweden)

    Giorgio Fagiolo

    Full Text Available This paper explores the relationships between international human migration and merchandise trade, using a complex-network approach. We firstly compare the topological structure of worldwide networks of human migration and bilateral trade over the period 1960-2000. Next, we ask whether the position of any pair of countries in the migration network affects their bilateral trade flows. We show that: (i both weighted and binary versions of the networks of international migration and trade are strongly correlated; (ii such correlations can be mostly explained by country economic/demographic size and geographical distance; and (iii pairs of countries that are more central in the international-migration network trade more. Our findings suggest that bilateral trade between any two countries is not only affected by the presence of migrants from either countries but also by their relative embeddedness in the complex web of corridors making up the network of international human migration.

  14. Retrospective analysis of main and interaction effects in genetic association studies of human complex traits

    DEFF Research Database (Denmark)

    Tan, Qihua; Christiansen, Lene; Brasch-Andersen, Charlotte;

    2007-01-01

    BACKGROUND: The etiology of multifactorial human diseases involves complex interactions between numerous environmental factors and alleles of many genes. Efficient statistical tools are demanded in identifying the genetic and environmental variants that affect the risk of disease development....... This paper introduces a retrospective polytomous logistic regression model to measure both the main and interaction effects in genetic association studies of human discrete and continuous complex traits. In this model, combinations of genotypes at two interacting loci or of environmental exposure...... regression model can be used as a convenient tool for assessing both main and interaction effects in genetic association studies of human multifactorial diseases involving genetic and non-genetic factors as well as categorical or continuous traits....

  15. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells*

    Science.gov (United States)

    Matheson, Nicholas J.; Wals, Kim; Antrobus, Robin; Göttgens, Berthold; Dougan, Gordon; Dawson, Mark A.; Lehner, Paul J.

    2015-01-01

    Forward genetic screens in Drosophila melanogaster for modifiers of position-effect variegation have revealed the basis of much of our understanding of heterochromatin. We took an analogous approach to identify genes required for epigenetic repression in human cells. A non-lethal forward genetic screen in near-haploid KBM7 cells identified the Human Silencing Hub (HUSH), a complex of three poorly-characterised proteins, TASOR, MPP8, and periphilin, which is absent from Drosophila but conserved from fish to humans. Loss of HUSH subunits resulted in decreased H3K9me3 at both endogenous genomic loci and retroviruses integrated into heterochromatin. Our results suggest that the HUSH complex is recruited to genomic loci rich in H3K9me3, where subsequent recruitment of the methyltransferase SETDB1 is required for further H3K9me3 deposition to maintain transcriptional silencing. PMID:26022416

  16. Complex for monitoring visual acuity and its application for evaluation of human psycho-physiological state

    Science.gov (United States)

    Sorokoumov, P. S.; Khabibullin, T. R.; Tolstaya, A. M.

    2017-01-01

    The existing psychological theories associate the movement of a human eye with its reactions to external change: what we see, hear and feel. By analyzing the glance, we can compare the external human response (which shows the behavior of a person), and the natural reaction (that they actually feels). This article describes the complex for detection of visual activity and its application for evaluation of the psycho-physiological state of a person. The glasses with a camera capture all the movements of the human eye in real time. The data recorded by the camera are transmitted to the computer for processing implemented with the help of the software developed by the authors. The result is given in an informative and an understandable report, which can be used for further analysis. The complex shows a high efficiency and stable operation and can be used both, for the pedagogic personnel recruitment and for testing students during the educational process.

  17. Does human migration affect international trade? A complex-network perspective.

    Science.gov (United States)

    Fagiolo, Giorgio; Mastrorillo, Marina

    2014-01-01

    This paper explores the relationships between international human migration and merchandise trade, using a complex-network approach. We firstly compare the topological structure of worldwide networks of human migration and bilateral trade over the period 1960-2000. Next, we ask whether the position of any pair of countries in the migration network affects their bilateral trade flows. We show that: (i) both weighted and binary versions of the networks of international migration and trade are strongly correlated; (ii) such correlations can be mostly explained by country economic/demographic size and geographical distance; and (iii) pairs of countries that are more central in the international-migration network trade more. Our findings suggest that bilateral trade between any two countries is not only affected by the presence of migrants from either countries but also by their relative embeddedness in the complex web of corridors making up the network of international human migration.

  18. Early modern human diversity suggests subdivided population structure and a complex out-of-Africa scenario.

    Science.gov (United States)

    Gunz, Philipp; Bookstein, Fred L; Mitteroecker, Philipp; Stadlmayr, Andrea; Seidler, Horst; Weber, Gerhard W

    2009-04-14

    The interpretation of genetic evidence regarding modern human origins depends, among other things, on assessments of the structure and the variation of ancient populations. Because we lack genetic data from the time when the first anatomically modern humans appeared, between 200,000 and 60,000 years ago, instead we exploit the phenotype of neurocranial geometry to compare the variation in early modern human fossils with that in other groups of fossil Homo and recent modern humans. Variation is assessed as the mean-squared Procrustes distance from the group average shape in a representation based on several hundred neurocranial landmarks and semilandmarks. We find that the early modern group has more shape variation than any other group in our sample, which covers 1.8 million years, and that they are morphologically similar to recent modern humans of diverse geographically dispersed populations but not to archaic groups. Of the currently competing models of modern human origins, some are inconsistent with these findings. Rather than a single out-of-Africa dispersal scenario, we suggest that early modern humans were already divided into different populations in Pleistocene Africa, after which there followed a complex migration pattern. Our conclusions bear implications for the inference of ancient human demography from genetic models and emphasize the importance of focusing research on those early modern humans, in particular, in Africa.

  19. Complex

    African Journals Online (AJOL)

    CLEMENT O BEWAJI

    Schiff bases and their complex compounds have been studied for their .... establishing coordination of the N–(2 – hydroxybenzyl) - L - α - valine Schiff base ..... (1967); “Spectrophotometric Identification of Organic Compounds”, Willey, New.

  20. How Humans Solve Complex Problems: The Case of the Knapsack Problem

    Science.gov (United States)

    Murawski, Carsten; Bossaerts, Peter

    2016-01-01

    Life presents us with problems of varying complexity. Yet, complexity is not accounted for in theories of human decision-making. Here we study instances of the knapsack problem, a discrete optimisation problem commonly encountered at all levels of cognition, from attention gating to intellectual discovery. Complexity of this problem is well understood from the perspective of a mechanical device like a computer. We show experimentally that human performance too decreased with complexity as defined in computer science. Defying traditional economic principles, participants spent effort way beyond the point where marginal gain was positive, and economic performance increased with instance difficulty. Human attempts at solving the instances exhibited commonalities with algorithms developed for computers, although biological resource constraints–limited working and episodic memories–had noticeable impact. Consistent with the very nature of the knapsack problem, only a minority of participants found the solution–often quickly–but the ones who did appeared not to realise. Substantial heterogeneity emerged, suggesting why prizes and patents, schemes that incentivise intellectual discovery but discourage information sharing, have been found to be less effective than mechanisms that reveal private information, such as markets. PMID:27713516

  1. Inclusion complexes of Ketoprofen with β-cyclodextrins: Oral pharmacokinetics of Ketoprofen in human

    Directory of Open Access Journals (Sweden)

    Tayade P

    2006-01-01

    Full Text Available The inclusion behavior of hydroxypropyl b-cyclodextrin and natural b-cyclodextrin was studied toward ketoprofen, in order to develop a new oral dosage form with enhanced dissolution rate and bioavailability, and to study the oral pharmacokinetics of ketoprofen in humans, following cyclodextrin complexation. Drug-cyclodextrin solid systems were prepared by kneading, co-evaporation, and freeze-drying. The formation of inclusion complexes with b-cyclodextrin and hydroxypropyl b-cyclodextrin in the solid state, were confirmed by differential scanning calorimetry, Fourier transform infrared spectroscopy, powder X-ray diffractometry, scanning electron microscopy studies, and comparative studies on the in vitro dissolution and in vivo absorption of ketoprofen in humans volunteers, were carried out. The initial dissolution rate of ketoprofen in the inclusion complexes was 15 fold higher, than that of plain drug powder. The maximal plasma concentration of ketoprofen after the oral administration of inclusion complexes to human volunteers increased about 1.5 fold (7.15 vs 4.65 mg/ml, and there was no significant increase in area under concentration-time curve, AUC0-5 (10.35 vs. 9.35 mg. hr/ml, compared to those of ketoprofen powder alone.

  2. Current theoretical models fail to predict the topological complexity of the human genome.

    Science.gov (United States)

    Arsuaga, Javier; Jayasinghe, Reyka G; Scharein, Robert G; Segal, Mark R; Stolz, Robert H; Vazquez, Mariel

    2015-01-01

    Understanding the folding of the human genome is a key challenge of modern structural biology. The emergence of chromatin conformation capture assays (e.g., Hi-C) has revolutionized chromosome biology and provided new insights into the three dimensional structure of the genome. The experimental data are highly complex and need to be analyzed with quantitative tools. It has been argued that the data obtained from Hi-C assays are consistent with a fractal organization of the genome. A key characteristic of the fractal globule is the lack of topological complexity (knotting or inter-linking). However, the absence of topological complexity contradicts results from polymer physics showing that the entanglement of long linear polymers in a confined volume increases rapidly with the length and with decreasing volume. In vivo and in vitro assays support this claim in some biological systems. We simulate knotted lattice polygons confined inside a sphere and demonstrate that their contact frequencies agree with the human Hi-C data. We conclude that the topological complexity of the human genome cannot be inferred from current Hi-C data.

  3. Three-dimensional cartography of functional territories in the human striatopallidal complex by using calbindin immunoreactivity.

    Science.gov (United States)

    Karachi, Carine; François, Chantal; Parain, Karine; Bardinet, Eric; Tandé, Dominique; Hirsch, Etienne; Yelnik, Jérôme

    2002-08-19

    This anatomic study presents an analysis of the distribution of calbindin immunohistochemistry in the human striatopallidal complex. Entire brains were sectioned perpendicularly to the mid-commissural line into 70-microm-thick sections. Every tenth section was immunostained for calbindin. Calbindin labeling exhibited a gradient on the basis of which three different regions were defined: poorly labeled, strongly labeled, and intermediate. Corresponding contours were traced in individual sections and reformatted as three-dimensional structures. The poorly labeled region corresponded to the dorsal part of the striatum and to the central part of the pallidum. The strongly labeled region included the ventral part of the striatum, the subcommissural part of the external pallidum but also the adjacent portion of its suscommissural part, and the anterior pole of the internal pallidum. The intermediate region was located between the poorly and strongly labeled regions. As axonal tracing and immunohistochemical studies in monkeys show a similar pattern, poorly, intermediate, and strongly labeled regions were considered as the sensorimotor, associative, and limbic territories of the human striatopallidal complex, respectively. However, the boundaries between these territories were not sharp but formed gradients of labeling, which suggests overlapping between adjacent territories. Similarly, the ventral boundary of the striatopallidal complex was blurred, suggesting a structural intermingling with the substantia innominata. This three-dimensional partitioning of the human striatopallidal complex could help to define functional targets for high-frequency stimulation with greater accuracy and help to identify new stimulation sites.

  4. Ontogeny of neuro-insular complexes and islets innervation in the human pancreas.

    Directory of Open Access Journals (Sweden)

    Alexandra E. Proshchina

    2014-04-01

    Full Text Available The ontogeny of the neuro-insular complexes (NIC and the islets innervation in human pancreas has not been studied in detail. Our aim was to describe the developmental dynamics and distribution of the nervous system structures in the endocrine part of human pancreas. We used doublestaining with antibodies specific to pan-neural markers (neuron-specific enolase (NSE and S100 protein and to hormones of pancreatic endocrine cells. NSE and S100-positive nerves and ganglia were identified in the human fetal pancreas from gestation week (gw 10 onwards. Later the density of S100 and NSE-positive fibers increased. In adults this network was sparse. The islets innervation started to form from gw 14. NSE-containing endocrine cells were identified from gw 12 onwards. Additionally, S100-positive cells were detected both in the periphery and within some of the islets starting at gw 14. The analysis of islets innervation has shown that the fetal pancreas contained neuro-insular complexes and the number of these complexes was reduced in adults. The highest density of neuro-insular complexes is detected during middle and late fetal periods, when the mosaic islets, typical for adults, form. The close integration between the developing pancreatic islets and the nervous system structures may play an important role not only in the hormone secretion, but also in the islets morphogenesis.

  5. Adsorption of an amphiphilic penicillin onto human serum albumin: characterisation of the complex.

    Science.gov (United States)

    Ruso, J M; Taboada, P; Varela, L M; Attwood, D; Mosquera, V

    2001-08-30

    The complex formed by the interaction of the amphiphilic penicillin drug nafcillin and human serum albumin (HSA) in water at 25 degrees C has been characterised using a range of physicochemical techniques. Measurements of the solution conductivity and the electrophoretic mobility of the complexes have shown an ionic adsorption of the drug on the protein surface leading to a surface saturation at a nafcillin concentration of 0.012 mmol kg(-1) and subsequent formation of drug micelles in solutions of higher nafcillin concentration. Measurements of the size of the complex and the thickness of the adsorbed layer by static and dynamic light scattering have shown a gradual change in hydrodynamic radius of the complex with increasing drug concentration typical of a saturation rather than a denaturation process, the magnitude of the change being insufficient to account for any appreciable extension or unfolding of the HSA molecule. The interaction potential between the HSA/nafcillin complexes, and the stability of the complexes were determined from the dependence of diffusion coefficients on protein concentration by application of the DLVO colloidal stability theory. The results indicate decreasing stability of the colloidal dispersion of the drug/protein complexes with an increase in the concentration of added drug.

  6. Noncovalent interactions between a trinuclear monofunctional platinum complex and human serum albumin.

    Science.gov (United States)

    Wang, Yanqing; Wang, Xiaoyong; Wang, Jing; Zhao, Yongmei; He, Weijiang; Guo, Zijian

    2011-12-19

    Interactions between platinum complexes and human serum albumin (HSA) play crucial roles in the metabolism, distribution, and efficacy of platinum-based anticancer drugs. Polynuclear monofunctional platinum(II) complexes represent a new class of anticancer agents that display distinct molecular characters of pharmacological action from those of cisplatin. In this study, the interaction between a trinuclear monofunctional platinum(II) complex, [Pt(3)LCl(3)](ClO(4))(3) (L = N,N,N',N',N",N"-hexakis(2-pyridylmethyl)-1,3,5-tris(aminomethyl)benzene) (1), and HSA was investigated using ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, circular dichroism spectroscopy, fluorescence spectroscopy, molecular docking, and inductively coupled plasma mass spectrometry. The spectroscopic and thermodynamic data show that the interaction is a spontaneous process with the estimated enthalpy and entropy changes being 14.6 kJ mol(-1) and 145.5 J mol(-1) K(-1), respectively. The reactive sites of HSA to complex 1 mainly locate within its hydrophobic cavity in domain II. Noncovalent actions such as π-π stacking and hydrophobic bonding are the primary contributors to the interaction between HSA and complex 1, which is different from the scenario for cisplatin in similar conditions. The results suggest that the connection between complex 1 and HSA is reversible, and therefore the cytotoxic activity of the complex could be preserved during blood circulation.

  7. Regulation of human ornithine decarboxylase expression by the c-Myc.Max protein complex.

    Science.gov (United States)

    Peña, A; Reddy, C D; Wu, S; Hickok, N J; Reddy, E P; Yumet, G; Soprano, D R; Soprano, K J

    1993-12-25

    The presence of a CACGTG element within a region of the human ornithine decarboxylase (ODC) promoter located at -491 to -474 base pairs 5' to the start site of transcription suggested that the c-Myc.Max protein complex may play a role in the regulation of ODC expression during growth. Electrophoretic mobility shift assays and methylation interference analysis showed that the nuclei of WI-38 cells expressing ODC contained proteins that bound to this region of the ODC gene in a manner that correlated with growth-associated ODC expression. Also, use of antibodies against c-Myc and Max and purified recombinant c-Myc and Max protein in the electrophoretic mobility shift assay confirmed that these proteins can specifically bind this portion of the human ODC promoter. Transient transfection studies showed that increase in the level of c-Myc and/or Max led to a significant enhancement of expression of a human ODC promoter-CAT reporter construct. Moreover, treatment of actively growing WI-38 cells with an antisense oligomer to c-Myc reduced the amount of endogenous protein complex formed and the amount of endogenous ODC mRNA expressed. These studies show that the c-Myc.Max protein complex plays a role in the transcriptional regulation of human ODC in vivo.

  8. Information Sharing from 9-1-1 Centers

    Science.gov (United States)

    2014-09-01

    standardize the management, police, and operational procedures of PSAPs and 67 “ ISO 9001 Quality Management...International Organization for Standards. “ ISO 9001 Quality Management System: Business and Quality Management.” 2011. http://www.standards.org

  9. Stereological estimation of the number of neurons in the human amygdaloid complex.

    Science.gov (United States)

    Schumann, Cynthia Mills; Amaral, David G

    2005-10-31

    Pathological changes in neuronal density in the amygdaloid complex have been associated with various neurological disorders. However, due to variable shrinkage during tissue processing, the only way to determine changes in neuron number unambiguously is to estimate absolute counts, rather than neuronal density. As the first stage in evaluating potential neuropathology of the amygdala in autism, the total number of neurons was estimated in the control human amygdaloid complex by using stereological sampling. The intact amygdaloid complex from one hemisphere of 10 brains was frozen and sectioned. One 100-microm section was selected every 500 microm and stained by the standard Nissl method. The entire amygdaloid complex was outlined and then further partitioned into five reliably defined subdivisions: 1) the lateral nucleus, 2) the basal nucleus, 3) the accessory basal nucleus, 4) the central nucleus, and 5) the remaining nuclei (including anterior cortical, anterior amygdaloid area, periamygdaloid cortex, medial, posterior cortical, nucleus of the lateral olfactory tract, amygdalohippocampal area, and intercalated nuclei). The number of neurons was measured by using an optical fractionator with Stereoinvestigator software. The mean number of neurons (x 10(6)) for each region was as follows: lateral nucleus 4.00, basal nucleus 3.24, accessory basal nucleus 1.28, central nucleus 0.36, remaining nuclei 3.33, and total amygdaloid complex 12.21. The stereological assessment of neuron number in the human amygdala provides an essential baseline for comparison of patient populations, such as autism, in which the amygdala may develop abnormally. To facilitate these types of analyses, this paper provides a detailed anatomical description of the methods used to define subdivisions of the human amygdaloid complex.

  10. Uptake of Plasmin-PN-1 Complexes in Early Human Atheroma.

    Science.gov (United States)

    Boukais, Kamel; Bayles, Richard; Borges, Luciano de Figueiredo; Louedec, Liliane; Boulaftali, Yacine; Ho-Tin-Noé, Benoit; Arocas, Véronique; Bouton, Marie-Christine; Michel, Jean-Baptiste

    2016-01-01

    Zymogens are delivered to the arterial wall by radial transmural convection. Plasminogen can be activated within the arterial wall to produce plasmin, which is involved in evolution of the atherosclerotic plaque. Vascular smooth muscle cells (vSMCs) protect the vessels from proteolytic injury due to atherosclerosis development by highly expressing endocytic LDL receptor-related protein-1 (LRP-1), and by producing anti-proteases, such as Protease Nexin-1 (PN-1). PN-1 is able to form covalent complexes with plasmin. We hypothesized that plasmin-PN-1 complexes could be internalized via LRP-1 by vSMCs during the early stages of human atheroma. LRP-1 is also responsible for the capture of aggregated LDL in human atheroma. Plasmin activity and immunohistochemical analyses of early human atheroma showed that the plasminergic system is activated within the arterial wall, where intimal foam cells, including vSMCs and platelets, are the major sites of PN-1 accumulation. Both PN-1 and LRP-1 are overexpressed in early atheroma at both messenger and protein levels. Cell biology studies demonstrated an increased expression of PN-1 and tissue plasminogen activator by vSMCs in response to LDL. Plasmin-PN-1 complexes are internalized via LRP-1 in vSMCs, whereas plasmin alone is not. Tissue PN-1 interacts with plasmin in early human atheroma via two complementary mechanisms: plasmin inhibition and tissue uptake of plasmin-PN-1 complexes via LRP-1 in vSMCs. Despite this potential protective effect, plasminogen activation by vSMCs remains abnormally elevated in the intima in early stages of human atheroma.

  11. DNA methylation profiling of the human major histocompatibility complex: a pilot study for the human epigenome project.

    Directory of Open Access Journals (Sweden)

    Vardhman K Rakyan

    2004-12-01

    Full Text Available The Human Epigenome Project aims to identify, catalogue, and interpret genome-wide DNA methylation phenomena. Occurring naturally on cytosine bases at cytosine-guanine dinucleotides, DNA methylation is intimately involved in diverse biological processes and the aetiology of many diseases. Differentially methylated cytosines give rise to distinct profiles, thought to be specific for gene activity, tissue type, and disease state. The identification of such methylation variable positions will significantly improve our understanding of genome biology and our ability to diagnose disease. Here, we report the results of the pilot study for the Human Epigenome Project entailing the methylation analysis of the human major histocompatibility complex. This study involved the development of an integrated pipeline for high-throughput methylation analysis using bisulphite DNA sequencing, discovery of methylation variable positions, epigenotyping by matrix-assisted laser desorption/ionisation mass spectrometry, and development of an integrated public database available at http://www.epigenome.org. Our analysis of DNA methylation levels within the major histocompatibility complex, including regulatory exonic and intronic regions associated with 90 genes in multiple tissues and individuals, reveals a bimodal distribution of methylation profiles (i.e., the vast majority of the analysed regions were either hypo- or hypermethylated, tissue specificity, inter-individual variation, and correlation with independent gene expression data.

  12. Modelling of spatially complex human-ecosystem, rural-urban and rich-poor interactions

    CSIR Research Space (South Africa)

    Naude, AH

    2008-06-01

    Full Text Available ., Forsyth, G., Mans, G. and Hugo, W. (2008) Modeling of spatially complex human-ecosystem, rural-urban snd rich-poor interactions. Paper submitted to International Conference: “Studying, Modelling and Sense Making of Planet Earth”; 1 – 6 June, 2008... human-ecosystem, rural-urban snd rich-poor interactions. Paper submitted to International Conference: “Studying, Modelling and Sense Making of Planet Earth”; 1 – 6 June, 2008, Department of Geography, University of the Aegean. 2 Initially, most...

  13. A model of the complex between human beta-microseminoprotein and CRISP-3 based on NMR data

    DEFF Research Database (Denmark)

    Ghasriani, Houman; Fernlund, Per; Udby, Lene

    2008-01-01

    beta-Microseminoprotein (MSP), a 10kDa seminal plasma protein, forms a tight complex with cysteine-rich secretory protein 3 (CRISP-3) from granulocytes. The 3D structure of human MSP has been determined but there is as yet no 3D structure for CRISP-3. We have now studied the complex between human...

  14. The Fungal Sexual Pheromone Sirenin Activates the Human CatSper Channel Complex.

    Science.gov (United States)

    Syeda, Shameem Sultana; Carlson, Erick J; Miller, Melissa R; Francis, Rawle; Clapham, David E; Lishko, Polina V; Hawkinson, Jon E; Hook, Derek; Georg, Gunda I

    2016-02-19

    The basal fungus Allomyces macrogynus (A. macrogynus) produces motile male gametes displaying well-studied chemotaxis toward their female counterparts. This chemotaxis is driven by sirenin, a sexual pheromone released by the female gametes. The pheromone evokes a large calcium influx in the motile gametes, which could proceed through the cation channel of sperm (CatSper) complex. Herein, we report the total synthesis of sirenin in 10 steps and 8% overall yield and show that the synthetic pheromone activates the CatSper channel complex, indicated by a concentration-dependent increase in intracellular calcium in human sperm. Sirenin activation of the CatSper channel was confirmed using whole-cell patch clamp electrophysiology with human sperm. Based on this proficient synthetic route and confirmed activation of CatSper, analogues of sirenin can be designed as blockers of the CatSper channel that could provide male contraceptive agents.

  15. Better decision making in complex, dynamic tasks training with human-facilitated interactive learning environments

    CERN Document Server

    Qudrat-Ullah, Hassan

    2015-01-01

    This book describes interactive learning environments (ILEs) and their underlying concepts. It explains how ILEs can be used to improve the decision-making process and how these improvements can be empirically verified. The objective of this book is to enhance our understanding of and to gain insights into the process by which human facilitated ILEs are effectively designed and used in improving users’ decision making in complex, dynamic tasks. This book is divided into four major parts. Part I serves as an introduction to the importance and complexity of decision making in dynamic tasks. Part II provides background material, drawing upon relevant literature, for the development of an integrated process model on the effectiveness of human facilitated ILEs in improving decision making in dynamic tasks. Part III focuses on the design, development, and application of FishBankILE in laboratory experiments to gather empirical evidence for the validity of the process model. Finally, part IV presents a comprehensi...

  16. Tonotopic representation of missing fundamental complex sounds in the human auditory cortex.

    Science.gov (United States)

    Fujioka, Takako; Ross, Bernhard; Okamoto, Hidehiko; Takeshima, Yasuyuki; Kakigi, Ryusuke; Pantev, Christo

    2003-07-01

    The N1m component of the auditory evoked magnetic field in response to tones and complex sounds was examined in order to clarify whether the tonotopic representation in the human secondary auditory cortex is based on perceived pitch or the physical frequency spectrum of the sound. The investigated stimulus parameters were the fundamental frequencies (F0 = 250, 500 and 1000 Hz), the spectral composition of the higher harmonics of the missing fundamental sounds (2nd to 5th, 6th to 9th and 10th to 13th harmonic) and the frequencies of pure tones corresponding to F0 and to the lowest component of each complex sound. Tonotopic gradients showed that high frequencies were more medially located than low frequencies for the pure tones and for the centre frequency of the complex tones. Furthermore, in the superior-inferior direction, the tonotopic gradients were different between pure tones and complex sounds. The results were interpreted as reflecting different processing in the auditory cortex for pure tones and complex sounds. This hypothesis was supported by the result of evoked responses to complex sounds having longer latencies. A more pronounced tonotopic representation in the right hemisphere gave evidence for right hemispheric dominance in spectral processing.

  17. A major prolactin-binding complex on human milk fat globule membranes contains cyclophilins A and B: the complex is not the prolactin receptor.

    Science.gov (United States)

    Lorenson, Mary Y; Ueda, Eric K; Chen, KuanHui E; Walker, Ameae M

    2012-03-01

    Prolactin (PRL) in milk influences maturation of gastrointestinal epithelium and development of both the hypothalamo-pituitary and immune systems of offspring. Here, we demonstrate that most PRL in human milk is part of a novel, high-affinity, multicomponent binding complex found on the milk fat globule membrane and not in whey. To examine properties of the complex, a sensitive ELISA was developed such that human PRL (hPRL) binding to the complex was measured by loss of hPRL detectability; thus, as much as 50 ng of hPRL was undetectable in the presence of 10 μl of human milk. Using the same methodology, no comparable complex formation was observed with human serum or amniotic fluid. hPRL complexation in milk was rapid, time dependent, and cooperative. Antibodies to or competitors of the hPRL receptor (placental lactogen and growth hormone) showed the hPRL receptor was not involved in the complex. However, hPRL complexation was antagonized by cyclosporine A and anti-cyclophilins. The complex was very stable, resisting dissociation in SDS, urea, and dithiothreitol. Western analysis revealed an ∼75-kDa complex that included hPRL, cyclophilins A and B, and a 16-kDa cyclophilin A. Compared with noncomplexed hPRL, complexed hPRL in whole milk showed similar activation of STAT5 but markedly delayed activation of ERK. Alteration of signaling suggests that complex formation may alter hPRL biological activity. This is the first report of a unique, multicomponent, high-capacity milk fat reservoir of hPRL; all other analyses of milk PRL have utilized defatted milk.

  18. Targeting the Human Complement Membrane Attack Complex to Selectively Kill Prostate Cancer Cells

    Science.gov (United States)

    2012-10-01

    Kill Prostate Cancer Cells PRINCIPAL INVESTIGATOR: Samuel R. Denmeade, MD CONTRACTING ORGANIZATION: Johns Hopkins University...Annual 3. DATES COVERED t 2011- 29 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER . Targeting the Human Complement Membrane Attack Complex to...Support: DOD Idea Award W81XWH-10-PCRP-IDA to SRD; DOD Predoctoral Fellowship W81XWH-09-1-0219 to MLM ; DOD Post-Doctoral Fellowship to MBK; Prostate

  19. Validating cognitive support for operators of complex human-machine systems

    Energy Technology Data Exchange (ETDEWEB)

    O`Hara, J. [Brookhaven National Lab., Upton, NY (United States); Wachtel, J. [US Nuclear Regulatory Commission, Washington, DC (United States)

    1995-10-01

    Modem nuclear power plants (NPPs) are complex systems whose performance is the result of an intricate interaction of human and system control. A complex system may be defined as one which supports a dynamic process involving a large number of elements that interact in many different ways. Safety is addressed through defense-in-depth design and preplanning; i.e., designers consider the types of failures that are most likely to occur and those of high consequence, and design their solutions in advance. However, complex interactions and their failure modes cannot always be anticipated by the designer and may be unfamiliar to plant personnel. These situations may pose cognitive demands on plant personnel, both individually and as a crew. Other factors may contribute to the cognitive challenges of NPP operation as well, including hierarchal processes, dynamic pace, system redundancy and reliability, and conflicting objectives. These factors are discussed in this paper.

  20. Saving Human Lives: What Complexity Science and Information Systems can Contribute.

    Science.gov (United States)

    Helbing, Dirk; Brockmann, Dirk; Chadefaux, Thomas; Donnay, Karsten; Blanke, Ulf; Woolley-Meza, Olivia; Moussaid, Mehdi; Johansson, Anders; Krause, Jens; Schutte, Sebastian; Perc, Matjaž

    We discuss models and data of crowd disasters, crime, terrorism, war and disease spreading to show that conventional recipes, such as deterrence strategies, are often not effective and sufficient to contain them. Many common approaches do not provide a good picture of the actual system behavior, because they neglect feedback loops, instabilities and cascade effects. The complex and often counter-intuitive behavior of social systems and their macro-level collective dynamics can be better understood by means of complexity science. We highlight that a suitable system design and management can help to stop undesirable cascade effects and to enable favorable kinds of self-organization in the system. In such a way, complexity science can help to save human lives.

  1. Complex forms of mitochondrial DNA in human B cells transformed by Epstein-Barr virus (EBV)

    DEFF Research Database (Denmark)

    Christiansen, Gunna; Christiansen, C; Zeuthen, J

    1983-01-01

    Human lymphocytes and lymphoid cell lines were analyzed for the presence of complex forms of mitochondrial DNA (mtDNA) by electron microscopy. A high frequency (9%-14.5%) of catenated dimers, circular dimers, or oligomers were found in samples from Epstein-Barr-virus-(EBV) transformed lymphoblast......Human lymphocytes and lymphoid cell lines were analyzed for the presence of complex forms of mitochondrial DNA (mtDNA) by electron microscopy. A high frequency (9%-14.5%) of catenated dimers, circular dimers, or oligomers were found in samples from Epstein-Barr-virus-(EBV) transformed...... lymphoblastoid cell lines. These complex forms of mtDNA were present in much lower frequencies in lymphocytes isolated from donor blood (1.3%-4.6%). Similar low frequencies were found with primary fibroblasts (1.1%) or freshly isolated monkey liver cells (2.1%). Samples from cultures of Burkitt lymphoma (BL......) cell lines of EBV-positive or -negative origin contained intermediate (5%-7%) frequencies of complex forms of mtDNA....

  2. Parkin Mutations Reduce the Complexity of Neuronal Processes in iPSC-derived Human Neurons

    Science.gov (United States)

    Ren, Yong; Jiang, Houbo; Hu, Zhixing; Fan, Kevin; Wang, Jun; Janoschka, Stephen; Wang, Xiaomin; Ge, Shaoyu; Feng, Jian

    2015-01-01

    Parkinson’s disease (PD) is characterized by the degeneration of nigral dopaminergic (DA) neurons and non-DA neurons in many parts of the brain. Mutations of parkin, an E3 ubiquitin ligase that strongly binds to microtubules, are the most frequent cause of recessively inherited Parkinson’s disease. The lack of robust PD phenotype in parkin knockout mice suggests a unique vulnerability of human neurons to parkin mutations. Here, we show that the complexity of neuronal processes as measured by total neurite length, number of terminals, number of branch points and Sholl analysis, was greatly reduced in induced pluripotent stem cell (iPSC)-derived TH+ or TH− neurons from PD patients with parkin mutations. Consistent with these, microtubule stability was significantly decreased by parkin mutations in iPSC-derived neurons. Overexpression of parkin, but not its PD-linked mutant nor GFP, restored the complexity of neuronal processes and the stability of microtubules. Consistent with these, the microtubule-depolymerizing agent colchicine mimicked the effect of parkin mutations by decreasing neurite length and complexity in control neurons while the microtubule-stabilizing drug taxol mimicked the effect of parkin overexpression by enhancing the morphology of parkin-deficient neurons. The results suggest that parkin maintains the morphological complexity of human neurons by stabilizing microtubules. PMID:25332110

  3. Neurochemical dynamics of acute orofacial pain in the human trigeminal brainstem nuclear complex.

    Science.gov (United States)

    de Matos, Nuno M P; Hock, Andreas; Wyss, Michael; Ettlin, Dominik A; Brügger, Mike

    2017-09-04

    The trigeminal brainstem sensory nuclear complex is the first central relay structure mediating orofacial somatosensory and nociceptive perception. Animal studies suggest a substantial involvement of neurochemical alterations at such basal CNS levels in acute and chronic pain processing. Translating this animal based knowledge to humans is challenging. Human related examining of brainstem functions are challenged by MR related peculiarities as well as applicability aspects of experimentally standardized paradigms. Based on our experience with an MR compatible human orofacial pain model, the aims of the present study were twofold: 1) from a technical perspective, the evaluation of proton magnetic resonance spectroscopy at 3 T regarding measurement accuracy of neurochemical profiles in this small brainstem nuclear complex and 2) the examination of possible neurochemical alterations induced by an experimental orofacial pain model. Data from 13 healthy volunteers aged 19-46 years were analyzed and revealed high quality spectra with significant reductions in total N-acetylaspartate (N-acetylaspartate + N-acetylaspartylglutamate) (-3.7%, p = 0.009) and GABA (-10.88%, p = 0.041) during the pain condition. These results might reflect contributions of N-acetylaspartate and N-acetylaspartylglutamate in neuronal activity-dependent physiologic processes and/or excitatory neurotransmission, whereas changes in GABA might indicate towards a reduction in tonic GABAergic functioning during nociceptive signaling. Summarized, the present study indicates the applicability of (1)H-MRS to obtain neurochemical dynamics within the human trigeminal brainstem sensory nuclear complex. Further developments are needed to pave the way towards bridging important animal based knowledge with human research to understand the neurochemistry of orofacial nociception and pain. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. The nasal complex of Neanderthals: an entry portal to their place in human ancestry.

    Science.gov (United States)

    Márquez, Samuel; Pagano, Anthony S; Delson, Eric; Lawson, William; Laitman, Jeffrey T

    2014-11-01

    Neanderthals are one of the most intensely studied groups of extinct humans, as aspects of their phylogeny and functional morphology remain controversial. They have long been described as cold adapted but recent analyses of their nasal anatomy suggest that traits formerly considered adaptations may be the result of genetic drift. This study performs quantitative and qualitative analysis of aspects of the nasal complex (NC) in Neanderthals and other later Pleistocene fossils from Europe and Africa. A geographically diverse sample of modern human crania was used to establish an anatomical baseline for populations inhabiting cold and tropical climates. Nasofrontal angle, piriform aperture dimensions, and relative maxillary sinus volume were analyzed along with qualitative features of the piriform aperture rim. Results indicate that Neanderthals and other later Pleistocene Homo possessed NC's that align them with tropical modern humans. Thus comparison of Neanderthal nasal morphology with that of modern humans from cold climates may not be appropriate as differences in overall craniofacial architecture may constrain the narrowing of the piriform apertures in Neanderthals. They retain primitively long, low crania, large maxillary sinuses, and large piriform aperture area similar to mid-Pleistocene Homo specimens such as Petralona 1 and Kabwe 1. Adaptation to cold climate may have necessitated other adaptations such as bony medial projections at the piriform aperture rim and, potentially, midfacial prognathism. Nasal complex components of the upper respiratory tract remain a critical but poorly understood area that may yet offer novel insight into one of the greatest continuing controversies in paleoanthropology.

  5. Ru-indoloquinoline complex as a selective and effective human telomeric G-quadruplex binder

    Science.gov (United States)

    Yu, Hui-juan; Zhao, Ying; Mo, Wei-jie; Hao, Zhi-feng; Yu, Lin

    2014-11-01

    Indoloquinoline and its derivatives have been reported to be a kind of efficient G-quadruplex binder and have been found to interact preferentially to intramolecular G-quadruplex and inhibit telomerase activity in human K562 cells and SW620 cells. In contrast to indoloquinoline derivatives, much less is known about the metal complex based on indoloquinoline or its derivative. In this report, we studied the interaction of ruthenium complex [Ru(bpy)2(itatp)]2+ containing indoloquinoline moiety with human telomeric G-quadruplex DNA (Telo22) and c-myc G-quadruplex DNA (Pu27) by UV-visible (UV-Vis), fluorescence spectroscopy, fluorescent intercalator displacement (FID), thermal denaturation studies and CD spectroscopy. The results suggest that [Ru(bpy)2(itatp)]2+ displays a strong π-π stacking interaction with human telomeric G-quadruplex with a high binding constant (∼107 M-1), but just exhibits moderate binding affinity to c-myc G-quadruplex, thus showing significant selectivity to human telomeric G-quadruplex. The CD titration results indicate that [Ru(bpy)2(itatp)]2+ could effectively convert Telo22 into antiparallel G-quadruplex conformation, while in the c-myc G-quadruplex case, instead of promoting Pu27 to fold into G-quadruplex, [Ru(bpy)2(itatp)]2+ destroys the parallel G-quadruplex structure of Pu27.

  6. Crystal structure of a complex of human chymase with its benzimidazole derived inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Matsumoto, Yoshiyuki; Kakuda, Shinji; Koizumi, Masahiro; Mizuno, Tsuyoshi; Muroga, Yumiko; Kawamura, Takashi; Takimoto-Kamimura, Midori, E-mail: m.kamimura@teijin.co.jp [Teijin Institute for Bio-medical Research, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512 (Japan)

    2013-11-01

    The crystal structure of human chymase complexed with a novel benzimidazole inhibitor, TJK002, was determined at 2.8 Å resolution. The present study shows that the benzimidazole ring of the inhibitor takes the stable stacking interaction with the protonated His57 in the catalytic domain of human chymase. The crystal structure of human chymase complexed with a novel benzimidazole inhibitor, TJK002, was determined at 2.8 Å resolution. The X-ray crystallographic study shows that the benzimidazole inhibitor forms a non-covalent interaction with the catalytic domain of human chymase. The hydrophobic fragment of the inhibitor occupies the S1 pocket. The carboxylic acid group of the inhibitor forms hydrogen bonds with the imidazole N(∊) atom of His57 and/or the O(γ) atom of Ser195 which are members of the catalytic triad. This imidazole ring of His57 induces π–π stacking to the benzene ring of the benzimidazole scaffold as P2 moiety. Fragment molecular orbital calculation of the atomic coordinates by X-ray crystallography shows that this imidazole ring of His57 could be protonated with the carboxyl group of Asp102 or hydroxyl group of Ser195 and the stacking interaction is stabilized. A new drug design strategy is proposed where the stacking to the protonated imidazole of the drug target protein with the benzimidazole scaffold inhibitor causes unpredicted potent inhibitory activity for some enzymes.

  7. Integrated Genomic and Network-Based Analyses of Complex Diseases and Human Disease Network.

    Science.gov (United States)

    Al-Harazi, Olfat; Al Insaif, Sadiq; Al-Ajlan, Monirah A; Kaya, Namik; Dzimiri, Nduna; Colak, Dilek

    2016-06-20

    A disease phenotype generally reflects various pathobiological processes that interact in a complex network. The highly interconnected nature of the human protein interaction network (interactome) indicates that, at the molecular level, it is difficult to consider diseases as being independent of one another. Recently, genome-wide molecular measurements, data mining and bioinformatics approaches have provided the means to explore human diseases from a molecular basis. The exploration of diseases and a system of disease relationships based on the integration of genome-wide molecular data with the human interactome could offer a powerful perspective for understanding the molecular architecture of diseases. Recently, subnetwork markers have proven to be more robust and reliable than individual biomarker genes selected based on gene expression profiles alone, and achieve higher accuracy in disease classification. We have applied one of these methodologies to idiopathic dilated cardiomyopathy (IDCM) data that we have generated using a microarray and identified significant subnetworks associated with the disease. In this paper, we review the recent endeavours in this direction, and summarize the existing methodologies and computational tools for network-based analysis of complex diseases and molecular relationships among apparently different disorders and human disease network. We also discuss the future research trends and topics of this promising field.

  8. Aviation Safety: Modeling and Analyzing Complex Interactions between Humans and Automated Systems

    Science.gov (United States)

    Rungta, Neha; Brat, Guillaume; Clancey, William J.; Linde, Charlotte; Raimondi, Franco; Seah, Chin; Shafto, Michael

    2013-01-01

    The on-going transformation from the current US Air Traffic System (ATS) to the Next Generation Air Traffic System (NextGen) will force the introduction of new automated systems and most likely will cause automation to migrate from ground to air. This will yield new function allocations between humans and automation and therefore change the roles and responsibilities in the ATS. Yet, safety in NextGen is required to be at least as good as in the current system. We therefore need techniques to evaluate the safety of the interactions between humans and automation. We think that current human factor studies and simulation-based techniques will fall short in front of the ATS complexity, and that we need to add more automated techniques to simulations, such as model checking, which offers exhaustive coverage of the non-deterministic behaviors in nominal and off-nominal scenarios. In this work, we present a verification approach based both on simulations and on model checking for evaluating the roles and responsibilities of humans and automation. Models are created using Brahms (a multi-agent framework) and we show that the traditional Brahms simulations can be integrated with automated exploration techniques based on model checking, thus offering a complete exploration of the behavioral space of the scenario. Our formal analysis supports the notion of beliefs and probabilities to reason about human behavior. We demonstrate the technique with the Ueberligen accident since it exemplifies authority problems when receiving conflicting advices from human and automated systems.

  9. [The evolution of human cultural behavior: notes on Darwinism and complexity].

    Science.gov (United States)

    Peric, Mikael; Murrieta, Rui Sérgio Sereni

    2015-12-01

    The article analyzes three schools that can be understood as central in studies of the evolution of human behavior within the paradigm of evolution by natural selection: human behavioral ecology (HBE), evolutionary psychology, and dual inheritance. These three streams of thought are used to depict the Darwinist landscape and pinpoint its strong suits and limitations. Theoretical gaps were identified that seem to reduce these schools' ability to account for the diversity of human evolutionary behavior. Their weak points include issues related to the concept of reproductive success, types of adaptation, and targets of selection. An interdisciplinary approach is proposed as the solution to this dilemma, where complex adaptive systems would serve as a source.

  10. Humans with chimpanzee-like major histocompatibility complex-specificities control HIV-1 infection

    DEFF Research Database (Denmark)

    Hoof, Ilka; Kesmir, Can; Lund, Ole;

    2008-01-01

    Background: Major histocompatibility complex (MHC) class I molecules allow immune surveillance by presenting a snapshot of the intracellular state of a cell to circulating cytotoxic T lymphocytes. The MHC class I alleles of an HIV-1 infected individual strongly influence the level of viremia...... and the progression rate to AIDS. Chimpanzees control HIV-1 viral replication and develop a chronic infection without progressing to AIDS. A similar course of disease is observed in human long-term non-progressors. Objective: To investigate if long-term non-progressors and chimpanzees have functional similarities...... in their MHC class I repertoire. Methods: We compared the specificity of groups of human MHC molecules associated with different levels of viremia in HIV-1 infected individuals with those of chimpanzee. Results and conclusion: We demonstrate that human MHC with control of HIV-1 viral load share binding motifs...

  11. The complexity of the calretinin-expressing progenitors in the human cerebral cortex

    Directory of Open Access Journals (Sweden)

    Nevena V Radonjic

    2014-08-01

    Full Text Available The complex structure and function of the cerebral cortex critically depend on the balance of excitation and inhibition provided by the pyramidal projection neurons and GABAergic interneurons, respectively. The calretinin-expressing (CalR+ cell is a subtype of GABAergic cortical interneurons that is more prevalent in humans than in rodents. In rodents, CalR+ interneurons originate in the caudal ganglionic eminence (CGE from Gsx2+ progenitors, but in humans it has been suggested that a subpopulation of CalR+ cells can also be generated in the cortical ventricular/subventricular zone (VZ/SVZ. The progenitors for cortically generated CalR+ subpopulation in primates are not yet characterized. Hence, the aim of this study was to identify patterns of expression of the transcription factors (TFs that commit cortical stem cells to the CalR fate, with a focus on Gsx2. First, we studied the expression of Gsx2 and its downstream effectors, Ascl1 and Sp8 in the cortical regions of the fetal human forebrain at midgestation. Next, we established that a subpopulation of cells expressing these TFs are proliferating in the cortical SVZ, and can be co-labeled with CalR. The presence and proliferation of Gsx2+ cells, not only in the ventral telencephalon (GE as previously reported, but also in the cerebral cortex suggests cortical origin of a subpopulation of CalR+ neurons in humans. In vitro treatment of human cortical progenitors with Sonic hedgehog (Shh, an important morphogen in the specification of interneurons, decreased levels of Ascl1 and Sp8 proteins, but did not affect Gsx2 levels. Taken together, our ex-vivo and in vitro results on human fetal brain suggest complex endogenous and exogenous regulation of TFs implied in the specification of different subtypes of CalR+ cortical interneurons.

  12. Structure of the active form of human origin recognition complex and its ATPase motor module

    Energy Technology Data Exchange (ETDEWEB)

    Tocilj, Ante; On, Kin Fan; Yuan, Zuanning; Sun, Jingchuan; Elkayam, Elad; Li, Huilin; Stillman, Bruce; Joshua-Tor, Leemor

    2017-01-23

    Binding of the Origin Recognition Complex (ORC) to origins of replication marks the first step in the initiation of replication of the genome in all eukaryotic cells. Here, we report the structure of the active form of human ORC determined by X-ray crystallography and cryo-electron microscopy. The complex is composed of an ORC1/4/5 motor module lobe in an organization reminiscent of the DNA polymerase clamp loader complexes. A second lobe contains the ORC2/3 subunits. The complex is organized as a double-layered shallow corkscrew, with the AAA+ and AAA+-like domains forming one layer, and the winged-helix domains (WHDs) forming a top layer. CDC6 fits easily between ORC1 and ORC2, completing the ring and the DNA-binding channel, forming an additional ATP hydrolysis site. Analysis of the ATPase activity of the complex provides a basis for understanding ORC activity as well as molecular defects observed in Meier-Gorlin Syndrome mutations.

  13. Complexity in neurobiology: perspectives from the study of noise in human motor systems.

    Science.gov (United States)

    Balasubramaniam, Ramesh; Torre, Kjerstin

    2012-01-01

    This article serves as an introduction to the themed special issue on "Complex Systems in Neurobiology." The study of complexity in neurobiology has been sensitive to the stochastic processes that dominate the micro-level architecture of neurobiological systems and the deterministic processes that govern the macroscopic behavior of these systems. A large body of research has traversed these scales of interest, seeking to determine how noise at one spatial or temporal scale influences the activity of the system at another scale. In introducing this special issue, we pay special attention to the history of inquiry in complex systems and why scientists have tended to favor linear, causally driven, reductionist approaches in Neurobiology. We follow this with an elaboration of how an alternative approach might be formulated. To illustrate our position on how the sciences of complexity and the study of noise can inform neurobiology, we use three systematic examples from the study of human motor control and learning: 1) phase transitions in bimanual coordination; 2) balance, intermittency, and discontinuous control; and 3) sensorimotor synchronization and timing. Using these examples and showing that noise is adaptively utilized by the nervous system, we make the case for the studying complexity with a perspective of understanding the macroscopic stability in biological systems by focusing on component processes at extended spatial and temporal scales. This special issue continues this theme with contributions in topics as diverse as neural network models, physical biology, motor learning, and statistical physics.

  14. Complexities in human herpesvirus-6A and -6B binding to host cells

    DEFF Research Database (Denmark)

    Pedersen, Simon Metz; Höllsberg, Per

    2006-01-01

    Human herpesvirus-6A and -6B uses the cellular receptor CD46 for fusion and infection of the host cell. The viral glycoprotein complex gH-gL from HHV-6A binds to the short consensus repeat 2 and 3 in CD46. Although all the major isoforms of CD46 bind the virus, certain isoforms may have higher...... affinity than others for the virus. Within recent years, elucidation of the viral complex has identified additional HHV-6A and -6B specific glycoproteins. Thus, gH-gL associates with a gQ1-gQ2 dimer to form a heterotetrameric complex. In addition, a novel complex consisting of gH-gL-gO has been described...... that does not bind CD46. Accumulating evidence suggests that an additional HHV-6A and -6B receptor exists. The previous simple picture of HHV-6A/B-host cell contact therefore includes more layers of complexities on both the viral and the host cell side of the interaction....

  15. Structure of the active form of human origin recognition complex and its ATPase motor module

    Science.gov (United States)

    Tocilj, Ante; On, Kin Fan; Yuan, Zuanning; Sun, Jingchuan; Elkayam, Elad; Li, Huilin; Stillman, Bruce; Joshua-Tor, Leemor

    2017-01-01

    Binding of the Origin Recognition Complex (ORC) to origins of replication marks the first step in the initiation of replication of the genome in all eukaryotic cells. Here, we report the structure of the active form of human ORC determined by X-ray crystallography and cryo-electron microscopy. The complex is composed of an ORC1/4/5 motor module lobe in an organization reminiscent of the DNA polymerase clamp loader complexes. A second lobe contains the ORC2/3 subunits. The complex is organized as a double-layered shallow corkscrew, with the AAA+ and AAA+-like domains forming one layer, and the winged-helix domains (WHDs) forming a top layer. CDC6 fits easily between ORC1 and ORC2, completing the ring and the DNA-binding channel, forming an additional ATP hydrolysis site. Analysis of the ATPase activity of the complex provides a basis for understanding ORC activity as well as molecular defects observed in Meier-Gorlin Syndrome mutations. DOI: http://dx.doi.org/10.7554/eLife.20818.001 PMID:28112645

  16. Targeting androgen receptor/Src complex impairs the aggressive phenotype of human fibrosarcoma cells.

    Science.gov (United States)

    Castoria, Gabriella; Giovannelli, Pia; Di Donato, Marzia; Hayashi, Ryo; Arra, Claudio; Appella, Ettore; Auricchio, Ferdinando; Migliaccio, Antimo

    2013-01-01

    Hormones and growth factors influence the proliferation and invasiveness of human mesenchymal tumors. The highly aggressive human fibrosarcoma HT1080 cell line harbors classical androgen receptor (AR) that responds to androgens triggering cell migration in the absence of significant mitogenesis. As occurs in many human cancer cells, HT1080 cells also express epidermal growth factor receptor (EGFR). We report that the pure anti-androgen Casodex inhibits the growth of HT1080 cell xenografts in immune-depressed mice, revealing a novel role of AR in fibrosarcoma progression. In HT1080 cultured cells EGF, but not androgens, robustly increases DNA synthesis. Casodex abolishes the EGF mitogenic effect, implying a crosstalk between EGFR and AR. The mechanism underlying this crosstalk has been analyzed using an AR-derived small peptide, S1, which prevents AR/Src tyrosine kinase association and androgen-dependent Src activation. Present findings show that in HT1080 cells EGF induces AR/Src Association, and the S1 peptide abolishes both the assembly of this complex and Src activation. The S1 peptide inhibits EGF-stimulated DNA synthesis, cell matrix metalloproteinase-9 (MMP-9) secretion and invasiveness of HT1080 cells. Both Casodex and S1 peptide also prevent DNA synthesis and migration triggered by EGF in various human cancer-derived cells (prostate, breast, colon and pancreas) that express AR. This study shows that targeting the AR domain involved in AR/Src association impairs EGF signaling in human fibrosarcoma HT1080 cells. The EGF-elicited processes inhibited by the peptide (DNA synthesis, MMP-9 secretion and invasiveness) cooperate in increasing the aggressive phenotype of HT1080 cells. Therefore, AR represents a new potential therapeutic target in human fibrosarcoma, as supported by Casodex inhibition of HT1080 cell xenografts. The extension of these findings in various human cancer-derived cell lines highlights the conservation of this process across divergent cancer

  17. Assessment of the microclimatic and human comfort conditions in a complex urban environment: Modelling and measurements

    Energy Technology Data Exchange (ETDEWEB)

    Gulyas, Agnes; Unger, Janos [University of Szeged, Szeged (Hungary). Department of Climatology and Landscape Ecology; Matzarakis, Andreas [Meteorological Institute, University of Freiburg, Freiburg im Breisgau (Germany)

    2006-12-15

    Several complex thermal indices (e.g. Predicted Mean Vote and Physiological Equivalent Temperature) were developed in the last decades to describe and quantify the thermal environment of humans and the energy fluxes between body and environment. Compared to open spaces/landscapes the complex surface structure of urban areas creates an environment with special microclimatic characteristics, which have a dominant effect on the energy balance of the human body. In this study, outdoor thermal comfort conditions are examined through two field-surveys in Szeged, a South-Hungarian city (population 160,000). The intensity of radiation fluxes is dependent on several factors, such as surface structure and housing density. Since our sample area is located in a heavily built-up city centre, radiation fluxes are mainly influenced by narrow streets and several 20-30-year-old (20-30m tall) trees. Special emphasis is given to the human-biometeorological assessment of the microclimate of complex urban environments through the application of the thermal index PET. The analysis is carried out by the utilization of the RayMan model. Firstly, bioclimatic conditions of sites located close to each other but shaded differently by buildings and plants are compared. The results show that differences in the PET index amongst these places can be as high as 15-20{sup |}C due to the different irradiation. Secondly, the investigation of different modelled environments by RayMan (only buildings, buildings+trees and only trees) shows significant alterations in the human comfort sensation between the situations. (author)

  18. Pharmacological NAD-Boosting Strategies Improve Mitochondrial Homeostasis in Human Complex I-Mutant Fibroblasts.

    Science.gov (United States)

    Felici, Roberta; Lapucci, Andrea; Cavone, Leonardo; Pratesi, Sara; Berlinguer-Palmini, Rolando; Chiarugi, Alberto

    2015-06-01

    Mitochondrial disorders are devastating genetic diseases for which efficacious therapies are still an unmet need. Recent studies report that increased availability of intracellular NAD obtained by inhibition of the NAD-consuming enzyme poly(ADP-ribose) polymerase (PARP)-1 or supplementation with the NAD-precursor nicotinamide riboside (NR) ameliorates energetic derangement and symptoms in mouse models of mitochondrial disorders. Whether these pharmacological approaches also improve bioenergetics of human cells harboring mitochondrial defects is unknown. It is also unclear whether the same signaling cascade is prompted by PARP-1 inhibitors and NR supplementation to improve mitochondrial homeostasis. Here, we show that human fibroblasts mutant for the NADH dehydrogenase (ubiquinone) Fe-S protein 1 (NDUFS1) subunit of respiratory complex I have similar ATP, NAD, and mitochondrial content compared with control cells, but show reduced mitochondrial membrane potential. Interestingly, mutant cells also show increased transcript levels of mitochondrial DNA but not nuclear DNA respiratory complex subunits, suggesting activation of a compensatory response. At variance with prior work in mice, however, NR supplementation, but not PARP-1 inhibition, increased intracellular NAD content in NDUFS1 mutant human fibroblasts. Conversely, PARP-1 inhibitors, but not NR supplementation, increased transcription of mitochondrial transcription factor A and mitochondrial DNA-encoded respiratory complexes constitutively induced in mutant cells. Still, both NR and PARP-1 inhibitors restored mitochondrial membrane potential and increased organelle content as well as oxidative activity of NDUFS1-deficient fibroblasts. Overall, data provide the first evidence that in human cells harboring a mitochondrial respiratory defect exposure to NR or PARP-1, inhibitors activate different signaling pathways that are not invariantly prompted by NAD increases, but equally able to improve energetic

  19. Frataxin Accelerates [2Fe-2S] Cluster Formation on the Human Fe–S Assembly Complex

    Science.gov (United States)

    Fox, Nicholas G.; Das, Deepika; Chakrabarti, Mrinmoy; Lindahl, Paul A.; Barondeau, David P.

    2015-01-01

    Iron–sulfur (Fe–S) clusters function as protein cofactors for a wide variety of critical cellular reactions. In human mitochondria, a core Fe–S assembly complex [called SDUF and composed of NFS1, ISD11, ISCU2, and frataxin (FXN) proteins] synthesizes Fe–S clusters from iron, cysteine sulfur, and reducing equivalents and then transfers these intact clusters to target proteins. In vitro assays have relied on reducing the complexity of this complicated Fe–S assembly process by using surrogate electron donor molecules and monitoring simplified reactions. Recent studies have concluded that FXN promotes the synthesis of [4Fe-4S] clusters on the mammalian Fe–S assembly complex. Here the kinetics of Fe–S synthesis reactions were determined using different electron donation systems and by monitoring the products with circular dichroism and absorbance spectroscopies. We discovered that common surrogate electron donor molecules intercepted Fe–S cluster intermediates and formed high-molecular weight species (HMWS). The HMWS are associated with iron, sulfide, and thiol-containing proteins and have properties of a heterogeneous solubilized mineral with spectroscopic properties remarkably reminiscent of those of [4Fe-4S] clusters. In contrast, reactions using physiological reagents revealed that FXN accelerates the formation of [2Fe-2S] clusters rather than [4Fe-4S] clusters as previously reported. In the preceding paper [Fox, N. G., et al. (2015) Biochemistry 54, DOI: 10.1021/bi5014485], [2Fe-2S] intermediates on the SDUF complex were shown to readily transfer to uncomplexed ISCU2 or apo acceptor proteins, depending on the reaction conditions. Our results indicate that FXN accelerates a rate-limiting sulfur transfer step in the synthesis of [2Fe-2S] clusters on the human Fe–S assembly complex. PMID:26016518

  20. Lateral gene transfer of an ABC transporter complex between major constituents of the human gut microbiome

    Directory of Open Access Journals (Sweden)

    Meehan Conor J

    2012-11-01

    Full Text Available Abstract Background Several links have been established between the human gut microbiome and conditions such as obesity and inflammatory bowel syndrome. This highlights the importance of understanding what properties of the gut microbiome can affect the health of the human host. Studies have been undertaken to determine the species composition of this microbiome and infer functional profiles associated with such host properties. However, lateral gene transfer (LGT between community members may result in misleading taxonomic attributions for the recipient organisms, thus making species-function links difficult to establish. Results We identified a peptides/nickel transport complex whose components differed in abundance based upon levels of host obesity, and assigned the encoded proteins to members of the microbial community. Each protein was assigned to several distinct taxonomic groups, with moderate levels of agreement observed among different proteins in the complex. Phylogenetic trees of these proteins produced clusters that differed greatly from taxonomic attributions and indicated that habitat-directed LGT of this complex is likely to have occurred, though not always between the same partners. Conclusions These findings demonstrate that certain membrane transport systems may be an important factor within an obese-associated gut microbiome and that such complexes may be acquired several times by different strains of the same species. Additionally, an example of individual proteins from different organisms being transferred into one operon was observed, potentially demonstrating a functional complex despite the donors of the subunits being taxonomically disparate. Our results also highlight the potential impact of habitat-directed LGT on the resident microbiota.

  1. Multistructure index in revealing complexity of regulatory mechanisms of human cardiovascular system at rest and orthostatic stress in healthy humans

    Science.gov (United States)

    Makowiec, Danuta; Graff, Beata; Struzik, Zbigniew R.

    2017-02-01

    Biological regulation is sufficiently complex to pose an enduring challenge for characterization of both its equilibrium and transient non-equilibrium dynamics. Two univariate but coupled observables, heart rate and systolic blood pressure, are commonly characterized in the benchmark example of the human cardiovascular regulatory system. Asymmetric distributions of accelerations and decelerations of heart rate, as well as rises and falls in systolic blood pressure, recorded in humans during a head-up tilt test provide insights into the dynamics of cardiovascular response to a rapid, controlled deregulation of the system's homeostasis. The baroreflex feedback loop is assumed to be the fundamental physiological mechanism for ensuring homeostatic blood supply to distant organs at rest and during orthostatic stress, captured in a classical beat-to-beat autoregressive model of baroreflex by de Boer et al. (1987). For model corroboration, a multistructure index statistic is proposed, seamlessly evaluating the size spectrum of magnitudes of neural reflexes such as baroreflex, responsible for maintaining the homeostatic dynamics. The multistructure index exposes a distinctly different dynamics of multiscale asymmetry between results obtained from real-life signals recorded from healthy subjects and those simulated using both the classical and perturbed versions of the model. Nonlinear effects observed suggest the pronounced presence of complex mechanisms resulting from baroreflex regulation when a human is at rest, which is aggravated in the system's response to orthostatic stress. Using our methodology of multistructure index, we therefore show a marked difference between model and real-life scenarios, which we attribute to multiscale asymmetry of non-linear origin in real-life signals, which we are not reproducible by the classical model.

  2. Distribution of CPP-Protein Complexes in Freshly Resected Human Tissue Material

    Directory of Open Access Journals (Sweden)

    Ülo Langel

    2010-03-01

    Full Text Available Interest in cell-penetrating peptides (CPPs as delivery agents has fuelled a large number of studies conducted on cultured cells and in mice. However, only a few studies have been devoted to the behaviour of CPPs in human tissues. Therefore, we performed ex vivo tissue-dipping experiments where we studied the distribution of CPP-protein complexes in samples of freshly harvested human tissue material. We used the carcinoma or hyperplasia-containing specimens of the uterus and the cervix, obtained as surgical waste from nine hysterectomies. Our aim was to evaluate the tissue of preference (epithelial versus muscular/connective tissue, carcinoma versus adjacent histologically normal tissue for two well-studied CPPs, the transportan and the TAT-peptide. We complexed biotinylated CPPs with avidin--galactosidase (ABG, which enabled us to apply whole-mount X-gal staining as a robust detection method. Our results demonstrate that both peptides enhanced the tissue distribution of ABG. The enhancing effect of the tested CPPs was more obvious in the normal tissue and in some specimens we detected a striking selectivity of CPP-ABG complexes for the normal tissue. This unexpected finding encourages the evaluation of CPPs as local delivery agents in non-malignant situations, for example in the intrauterine gene therapy of benign gynaecological diseases.

  3. Equivalent dynamical complexity in a many-body quantum and collective human system

    Directory of Open Access Journals (Sweden)

    Neil F. Johnson

    2011-03-01

    Full Text Available Proponents of Complexity Science believe that the huge variety of emergent phenomena observed throughout nature, are generated by relatively few microscopic mechanisms. Skeptics however point to the lack of concrete examples in which a single mechanistic model manages to capture relevant macroscopic and microscopic properties for two or more distinct systems operating across radically different length and time scales. Here we show how a single complexity model built around cluster coalescence and fragmentation, can cross the fundamental divide between many-body quantum physics and social science. It simultaneously (i explains a mysterious recent finding of Fratini et al. concerning quantum many-body effects in cuprate superconductors (i.e. scale of 10−9 − 10−4 meters and 10−12 − 10−6 seconds, (ii explains the apparent universality of the casualty distributions in distinct human insurgencies and terrorism (i.e. scale of 103 − 106 meters and 104 − 108 seconds, (iii shows consistency with various established empirical facts for financial markets, neurons and human gangs and (iv makes microscopic sense for each application. Our findings also suggest that a potentially productive shift can be made in Complexity research toward the identification of equivalent many-body dynamics in both classical and quantum regimes.

  4. Ancient, highly polymorphic human major histocompatibility complex DQA1 intron sequence

    Energy Technology Data Exchange (ETDEWEB)

    McGinnis, M.D.; Quinn, D.L.; Lebo, R.V. [Univ. of California, San Francisco, CA (United States); Simons, M.J. [GeneType Pty. Ltd., Fitzroy, Victoria (Australia)

    1994-10-01

    A 438 basepair intron 1 sequence adjacent to exon 2 in the human major histocompatibility complex DQA1 gene defined 16 allelic variants in 69 individuals from wide ethnic backgrounds. In contrast, the most variable coding region spanned by the 247 basepair exon 2 defined 11 allelic variants. Our phylogenetic human intron 1 tree derived by the Bootstrap algorithm reflects the same relative allelic relationships as the reported DQA1 exon 2 have cosegregated since divergence of the human races. Comparison of human alleles to a Rhesus monkey DQA1 first intron sequence found only 10 nucleotide substitutions unique to Rhesus, with the other 428 positions (98%) found in at least one human allele. This high degree of homology reflects the evolutionary stability of intron sequences since these two species diverged over 20 million years ago. Because more intron 1 alleles exist than exon 2 alleles, these polymorphic introns can be used to improve tissue typing for transplantation, paternity testing, and forensics and to derive more complete phylogenetic trees. These results suggest that introns represent a previously underutilized polymorphic resource. 42 refs., 3 figs., 1 tab.

  5. Crystal structure of HIV-1 Tat complexed with human P-TEFb

    Energy Technology Data Exchange (ETDEWEB)

    Tahirov, Tahir H.; Babayeva, Nigar D.; Varzavand, Katayoun; Cooper, Jeffrey J.; Sedore, Stanley C.; Price, David H. (Nebraska-Med); (Iowa)

    2010-08-23

    Regulation of the expression of the human immunodeficiency virus (HIV) genome is accomplished in large part by controlling transcription elongation. The viral protein Tat hijacks the host cell's RNA polymerase II elongation control machinery through interaction with the positive transcription elongation factor, P-TEFb, and directs the factor to promote productive elongation of HIV mRNA. Here we describe the crystal structure of the Tat-P-TEFb complex containing HIV-1 Tat, human Cdk9 (also known as CDK9), and human cyclin T1 (also known as CCNT1). Tat adopts a structure complementary to the surface of P-TEFb and makes extensive contacts, mainly with the cyclin T1 subunit of P-TEFb, but also with the T-loop of the Cdk9 subunit. The structure provides a plausible explanation for the tolerance of Tat to sequence variations at certain sites. Importantly, Tat induces significant conformational changes in P-TEFb. This finding lays a foundation for the design of compounds that would specifically inhibit the Tat-P-TEFb complex and block HIV replication.

  6. Complex epithelial remodeling underlie the fusion event in early fetal development of the human penile urethra.

    Science.gov (United States)

    Shen, Joel; Overland, Maya; Sinclair, Adriane; Cao, Mei; Yue, Xuan; Cunha, Gerald; Baskin, Laurence

    We recently described a two-step process of urethral plate canalization and urethral fold fusion to form the human penile urethra. Canalization ("opening zipper") opens the solid urethral plate into a groove, and fusion ("closing zipper") closes the urethral groove to form the penile urethra. We hypothesize that failure of canalization and/or fusion during human urethral formation can lead to hypospadias. Herein, we use scanning electron microscopy (SEM) and analysis of transverse serial sections to better characterize development of the human fetal penile urethra as contrasted to the development of the human fetal clitoris. Eighteen 7-13 week human fetal external genitalia specimens were analyzed by SEM, and fifteen additional human fetal specimens were sectioned for histologic analysis. SEM images demonstrate canalization of the urethral/vestibular plate in the developing male and female external genitalia, respectively, followed by proximal to distal fusion of the urethral folds in males only. The fusion process during penile development occurs sequentially in multiple layers and through the interlacing of epidermal "cords". Complex epithelial organization is also noted at the site of active canalization. The demarcation between the epidermis of the shaft and the glans becomes distinct during development, and the epithelial tag at the distal tip of the penile and clitoral glans regresses as development progresses. In summary, SEM analysis of human fetal specimens supports the two-zipper hypothesis of formation of the penile urethra. The opening zipper progresses from proximal to distal along the shaft of the penis and clitoris into the glans in identical fashion in both sexes. The closing zipper mechanism is active only in males and is not a single process but rather a series of layered fusion events, uniquely different from the simple fusion of two epithelial surfaces as occurs in formation of the palate and neural tube. Copyright © 2016 International Society

  7. Complex epithelial remodeling underlie the fusion event in early fetal development of the human penile urethra

    Science.gov (United States)

    Sinclair, Adriane; Cao, Mei; Yue, Xuan; Cunha, Gerald; Baskin, Laurence

    2016-01-01

    We recently described a two-step process of urethral plate canalization and urethral fold fusion to form the human penile urethra. Canalization (“opening zipper”) opens the solid urethral plate into a groove, and fusion (“closing zipper”) closes the urethral groove to form the penile urethra. We hypothesize that failure of canalization and/or fusion during human urethral formation can lead to hypospadias. Herein, we use scanning electron microscopy (SEM) and analysis of transverse serial sections to better characterize development of the human fetal penile urethra as contrasted to the development of the human fetal clitoris. Eighteen 7-13 week human fetal external genitalia specimens were analyzed by SEM, and fifteen additional human fetal specimens were sectioned for histologic analysis. SEM images demonstrate canalization of the urethral/vestibular plate in the developing male and female external genitalia, respectively, followed by proximal to distal fusion of the urethral folds in males only. The fusion process during penile development occurs sequentially in multiple layers and through the interlacing of epidermal “cords”. Complex epithelial organization is also noted at the site of active canalization. The demarcation between the epidermis of the shaft and the glans becomes distinct during development, and the epithelial tag at the distal tip of the penile and clitoral glans regresses as development progresses. In summary, SEM analysis of human fetal specimens supports the two-zipper hypothesis of formation of the penile urethra. The opening zipper progresses from proximal to distal along the shaft of the penis and clitoris into the glans in identical fashion in both sexes. The closing zipper mechanism is active only in males and is not a single process but rather a series of layered fusion events, uniquely different from the simple fusion of two epithelial surfaces as occurs in formation of the palate and neural tube. PMID:27397682

  8. Complexity and multifractality of neuronal noise in mouse and human hippocampal epileptiform dynamics

    Science.gov (United States)

    Serletis, Demitre; Bardakjian, Berj L.; Valiante, Taufik A.; Carlen, Peter L.

    2012-10-01

    Fractal methods offer an invaluable means of investigating turbulent nonlinearity in non-stationary biomedical recordings from the brain. Here, we investigate properties of complexity (i.e. the correlation dimension, maximum Lyapunov exponent, 1/fγ noise and approximate entropy) and multifractality in background neuronal noise-like activity underlying epileptiform transitions recorded at the intracellular and local network scales from two in vitro models: the whole-intact mouse hippocampus and lesional human hippocampal slices. Our results show evidence for reduced dynamical complexity and multifractal signal features following transition to the ictal epileptiform state. These findings suggest that pathological breakdown in multifractal complexity coincides with loss of signal variability or heterogeneity, consistent with an unhealthy ictal state that is far from the equilibrium of turbulent yet healthy fractal dynamics in the brain. Thus, it appears that background noise-like activity successfully captures complex and multifractal signal features that may, at least in part, be used to classify and identify brain state transitions in the healthy and epileptic brain, offering potential promise for therapeutic neuromodulatory strategies for afflicted patients suffering from epilepsy and other related neurological disorders. This paper is based on chapter 5 of Serletis (2010 PhD Dissertation Department of Physiology, Institute of Biomaterials and Biomedical Engineering, University of Toronto).

  9. [Regularities of formation of chlorophyll-human serum albumin functionally active complexes in the aqueous medium].

    Science.gov (United States)

    Semichaevskiĭ, V D

    1975-01-01

    In the system with constant content of the chlorophyll a and increasing amounts of human serum albumin, dependence of pigment incorporation into the complex upon interaction of its aqueous associates with protein solutions was studied by applying the gel filtration on Sephadex G-75 and by measuring light scattering and rate of sensitized photoreduction of the methyl red by ascorbic-acid. The curves were obtained after extraction of the chlorophyll by acetone from dry pigment-protein films formed after desiccation of the aqueous systems. Sigmoid character of the above dependences, their linearization in Hill's coordinates and the value of cooperativity coefficient close to 2 testifies in favour of the cooperative character of the complex formation, two pigment molecules reacting with a single protein molecule. Measurement of adsorption isotherms and their treatment with use of the Brunauer-Emmett-Teller theory of polymolecular adsorption make it possible to evaluate the maximum molar ratio of the pigment to the protein in the complex (close to 2). The pigment-pigment interaction suggests that the chlorophyll molecules adsorbed on the protein are in the state of loosely packed dimers. Deaggregation of aqueus pigment associates by the protein in the course of complex formation results in a considerable increase of the protosensitizing chlorophyll activity.

  10. Comprehensive analysis of the transcriptional profile of the Mediator complex across human cancer types.

    Science.gov (United States)

    Syring, Isabella; Klümper, Niklas; Offermann, Anne; Braun, Martin; Deng, Mario; Boehm, Diana; Queisser, Angela; von Mässenhausen, Anne; Brägelmann, Johannes; Vogel, Wenzel; Schmidt, Doris; Majores, Michael; Schindler, Anne; Kristiansen, Glen; Müller, Stefan C; Ellinger, Jörg; Shaikhibrahim, Zaki; Perner, Sven

    2016-04-26

    The Mediator complex is a key regulator of gene transcription and several studies demonstrated altered expressions of particular subunits in diverse human diseases, especially cancer. However a systematic study deciphering the transcriptional expression of the Mediator across different cancer entities is still lacking.We therefore performed a comprehensive in silico cancer vs. benign analysis of the Mediator complex subunits (MEDs) for 20 tumor entities using Oncomine datasets. The transcriptional expression profiles across almost all cancer entities showed differentially expressed MEDs as compared to benign tissue. Differential expression of MED8 in renal cell carcinoma (RCC) and MED12 in lung cancer (LCa) were validated and further investigated by immunohistochemical staining on tissue microarrays containing large numbers of specimen. MED8 in clear cell RCC (ccRCC) associated with shorter survival and advanced TNM stage and showed higher expression in metastatic than primary tumors. In vitro, siRNA mediated MED8 knockdown significantly impaired proliferation and motility in ccRCC cell lines, hinting at a role for MED8 to serve as a novel therapeutic target in ccRCC. Taken together, our Mediator complex transcriptome proved to be a valid tool for identifying cancer-related shifts in Mediator complex composition, revealing that MEDs do exhibit cancer specific transcriptional expression profiles.

  11. The critical phase for visual control of human walking over complex terrain

    Science.gov (United States)

    Matthis, Jonathan Samir; Barton, Sean L.; Fajen, Brett R.

    2017-01-01

    To walk efficiently over complex terrain, humans must use vision to tailor their gait to the upcoming ground surface without interfering with the exploitation of passive mechanical forces. We propose that walkers use visual information to initialize the mechanical state of the body before the beginning of each step so the resulting ballistic trajectory of the walker’s center-of-mass will facilitate stepping on target footholds. Using a precision stepping task and synchronizing target visibility to the gait cycle, we empirically validated two predictions derived from this strategy: (1) Walkers must have information about upcoming footholds during the second half of the preceding step, and (2) foot placement is guided by information about the position of the target foothold relative to the preceding base of support. We conclude that active and passive modes of control work synergistically to allow walkers to negotiate complex terrain with efficiency, stability, and precision. PMID:28739912

  12. The critical phase for visual control of human walking over complex terrain.

    Science.gov (United States)

    Matthis, Jonathan Samir; Barton, Sean L; Fajen, Brett R

    2017-08-08

    To walk efficiently over complex terrain, humans must use vision to tailor their gait to the upcoming ground surface without interfering with the exploitation of passive mechanical forces. We propose that walkers use visual information to initialize the mechanical state of the body before the beginning of each step so the resulting ballistic trajectory of the walker's center-of-mass will facilitate stepping on target footholds. Using a precision stepping task and synchronizing target visibility to the gait cycle, we empirically validated two predictions derived from this strategy: (1) Walkers must have information about upcoming footholds during the second half of the preceding step, and (2) foot placement is guided by information about the position of the target foothold relative to the preceding base of support. We conclude that active and passive modes of control work synergistically to allow walkers to negotiate complex terrain with efficiency, stability, and precision.

  13. Studies on stabilities of some human chorionic gonadotropin complexes with {beta}-emitting radionuclides

    Energy Technology Data Exchange (ETDEWEB)

    Maiti, Moumita [Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064 (India); Sen, Kamalika [Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700009 (India); Sen, Souvik [Malda Town Divisional Railway Hospital, Malda 732102 (India); Lahiri, Susanta, E-mail: susanta.lahiri@saha.ac.i [Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064 (India)

    2011-02-15

    Human chorionic gonadotropin (hCG) is a peptide hormone, whose one of the structural subunits is identical to that of thyroid-stimulating hormone (TSH). As a consequence, the receptors of TSH also act as receptor for hCG hormone. Keeping in mind this interesting property of hCG we have studied the complex formation ability of various no-carrier-added {beta}-emitting isotopes of {sup 61}Cu (3.3 h), {sup 62}Zn (9.2 h), {sup 90}Nb (14.60 h) and {sup 99}Mo (66.02 h) with hCG molecule. Stability of the hCG-M (M=metal ions) complexes was investigated by dialysis with respect to triple distilled water and ringer lactate solution, which has the same composition as extracellular fluid.

  14. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma.

    Science.gov (United States)

    Verstraete, Kenneth; Peelman, Frank; Braun, Harald; Lopez, Juan; Van Rompaey, Dries; Dansercoer, Ann; Vandenberghe, Isabel; Pauwels, Kris; Tavernier, Jan; Lambrecht, Bart N; Hammad, Hamida; De Winter, Hans; Beyaert, Rudi; Lippens, Guy; Savvides, Savvas N

    2017-04-03

    The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via structural and mechanistic considerations. Here we employ an integrative experimental approach focusing on productive and antagonized TSLP complexes and free cytokine. We reveal how cognate receptor TSLPR allosterically activates TSLP to potentiate the recruitment of the shared interleukin 7 receptor α-chain (IL-7Rα) by leveraging the flexibility, conformational heterogeneity and electrostatics of the cytokine. We further show that the monoclonal antibody Tezepelumab partly exploits these principles to neutralize TSLP activity. Finally, we introduce a fusion protein comprising a tandem of the TSLPR and IL-7Rα extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency.

  15. Juvenile nephropathy in a Boxer dog resembling the human nephronophthisis-medullary cystic kidney disease complex.

    Science.gov (United States)

    Basile, Angelo; Onetti-Muda, Andrea; Giannakakis, Konstantinos; Faraggiana, Tullio; Aresu, Luca

    2011-12-01

    A juvenile nephropathy in a 4-year-old male Boxer dog, closely resembling the Nephronophthisis (NPHP)-Medullary Cystic Kidney Disease Complex (MCKD) in humans is described. Gross examination of the kidneys revealed several multiple cysts at the corticomedullary junction and in the medulla. Histological examination was characterized by a widespread tubular atrophy and dilatation, with a marked thickening of the tubular basement membrane, interstitial lymphocytic infiltration and fibrosis. Ultrastructural studies revealed dilated tubules with irregular basement membrane thickening and splitting. Lectin histochemistry investigation revealed that the cysts originated in the distal convoluted tubule and collecting duct. Having excluded all other known cystic diseases of the kidney, and based on the lectin histochemistry results, the macroscopic and histological findings of our case are highly compatible with a diagnosis of the NPHP-MCKD complex. To our knowledge, this is the first report describing this particular lesion.

  16. Cognitive engineering models: A prerequisite to the design of human-computer interaction in complex dynamic systems

    Science.gov (United States)

    Mitchell, Christine M.

    1993-01-01

    This chapter examines a class of human-computer interaction applications, specifically the design of human-computer interaction for the operators of complex systems. Such systems include space systems (e.g., manned systems such as the Shuttle or space station, and unmanned systems such as NASA scientific satellites), aviation systems (e.g., the flight deck of 'glass cockpit' airplanes or air traffic control) and industrial systems (e.g., power plants, telephone networks, and sophisticated, e.g., 'lights out,' manufacturing facilities). The main body of human-computer interaction (HCI) research complements but does not directly address the primary issues involved in human-computer interaction design for operators of complex systems. Interfaces to complex systems are somewhat special. The 'user' in such systems - i.e., the human operator responsible for safe and effective system operation - is highly skilled, someone who in human-machine systems engineering is sometimes characterized as 'well trained, well motivated'. The 'job' or task context is paramount and, thus, human-computer interaction is subordinate to human job interaction. The design of human interaction with complex systems, i.e., the design of human job interaction, is sometimes called cognitive engineering.

  17. Structures of native human thymidine phosphorylase and in complex with 5-iodouracil

    OpenAIRE

    Mitsiki, Eirini; Papageorgiou, Anastassios C.; Iyer, Shalini; Thiyagarajan, Nethaji; Prior, Steven H.; Sleep, Darrell; Finnis, Chris; Acharya, K. Ravi

    2009-01-01

    Thymidine phosphorylase (TP) first identified as platelet derived endothelial cell growth factor (PD-ECGF) plays a key role in nucleoside metabolism. Human TP (hTP) is implicated in angiogenesis and is overexpressed in several solid tumors. Here, we report the crystal structures of recombinant hTP and its complex with a substrate 5-iodouracil (5IUR) at 3.0 and 2.5 Å, respectively. In addition, we provide information on the role of specific residues in the enzymatic activity of hTP through mut...

  18. The Major Histocompatibility Complex and Perfumers' Descriptions of Human Body Odors

    Directory of Open Access Journals (Sweden)

    Claus Wedekind

    2007-04-01

    Full Text Available The MHC (major histocompatibility complex is a group of genes that play a crucial role in immune recognition and in tolerance of tissue grafting. The MHC has also been found to influence body odors, body odor preferences, and mate choice in mice and humans. Here we test whether verbal descriptions of human body odors can be linked to the MHC. We asked 45 male students to live as odor neutral as possible for two consecutive days and to wear a T-shirt during the nights. The odors of these T-shirts were then described by five evaluators: two professional perfumers and three laymen. One of the perfumers was able to describe the T-shirt odors in such a way that some of the allelic specificity of the MHC was significantly revealed (after Bonferroni correction for multiple testing. This shows that, although difficult, some people are able to describe MHC-correlated body odor components.

  19. Ubiquitous polygenicity of human complex traits: genome-wide analysis of 49 traits in Koreans.

    Directory of Open Access Journals (Sweden)

    Jian Yang

    Full Text Available Recent studies in population of European ancestry have shown that 30% ~ 50% of heritability for human complex traits such as height and body mass index, and common diseases such as schizophrenia and rheumatoid arthritis, can be captured by common SNPs and that genetic variation attributed to chromosomes are in proportion to their length. Using genome-wide estimation and partitioning approaches, we analysed 49 human quantitative traits, many of which are relevant to human diseases, in 7,170 unrelated Korean individuals genotyped on 326,262 SNPs. For 43 of the 49 traits, we estimated a nominally significant (P<0.05 proportion of variance explained by all SNPs on the Affymetrix 5.0 genotyping array ([Formula: see text]. On average across 47 of the 49 traits for which the estimate of h(G(2 is non-zero, common SNPs explain approximately one-third (range of 7.8% to 76.8% of narrow sense heritability. The estimate of h(G(2 is highly correlated with the proportion of SNPs with association P<0.031 (r(2 = 0.92. Longer genomic segments tend to explain more phenotypic variation, with a correlation of 0.78 between the estimate of variance explained by individual chromosomes and their physical length, and 1% of the genome explains approximately 1% of the genetic variance. Despite the fact that there are a few SNPs with large effects for some traits, these results suggest that polygenicity is ubiquitous for most human complex traits and that a substantial proportion of the "missing heritability" is captured by common SNPs.

  20. Organic cadmium complexes as proteasome inhibitors and apoptosis inducers in human breast cancer cells.

    Science.gov (United States)

    Zhang, Zhen; Bi, Caifeng; Buac, Daniela; Fan, Yuhua; Zhang, Xia; Zuo, Jian; Zhang, Pengfei; Zhang, Nan; Dong, Lili; Dou, Q Ping

    2013-06-01

    Although cadmium (Cd) is a widespread environmental contaminant and human carcinogen, our studies indicate an organic Cd complex to be a potent inhibitor of proteasomal chymotrypsin-like (CT-like) activity, further capable of inducing apoptosis in a cancer cell-specific manner. It has been reported that the ligands indole-3-butyric acid (L1) and indole-3-propionic acid (L2) have cancer-fighting effects when tested in a rat carcinoma model. In addition, 3, 5-diaminobenzoic acid o-vanillin Schiff bases (L3) have high antimicrobial activity and a large number of Schiff base complexes have been reported to have proteasome-inhibitory activity. We therefore hypothesized that synthetic forms of Cd in combination with L1, L2 and L3 may have proteasome-inhibitory and apoptosis-inducing activities, which would be cancer cell-specific. To test this hypothesis, we have synthesized three novel Cd-containing complexes: [Cd2(C12H12O2N)4(H2O)2]·2H2O (Cd1), [Cd2(C11H10O2N)4(H2O)2]·2H2O (Cd2) and [Cd(C7H4N2O2)(C8H6O2)2]·2H2O (Cd3), by using these three ligands. We sought out to characterize and assess the proteasome-inhibitory and anti-proliferative properties of these three Cd complexes in human breast cancer cells. Cd1, Cd2 and Cd3 were found to effectively inhibit the chymotrypsin-like activity of purified 20S proteasome with IC50 values of 2.6, 3.0 and 3.3 μΜ, respectively. Moreover, inhibition of cancer cell proliferation also correlated with this effect. As a result of proteasomal shutdown, the accumulation of ubiquitinated proteins and the proteasome target IκB-α protein as well as induction of apoptosis were observed. To account for the cancer specificity of this effect, immortalized, non-tumorigenic breast MCF10A cells were used under the same experimental conditions. Our results indicate that MCF10A cells are much less sensitive to the Cd1, Cd2 and Cd3 complexes when compared to MDA MB 231 breast cancer cells. Therefore, our study suggests that these Cd organic

  1. Specificity-Determining DNA Triplet Code for Positioning of Human Preinitiation Complex.

    Science.gov (United States)

    Goldshtein, Matan; Lukatsky, David B

    2017-05-23

    The notion that transcription factors bind DNA only through specific, consensus binding sites has been recently questioned. No specific consensus motif for the positioning of the human preinitiation complex (PIC) has been identified. Here, we reveal that nonconsensus, statistical, DNA triplet code provides specificity for the positioning of the human PIC. In particular, we reveal a highly nonrandom, statistical pattern of repetitive nucleotide triplets that correlates with the genomewide binding preferences of PIC measured by Chip-exo. We analyze the triplet enrichment and depletion near the transcription start site and identify triplets that have the strongest effect on PIC-DNA nonconsensus binding. Using statistical mechanics, a random-binder model without fitting parameters, with genomic DNA sequence being the only input, we further validate that the nonconsensus nucleotide triplet code constitutes a key signature providing PIC binding specificity in the human genome. Our results constitute a proof-of-concept for, to our knowledge, a new design principle for protein-DNA recognition in the human genome, which can lead to a better mechanistic understanding of transcriptional regulation. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  2. In Vitro Culture Conditions for Maintaining a Complex Population of Human Gastrointestinal Tract Microbiota

    Directory of Open Access Journals (Sweden)

    Bong-Soo Kim

    2011-01-01

    Full Text Available A stable intestinal microbiota is important in maintaining human physiology and health. Although there have been a number of studies using in vitro and in vivo approaches to determine the impact of diet and xenobiotics on intestinal microbiota, there is no consensus for the best in vitro culture conditions for growth of the human gastrointestinal microbiota. To investigate the dynamics and activities of intestinal microbiota, it is important for the culture conditions to support the growth of a wide range of intestinal bacteria and maintain a complex microbial community representative of the human gastrointestinal tract. Here, we compared the bacterial community in three culture media: brain heart infusion broth and high- and low-carbohydrate medium with different growth supplements. The bacterial community was analyzed using denaturing gradient gel electrophoresis (DGGE, pyrosequencing and real-time PCR. Based on the molecular analysis, this study indicated that the 3% fecal inoculum in low-concentration carbohydrate medium with 1% autoclaved fecal supernatant provided enhanced growth conditions to conduct in vitro studies representative of the human intestinal microbiota.

  3. Molecular architecture of the human sperm IZUMO1 and egg JUNO fertilization complex.

    Science.gov (United States)

    Aydin, Halil; Sultana, Azmiri; Li, Sheng; Thavalingam, Annoj; Lee, Jeffrey E

    2016-06-23

    Fertilization is an essential biological process in sexual reproduction and comprises a series of molecular interactions between the sperm and egg. The fusion of the haploid spermatozoon and oocyte is the culminating event in mammalian fertilization, enabling the creation of a new, genetically distinct diploid organism. The merger of two gametes is achieved through a two-step mechanism in which the sperm protein IZUMO1 on the equatorial segment of the acrosome-reacted sperm recognizes its receptor, JUNO, on the egg surface. This recognition is followed by the fusion of the two plasma membranes. IZUMO1 and JUNO proteins are indispensable for fertilization, as constitutive knockdown of either protein results in mice that are healthy but infertile. Despite their central importance in reproductive medicine, the molecular architectures of these proteins and the details of their functional roles in fertilization are not known. Here we present the crystal structures of human IZUMO1 and JUNO in unbound and bound conformations. The human IZUMO1 structure exhibits a distinct boomerang shape and provides structural insights into the IZUMO family of proteins. Human IZUMO1 forms a high-affinity complex with JUNO and undergoes a major conformational change within its N-terminal domain upon binding to the egg-surface receptor. Our results provide insights into the molecular basis of sperm-egg recognition, cross-species fertilization, and the barrier to polyspermy, thereby promising benefits for the rational development of non-hormonal contraceptives and fertility treatments for humans and other mammals.

  4. Complex events initiated by individual spikes in the human cerebral cortex.

    Directory of Open Access Journals (Sweden)

    Gábor Molnár

    2008-09-01

    Full Text Available Synaptic interactions between neurons of the human cerebral cortex were not directly studied to date. We recorded the first dataset, to our knowledge, on the synaptic effect of identified human pyramidal cells on various types of postsynaptic neurons and reveal complex events triggered by individual action potentials in the human neocortical network. Brain slices were prepared from nonpathological samples of cortex that had to be removed for the surgical treatment of brain areas beneath association cortices of 58 patients aged 18 to 73 y. Simultaneous triple and quadruple whole-cell patch clamp recordings were performed testing mono- and polysynaptic potentials in target neurons following a single action potential fired by layer 2/3 pyramidal cells, and the temporal structure of events and underlying mechanisms were analyzed. In addition to monosynaptic postsynaptic potentials, individual action potentials in presynaptic pyramidal cells initiated long-lasting (37 +/- 17 ms sequences of events in the network lasting an order of magnitude longer than detected previously in other species. These event series were composed of specifically alternating glutamatergic and GABAergic postsynaptic potentials and required selective spike-to-spike coupling from pyramidal cells to GABAergic interneurons producing concomitant inhibitory as well as excitatory feed-forward action of GABA. Single action potentials of human neurons are sufficient to recruit Hebbian-like neuronal assemblies that are proposed to participate in cognitive processes.

  5. A rationally engineered yeast pyruvyltransferase Pvg1p introduces sialylation-like properties in neo-human-type complex oligosaccharide.

    Science.gov (United States)

    Higuchi, Yujiro; Yoshinaga, Sho; Yoritsune, Ken-Ichi; Tateno, Hiroaki; Hirabayashi, Jun; Nakakita, Shin-Ichi; Kanekiyo, Miho; Kakuta, Yoshimitsu; Takegawa, Kaoru

    2016-05-19

    Pyruvylation onto the terminus of oligosaccharide, widely seen from prokaryote to eukaryote, confers negative charges on the cell surface and seems to be functionally similar to sialylation, which is found at the end of human-type complex oligosaccharide. However, detailed molecular mechanisms underlying pyruvylation have not been clarified well. Here, we first determined the crystal structure of fission yeast pyruvyltransferase Pvg1p at a resolution of 2.46 Å. Subsequently, by combining molecular modeling with mutational analysis of active site residues, we obtained a Pvg1p mutant (Pvg1p(H168C)) that efficiently transferred pyruvyl moiety onto a human-type complex glycopeptide. The resultant pyruvylated human-type complex glycopeptide recognized similar lectins on lectin arrays as the α2,6-sialyl glycopeptides. This newly-generated pyruvylation of human-type complex oligosaccharides would provide a novel method for glyco-bioengineering.

  6. Chromosome segregation regulation in human zygotes : Altered mitotic histone phosphorylation dynamics underlying centromeric targeting of the chromosomal passenger complex

    NARCIS (Netherlands)

    Van De Werken, C.; Avo Santos, M.; Laven, J. S E; Eleveld, C.; Fauser, B. C J M; Lens, S. M A; Baart, E. B.

    2015-01-01

    STUDY QUESTION Are the kinase feedback loops that regulate activation and centromeric targeting of the chromosomal passenger complex (CPC), functional during mitosis in human embryos? SUMMARY ANSWER Investigation of the regulatory kinase pathways involved in centromeric CPC targeting revealed normal

  7. Chromosome segregation regulation in human zygotes : Altered mitotic histone phosphorylation dynamics underlying centromeric targeting of the chromosomal passenger complex

    NARCIS (Netherlands)

    Van De Werken, C.; Avo Santos, M.; Laven, J. S E; Eleveld, C.; Fauser, B. C J M; Lens, S. M A; Baart, E. B.

    2015-01-01

    STUDY QUESTION Are the kinase feedback loops that regulate activation and centromeric targeting of the chromosomal passenger complex (CPC), functional during mitosis in human embryos? SUMMARY ANSWER Investigation of the regulatory kinase pathways involved in centromeric CPC targeting revealed normal

  8. NDUFAF5 Hydroxylates NDUFS7 at an Early Stage in the Assembly of Human Complex I.

    Science.gov (United States)

    Rhein, Virginie F; Carroll, Joe; Ding, Shujing; Fearnley, Ian M; Walker, John E

    2016-07-08

    Complex I (NADH ubiquinone oxidoreductase) in mammalian mitochondria is an L-shaped assembly of 45 proteins. One arm lies in the inner membrane, and the other extends about 100 Å into the matrix of the organelle. The extrinsic arm contains binding sites for NADH, the primary electron acceptor FMN, and seven iron-sulfur clusters that form a pathway for electrons linking FMN to the terminal electron acceptor, ubiquinone, which is bound in a tunnel in the region of the junction between the arms. The membrane arm contains four antiporter-like domains, energetically coupled to the quinone site and involved in pumping protons from the matrix into the intermembrane space contributing to the proton motive force. Seven of the subunits, forming the core of the membrane arm, are translated from mitochondrial genes, and the remaining subunits, the products of nuclear genes, are imported from the cytosol. Their assembly is coordinated by at least thirteen extrinsic assembly factor proteins that are not part of the fully assembled complex. They assist in insertion of co-factors and in building up the complex from smaller sub-assemblies. One such factor, NDUFAF5, belongs to the family of seven-β-strand S-adenosylmethionine-dependent methyltransferases. However, similar to another family member, RdmB, it catalyzes the introduction of a hydroxyl group, in the case of NDUFAF5, into Arg-73 in the NDUFS7 subunit of human complex I. This modification occurs early in the pathway of assembly of complex I, before the formation of the juncture between peripheral and membrane arms.

  9. Cryo-EM structure of a human cytoplasmic actomyosin complex at near-atomic resolution.

    Science.gov (United States)

    von der Ecken, Julian; Heissler, Sarah M; Pathan-Chhatbar, Salma; Manstein, Dietmar J; Raunser, Stefan

    2016-06-30

    The interaction of myosin with actin filaments is the central feature of muscle contraction and cargo movement along actin filaments of the cytoskeleton. The energy for these movements is generated during a complex mechanochemical reaction cycle. Crystal structures of myosin in different states have provided important structural insights into the myosin motor cycle when myosin is detached from F-actin. The difficulty of obtaining diffracting crystals, however, has prevented structure determination by crystallography of actomyosin complexes. Thus, although structural models exist of F-actin in complex with various myosins, a high-resolution structure of the F-actin–myosin complex is missing. Here, using electron cryomicroscopy, we present the structure of a human rigor actomyosin complex at an average resolution of 3.9 Å. The structure reveals details of the actomyosin interface, which is mainly stabilized by hydrophobic interactions. The negatively charged amino (N) terminus of actin interacts with a conserved basic motif in loop 2 of myosin, promoting cleft closure in myosin. Surprisingly, the overall structure of myosin is similar to rigor-like myosin structures in the absence of F-actin, indicating that F-actin binding induces only minimal conformational changes in myosin. A comparison with pre-powerstroke and intermediate (Pi-release) states of myosin allows us to discuss the general mechanism of myosin binding to F-actin. Our results serve as a strong foundation for the molecular understanding of cytoskeletal diseases, such as autosomal dominant hearing loss and diseases affecting skeletal and cardiac muscles, in particular nemaline myopathy and hypertrophic cardiomyopathy.

  10. Structural Disorder in the Complex of Human Pregnane X Receptor and the Macrolide Antibiotic Rifampicin

    Energy Technology Data Exchange (ETDEWEB)

    Chrencik, Jill E.; Orans, Jillian; Moore, Linda B.; Xue, Yu; Peng, Li; Collins, Jon L.; Wisely, G. Bruce; Lambert, Millard H.; Kliewer, Steven A.; Redinbo, Matthew R. (U. of Texas-SMED); (UNC)

    2010-07-13

    The human nuclear xenobiotic receptor, pregnane X receptor (PXR), detects a variety of structurally distinct endogenous and xenobiotic compounds and controls expression of genes central to drug and cholesterol metabolism. The macrolide antibiotic rifampicin, a front-line treatment for tuberculosis, is an established PXR agonist and, at 823 Da, is one of the largest known ligands for the receptor. We present the 2.8 {angstrom} crystal structure of the ligand-binding domain of human PXR in complex with rifampicin. We also use structural and mutagenesis data to examine the origins of the directed promiscuity exhibited by the PXRs across species. Three structurally flexible loops adjacent to the ligand-binding pocket of PXR are disordered in this crystal structure, including the 200-210 region that is part of a sequence insert novel to the promiscuous PXRs relative to other members of the nuclear receptor superfamily. The 4-methyl-1-piperazinyl ring of rifampicin, which would lie adjacent to the disordered protein regions, is also disordered and not observed in the structure. Taken together, our results indicate that one wall of the PXR ligand-binding cavity can remain flexible even when the receptor is in complex with an activating ligand. These observations highlight the key role that structural flexibility plays in PXR's promiscuous response to xenobiotics.

  11. Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.

    Science.gov (United States)

    Marcon, Edyta; Ni, Zuyao; Pu, Shuye; Turinsky, Andrei L; Trimble, Sandra Smiley; Olsen, Jonathan B; Silverman-Gavrila, Rosalind; Silverman-Gavrila, Lorelei; Phanse, Sadhna; Guo, Hongbo; Zhong, Guoqing; Guo, Xinghua; Young, Peter; Bailey, Swneke; Roudeva, Denitza; Zhao, Dorothy; Hewel, Johannes; Li, Joyce; Gräslund, Susanne; Paduch, Marcin; Kossiakoff, Anthony A; Lupien, Mathieu; Emili, Andrew; Wodak, Shoshana J; Greenblatt, Jack

    2014-07-10

    Chromatin regulation is driven by multicomponent protein complexes, which form functional modules. Deciphering the components of these modules and their interactions is central to understanding the molecular pathways these proteins are regulating, their functions, and their relation to both normal development and disease. We describe the use of affinity purifications of tagged human proteins coupled with mass spectrometry to generate a protein-protein interaction map encompassing known and predicted chromatin-related proteins. On the basis of 1,394 successful purifications of 293 proteins, we report a high-confidence (85% precision) network involving 11,464 protein-protein interactions among 1,738 different human proteins, grouped into 164 often overlapping protein complexes with a particular focus on the family of JmjC-containing lysine demethylases, their partners, and their roles in chromatin remodeling. We show that RCCD1 is a partner of histone H3K36 demethylase KDM8 and demonstrate that both are important for cell-cycle-regulated transcriptional repression in centromeric regions and accurate mitotic division.

  12. Human-Chromatin-Related Protein Interactions Identify a Demethylase Complex Required for Chromosome Segregation

    Directory of Open Access Journals (Sweden)

    Edyta Marcon

    2014-07-01

    Full Text Available Chromatin regulation is driven by multicomponent protein complexes, which form functional modules. Deciphering the components of these modules and their interactions is central to understanding the molecular pathways these proteins are regulating, their functions, and their relation to both normal development and disease. We describe the use of affinity purifications of tagged human proteins coupled with mass spectrometry to generate a protein-protein interaction map encompassing known and predicted chromatin-related proteins. On the basis of 1,394 successful purifications of 293 proteins, we report a high-confidence (85% precision network involving 11,464 protein-protein interactions among 1,738 different human proteins, grouped into 164 often overlapping protein complexes with a particular focus on the family of JmjC-containing lysine demethylases, their partners, and their roles in chromatin remodeling. We show that RCCD1 is a partner of histone H3K36 demethylase KDM8 and demonstrate that both are important for cell-cycle-regulated transcriptional repression in centromeric regions and accurate mitotic division.

  13. α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8.

    LENUS (Irish Health Repository)

    Bergin, David A

    2010-12-01

    Hereditary deficiency of the protein α-1 antitrypsin (AAT) causes a chronic lung disease in humans that is characterized by excessive mobilization of neutrophils into the lung. However, the reason for the increased neutrophil burden has not been fully elucidated. In this study we have demonstrated using human neutrophils that serum AAT coordinates both CXCR1- and soluble immune complex (sIC) receptor-mediated chemotaxis by divergent pathways. We demonstrated that glycosylated AAT can bind to IL-8 (a ligand for CXCR1) and that AAT-IL-8 complex formation prevented IL-8 interaction with CXCR1. Second, AAT modulated neutrophil chemotaxis in response to sIC by controlling membrane expression of the glycosylphosphatidylinositol-anchored (GPI-anchored) Fc receptor FcγRIIIb. This process was mediated through inhibition of ADAM-17 enzymatic activity. Neutrophils isolated from clinically stable AAT-deficient patients were characterized by low membrane expression of FcγRIIIb and increased chemotaxis in response to IL-8 and sIC. Treatment of AAT-deficient individuals with AAT augmentation therapy resulted in increased AAT binding to IL-8, increased AAT binding to the neutrophil membrane, decreased FcγRIIIb release from the neutrophil membrane, and normalization of chemotaxis. These results provide new insight into the mechanism underlying the effect of AAT augmentation therapy in the pulmonary disease associated with AAT deficiency.

  14. Targeting androgen receptor/Src complex impairs the aggressive phenotype of human fibrosarcoma cells.

    Directory of Open Access Journals (Sweden)

    Gabriella Castoria

    Full Text Available BACKGROUND: Hormones and growth factors influence the proliferation and invasiveness of human mesenchymal tumors. The highly aggressive human fibrosarcoma HT1080 cell line harbors classical androgen receptor (AR that responds to androgens triggering cell migration in the absence of significant mitogenesis. As occurs in many human cancer cells, HT1080 cells also express epidermal growth factor receptor (EGFR. EXPERIMENTAL: FINDINGS: We report that the pure anti-androgen Casodex inhibits the growth of HT1080 cell xenografts in immune-depressed mice, revealing a novel role of AR in fibrosarcoma progression. In HT1080 cultured cells EGF, but not androgens, robustly increases DNA synthesis. Casodex abolishes the EGF mitogenic effect, implying a crosstalk between EGFR and AR. The mechanism underlying this crosstalk has been analyzed using an AR-derived small peptide, S1, which prevents AR/Src tyrosine kinase association and androgen-dependent Src activation. Present findings show that in HT1080 cells EGF induces AR/Src Association, and the S1 peptide abolishes both the assembly of this complex and Src activation. The S1 peptide inhibits EGF-stimulated DNA synthesis, cell matrix metalloproteinase-9 (MMP-9 secretion and invasiveness of HT1080 cells. Both Casodex and S1 peptide also prevent DNA synthesis and migration triggered by EGF in various human cancer-derived cells (prostate, breast, colon and pancreas that express AR. CONCLUSION: This study shows that targeting the AR domain involved in AR/Src association impairs EGF signaling in human fibrosarcoma HT1080 cells. The EGF-elicited processes inhibited by the peptide (DNA synthesis, MMP-9 secretion and invasiveness cooperate in increasing the aggressive phenotype of HT1080 cells. Therefore, AR represents a new potential therapeutic target in human fibrosarcoma, as supported by Casodex inhibition of HT1080 cell xenografts. The extension of these findings in various human cancer-derived cell lines

  15. PKCα-specific phosphorylation of the troponin complex in human myocardium: a functional and proteomics analysis.

    Directory of Open Access Journals (Sweden)

    Viola Kooij

    Full Text Available Protein kinase Cα (PKCα is one of the predominant PKC isoforms that phosphorylate cardiac troponin. PKCα is implicated in heart failure and serves as a potential therapeutic target, however, the exact consequences for contractile function in human myocardium are unclear. This study aimed to investigate the effects of PKCα phosphorylation of cardiac troponin (cTn on myofilament function in human failing cardiomyocytes and to resolve the potential targets involved.Endogenous cTn from permeabilized cardiomyocytes from patients with end-stage idiopathic dilated cardiomyopathy was exchanged (∼69% with PKCα-treated recombinant human cTn (cTn (DD+PKCα. This complex has Ser23/24 on cTnI mutated into aspartic acids (D to rule out in vitro cross-phosphorylation of the PKA sites by PKCα. Isometric force was measured at various [Ca(2+] after exchange. The maximal force (Fmax in the cTn (DD+PKCα group (17.1±1.9 kN/m(2 was significantly reduced compared to the cTn (DD group (26.1±1.9 kN/m(2. Exchange of endogenous cTn with cTn (DD+PKCα increased Ca(2+-sensitivity of force (pCa50 = 5.59±0.02 compared to cTn (DD (pCa50 = 5.51±0.02. In contrast, subsequent PKCα treatment of the cells exchanged with cTn (DD+PKCα reduced pCa50 to 5.45±0.02. Two PKCα-phosphorylated residues were identified with mass spectrometry: Ser198 on cTnI and Ser179 on cTnT, although phosphorylation of Ser198 is very low. Using mass spectrometry based-multiple reaction monitoring, the extent of phosphorylation of the cTnI sites was quantified before and after treatment with PKCα and showed the highest phosphorylation increase on Thr143.PKCα-mediated phosphorylation of the cTn complex decreases Fmax and increases myofilament Ca(2+-sensitivity, while subsequent treatment with PKCα in situ decreased myofilament Ca(2+-sensitivity. The known PKC sites as well as two sites which have not been previously linked to PKCα are phosphorylated in human cTn complex treated

  16. Preparation of the Human Cytomegalovirus Nuclear Egress Complex and Associated Proteins.

    Science.gov (United States)

    Sharma, Mayuri; Kamil, Jeremy P; Coen, Donald M

    2016-01-01

    Herpesviruses, like most DNA viruses, replicate their genomes in the host cell nucleus. Their DNA is then packaged and assembled into viral nucleocapsids, which, in most cases, are too large to pass through the nuclear pore complex. Instead, herpesviruses use a complex multistep pathway, termed nuclear egress, to exit the nucleus. Key players in this process include two conserved viral proteins that form the nuclear egress complex (NEC). In human cytomegalovirus, these NEC proteins are UL50, embedded in the inner nuclear membrane, and its nucleoplasmic partner UL53. Both are essential for viral nuclear egress. However, other viral components as well as host nuclear envelope proteins may also participate in nuclear egress. Identifying these viral and cellular factors may provide important insight into the herpesvirus lifecycle and its relationship to the underlying, yet still-mysterious, host nuclear egress pathway. We developed an immunoprecipitation-based protocol, described herein, to identify protein-protein interactions involving the NEC from the nuclear fraction of infected cells that express an epitope-tagged version of NEC subunit UL53.

  17. Multiplex matrix network analysis of protein complexes in the human TCR signalosome.

    Science.gov (United States)

    Smith, Stephen E P; Neier, Steven C; Reed, Brendan K; Davis, Tessa R; Sinnwell, Jason P; Eckel-Passow, Jeanette E; Sciallis, Gabriel F; Wieland, Carilyn N; Torgerson, Rochelle R; Gil, Diana; Neuhauser, Claudia; Schrum, Adam G

    2016-08-02

    Multiprotein complexes transduce cellular signals through extensive interaction networks, but the ability to analyze these networks in cells from small clinical biopsies is limited. To address this, we applied an adaptable multiplex matrix system to physiologically relevant signaling protein complexes isolated from a cell line or from human patient samples. Focusing on the proximal T cell receptor (TCR) signalosome, we assessed 210 pairs of PiSCES (proteins in shared complexes detected by exposed surface epitopes). Upon stimulation of Jurkat cells with superantigen-loaded antigen-presenting cells, this system produced high-dimensional data that enabled visualization of network activity. A comprehensive analysis platform generated PiSCES biosignatures by applying unsupervised hierarchical clustering, principal component analysis, an adaptive nonparametric with empirical cutoff analysis, and weighted correlation network analysis. We generated PiSCES biosignatures from 4-mm skin punch biopsies from control patients or patients with the autoimmune skin disease alopecia areata. This analysis distinguished disease patients from the controls, detected enhanced basal TCR signaling in the autoimmune patients, and identified a potential signaling network signature that may be indicative of disease. Thus, generation of PiSCES biosignatures represents an approach that can provide information about the activity of protein signaling networks in samples including low-abundance primary cells from clinical biopsies.

  18. Enhancing the copper(II) complexes cytotoxicity to cancer cells through bound to human serum albumin.

    Science.gov (United States)

    Gou, Yi; Zhang, Yao; Qi, Jinxu; Zhou, Zuping; Yang, Feng; Liang, Hong

    2015-03-01

    We use Schiff-base salicylaldehyde benzoylhydrazone (HL) as the ligand for copper(II), resulting in the complexes [CuCl(L)]·H2O (C1), [CuNO3(L)]·H2O (C2) and [CuBr(L)]2 (C3). We characterize the Cu(II) compounds' interactions with human serum albumin (HSA) using fluorescence spectroscopy and molecular docking. These studies revealed that Cu(II) compounds propensity bound to IIA subdomain of HSA possible by hydrophobic interactions and hydrogen bond. Cu(II) compounds produce intracellular reactive oxygen species (ROS) in cancer cells. Complexes of HSA and copper(II) compounds enhance about 2-fold cytotoxicity in cancer cells but do not raise cytotoxicity levels in normal cells in vitro. Compared with C3 alone, HSA-C3 complex promotes HepG2 cell apoptosis and has a stronger capacity to promote cell cycle arrest at the G2/M phase of HepG2.

  19. Genome-wide uniformity of human ‘open’ pre-initiation complexes

    Science.gov (United States)

    Lai, William K.M.; Pugh, B. Franklin

    2017-01-01

    Transcription of protein-coding and noncoding DNA occurs pervasively throughout the mammalian genome. Their sites of initiation are generally inferred from transcript 5′ ends and are thought to be either locally dispersed or focused. How these two modes of initiation relate is unclear. Here, we apply permanganate treatment and chromatin immunoprecipitation (PIP-seq) of initiation factors to identify the precise location of melted DNA separately associated with the preinitiation complex (PIC) and the adjacent paused complex (PC). This approach revealed the two known modes of transcription initiation. However, in contrast to prevailing views, they co-occurred within the same promoter region: initiation originating from a focused PIC, and broad nucleosome-linked initiation. PIP-seq allowed transcriptional orientation of Pol II to be determined, which may be useful near promoters where sufficient sense/anti-sense transcript mapping information is lacking. PIP-seq detected divergently oriented Pol II at both coding and noncoding promoters, as well as at enhancers. Their occupancy levels were not necessarily coupled in the two orientations. DNA sequence and shape analysis of initiation complex sites suggest that both sequence and shape contribute to specificity, but in a context-restricted manner. That is, initiation sites have the locally “best” initiator (INR) sequence and/or shape. These findings reveal a common core to pervasive Pol II initiation throughout the human genome. PMID:27927716

  20. Twin-Based DNA Methylation Analysis Takes the Center Stage of Studies of Human Complex Diseases

    Institute of Scientific and Technical Information of China (English)

    Dongfeng Zhang; Shuxia Li; Qihua Tan; Zengchang Pang

    2012-01-01

    The etiology of complex diseases is characterized by the interaction between the genome and environmental conditions and the interface of epigenetics may be a central mechanism.Current technologies already allow us high-throughput profiling of epigenetic patterns at genome level.However,our understanding of the epigenetic processes remains limited.Twins are special samples in genetic studies due to their genetic similarity and rearing-environment sharing.In the past decades,twins have made a great contribution in dissecting the genetic and environmental contributions to human diseases and complex traits.In the era of functional genomics,the valuable samples of twins are helping to bridge the gap between gene activity and environmental conditions through epigenetic mechanisms unlimited to DNA sequence variations.We review the recent progresses in using twins to study disease-related molecular epigenetic phenotypes and link them with environmental exposures especially early life events.Various study designs and application issues will be highlighted and discussed with aim at making uses of twins in assessing the environmental impact on epigenetic changes during the development of complex diseases.

  1. Literature and Cinema from "Adaptation" to Re-creation: Coping with the Complexity of Human Recollection

    Directory of Open Access Journals (Sweden)

    Carlo Testa

    2012-12-01

    Full Text Available Early 20th-century avant-gardes put a premium on the notion of "originality" and so created a cultural context in which "adaptation" -- in particular, lit-to cinema adaptation -- later came to be construed by film theory as a kind of derivative, inferior notion. This article offers the proof, based on work on the little-known original Russian sources, that none other than Èizenshtein opined differently, so much so that he preferred to argue instead for the use of the term "re-creation"; and that later semiotic theory, especially thanks to Iurii Lotman, provides us with the tools to develop the "re-creation" concept fully. In the process of re-creation, which is always a process of cultural re-contextualization, the original literary complexity lost in the transmutation must be made up in specific cinematic ways, in order to offer a final re-created artefact worthy of recollection by human society. In times of an overburdened human ability to remember historic sufferings, re-created artefacts that lose information vis-a-vis the original will be quite justly forgotten. On this basis, the article concludes with an elaboration on contemporary Italian cinema -- especially some commercially successful noirs -- drawn from literature (or rather, books of fiction and pinpoints the nature of one of that type of cinema's recurrent shortcomings. The essential defect of such films is identified in their inability to make up by cinematic means for the loss of complexity which they endure in the transition from one medium to another. This is all the more true when, as in the case of the noirs examined here, complexity is already scant in the original books in the first place.

  2. The synaptonemal complex and meiotic recombination in humans: new approaches to old questions.

    Science.gov (United States)

    Vallente, Rhea U; Cheng, Edith Y; Hassold, Terry J

    2006-06-01

    Meiotic prophase serves as an arena for the interplay of two important cellular activities, meiotic recombination and synapsis of homologous chromosomes. Synapsis is mediated by the synaptonemal complex (SC), originally characterized as a structure linked to pairing of meiotic chromosomes (Moses (1958) J Biophys Biochem Cytol 4:633-638). In 1975, the first electron micrographs of human pachytene stage SCs were presented (Moses et al. (1975) Science 187:363-365) and over the next 15 years the importance of the SC to normal meiotic progression in human males and females was established (Jhanwar and Chaganti (1980) Hum Genet 54:405-408; Pathak and Elder (1980) Hum Genet 54:171-175; Solari (1980) Chromosoma 81:315-337; Speed (1984) Hum Genet 66:176-180; Wallace and Hulten (1985) Ann Hum Genet 49(Pt 3):215-226). Further, these studies made it clear that abnormalities in the assembly or maintenance of the SC were an important contributor to human infertility (Chaganti et al. (1980) Am J Hum Genet 32:833-848; Vidal et al. (1982) Hum Genet 60:301-304; Bojko (1983) Carlsberg Res Commun 48:285-305; Bojko (1985) Carlsberg Res Commun 50:43-72; Templado et al. (1984) Hum Genet 67:162-165; Navarro et al. (1986) Hum Reprod 1:523-527; Garcia et al. (1989) Hum Genet 2:147-53). However, the utility of these early studies was limited by lack of information on the structural composition of the SC and the identity of other SC-associated proteins. Fortunately, studies of the past 15 years have gone a long way toward remedying this problem. In this minireview, we highlight the most important of these advances as they pertain to human meiosis, focusing on temporal aspects of SC assembly, the relationship between the SC and meiotic recombination, and the contribution of SC abnormalities to human infertility.

  3. Immune-Complexed Adenovirus Induce AIM2-Mediated Pyroptosis in Human Dendritic Cells

    Science.gov (United States)

    Eichholz, Karsten; Bru, Thierry; Tran, Thi Thu Phuong; Fernandes, Paulo; Mennechet, Franck J. D.; Manel, Nicolas; Alves, Paula; Perreau, Matthieu

    2016-01-01

    Human adenoviruses (HAdVs) are nonenveloped proteinaceous particles containing a linear double-stranded DNA genome. HAdVs cause a spectrum of pathologies in all populations regardless of health standards. Following repeat exposure to multiple HAdV types, we develop robust and long-lived humoral and cellular immune responses that provide life-long protection from de novo infections and persistent HAdV. How HAdVs, anti-HAdV antibodies and antigen presenting cells (APCs) interact to influence infection is still incompletely understood. In our study, we used physical, pharmacological, biochemical, fluorescence and electron microscopy, molecular and cell biology approaches to dissect the impact of immune-complexed HAdV (IC-HAdV) on human monocyte-derived dendritic cells (MoDCs). We show that IC-HAdV generate stabilized complexes of ~200 nm that are efficiently internalized by, and aggregate in, MoDCs. By comparing IC-HAdV, IC-empty capsid, IC-Ad2ts1 (a HAdV-C2 impaired in endosomal escape due to a mutation that impacts protease encapsidation) and IC-AdL40Q (a HAdV-C5 impaired in endosomal escape due to a mutation in protein VI), we demonstrate that protein VI-dependent endosomal escape is required for the HAdV genome to engage the DNA pattern recognition receptor AIM2 (absent in melanoma 2). AIM2 engagement induces pyroptotic MoDC death via ASC (apoptosis-associated speck protein containing a caspase activation/recruitment domain) aggregation, inflammasome formation, caspase 1 activation, and IL-1β and gasdermin D (GSDMD) cleavage. Our study provides mechanistic insight into how humoral immunity initiates an innate immune response to HAdV-C5 in human professional APCs. PMID:27636895

  4. The evolution of the complex sensory and motor systems of the human brain.

    Science.gov (United States)

    Kaas, Jon H

    2008-03-18

    Inferences about how the complex sensory and motor systems of the human brain evolved are based on the results of comparative studies of brain organization across a range of mammalian species, and evidence from the endocasts of fossil skulls of key extinct species. The endocasts of the skulls of early mammals indicate that they had small brains with little neocortex. Evidence from comparative studies of cortical organization from small-brained mammals of the six major branches of mammalian evolution supports the conclusion that the small neocortex of early mammals was divided into roughly 20-25 cortical areas, including primary and secondary sensory fields. In early primates, vision was the dominant sense, and cortical areas associated with vision in temporal and occipital cortex underwent a significant expansion. Comparative studies indicate that early primates had 10 or more visual areas, and somatosensory areas with expanded representations of the forepaw. Posterior parietal cortex was also expanded, with a caudal half dominated by visual inputs, and a rostral half dominated by somatosensory inputs with outputs to an array of seven or more motor and visuomotor areas of the frontal lobe. Somatosensory areas and posterior parietal cortex became further differentiated in early anthropoid primates. As larger brains evolved in early apes and in our hominin ancestors, the number of cortical areas increased to reach an estimated 200 or so in present day humans, and hemispheric specializations emerged. The large human brain grew primarily by increasing neuron number rather than increasing average neuron size.

  5. Genomic approaches uncover increasing complexities in the regulatory landscape at the human SCL (TAL1 locus.

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    Pawandeep Dhami

    Full Text Available The SCL (TAL1 transcription factor is a critical regulator of haematopoiesis and its expression is tightly controlled by multiple cis-acting regulatory elements. To elaborate further the DNA elements which control its regulation, we used genomic tiling microarrays covering 256 kb of the human SCL locus to perform a concerted analysis of chromatin structure and binding of regulatory proteins in human haematopoietic cell lines. This approach allowed us to characterise further or redefine known human SCL regulatory elements and led to the identification of six novel elements with putative regulatory function both up and downstream of the SCL gene. They bind a number of haematopoietic transcription factors (GATA1, E2A LMO2, SCL, LDB1, CTCF or components of the transcriptional machinery and are associated with relevant histone modifications, accessible chromatin and low nucleosomal density. Functional characterisation shows that these novel elements are able to enhance or repress SCL promoter activity, have endogenous promoter function or enhancer-blocking insulator function. Our analysis opens up several areas for further investigation and adds new layers of complexity to our understanding of the regulation of SCL expression.

  6. Neandertal demise: an archaeological analysis of the modern human superiority complex.

    Science.gov (United States)

    Villa, Paola; Roebroeks, Wil

    2014-01-01

    Neandertals are the best-studied of all extinct hominins, with a rich fossil record sampling hundreds of individuals, roughly dating from between 350,000 and 40,000 years ago. Their distinct fossil remains have been retrieved from Portugal in the west to the Altai area in central Asia in the east and from below the waters of the North Sea in the north to a series of caves in Israel in the south. Having thrived in Eurasia for more than 300,000 years, Neandertals vanished from the record around 40,000 years ago, when modern humans entered Europe. Modern humans are usually seen as superior in a wide range of domains, including weaponry and subsistence strategies, which would have led to the demise of Neandertals. This systematic review of the archaeological records of Neandertals and their modern human contemporaries finds no support for such interpretations, as the Neandertal archaeological record is not different enough to explain the demise in terms of inferiority in archaeologically visible domains. Instead, current genetic data suggest that complex processes of interbreeding and assimilation may have been responsible for the disappearance of the specific Neandertal morphology from the fossil record.

  7. Neandertal demise: an archaeological analysis of the modern human superiority complex.

    Directory of Open Access Journals (Sweden)

    Paola Villa

    Full Text Available Neandertals are the best-studied of all extinct hominins, with a rich fossil record sampling hundreds of individuals, roughly dating from between 350,000 and 40,000 years ago. Their distinct fossil remains have been retrieved from Portugal in the west to the Altai area in central Asia in the east and from below the waters of the North Sea in the north to a series of caves in Israel in the south. Having thrived in Eurasia for more than 300,000 years, Neandertals vanished from the record around 40,000 years ago, when modern humans entered Europe. Modern humans are usually seen as superior in a wide range of domains, including weaponry and subsistence strategies, which would have led to the demise of Neandertals. This systematic review of the archaeological records of Neandertals and their modern human contemporaries finds no support for such interpretations, as the Neandertal archaeological record is not different enough to explain the demise in terms of inferiority in archaeologically visible domains. Instead, current genetic data suggest that complex processes of interbreeding and assimilation may have been responsible for the disappearance of the specific Neandertal morphology from the fossil record.

  8. Structure of the human [kappa]-opioid receptor in complex with JDTic

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Huixian; Wacker, Daniel; Mileni, Mauro; Katritch, Vsevolod; Han, Gye Won; Vardy, Eyal; Liu, Wei; Thompson, Aaron A.; Huang, Xi-Ping; Carroll, F. Ivy; Mascarella, S. Wayne; Westkaemper, Richard B.; Mosier, Philip D.; Roth, Bryan L.; Cherezov, Vadim; Stevens, Raymond C. (VCU); (Scripps); (UNC); (Res. Tri. Inst.)

    2013-04-25

    Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and - in the case of {kappa}-opioid receptor ({kappa}-OR) - dysphoria and psychotomimesis. Here we report the crystal structure of the human {kappa}-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 {angstrom} resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human {kappa}-OR. Modelling of other important {kappa}-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for {kappa}-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human {kappa}-OR.

  9. Tracking a Subset of Skeleton Joints: An Effective Approach towards Complex Human Activity Recognition

    Directory of Open Access Journals (Sweden)

    Muhammad Latif Anjum

    2017-01-01

    Full Text Available We present a robust algorithm for complex human activity recognition for natural human-robot interaction. The algorithm is based on tracking the position of selected joints in human skeleton. For any given activity, only a few skeleton joints are involved in performing the activity, so a subset of joints contributing the most towards the activity is selected. Our approach of tracking a subset of skeleton joints (instead of tracking the whole skeleton is computationally efficient and provides better recognition accuracy. We have developed both manual and automatic approaches for the selection of these joints. The position of the selected joints is tracked for the duration of the activity and is used to construct feature vectors for each activity. Once the feature vectors have been constructed, we use a Support Vector Machines (SVM multiclass classifier for training and testing the algorithm. The algorithm has been tested on a purposely built dataset of depth videos recorded using Kinect camera. The dataset consists of 250 videos of 10 different activities being performed by different users. Experimental results show classification accuracy of 83% when tracking all skeleton joints, 95% when using manual selection of subset joints, and 89% when using automatic selection of subset joints.

  10. Genome-Wide Prediction of DNA Methylation Using DNA Composition and Sequence Complexity in Human

    Science.gov (United States)

    Wu, Chengchao; Yao, Shixin; Li, Xinghao; Chen, Chujia; Hu, Xuehai

    2017-01-01

    DNA methylation plays a significant role in transcriptional regulation by repressing activity. Change of the DNA methylation level is an important factor affecting the expression of target genes and downstream phenotypes. Because current experimental technologies can only assay a small proportion of CpG sites in the human genome, it is urgent to develop reliable computational models for predicting genome-wide DNA methylation. Here, we proposed a novel algorithm that accurately extracted sequence complexity features (seven features) and developed a support-vector-machine-based prediction model with integration of the reported DNA composition features (trinucleotide frequency and GC content, 65 features) by utilizing the methylation profiles of embryonic stem cells in human. The prediction results from 22 human chromosomes with size-varied windows showed that the 600-bp window achieved the best average accuracy of 94.7%. Moreover, comparisons with two existing methods further showed the superiority of our model, and cross-species predictions on mouse data also demonstrated that our model has certain generalization ability. Finally, a statistical test of the experimental data and the predicted data on functional regions annotated by ChromHMM found that six out of 10 regions were consistent, which implies reliable prediction of unassayed CpG sites. Accordingly, we believe that our novel model will be useful and reliable in predicting DNA methylation. PMID:28212312

  11. Rare and low-frequency variants in human common diseases and other complex traits.

    Science.gov (United States)

    Lettre, Guillaume

    2014-11-01

    In humans, most of the genetic variation is rare and often population-specific. Whereas the role of rare genetic variants in familial monogenic diseases is firmly established, we are only now starting to explore the contribution of this class of genetic variation to human common diseases and other complex traits. Such large-scale experiments are possible due to the development of next-generation DNA sequencing. Early findings suggested that rare and low-frequency coding variation might have a large effect on human phenotypes (eg, PCSK9 missense variants on low-density lipoprotein-cholesterol and coronary heart diseases). This observation sparked excitement in prognostic and diagnostic medicine, as well as in genetics-driven strategies to develop new drugs. In this review, I describe results and present initial conclusions regarding some of the recent rare and low-frequency variant discoveries. We can already assume that most phenotype-associated rare and low-frequency variants have modest-to-weak phenotypical effect. Thus, we will need large cohorts to identify them, as for common variants in genome-wide association studies. As we expand the list of associated rare and low-frequency variants, we can also better recognise the current limitations: we need to develop better statistical methods to optimally test association with rare variants, including non-coding variation, and to account for potential confounders such as population stratification.

  12. Complex assembly, crystallization and preliminary X-ray crystallographic analysis of the human Rod-Zwilch-ZW10 (RZZ) complex.

    Science.gov (United States)

    Altenfeld, Anika; Wohlgemuth, Sabine; Wehenkel, Annemarie; Vetter, Ingrid R; Musacchio, Andrea

    2015-04-01

    The spindle-assembly checkpoint (SAC) monitors kinetochore-microtubule attachment during mitosis. In metazoans, the three-subunit Rod-Zwilch-ZW10 (RZZ) complex is a crucial SAC component that interacts with additional SAC-activating and SAC-silencing components, including the Mad1-Mad2 complex and cytoplasmic dynein. The RZZ complex contains two copies of each subunit and has a predicted molecular mass of ∼800 kDa. Given the low abundance of the RZZ complex in natural sources, its recombinant reconstitution was attempted by co-expression of its subunits in insect cells. The RZZ complex was purified to homogeneity and subjected to systematic crystallization attempts. Initial crystals containing the entire RZZ complex were obtained using the sitting-drop method and were subjected to optimization to improve the diffraction resolution limit. The crystals belonged to space group P3₁ (No. 144) or P3₂ (No. 145), with unit-cell parameters a = b = 215.45, c = 458.7 Å, α = β = 90.0, γ = 120.0°.

  13. Platelet-neutrophil complex formation-a detailed in vitro analysis of murine and human blood samples.

    Science.gov (United States)

    Mauler, Maximilian; Seyfert, Julia; Haenel, David; Seeba, Hannah; Guenther, Janine; Stallmann, Daniela; Schoenichen, Claudia; Hilgendorf, Ingo; Bode, Christoph; Ahrens, Ingo; Duerschmied, Daniel

    2016-05-01

    Platelets form complexes with neutrophils during inflammatory processes. These aggregates migrate into affected tissues and also circulate within the organism. Several studies have evaluated platelet-neutrophil complexes as a marker of cardiovascular diseases in human and mouse. Although multiple publications have reported platelet-neutrophil complex counts, we noticed that different methods were used to analyze platelet-neutrophil complex formation, resulting in significant differences, even in baseline values. We established a protocol for platelet-neutrophil complex measurement with flow cytometry in murine and human whole blood samples. In vitro platelet-neutrophil complex formation was stimulated with ADP or PMA. We tested the effect of different sample preparation steps and cytometer settings on platelet-neutrophil complex detection and noticed false-positive counts with increasing acquisition speed. Platelet-neutrophil complex formation depends on platelet P-selectin expression, and antibody blocking of P-selectin consequently prevented ADP-induced platelet-neutrophil complex formation. These findings may help generating more comparable data among different research groups that examine platelet-neutrophil complexes as a marker for cardiovascular disease and novel therapeutic interventions.

  14. Molecular architecture of the recombinant human MCM2-7 helicase in complex with nucleotides and DNA

    DEFF Research Database (Denmark)

    Boskovic, Jasminka; Bragado-Nilsson, Elisabeth; Saligram Prabhakar, Bhargav

    2016-01-01

    DNA replication is a key biological process that involves different protein complexes whose assembly is rigorously regulated in a successive order. One of these complexes is a replicative hexameric helicase, the MCM complex, which is essential for the initiation and elongation phases of replication....... After the assembly of a double heterohexameric MCM2-7 complex at replication origins in G1, the 2 heterohexamers separate from each other and associate with Cdc45 and GINS proteins in a CMG complex that is capable of unwinding dsDNA during S phase. Here, we have reconstituted and characterized...... the purified human MCM2-7 (hMCM2-7) hexameric complex by co-expression of its 6 different subunits in insect cells. The conformational variability of the complex has been analyzed by single particle electron microscopy in the presence of different nucleotide analogs and DNA. The interaction with nucleotide...

  15. A novel V(IV)O-pyrimidinone complex: synthesis, solution speciation and human serum protein binding.

    Science.gov (United States)

    Gonçalves, Gisela; Tomaz, Isabel; Correia, Isabel; Veiros, Luís F; Castro, M Margarida C A; Avecilla, Fernando; Palacio, Lorena; Maestro, Miguel; Kiss, Tamás; Jakusch, Tamás; Garcia, M Helena V; Pessoa, João Costa

    2013-09-07

    The pyrimidinones mhcpe, 2-methyl-3H-5-hydroxy-6-carboxy-4-pyrimidinone ethyl ester (mhcpe, 1), 2,3-dimethyl-5-benzyloxy-6-carboxy-4-pyrimidinone ethyl ester (dbcpe, 2) and N-methyl-2,3-dimethyl-5-hydroxy-6-carboxyamido-4-pyrimidinone (N-MeHOPY, 3), are synthesized and their structures determined by single crystal X-ray diffraction. The acid-base properties of 1 are studied by potentiometric and spectrophotometric methods, the pK(a) values being 1.14 and 6.35. DFT calculations were carried out to determine the most stable structure for each of the H2L(+), HL and L(-) forms (HL = mhcpe) and assign the groups involved in the protonation-deprotonation processes. The mhcpe(-) ligand forms stable complexes with V(IV)O(2+) in the pH range 2 to 10, and potentiometry, EPR and UV-Vis techniques are used to identify and characterize the V(IV)O-mhcpe species formed. The results are consistent with the formation of V(IV)O, (V(IV)O)L, (V(IV)O)L2, (V(IV)O)2L2H(-2), (V(IV)O)L2H(-1), (V(IV)O)2L2H(-3), (V(IV)O)LH(-2) species and V(IV)O-hydrolysis products. Calculations indicate that the global binding ability of mhcpe towards V(IV)O(2+) is similar to that of maltol (Hmaltol = 3-hydroxy-2-methyl-4H-pyran-4-one) and lower than that of 1,2-dimethyl-3-hydroxy-4-pyridinone (Hdhp). The interaction of V(IV)O-complexes with human plasma proteins (transferrin and albumin) is studied by circular dichroism (CD), EPR and (51)V NMR spectroscopy. V(IV)O-mhcpe-protein ternary complexes are formed in both cases. The binding of V(IV)O(2+) to transferrin (hTF) in the presence of mhcpe involves mainly (V(IV)O)1(hTF)(mhcpe)1, (V(IV)O)2(hTF)(mhcpe)1 and (V(IV)O)2(hTF)(mhcpe)2 species, bound at the Fe(III) binding sites, and the corresponding conditional formation constants are determined. Under the conditions expected to prevail in human blood serum, CD data indicate that the V(IV)O-mhcpe complexes mainly bind to hTF; the formation of V(IV)O-hTF-mhcpe complexes occurs in the presence of Fe(III) as well

  16. Cellular responses induced by Cu(II quinolinonato complexes in human tumor and hepatic cells

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    Trávníček Zdeněk

    2012-12-01

    Full Text Available Abstract Background Inspired by the unprecedented historical success of cisplatin, one of the most important research directions in bioinorganic and medicinal chemistry is dedicated to the development of new anticancer compounds with the potential to surpass it in antitumor activity, while having lower unwanted side-effects. Therefore, a series of copper(II mixed-ligand complexes of the type [Cu(qui(L]Y · xH2O (1–6, where Hqui = 2-phenyl-3-hydroxy-4(1H-quinolinone, Y = NO3 (1, 3, 5 or BF4 (2, 4, 6, and L = 1,10-phenanthroline (phen (1, 2, 5-methyl-1,10-phenanthroline (mphen (3, 4 and bathophenanthroline (bphen (5, 6, was studied for their in vitro cytotoxicity against several human cancer cell lines (A549 lung carcinoma, HeLa cervix epitheloid carcinoma, G361 melanoma cells, A2780 ovarian carcinoma, A2780cis cisplatin-resistant ovarian carcinoma, LNCaP androgen-sensitive prostate adenocarcinoma and THP-1 monocytic leukemia. Results The tested complexes displayed a stronger cytotoxic effect against all the cancer cells as compared to cisplatin. The highest cytotoxicity was found for the complexes 4 (IC50 = 0.36 ± 0.05 μM and 0.56 ± 0.15 μM, 5 (IC50 = 0.66 ± 0.07 μM and 0.73 ± 0.08 μM and 6 (IC50 = 0.57 ± 0.11 μM and 0.70 ± 0.20 μM against A2780, and A2780cis respectively, as compared with the values of 12.0 ± 0.8 μM and 27.0 ± 4.6 μM determined for cisplatin. Moreover, the tested complexes were much less cytotoxic to primary human hepatocytes than to the cancer cells. The complexes 5 and 6 exhibited significantly high ability to modulate secretion of the pro-inflammatory cytokines TNF-α (2873 ± 238 pg/mL and 3284 ± 139 pg/mL for 5, and 6 respectively and IL-1β (1177 ± 128 pg/mL and 1087 ± 101 pg/mL for 5, and 6 respectively tested on the lipopolysaccharide (LPS-stimulated THP-1 cells as compared with the values of 1173

  17. Recent emergence of Staphylococcus aureus clonal complex 398 in human blood cultures.

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    Erwin Verkade

    Full Text Available BACKGROUND: Recently, a clone of MRSA with clonal complex 398 (CC398 has emerged that is related to an extensive reservoir in animals, especially pigs and veal calves. It has been reported previously that methicillin-susceptible variants of CC398 circulate among humans at low frequency, and these have been isolated in a few cases of bloodstream infections (BSI. The purpose of this study was to determine the prevalence of S. aureus CC398 in blood cultures taken from patients in a geographic area with a high density of pigs. METHODOLOGY/PRINCIPAL FINDINGS: In total, 612 consecutive episodes of S. aureus BSI diagnosed before and during the emergence of CC398 were included. Three strains (2 MSSA and 1 MRSA that were isolated from bacteremic patients between 2010-2011 were positive in a CC398 specific PCR. There was a marked increase in prevalence of S. aureus CC398 BSI isolated between 2010-2011 compared to the combined collections that were isolated between 1996-1998 and 2002-2005 (3/157, 1.9% vs. 0/455, 0.0%; p = 0.017. CONCLUSIONS/SIGNIFICANCE: In conclusion, in an area with a relative high density of pigs, S. aureus CC398 was found as a cause of BSI in humans only recently. This indicates that S. aureus CC398 is able to cause invasive infections in humans and that the prevalence is rising. Careful monitoring of the evolution and epidemiology of S. aureus CC398 in animals and humans is therefore important.

  18. Complexity, Compassion and Self-Organisation: Human Evolution and the Vulnerable Ape Hypothesis

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    Nick P. Winder

    2015-06-01

    Full Text Available Humans are agents capable of helping others, learning new behaviours and forgetting old ones. The evolutionary approach to archaeological systems has therefore been hampered by the 'modern synthesis' - a gene-centred model of evolution as a process that eliminates those that cannot handle stress. The result has been a form of environmental determinism that explains human evolution in terms of heroic struggles and selective winnowing. Biologists committed to the modern synthesis have either dismissed agency as a delusion wrought in our bodies by natural selection, or imposed a sharp, Cartesian split between 'natural' and 'artificial' ecologies. We revisit the seminal literature of evolutionary biology and show that the paradigmatic fault lines of 21st century anthropology can be traced back to the 19th century and beyond. Lamarck had developed a two-factor evolutionary theory - one factor an endogenous tendency to become more advanced and complex, the other an exogenous constraint that drove organisms into conformity with environment. Darwin tried to eliminate the progressive tendency and imposed linearity constraints on evolution that Thomas Henry Huxley rejected. When experimental evidence falsified Darwin's linear hypothesis, the race began to develop a new, gene-centred model of evolution. This became the modern synthesis. The modern synthesis is now under pressure from the evidence of anthropology, sociology, palaeontology, ecology and genetics. An 'extended synthesis' is emerging. If evolution is adequately summarised by the aphorism survival of the fittest, then 'fitness' cannot always be defined in the heroic sense of 'better able to compete and reproduce'. The fittest organisms are often those that evade selective winnowing, even when their ability to compete and reproduce has been compromised by their genes. Characteristically human traits like language, abstraction, compassion and altruism may have arisen as coping strategies that

  19. MTO1-deficient mouse model mirrors the human phenotype showing complex I defect and cardiomyopathy.

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    Lore Becker

    Full Text Available Recently, mutations in the mitochondrial translation optimization factor 1 gene (MTO1 were identified as causative in children with hypertrophic cardiomyopathy, lactic acidosis and respiratory chain defect. Here, we describe an MTO1-deficient mouse model generated by gene trap mutagenesis that mirrors the human phenotype remarkably well. As in patients, the most prominent signs and symptoms were cardiovascular and included bradycardia and cardiomyopathy. In addition, the mutant mice showed a marked worsening of arrhythmias during induction and reversal of anaesthesia. The detailed morphological and biochemical workup of murine hearts indicated that the myocardial damage was due to complex I deficiency and mitochondrial dysfunction. In contrast, neurological examination was largely normal in Mto1-deficient mice. A translational consequence of this mouse model may be to caution against anaesthesia-related cardiac arrhythmias which may be fatal in patients.

  20. Using virtual humans and computer animations to learn complex motor skills: a case study in karate

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    Spanlang Bernhard

    2011-12-01

    Full Text Available Learning motor skills is a complex task involving a lot of cognitive issues. One of the main issues consists in retrieving the relevant information from the learning environment. In a traditional learning situation, a teacher gives oral explanations and performs actions to provide the learner with visual examples. Using virtual reality (VR as a tool for learning motor tasks is promising. However, it raises questions about the type of information this kind of environments can offer. In this paper, we propose to analyze the impact of virtual humans on the perception of the learners. As a case study, we propose to apply this research problem to karate gestures. The results of this study show no significant difference on the after training performance of learners confronted to three different learning environments (traditional group, video and VR.

  1. A model of human collective decision-making in complex environments

    CERN Document Server

    Carbone, Giuseppe

    2015-01-01

    A continuous-time Markov process is proposed to analyze how a group of humans solves a complex task, consisting in the search of the optimal set of decisions on a fitness landscape. Individuals change their opinions driven by two different forces: (i) the rational behavior which pushes them to change their opinions as to increase their own fitness values, and (ii) the social interactions which push individuals to reduce the diversity of their opinions in order to reach consensus. Results show that the performance of the group is strongly affected by the strength of social interactions and by the level of knowledge of the individuals. Increasing the strength of social interactions improves the performance of the team. However, too strong social interactions slow down the search of the optimal solution and worsen the performance of the group. We prove that a moderate level of knowledge is already enough to guarantee high performance of the group in making decisions.

  2. A novel therapeutic strategy for experimental stroke using docosahexaenoic acid complexed to human albumin

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    Belayev Ludmila

    2016-01-01

    Full Text Available Despite tremendous efforts in ischemic stroke research and significant improvements in patient care within the last decade, therapy is still insufficient. There is a compelling, urgent need for safe and effective neuroprotective strategies to limit brain injury, facilitate brain repair, and improve functional outcome. Recently, we reported that docosahexaenoic acid (DHA; 22:6, n-3 complexed to human albumin (DHA-Alb is highly neuroprotective after temporary middle cerebral artery occlusion (MCAo in young rats. This review highlights the potency of DHA-Alb therapy in permanent MCAo and aged rats and whether protection persists with chronic survival. We discovered that a novel therapy with DHA-Alb improved behavioral outcomes accompanied by attenuation of lesion volumes even when animals were allowed to survive three weeks after experimental stroke. This treatment might provide the basis for future therapeutics for patients suffering from ischemic stroke.

  3. Interplay between Human Cytomegalovirus and Intrinsic/Innate Host Responses: A Complex Bidirectional Relationship

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    Giada Rossini

    2012-01-01

    Full Text Available The interaction between human cytomegalovirus (HCMV and its host is a complex process that begins with viral attachment and entry into host cells, culminating in the development of a specific adaptive response that clears the acute infection but fails to eradicate HCMV. We review the viral and cellular partners that mediate early host responses to HCMV with regard to the interaction between structural components of virions (viral glycoproteins and cellular receptors (attachment/entry receptors, toll-like receptors, and other nucleic acid sensors or intrinsic factors (PML, hDaxx, Sp100, viperin, interferon inducible protein 16, the reactions of innate immune cells (antigen presenting cells and natural killer cells, the numerous mechanisms of viral immunoevasion, and the potential exploitation of events that are associated with early phases of virus-host interplay as a therapeutic strategy.

  4. Prediction of Complex Human Traits Using the Genomic Best Linear Unbiased Predictor

    DEFF Research Database (Denmark)

    de los Campos, Gustavo; Vazquez, Ana I; Fernando, Rohan;

    2013-01-01

    ) models where phenotypes are regressed on hundreds of thousands of variants simultaneously. The Genomic Best Linear Unbiased Prediction G-BLUP, a ridge-regression type method) is a commonly used WGR method and has shown good predictive performance when applied to plant and animal breeding populations......Despite important advances from Genome Wide Association Studies (GWAS), for most complex human traits and diseases, a sizable proportion of genetic variance remains unexplained and prediction accuracy (PA) is usually low. Evidence suggests that PA can be improved using Whole-Genome Regression (WGR...... by imperfect LD between markers and QTL is given by (12b) 2, where b is the regression of marker-derived genomic relationships on those realized at causal loci. For pairs of related individuals, due to within-family disequilibrium, the patterns of realized genomic similarity are similar across the genome...

  5. Advanced design technique of human-machine interfaces for PLC control of complex systems

    Directory of Open Access Journals (Sweden)

    Árpád-István Sütő

    2008-05-01

    Full Text Available Touchscreen operator panels proved to be a convenient succesor for clasical operator panels for implementing human-machine interfaces (HMIs in programmable logic controllers (PLC systems. The paper introduces a new technique for HMIs design in such systems, based on the idea of touchscreens replication. This redundancy allow actions which are not possible within the menus and sub-menus of a single touchscreen. Its strenght is revealed especially in complex systems, where operators can easily be overwhelmed by the huge amount of process information. The technique was applied on a mill tube rolling installation. The results also proved an increase of system security and zero downtime for HMI maintenance activities.

  6. Mechanical properties of the normal human cartilage-bone complex in relation to age

    DEFF Research Database (Denmark)

    Ding, Ming; Dalstra, M; Linde, F

    1998-01-01

    OBJECTIVE: This study investigates the age-related variations in the mechanical properties of the normal human tibial cartilage-bone complex and the relationships between cartilage and bone. DESIGN: A novel technique was applied to assess the mechanical properties of the cartilage and bone by means...... normal donors aged 16-83 years were tested in compression. The deformation was measured simultaneously in bone and cartilage to obtain the mechanical properties of both tissues. RESULTS: The stiffnesses and elastic energies of both cartilage and bone showed an initial increase, with maxima at 40 years......, followed by a steady decline. The viscoelastic energy was maximal at younger ages (16-29 years), followed by a steady decline. The energy absorption capacity did not vary with age. Stiffnesses and elastic energies were correlated significantly between cartilage and bone. CONCLUSIONS: The present study...

  7. Processing of audiovisual associations in the human brain: dependency on expectations and rule complexity

    Directory of Open Access Journals (Sweden)

    Riikka eLindström

    2012-05-01

    Full Text Available In order to respond to environmental changes appropriately, the human brain must not only be able to detect environmental changes but also to form expectations of forthcoming events. The events in the external environment often have a number of multisensory features such as pitch and form. For integrated percepts of objects and events, crossmodal processing and crossmodally induced expectations of forthcoming events are needed. The aim of the present study was to determine whether the expectations created by visual stimuli can modulate the deviance detection in the auditory modality, as reflected by auditory event-related potentials (ERPs. Additionally, it was studied whether the complexity of the rules linking auditory and visual stimuli together affects this process. The N2 deflection of the ERP was observed in response to violations in the subjects' expectation of a forthcoming tone. Both temporal aspects and cognitive demands during the audiovisual deviance detection task modulated the brain processes involved.

  8. The Analysis of the Influence of Odorant’s Complexity on Fractal Dynamics of Human Respiration

    Science.gov (United States)

    Namazi, Hamidreza; Akrami, Amin; Kulish, Vladimir V.

    2016-05-01

    One of the major challenges in olfaction research is to relate the structural features of the odorants to different features of olfactory system. However, no relationship has been yet discovered between the structure of the olfactory stimulus, and the structure of respiratory signal. This study reveals the plasticity of human respiratory signal in relation to ‘complex’ olfactory stimulus (odorant). We demonstrated that fractal temporal structure of respiration dynamics shifts towards the properties of the odorants used. The results show for the first time that more structurally complex a monomolecular odorant will result in less fractal respiratory signal. On the other hand, odorant with higher entropy will result the respiratory signal with lower entropy. The capability observed in this research can be further investigated and applied for treatment of patients with different respiratory diseases.

  9. Hsp60 and p70S6K form a complex in human cardiomyocytes

    Directory of Open Access Journals (Sweden)

    Kroupskaya I. V.

    2011-02-01

    Full Text Available Molecular chaperon Hsp60 and protein kinase p70S6K play an important functional role in the regulation of cardiomyocytes vital function or apoptosis. Aim. To study a possibility of in vivo complex formation between Hsp60 and p70S6K in cardiomyocytes. Methods. Co-immunoprecipitation, Western-blot analysis. Results. We have identified in vivo interaction between molecular chaperone Hsp60 and two isoforms of proteinkinase p70S6K in human myocardium, normal and affected by cardiomyopathy. Conclusions. The results obtained suggest a possible participation of molecular chaperon Hsp60 in regulation of p70S6K activity in stressinduced apoptotic signaling pathway in cardiomyocytes.

  10. A New Method to Develop Human Dental Pulp Cells and Platelet-rich Fibrin Complex.

    Science.gov (United States)

    He, Xuan; Chen, Wen-Xia; Ban, Guifei; Wei, Wei; Zhou, Jun; Chen, Wen-Jin; Li, Xian-Yu

    2016-11-01

    Platelet-rich fibrin (PRF) has been used as a scaffold material in various tissue regeneration studies. In the previous methods to combine seed cells with PRF, the structure of PRF was damaged, and the manipulation time in vitro was also increased. The objective of this in vitro study was to explore an appropriate method to develop a PRF-human dental pulp cell (hDPC) complex to maintain PRF structure integrity and to find out the most efficient part of PRF. The PRF-hDPC complex was developed at 3 different time points during PRF preparation: (1) the before centrifugation (BC) group, the hDPC suspension was added to the venous blood before blood centrifugation; (2) the immediately after centrifugation (IAC) group, the hDPC suspension was added immediately after blood centrifugation; (3) the after centrifugation (AC) group, the hDPC suspension was added 10 minutes after blood centrifugation; and (4) the control group, PRF without hDPC suspension. The prepared PRF-hDPC complexes were cultured for 7 days. The samples were fixed for histologic, immunohistochemistry, and scanning electron microscopic evaluation. Real-time polymerase chain reaction was performed to evaluate messenger RNA expression of alkaline phosphatase and dentin sialophosphoprotein. Enzyme-linked immunosorbent assay quantification for growth factors was performed within the different parts of the PRF. Histologic, immunohistochemistry, and scanning electron microscopic results revealed that hDPCs were only found in the BC group and exhibited favorable proliferation. Real-time polymerase chain reaction revealed that alkaline phosphatase and dentin sialophosphoprotein expression increased in the cultured PRF-hDPC complex. The lower part of the PRF released the maximum quantity of growth factors. Our new method to develop a PRF-hDPCs complex maintained PRF structure integrity. The hDPCs were distributed in the buffy coat, which might be the most efficient part of PRF. Copyright © 2016 American

  11. Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases.

    Science.gov (United States)

    Sun, Yan V; Hu, Yi-Juan

    2016-01-01

    Complex and dynamic networks of molecules are involved in human diseases. High-throughput technologies enable omics studies interrogating thousands to millions of makers with similar biochemical properties (eg, transcriptomics for RNA transcripts). However, a single layer of "omics" can only provide limited insights into the biological mechanisms of a disease. In the case of genome-wide association studies, although thousands of single nucleotide polymorphisms have been identified for complex diseases and traits, the functional implications and mechanisms of the associated loci are largely unknown. Additionally, the genomic variants alone are not able to explain the changing disease risk across the life span. DNA, RNA, protein, and metabolite often have complementary roles to jointly perform a certain biological function. Such complementary effects and synergistic interactions between omic layers in the life course can only be captured by integrative study of multiple molecular layers. Building upon the success in single-omics discovery research, population studies started adopting the multi-omics approach to better understanding the molecular function and disease etiology. Multi-omics approaches integrate data obtained from different omic levels to understand their interrelation and combined influence on the disease processes. Here, we summarize major omics approaches available in population research, and review integrative approaches and methodologies interrogating multiple omic layers, which enhance the gene discovery and functional analysis of human diseases. We seek to provide analytical recommendations for different types of multi-omics data and study designs to guide the emerging multi-omic research, and to suggest improvement of the existing analytical methods. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. A dynamic finite element analysis of human foot complex in the sagittal plane during level walking.

    Science.gov (United States)

    Qian, Zhihui; Ren, Lei; Ding, Yun; Hutchinson, John R; Ren, Luquan

    2013-01-01

    The objective of this study is to develop a computational framework for investigating the dynamic behavior and the internal loading conditions of the human foot complex during locomotion. A subject-specific dynamic finite element model in the sagittal plane was constructed based on anatomical structures segmented from medical CT scan images. Three-dimensional gait measurements were conducted to support and validate the model. Ankle joint forces and moment derived from gait measurements were used to drive the model. Explicit finite element simulations were conducted, covering the entire stance phase from heel-strike impact to toe-off. The predicted ground reaction forces, center of pressure, foot bone motions and plantar surface pressure showed reasonably good agreement with the gait measurement data over most of the stance phase. The prediction discrepancies can be explained by the assumptions and limitations of the model. Our analysis showed that a dynamic FE simulation can improve the prediction accuracy in the peak plantar pressures at some parts of the foot complex by 10%-33% compared to a quasi-static FE simulation. However, to simplify the costly explicit FE simulation, the proposed model is confined only to the sagittal plane and has a simplified representation of foot structure. The dynamic finite element foot model proposed in this study would provide a useful tool for future extension to a fully muscle-driven dynamic three-dimensional model with detailed representation of all major anatomical structures, in order to investigate the structural dynamics of the human foot musculoskeletal system during normal or even pathological functioning.

  13. A dynamic finite element analysis of human foot complex in the sagittal plane during level walking.

    Directory of Open Access Journals (Sweden)

    Zhihui Qian

    Full Text Available The objective of this study is to develop a computational framework for investigating the dynamic behavior and the internal loading conditions of the human foot complex during locomotion. A subject-specific dynamic finite element model in the sagittal plane was constructed based on anatomical structures segmented from medical CT scan images. Three-dimensional gait measurements were conducted to support and validate the model. Ankle joint forces and moment derived from gait measurements were used to drive the model. Explicit finite element simulations were conducted, covering the entire stance phase from heel-strike impact to toe-off. The predicted ground reaction forces, center of pressure, foot bone motions and plantar surface pressure showed reasonably good agreement with the gait measurement data over most of the stance phase. The prediction discrepancies can be explained by the assumptions and limitations of the model. Our analysis showed that a dynamic FE simulation can improve the prediction accuracy in the peak plantar pressures at some parts of the foot complex by 10%-33% compared to a quasi-static FE simulation. However, to simplify the costly explicit FE simulation, the proposed model is confined only to the sagittal plane and has a simplified representation of foot structure. The dynamic finite element foot model proposed in this study would provide a useful tool for future extension to a fully muscle-driven dynamic three-dimensional model with detailed representation of all major anatomical structures, in order to investigate the structural dynamics of the human foot musculoskeletal system during normal or even pathological functioning.

  14. Nodal recovery, dual pathway physiology, and concealed conduction determine complex AV dynamics in human atrial tachyarrhythmias.

    Science.gov (United States)

    Masè, Michela; Glass, Leon; Disertori, Marcello; Ravelli, Flavia

    2012-11-15

    The genesis of complex ventricular rhythms during atrial tachyarrhythmias in humans is not fully understood. To clarify the dynamics of atrioventricular (AV) conduction in response to a regular high-rate atrial activation, 29 episodes of spontaneous or pacing-induced atrial flutter (AFL), covering a wide range of atrial rates (cycle lengths from 145 to 270 ms), were analyzed in 10 patients. AV patterns were identified by applying firing sequence and surrogate data analysis to atrial and ventricular activation series, whereas modular simulation with a difference-equation AV node model was used to correlate the patterns with specific nodal properties. AV node response at high atrial rate was characterized by 1) AV patterns of decreasing conduction ratios at the shortening of atrial cycle length (from 236.3 ± 32.4 to 172.6 ± 17.8 ms) according to a Farey sequence ordering (conduction ratio from 0.34 ± 0.12 to 0.23 ± 0.06; P AV block patterns occurring during regular atrial tachyarrhythmias. The characterization of AV nodal function during different AFL forms constitutes an intermediate step toward the understanding of complex ventricular rhythms during atrial fibrillation.

  15. Structure of Human O-GlcNAc Transferase and its Complex with a Peptide Substrate

    Energy Technology Data Exchange (ETDEWEB)

    M Lazarus; Y Nam; J Jiang; P Sliz; S Walker

    2011-12-31

    The essential mammalian enzyme O-linked {beta}-N-acetylglucosamine transferase (O-GlcNAc transferase, here OGT) couples metabolic status to the regulation of a wide variety of cellular signalling pathways by acting as a nutrient sensor. OGT catalyses the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine (UDP-GlcNAc) to serines and threonines of cytoplasmic, nuclear and mitochondrial proteins, including numerous transcription factors, tumour suppressors, kinases, phosphatases and histone-modifying proteins. Aberrant glycosylation by OGT has been linked to insulin resistance, diabetic complications, cancer and neurodegenerative diseases including Alzheimer's. Despite the importance of OGT, the details of how it recognizes and glycosylates its protein substrates are largely unknown. We report here two crystal structures of human OGT, as a binary complex with UDP (2.8 {angstrom} resolution) and as a ternary complex with UDP and a peptide substrate (1.95 {angstrom}). The structures provide clues to the enzyme mechanism, show how OGT recognizes target peptide sequences, and reveal the fold of the unique domain between the two halves of the catalytic region. This information will accelerate the rational design of biological experiments to investigate OGT's functions; it will also help the design of inhibitors for use as cellular probes and help to assess its potential as a therapeutic target.

  16. Substrate complexes of human dipeptidyl peptidase III reveal the mechanism of enzyme inhibition

    Science.gov (United States)

    Kumar, Prashant; Reithofer, Viktoria; Reisinger, Manuel; Wallner, Silvia; Pavkov-Keller, Tea; Macheroux, Peter; Gruber, Karl

    2016-01-01

    Human dipeptidyl-peptidase III (hDPP III) is a zinc-dependent hydrolase cleaving dipeptides off the N-termini of various bioactive peptides. Thus, the enzyme is likely involved in a number of physiological processes such as nociception and is also implicated in several forms of cancer. We present high-resolution crystal structures of hDPP III in complex with opioid peptides (Met-and Leu-enkephalin, endomorphin-2) as well as with angiotensin-II and the peptide inhibitor IVYPW. These structures confirm the previously reported large conformational change of the enzyme upon ligand binding and show that the structure of the closed conformation is independent of the nature of the bound peptide. The overall peptide-binding mode is also conserved ensuring the correct positioning of the scissile peptide bond with respect to the catalytic zinc ion. The structure of the angiotensin-II complex shows, how longer peptides are accommodated in the binding cleft of hDPP III. Differences in the binding modes allow a distinction between real substrates and inhibitory peptides or “slow” substrates. The latter displace a zinc bound water molecule necessitating the energetically much less favoured anhydride mechanism as opposed to the favoured promoted-water mechanism. The structural data also form the necessary framework for the design of specific hDPP III inhibitors. PMID:27025154

  17. Crystal structures of human pancreatic alpha-amylase in complex with carbohydrate and proteinaceous inhibitors.

    Science.gov (United States)

    Nahoum, V; Roux, G; Anton, V; Rougé, P; Puigserver, A; Bischoff, H; Henrissat, B; Payan, F

    2000-01-01

    Crystal structures of human pancreatic alpha-amylase (HPA) in complex with naturally occurring inhibitors have been solved. The tetrasaccharide acarbose and a pseudo-pentasaccharide of the trestatin family produced identical continuous electron densities corresponding to a pentasaccharide species, spanning the -3 to +2 subsites of the enzyme, presumably resulting from transglycosylation. Binding of the acarviosine core linked to a glucose residue at subsites -1 to +2 appears to be a critical part of the interaction process between alpha-amylases and trestatin-derived inhibitors. Two crystal forms, obtained at different values of pH, for the complex of HPA with the protein inhibitor from Phaseolus vulgaris (alpha-amylase inhibitor) have been solved. The flexible loop typical of the mammalian alpha-amylases was shown to exist in two different conformations, suggesting that loop closure is pH-sensitive. Structural information is provided for the important inhibitor residue, Arg-74, which has not been observed previously in structural analyses. PMID:10657258

  18. Specific activation of human interleukin-5 depends on de novo synthesis of an AP-1 complex.

    Science.gov (United States)

    Schwenger, Gretchen T F; Kok, Chee Choy; Arthaningtyas, Estri; Thomas, Marc A; Sanderson, Colin J; Mordvinov, Viatcheslav A

    2002-12-06

    It is clear from the biology of eosinophilia that a specific regulatory mechanism must exist. Because interleukin-5 (IL5) is the key regulatory cytokine, it follows that a gene-specific control of IL5 expression must exist that differs even from closely related cytokines such as IL4. Two features of IL5 induction make it unique compared with other cytokines; first, induction by cyclic adenosine monophosphate (cAMP), which inhibits other T-cell-derived cytokines, and second, sensitivity to protein synthesis inhibitors, which have no effect on other cytokines. This study has utilized the activation of different transcription factors by different stimuli in a human T-cell line to study the role of conserved lymphokine element 0 (CLE0) in the specific induction of IL5. In unstimulated cells the ubiquitous Oct-1 binds to CLE0. Stimulation induces de novo synthesis of the AP-1 members JunD and Fra-2, which bind to CLE0. The amount of IL5 produced correlates with the production of the AP-1 complex, suggesting a key role in IL5 expression. The formation of the AP-1 complex is essential, but the rate-limiting step is the synthesis of AP-1, especially Fra-2. This provides an explanation for the sensitivity of IL5 to protein synthesis inhibitors and a mechanism for the specific induction of IL5 compared with other cytokines.

  19. A closer look at the complex hydrophilic/hydrophobic interactions forces at the human hair surface

    Science.gov (United States)

    Baghdadli, N.; Luengo, G. S.; Recherche, L.

    2008-03-01

    The complex chemical structure of the hair surface is far from being completely understood. Current understanding is based on Rivett's model1 that was proposed to explain the macroscopic hydrophobic nature of the surface of natural hair. In this model covalently-linked fatty acids are chemically grafted to the amorphous protein (keratin) through a thio-ester linkage2,3. Nevertheless, experience like wetting and electrical properties of human hair surface4 shows that the complexity of the hair surface is not fully understand based on this model in literature. Recent studies in our laboratory show for the first time microscopic evidence of the heterogeneous physico-chemical character of the hair surface. By using Chemical Force Microscopy, the presence of hydrophobic and ionic species are detected and localized, before and after a cosmetic treatment (bleaching). Based on force curve analysis the mapping of the local distribution of hydrophilic and hydrophobic groups of hair surface is obtained. A discussion on a more plausible hair model and its implications will be presented based on these new results.

  20. A closer look at the complex hydrophilic/hydrophobic interactions forces at the human hair surface

    Energy Technology Data Exchange (ETDEWEB)

    Baghdadli, N; Luengo, G S; Recherche, L [Avenue Eugene Schueller, Aulnay-Sous Bois, 93100 (France)], E-mail: nbaghdadli@rd.loreal.com, E-mail: gluengo@rd.loreal.com

    2008-03-15

    The complex chemical structure of the hair surface is far from being completely understood. Current understanding is based on Rivett's model{sup 1} that was proposed to explain the macroscopic hydrophobic nature of the surface of natural hair. In this model covalently-linked fatty acids are chemically grafted to the amorphous protein (keratin) through a thio-ester linkage{sup 2,3}. Nevertheless, experience like wetting and electrical properties of human hair surface{sup 4} shows that the complexity of the hair surface is not fully understand based on this model in literature. Recent studies in our laboratory show for the first time microscopic evidence of the heterogeneous physico-chemical character of the hair surface. By using Chemical Force Microscopy, the presence of hydrophobic and ionic species are detected and localized, before and after a cosmetic treatment (bleaching). Based on force curve analysis the mapping of the local distribution of hydrophilic and hydrophobic groups of hair surface is obtained. A discussion on a more plausible hair model and its implications will be presented based on these new results.

  1. Structural characterization of human heme oxygenase-1 in complex with azole-based inhibitors.

    Science.gov (United States)

    Rahman, Mona N; Vlahakis, Jason Z; Roman, Gheorghe; Vukomanovic, Dragic; Szarek, Walter A; Nakatsu, Kanji; Jia, Zongchao

    2010-03-01

    The development of inhibitors specific for heme oxygenases (HO) aims to provide powerful tools in understanding the HO system. Based on the lead structure (2S, 4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-[((4-aminophenyl)thio)methyl]-1,3-dioxolane (azalanstat, QC-1) we have synthesized structural modifications to develop novel and selective HO inhibitors. The structural study of human HO-1 (hHO-1) in complex with a select group of the inhibitors was initiated using X-ray crystallographic techniques. Comparison of the structures of four such compounds each in complex with hHO-1 revealed a common binding mode, despite having different structural fragments. The compounds bind to the distal side of heme through an azole "anchor" which coordinates with the heme iron. An expansion of the distal pocket, mainly due to distal helix flexibility, allows accommodation of the compounds without displacing heme or the critical Asp140 residue. Rather, binding displaces a catalytically critical water molecule and disrupts an ordered hydrogen-bond network involving Asp140. The presence of a triazole "anchor" may provide further stability via a hydrogen bond with the protein. A hydrophobic pocket acts to stabilize the region occupied by the phenyl or adamantanyl moieties of these compounds. Further, a secondary hydrophobic pocket is formed via "induced fit" to accommodate bulky substituents at the 4-position of the dioxolane ring. Copyright 2009 Elsevier Inc. All rights reserved.

  2. Genetic recombination within the human T-cell receptor. cap alpha. -chain gene complex

    Energy Technology Data Exchange (ETDEWEB)

    Robinson, M.A.; Kindt, T.J.

    1987-12-01

    Genetic analyses of the human T-cell receptor (TCR) ..cap alpha..-chain genes indicate that recombination events may occur frequently within this gene complex. Examination of the inheritance of restriction fragment length polymorphisms (RFLP) detected by using probes for constant or variable region gene segments made it possible to assign TCR..cap alpha.. haplotypes to the 16 parents and 43 offspring of eight families studied. A total of six RFLP, three for the constant region and three for variable region segments, were examined in the present studies. Most enzyme and probe combinations tested revealed no polymorphism and those finally selected for the study showed limited polymorphism in that only two or, in one case, three allelic forms of the gene were seen. In spite of limited variability at this level, extensive heterogeneity was observed for the combinations of markers present in haplotypes, suggesting that frequent recombination events have occurred. Most strikingly, multiple combinations of RFLP occurring in close proximity of the TCR..cap alpha.. constant region gene were observed in this study. A high recombination frequency for the TCR..cap alpha.. gene complex is further supported by the observation that two children, one in each of two families, inherited recombinant TCR..cap alpha.. haplotypes.

  3. Equivalent dynamical complexity in a many-body quantum and collective human system

    CERN Document Server

    Johnson, Neil F; Zhao, Zhenyuan; Quiroga, Luis

    2010-01-01

    Proponents of Complexity Science believe that the huge variety of emergent phenomena observed throughout nature, are generated by relatively few microscopic mechanisms [1-7]. Skeptics however point to the lack of concrete examples in which a single mechanistic model manages to capture relevant macroscopic and microscopic properties for two or more distinct systems operating across radically different length and time scales. Here we show how a single complexity model built around cluster coalescence and fragmentation, can cross the fundamental divide between many-body quantum physics and social science. It simultaneously (i) explains a mysterious recent finding concerning quantum many-body effects in cuprate superconductors [8,9] (i.e. scale of 10^{-9}-10^{-4} meters and 10^{-12}-10^{-6} seconds), (ii) explains the apparent universality of the casualty distributions in distinct human insurgencies and terrorism [10] (i.e. scale of 10^{3}-10^{6} meters and 10^{4}-10^{8} seconds), (iii) shows consistency with var...

  4. Microfluorometric assessment of the DNA-DNP complex in human spermatozoa.

    Science.gov (United States)

    Johannisson, E; Jacolino, H

    1987-06-01

    During spermiogenesis, the DNA-nucleoprotein complex undergoes alterations that are reflected in a decreasing capacity for binding DNA-specific dyes, such as ethidium bromide (EB). Human spermatozoa with a low or high capacity for EB binding were depleted of RNA and most nuclear proteins by exposure to RNAse, EDTA and trypsin, with and without additional high salt buffer (HSB) treatment. When treated with RNAse, EDTA and trypsin only, the haploid DNA fluorescence value (calculated from the diploid value of the standard cell population) was found at EB concentrations of 6.5 to 12.5 micrograms/mL. At these EB concentrations, a significantly lower fluorescence was found in the material also treated with HSB, probably reflecting an unwinding of the highly negatively supercoiled DNA loops that are induced by HSB treatment. Maximal fluorescence was not found until a concentration of 50 micrograms EB/mL. This may be due to an overwinding of the DNA by the positive supercoiling caused by EB. The significant difference in EB uptake initially found between the two groups whose spermatozoa showed low and high capacities for EB binding disappeared after removal of the nucleoproteins, suggesting that this compartment of the nucleoprotein-DNA complex is responsible for the different uptakes of EB.

  5. Unique cell type-specific junctional complexes in vascular endothelium of human and rat liver sinusoids.

    Directory of Open Access Journals (Sweden)

    Cyrill Géraud

    Full Text Available Liver sinusoidal endothelium is strategically positioned to control access of fluids, macromolecules and cells to the liver parenchyma and to serve clearance functions upstream of the hepatocytes. While clearance of macromolecular debris from the peripheral blood is performed by liver sinusoidal endothelial cells (LSECs using a delicate endocytic receptor system featuring stabilin-1 and -2, the mannose receptor and CD32b, vascular permeability and cell trafficking are controlled by transcellular pores, i.e. the fenestrae, and by intercellular junctional complexes. In contrast to blood vascular and lymphatic endothelial cells in other organs, the junctional complexes of LSECs have not yet been consistently characterized in molecular terms. In a comprehensive analysis, we here show that LSECs express the typical proteins found in endothelial adherens junctions (AJ, i.e. VE-cadherin as well as α-, β-, p120-catenin and plakoglobin. Tight junction (TJ transmembrane proteins typical of endothelial cells, i.e. claudin-5 and occludin, were not expressed by rat LSECs while heterogenous immunreactivity for claudin-5 was detected in human LSECs. In contrast, junctional molecules preferentially associating with TJ such as JAM-A, B and C and zonula occludens proteins ZO-1 and ZO-2 were readily detected in LSECs. Remarkably, among the JAMs JAM-C was considerably over-expressed in LSECs as compared to lung microvascular endothelial cells. In conclusion, we show here that LSECs form a special kind of mixed-type intercellular junctions characterized by co-occurrence of endothelial AJ proteins, and of ZO-1 and -2, and JAMs. The distinct molecular architecture of the intercellular junctional complexes of LSECs corroborates previous ultrastructural findings and provides the molecular basis for further analyses of the endothelial barrier function of liver sinusoids under pathologic conditions ranging from hepatic inflammation to formation of liver metastasis.

  6. Characterization of interactions of dihydrolipoamide dehydrogenase with its binding protein in the human pyruvate dehydrogenase complex

    Energy Technology Data Exchange (ETDEWEB)

    Park, Yun-Hee [Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214 (United States); Patel, Mulchand S., E-mail: mspatel@buffalo.edu [Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214 (United States)

    2010-05-07

    Unlike pyruvate dehydrogenase complexes (PDCs) from prokaryotes, PDCs from higher eukaryotes have an additional structural component, E3-binding protein (BP), for binding of dihydrolipoamide dehydrogenase (E3) in the complex. Based on the 3D structure of the subcomplex of human (h) E3 with the di-domain (L3S1) of hBP, the amino acid residues (H348, D413, Y438, and R447) of hE3 for binding to hBP were substituted singly by alanine or other residues. These substitutions did not have large effects on hE3 activity when measured in its free form. However, when these hE3 mutants were reconstituted in the complex, the PDC activity was significantly reduced to 9% for Y438A, 20% for Y438H, and 18% for D413A. The binding of hE3 mutants with L3S1 determined by isothermal titration calorimetry revealed that the binding affinities of the Y438A, Y438H, and D413A mutants to L3S1 were severely reduced (1019-, 607-, and 402-fold, respectively). Unlike wild-type hE3 the binding of the Y438A mutant to L3S1 was accompanied by an unfavorable enthalpy change and a large positive entropy change. These results indicate that hE3-Y438 and hE3-D413 play important roles in binding of hE3 to hBP.

  7. Effectiveness of Shrinkage and Variable Selection Methods for the Prediction of Complex Human Traits using Data from Distantly Related Individuals

    Science.gov (United States)

    Pérez‐Rodríguez, Paulino; Veturi, Yogasudha; Simianer, Henner; de los Campos, Gustavo

    2015-01-01

    Summary Genome‐wide association studies (GWAS) have detected large numbers of variants associated with complex human traits and diseases. However, the proportion of variance explained by GWAS‐significant single nucleotide polymorphisms has been usually small. This brought interest in the use of whole‐genome regression (WGR) methods. However, there has been limited research on the factors that affect prediction accuracy (PA) of WGRs when applied to human data of distantly related individuals. Here, we examine, using real human genotypes and simulated phenotypes, how trait complexity, marker‐quantitative trait loci (QTL) linkage disequilibrium (LD), and the model used affect the performance of WGRs. Our results indicated that the estimated rate of missing heritability is dependent on the extent of marker‐QTL LD. However, this parameter was not greatly affected by trait complexity. Regarding PA our results indicated that: (a) under perfect marker‐QTL LD WGR can achieve moderately high prediction accuracy, and with simple genetic architectures variable selection methods outperform shrinkage procedures and (b) under imperfect marker‐QTL LD, variable selection methods can achieved reasonably good PA with simple or moderately complex genetic architectures; however, the PA of these methods deteriorated as trait complexity increases and with highly complex traits variable selection and shrinkage methods both performed poorly. This was confirmed with an analysis of human height. PMID:25600682

  8. Multiple Human Tracking in Complex Situation by Data Assimilation with Pedestrian Behavior Model

    Science.gov (United States)

    Nakanishi, W.; Fuse, T.

    2012-07-01

    A new method of multiple human tracking is proposed. The key concept is that to assume a tracking process as a data assimilation process. Despite the importance of understanding pedestrian behavior in public space with regard to achieving more sophisticated space design and flow control, automatic human tracking in complex situation is still challenging when people move close to each other or are occluded by others. For this difficulty, we stochastically combine existing tracking method by image processing with simulation models of walking behavior. We describe a system in a form of general state space model and define the components of the model according to the review on related works. Then we apply the proposed method to the data acquired at the ticket gate of the railway station. We show the high performance of the method, as well as compare the result with other model to present the advantage of integrating the behavior model to the tracking method. We also show the method's ability to acquire passenger flow information such as ticket gate choice and OD data automatically from the tracking result.

  9. Complexes of Amyloid-β and Cystatin C in the Human Central Nervous System

    Science.gov (United States)

    Mi, Weiqian; Jung, Sonia S.; Yu, Haung; Schmidt, Stephen D.; Nixon, Ralph A.; Mathews, Paul M.; Tagliavini, Fabrizio; Levy, Efrat

    2009-01-01

    A role for cystatin C (CysC) in the pathogenesis of Alzheimer’s disease (AD) has been suggested by the genetic linkage of a CysC gene (CST3) polymorphism with late-onset AD, the co-localization of CysC with amyloid-β (Aβ) in AD brains, and binding of CysC to soluble Aβ in vitro and in mouse models of AD. This study investigates the binding between Aβ and CysC in the human central nervous system. While CysC binding to soluble Aβ was observed in AD patients and controls, a SDS-resistant CysC/Aβ complex was detected exclusively in brains of neuropathologically normal controls, but not in AD cases. The association of CysC with Aβ in brain from control individuals and in cerebrospinal fluid reveals an interaction of these two polypeptides in their soluble form. The association between Aβ and CysC prevented Aβ accumulation and fibrillogenesis in experimental systems, arguing that CysC plays a protective role in the pathogenesis of AD in humans and explains why decreases in CysC concentration caused by the CST3 polymorphism or by specific presenilin 2 mutations can lead to the development of the disease. Thus, enhancing CysC expression or modulating CysC binding to Aβ have important disease-modifying effects, suggesting a novel therapeutic intervention for AD. PMID:19584436

  10. Native gel electrophoresis of human telomerase distinguishes active complexes with or without dyskerin

    Science.gov (United States)

    Gardano, Laura; Holland, Linda; Oulton, Rena; Le Bihan, Thierry; Harrington, Lea

    2012-01-01

    Telomeres, the ends of linear chromosomes, safeguard against genome instability. The enzyme responsible for extension of the telomere 3′ terminus is the ribonucleoprotein telomerase. Whereas telomerase activity can be reconstituted in vitro with only the telomerase RNA (hTR) and telomerase reverse transcriptase (TERT), additional components are required in vivo for enzyme assembly, stability and telomere extension activity. One such associated protein, dyskerin, promotes hTR stability in vivo and is the only component to co-purify with active, endogenous human telomerase. We used oligonucleotide-based affinity purification of hTR followed by native gel electrophoresis and in-gel telomerase activity detection to query the composition of telomerase at different purification stringencies. At low salt concentrations (0.1 M NaCl), affinity-purified telomerase was ‘supershifted’ with an anti-dyskerin antibody, however the association with dyskerin was lost after purification at 0.6 M NaCl, despite the retention of telomerase activity and a comparable yield of hTR. The interaction of purified hTR and dyskerin in vitro displayed a similar salt-sensitive interaction. These results demonstrate that endogenous human telomerase, once assembled and active, does not require dyskerin for catalytic activity. Native gel electrophoresis may prove useful in the characterization of telomerase complexes under various physiological conditions. PMID:22187156

  11. Human Herpesvirus 7 U21 Tetramerizes To Associate with Class I Major Histocompatibility Complex Molecules

    Science.gov (United States)

    May, Nathan A.; Wang, Qiuhong; Balbo, Andrea; Konrad, Sheryl L.; Buchli, Rico; Hildebrand, William H.; Schuck, Peter

    2014-01-01

    ABSTRACT The U21 gene product from human herpesvirus 7 binds to and redirects class I major histocompatibility complex (MHC) molecules to a lysosomal compartment. The molecular mechanism by which U21 reroutes class I MHC molecules to lysosomes is not known. Here, we have reconstituted the interaction between purified soluble U21 and class I MHC molecules, suggesting that U21 does not require additional cellular proteins to interact with class I MHC molecules. Our results demonstrate that U21, itself predicted to contain an MHC class I-like protein fold, interacts tightly with class I MHC molecules as a tetramer, in a 4:2 stoichiometry. These observations have helped to elucidate a refined model describing the mechanism by which U21 escorts class I MHC molecules to the lysosomal compartment. IMPORTANCE In this report, we show that the human herpesvirus 7 (HHV-7) immunoevasin U21, itself a class I MHC-like protein, binds with high affinity to class I MHC molecules as a tetramer and escorts them to lysosomes, where they are degraded. While many class I MHC-like molecules have been described in detail, this unusual viral class I-like protein functions as a tetramer, associating with class I MHC molecules in a 4:2 ratio, illuminating a functional significance of homooligomerization of a class I MHC-like protein. PMID:24390327

  12. Balancing Human-machine Interface (HMI) Design in Complex Supervisory Tasks

    Energy Technology Data Exchange (ETDEWEB)

    Ha, Junsu [Khalifa Univ. of Science, Abu Dhabi (United Arab Emirates); Kim, Arryum; Jang, Inseok; Seong, Poonghyun [Korea Advanced Institute of Science and Technology, Daejeon (Korea, Republic of)

    2013-05-15

    Human performance aspects such as plant performance, personnel task performance, situation awareness, cognitive workload, teamwork, and anthropomorphic/physiological factor are evaluated with the HUPESS. Even though the HUPESS provides evaluation results in each of the performance aspects for the integrated system validation (ISV), additional researches have been needed to develop methods on how to find out design deficiency leading to poor performance and give a solution for design improvement in HMI. The authors have developed a method of HMI design improvement for the monitoring and detection tasks which was named as 'DEMIS (Difficulty Evaluation Method in Information Searching)'. The DEMIS is a HMI evaluation method which bridge poor performance and design improvement. Lessons learned from the existing studies lead to a question about how to optimize the whole HMI design. Human factors principles provide the foundation for guidelines of various codes and standards in designing HMIs. Also in NPPs, a lot of guidelines directly from various codes and standard and derived from various research and development projects are available for designing MCR HMIs. In this study, a balancing principle and relevant two measures for HMI design optimization are proposed to be used in the HMI design of complex supervisory tasks in NPPs. The balancing principle is that a HMI element (e. g., an indicator or a push button) should be designed according to its importance.

  13. Quinolinic acid selectively induces apoptosis of human astrocytes: potential role in AIDS dementia complex

    Directory of Open Access Journals (Sweden)

    Wang Lily

    2005-07-01

    Full Text Available Abstract There is evidence that the kynurenine pathway (KP and particularly one of its end products, quinolinic acid (QUIN play a role in the pathogenesis of several major neuroinflammatory diseases, and more particularly AIDS dementia complex (ADC. We hypothesized that QUIN may be involved in astrocyte apoptosis because: 1 apoptotic astrocytes have been observed in the brains of ADC patients, 2 ADC patients have elevated cerebrospinal fluid QUIN concentrations, and 3 QUIN can induce astrocyte death. Primary cultures of human fetal astrocytes were treated with three pathophysiological concentrations of QUIN. Numeration of apoptotic cells was assessed using double immunocytochemistry for expression of active caspase 3 and for nucleus condensation. We found that treatment of human astrocytes with QUIN induced morphological (cell body shrinking and biochemical changes (nucleus condensation and over-expression of active caspase 3 of apoptosis. After 24 hours of treatment with QUIN 500 nM and 1200 nM respectively 10 and 14% of astrocytes were undergoing apoptosis. This would be expected to lead to a relative lack of trophic support factors with consequent neuronal dysfunction and possibly death. Astroglial apoptosis induced by QUIN provides another potential mechanism for the neurotoxicity of QUIN during ADC.

  14. Unravelling the Complexity and Functions of MTA Coregulators in Human Cancer.

    Science.gov (United States)

    Li, Da-Qiang; Kumar, Rakesh

    2015-01-01

    Since the initial recognition of the metastasis-associated protein 1 (MTA1) as a metastasis-relevant gene approximately 20 years ago, our appreciation for the complex role of the MTA family of coregulatory proteins in human cancer has profoundly grown. MTA proteins consist of six family members with similar structural units and act as central signaling nodes for integrating upstream signals into regulatory chromatin-remodeling networks, leading to regulation of gene expression in cancer cells. Substantial experimental and clinical evidence demonstrates that MTA proteins, particularly MTA1, are frequently deregulated in a wide range of human cancers. The MTA family governs cell survival, the invasive and metastatic phenotypes of cancer cells, and the aggressiveness of cancer and the prognosis of patients with MTA1 overexpressing cancers. Our discussion here highlights our current understanding of the regulatory mechanisms and functional roles of MTA proteins in cancer progression and expands upon the potential implications of MTA proteins in cancer biology and cancer therapeutics.

  15. Categorial Ontology of Complex Systems, Meta-Systems and Levels: The Emergence of Life, Human Consciousness and Society

    Directory of Open Access Journals (Sweden)

    James F. Glazebrook

    2010-06-01

    Full Text Available Relational structures of organisms and the human mind are naturally represented in terms of novel variable topology concepts, non-Abelian categories and Higher Dimensional Algebra{ relatively new concepts that would be defined in
    this tutorial paper. A unifying theme of local-to-global approaches to organismic development, evolution and human consciousness leads to novel patterns of relations that emerge in super- and ultra- complex systems in terms of compositions of local procedures [1]. The claim is defended in this paper that human consciousness is unique and should be viewed as an ultra-complex, global process of processes, at a meta-level not sub{summed by, but compatible with, human brain dynamics [2]-[5]. The emergence of consciousness and its existence
    are considered to be dependent upon an extremely complex structural and functional unit with an asymmetric network topology and connectivities{the human brain. However, the appearance of human consciousness is shown to be critically dependent upon societal co-evolution, elaborate language-symbolic communication and `virtual', higher dimensional, non{commutative processes involving separate space and time perceptions. Theories of the mind are approached from the theory of levels and ultra-complexity viewpoints that throw
    new light on previous semantic models in cognitive science. Anticipatory systems and complex causality at the top levels of reality are discussed in the context of psychology, sociology and ecology. A paradigm shift towards non-commutative, or more generally, non-Abelian theories of highly complex dynamics [6] is suggested to unfold now in physics, mathematics, life and cognitive sciences, thus leading to the realizations of higher dimensional algebras in neurosciences and psychology, as well as in human genomics, bioinformatics and interactomics. The presence of strange attractors in modern society dynamics gives rise to very serious concerns for the future

  16. Structure of a Human Astrovirus Capsid-Antibody Complex and Mechanistic Insights into Virus Neutralization

    Energy Technology Data Exchange (ETDEWEB)

    Bogdanoff, Walter A.; Campos, Jocelyn; Perez, Edmundo I.; Yin, Lu; Alexander, David L.; DuBois, Rebecca M. (UCSC)

    2016-11-02

    ABSTRACT

    Human astroviruses (HAstVs) are a leading cause of viral diarrhea in young children, the immunocompromised, and the elderly. There are no vaccines or antiviral therapies against HAstV disease. Several lines of evidence point to the presence of protective antibodies in healthy adults as a mechanism governing protection against reinfection by HAstV. However, development of anti-HAstV therapies is hampered by the gap in knowledge of protective antibody epitopes on the HAstV capsid surface. Here, we report the structure of the HAstV capsid spike domain bound to the neutralizing monoclonal antibody PL-2. The antibody uses all six complementarity-determining regions to bind to a quaternary epitope on each side of the dimeric capsid spike. We provide evidence that the HAstV capsid spike is a receptor-binding domain and that the antibody neutralizes HAstV by blocking virus attachment to cells. We identify patches of conserved amino acids that overlap the antibody epitope and may comprise a receptor-binding site. Our studies provide a foundation for the development of therapies to prevent and treat HAstV diarrheal disease.

    IMPORTANCEHuman astroviruses (HAstVs) infect nearly every person in the world during childhood and cause diarrhea, vomiting, and fever. Despite the prevalence of this virus, little is known about how antibodies in healthy adults protect them against reinfection. Here, we determined the crystal structure of a complex of the HAstV capsid protein and a virus-neutralizing antibody. We show that the antibody binds to the outermost spike domain of the capsid, and we provide evidence that the antibody blocks virus attachment to human cells. Importantly, our findings suggest that a subunit-based vaccine focusing the immune system on the HAstV capsid spike domain could be effective in protecting children against HAstV disease.

  17. Structural comparison of the Caenorhabditis elegans and human Ndc80 complexes bound to microtubules reveals distinct binding behavior

    Science.gov (United States)

    Wilson-Kubalek, Elizabeth M.; Cheeseman, Iain M.; Milligan, Ronald A.

    2016-01-01

    During cell division, kinetochores must remain tethered to the plus ends of dynamic microtubule polymers. However, the molecular basis for robust kinetochore–microtubule interactions remains poorly understood. The conserved four-subunit Ndc80 complex plays an essential and direct role in generating dynamic kinetochore–microtubule attachments. Here we compare the binding of the Caenorhabditis elegans and human Ndc80 complexes to microtubules at high resolution using cryo–electron microscopy reconstructions. Despite the conserved roles of the Ndc80 complex in diverse organisms, we find that the attachment mode of these complexes for microtubules is distinct. The human Ndc80 complex binds every tubulin monomer along the microtubule protofilament, whereas the C. elegans Ndc80 complex binds more tightly to β-tubulin. In addition, the C. elegans Ndc80 complex tilts more toward the adjacent protofilament. These structural differences in the Ndc80 complex between different species may play significant roles in the nature of kinetochore–microtubule interactions. PMID:26941333

  18. Molecular architecture of the recombinant human MCM2-7 helicase in complex with nucleotides and DNA.

    Science.gov (United States)

    Boskovic, Jasminka; Bragado-Nilsson, Elisabeth; Saligram Prabhakar, Bhargrav; Yefimenko, Igor; Martínez-Gago, Jaime; Muñoz, Sergio; Méndez, Juan; Montoya, Guillermo

    2016-09-16

    DNA replication is a key biological process that involves different protein complexes whose assembly is rigorously regulated in a successive order. One of these complexes is a replicative hexameric helicase, the MCM complex, which is essential for the initiation and elongation phases of replication. After the assembly of a double heterohexameric MCM2-7 complex at replication origins in G1, the 2 heterohexamers separate from each other and associate with Cdc45 and GINS proteins in a CMG complex that is capable of unwinding dsDNA during S phase. Here, we have reconstituted and characterized the purified human MCM2-7 (hMCM2-7) hexameric complex by co-expression of its 6 different subunits in insect cells. The conformational variability of the complex has been analyzed by single particle electron microscopy in the presence of different nucleotide analogs and DNA. The interaction with nucleotide stabilizes the complex while DNA introduces conformational changes in the hexamer inducing a cylindrical shape. Our studies suggest that the assembly of GINS and Cdc45 to the hMCM2-7 hexamer would favor conformational changes on the hexamer bound to ssDNA shifting the cylindrical shape of the complex into a right-handed spiral conformation as observed in the CMG complex bound to DNA.

  19. Inferring condition-specific targets of human TF-TF complexes using ChIP-seq data.

    Science.gov (United States)

    Yang, Chia-Chun; Chen, Min-Hsuan; Lin, Sheng-Yi; Andrews, Erik H; Cheng, Chao; Liu, Chun-Chi; Chen, Jeremy J W

    2017-01-10

    Transcription factors (TFs) often interact with one another to form TF complexes that bind DNA and regulate gene expression. Many databases are created to describe known TF complexes identified by either mammalian two-hybrid experiments or data mining. Lately, a wealth of ChIP-seq data on human TFs under different experiment conditions are available, making it possible to investigate condition-specific (cell type and/or physiologic state) TF complexes and their target genes. Here, we developed a systematic pipeline to infer Condition-Specific Targets of human TF-TF complexes (called the CST pipeline) by integrating ChIP-seq data and TF motifs. In total, we predicted 2,392 TF complexes and 13,504 high-confidence or 127,994 low-confidence regulatory interactions amongst TF complexes and their target genes. We validated our predictions by (i) comparing predicted TF complexes to external TF complex databases, (ii) validating selected target genes of TF complexes using ChIP-qPCR and RT-PCR experiments, and (iii) analysing target genes of select TF complexes using gene ontology enrichment to demonstrate the accuracy of our work. Finally, the predicted results above were integrated and employed to construct a CST database. We built up a methodology to construct the CST database, which contributes to the analysis of transcriptional regulation and the identification of novel TF-TF complex formation in a certain condition. This database also allows users to visualize condition-specific TF regulatory networks through a user-friendly web interface.

  20. Crystal Structure of the Human Symplekin-Ssu72-CTD Phosphopeptide Complex

    Energy Technology Data Exchange (ETDEWEB)

    K Xiang; T Nigaike; S Xiang; T Kilic; M Beh; J Manley; L Tong

    2011-12-31

    Symplekin (Pta1 in yeast) is a scaffold in the large protein complex that is required for 3'-end cleavage and polyadenylation of eukaryotic messenger RNA precursors (pre-mRNAs); it also participates in transcription initiation and termination by RNA polymerase II (Pol II). Symplekin mediates interactions between many different proteins in this machinery, although the molecular basis for its function is not known. Here we report the crystal structure at 2.4 {angstrom} resolution of the amino-terminal domain (residues 30-340) of human symplekin in a ternary complex with the Pol II carboxy-terminal domain (CTD) Ser5 phosphatase Ssu72 and a CTD Ser5 phosphopeptide. The N-terminal domain of symplekin has the ARM or HEAT fold, with seven pairs of antiparallel {alpha}-helices arranged in the shape of an arc. The structure of Ssu72 has some similarity to that of low-molecular-mass phosphotyrosine protein phosphatase, although Ssu72 has a unique active-site landscape as well as extra structural features at the C terminus that are important for interaction with symplekin. Ssu72 is bound to the concave face of symplekin, and engineered mutations in this interface can abolish interactions between the two proteins. The CTD peptide is bound in the active site of Ssu72, with the pSer5-Pro6 peptide bond in the cis configuration, which contrasts with all other known CTD peptide conformations. Although the active site of Ssu72 is about 25 {angstrom} from the interface with symplekin, we found that the symplekin N-terminal domain stimulates Ssu72 CTD phosphatase activity in vitro. Furthermore, the N-terminal domain of symplekin inhibits polyadenylation in vitro, but only when coupled to transcription. Because catalytically active Ssu72 overcomes this inhibition, our results show a role for mammalian Ssu72 in transcription-coupled pre-mRNA 3'-end processing.

  1. Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human African trypanosomiasis.

    Directory of Open Access Journals (Sweden)

    Jean Rodgers

    2011-09-01

    Full Text Available Human African trypanosomiasis (HAT, or sleeping sickness, results from infection with the protozoan parasites Trypanosoma brucei (T. b. gambiense or T. b. rhodesiense and is invariably fatal if untreated. There are 60 million people at risk from the disease throughout sub-Saharan Africa. The infection progresses from the haemolymphatic stage where parasites invade the blood, lymphatics and peripheral organs, to the late encephalitic stage where they enter the central nervous system (CNS to cause serious neurological disease. The trivalent arsenical drug melarsoprol (Arsobal is the only currently available treatment for CNS-stage T. b. rhodesiense infection. However, it must be administered intravenously due to the presence of propylene glycol solvent and is associated with numerous adverse reactions. A severe post-treatment reactive encephalopathy occurs in about 10% of treated patients, half of whom die. Thus melarsoprol kills 5% of all patients receiving it. Cyclodextrins have been used to improve the solubility and reduce the toxicity of a wide variety of drugs. We therefore investigated two melarsoprol cyclodextrin inclusion complexes; melarsoprol hydroxypropyl-β-cyclodextrin and melarsoprol randomly-methylated-β-cyclodextrin. We found that these compounds retain trypanocidal properties in vitro and cure CNS-stage murine infections when delivered orally, once per day for 7-days, at a dosage of 0.05 mmol/kg. No overt signs of toxicity were detected. Parasite load within the brain was rapidly reduced following treatment onset and magnetic resonance imaging showed restoration of normal blood-brain barrier integrity on completion of chemotherapy. These findings strongly suggest that complexed melarsoprol could be employed as an oral treatment for CNS-stage HAT, delivering considerable improvements over current parenteral chemotherapy.

  2. Learning, adaptation, and the complexity of human and natural interactions in the ocean

    Directory of Open Access Journals (Sweden)

    James Wilson

    2017-06-01

    Full Text Available Here, I explore the system-level consequences of learning and adaptation among fish and fishers. The fundamental idea is that the cost of acquiring the knowledge needed to resolve uncertainty is the principal driver of social and spatial organization. This cost limits agents' actions and leads them to prefer relatively persistent associations with familiar agents and places. When all agents act in this way, the regularity and self-reinforcing nature of familiarity leads to the emergence of a self-organized system. Systems like this are characterized by diverse, place-based, and relatively durable groups, groups of groups, and rough hierarchical structure. This occurs in both the natural and human parts of the system. The costs of resolving uncertainty also determine the interactions of fish and fishers. The uncertainty of search leads fishers preferentially to target older fish and aggregations of fish. These are the repositories and mechanisms for the replication of the knowledge needed for self-organization. The loss of this information selectively, but unintentionally, disrupts the behavioral regularity that organizes the natural system, leading eventually to its disorganization. From this theoretical perspective, sustainable fishing requires conservation of the knowledge in DNA and memory because this is the fundamental basis for the self-organization of the natural system. Collective action is also subject to the costs of resolving uncertainty. In complex systems, these costs are minimized at the local level in the system, where the most direct, but not the only, feedback occurs. This implies the need for multiscale governance with an emphasis on collective learning through localized science and user participation. Finally, the complexity of ecosystem interactions argues for qualitative harvesting rules governing how, when, and where fishing takes place. These rules are most likely to generate a persistent signal and rapid learning, but

  3. Equilibrium and kinetic analysis of human interleukin-13 and IL-13 receptor alpha-2 complex formation.

    Science.gov (United States)

    Lacy, Eilyn R

    2012-03-01

    Interleukin 13 (IL-13) is a pleiotropic cytokine secreted by activated T cells. Both IL-13 and its polymorphic variant (IL-13-R110Q) have been shown to be associated with multiple diseases such as asthma and allergy. Two IL-13 receptors have been identified, IL-13R alpha-1 receptor (IL-13Rα1) and IL-13R alpha-2 receptor (IL-13Rα2). It has been well established that IL-13 binds to IL-13Rα1 alone with low nM affinity while binding to the IL-13Rα1/IL-4R receptor complex is significantly tighter (pM). The affinity between IL-13 and IL-13Rα2, however, remains elusive. Several values have been reported in the literature varying from 20 pM to 2.5 nM. The affinities previously reported were obtained using surface plasmon resonance (SPR) or Scatchard analysis of (125) I-IL-13 binding data. This report presents the results for the kinetics and equilibrium binding analysis studies performed using label-free kinetic exclusion assay (KEA) for the interaction of human IL-13 and IL-13Rα2. KEA equilibrium analysis showed that the affinities of IL-13Rα2 are 107 and 56 pM for IL-13 and its variant (IL-13-R110Q), respectively. KEA kinetic analysis showed that a tight and very stable complex is formed between IL-13Rα2 and IL-13, as shown by calculated dissociation rate constants slower than 5 × 10(-5) per second. Kinetic analysis also showed significant differences in the kinetic behavior of wild type (wt) versus IL-13-R110Q. IL-13-R110Q not only associates to IL-13Rα2 slower than wt human IL-13 (wt-IL-13), as previously reported, but IL-13-R110Q also dissociates slower than wt-IL-13. These results show that IL-13Rα2 is a high affinity receptor and provide a new perspective on kinetic behavior that could have significant implications in the understanding of the role of IL-13-R110Q in the disease state.

  4. Interaction between immobilized polyelectrolyte complex nanoparticles and human mesenchymal stromal cells

    Directory of Open Access Journals (Sweden)

    Woltmann B

    2014-05-01

    Full Text Available Beatrice Woltmann,1 Bernhard Torger,2,3 Martin Müller,2,3,* Ute Hempel1,*1Dresden University of Technology, Faculty of Medicine Carl Gustav Carus, Institute of Physiological Chemistry, Dresden, Germany; 2Leibniz Institute of Polymer Research Dresden, Department of Polyelectrolytes and Dispersions, Dresden, Germany; 3Dresden University of Technology, Department of Chemistry and Food Chemistry, Dresden, Germany*These authors contributed equally to this workBackground: Implant loosening or deficient osseointegration is a major problem in patients with systemic bone diseases (eg, osteoporosis. For this reason, the stimulation of the regional cell population by local and sustained drug delivery at the bone/implant interface to induce the formation of a mechanical stable bone is promising. The purpose of this study was to investigate the interaction of polymer-based nanoparticles with human bone marrow-derived cells, considering nanoparticles’ composition and surface net charge.Materials and methods: Polyelectrolyte complex nanoparticles (PECNPs composed of the polycations poly(ethyleneimine (PEI, poly(L-lysine (PLL, or (N,N-diethylaminoethyldextran (DEAE in combination with the polyanions dextran sulfate (DS or cellulose sulfate (CS were prepared. PECNPs’ physicochemical properties (size, net charge were characterized by dynamic light scattering and particle charge detector measurements. Biocompatibility was investigated using human mesenchymal stromal cells (hMSCs cultured on immobilized PECNP films (5–50 nmol·cm-2 by analysis for metabolic activity of hMSCs in dependence of PECNP surface concentration by MTS (3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt assay, as well as cell morphology (phase contrast microscopy.Results: PECNPs ranging between ~50 nm and 150 nm were prepared. By varying the ratio of polycations and polyanions, PECNPs with a slightly positive (PEC+NP or negative (PEC

  5. Structure of Human G Protein-Coupled Receptor Kinase 2 in Complex with the Kinase Inhibitor Balanol

    Energy Technology Data Exchange (ETDEWEB)

    Tesmer, John J.G.; Tesmer, Valerie M.; Lodowski, David T.; Steinhagen, Henning; Huber, Jochen (Sanofi); (Michigan); (Texas)

    2010-07-19

    G protein-coupled receptor kinase 2 (GRK2) is a pharmaceutical target for the treatment of cardiovascular diseases such as congestive heart failure, myocardial infarction, and hypertension. To better understand how nanomolar inhibition and selectivity for GRK2 might be achieved, we have determined crystal structures of human GRK2 in complex with G{beta}{gamma} in the presence and absence of the AGC kinase inhibitor balanol. The selectivity of balanol among human GRKs is assessed.

  6. Complex Adaptive Immunity to enteric fevers in humans: Lessons learned and the path forward

    Directory of Open Access Journals (Sweden)

    Marcelo B. Sztein

    2014-10-01

    Full Text Available Salmonella enterica serovar Typhi (S. Typhi, the causative agent of typhoid fever, and S. Paratyphi A and B, causative agents of paratyphoid fever, are major public health threats throughout the world. Although two licensed typhoid vaccines are currently available, they are only moderately protective and immunogenic necessitating the development of novel vaccines. A major obstacle in the development of improved typhoid, as well as paratyphoid vaccines is the lack of known immunological correlates of protection in humans. Considerable progress has been made in recent years in understanding the complex adaptive host responses against S. Typhi. Although the induction of S. Typhi-specific antibodies (including their functional properties and memory B cells, as well as their cross-reactivity with S. Paratyphi A and S. Paratyphi B has been shown, the role of humoral immunity in protection remains undefined. Cell mediated immunity (CMI is likely to play a dominant role in protection against enteric fever pathogens. Detailed measurements of CMI performed in volunteers immunized with attenuated strains of S. Typhi have shown, among others, the induction of lymphoproliferation, multifunctional type 1 cytokine production and CD8+ cytotoxic T cell responses. In addition to systemic responses, the local microenvironment of the gut is likely to be of paramount importance in protection from these infections. In this review we will critically assess current knowledge regarding the role of CMI and humoral immunity following natural S. Typhi and S. Paratyphi infections, experimental challenge, and immunization in humans. We will also address recent advances regarding cross-talk between the host’s gut microbiota and immunization with attenuated S. Typhi, mechanisms of systemic immune responses, and the homing potential of S. Typhi-specific B and T cells to the gut and other tissues.

  7. Ku80 binds to human replication origins prior to the assembly of the ORC complex.

    Science.gov (United States)

    Sibani, Sahar; Price, Gerald B; Zannis-Hadjopoulos, Maria

    2005-05-31

    The Ku heterodimer, an abundant nuclear protein, binds DNA replication origins in a sequence-specific manner and promotes initiation. In this study, using HCT116 Ku80+/- haplo-insufficient and Orc2(delta/-) hypomorphic cells, the order of binding of Ku and the human origin recognition complex (HsORC) was determined. The nuclear expression of Ku80 was found to be decreased by 60% in Ku80+/- cells, while its general association with chromatin was decreased by 33%. Coimmunoprecipitation studies indicated that the Ku heterodimer associates specifically with the human HsOrc-2, -3, -4, and -6 subunits. Chromatin immunoprecipitation (ChIP) experiments, using cells synchronized to late G1, showed that the association of Ku80 with the lamin B2, beta-globin, and c-myc origins in vivo was decreased by 1.5-, 2.3-, and 2.5-fold, respectively, in Ku80+/- cells. The association of HsOrc-3, -4, and -6 was consistently decreased in all three origins examined in Ku80+/- cells, while that of HsOrc-2 showed no significant variation, indicating that the HsOrc-3, -4, and -6 subunits bind to the origins after Ku80. In Orc2(delta/-) cells, the association of HsOrc-2 with the lamin B2, beta-globin, and c-myc origins was decreased by 2.8-, 4.9-, and 2.8-fold, respectively, relative to wild-type HCT116 cells. Furthermore, nascent strand abundance at these three origins was decreased by 4.5-, 2.3-, and 2.6-fold in Orc2(delta/-) relative to HCT116 cells, respectively. Interestingly, the association of Ku80 with these origins was not affected in this hypomorphic cell line, indicating that Ku and HsOrc-2 bind to origins independently of each other.

  8. Endocytosis and intracellular traffic of cholesterol-PDMAEMA liposome complexes in human epithelial-like cells.

    Science.gov (United States)

    Szymanowski, F; Hugo, A A; Alves, P; Simões, P N; Gómez-Zavaglia, A; Pérez, Pablo F

    2017-08-01

    Liposomes are generally used as delivery systems, as they are capable of encapsulating a wide variety of molecules (i.e. plasmids, recombinant proteins, therapeutic drugs). However, liposomal drug delivery have to fulfill different requirements, such as the effective internalization by the target cells and avoidance of the degradative activity of the intracellular compartments. The use of polymer lipid complexes (PLCs), by including different polymers in the liposome formulation, could improve internalization and intracellular release of drugs. The aim of the present work is to study the mechanisms of cellular uptaking and the intracellular trafficking of PLCs formed with cholesterol-poly(2-(dimethylamino)ethyl methacrylate) CHO-PDMAEMA and lecithin (LC CHO-PD). Calcein-loaded liposomes were used to determine cellular uptake and intracellular localization by flow cytometry and confocal microscopy. Incorporation of CHO-PDMAEMA to lecithin liposomes enhanced the internalization capacity of PLCs. Internalization of PLCs by human epithelial-like cells (HEK-293) diminished at 4°C, suggesting uptake by endocytosis. PLCs showed no co-localization with acidic compartments after internalization. Experiments with endocytosis inhibitors and co-localization of liposomes and albumin, suggested the caveolae endocytic pathway as the most probable route for intracellular trafficking of PLCs. In this work, we demonstrated an efficient uptake of LC CHO-PDs by human epithelial-like cells (HEK-293) through the non-degradative caveolae endocytic pathway. The mode of internalization and the intracellular fate of liposomes under study, suggest a promising use of LC CHO-PDs as drug delivery systems. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Biophysical study on the interaction between two palladium(II) complexes and human serum albumin by Multispectroscopic methods

    Energy Technology Data Exchange (ETDEWEB)

    Saeidifar, Maryam, E-mail: saeidifar@merc.ac.ir [Department of Nanotechnology and Advanced Materials, Materials and Energy Research Center, Karaj (Iran, Islamic Republic of); Mansouri-Torshizi, Hassan [Department of Chemistry, University of Sistan and Baluchestan, Zahedan (Iran, Islamic Republic of); Akbar Saboury, Ali [Institute of Biochemistry and Biophysics, University of Tehran, Tehran (Iran, Islamic Republic of)

    2015-11-15

    The interaction of [Pd(bpy)(n-pr-dtc)]Br (I) and ([Pd(phen)(n-pr-dtc)]Br (II) (bpy=2,2′-bipyridine, phen=1,10-phenanthroline and n-pr-dtc=n-propyldithiocarbamate) with human serum albumin (HSA) was investigated using fluorescence, UV–vis absorption and circular dichroism (CD) spectroscopy techniques under simulative physiological conditions (pH=7.4). It was observed that the two complexes interact with HSA via static fluorescence quenching. The thermodynamic parameters indicate that the binding process was spontaneous and that hydrogen bonds and van der Waals forces play a major role in the association of the HSA–Pd(II) complexes. The activation energy (E{sub a}), binding constant (K{sub b}) and number of binding sites (n) of the HSA–Pd(II) complexes were calculated from fluorescence data at 293 K, 303 K and 311 K. The conformational alternations of protein secondary structure in the presence of Pd(II) complexes were demonstrated using synchronous fluorescence, three-dimensional fluorescence spectra, UV–vis absorption and circular dichroism techniques. Furthermore, the apparent distance between donor (HSA) and acceptor (Pd(II) complexes) was determined using fluorescence resonance energy transfer (FRET). The binding studies between these complexes and HSA give us key insights into the transportation, distribution and toxicity of newly design antitumor Pd(II) complexes in human blood. - Highlights: • The HSA binding properties of two Palladium (II) complexes were studied. • Static quenching mechanism is effective in the interaction of HSA with Pd(II) complexes. • Hydrogen bonds and van der Waals forces were involved in the Pd(II) complexes–HSA interaction. • 3D fluorescence was used to study the interaction between two complexes and HSA.

  10. Crystal structure of the human NKX2.5 homeodomain in complex with DNA target.

    Science.gov (United States)

    Pradhan, Lagnajeet; Genis, Caroli; Scone, Peyton; Weinberg, Ellen O; Kasahara, Hideko; Nam, Hyun-Joo

    2012-08-14

    NKX2.5 is a homeodomain containing transcription factor regulating cardiac formation and function, and its mutations are linked to congenital heart disease. Here we provide the first report of the crystal structure of the NKX2.5 homeodomain in complex with double-stranded DNA of its endogenous target, locating within the proximal promoter -242 site of the atrial natriuretic factor gene. The crystal structure, determined at 1.8 Å resolution, demonstrates that NKX2.5 homeodomains occupy both DNA binding sites separated by five nucleotides without physical interaction between themselves. The two homeodomains show identical conformation despite the differences in the DNA sequences they bind, and no significant bending of the DNA was observed. Tyr54, absolutely conserved in NK2 family proteins, mediates sequence-specific interaction with the TAAG motif. This high resolution crystal structure of NKX2.5 protein provides a detailed picture of protein and DNA interactions, which allows us to predict DNA binding of mutants identified in human patients.

  11. Crystal Structure of the Human NKX2.5 Homeodomain in Complex with DNA Target

    Energy Technology Data Exchange (ETDEWEB)

    Pradhan, Lagnajeet; Genis, Caroli; Scone, Peyton; Weinberg, Ellen O.; Kasahara, Hideko; Nam, Hyun-Joo (BU-M); (Florida); (Texas)

    2012-10-16

    NKX2.5 is a homeodomain containing transcription factor regulating cardiac formation and function, and its mutations are linked to congenital heart disease. Here we provide the first report of the crystal structure of the NKX2.5 homeodomain in complex with double-stranded DNA of its endogenous target, locating within the proximal promoter -242 site of the atrial natriuretic factor gene. The crystal structure, determined at 1.8 {angstrom} resolution, demonstrates that NKX2.5 homeodomains occupy both DNA binding sites separated by five nucleotides without physical interaction between themselves. The two homeodomains show identical conformation despite the differences in the DNA sequences they bind, and no significant bending of the DNA was observed. Tyr54, absolutely conserved in NK2 family proteins, mediates sequence-specific interaction with the TAAG motif. This high resolution crystal structure of NKX2.5 protein provides a detailed picture of protein and DNA interactions, which allows us to predict DNA binding of mutants identified in human patients.

  12. Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus

    DEFF Research Database (Denmark)

    Giang, Erick; Dorner, Marcus; Prentoe, Jannick C

    2012-01-01

    Hepatitis C virus (HCV) infects ∼2% of the world's population. It is estimated that there are more than 500,000 new infections annually in Egypt, the country with the highest HCV prevalence. An effective vaccine would help control this expanding global health burden. HCV is highly variable......, and an effective vaccine should target conserved T- and B-cell epitopes of the virus. Conserved B-cell epitopes overlapping the CD81 receptor-binding site (CD81bs) on the E2 viral envelope glycoprotein have been reported previously and provide promising vaccine targets. In this study, we isolated 73 human m......Abs recognizing five distinct antigenic regions on the virus envelope glycoprotein complex E1E2 from an HCV-immune phage-display antibody library by using an exhaustive-panning strategy. Many of these mAbs were broadly neutralizing. In particular, the mAb AR4A, recognizing a discontinuous epitope outside the CD81...

  13. Crystal Structures of Human Dipeptidyl Peptidase Ⅳ in its Apo and Diprotin B-complexed Forms

    Institute of Scientific and Technical Information of China (English)

    Hajime HIRAMATSU; Kiyoshi KYONO; Atsushi YAMAMOTO; Kazuhiko SAEKI; Hideaki SHIMA; Shigeru SUGIYAMA; Koji INAKA; Ryo SHIMIZU

    2007-01-01

    Dipeptidyl peptidase Ⅳ (DPPIV), which belongs to the prolyl oligopeptidase family of serine proteases, is known to have a variety of regulatory biological functions and has been shown to be implicated in type 2 diabetes. It is therefore important to develop selective human DPPIV (hDPPIV) inhibitors. In this study, we determined the crystal structure of apo hDPPIV at 1.9 (A) resolution. Our high-resolution crystal structure of apo hDPPIV revealed the presence of sodium ion and glycerol molecules at the active site. In order to elucidate the hDPPIV binding mode and substrate specificity, we determined the crystal structure of hDPPIV-diprotin B (Val-Pro-Leu) complex at 2.1 (A) resolution, and clarified the difference in binding mode between diprotin B and diprotin A (Ile-Pro-Ile) into the active site of hDPPIV. Comparison between our crystal structures and the reported apo hDPPIV structures revealed that positively charged functional groups and conserved water molecules contributed to the interaction of ligands with hDPPIV. These results are useful for the design of potent hDPPIV inhibitors.

  14. Use of gene expression and pathway signatures to characterize the complexity of human melanoma.

    Science.gov (United States)

    Freedman, Jennifer A; Tyler, Douglas S; Nevins, Joseph R; Augustine, Christina K

    2011-06-01

    A defining characteristic of most human cancers is heterogeneity, resulting from the somatic acquisition of a complex array of genetic and genomic alterations. Dissecting this heterogeneity is critical to developing an understanding of the underlying mechanisms of disease and to paving the way toward personalized treatments of the disease. We used gene expression data sets from the analysis of primary and metastatic melanomas to develop a molecular description of the heterogeneity that characterizes this disease. Unsupervised hierarchical clustering, gene set enrichment analyses, and pathway activity analyses were used to describe the genetic heterogeneity of melanomas. Patterns of gene expression that revealed two distinct classes of primary melanoma, two distinct classes of in-transit melanoma, and at least three subgroups of metastatic melanoma were identified. Expression signatures developed to predict the status of oncogenic signaling pathways were used to explore the biological basis underlying these differential patterns of expression. This analysis of activities revealed unique pathways that distinguished the primary and metastatic subgroups of melanoma. Distinct patterns of gene expression across primary, in-transit, and metastatic melanomas underline the genetic heterogeneity of this disease. This heterogeneity can be described in terms of deregulation of signaling pathways, thus increasing the knowledge of the biological features underlying individual melanomas and potentially directing therapeutic opportunities to individual patients with melanoma.

  15. Biomolecular identification of ancient Mycobacterium tuberculosis complex DNA in human remains from Britain and continental Europe.

    Science.gov (United States)

    Müller, Romy; Roberts, Charlotte A; Brown, Terence A

    2014-02-01

    Tuberculosis is known to have afflicted humans throughout history and re-emerged towards the end of the 20th century, to an extent that it was declared a global emergency in 1993. The aim of this study was to apply a rigorous analytical regime to the detection of Mycobacterium tuberculosis complex (MTBC) DNA in 77 bone and tooth samples from 70 individuals from Britain and continental Europe, spanning the 1st-19th centuries AD. We performed the work in dedicated ancient DNA facilities designed to prevent all types of modern contamination, we checked the authenticity of all products obtained by the polymerase chain reaction, and we based our conclusions on up to four replicate experiments for each sample, some carried out in an independent laboratory. We identified 12 samples that, according to our strict criteria, gave definite evidence for the presence of MTBC DNA, and another 22 that we classified as "probable" or "possible." None of the definite samples came from vertebrae displaying lesions associated with TB. Instead, eight were from ribs displaying visceral new bone formation, one was a tooth from a skeleton with rib lesions, one was taken from a skeleton with endocranial lesions, one from an individual with lesions to the sacrum and sacroiliac joint and the last was from an individual with no lesions indicative of TB or possible TB. Our results add to information on the past temporal and geographical distribution of TB and affirm the suitability of ribs for studying ancient TB.

  16. Crystal structure of truncated human coatomer protein complex subunit ζ1 (Copζ1).

    Science.gov (United States)

    Lunev, Sergey; Semmelink, Marije F W; Xian, Jia Ling; Ma, Kai Yu; Leenders, Anna J A; Dömling, Alexander S S; Shtutman, Michael; Groves, Matthew R

    2017-01-01

    The majority of modern anticancer approaches target DNA/protein targets involved in tumour-cell proliferation. Such approaches have a major drawback, as nonproliferating cancer cells remain unaffected and may cause relapse or remission. Human coatomer protein complex I (COPI) subunit ζ (Copζ), a component of the coat protein involved in cell apoptosis and intracellular trafficking, has recently been proposed as a potential anticancer drug target. Previous studies have shown that two different isoforms of the Copζ subunit exist in mammalian cells. While normal cells express both Copζ1 and Copζ2 isoforms, various types of tumour cells display a loss of Copζ2 expression and rely solely on Copζ1 for growth and survival. Subsequent knockdown of Copζ1 results in specific inhibition of both proliferating and dormant tumour-cell populations, with no adverse growth effects on normal cells. Therefore, a Copζ1-targeting therapy was proposed to bypass the problem of dormant cancer cells that are resistant to conventional antiproliferative drugs, which is the major cause of tumour relapse. In order to aid in structure-based inhibitor design, a crystal structure is required. In this article, the recombinant expression, purification, crystallization and crystal structure of Copζ1, as well as the expression and purification of Copζ2, are reported.

  17. A STUDY OF NEURONAL PROFILE OF INFERIOR OLIVARY NUCLEAR COMPLEX IN FOETAL AND ADULT HUMAN MEDULLA

    Directory of Open Access Journals (Sweden)

    B.Narasinga Rao

    2013-09-01

    Full Text Available Abstract: Background: ION receives proprioceptive impulses from spino-olivary tract and conveys the fibers to the cerebellum through olivo-cerebellar tract. There is paucity of data in human olivary complex, hence the present study is done. Materials And Methods: 15 adult brains and 25 fetuses of different gestations were perfused with 10% formalin and processed for histological examination. Results: Rounded cells have been seen infiltrating the entire field. at 16 weeks of gestation. Segregation of neurons into principal, medial, and dorsal accessory olivary nuclei at 20 wks gestation. Discussion: Neuron differentiation into oval, round, multipolar types has begun at 40 wks gestation. Neurons in the olivary subdivisions are grouped in separate clusters as per Ramon y Cajal,1909; Scheibel and Scheibel, 1955, Bowman and King, 1973. Multipolar neurons dominated in adult inferior olivary nucleus. Conclusion:The greater development of neurons is a consequence of finer regulation of various movements of hands and finger associated with movement of head and eyes

  18. Structure of Human Dual Specificity Protein Phosphatase 23, VHZ, Enzyme-Substrate/Product Complex

    Energy Technology Data Exchange (ETDEWEB)

    Agarwal,R.; Burley, S.; Swaminathan, S.

    2008-01-01

    Protein phosphorylation plays a crucial role in mitogenic signal transduction and regulation of cell growth and differentiation. Dual specificity protein phosphatase 23 (DUSP23) or VHZ mediates dephosphorylation of phospho-tyrosyl (pTyr) and phospho-seryl/threonyl (pSer/pThr) residues in specific proteins. In vitro, it can dephosphorylate p44ERK1 but not p54SAPK-{beta} and enhance activation of c-Jun N-terminal kinase (JNK) and p38. Human VHZ, the smallest of the catalytically active protein-tyrosine phosphatases (PTP) reported to date (150 residues), is a class I Cys-based PTP and bears the distinctive active site signature motif HCXXGXXRS(T). We present the crystal structure of VHZ determined at 1.93 angstrom resolution. The polypeptide chain adopts the typical a{beta}a PTP fold, giving rise to a shallow active site cleft that supports dual phosphorylated substrate specificity. Within our crystals, the Thr-135-Tyr-136 from a symmetry-related molecule bind in the active site with a malate ion, where they mimic the phosphorylated TY motif of the MAPK activation loop in an enzyme-substrate/product complex. Analyses of intermolecular interactions between the enzyme and this pseudo substrate/product along with functional analysis of Phe-66, Leu-97, and Phe-99 residues provide insights into the mechanism of substrate binding and catalysis in VHZ.

  19. The N-glycan glycoprotein deglycosylation complex (Gpd from Capnocytophaga canimorsus deglycosylates human IgG.

    Directory of Open Access Journals (Sweden)

    Francesco Renzi

    2011-06-01

    Full Text Available C. canimorsus 5 has the capacity to grow at the expenses of glycan moieties from host cells N-glycoproteins. Here, we show that C. canimorsus 5 also has the capacity to deglycosylate human IgG and we analyze the deglycosylation mechanism. We show that deglycosylation is achieved by a large complex spanning the outer membrane and consisting of the Gpd proteins and sialidase SiaC. GpdD, -G, -E and -F are surface-exposed outer membrane lipoproteins. GpdDEF could contribute to the binding of glycoproteins at the bacterial surface while GpdG is a endo-β-N-acetylglucosaminidase cleaving the N-linked oligosaccharide after the first N-linked GlcNAc residue. GpdC, resembling a TonB-dependent OM transporter is presumed to import the oligosaccharide into the periplasm after its cleavage from the glycoprotein. The terminal sialic acid residue of the oligosaccharide is then removed by SiaC, a periplasm-exposed lipoprotein in direct contact with GpdC. Finally, most likely degradation of the oligosaccharide proceeds sequentially from the desialylated non reducing end by the action of periplasmic exoglycosidases, including β-galactosidases, β-N-Acetylhexosaminidases and α-mannosidases.

  20. Proteomic identification of dysferlin-interacting protein complexes in human vascular endothelium

    Energy Technology Data Exchange (ETDEWEB)

    Leung, Cleo; Utokaparch, Soraya; Sharma, Arpeeta; Yu, Carol; Abraham, Thomas; Borchers, Christoph [UBC James Hogg Research Centre, Institute for Heart and Lung Health, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia (Canada); University of Victoria - Genome BC Proteomics Centre, University of Victoria, Victoria, British Columbia (Canada); Bernatchez, Pascal, E-mail: pbernatc@mail.ubc.ca [UBC James Hogg Research Centre, Institute for Heart and Lung Health, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia (Canada); University of Victoria - Genome BC Proteomics Centre, University of Victoria, Victoria, British Columbia (Canada)

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Bi-directional (inward and outward) movement of GFP-dysferlin in COS-7 cells. Black-Right-Pointing-Pointer Dysferlin interacts with key signaling proteins for transcytosis in EC. Black-Right-Pointing-Pointer Dysferlin mediates trafficking of vesicles carrying protein cargos in EC. -- Abstract: Dysferlin is a membrane-anchored protein known to facilitate membrane repair in skeletal muscles following mechanical injury. Mutations of dysferlin gene impair sarcolemma integrity, a hallmark of certain forms of muscular dystrophy in patients. Dysferlin contains seven calcium-dependent C2 binding domains, which are required to promote fusion of intracellular membrane vesicles. Emerging evidence reveal the unexpected expression of dysferlin in non-muscle, non-mechanically active tissues, such as endothelial cells, which cast doubts over the belief that ferlin proteins act exclusively as membrane repair proteins. We and others have shown that deficient trafficking of membrane bound proteins in dysferlin-deficient cells, suggesting that dysferlin might mediate trafficking of client proteins. Herein, we describe the intracellular trafficking and movement of GFP-dysferlin positive vesicles in unfixed reconstituted cells using live microscopy. By performing GST pull-down assays followed by mass spectrometry, we identified dysferlin binding protein complexes in human vascular endothelial cells. Together, our data further support the claims that dysferlin not only mediates membrane repair but also trafficking of client proteins, ultimately, help bridging dysferlinopathies to aberrant membrane signaling.

  1. Clinical heterogeneity of human neurocysticercosis results from complex interactions among parasite, host and environmental factors.

    Science.gov (United States)

    Fleury, Agnès; Escobar, Alfonso; Fragoso, Gladis; Sciutto, Edda; Larralde, Carlos

    2010-04-01

    Human neurocysticercosis (NC) is endemic in most countries of Latin America, Asia and Africa and is re-emerging in some industrialized nations. Both within and among endemic countries, NC is very variable in its clinical and radiological features, as well as in the intensity of the immuno-inflammatory reactions of the hosts. This review, focusing on the Mexican experience, describes and interprets the heterogeneity of NC as the result of different combinations among factors associated with the parasite, host and environment. The review may serve to foster similar descriptive efforts in other endemic areas of the world in order to facilitate the identification of the distinct factors that participate in the complex pathogenesis and diverse clinical outcomes of NC. In particular, it is necessary to understand the precise physiopathology of the inflammatory reaction associated with NC, as inflammation is one of the characteristics of those NC cases that are clinically more severe and less responsive to current treatments. Devising new medical interventions through the use of molecular regulators of the innate and adaptive immune responses of the host is a largely unexplored approach that could improve the existing forms of treatment. Copyright 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

  2. The human translational vestibulo-ocular reflex in response to complex motion.

    Science.gov (United States)

    Walker, Mark; Liao, Ke

    2011-09-01

    We studied the translational vestibulo-ocular reflex (tVOR) in four healthy human subjects during complex, unpredictable sum-of-sines head motion (combination of 0.73, 1.33, 1.93, and 2.93 Hz), while subjects viewed a target 15 cm away. Ideal eye velocity was calculated from recorded head motion; actual eye velocity was measured with scleral coils. The gain and phase for each frequency component was determined by least-squares optimization. Gain averaged approximately 40% and did not change with frequency; phase lag increased with frequency to a maximum of 66°. Fitting actual to ideal eye velocity predicted a tVOR latency of 48 m/s for vertical and 38 m/s for horizontal translation. These findings provide further evidence that the normal tVOR is considerably undercompensatory, even at low frequencies if the stimulus is not predictable. The similarity of this behavior to that of pursuit suggests that these two eye movements may share some aspects of neural processing.

  3. Statistical inference on genetic data reveals the complex demographic history of human populations in central Asia.

    Science.gov (United States)

    Palstra, Friso P; Heyer, Evelyne; Austerlitz, Frédéric

    2015-06-01

    The demographic history of modern humans constitutes a combination of expansions, colonizations, contractions, and remigrations. The advent of large scale genetic data combined with statistically refined methods facilitates inference of this complex history. Here we study the demographic history of two genetically admixed ethnic groups in Central Asia, an area characterized by high levels of genetic diversity and a history of recurrent immigration. Using Approximate Bayesian Computation, we infer that the timing of admixture markedly differs between the two groups. Admixture in the traditionally agricultural Tajiks could be dated back to the onset of the Neolithic transition in the region, whereas admixture in Kyrgyz is more recent, and may have involved the westward movement of Turkic peoples. These results are confirmed by a coalescent method that fits an isolation-with-migration model to the genetic data, with both Central Asian groups having received gene flow from the extremities of Eurasia. Interestingly, our analyses also uncover signatures of gene flow from Eastern to Western Eurasia during Paleolithic times. In conclusion, the high genetic diversity currently observed in these two Central Asian peoples most likely reflects the effects of recurrent immigration that likely started before historical times. Conversely, conquests during historical times may have had a relatively limited genetic impact. These results emphasize the need for a better understanding of the genetic consequences of transmission of culture and technological innovations, as well as those of invasions and conquests.

  4. Prioritising risk pathways of complex human diseases based on functional profiling.

    Science.gov (United States)

    Li, Yan; Huang, Teng; Xiao, Yun; Ning, Shangwei; Wang, Peng; Wang, Qianghu; Chen, Xin; Chaohan, Xu; Sun, Donglin; Li, Xia; Li, Yixue

    2013-06-01

    Analysis of the biological pathways involved in complex human diseases is an important step in elucidating the pathogenesis and mechanism of diseases. Most pathway analysis approaches identify disease-related biological pathways using overlapping genes between pathways and diseases. However, these approaches ignore the functional biological association between pathways and diseases. In this paper, we designed a novel computational framework for prioritising disease-risk pathways based on functional profiling. The disease gene set and biological pathways were translated into functional profiles in the context of GO annotations. We then implemented a semantic similarity measurement for calculating the concordance score between a functional profile of disease genes and a functional profile of pathways (FPP); the concordance score was then used to prioritise and infer disease-risk pathways. A freely accessible web toolkit, 'Functional Profiling-based Pathway Prioritisation' (FPPP), was developed (http://bioinfo.hrbmu.edu.cn/FPPP). During validation, our method successfully identified known disease-pathway pairs with area under the ROC curve (AUC) values of 96.73 and 95.02% in tests using both pathway randomisation and disease randomisation. A robustness analysis showed that FPPP is reliable even when using data containing noise. A case study based on a dilated cardiomyopathy data set indicated that the high-ranking pathways from FPPP are well known to be linked with this disease. Furthermore, we predicted the risk pathways of 413 diseases by using FPPP to build a disease similarity landscape that systematically reveals the global modular organisation of disease associations.

  5. Effect of pulmonary vein isolation on the distribution of complex fractionated electrograms in humans.

    Science.gov (United States)

    Roux, Jean-François; Gojraty, Sattar; Bala, Rupa; Liu, Christopher F; Dixit, Sanjay; Hutchinson, Mathew D; Garcia, Fermin; Lin, David; Callans, David J; Riley, Michael; Marchlinski, Francis; Gerstenfeld, Edward P

    2009-02-01

    Targeting of complex fractionated electrograms (CFEs) has been used as an adjunctive strategy to pulmonary vein isolation (PVI) in patients with persistent atrial fibrillation (AF). However, it is unclear whether CFEs should be targeted before or after PVI. The purpose of this study was to examine the effect of PVI on CFE distribution in humans. We compared left atrial (LA) CFE maps acquired using the NavX system before and after PVI in patients with persistent AF. CFE maps were constructed from bipolar electrograms acquired from a circular mapping catheter. At each point, the mean AF cycle length (CL) was calculated automatically by averaging the intervals between deflections over a 4-second window. Sites with mean CL CFE+. A total of 22 consecutive patients (82% male, age 58 +/- 9 years) were studied. At baseline, 47% of the LA was encompassed by electrograms with CL CFE characteristics, with an increase in mean LA AF CL (144 ms pre-PVI vs. 214 ms post-PVI; P CFE+ LA surface area (47% vs 23%; P CFE burden after PVI in both PV (50% vs. 6%; P CFE. To limit extensive LA ablation, PVI should be performed before targeting CFE when a combined approach is pursued.

  6. Properties of human disease genes and the role of genes linked to Mendelian disorders in complex disease aetiology

    Science.gov (United States)

    Spataro, Nino; Rodríguez, Juan Antonio; Navarro, Arcadi

    2017-01-01

    Abstract Do genes presenting variation that has been linked to human disease have different biological properties than genes that have never been related to disease? What is the relationship between disease and fitness? Are the evolutionary pressures that affect genes linked to Mendelian diseases the same to those acting on genes whose variation contributes to complex disorders? The answers to these questions could shed light on the architecture of human genetic disorders and may have relevant implications when designing mapping strategies in future genetic studies. Here we show that, relative to non-disease genes, human disease (HD) genes have specific evolutionary profiles and protein network properties. Additionally, our results indicate that the mutation-selection balance renders an insufficient account of the evolutionary history of some HD genes and that adaptive selection could also contribute to shape their genetic architecture. Notably, several biological features of HD genes depend on the type of pathology (complex or Mendelian) with which they are related. For example, genes harbouring both causal variants for Mendelian disorders and risk factors for complex disease traits (Complex-Mendelian genes), tend to present higher functional relevance in the protein network and higher expression levels than genes associated only with complex disorders. Moreover, risk variants in Complex-Mendelian genes tend to present higher odds ratios than those on genes associated with the same complex disorders but with no link to Mendelian diseases. Taken together, our results suggest that genetic variation at genes linked to Mendelian disorders plays an important role in driving susceptibility to complex disease. PMID:28053046

  7. Inhibition of mitochondrial Na+-Ca2+ exchange restores agonist-induced ATP production and Ca2+ handling in human complex I deficiency.

    NARCIS (Netherlands)

    Visch, H.J.; Rutter, G.A.; Koopman, W.J.H.; Koenderink, J.B.; Verkaart, S.A.J.; Groot, T. de; Varadi, A.; Mitchell, K.J.; Heuvel, L.P.W.J. van den; Smeitink, J.A.M.; Willems, P.H.G.M.

    2004-01-01

    Human mitochondrial complex I (NADH:ubiquinone oxidoreductase) of the oxidative phosphorylation system is a multiprotein assembly comprising both nuclear and mitochondrially encoded subunits. Deficiency of this complex is associated with numerous clinical syndromes ranging from highly progressive, o

  8. XPC and human homologs of RAD23: intracellular localization and relationship to other nucleotide excision repair complexes.

    NARCIS (Netherlands)

    P.J. van der Spek (Peter); A.P.M. Eker (André); S. Rademakers (Suzanne); C.E. Visser (Cécile); K. Sugasawa (Kaoru); C. Masutani (Chikahide); F. Hanaoka (Fumio); D. Bootsma (Dirk); J.H.J. Hoeijmakers (Jan)

    1996-01-01

    textabstractThe xeroderma pigmentosum syndrome complementation group C (XP-C) is due to a defect in the global genome repair subpathway of nucleotide excision repair (NER). The XPC protein is complexed with HHR23B, one of the two human homologs of the yeast NER protein, RAD23 (Masutani at al. (1994)

  9. Ultrasonography as a tool to study afferent feedback from the muscle–tendon complex during human walking

    DEFF Research Database (Denmark)

    Cronin, Neil J.; Klint, Richard Albin Ivar af; Grey, Michael J.

    2011-01-01

    of these receptors to act as length, velocity and force transducers is the complex pattern of interaction between muscle and tendinous tissues, as tendon length is often considerably greater than muscle fibre length in the human lower limb. In essence, changes in muscle-tendon mechanics can influence the firing...

  10. Post-transcriptional modifications modulate conformational dynamics in human U2-U6 snRNA complex.

    Science.gov (United States)

    Karunatilaka, Krishanthi S; Rueda, David

    2014-01-01

    The spliceosome catalyzes precursor-mRNA splicing in all eukaryotes. It consists of over 100 proteins and five small nuclear RNAs (snRNAs), including U2 and U6 snRNAs, which are essential for catalysis. Human and yeast snRNAs share structural similarities despite the fact that human snRNAs contain numerous post-transcriptional modifications. Although functions for these modifications have been proposed, their exact roles are still not well understood. To help elucidate these roles in pre-mRNA splicing, we have used single-molecule fluorescence to characterize the effect of several post-transcriptional modifications in U2 snRNA on the conformation and dynamics of the U2-U6 complex in vitro. Consistent with yeast, the human U2-U6 complex reveals the presence of a magnesium-dependent dynamic equilibrium among three conformations. Interestingly, our data show that modifications in human U2 stem I modulate the dynamic equilibrium of the U2-U6 complex by stabilizing the four-helix structure. However, the small magnitude of this effect suggests that post-transcriptional modifications in human snRNAs may have a primary role in the mediation of specific RNA-protein interactions in vivo.

  11. Post-transcriptional modifications modulate conformational dynamics in human U2–U6 snRNA complex

    Science.gov (United States)

    Karunatilaka, Krishanthi S.; Rueda, David

    2014-01-01

    The spliceosome catalyzes precursor-mRNA splicing in all eukaryotes. It consists of over 100 proteins and five small nuclear RNAs (snRNAs), including U2 and U6 snRNAs, which are essential for catalysis. Human and yeast snRNAs share structural similarities despite the fact that human snRNAs contain numerous post-transcriptional modifications. Although functions for these modifications have been proposed, their exact roles are still not well understood. To help elucidate these roles in pre-mRNA splicing, we have used single-molecule fluorescence to characterize the effect of several post-transcriptional modifications in U2 snRNA on the conformation and dynamics of the U2–U6 complex in vitro. Consistent with yeast, the human U2–U6 complex reveals the presence of a magnesium-dependent dynamic equilibrium among three conformations. Interestingly, our data show that modifications in human U2 stem I modulate the dynamic equilibrium of the U2–U6 complex by stabilizing the four-helix structure. However, the small magnitude of this effect suggests that post-transcriptional modifications in human snRNAs may have a primary role in the mediation of specific RNA–protein interactions in vivo. PMID:24243115

  12. Spectroscopic, docking and molecular dynamics simulation studies on the interaction of two Schiff base complexes with human serum albumin

    Energy Technology Data Exchange (ETDEWEB)

    Fani, N. [Department of Chemistry, Isfahan University of Technology, Isfahan 84156-83111 (Iran, Islamic Republic of); Bordbar, A.K., E-mail: bordbar@chem.ui.ac.ir [Department of Chemistry, University of Isfahan, Isfahan 81746-73441 (Iran, Islamic Republic of); Ghayeb, Y. [Department of Chemistry, Isfahan University of Technology, Isfahan 84156-83111 (Iran, Islamic Republic of)

    2013-09-15

    This study was designed to examine the interaction of two Schiff base complexes with human serum albumin (HSA), by different kinds of spectroscopic and molecular modeling techniques. Fluorescence quenching and absorption spectra were investigated in order to estimate the binding parameters. The analysis of absorption data at different temperatures were done in order to estimate the thermodynamics parameters of interactions between Schiff base complexes and HSA. The experimental data suggested that both complexes demonstrated a significant binding affinity to HSA and the process is enthalpy driven. Molecular docking study indicated that both Schiff base complexes bind to polar and apolar residues located in the subdomain IB of HSA. Molecular dynamics (MD) simulations were also performed with the GROMACS program package to study the characters of HSA in binding states. Molecular dynamics results suggested that both Schiff base complexes can interact with HSA, without affecting the secondary structure of HSA but probably with a slight modification of its tertiary structure. All the molecular docking and molecular dynamics results kept in good consistence with experimental data. -- Highlights: • The fluorescence of HSA quenched due to reacting with Schiff base complexes. • The absorbance of Schiff base complexes in the presence of HSA changed. • Binding parameters and the pose of the molecules in the binding site were estimated. • Both complexes can interact with HSA, without affecting the secondary structure. • Simulation results predicted slight compactness of tertiary structure for HSA.

  13. The evolution of signaling complexity suggests a mechanism for reducing the genomic search space in human association studies.

    Science.gov (United States)

    Irizarry, K J L; Merriman, B; Bahamonde, M E; Wong, M-L; Licinio, J

    2005-01-01

    The size complexity of the human genome has been traditionally viewed as an obstacle that frustrates efforts aimed at identifying the genetic correlates of complex human phenotypes. As such complex phenotypes are attributed to the combined action of numerous genomic loci, attempts to identify the underlying multi-locus interactions may produce a combinatorial sum of false positives that drown out the real signal. Faced with such grim prospects for successfully identifying the genetic basis of complex phenotypes, many geneticists simply disregard epistatic interactions altogether. However, the emerging picture from systems biology is that the cellular programs encoded by the genome utilize nested signaling hierarchies to integrate a number of loosely coupled, semiautonomous, and functionally distinct genetic networks. The current view of these modules is that connections encoding inter-module signaling are relatively sparse, while the gene-to-gene (protein-to-protein) interactions within a particular module are typically denser. We believe that each of these modules is encoded by a finite set of discontinuous, sequence-specific, genomic intervals that are functionally linked to association rules, which correlate directly to features in the environment. Furthermore, because these environmental association rules have evolved incrementally over time, we explore theoretical models of cellular evolution to better understand the role of evolution in genomic complexity. Specifically, we present a conceptual framework for (1) reducing genomic complexity by partitioning the genome into subsets composed of functionally distinct genetic modules and (2) improving the selection of coding region SNPs, which results in an increased probability of identifying functionally relevant SNPs. Additionally, we introduce the notion of 'genomic closure,' which provides a quantitative measure of how functionally insulated a specific genetic module might be from the influence of the rest of

  14. Activation of the Human MT Complex by Motion in Depth Induced by a Moving Cast Shadow.

    Science.gov (United States)

    Katsuyama, Narumi; Usui, Nobuo; Taira, Masato

    2016-01-01

    A moving cast shadow is a powerful monocular depth cue for motion perception in depth. For example, when a cast shadow moves away from or toward an object in a two-dimensional plane, the object appears to move toward or away from the observer in depth, respectively, whereas the size and position of the object are constant. Although the cortical mechanisms underlying motion perception in depth by cast shadow are unknown, the human MT complex (hMT+) is likely involved in the process, as it is sensitive to motion in depth represented by binocular depth cues. In the present study, we examined this possibility by using a functional magnetic resonance imaging (fMRI) technique. First, we identified the cortical regions sensitive to the motion of a square in depth represented via binocular disparity. Consistent with previous studies, we observed significant activation in the bilateral hMT+, and defined functional regions of interest (ROIs) there. We then investigated the activity of the ROIs during observation of the following stimuli: 1) a central square that appeared to move back and forth via a moving cast shadow (mCS); 2) a segmented and scrambled cast shadow presented beside the square (sCS); and 3) no cast shadow (nCS). Participants perceived motion of the square in depth in the mCS condition only. The activity of the hMT+ was significantly higher in the mCS compared with the sCS and nCS conditions. Moreover, the hMT+ was activated equally in both hemispheres in the mCS condition, despite presentation of the cast shadow in the bottom-right quadrant of the stimulus. Perception of the square moving in depth across visual hemifields may be reflected in the bilateral activation of the hMT+. We concluded that the hMT+ is involved in motion perception in depth induced by moving cast shadow and by binocular disparity.

  15. Complex nature of SNP genotype effects on gene expression in primary human leucocytes

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    Dinesen Lotte C

    2009-01-01

    Full Text Available Abstract Background Genome wide association studies have been hugely successful in identifying disease risk variants, yet most variants do not lead to coding changes and how variants influence biological function is usually unknown. Methods We correlated gene expression and genetic variation in untouched primary leucocytes (n = 110 from individuals with celiac disease – a common condition with multiple risk variants identified. We compared our observations with an EBV-transformed HapMap B cell line dataset (n = 90, and performed a meta-analysis to increase power to detect non-tissue specific effects. Results In celiac peripheral blood, 2,315 SNP variants influenced gene expression at 765 different transcripts (cis expression quantitative trait loci, eQTLs. 135 of the detected SNP-probe effects (reflecting 51 unique probes were also detected in a HapMap B cell line published dataset, all with effects in the same allelic direction. Overall gene expression differences within the two datasets predominantly explain the limited overlap in observed cis-eQTLs. Celiac associated risk variants from two regions, containing genes IL18RAP and CCR3, showed significant cis genotype-expression correlations in the peripheral blood but not in the B cell line datasets. We identified 14 genes where a SNP affected the expression of different probes within the same gene, but in opposite allelic directions. By incorporating genetic variation in co-expression analyses, functional relationships between genes can be more significantly detected. Conclusion In conclusion, the complex nature of genotypic effects in human populations makes the use of a relevant tissue, large datasets, and analysis of different exons essential to enable the identification of the function for many genetic risk variants in common diseases.

  16. The human milk protein-lipid complex HAMLET sensitizes bacterial pathogens to traditional antimicrobial agents.

    Directory of Open Access Journals (Sweden)

    Laura R Marks

    Full Text Available The fight against antibiotic resistance is one of the most significant challenges to public health of our time. The inevitable development of resistance following the introduction of novel antibiotics has led to an urgent need for the development of new antibacterial drugs with new mechanisms of action that are not susceptible to existing resistance mechanisms. One such compound is HAMLET, a natural complex from human milk that kills Streptococcus pneumoniae (the pneumococcus using a mechanism different from common antibiotics and is immune to resistance-development. In this study we show that sublethal concentrations of HAMLET potentiate the effect of common antibiotics (penicillins, macrolides, and aminoglycosides against pneumococci. Using MIC assays and short-time killing assays we dramatically reduced the concentrations of antibiotics needed to kill pneumococci, especially for antibiotic-resistant strains that in the presence of HAMLET fell into the clinically sensitive range. Using a biofilm model in vitro and nasopharyngeal colonization in vivo, a combination of HAMLET and antibiotics completely eradicated both biofilms and colonization in mice of both antibiotic-sensitive and resistant strains, something each agent alone was unable to do. HAMLET-potentiation of antibiotics was partially due to increased accessibility of antibiotics to the bacteria, but relied more on calcium import and kinase activation, the same activation pathway HAMLET uses when killing pneumococci by itself. Finally, the sensitizing effect was not confined to species sensitive to HAMLET. The HAMLET-resistant respiratory species Acinetobacter baumanii and Moraxella catarrhalis were all sensitized to various classes of antibiotics in the presence of HAMLET, activating the same mechanism as in pneumococci. Combined these results suggest the presence of a conserved HAMLET-activated pathway that circumvents antibiotic resistance in bacteria. The ability to activate this

  17. Apoptosis-like death in bacteria induced by HAMLET, a human milk lipid-protein complex.

    Directory of Open Access Journals (Sweden)

    Anders P Hakansson

    Full Text Available BACKGROUND: Apoptosis is the primary means for eliminating unwanted cells in multicellular organisms in order to preserve tissue homeostasis and function. It is characterized by distinct changes in the morphology of the dying cell that are orchestrated by a series of discrete biochemical events. Although there is evidence of primitive forms of programmed cell death also in prokaryotes, no information is available to suggest that prokaryotic death displays mechanistic similarities to the highly regulated programmed death of eukaryotic cells. In this study we compared the characteristics of tumor and bacterial cell death induced by HAMLET, a human milk complex of alpha-lactalbumin and oleic acid. METHODOLOGY/PRINCIPAL FINDINGS: We show that HAMLET-treated bacteria undergo cell death with mechanistic and morphologic similarities to apoptotic death of tumor cells. In Jurkat cells and Streptococcus pneumoniae death was accompanied by apoptosis-like morphology such as cell shrinkage, DNA condensation, and DNA degradation into high molecular weight fragments of similar sizes, detected by field inverse gel electrophoresis. HAMLET was internalized into tumor cells and associated with mitochondria, causing a rapid depolarization of the mitochondrial membrane and bound to and induced depolarization of the pneumococcal membrane with similar kinetic and magnitude as in mitochondria. Membrane depolarization in both systems required calcium transport, and both tumor cells and bacteria were found to require serine protease activity (but not caspase activity to execute cell death. CONCLUSIONS/SIGNIFICANCE: Our results suggest that many of the morphological changes and biochemical responses associated with apoptosis are present in prokaryotes. Identifying the mechanisms of bacterial cell death has the potential to reveal novel targets for future antimicrobial therapy and to further our understanding of core activation mechanisms of cell death in eukaryote cells.

  18. The Human Milk Protein-Lipid Complex HAMLET Sensitizes Bacterial Pathogens to Traditional Antimicrobial Agents

    Science.gov (United States)

    Marks, Laura R.; Clementi, Emily A.; Hakansson, Anders P.

    2012-01-01

    The fight against antibiotic resistance is one of the most significant challenges to public health of our time. The inevitable development of resistance following the introduction of novel antibiotics has led to an urgent need for the development of new antibacterial drugs with new mechanisms of action that are not susceptible to existing resistance mechanisms. One such compound is HAMLET, a natural complex from human milk that kills Streptococcus pneumoniae (the pneumococcus) using a mechanism different from common antibiotics and is immune to resistance-development. In this study we show that sublethal concentrations of HAMLET potentiate the effect of common antibiotics (penicillins, macrolides, and aminoglycosides) against pneumococci. Using MIC assays and short-time killing assays we dramatically reduced the concentrations of antibiotics needed to kill pneumococci, especially for antibiotic-resistant strains that in the presence of HAMLET fell into the clinically sensitive range. Using a biofilm model in vitro and nasopharyngeal colonization in vivo, a combination of HAMLET and antibiotics completely eradicated both biofilms and colonization in mice of both antibiotic-sensitive and resistant strains, something each agent alone was unable to do. HAMLET-potentiation of antibiotics was partially due to increased accessibility of antibiotics to the bacteria, but relied more on calcium import and kinase activation, the same activation pathway HAMLET uses when killing pneumococci by itself. Finally, the sensitizing effect was not confined to species sensitive to HAMLET. The HAMLET-resistant respiratory species Acinetobacter baumanii and Moraxella catarrhalis were all sensitized to various classes of antibiotics in the presence of HAMLET, activating the same mechanism as in pneumococci. Combined these results suggest the presence of a conserved HAMLET-activated pathway that circumvents antibiotic resistance in bacteria. The ability to activate this pathway may extend

  19. The human milk protein-lipid complex HAMLET sensitizes bacterial pathogens to traditional antimicrobial agents.

    Science.gov (United States)

    Marks, Laura R; Clementi, Emily A; Hakansson, Anders P

    2012-01-01

    The fight against antibiotic resistance is one of the most significant challenges to public health of our time. The inevitable development of resistance following the introduction of novel antibiotics has led to an urgent need for the development of new antibacterial drugs with new mechanisms of action that are not susceptible to existing resistance mechanisms. One such compound is HAMLET, a natural complex from human milk that kills Streptococcus pneumoniae (the pneumococcus) using a mechanism different from common antibiotics and is immune to resistance-development. In this study we show that sublethal concentrations of HAMLET potentiate the effect of common antibiotics (penicillins, macrolides, and aminoglycosides) against pneumococci. Using MIC assays and short-time killing assays we dramatically reduced the concentrations of antibiotics needed to kill pneumococci, especially for antibiotic-resistant strains that in the presence of HAMLET fell into the clinically sensitive range. Using a biofilm model in vitro and nasopharyngeal colonization in vivo, a combination of HAMLET and antibiotics completely eradicated both biofilms and colonization in mice of both antibiotic-sensitive and resistant strains, something each agent alone was unable to do. HAMLET-potentiation of antibiotics was partially due to increased accessibility of antibiotics to the bacteria, but relied more on calcium import and kinase activation, the same activation pathway HAMLET uses when killing pneumococci by itself. Finally, the sensitizing effect was not confined to species sensitive to HAMLET. The HAMLET-resistant respiratory species Acinetobacter baumanii and Moraxella catarrhalis were all sensitized to various classes of antibiotics in the presence of HAMLET, activating the same mechanism as in pneumococci. Combined these results suggest the presence of a conserved HAMLET-activated pathway that circumvents antibiotic resistance in bacteria. The ability to activate this pathway may extend

  20. Apoptosis-like death in bacteria induced by HAMLET, a human milk lipid-protein complex.

    Science.gov (United States)

    Hakansson, Anders P; Roche-Hakansson, Hazeline; Mossberg, Ann-Kristin; Svanborg, Catharina

    2011-03-10

    Apoptosis is the primary means for eliminating unwanted cells in multicellular organisms in order to preserve tissue homeostasis and function. It is characterized by distinct changes in the morphology of the dying cell that are orchestrated by a series of discrete biochemical events. Although there is evidence of primitive forms of programmed cell death also in prokaryotes, no information is available to suggest that prokaryotic death displays mechanistic similarities to the highly regulated programmed death of eukaryotic cells. In this study we compared the characteristics of tumor and bacterial cell death induced by HAMLET, a human milk complex of alpha-lactalbumin and oleic acid. We show that HAMLET-treated bacteria undergo cell death with mechanistic and morphologic similarities to apoptotic death of tumor cells. In Jurkat cells and Streptococcus pneumoniae death was accompanied by apoptosis-like morphology such as cell shrinkage, DNA condensation, and DNA degradation into high molecular weight fragments of similar sizes, detected by field inverse gel electrophoresis. HAMLET was internalized into tumor cells and associated with mitochondria, causing a rapid depolarization of the mitochondrial membrane and bound to and induced depolarization of the pneumococcal membrane with similar kinetic and magnitude as in mitochondria. Membrane depolarization in both systems required calcium transport, and both tumor cells and bacteria were found to require serine protease activity (but not caspase activity) to execute cell death. Our results suggest that many of the morphological changes and biochemical responses associated with apoptosis are present in prokaryotes. Identifying the mechanisms of bacterial cell death has the potential to reveal novel targets for future antimicrobial therapy and to further our understanding of core activation mechanisms of cell death in eukaryote cells.

  1. Complex and multi-allelic copy number variation in human disease.

    Science.gov (United States)

    Usher, Christina L; McCarroll, Steven A

    2015-09-01

    Hundreds of copy number variants are complex and multi-allelic, in that they have many structural alleles and have rearranged multiple times in the ancestors who contributed chromosomes to current humans. Not only are the relationships of these multi-allelic CNVs (mCNVs) to phenotypes generally unknown, but many mCNVs have not yet been described at the basic levels-alleles, allele frequencies, structural features-that support genetic investigation. To date, most reported disease associations to these variants have been ascertained through candidate gene studies. However, only a few associations have reached the level of acceptance defined by durable replications in many cohorts. This likely stems from longstanding challenges in making precise molecular measurements of the alleles individuals have at these loci. However, approaches for mCNV analysis are improving quickly, and some of the unique characteristics of mCNVs may assist future association studies. Their various structural alleles are likely to have different magnitudes of effect, creating a natural allelic series of growing phenotypic impact and giving investigators a set of natural predictions and testable hypotheses about the extent to which each allele of an mCNV predisposes to a phenotype. Also, mCNVs' low-to-modest correlation to individual single-nucleotide polymorphisms (SNPs) may make it easier to distinguish between mCNVs and nearby SNPs as the drivers of an association signal, and perhaps, make it possible to preliminarily screen candidate loci, or the entire genome, for the many mCNV-disease relationships that remain to be discovered.

  2. Differential association of protein subunits with the human RNase MRP and RNase P complexes.

    Science.gov (United States)

    Welting, Tim J M; Kikkert, Bastiaan J; van Venrooij, Walther J; Pruijn, Ger J M

    2006-07-01

    RNase MRP is a eukaryotic endoribonuclease involved in nucleolar and mitochondrial RNA processing events. RNase MRP is a ribonucleoprotein particle, which is structurally related to RNase P, an endoribonuclease involved in pre-tRNA processing. Most of the protein components of RNase MRP have been reported to be associated with RNase P as well. In this study we determined the association of these protein subunits with the human RNase MRP and RNase P particles by glycerol gradient sedimentation and coimmunoprecipitation. In agreement with previous studies, RNase MRP sedimented at 12S and 60-80S. In contrast, only a single major peak was observed for RNase P at 12S. The analysis of individual protein subunits revealed that hPop4 (also known as Rpp29), Rpp21, Rpp20, and Rpp25 only sedimented in 12S fractions, whereas hPop1, Rpp40, Rpp38, and Rpp30 were also found in 60-80S fractions. In agreement with their cosedimentation with RNase P RNA in the 12S peak, coimmunoprecipitation with VSV-epitope-tagged protein subunits revealed that hPop4, Rpp21, and in addition Rpp14 preferentially associate with RNase P. These data show that hPop4, Rpp21, and Rpp14 may not be associated with RNase MRP. Furthermore, Rpp20 and Rpp25 appear to be associated with only a subset of RNase MRP particles, in contrast to hPop1, Rpp40, Rpp38, and Rpp30 (and possibly also hPop5), which are probably associated with all RNase MRP complexes. Our data are consistent with a transient association of Rpp20 and Rpp25 with RNase MRP, which may be inversely correlated to its involvement in pre-rRNA processing.

  3. Specificity of recognition of mRNA 5' cap by human nuclear cap-binding complex.

    Science.gov (United States)

    Worch, Remigiusz; Niedzwiecka, Anna; Stepinski, Janusz; Mazza, Catherine; Jankowska-Anyszka, Marzena; Darzynkiewicz, Edward; Cusack, Stephen; Stolarski, Ryszard

    2005-09-01

    The heterodimeric nuclear cap-binding complex (CBC) binds to the mono-methylated 5' cap of eukaryotic RNA polymerase II transcripts such as mRNA and U snRNA. The binding is important for nuclear maturation of mRNAs and possibly in the first round of translation and nonsense-mediated decay. It is also essential for nuclear export of U snRNAs in metazoans. We report characterization by fluorescence spectroscopy of the recognition of 5' capped RNA by human CBC. The association constants (K(as)) for 17 mono- and dinucleotide cap analogs as well as for the oligomer m7GpppA(m2') pU(m2')pA(m2') cover the range from 1.8 x 10(6) M(-1) to 2.3 x 10(8) M(-1). Higher affinity for CBC is observed for the dinucleotide compared with mononucleotide analogs, especially for those containing a purine nucleoside next to m7G. The mRNA tetramer associates with CBC as tightly as the dinucleotide analogs. Replacement of Tyr138 by alanine in the CBP20 subunit of CBC reduces the cap affinity except for the mononucleotide analogs, consistent with the crystallographic observation of the second base stacking on this residue. Our spectroscopic studies showed that contrary to the other known cap-binding proteins, the first two nucleotides of a capped-RNA are indispensable for its specific recognition by CBC. Differences in the cap binding of CBC compared with the eukaryotic translation initiation factor 4E (eIF4E) are analyzed and discussed regarding replacement of CBC by eIF4E.

  4. Complex and changing patterns of natural selection explain the evolution of the human hip.

    Science.gov (United States)

    Grabowski, Mark; Roseman, Charles C

    2015-08-01

    Causal explanations for the dramatic changes that occurred during the evolution of the human hip focus largely on selection for bipedal function and locomotor efficiency. These hypotheses rest on two critical assumptions. The first-that these anatomical changes served functional roles in bipedalism-has been supported in numerous analyses showing how postcranial changes likely affected locomotion. The second-that morphological changes that did play functional roles in bipedalism were the result of selection for that behavior-has not been previously explored and represents a major gap in our understanding of hominin hip evolution. Here we use evolutionary quantitative genetic models to test the hypothesis that strong directional selection on many individual aspects of morphology was responsible for the large differences observed across a sample of fossil hominin hips spanning the Plio-Pleistocene. Our approach uses covariance among traits and the differences between relatively complete fossils to estimate the net selection pressures that drove the major transitions in hominin hip evolution. Our findings show a complex and changing pattern of natural selection drove hominin hip evolution, and that many, but not all, traits hypothesized to play functional roles in bipedalism evolved as a direct result of natural selection. While the rate of evolutionary change for all transitions explored here does not exceed the amount expected if evolution was occurring solely through neutral processes, it was far above rates of evolution for morphological traits in other mammalian groups. Given that stasis is the norm in the mammalian fossil record, our results suggest that large shifts in the adaptive landscape drove hominin evolution.

  5. Differential maturation of brain signal complexity in the human auditory and visual system

    Directory of Open Access Journals (Sweden)

    Sarah Lippe

    2009-11-01

    Full Text Available Brain development carries with it a large number of structural changes at the local level which impact on the functional interactions of distributed neuronal networks for perceptual processing. Such changes enhance information processing capacity, which can be indexed by estimation of neural signal complexity. Here, we show that during development, EEG signal complexity increases from one month to 5 years of age in response to auditory and visual stimulation. However, the rates of change in complexity were not equivalent for the two responses. Infants’ signal complexity for the visual condition was greater than auditory signal complexity, whereas adults showed the same level of complexity to both types of stimuli. The differential rates of complexity change may reflect a combination of innate and experiential factors on the structure and function of the two sensory systems.

  6. Superoxide dismutase activity of the naturally occurring human serum albumin-copper complex without hydroxyl radical formation.

    Science.gov (United States)

    Kato, Ryunosuke; Akiyama, Matofusa; Kawakami, Hiroyoshi; Komatsu, Teruyuki

    2014-01-01

    The superoxide radical anion (O2(.-)) is biologically toxic and contributes to the pathogenesis of various diseases. Here we describe the superoxide dismutase (SOD) activity of human serum albumin (HSA) complexed with a single Cu(II) ion at the N-terminal end (HSA-Cu complex). The structure of this naturally occurring copper-coordinated blood serum protein has been characterized by several physicochemical measurements. The O2(.-) dismutation ability of the HSA-Cu (1:1) complex is almost the same as that of the well-known SOD mimics, such as Mn(III) -tetrakis(N-methylpyridinium)porphyrin. Interestingly, the HSA-Cu complex does not induce a subsequent Fenton reaction to produce the hydroxyl radical (OH(.)), which is one of the most harmful reactive oxygen species.

  7. Mixed-ligand copper(II) complexes activate aryl hydrocarbon receptor AhR and induce CYP1A genes expression in human hepatocytes and human cell lines.

    Science.gov (United States)

    Kubešová, Kateřina; Dořičáková, Aneta; Trávníček, Zdeněk; Dvořák, Zdeněk

    2016-07-25

    The effects of four copper(II) mixed-ligand complexes [Cu(qui1)(L)]NO3·H2O (1-3) and [Cu(qui2)(phen)]NO3 (4), where qui1=2-phenyl-3-hydroxy-4(1H)-quinolinone, Hqui2=2-(4-amino-3,5-dichlorophenyl)-N-propyl-3-hydroxy-4(1H)-quinolinone-7-carboxamide, L=1,10-phenanthroline (phen) (1), 5-methyl-1,10-phenanthroline (mphen) (2), bathophenanthroline (bphen) (3), on transcriptional activities of steroid receptors, nuclear receptors and xenoreceptors have been studied. The complexes (1-4) did not influence basal or ligand-inducible activities of glucocorticoid receptor, androgen receptor, thyroid receptor, pregnane X receptor and vitamin D receptor, as revealed by gene reporter assays. The complexes 1 and 2 dose-dependently induced luciferase activity in stable gene reporter AZ-AhR cell line, and this induction was reverted by resveratrol, indicating involvement of aryl hydrocarbon receptor (AhR) in the process. The complexes 1, 2 and 3 induced CYP1A1 mRNA in LS180 cells and CYP1A1/CYP1A2 in human hepatocytes through AhR. Electrophoretic mobility shift assay EMSA showed that the complexes 1 and 2 transformed AhR in its DNA-binding form. Collectively, we demonstrate that the complexes 1 and 2 activate AhR and induce AhR-dependent genes in human hepatocytes and cancer cell lines. In conclusion, the data presented here might be of toxicological importance, regarding the multiple roles of AhR in human physiology and pathophysiology.

  8. Purification and characterization of a native zinc-binding high molecular weight multiprotein complex from human seminal plasma.

    Science.gov (United States)

    Yadav, Vikash Kumar; Kumar, Vijay; Chhikara, Nirmal; Kumar, Sanjay; Manral, Pallavi; Kashav, Tara; Saini, Savita; Srinivasan, A; Singh, Sarman; Singh, Tej P; Yadav, Savita

    2011-05-01

    The seminal plasma comprises secretions from various accessory sex glands. During fertilization spermatozoa undergo complex sequences of precisely timed events that are regulated by the activation of different intracellular signaling pathways. The precision and efficacy of these pathways are often influenced by the assembly and interactions of multiprotein complexes, thereby directing the flow of regulatory information. Our knowledge about these protein complexes present in human seminal plasma (HuSP) is limited. Here we report the identification and characterization of a native high molecular weight zinc-binding multiprotein complex from HuSP by utilizing 2-DE followed by MS. Twenty-six proteins representing isoforms and/or fragments of 11 different proteins were found to be assembled in this complex. Prostate-specific antigen, zinc α2-glycoprotein, prostatic acid phosphatase, and prolactin inducible protein were the major proteins of this complex. Dynamic light scattering experiments revealed changes in aggregation pattern accompanied with deviation from physiological pH and in presence of SDS. However, no significant changes were observed in the presence of physiological ligands such as zinc and fructose. The present study will be useful and contribute to guide the future studies performed for elucidation of biological significance of this native complex in HuSP.

  9. “BIRD BITING” MOSQUITOES AND HUMAN DISEASE: A REVIEW OF THE ROLE OF CULEX PIPIENS COMPLEX MOSQUITOES IN EPIDEMIOLOGY

    Science.gov (United States)

    Farajollahi, Ary; Fonseca, Dina M.; Kramer, Laura D.; Kilpatrick, A. Marm

    2011-01-01

    The transmission of vector-borne pathogens is greatly influenced by the ecology of their vector, which is in turn shaped by genetic ancestry, the environment, and the hosts it feeds on. One group of vectors, the mosquitoes in the Culex pipiens complex, play key roles in the transmission of a range of pathogens including several viruses such as West Nile and St. Louis encephalitis viruses, avian malaria (Plasmodium spp.), and filarial worms. The Cx. pipiens complex includes Cx. pipiens pipiens with two forms, pipiens and molestus, Cx. pipiens pallens, Cx. quinquefasciatus, Cx. australicus, and Cx. globocoxitus. While several members of the complex have limited geographic distributions, Cx. pipiens pipiens and Cx. quinquefasciatus are found in all known urban and sub-urban temperate and tropical regions, respectively, across the world, where they are often principal disease vectors. In addition, hybrids are common in areas of overlap. Although gaps in our knowledge still remain, the advent of genetic tools has greatly enhanced our understanding of the history of speciation, domestication, dispersal, and hybridization. We review the taxonomy, genetics, evolution, behavior, and ecology, of members of the Cx. pipiens complex and their role in the transmission of medically important pathogens. The adaptation of Cx. pipiens complex mosquitoes to human-altered environments led to their global distribution through dispersal via humans and, combined with their mixed feeding patterns on birds and mammals (including humans), increased the transmission of several avian pathogens to humans. We highlight several unanswered questions that will increase our ability to control diseases transmitted by these mosquitoes. PMID:21875691

  10. Multi-view 3D human pose recovery in complex environment

    NARCIS (Netherlands)

    Hofmann, K.M.

    2011-01-01

    The recovery of 3D human pose is an important problem in computer vision with many potential applications in human computer interfaces, motion analysis (e.g. sports, medical) and surveillance. 3D human pose also provides informative, viewinvariant features for a subsequent activity recognition step.

  11. Multi-view 3D human pose recovery in complex environment

    NARCIS (Netherlands)

    Hofmann, K.M.

    2011-01-01

    The recovery of 3D human pose is an important problem in computer vision with many potential applications in human computer interfaces, motion analysis (e.g. sports, medical) and surveillance. 3D human pose also provides informative, viewinvariant features for a subsequent activity recognition step.

  12. Metabolites from invasive pests inhibit mitochondrial complex II: A potential strategy for the treatment of human ovarian carcinoma?

    Energy Technology Data Exchange (ETDEWEB)

    Ferramosca, Alessandra, E-mail: alessandra.ferramosca@unisalento.it [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Conte, Annalea; Guerra, Flora; Felline, Serena [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Rimoli, Maria Grazia [Dipartimento di Farmacia, Università di Napoli Federico II, Napoli (Italy); Mollo, Ernesto [Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli (Italy); Zara, Vincenzo [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Terlizzi, Antonio [Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Lecce (Italy); Stazione Zoologica Anton Dohrn, Napoli (Italy)

    2016-05-13

    The red pigment caulerpin, a secondary metabolite from the marine invasive green algae Caulerpa cylindracea can be accumulated and transferred along the trophic chain, with detrimental consequences on biodiversity and ecosystem functioning. Despite increasing research efforts to understand how caulerpin modifies fish physiology, little is known on the effects of algal metabolites on mammalian cells. Here we report for the first time the mitochondrial targeting activity of both caulerpin, and its closely related derivative caulerpinic acid, by using as experimental model rat liver mitochondria, a system in which bioenergetics mechanisms are not altered. Mitochondrial function was tested by polarographic and spectrophotometric methods. Both compounds were found to selectively inhibit respiratory complex II activity, while complexes I, III, and IV remained functional. These results led us to hypothesize that both algal metabolites could be used as antitumor agents in cell lines with defects in mitochondrial complex I. Ovarian cancer cisplatin-resistant cells are a good example of cell lines with a defective complex I function on which these molecules seem to have a toxic effect on proliferation. This provided novel insight toward the potential use of metabolites from invasive Caulerpa species for the treatment of human ovarian carcinoma cisplatin-resistant cells. -- Highlights: •Novel insight toward the potential use of the algal metabolites for the treatment of human diseases. •Caulerpin and caulerpinic acid inhibit respiratory complex II activity. •Both algal metabolites could be used as antitumor agents in ovarian cancer cisplatin-resistant cells.

  13. Amyloid-beta leads to impaired cellular respiration, energy production and mitochondrial electron chain complex activities in human neuroblastoma cells.

    Science.gov (United States)

    Rhein, V; Baysang, G; Rao, S; Meier, F; Bonert, A; Müller-Spahn, F; Eckert, A

    2009-09-01

    Evidence suggests that amyloid-beta (Abeta) protein is a key factor in the pathogenesis of Alzheimer's disease (AD) and it has been recently proposed that mitochondria are involved in the biochemical pathway by which Abeta can lead to neuronal dysfunction. Here we investigated the specific effects of Abeta on mitochondrial function under physiological conditions. Mitochondrial respiratory functions and energy metabolism were analyzed in control and in human wild-type amyloid precursor protein (APP) stably transfected human neuroblastoma cells (SH-SY5Y). Mitochondrial respiratory capacity of mitochondrial electron transport chain (ETC) in vital cells was measured with a high-resolution respirometry system (Oxygraph-2k). In addition, we determined the individual activities of mitochondrial complexes I-IV that compose ETC and ATP cellular levels. While the activities of complexes I and II did not change between cell types, complex IV activity was significantly reduced in APP cells. In contrast, activity of complex III was significantly enhanced in APP cells, as compensatory response in order to balance the defect of complex IV. However, this compensatory mechanism could not prevent the strong impairment of total respiration in vital APP cells. As a result, the respiratory control ratio (state3/state4) together with ATP production decreased in the APP cells in comparison with the control cells. Chronic exposure to soluble Abeta protein may result in an impairment of energy homeostasis due to a decreased respiratory capacity of mitochondrial electron transport chain which, in turn, may accelerate neurons demise.

  14. Proteasome activator complex PA28 identified as an accessible target in prostate cancer by in vivo selection of human antibodies

    Science.gov (United States)

    Sánchez-Martín, David; Martínez-Torrecuadrada, Jorge; Teesalu, Tambet; Sugahara, Kazuki N.; Alvarez-Cienfuegos, Ana; Ximénez-Embún, Pilar; Fernández-Periáñez, Rodrigo; Martín, M. Teresa; Molina-Privado, Irene; Ruppen-Cañás, Isabel; Blanco-Toribio, Ana; Cañamero, Marta; Cuesta, Ángel M.; Compte, Marta; Kremer, Leonor; Bellas, Carmen; Alonso-Camino, Vanesa; Guijarro-Muñoz, Irene; Sanz, Laura; Ruoslahti, Erkki; Alvarez-Vallina, Luis

    2013-01-01

    Antibody cancer therapies rely on systemically accessible targets and suitable antibodies that exert a functional activity or deliver a payload to the tumor site. Here, we present proof-of-principle of in vivo selection of human antibodies in tumor-bearing mice that identified a tumor-specific antibody able to deliver a payload and unveils the target antigen. By using an ex vivo enrichment process against freshly disaggregated tumors to purge the repertoire, in combination with in vivo biopanning at optimized phage circulation time, we have identified a human domain antibody capable of mediating selective localization of phage to human prostate cancer xenografts. Affinity chromatography followed by mass spectrometry analysis showed that the antibody recognizes the proteasome activator complex PA28. The specificity of soluble antibody was confirmed by demonstrating its binding to the active human PA28αβ complex. Whereas systemically administered control phage was confined in the lumen of blood vessels of both normal tissues and tumors, the selected phage spread from tumor vessels into the perivascular tumor parenchyma. In these areas, the selected phage partially colocalized with PA28 complex. Furthermore, we found that the expression of the α subunit of PA28 [proteasome activator complex subunit 1 (PSME1)] is elevated in primary and metastatic human prostate cancer and used anti-PSME1 antibodies to show that PSME1 is an accessible marker in mouse xenograft tumors. These results support the use of PA28 as a tumor marker and a potential target for therapeutic intervention in prostate cancer. PMID:23918357

  15. HISTOLOGICAL ANALYSIS OF IN VITRO REGENERATION OF HUMAN DENTAL PULP COMPLEX WITH AUTOLOGOUS TISSULAR ENGINEERING

    OpenAIRE

    Romero Márquez, Ricardo Manuel; Docente Colaborador del Departamento de Ciencias Básicas Estomatológicas, Curso de Patología General y del Sistema Estomatognático. Facultad de Odontología. UNMSM.

    2014-01-01

    A long time ago, dental pulp-complex regeneration was our main objective in radicular reparation which could guarantee all appropiate growth of healthy and functional tissue. The present study is about a histological assay of a new dentinal-pulp complex formation using platelet rich plasm, pulpar tissue and fibrina, all autolougus, as components of dental pulp tissular engineering treatment. Qualitative and quantitative assays about the dentin pulp-complex regeneration grade on experimental a...

  16. Extending network approach to language dynamics and human cognition. Comment on "Approaching human language with complex networks" by Cong and Liu

    Science.gov (United States)

    Gong, Tao; Shuai, Lan; Wu, Yicheng

    2014-12-01

    By analyzing complex networks constructed from authentic language data, Cong and Liu [1] advance linguistics research into the big data era. The network approach has revealed many intrinsic generalities and crucial differences at both the macro and micro scales between human languages. The axiom behind this research is that language is a complex adaptive system [2]. Although many lexical, semantic, or syntactic features have been discovered by means of analyzing the static and dynamic linguistic networks of world languages, available network-based language studies have not explicitly addressed the evolutionary dynamics of language systems and the correlations between language and human cognition. This commentary aims to provide some insights on how to use the network approach to study these issues.

  17. Evaluation of human exposure to complex waveform magnetic fields generated by arc-welding equipment according to European safety standards.

    Science.gov (United States)

    Zoppetti, Nicola; Bogi, Andrea; Pinto, Iole; Andreuccetti, Daniele

    2015-02-01

    In this paper, a procedure is described for the assessment of human exposure to magnetic fields with complex waveforms generated by arc-welding equipment. The work moves from the analysis of relevant guidelines and technical standards, underlining their strengths and their limits. Then, the procedure is described with particular attention to the techniques used to treat complex waveform fields. Finally, the procedure is applied to concrete cases encountered in the workplace. The discussion of the results highlights the critical points in the procedure, as well as those related to the evolution of the technical and exposure standards.

  18. Linguistic complex networks as a young field of quantitative linguistics. Comment on "Approaching human language with complex networks" by J. Cong and H. Liu

    Science.gov (United States)

    Köhler, Reinhard

    2014-12-01

    We have long been used to the domination of qualitative methods in modern linguistics. Indeed, qualitative methods have advantages such as ease of use and wide applicability to many types of linguistic phenomena. However, this shall not overshadow the fact that a great part of human language is amenable to quantification. Moreover, qualitative methods may lead to over-simplification by employing the rigid yes/no scale. When variability and vagueness of human language must be taken into account, qualitative methods will prove inadequate and give way to quantitative methods [1, p. 11]. In addition to such advantages as exactness and precision, quantitative concepts and methods make it possible to find laws of human language which are just like those in natural sciences. These laws are fundamental elements of linguistic theories in the spirit of the philosophy of science [2,3]. Theorization effort of this type is what quantitative linguistics [1,4,5] is devoted to. The review of Cong and Liu [6] has provided an informative and insightful survey of linguistic complex networks as a young field of quantitative linguistics, including the basic concepts and measures, the major lines of research with linguistic motivation, and suggestions for future research.

  19. Structural basis for the dysfunctioning of human 2-oxo acid dehydrogenase complexes

    NARCIS (Netherlands)

    Hengeveld, A.F.; Kok, de A.

    2002-01-01

    2-oxo acid dehydrogenase complexes are a ubiquitous family of multienzyme systems that catalyse the oxidative decarboxylation of various 2-oxo acid substrates. They play a key role in the primary energy metabolism: in glycolysis (pyruvate dehydrogenase complex), the citric acid cycle (2-oxoglutarate

  20. [The application of genetic risk score in genetic studies of complex human diseases].

    Science.gov (United States)

    Dayan, Niu; Weili, Yan

    2015-12-01

    Complex diseases such as cardiovascular disease, type 2 diabetes, essential hypertension, asthma, obesity and cancer have spread across the globe and become the predominant cause of death. There are growing concerns over the role of genetic susceptibility in pathogenesis of complex diseases. However, the related susceptibility genes and sequence variations are still unknown. To elucidate the genetic basis of complex diseases, researchers have identified a large number of genetic variants associated with complex diseases through genome-wide association studies (GWAS) and candidate gene studies recently. The identification of these causal and/or associated variants promotes the development of approaches for complex diseases prediction and prevention. Genetic risk score (GRS), an emerging method for exploring correlation between single nucleotide polymorphisms (SNPs) and clinical phenotypes of complex diseases, integrates weak effects of multiple SNPs and dramatically enhances predictability of complex diseases by gene polymorphisms. This method has been applied successfully in genetic studies of many complex diseases. Here we focus on the introduction of the computational methods and evaluation criteria of GRS, enumerate a series of achievements through GRS application, discuss some limitations during application, and finally prospect the future of GRS.

  1. Structural basis for the dysfunctioning of human 2-oxo acid dehydrogenase complexes

    NARCIS (Netherlands)

    Hengeveld, A.F.; Kok, de A.

    2002-01-01

    2-oxo acid dehydrogenase complexes are a ubiquitous family of multienzyme systems that catalyse the oxidative decarboxylation of various 2-oxo acid substrates. They play a key role in the primary energy metabolism: in glycolysis (pyruvate dehydrogenase complex), the citric acid cycle (2-oxoglutarate

  2. Spectroscopic and molecular docking studies on the interaction of human serum albumin with copper(II) complexes

    Science.gov (United States)

    Guhathakurta, Bhargab; Pradhan, Ankur Bikash; Das, Suman; Bandyopadhyay, Nirmalya; Lu, Liping; Zhu, Miaoli; Naskar, Jnan Prakash

    2017-02-01

    Two osazone based ligands, butane-2,3-dione bis(2‧-pyridylhydrazone) (BDBPH) and hexane-3,4-dione bis(2‧-pyridylhydrazone) (HDBPH), were synthesized out of the 2:1 M Schiff base condensation of 2-hydrazino pyridine respectively with 2,3-butanedione and 3,4-hexanedione. The X-ray crystal structures of both the ligands have been determined. The copper(II) complex of HDBPH has also been synthesized and structurally characterized. HDBPH and its copper(II) complex have thoroughly been characterized through various spectroscopic and analytical techniques. The X-ray crystal structure of the copper complex of HDBPH shows that it is a monomeric Cu(II) complex having 'N4O2' co-ordination chromophore. Interaction of human serum albumin (HSA) with these ligands and their monomeric copper(II) complexes have been studied by various spectroscopic means. The experimental findings show that the ligands as well as their copper complexes are good HSA binders. Molecular docking investigations have also been done to unravel the mode of binding of the species with HSA.

  3. Cell surface expression and function of the macromolecular C1 complex on the surface of human monocytes

    Directory of Open Access Journals (Sweden)

    Kinga K Hosszu

    2012-03-01

    Full Text Available The synthesis of the subunits of the C1 complex (C1q, C1s, C1r, and its regulator C1 inhibitor (C1-Inh by human monocytes has been previously established. However, surface expression of these molecules by monocytes has not been shown. Using flow cytometry and antigen-capture ELISA, we show here for the first time that, in addition to C1q, PB monocytes and the monocyte-derived U937 cells express C1s and C1r, as well as Factor B and C1-Inh on their surface. C1s and C1r immunoprecipitated with C1q, suggesting that at least some of the C1q on these cells is part of the C1 complex. Furthermore, the C1 complex on U937 cells was able to trigger complement activation via the classical pathway. The presence of C1-Inh may ensure that an unwarranted autoactivation of the C1 complex does not take place. Since C1-Inh closely monitors the activation of the C1 complex in a sterile or infectious inflammatory environment, further elucidation of the role of C1 complex is crucial to dissect its function in monocyte, DC and T cell activities, and its implications in host defense and tolerance.

  4. Synthesis, characterization and the interaction of some new water-soluble metal Schiff base complexes with human serum albumin.

    Science.gov (United States)

    Asadi, Mozaffar; Asadi, Zahra; Sadi, Somaye Barzegar; Zarei, Leila; Baigi, Fatemeh Moosavi; Amirghofran, Zahra

    2014-03-25

    Some new water-soluble Schiff base complexes of Na2[M(L)(H2O)n]; (M=Zn, Cu, Ni, Mn) with a new water-soluble Schiff base ligand where L denotes an asymmetric N2O2 Schiff base ligands; N,N'-bis(5-sulfosalicyliden)-3,4-diaminobenzophenone (5-SO3-3,4-salbenz) were synthesized and characterized. The formation constants of the water soluble Schiff base complexes were calculated by Ketelaar's equation. The theoretical molecular structure for the complexes was computed by using the HF method and the 6-311G basis set. The mechanism of binding of Na2[M(L)(H2O)n] with human serum albumin (HSA) was studied by fluorescence spectroscopic technique. The results of fluorescence titration showed that the intrinsic fluorescence of HSA was quenched by the complexes; which was rationalized in terms of the dynamic quenching mechanism. The values of Stern-Volmer constants, quenching rate constants, binding constants, binding sites and average aggregation number of HSA have been determined. The thermodynamic parameters, were calculated by van't Hoff equation, indicate that the binding is entropy driven and enthalpically disfavored. Based on the Förster theory of non-radiation energy transfer, the efficiency of energy transfer and the distance between the donor (Trp residues) and the acceptor (complex) were obtained. Finally, the growth inhibitory effects of the complexes toward the K562 cancer cell line were measured.

  5. Targeting Androgen Receptor/Src Complex Impairs the Aggressive Phenotype of Human Fibrosarcoma Cells

    OpenAIRE

    Gabriella Castoria; Pia Giovannelli; Marzia Di Donato; Ryo Hayashi; Claudio Arra; Ettore Appella; Ferdinando Auricchio; Antimo Migliaccio

    2013-01-01

    BACKGROUND: Hormones and growth factors influence the proliferation and invasiveness of human mesenchymal tumors. The highly aggressive human fibrosarcoma HT1080 cell line harbors classical androgen receptor (AR) that responds to androgens triggering cell migration in the absence of significant mitogenesis. As occurs in many human cancer cells, HT1080 cells also express epidermal growth factor receptor (EGFR). EXPERIMENTAL: FINDINGS: We report that the pure anti-androgen Casodex inhibits the...

  6. Crystal structure of the FK506 binding domain of human FKBP25 in complex with FK506.

    Science.gov (United States)

    Prakash, Ajit; Rajan, Sreekanth; Yoon, Ho Sup

    2016-04-01

    Human FKBP25 (hFKBP25) is a nuclear immunophilin and interacts with several nuclear proteins, hence involving in many nuclear events. Similar to other FKBPs, FK506 binding domain (FKBD) of hFKBP25 also binds to immunosuppressive drugs such as rapamycin and FK506, albeit with a lower affinity for the latter. The molecular basis underlying this difference in affinity could not be addressed due to the lack of the crystal structure of hFKBD25 in complex with FK506. Here, we report the crystal structure of hFKBD25 in complex with FK506 determined at 1.8 Å resolution and its comparison with the hFKBD25-rapamycin complex, bringing out the microheterogeneity in the mode of interaction of these drugs, which could possibly explain the lower affinity for FK506.

  7. A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes

    DEFF Research Database (Denmark)

    Hansen, Kasper Lage; Hansen, Niclas Tue; Karlberg, Erik, Olof, Linnart

    2008-01-01

    Heritable diseases are caused by germ-line mutations that, despite tissuewide presence, often lead to tissue-specific pathology. Here, we make a systematic analysis of the link between tissue-specific gene expression and pathological manifestations in many human diseases and cancers. Diseases were...... to be overexpressed in the normal tissues where defects cause pathology. In contrast, cancer genes and complexes were not overexpressed in the tissues from which the tumors emanate. We specifically identified a complex involved in XY sex reversal that is testis-specific and down-regulated in ovaries. We also...... identified complexes in Parkinson disease, cardiomyopathies, and muscular dystrophy syndromes that are similarly tissue specific. Our method represents a conceptual scaffold for organism-spanning analyses and reveals an extensive list of tissue-specific draft molecular pathways, both known and unexpected...

  8. Members of the Candida parapsilosis complex and Candida albicans are differentially recognized by human peripheral blood mononuclear cells

    Directory of Open Access Journals (Sweden)

    Eine eEstrada-Mata

    2016-01-01

    Full Text Available The systemic infections caused by members of the Candida parapsilosis complex are currently associated to high mobility and mortality rates, and are considered as relevant as those caused by Candida albicans. Since the fungal cell wall is the first point of contact with the host cells, here we performed a comparison of this organelle in members of the C. parapsilosis complex, and its relevance during interaction with human peripheral blood mononuclear cells. We found that the wall of the C. parapsilosis complex members is similar in composition, but differs to that from C. albicans, with less mannan content and more β-glucan and porosity levels. Furthermore, lectin-based analysis showed increased chitin and β1,3-glucan exposure at the surface of C. parapsilosis sensu lato when compared to C. albicans. Yeast cells of members of the C. parapsilosis complex stimulated more cytokine production by human peripheral blood mononuclear cells than C. albicans cells; and this significantly changed upon removal of O-linked mannans, indicating this wall component plays a significant role in cytokine stimulation by C. parapsilosis sensu lato. When inner wall components were exposed on the wall surface, C. parapsilosis sensu stricto and C. metapsilosis, but not C. orthopsilosis, stimulated higher cytokine production. Moreover, we found a strong dependency on β1,3-glucan recognition for the members of the C. parapsilosis complex, but not for live C. albicans cells; whereas TLR4 was required for TNFα production by the three members of the complex, and stimulation of IL-6 by C. orthopsilosis. Mannose receptor had a significant role during TNF and IL-1β stimulation by members of the complex. Finally, we demonstrated that purified N- and O-mannans from either C. parapsilosis sensu lato or C. albicans are capable to block the recognition of these pathogens by human peripheral blood mononuclear cells. Together; our results suggest that the innate immune

  9. Members of the Candida parapsilosis Complex and Candida albicans are Differentially Recognized by Human Peripheral Blood Mononuclear Cells.

    Science.gov (United States)

    Estrada-Mata, Eine; Navarro-Arias, María J; Pérez-García, Luis A; Mellado-Mojica, Erika; López, Mercedes G; Csonka, Katalin; Gacser, Attila; Mora-Montes, Héctor M

    2015-01-01

    The systemic infections caused by members of the Candida parapsilosis complex are currently associated to high morbility and mortality rates, and are considered as relevant as those caused by Candida albicans. Since the fungal cell wall is the first point of contact with the host cells, here we performed a comparison of this organelle in members of the C. parapsilosis complex, and its relevance during interaction with human peripheral blood mononuclear cells (PBMCs). We found that the wall of the C. parapsilosis complex members is similar in composition, but differs to that from C. albicans, with less mannan content and more β-glucan and porosity levels. Furthermore, lectin-based analysis showed increased chitin and β1,3-glucan exposure at the surface of C. parapsilosis sensu lato when compared to C. albicans. Yeast cells of members of the C. parapsilosis complex stimulated more cytokine production by human PBMCs than C. albicans cells; and this significantly changed upon removal of O-linked mannans, indicating this wall component plays a significant role in cytokine stimulation by C. parapsilosis sensu lato. When inner wall components were exposed on the wall surface, C. parapsilosis sensu stricto and C. metapsilosis, but not C. orthopsilosis, stimulated higher cytokine production. Moreover, we found a strong dependency on β1,3-glucan recognition for the members of the C. parapsilosis complex, but not for live C. albicans cells; whereas TLR4 was required for TNFα production by the three members of the complex, and stimulation of IL-6 by C. orthopsilosis. Mannose receptor had a significant role during TNFα and IL-1β stimulation by members of the complex. Finally, we demonstrated that purified N- and O-mannans from either C. parapsilosis sensu lato or C. albicans are capable to block the recognition of these pathogens by human PBMCs. Together; our results suggest that the innate immune recognition of the members of the C. parapsilosis complex is differential

  10. Detection of long-lived bound water molecules in complexes of human dihydrofolate reductase with methotrexate and NADPH.

    Science.gov (United States)

    Meiering, E M; Wagner, G

    1995-03-24

    The locations of long-lived bound water molecules in the binary complex of human dihydrofolate reductase (hDHFR) with methotrexate (MTX) and the ternary complex of hDHFR with MTX and NADPH have been investigated using 15N-resolved, three-dimensional ROESY-HMQC and NOESY-HSQC spectra acquired at 25 degrees C and 8 degrees C. NOEs with NH groups of the protein are detected for five bound water molecules in the binary complex and six bound water molecules in the ternary complex. Inspection of crystal structures of hDHFR reveals that the bound water molecules perform structural and functional roles in the complexes. Two water molecules located outside the active site, WatA and WatB, have similar NOEs in the binary and ternary complexes. These water molecules from multiple hydrogen bonds bridging loops and/or secondary structural elements in crystal structures of hDHFR and so stabilize the tertiary fold of the enzyme. Two water molecules in the active site, WatC and WatD, also have similar NOEs in both complexes. In crystal structures of hDHFR, WatC is involved in MTX binding by forming hydrogen bonds to the ligand and protein, while WatD stabilizes WatC by hydrogen bonding to it and the protein. A third active-site water molecule, WatE, has a markedly stronger NOE in the ternary complex than in the binary complex. Differences in the binding of WatE in the binary and ternary complexes are important for understanding the mechanism of DHFR, since this water molecule is believed to be involved in substrate protonation. Although the increased NOE intensity for WatE could be caused by a change in the position of water molecule, it may also be caused by an increase in its lifetime, since structural fluctuations in the active site are decreased upon cofactor binding. NOEs for one other water molecule, WatF, may be observed in the ternary complex but not the binary complex. WatF forms hydrogen bonds bridging the cofactor and the protein in crystal structures of hDHFR.

  11. Contributions for the construction of a science: transdisciplinary, critical, human and complex

    Directory of Open Access Journals (Sweden)

    Hernán Fair

    2013-12-01

    Full Text Available The paper makes some reflections to contribute to the development of a complex thought in science. Starting from a transdisciplinary framework based on the Edgar Morin´s epistemology of complexity, complemented with some conceptual tools of post-Marxist theory of Ernesto Laclau and Chantal Mouffe, examines the theoretical, ethical-political and epistemological basic criterias to think about a new complex science that promotes a radicalized political critique and a explicit recognition of the subjective values, ​​without losing the rigor and the relative autonomy of scientific knowledge.

  12. The CARD11-BCL10-MALT1 (CBM) signalosome complex: Stepping into the limelight of human primary immunodeficiency.

    Science.gov (United States)

    Turvey, Stuart E; Durandy, Anne; Fischer, Alain; Fung, Shan-Yu; Geha, Raif S; Gewies, Andreas; Giese, Thomas; Greil, Johann; Keller, Bärbel; McKinnon, Margaret L; Neven, Bénédicte; Rozmus, Jacob; Ruland, Jürgen; Snow, Andrew L; Stepensky, Polina; Warnatz, Klaus

    2014-08-01

    Next-generation DNA sequencing has accelerated the genetic characterization of many human primary immunodeficiency diseases (PIDs). These discoveries can be lifesaving for the affected patients and also provide a unique opportunity to study the effect of specific genes on human immune function. In the past 18 months, a number of independent groups have begun to define novel PIDs caused by defects in the caspase recruitment domain family, member 11 (CARD11)-B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1 [CBM]) signalosome complex. The CBM complex forms an essential molecular link between the triggering of cell-surface antigen receptors and nuclear factor κB activation. Germline mutations affecting the CBM complex are now recognized as the cause of novel combined immunodeficiency phenotypes, which all share abnormal nuclear factor κB activation and dysregulated B-cell development as defining features. For this "Current perspectives" article, we have engaged experts in both basic biology and clinical immunology to capture the worldwide experience in recognizing and managing patients with PIDs caused by CBM complex mutations.

  13. Comparative Genomic Analyses of the Human NPHP1 Locus Reveal Complex Genomic Architecture and Its Regional Evolution in Primates.

    Directory of Open Access Journals (Sweden)

    Bo Yuan

    2015-12-01

    Full Text Available Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100 is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases-about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via nonallelic homologous recombination (NAHR between two flanking directly oriented ~45 kb LCRs. Published data revealed a non-pathogenic inversion polymorphism involving the NPHP1 gene flanked by two inverted ~358 kb LCRs. Using optical mapping and array-comparative genomic hybridization, we identified three potential novel structural variant (SV haplotypes at the NPHP1 locus that may protect a haploid genome from the NPHP1 deletion. Inter-species comparative genomic analyses among primate genomes revealed massive genomic changes during evolution. The aggregated data suggest that dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may confer differential susceptibility to genomic instability and the NPHP1 deletion within a personal genome. Our study documents diverse SV haplotypes at a complex LCR-laden human genomic region. Comparative analyses provide a model for how this complex region arose during primate evolution, and studies among humans suggest that intra-species polymorphism may potentially modulate an individual's susceptibility to acquiring disease-associated alleles.

  14. Effect of the Schiff base complex diaqua-(N-salicylidene-l-glutamato)copper(II) monohydrate on human tumor cells.

    Science.gov (United States)

    Konarikova, Katarina; Andrezalova, Lucia; Rapta, Peter; Slovakova, Marianna; Durackova, Zdenka; Laubertova, Lucia; Gbelcova, Helena; Danisovic, Lubomir; Bohmer, Daniel; Ruml, Tomas; Sveda, Martin; Zitnanova, Ingrid

    2013-12-05

    The aim of our study was to estimate cytostatic/cytotoxic activity of the copper(II) Schiff base complex of the composition [Cu(N-salicylidene-l-glutamato)(H2O)2]·H2O, further Cu(SG-L)H2O, against human colon carcinoma cell line HT-29, as well as to determine type of cell death and to find out the molecular mechanism of apoptosis induced by this complex. Two highest concentrations (50, 100 µmol/l) of the complex showed a strong cytotoxic activity against human colon carcinoma cells HT-29 after 72 h of influence. Other concentrations had a cytostatic activity. Unchelated copper(II) ions and free ligands had no effect on the cell growth. Cu(SG-L)H2O preferentially reduced cancer cell viability compared to healthy cells (NIH-3T3). Cu(SG-L)H2O induced apoptosis of cells HT-29 at all concentrations used (1-100 µmol/l) after 48 h of influence. Apoptosis was carried out by the mitochondrial pathway with active caspases 3 and 9. By the spin-trapping technique combined with electron paramagnetic resonance we found that our complex is photochemically stable in aqueous systems and does not exhibit radical-scavenging activity when 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) cation radical was used as an oxidant. The complex exhibits a strong prooxidant property in the initial stages of thermal decomposition of K2S2O8 in water solutions leading to the massive production of (·)OH radicals. Therefore, this complex could strongly participate in anticancer action via a free radical mechanism.

  15. Sitting is the new smoking : online complex human activity recognition with smartphones and wearables

    NARCIS (Netherlands)

    Shoaib, Muhammad

    2017-01-01

    Human activity recognition plays an important role in fitness tracking, health monitoring, context-aware feedback and self-management of smartphones and wearable devices. These devices are equipped with different sensors which can be used to recognize various human activities. A significant amount of

  16. Human Caring in the Social Work Context: Continued Development and Validation of a Complex Measure

    Science.gov (United States)

    Ellis, Jacquelyn I.; Ellett, Alberta J.; DeWeaver, Kevin

    2007-01-01

    Objectives: (a) to continue the development of a measure of human caring in the context of social work practice and (b) to expand a line of inquiry exploring the relationship between human caring characteristics and the retention of public child welfare workers. Methodology: Surveys were received from a sample (n = 786) child welfare workers in…

  17. Representation of head-centric flow in the human motion complex.

    NARCIS (Netherlands)

    Goossens, J.; Dukelow, S.P.; Menon, R.S.; Vilis, T.; Berg, A.V. van den

    2006-01-01

    Recent neuroimaging studies have identified putative homologs of macaque middle temporal area (area MT) and medial superior temporal area (area MST) in humans. Little is known about the integration of visual and nonvisual signals in human motion areas compared with monkeys. Through extra-retinal sig

  18. DNA methylation profiling of the human major histocompatibility complex: a pilot study for the human epigenome project.

    OpenAIRE

    Rakyan, Vardhman K.; Thomas Hildmann; Novik, Karen L; Jörn Lewin; Jörg Tost; Antony V Cox; T Dan Andrews; Howe, Kevin L.; Thomas Otto; Alexander Olek; Judith Fischer; Gut, Ivo G.; Kurt Berlin; Stephan Beck

    2004-01-01

    The Human Epigenome Project aims to identify, catalogue, and interpret genome-wide DNA methylation phenomena. Occurring naturally on cytosine bases at cytosine–guanine dinucleotides, DNA methylation is intimately involved in diverse biological processes and the aetiology of many diseases. Differentially methylated cytosines give rise to distinct profiles, thought to be specific for gene activity, tissue type, and disease state. The identification of such methylation variable positions will si...

  19. Effect of meditation on scaling behavior and complexity of human heart rate variability

    OpenAIRE

    Sarkar, A.; Barat, P.

    2006-01-01

    The heart beat data recorded from samples before and during meditation are analyzed using two different scaling analysis methods. These analyses revealed that mediation severely affects the long range correlation of heart beat of a normal heart. Moreover, it is found that meditation induces periodic behavior in the heart beat. The complexity of the heart rate variability is quantified using multiscale entropy analysis and recurrence analysis. The complexity of the heart beat during mediation ...

  20. Effect of meditation on scaling behavior and complexity of human heart rate variability

    CERN Document Server

    Sarkar, A

    2006-01-01

    The heart beat data recorded from samples before and during meditation are analyzed using two different scaling analysis methods. These analyses revealed that mediation severely affects the long range correlation of heart beat of a normal heart. Moreover, it is found that meditation induces periodic behavior in the heart beat. The complexity of the heart rate variability is quantified using multiscale entropy analysis and recurrence analysis. The complexity of the heart beat during mediation is found to be more.

  1. LUPA: a European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs.

    Science.gov (United States)

    Lequarré, Anne-Sophie; Andersson, Leif; André, Catherine; Fredholm, Merete; Hitte, Christophe; Leeb, Tosso; Lohi, Hannes; Lindblad-Toh, Kerstin; Georges, Michel

    2011-08-01

    The domestic dog offers a unique opportunity to explore the genetic basis of disease, morphology and behaviour. Humans share many diseases with our canine companions, making dogs an ideal model organism for comparative disease genetics. Using newly developed resources, genome-wide association studies in dog breeds are proving to be exceptionally powerful. Towards this aim, veterinarians and geneticists from 12 European countries are collaborating to collect and analyse the DNA from large cohorts of dogs suffering from a range of carefully defined diseases of relevance to human health. This project, named LUPA, has already delivered considerable results. The consortium has collaborated to develop a new high density single nucleotide polymorphism (SNP) array. Mutations for four monogenic diseases have been identified and the information has been utilised to find mutations in human patients. Several complex diseases have been mapped and fine mapping is underway. These findings should ultimately lead to a better understanding of the molecular mechanisms underlying complex diseases in both humans and their best friend.

  2. hELP3 Subunit of the Elongator Complex Regulates the Transcription of HSP70 Gene in Human Cells

    Institute of Scientific and Technical Information of China (English)

    Qiuju HAN; Xiaozhe HOU; Dongmei SU; Lina PAN; Jizhou DUAN; Liguo CUI; Baiqu HUANG; Jun LU

    2007-01-01

    The human Elongator complex is remarkably similar to its yeast counterpart in several aspects.In a previous study, we analyzed the functions of the human elongation protein 3 (hELP3) subunit of the human Elongator by using an in vivo yeast complementation system. However, direct evidence for hELP3 functions in regulating gene expression in human cells was not obtained. In this study, we used hELP3 antisense oligonucleotide inhibitors to knock down hELP3 gene expression to investigate its function in human 293T cells. The results showed that specific reduction of hELP3 mRNA and protein caused a significant suppression of HSP70-2 gene expression, and this was accompanied by histone H3 hypoacetylation and decreased RNA polymerase Ⅱ density at the HSP70-2 gene. Moreover, the data also showed that hELP3 exerted the transcriptional regulatory function directly through its presence on the HSP70-2 gene. Data presented in this report provide further insight and direct evidence of the functions of hELP3 in HSP70-2 gene transcriptional elongation in human cells.

  3. Drosophila and genome-wide association studies: a review and resource for the functional dissection of human complex traits

    Science.gov (United States)

    Wangler, Michael F.; Hu, Yanhui

    2017-01-01

    ABSTRACT Human genome-wide association studies (GWAS) have successfully identified thousands of susceptibility loci for common diseases with complex genetic etiologies. Although the susceptibility variants identified by GWAS usually have only modest effects on individual disease risk, they contribute to a substantial burden of trait variation in the overall population. GWAS also offer valuable clues to disease mechanisms that have long proven to be elusive. These insights could lead the way to breakthrough treatments; however, several challenges hinder progress, making innovative approaches to accelerate the follow-up of results from GWAS an urgent priority. Here, we discuss the largely untapped potential of the fruit fly, Drosophila melanogaster, for functional investigation of findings from human GWAS. We highlight selected examples where strong genomic conservation with humans along with the rapid and powerful genetic tools available for flies have already facilitated fine mapping of association signals, elucidated gene mechanisms, and revealed novel disease-relevant biology. We emphasize current research opportunities in this rapidly advancing field, and present bioinformatic analyses that systematically explore the applicability of Drosophila for interrogation of susceptibility signals implicated in more than 1000 human traits, based on all GWAS completed to date. Thus, our discussion is targeted at both human geneticists seeking innovative strategies for experimental validation of findings from GWAS, as well as the Drosophila research community, by whom ongoing investigations of the implicated genes will powerfully inform our understanding of human disease. PMID:28151408

  4. Comprehension and utilisation of pointing gestures and gazing in dog-human communication in relatively complex situations.

    Science.gov (United States)

    Lakatos, Gabriella; Gácsi, Márta; Topál, József; Miklósi, Adám

    2012-03-01

    The aim of the present investigation was to study the visual communication between humans and dogs in relatively complex situations. In the present research, we have modelled more lifelike situations in contrast to previous studies which often relied on using only two potential hiding locations and direct association between the communicative signal and the signalled object. In Study 1, we have provided the dogs with four potential hiding locations, two on each side of the experimenter to see whether dogs are able to choose the correct location based on the pointing gesture. In Study 2, dogs had to rely on a sequence of pointing gestures displayed by two different experimenters. We have investigated whether dogs are able to recognise an 'indirect signal', that is, a pointing toward a pointer. In Study 3, we have examined whether dogs can understand indirect information about a hidden object and direct the owner to the particular location. Study 1 has revealed that dogs are unlikely to rely on extrapolating precise linear vectors along the pointing arm when relying on human pointing gestures. Instead, they rely on a simple rule of following the side of the human gesturing. If there were more targets on the same side of the human, they showed a preference for the targets closer to the human. Study 2 has shown that dogs are able to rely on indirect pointing gestures but the individual performances suggest that this skill may be restricted to a certain level of complexity. In Study 3, we have found that dogs are able to localise the hidden object by utilising indirect human signals, and they are able to convey this information to their owner.

  5. Distribution of class ii major histocompatibility complex antigenexpressing cells in human dental pulp with carious lesions

    Directory of Open Access Journals (Sweden)

    Tetiana Haniastuti

    2012-09-01

    Full Text Available Background: Dental caries is a bacterial infection which causes destruction of the hard tissues of the tooth. Exposure of the dentin to the oral environment as a result of caries inevitably results in a cellular response in the pulp. The major histocompatibility complex (MHC is a group of genes that code for cell-surface histocompatibility antigens. Cells expressing class II MHC molecules participate in the initial recognition and the processing of antigenic substances to serve as antigen-presenting cells. Purpose: The aim of the study was to elucidate the alteration in the distribution of class II MHC antigen-expressing cells in human dental pulp as carious lesions progressed toward the pulp. Methods: Fifteen third molars with caries at the occlusal site at various stages of decay and 5 intact third molars were extracted and used in this study. Before decalcifying with 10% EDTA solution (pH 7.4, all the samples were observed by micro-computed tomography to confirm the lesion condition three-dimensionally. The specimens were then processed for cryosection and immunohistochemistry using an anti-MHC class II monoclonal antibody. Results: Class II MHC antigen-expressing cells were found both in normal and carious specimens. In normal tooth, the class II MHC-immunopositive cells were observed mainly at the periphery of the pulp tissue. In teeth with caries, class II MHC-immunopositive cells were located predominantly subjacent to the carious lesions. As the caries progressed, the number of class II MHC antigen-expressing cells was increased. Conclusion: The depth of carious lesions affects the distribution of class II MHC antigen-expressing cells in the dental pulp.Latar belakang: Karies merupakan penyakit infeksi bakteri yang mengakibatkan destruksi jaringan keras gigi. Dentin yang terbuka akibat karies akan menginduksi respon imun seluler pada pulpa. Kompleks histokompatibilitas utama (MHC merupakan sekumpulan gen yang mengkode histokompatibilitas

  6. Staphylococcus aureus complex from animals and humans in three remote African regions.

    Science.gov (United States)

    Schaumburg, Frieder; Pauly, Maude; Anoh, Etile; Mossoun, Arsene; Wiersma, Lidewij; Schubert, Grit; Flammen, Arnaud; Alabi, Abraham S; Muyembe-Tamfum, Jean-Jacques; Grobusch, Martin P; Karhemere, Stomy; Akoua-Koffi, Chantal; Couacy-Hymann, Emmanuel; Kremsner, Peter G; Mellmann, Alexander; Becker, Karsten; Leendertz, Fabian H; Peters, Georg

    2015-04-01

    Staphylococcus schweitzeri has been recently considered to be a highly divergent Staphylococcus aureus clade and usually colonises nonhuman primates and bats in sub-Saharan Africa. Its transmissibility to humans remains unclear. We therefore investigated the transmission of S. aureus and S. schweitzeri among humans, domestic animals, and wildlife in three remote African regions. A cross-sectional study on nasal and pharyngeal colonisation in humans (n = 1288) and animals (n = 698) was performed in Côte d'Ivoire, Gabon, and Democratic Republic of Congo (DR Congo). Isolates were subjected to spa typing and multilocus sequence typing. Antimicrobial susceptibility and selected virulence factors were tested. S. schweitzeri was found in monkeys from all study sites but no transmission to humans was evident, despite frequent contact of humans with wildlife. In contrast, human-associated S. aureus sequence types (ST1, ST6, ST15) were detected in domestic animals and nonhuman primates, pointing toward a human-to-monkey transmission in the wild. The proportion of methicillin-resistant S. aureus (MRSA) among all S. aureus was 0% (Gabon), 1.7% (DR Congo), and 5.3% (Côte d'Ivoire). The majority of MRSA isolates belonged to the African clone ST88. In conclusion, we did not find any evidence for a transmission of S. schweitzeri from animals to humans. However, such a transmission might remain possible due to the close phylogenetic relation of humans and nonhuman primates. The ST88-MRSA clone was widespread in Côte d'Ivoire but not in Gabon and DR Congo.

  7. A SAR study of novel antiproliferative ruthenium and osmium complexes with quinoxalinone ligands in human cancer cell lines.

    Science.gov (United States)

    Ginzinger, Werner; Mühlgassner, Gerhard; Arion, Vladimir B; Jakupec, Michael A; Roller, Alexander; Galanski, Markus; Reithofer, Michael; Berger, Walter; Keppler, Bernhard K

    2012-04-12

    A series of ruthenium(II) arene complexes with 3-(1H-benzimidazol-2-yl)-1H-quinoxalin-2-one, bearing pharmacophoric groups of known protein kinase inhibitors, and related benzoxazole and benzothiazole derivatives have been synthesized. In addition, the corresponding osmium complexes of the unsubstituted ligands have also been prepared. The compounds have been characterized by NMR, UV-vis, and IR spectroscopy, ESI mass spectrometry, elemental analysis, and by X-ray crystallography. Antiproliferative activity in three human cancer cell lines (A549, CH1, SW480) was determined by MTT assays, yielding IC(50) values of 6-60 μM for three unsubstituted metal-free ligands, whereas values for the metal complexes vary in a broad range from 0.3 to 140 μM. Complexation with osmium of quinoxalinone derivatives with benzimidazole or benzothiazole results in a more consistent increase in cytotoxicity than complexation with ruthenium. For selected compounds, the capacity to induce apoptosis was confirmed by fluorescence microscopy and flow-cytometric analysis, whereas cell cycle effects are only moderate.

  8. Structural Determinants of Human FANCF Protein That Function in the Assembly of a DNA Damage Signaling Complex

    Energy Technology Data Exchange (ETDEWEB)

    Kowal,P.; Gurtan, A.; Stuckert, P.; D' Andrea, A.; Ellenberger, T.

    2007-01-01

    Fanconi anemia (FA) is a rare autosomal recessive and X-linked chromosomal instability disorder. At least eight FA proteins (FANCA, B, C, E, F, G, L, and M) form a nuclear core complex required for monoubiquitination of a downstream protein, FANCD2. The human FANCF protein reportedly functions as a molecular adaptor within the FA nuclear complex, bridging between the subcomplexes A:G and C:E. Our x-ray crystallographic studies of the C-terminal domain of FANCF reveal a helical repeat structure similar to the Cand1 regulator of the Cul1-Rbx1-Skp1-Fbox(Skp2) ubiquitin ligase complex. Two C-terminal loops of FANCF are essential for monoubiquitination of FANCD2 and normal cellular resistance to the DNA cross-linking agent mitomycin C. FANCF mutants bearing amino acid substitutions in this C-terminal surface fail to interact with other components of the FA complex, indicating that this surface is critical for the proper assembly of the FA core complex.

  9. Organization of human interferon gamma-heparin complexes from solution properties and hydrodynamics.

    Science.gov (United States)

    Perez Sanchez, Horacio; Tatarenko, Karine; Nigen, Michael; Pavlov, Georges; Imberty, Anne; Lortat-Jacob, Hugues; Garcia de la Torre, Jose; Ebel, Christine

    2006-11-01

    Heparan sulfate (HS) recognizes a variety of proteins, one of which is the pleiotropic cytokine IFN-gamma, and as such modulates many biological processes. IFN-gamma is a homodimer with a well-defined core and two flexible C-termini that constitute HS binding domains. We show here using molecular modeling that an extended IFN-gamma structure overlaps a HS fragment of 16 disaccharides (16 nm). Since a 21-24-disaccharide HS fragment was experimentally defined as the minimum size that interacts with IFN-gamma [Lortat-Jacob, H., Turnbull, J. E., and Grimaud, J. A. (1995) Biochem. J. 310 (Part 2), 497-505], this raises the question of the complexe organization. We combine analytical ultracentrifugation, size exclusion chromatography, and hydrodynamic bead modeling to characterize the complexes formed in solution with heparin oligosaccharides. For oligosaccharides of 14 and 20 nm, two types of complexes are formed with one IFN-gamma and one or two heparin molecules. Complexes consisting of two IFN-gamma and one or two heparin molecules are present for a fragment of 25 nm and aggregates for a fragment of 35 nm. The complexes are rather compact and can be formed without major conformational changes of the partners. The complex pattern of interaction is related to the size of the partners and their multiple binding possibilities. These various possibilities suggest networks of interactions at the crowded surface of the cells. Hydrodynamic methods used here proved to be very efficient tools for describing protein-HS complexes that, due to the intrinsic heterogeneity and flexibility of the partners, are otherwise very difficult to analyze.

  10. Performance improvement through best practice team management: human factors in complex trauma.

    Science.gov (United States)

    Mercer, Simon; Arul, G S; Pugh, H E J

    2014-06-01

    Human factors or non-technical skills are now commonplace in the medical literature, having taken the lead from the airline and nuclear industries and more recently Formula One motor racing. They have been suggested as playing a vital role in the success of the trauma teams in recent conflicts. This article outlines the background to human factors, referring to early papers and reports and also outlines high profile cases that highlight their importance. We then describe the importance of human factors in the deployed setting and some of the lessons that have been learnt from current conflicts.

  11. Structure and function of human α-lactalbumin made lethal to tumor cells (HAMLET)-type complexes.

    Science.gov (United States)

    Mossberg, Ann-Kristin; Hun Mok, Kenneth; Morozova-Roche, Ludmilla A; Svanborg, Catharina

    2010-11-01

    Human α-lactalbumin made lethal to tumor cells (HAMLET) and equine lysozyme with oleic acid (ELOA) are complexes consisting of protein and fatty acid that exhibit cytotoxic activities, drastically differing from the activity of their respective proteinaceous compounds. Since the discovery of HAMLET in the 1990s, a wealth of information has been accumulated, illuminating the structural, functional and therapeutic properties of protein complexes with oleic acid, which is summarized in this review. In vitro, both HAMLET and ELOA are produced by using ion-exchange columns preconditioned with oleic acid. However, the complex of human α-lactalbumin with oleic acid with the antitumor activity of HAMLET was found to be naturally present in the acidic fraction of human milk, where it was discovered by serendipity. Structural studies have shown that α-lactalbumin in HAMLET and lysozyme in ELOA are partially unfolded, 'molten-globule'-like, thereby rendering the complexes dynamic and in conformational exchange. HAMLET exists in the monomeric form, whereas ELOA mostly exists as oligomers and the fatty acid stoichiometry varies, with HAMLET holding an average of approximately five oleic acid molecules, whereas ELOA contains a considerably larger number (11- 48). Potent tumoricidal activity is found in both HAMLET and ELOA, and HAMLET has also shown strong potential as an antitumor drug in different in vivo animal models and clinical studies. The gain of new, beneficial function upon partial protein unfolding and fatty acid binding is a remarkable phenomenon, and may reflect a significant generic route of functional diversification of proteins via varying their conformational states and associated ligands. © 2010 The Authors Journal compilation © 2010 FEBS.

  12. Structural and dynamical effects induced by the anticancer drug topotecan on the human topoisomerase I - DNA complex.

    Directory of Open Access Journals (Sweden)

    Giordano Mancini

    Full Text Available BACKGROUND: Human topoisomerase I catalyzes the relaxation of DNA supercoils in fundamental cell processes like transcription, replication and chromosomal segregation. It is the only target of the camptothecin family of anticancer drugs. Among these, topotecan has been used to treat lung and ovarian carcinoma for several years. Camptothecins reversibly binds to the covalent intermediate DNA-enzyme, stabilizing the cleavable complex and reducing the religation rate. The stalled complex then collides with the progression of the replication fork, producing lethal double strand DNA breaks and eventually cell death. METHODOLOGY/PRINCIPAL FINDINGS: Long lasting molecular dynamics simulations of the DNA-topoisomerase I binary complex and of the DNA-topoisomerase-topotecan ternary complex have been performed and compared. The conformational space sampled by the binary complex is reduced by the presence of the drug, as observed by principal component and cluster analyses. This conformational restraint is mainly due to the reduced flexibility of residues 633-643 (the region connecting the linker to the core domain that causes an overall mobility loss in the ternary complex linker domain. During the simulation, DNA/drug stacking interactions are fully maintained, and hydrogen bonds are maintained with the enzyme. Topotecan keeps the catalytic residue Lys532 far from the DNA, making it unable to participate to the religation reaction. Arg364 is observed to interact with both the B and E rings of topotecan with two stable direct hydrogen bonds. An interesting constrain exerted by the protein on the geometrical arrangement of topotecan is also observed. CONCLUSIONS/SIGNIFICANCE: Atomistic-scale understanding of topotecan interactions with the DNA-enzyme complex is fundamental to the explaining of its poisonous effect and of the drug resistance observed in several single residue topoisomerase mutants. We observed significant alterations due to topotecan in

  13. Power-law scaling for macroscopic entropy and microscopic complexity: Evidence from human movement and posture

    Science.gov (United States)

    Hong, S. Lee; Bodfish, James W.; Newell, Karl M.

    2006-03-01

    We investigated the relationship between macroscopic entropy and microscopic complexity of the dynamics of body rocking and sitting still across adults with stereotyped movement disorder and mental retardation (profound and severe) against controls matched for age, height, and weight. This analysis was performed through the examination of center of pressure (COP) motion on the mediolateral (side-to-side) and anteroposterior (fore-aft) dimensions and the entropy of the relative phase between the two dimensions of motion. Intentional body rocking and stereotypical body rocking possessed similar slopes for their respective frequency spectra, but differences were revealed during maintenance of sitting postures. The dynamics of sitting in the control group produced lower spectral slopes and higher complexity (approximate entropy). In the controls, the higher complexity found on each dimension of motion was related to a weaker coupling between dimensions. Information entropy of the relative phase between the two dimensions of COP motion and irregularity (complexity) of their respective motions fitted a power-law function, revealing a relationship between macroscopic entropy and microscopic complexity across both groups and behaviors. This power-law relation affords the postulation that the organization of movement and posture dynamics occurs as a fractal process.

  14. Abundance of sewage-pollution indicator and human pathogenic bacteria in a tropical estuarine complex

    Digital Repository Service at National Institute of Oceanography (India)

    Nagvenkar, G.S.; Ramaiah, N.

    Studies on abundance and types of various pollution indicator bacterial populations from tropical estuaries are rare. This study was aimed to estimate current levels of pollution indicator as well as many groups of human pathogenic bacteria...

  15. Can transcriptomics provide insight into the underlying chemopreventive mechanisms of complex mixtures of phytochemicals in humans?

    NARCIS (Netherlands)

    Breda, van S.G.; Wilms, L.C.; Gaj, S.; Briedé, J.J.; Helsper, J.P.F.G.; Kleinjans, J.C.; Kok, de T.M.

    2014-01-01

    Blueberries contain relatively large amounts of different phytochemicals which are suggested to have chemopreventive properties, but little information is available on the underlying molecular modes of action. This study investigates whole genome gene expression changes in lymphocytes of 143 humans

  16. Can transcriptomics provide insight into the underlying chemopreventive mechanisms of complex mixtures of phytochemicals in humans?

    NARCIS (Netherlands)

    Breda, van S.G.; Wilms, L.C.; Gaj, S.; Briedé, J.J.; Helsper, J.P.F.G.; Kleinjans, J.C.; Kok, de T.M.

    2014-01-01

    Blueberries contain relatively large amounts of different phytochemicals which are suggested to have chemopreventive properties, but little information is available on the underlying molecular modes of action. This study investigates whole genome gene expression changes in lymphocytes of 143 humans

  17. Risk managment of complex aquifers contaminated by chemical mixtures : numerical tools and human health risk assessment

    OpenAIRE

    Henri, Christopher

    2015-01-01

    Human impact on groundwater resources has led to a rapid growth of social concerns worldwide owing to an increasing presence of toxic chemicals released in the subsurface. Risk assessment provides the scientific tool needed to quantify the actual thread that these potential hazards pose to human health. Specifically, risk analysis enables decision makers to answer: What can happen? How likely is it to happen? What can be the consequences? Risk assessment is in this context essential. However,...

  18. The survival of mankind and human speciation in a complex astrobiological context

    Directory of Open Access Journals (Sweden)

    I. Valentin Petrescu-Mag

    2009-12-01

    Full Text Available The migration of Homo sapiens in the outer space brings one of the most significanenvironmental transformations in the history of a species. The astronomic isolation barrier is certainlystronger than the known geographic isolation. The future human colonies will split into new races,subspecies and finally new species. The survival of human civilization depends in a large extent onspread of these colonies outside our solar system and outside Milky Way.

  19. Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes

    Energy Technology Data Exchange (ETDEWEB)

    Samanta, Uttamkumar; Kirby, Stephen D.; Srinivasan, Prabhavathi; Cerasoli, Douglas M.; Bahnson, Brian J.; (Delaware); (USAMRIID)

    2009-09-02

    The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P{sub R} and P{sub S} stereoisomers at the P-chiral center. The tabun complex displayed only the P{sub R} stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents.

  20. Conformational heterogeneity of the protein-free human spliceosomal U2-U6 snRNA complex.

    Science.gov (United States)

    Zhao, Caijie; Bachu, Ravichandra; Popovic, Milena; Devany, Matthew; Brenowitz, Michael; Schlatterer, Jörg C; Greenbaum, Nancy L

    2013-04-01

    The complex formed between the U2 and U6 small nuclear (sn)RNA molecules of the eukaryotic spliceosome plays a critical role in the catalysis of precursor mRNA splicing. Here, we have used enzymatic structure probing, (19)F NMR, and analytical ultracentrifugation techniques to characterize the fold of a protein-free biophysically tractable paired construct representing the human U2-U6 snRNA complex. Results from enzymatic probing and (19)F NMR for the complex in the absence of Mg(2+) are consistent with formation of a four-helix junction structure as a predominant conformation. However, (19)F NMR data also identify a lesser fraction (up to 14% at 25°C) of a three-helix conformation. Based upon this distribution, the calculated ΔG for inter-conversion to the four-helix structure from the three-helix structure is approximately -4.6 kJ/mol. In the presence of 5 mM Mg(2+), the fraction of the three-helix conformation increased to ∼17% and the Stokes radius, measured by analytical ultracentrifugation, decreased by 2%, suggesting a slight shift to an alternative conformation. NMR measurements demonstrated that addition of an intron fragment to the U2-U6 snRNA complex results in displacement of U6 snRNA from the region of Helix III immediately 5' of the ACAGAGA sequence of U6 snRNA, which may facilitate binding of the segment of the intron adjacent to the 5' splice site to the ACAGAGA sequence. Taken together, these observations indicate conformational heterogeneity in the protein-free human U2-U6 snRNA complex consistent with a model in which the RNA has sufficient conformational flexibility to facilitate inter-conversion between steps of splicing in situ.

  1. Flawed Assumptions, Models and Decision Making: Misconceptions Concerning Human Elements in Complex System

    Energy Technology Data Exchange (ETDEWEB)

    FORSYTHE,JAMES C.; WENNER,CAREN A.

    1999-11-03

    The history of high consequence accidents is rich with events wherein the actions, or inaction, of humans was critical to the sequence of events preceding the accident. Moreover, it has been reported that human error may contribute to 80% of accidents, if not more (dougherty and Fragola, 1988). Within the safety community, this reality is widely recognized and there is a substantially greater awareness of the human contribution to system safety today than has ever existed in the past. Despite these facts, and some measurable reduction in accident rates, when accidents do occur, there is a common lament. No matter how hard we try, we continue to have accidents. Accompanying this lament, there is often bewilderment expressed in statements such as, ''There's no explanation for why he/she did what they did''. It is believed that these statements are a symptom of inadequacies in how they think about humans and their role within technological systems. In particular, while there has never been a greater awareness of human factors, conceptual models of human involvement in engineered systems are often incomplete and in some cases, inaccurate.

  2. Component co-expression and purification of recombinant human pyruvate dehydrogenase complex from baculovirus infected SF9 cells.

    Science.gov (United States)

    Jiang, Yong; Wang, Juan; Zhang, Guofeng; Oza, Khyati; Myers, Linda; Holbert, Marc A; Sweitzer, Sharon

    2014-05-01

    The mammalian pyruvate dehydrogenase complex (PDC) is a multi-component mitochondrial enzyme that plays a key role in the conversion of pyruvate to acetyl-CoA connecting glycolysis to the citric acid cycle. Recent studies indicate that targeting the regulation of PDC enzymatic activity might offer therapeutic opportunities by inhibiting cancer cell metabolism. To facilitate drug discovery in this area, a well defined PDC sample is needed. Here, we report a new method of producing functional, recombinant, high quality human PDC complex. All five components were co-expressed in the cytoplasm of baculovirus-infected SF9 cells by deletion of the mitochondrial localization signal sequences of all the components and E1a was FLAG-tagged to facilitate purification. The protein FLAG tagged E1a complex was purified using FLAG-M2 affinity resin, followed by Superdex 200 sizing chromatography. The E2 and E3BP components were then Lipoylated using an enzyme based in vitro process. The resulting PDC is over 90% pure and homogenous. This non-phosphorylated, lipoylated human PDC was demonstrated to produce a robust detection window when used to develop an enzyme coupled assay of PDHK.

  3. Predicting DNA-binding proteins and binding residues by complex structure prediction and application to human proteome.

    Directory of Open Access Journals (Sweden)

    Huiying Zhao

    Full Text Available As more and more protein sequences are uncovered from increasingly inexpensive sequencing techniques, an urgent task is to find their functions. This work presents a highly reliable computational technique for predicting DNA-binding function at the level of protein-DNA complex structures, rather than low-resolution two-state prediction of DNA-binding as most existing techniques do. The method first predicts protein-DNA complex structure by utilizing the template-based structure prediction technique HHblits, followed by binding affinity prediction based on a knowledge-based energy function (Distance-scaled finite ideal-gas reference state for protein-DNA interactions. A leave-one-out cross validation of the method based on 179 DNA-binding and 3797 non-binding protein domains achieves a Matthews correlation coefficient (MCC of 0.77 with high precision (94% and high sensitivity (65%. We further found 51% sensitivity for 82 newly determined structures of DNA-binding proteins and 56% sensitivity for the human proteome. In addition, the method provides a reasonably accurate prediction of DNA-binding residues in proteins based on predicted DNA-binding complex structures. Its application to human proteome leads to more than 300 novel DNA-binding proteins; some of these predicted structures were validated by known structures of homologous proteins in APO forms. The method [SPOT-Seq (DNA] is available as an on-line server at http://sparks-lab.org.

  4. A new platinum complex with tryptophan: synthesis, structural characterization, DFT studies and biological assays in vitro over human tumorigenic cells.

    Science.gov (United States)

    Carvalho, Marcos A; Shishido, Silvia M; Souza, Bárbara C; de Paiva, Raphael E F; Gomes, Alexandre F; Gozzo, Fábio C; Formiga, André L B; Corbi, Pedro P

    2014-03-25

    A new platinum(II) complex with the amino acid L-tryptophan (trp), named Pt-trp, was synthesized and characterized. Elemental, thermogravimetric and ESI-QTOF mass spectrometric analyses led to the composition [Pt(C11H11N2O2)2]⋅6H2O. Infrared spectroscopic data indicate the coordination of trp to Pt(II) through the oxygen of the carboxylate group and also through the nitrogen atom of the amino group. The (13)C CP/MAS NMR spectroscopic data confirm coordination through the oxygen atom of the carboxylate group, while the (15)N CP/MAS NMR data confirm coordination of the nitrogen of the NH2 group to the metal. Density functional theory (DFT) studies were applied to evaluate the cis and trans coordination modes of trp to platinum(II). The trans isomer was shown to be energetically more stable than the cis one. The Pt-trp complex was evaluated as a cytotoxic agent against SK-Mel 103 (human melanoma) and Panc-1 (human pancreatic carcinoma) cell lines. The complex was shown to be cytotoxic over the considered cells.

  5. Human macrophage responses to clinical isolates from the Mycobacterium tuberculosis complex discriminate between ancient and modern lineages.

    Directory of Open Access Journals (Sweden)

    Damien Portevin

    2011-03-01

    Full Text Available The aim of the present study was to determine whether there is a correlation between phylogenetic relationship and inflammatory response amongst a panel of clinical isolates representative of the global diversity of the human Mycobacterium tuberculosis Complex (MTBC. Measurement of cytokines from infected human peripheral blood monocyte-derived macrophages revealed a wide variation in the response to different strains. The same pattern of high or low response to individual strains was observed for different pro-inflammatory cytokines and chemokines, and was conserved across multiple human donors. Although each major phylogenetic lineage of MTBC included strains inducing a range of cytokine responses, we found that overall inflammatory phenotypes differed significantly across lineages. In particular, comparison of evolutionarily modern lineages demonstrated a significant skewing towards lower early inflammatory response. The differential response to ancient and modern lineages observed using GM-CSF derived macrophages was also observed in autologous monocyte-derived dendritic cells and murine bone marrow-derived macrophages, but not in human unfractionated peripheral blood mononuclear cells. We hypothesize that the reduced immune responses to modern lineages contribute to more rapid disease progression and transmission, which might be a selective advantage in the context of expanding human populations. In addition to the lineage effects, the large strain-to-strain variation in innate immune responses elicited by MTBC will need to be considered in tuberculosis vaccine development.

  6. Contributions and complexities from the use of in-vivo animal models to improve understanding of human neuroimaging signals.

    Directory of Open Access Journals (Sweden)

    Chris eMartin

    2014-08-01

    Full Text Available Many of the major advances in our understanding of how functional brain imaging signals relate to neuronal activity over the previous two decades have arisen from physiological research studies involving experimental animal models. This approach has been successful partly because it provides opportunities to measure both the hemodynamic changes that underpin many human functional brain imaging techniques and the neuronal activity about which we wish to make inferences. Although research into the coupling of neuronal and hemodynamic responses using animal models has provided a general validation of the correspondence of neuroimaging signals to specific types of neuronal activity, it is also highlighting the key complexities and uncertainties in estimating neural signals from hemodynamic markers. This review will detail how research in animal models is contributing to our rapidly evolving understanding of what human neuroimaging techniques tell us about neuronal activity. It will highlight emerging issues in the interpretation of neuroimaging data that arise from in-vivo research studies, for example spatial and temporal constraints to neuroimaging signal interpretation, or the effects of disease and modulatory neurotransmitters upon neurovascular coupling. We will also give critical consideration to the limitations and possible complexities of translating data acquired in the typical animals models used in this area to the arena of human fMRI. These include the commonplace use of anaesthesia in animal research studies and the fact that many neuropsychological questions that are being actively explored in humans have limited homologues within current animal models for neuroimaging research. Finally we will highlighting approaches, both in experimental animals models (e.g. imaging in conscious, behaving animals and human studies (e.g. combined fMRI-EEG, that mitigate against these challenges.

  7. Fractal analysis of the structural complexity of the connective tissue in human carotid bodies.

    Science.gov (United States)

    Guidolin, Diego; Porzionato, Andrea; Tortorella, Cinzia; Macchi, Veronica; De Caro, Raffaele

    2014-01-01

    The carotid body (CB) may undergo different structural changes during perinatal development, aging, or in response to environmental stimuli. In the previous literature, morphometric approaches to evaluate these changes have considered quantitative first order parameters, such as volumes or densities, while changes in spatial disposition and/or complexity of structural components have not yet been considered. In the present study, different strategies for addressing morphological complexity of CB, apart from the overall amount of each tissue component, were evaluated and compared. In particular, we considered the spatial distribution of connective tissue in the carotid bodies of young control subjects, young opiate-related deaths and aged subjects, through analysis of dispersion (Morisita's index), gray level co-occurrence matrix (entropy, angular second moment, variance, correlation), and fractal analysis (fractal dimension, lacunarity). Opiate-related deaths and aged subjects showed a comparable increase in connective tissue with respect to young controls. However, the Morisita's index (p lacunarity (p lacunarity, with areas under the ROC curve of 0.9651 (excellent accuracy) and 0.8835 (good accuracy), respectively, showed the highest discriminatory power. They evidenced higher level of structural complexity in the carotid bodies of opiate-related deaths than old controls, due to more complex branching of intralobular connective tissue. Further analyses will have to consider the suitability of these approaches to address other morphological features of the CB, such as different cell populations, vascularization, and innervation.

  8. Quantification of spatial structure of human proximal tibial bone biopsies using 3D measures of complexity

    DEFF Research Database (Denmark)

    Saparin, Peter I.; Thomsen, Jesper Skovhus; Prohaska, Steffen

    2005-01-01

    Changes in trabecular bone composition during development of osteoporosis are used as a model for bone loss in microgravity conditions during a space flight. Symbolic dynamics and measures of complexity are proposed and applied to assess quantitatively the structural composition of bone tissue fr...

  9. The Complexity Paradigm for Studying Human Communication: A Summary and Integration of Two Fields

    Directory of Open Access Journals (Sweden)

    John Sherry

    2015-01-01

    Full Text Available This popular quote from Hamlet might be recast for the field of communication as “There are more things in science than are dreamt of in our philosophies”. This article will review several new and strange ideas from complexity science about how the natural world is organized and how we can go about researching it. These strange ideas, (e.g., deterministic, but unpredictable systems resonate with many communication phenomena that our field has traditionally had difficulty studying. By reviewing these areas, we hope to add a new, compelling and useful way to think about science that goes beyond the current dominant philosophy of science employed in communication. Though the concepts reviewed here are difficult and often appear at odds with the dominant paradigm; they are not. Instead, this approach will facilitate research on problems of communication process and interaction that the dominant paradigm has struggled to study. Specifically, this article explores the question of process research in communication by reviewing three major paradigms of science and then delving more deeply into the most recent: complexity science. The article provides a broad overview of many of the major ideas in complexity science and how these ideas can be used to study many of the most difficult questions in communication science. It concludes with suggestions going forward for incorporating complexity science into communication.

  10. Twin-based DNA methylation analysis takes the center stage of studies of human complex diseases

    DEFF Research Database (Denmark)

    Zhang, Dongfeng; Li, Shuxia; Tan, Qihua

    2012-01-01

    The etiology of complex diseases is characterized by the interaction between the genome and environmental conditions and the interface of epigenetics may be a central mechanism. Current technologies already allow us high-throughput profiling of epigenetic patterns at genome level. However, our un...

  11. Specific cpb copies within the Leishmania donovani complex: evolutionary interpretations and potential clinical implications in humans.

    Science.gov (United States)

    Hide, M; Bras-Gonçalves, R; Bañuls, A L

    2007-03-01

    Leishmania infantum and Leishmania donovani both pertain to the L. (L.) donovani complex and are responsible for visceral leishmaniasis. To explore the L. donovani complex, we focused our study on cysteine protease B (cpb) and especially on 2 cpb copies: cpbE and cpbF. We selected cpb genes because of their phylogenetic interest and host-parasite interaction involvement. Sequencing these 2 copies revealed (i) that cpbE is specific to L. infantum and cpbF is specific to L. donovani and (ii) that these 2 copies are different in length and sequence. Phylogenetic analysis and protein predictions were carried out in order to compare these copies (i) with other trypanosomatid cpb, especially L. mexicana, and (ii) within the L. donovani complex. Our results revealed patterns specific to the L. donovani complex such as the COOH-terminal extension, potential epitopes and N-glycosylation sites. Moreover, phylogenetic analysis revealed different levels of polymorphism between L. infantum and L. donovani and confirmed the ancestral status of the latter. L. infantum has a shorter sequence and a deleted sequence responsible for modifications in protein conformation and catalytic triad. Considering the clinical aspect, L. infantum dermotropic strains appeared more polymorphic than L. infantum viscerotropic strains.

  12. An Investigation of Human-Computer Interaction Approaches Beneficial to Weak Learners in Complex Animation Learning

    Science.gov (United States)

    Yeh, Yu-Fang

    2016-01-01

    Animation is one of the useful contemporary educational technologies in teaching complex subjects. There is a growing interest in proper use of learner-technology interaction to promote learning quality for different groups of learner needs. The purpose of this study is to investigate if an interaction approach supports weak learners, who have…

  13. Tracing human mitochondrial complex I assembly by use of GFP-tagged subunits

    NARCIS (Netherlands)

    Dieteren, C.E.J.; Koopman, W.J.H.; Nijtmans, L.G.J.

    2009-01-01

    Disturbances in the assembly of mitochondrial complex I (CI) are a frequent cause of mitochondrial disorders. Several lines of evidence hint at a semi-sequential assembly pathway, in which the 45 individual subunits that form the holoenzyme are pieced together by means of smaller intermediates. To u

  14. Aging degrades the neural encoding of simple and complex sounds in the human brainstem.

    Science.gov (United States)

    Clinard, Christopher G; Tremblay, Kelly L

    2013-01-01

    Older adults, with or without normal peripheral hearing sensitivity, have difficulty understanding speech. This impaired speech perception may, in part, be due to desynchronization affecting the neural representation of acoustic features. Here we determine if phase-locked neural activity generating the brainstem frequency-following response (FFR) exhibits age-related desynchronization and how this degradation affects the neural representation of simple and complex sounds. The objectives of this study were to (1) characterize the effects of age on the neural representation of simple tones and complex consonant-vowel stimuli, (2) determine if sustained and transient components of the FFR are differentially affected by age, and (3) determine if the inability to encode a simple signal predicts degradation in representation for complex speech signals. Correlational. Thirty four adults (aged 22-77 yr) with hearing thresholds falling within normal limits. Stimuli used to evoke FFRs were 1000 Hz tone bursts as well as a consonant-vowel /da/ sound. The neural representation of simple (tone) and complex (/da/) stimuli declines with advancing age. Tone-FFR phase coherence decreased as chronological age increased. For the consonant-vowel FFRs, transient onset and offset response amplitudes were smaller, and offset responses were delayed with age. Sustained responses at the onset of vowel periodicity were prolonged in latency and smaller in amplitude as age increased. FFT amplitude of the consonant-vowel FFR fundamental frequency did not significantly decline with increasing age. The ability to encode a simple signal was related to degradation in the neural representation of a complex, speechlike sound. Tone-FFR phase coherence was significantly related to the later vowel response components but not the earlier vowel components. FFR components representing the tone and consonant-vowel /da/ stimulus were negatively affected by age, showing age-related reductions in response

  15. TGFbeta-mediated formation of pRb-E2F complexes in human myeloid leukemia cells.

    Science.gov (United States)

    Hu, Xiao Tang

    2008-05-01

    TGFbeta is well known for its inhibitory effect on cell cycle G1 checkpoint kinases. However, its role in the control of pRb-E2F complexes is not well established. TGFbeta inhibits phosphorylation of pRb at several serine and threonine residues and regulates the association of E2F transcription factors with pRb family proteins. Recent studies found that predominantly E2F-4, p130, and histone deacetylase (HDAC) are found to bind to corresponding E2F-responsive promoters in G0/G1 phase. As cells progress through mid-G1, p130-E2F4 complex are replaced by p107-E2F4 followed by activators E2F1, 2, and 3. pRb was not detectable in the promoters containing the E2F-responsive site in cycling cells but was associated with E2F4-p130 complexes or E2F4-p107 complexes during G0/G1 phase. In human myeloid leukemia cell line, MV4-11, TGFbeta upregulated pRb-E2F-4 and p130-E2F-4, and downregulated p107-E2F-4 complexes. However, pRB-E2F1 and pRb-E2F3 complexes were found in proliferating cells but not in TGFbeta arrested G1 cells. In addition, electrophoretic gel mobility shift assay (EMSA) could not detect pRb-E2F DNA-binding activities either in S or G1 phase but exhibited the existence of p107-E2F4 in proliferating cells and p130-E2F4 complexes in TGFbeta-arrested G1 cells, respectively. Our data suggest that p107 and p130, but not pRb, and the repressor E2F, but not activator E2Fs, play a critical role in regulating E2F-responsive gene expression in TGFbeta-mediated cell cycle control in human myeloid leukemia cells.

  16. Complex Etiology, Prophylaxis and Hygiene Control in Mycotoxic Nephropathies in Farm Animals and Humans

    Directory of Open Access Journals (Sweden)

    Stoycho D. Stoev

    2008-04-01

    Full Text Available Various etiological factors contributing to the development of mycotoxic nephropathy in farm animals and humans are reviewed. The possible synergistic effect between ochratoxin A (OTA and other mycotoxins, as penicillic acid (PA and fumonisin B1 (FB1, contributing to this nephropathy is also considered and discussed. The most convenient ways of prophylaxis and various preventive measures against OTA contamination of feeds or foods are reviewed. A reference is made concerning the most successful methods of veterinary hygiene control in the slaughterhouses in order to prevent the entering of OTA in commercial channels with a view to human health. The economic efficacy of these prophylactic procedures is also considered. An evaluation of human exposure to OTA is made.

  17. An experimental approach to validating a theory of human error in complex systems

    Science.gov (United States)

    Morris, N. M.; Rouse, W. B.

    1985-01-01

    The problem of 'human error' is pervasive in engineering systems in which the human is involved. In contrast to the common engineering approach of dealing with error probabilistically, the present research seeks to alleviate problems associated with error by gaining a greater understanding of causes and contributing factors from a human information processing perspective. The general approach involves identifying conditions which are hypothesized to contribute to errors, and experimentally creating the conditions in order to verify the hypotheses. The conceptual framework which serves as the basis for this research is discussed briefly, followed by a description of upcoming research. Finally, the potential relevance of this research to design, training, and aiding issues is discussed.

  18. Contribution of ankyrin-band 3 complexes to the organization and mechanical properties of the membrane skeleton of human erythrocyte

    Energy Technology Data Exchange (ETDEWEB)

    Shen, B.W. [Argonne National Lab., IL (United States). Biological and Medical Research Div.

    1995-02-01

    To understand the role of ankyrin-band 3 complexes in the organization of the spectrin-based membrane skeleton and its contribution to the mechanical properties of human erythrocytes, intact skeletons and single-layered skeleton leaflets were prepared from intact and physically sheared membrane ghosts, expanded in low salt buffer, and examined by transmission electron microscopy. While the structures of intact skeletons and single-layered skeleton leaflets shared many common features, including rigid junctional complexes of spectrin, actin, and band 4.1; short stretches ({approximately}50 {angstrom}) of flexible spectrin filaments; and globular masses of ankyrin-band 3 complexes situated close to the middle of the spectrin filaments, the definition of structural units in the intact skeleton is obscured by the superposition of the two layers. However, the spatial disposition of structural elements can be clearly defined in the images of the single-layered skeleton leaflets. Partially expanded skeletal leaflets contain conglomerates of ankyrin-band 3 complexes arranged in a circular or clove-leaf configuration that straddles multiple strands of thick spectrin cables, presumably reflecting the association of ankyrin-band 3 complexes on neighboring spectrin tetramers as well as the lateral association of the spectrin filaments. Hyperexpansion of the skeleton leaflets led to dissociation of the conglomerates of ankyrin-band 3 complexes, full-extension of the spectrin tetramers, and separation of the individual strands of spectrin tetramers. Clearly defined stands of spectrin tetramers in the hyperexpanded single-layered skeletal leaflets often contained two sets of globular protein masses that divided the spectrin tetramers into three segments of approximately equal length.

  19. A Conceptual Framework for Predicting Error in Complex Human-Machine Environments

    Science.gov (United States)

    Freed, Michael; Remington, Roger; Null, Cynthia H. (Technical Monitor)

    1998-01-01

    We present a Goals, Operators, Methods, and Selection Rules-Model Human Processor (GOMS-MHP) style model-based approach to the problem of predicting human habit capture errors. Habit captures occur when the model fails to allocate limited cognitive resources to retrieve task-relevant information from memory. Lacking the unretrieved information, decision mechanisms act in accordance with implicit default assumptions, resulting in error when relied upon assumptions prove incorrect. The model helps interface designers identify situations in which such failures are especially likely.

  20. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells

    OpenAIRE

    Tchasovnikarova, Iva A.; Timms, Richard T.; Matheson, Nicholas J.; Wals, Kim; Antrobus, Robin; Göttgens, Berthold; Dougan, Gordon; Dawson, Mark A.; Lehner, Paul J.

    2015-01-01

    This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aaa7227 Forward genetic screens in Drosophila melanogaster for modifiers of position-effect variegation have revealed the basis of much of our understanding of heterochromatin. We took an analogous approach to identify genes required for epigenetic repression in human cells. A non-lethal forward genetic screen in near-haploid KBM7 cells identified the Human Silencing Hub (...

  1. Study on the interaction of a copper(II) complex containing the artificial sweetener aspartame with human serum albumin.

    Science.gov (United States)

    Shahabadi, Nahid; Khodaei, Mohammad Mehdi; Kashanian, Soheila; Kheirdoosh, Fahimeh; Filli, Soraya Moradi

    2014-05-01

    A copper(II) complex containing aspartame (APM) as ligand, Cu(APM)2Cl2·2H2O, was synthesized and characterized. In vitro binding interaction of this complex with human serum albumin (HSA) was studied at physiological pH. Binding studies of this complex with HSA are useful for understanding the Cu(APM)2Cl2·2H2O-HSA interaction mechanism and providing guidance for the application and design of new and more efficient artificial sweeteners drive. The interaction was investigated by spectrophotometric, spectrofluorometric, competition experiment and circular dichroism. Hyperchromicity observed in UV absorption band of Cu(APM)2Cl2·2H2O. A strong fluorescence quenching reaction of HSA to Cu(APM)2Cl2·2H2O was observed and the binding constant (Kf) and corresponding numbers of binding sites (n) were calculated at different temperatures. Thermodynamic parameters, enthalpy change (∆H) and entropy change (∆S) were calculated to be -458.67 kJ mol(-1) and -1,339 J mol(-1 )K(-1) respectively. According to the van't Hoff equation, the reaction is predominantly enthalpically driven. In conformity with experimental results, we suggest that Cu(APM)2Cl2·2H2O interacts with HSA. In comparison with previous study, it is found that the Cu(II) complex binds stronger than aspartame.

  2. Transcriptional Repression by the BRG1-SWI/SNF Complex Affects the Pluripotency of Human Embryonic Stem Cells

    Directory of Open Access Journals (Sweden)

    Xiaoli Zhang

    2014-09-01

    Full Text Available The SWI/SNF complex plays an important role in mouse embryonic stem cells (mESCs, but it remains to be determined whether this complex is required for the pluripotency of human ESCs (hESCs. Using RNAi, we demonstrated that depletion of BRG1, the catalytic subunit of the SWI/SNF complex, led to impaired self-renewing ability and dysregulated lineage specification of hESCs. A unique composition of the BRG1-SWI/SNF complex in hESCs was further defined by the presence of BRG1, BAF250A, BAF170, BAF155, BAF53A, and BAF47. Genome-wide expression analyses revealed that BRG1 participated in a broad range of biological processes in hESCs through pathways different from those in mESCs. In addition, chromatin immunoprecipitation sequencing (ChIP-seq demonstrated that BRG1 played a repressive role in transcriptional regulation by modulating the acetylation levels of H3K27 at the enhancers of lineage-specific genes. Our data thus provide valuable insights into molecular mechanisms by which transcriptional repression affects the self-renewal and differentiation of hESCs.

  3. Deep sequencing and proteomic analysis of the microRNA-induced silencing complex in human red blood cells.

    Science.gov (United States)

    Azzouzi, Imane; Moest, Hansjoerg; Wollscheid, Bernd; Schmugge, Markus; Eekels, Julia J M; Speer, Oliver

    2015-05-01

    During maturation, erythropoietic cells extrude their nuclei but retain their ability to respond to oxidant stress by tightly regulating protein translation. Several studies have reported microRNA-mediated regulation of translation during terminal stages of erythropoiesis, even after enucleation. In the present study, we performed a detailed examination of the endogenous microRNA machinery in human red blood cells using a combination of deep sequencing analysis of microRNAs and proteomic analysis of the microRNA-induced silencing complex. Among the 197 different microRNAs detected, miR-451a was the most abundant, representing more than 60% of all read sequences. In addition, miR-451a and its known target, 14-3-3ζ mRNA, were bound to the microRNA-induced silencing complex, implying their direct interaction in red blood cells. The proteomic characterization of endogenous Argonaute 2-associated microRNA-induced silencing complex revealed 26 cofactor candidates. Among these cofactors, we identified several RNA-binding proteins, as well as motor proteins and vesicular trafficking proteins. Our results demonstrate that red blood cells contain complex microRNA machinery, which might enable immature red blood cells to control protein translation independent of de novo nuclei information.

  4. High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design.

    Science.gov (United States)

    Sippel, Katherine H; Robbins, Arthur H; Domsic, John; Genis, Caroli; Agbandje-McKenna, Mavis; McKenna, Robert

    2009-10-01

    The crystal structure of human carbonic anhydrase II (CA II) complexed with the inhibitor acetazolamide (AZM) has been determined at 1.1 A resolution and refined to an R(cryst) of 11.2% and an R(free) of 14.7%. As observed in previous CA II-inhibitor complexes, AZM binds directly to the zinc and makes several key interactions with active-site residues. The high-resolution data also showed a glycerol molecule adjacent to the AZM in the active site and two additional AZMs that are adventitiously bound on the surface of the enzyme. The co-binding of AZM and glycerol in the active site demonstrate that given an appropriate ring orientation and substituents, an isozyme-specific CA inhibitor may be developed.

  5. Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs.

    Science.gov (United States)

    Chamberlain, Philip P; Lopez-Girona, Antonia; Miller, Karen; Carmel, Gilles; Pagarigan, Barbra; Chie-Leon, Barbara; Rychak, Emily; Corral, Laura G; Ren, Yan J; Wang, Maria; Riley, Mariko; Delker, Silvia L; Ito, Takumi; Ando, Hideki; Mori, Tomoyuki; Hirano, Yoshinori; Handa, Hiroshi; Hakoshima, Toshio; Daniel, Thomas O; Cathers, Brian E

    2014-09-01

    The Cul4-Rbx1-DDB1-Cereblon E3 ubiquitin ligase complex is the target of thalidomide, lenalidomide and pomalidomide, therapeutically important drugs for multiple myeloma and other B-cell malignancies. These drugs directly bind Cereblon (CRBN) and promote the recruitment of substrates Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex, thus leading to substrate ubiquitination and degradation. Here we present the crystal structure of human CRBN bound to DDB1 and the drug lenalidomide. A hydrophobic pocket in the thalidomide-binding domain (TBD) of CRBN accommodates the glutarimide moiety of lenalidomide, whereas the isoindolinone ring is exposed to solvent. We also solved the structures of the mouse TBD in the apo state and with thalidomide or pomalidomide. Site-directed mutagenesis in lentiviral-expression myeloma models showed that key drug-binding residues are critical for antiproliferative effects.

  6. Age-related structural abnormalities in the human retina-choroid complex revealed by two-photon excited autofluorescence imaging.

    Science.gov (United States)

    Han, Meng; Giese, Guenter; Schmitz-Valckenberg, Steffen; Bindewald-Wittich, Almut; Holz, Frank G; Yu, Jiayi; Bille, Josef F; Niemz, Markolf H

    2007-01-01

    The intensive metabolism of photoreceptors is delicately maintained by the retinal pigment epithelium (RPE) and the choroid. Dysfunction of either the RPE or choroid may lead to severe damage to the retina. Two-photon excited autofluorescence (TPEF) from endogenous fluorophores in the human retina provides a novel opportunity to reveal age-related structural abnormalities in the retina-choroid complex prior to apparent pathological manifestations of age-related retinal diseases. In the photoreceptor layer, the regularity of the macular photoreceptor mosaic is preserved during aging. In the RPE, enlarged lipofuscin granules demonstrate significantly blue-shifted autofluorescence, which coincides with the depletion of melanin pigments. Prominent fibrillar structures in elderly Bruch's membrane and choriocapillaries represent choroidal structure and permeability alterations. Requiring neither slicing nor labeling, TPEF imaging is an elegant and highly efficient tool to delineate the thick, fragile, and opaque retina-choroid complex, and may provide clues to the trigger events of age-related macular degeneration.

  7. Animal and human studies of a new /sup 99m/Tc labelled phosphine-isocyanide complex with possible applications to radionuclide ventriculography

    Energy Technology Data Exchange (ETDEWEB)

    Zanelli, G.D; Patel, N.; Smith, T.; Crawley, J.C.W.; Lahiri, A.; Brady, F.; Radfar, G.; Silvester, D.J.; Cook, N.D.

    1987-04-01

    A new /sup 99m/Tc-phosphine-isocyanide complex with the general structure (/sup 99m/Tc (DEPE)/sub 2/(CNR)/sub 2/)/sup +/ has been synthesised and tested in animals and one human. In three animal species (rat, rabbit, dog), the complex is an efficient myocardial imaging agent, while in humans it remains in the blood pool. The complex is 100% protein bound in animals and humans, but whereas in humans it is attached to a 51.5 kdalton protein (probably prealbumin), in rabbits it appears to be bound to a larger macromolecule (M.W.>100 kdalton). The efficiency of the complex for blood pool labelling was tested in a human volunteer and compared with the standard in vivo red cell labelling technique with stannous pyrophosphate. A satisfactory radionuclide angiogram could be performed with less than 370 MBq of the complex. The count rate for the complex (cps/MBq) was 15% higher than that obtained with the labelled red cells and the absence of splenic activity was notable. In humans this complex appears to be an efficient blood pool labelling agent which might be useful for radionuclide ventriculography.

  8. Shared molecular and functional frameworks among five complex human disorders: a comparative study on interactomes linked to susceptibility genes.

    Directory of Open Access Journals (Sweden)

    Ramesh Menon

    Full Text Available BACKGROUND: Genome-wide association studies (gwas are invaluable in revealing the common variants predisposing to complex human diseases. Yet, until now, the large volumes of data generated from such analyses have not been explored extensively enough to identify the molecular and functional framework hosting the susceptibility genes. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the relationships among five neurodegenerative and/or autoimmune complex human diseases (Parkinson's disease--Park, Alzheimer's disease--Alz, multiple sclerosis--MS, rheumatoid arthritis--RA and Type 1 diabetes--T1D by characterising the interactomes linked to their gwas-genes. An initial study on the MS interactome indicated that several genes predisposing to the other autoimmune or neurodegenerative disorders may come into contact with it, suggesting that susceptibility to distinct diseases may converge towards common molecular and biological networks. In order to test this hypothesis, we performed pathway enrichment analyses on each disease interactome independently. Several issues related to immune function and growth factor signalling pathways appeared in all autoimmune diseases, and, surprisingly, in Alzheimer's disease. Furthermore, the paired analyses of disease interactomes revealed significant molecular and functional relatedness among autoimmune diseases, and, unexpectedly, between T1D and Alz. CONCLUSIONS/SIGNIFICANCE: The systems biology approach highlighted several known pathogenic processes, indicating that changes in these functions might be driven or sustained by the framework linked to genetic susceptibility. Moreover, the comparative analyses among the five genetic interactomes revealed unexpected genetic relationships, which await further biological validation. Overall, this study outlines the potential of systems biology to uncover links between genetics and pathogenesis of complex human disorders.

  9. The Heterodimeric TWIST1-E12 Complex Drives the Oncogenic Potential of TWIST1 in Human Mammary Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Laurent Jacqueroud

    2016-05-01

    Full Text Available The TWIST1 embryonic transcription factor displays biphasic functions during the course of carcinogenesis. It facilitates the escape of cells from oncogene-induced fail-safe programs (senescence, apoptosis and their consequent neoplastic transformation. Additionally, it promotes the epithelial-to-mesenchymal transition and the initiation of the metastatic spread of cancer cells. Interestingly, cancer cells recurrently remain dependent on TWIST1 for their survival and/or proliferation, making TWIST1 their Achilles’ heel. TWIST1 has been reported to form either homodimeric or heterodimeric complexes mainly in association with the E bHLH class I proteins. These complexes display distinct, sometimes even antagonistic, functions during development and unequal prometastatic functions in prostate cancer cells. Using a tethered dimer strategy, we successively assessed the ability of TWIST1 dimers to cooperate with an activated version of RAS in human mammary epithelial cell transformation, to provide mice with the ability to spontaneously develop breast tumors, and lastly to maintain a senescence program at a latent state in several breast cancer cell lines. We demonstrate that the TWIST1-E12 complex, unlike the homodimer, is an oncogenic form of TWIST1 in mammary epithelial cells and that efficient binding of both partners is a prerequisite for its activity. The detection of the heterodimer in human premalignant lesions by a proximity ligation assay, at a stage preceding the initiation of the metastatic cascade, is coherent with such an oncogenic function. TWIST1-E protein heterodimeric complexes may thus constitute the main active forms of TWIST1 with regard to senescence inhibition over the time course of breast tumorigenesis.

  10. Complex Human Activity Recognition Using Smartphone and Wrist-Worn Motion Sensors

    NARCIS (Netherlands)

    Shoaib, Muhammad; Bosch, Stephan; Durmaz Incel, Ozlem; Scholten, Hans; Havinga, Paul J.M.

    2016-01-01

    The position of on-body motion sensors plays an important role in human activity recognition. Most often, mobile phone sensors at the trouser pocket or an equivalent position are used for this purpose. However, this position is not suitable for recognizing activities that involve hand gestures, such

  11. Hippocampus, Perirhinal Cortex, and Complex Visual Discriminations in Rats and Humans

    Science.gov (United States)

    Hales, Jena B.; Broadbent, Nicola J.; Velu, Priya D.; Squire, Larry R.; Clark, Robert E.

    2015-01-01

    Structures in the medial temporal lobe, including the hippocampus and perirhinal cortex, are known to be essential for the formation of long-term memory. Recent animal and human studies have investigated whether perirhinal cortex might also be important for visual perception. In our study, using a simultaneous oddity discrimination task, rats with…

  12. Expression of LacdiNAc Groups on N-Glycans among Human Tumors Is Complex

    Directory of Open Access Journals (Sweden)

    Kiyoko Hirano

    2014-01-01

    Full Text Available Aberrant glycosylation of proteins and lipids is one of the characteristic features of malignantly transformed cells. The GalNAcβ1 → 4GlcNAc (LacdiNAc or LDN group at the nonreducing termini of both N- and O-glycans is not generally found in mammalian cells. We previously showed that the expression level of the LacdiNAc group in N-glycans decreases dramatically during the progression of human breast cancer. In contrast, the enhanced expression of the LacdiNAc group has been shown to be associated with the progression of human prostate, ovarian, and pancreatic cancers. Therefore, the expression of the disaccharide group appears to be dependent on types of tumors. The mechanism of formation of the LacdiNAc group in human tumors and cancer cells has been studied, and two β4-N-acetylgalacto-saminyltransferases (β4GalNAcTs, β4GalNAcT3 and β4GalNAcT4, have been shown to be involved in the biosynthesis of this disaccharide group in a tissue-dependent manner. Transfection of the β4GalNAcT3 gene brought about significant changes in the malignant phenotypes of human neuroblastoma, indicating that this disaccharide group is important for suppressing the tumor growth.

  13. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency

    DEFF Research Database (Denmark)

    Jackson, Robert S; Creemers, John W M; Farooqi, I Sadaf

    2003-01-01

    , some mature ACTH and glucagon-like peptide 17-36(amide) were detectable in her plasma, suggesting that the production of these hormones, at least in humans, does not have an absolute dependence on PC1. The presence of severe obesity and the absence of growth retardation in both subjects contrast...

  14. Hippocampus, Perirhinal Cortex, and Complex Visual Discriminations in Rats and Humans

    Science.gov (United States)

    Hales, Jena B.; Broadbent, Nicola J.; Velu, Priya D.; Squire, Larry R.; Clark, Robert E.

    2015-01-01

    Structures in the medial temporal lobe, including the hippocampus and perirhinal cortex, are known to be essential for the formation of long-term memory. Recent animal and human studies have investigated whether perirhinal cortex might also be important for visual perception. In our study, using a simultaneous oddity discrimination task, rats with…

  15. "Asexual propagation of a virulent clone complex in human and feline outbreak of sporotrichosis"

    NARCIS (Netherlands)

    Teixeira, Marcus de Melo; Rodrigues, Anderson Messias; Tsui, Clement K M; de Almeida, Luiz Gonzaga Paulo; Van Diepeningen, Anne D; Gerrits van den Ende, Bert; Fernandes, Geisa Ferreira; Kano, Rui; Hamelin, Richard C; Lopes-Bezerra, Leila Maria; Ribeiro Vasconcelos, Ana Tereza; de Hoog, Sybren; de Camargo, Zoilo Pires; Felipe, Maria Sueli Soares

    2014-01-01

    Sporotrichosis is one of the most frequent subcutaneous fungal infections to human and animals caused by members of the plant-associated, dimorphic genus Sporothrix. Three of the four medically important Sporothrix species found in Brazil have been considered asexual, as no sexual stage has ever bee

  16. Global spatio-temporal patterns in human migration: a complex network perspective.

    Science.gov (United States)

    Davis, Kyle F; D'Odorico, Paolo; Laio, Francesco; Ridolfi, Luca

    2013-01-01

    Migration is a powerful adaptive strategy for humans to navigate hardship and pursue a better quality of life. As a universal vehicle facilitating exchanges of ideas, culture, money and goods, international migration is a major contributor to globalization. Consisting of countries linked by multiple connections of human movements, global migration constitutes a network. Despite the important role of human migration in connecting various communities in different parts of the world, the topology and behavior of the international migration network and its changes through time remain poorly understood. Here we show that the global human migration network became more interconnected during the latter half of the twentieth century and that migrant destination choice partly reflects colonial and postcolonial histories, language, religion, and distances. From 1960 to 2000 we found a steady increase in network transitivity (i.e. connectivity between nodes connected to the same node), a decrease in average path length and an upward shift in degree distribution, all of which strengthened the 'small-world' behavior of the migration network. Furthermore, we found that distinct groups of countries preferentially interact to form migration communities based largely on historical, cultural and economic factors.

  17. Specificity and functional interaction of the polymerase complex proteins of human and avian metapneumoviruses

    NARCIS (Netherlands)

    M.T. de Graaf (Marieke); S. Herfst (Sander); E.J.A. Schrauwen (Eefje); Y. Choi (Ying); B.G. van den Hoogen (Bernadette); A.D.M.E. Osterhaus (Albert); R.A.M. Fouchier (Ron)

    2008-01-01

    textabstractHuman metapneumovirus (HMPV) and avian metapneumovirus (AMPV) have a similar genome organization and protein composition, but a different host range. AMPV subgroup C (AMPV-C) is more closely relaled to HMPV than other AMPVs. To investigate the specificity and functional interaction of th

  18. Complex stereoselectivity of human butyrylcholinesterase for the neurotoxic V-agents (Poster)

    NARCIS (Netherlands)

    Wandhammer, M.; Pattou, C.; Schans, M.J. van der; Daveloose, D.; Noort, D.; Nachon, F.

    2012-01-01

    Human butyrylcholinesterase (BChE ; 3.1.1.8) functions as a bioscavenger, protecting the cholinergic system against organophosphate compounds (OPs). The stereoselectivity of BChE is an important parameter for its efficiency at scavenging the most toxic OPs enantiomer for AChE. Crystals of BChE inhib

  19. Human-Automation Collaboration in Complex Multivariate Resource Allocation Decision Support Systems

    Science.gov (United States)

    2010-01-01

    the Office of Naval Research (Code 34). We would like to thank Cláudia Ferraz, Andrew Hsiao, Javier Garcia , Andrew Clare, Albert Leung, Anunaya...ASNE Human Systems Integration Symposium, Annapolis, MD, USA, 2007. [6] S. Bruni, J. Marquez , A. Brzezinski, and M.L. Cummings, Visualizing

  20. Read clouds uncover variation in complex regions of the human genome.

    Science.gov (United States)

    Bishara, Alex; Liu, Yuling; Weng, Ziming; Kashef-Haghighi, Dorna; Newburger, Daniel E; West, Robert; Sidow, Arend; Batzoglou, Serafim

    2015-10-01

    Although an increasing amount of human genetic variation is being identified and recorded, determining variants within repeated sequences of the human genome remains a challenge. Most population and genome-wide association studies have therefore been unable to consider variation in these regions. Core to the problem is the lack of a sequencing technology that produces reads with sufficient length and accuracy to enable unique mapping. Here, we present a novel methodology of using read clouds, obtained by accurate short-read sequencing of DNA derived from long fragment libraries, to confidently align short reads within repeat regions and enable accurate variant discovery. Our novel algorithm, Random Field Aligner (RFA), captures the relationships among the short reads governed by the long read process via a Markov Random Field. We utilized a modified version of the Illumina TruSeq synthetic long-read protocol, which yielded shallow-sequenced read clouds. We test RFA through extensive simulations and apply it to discover variants on the NA12878 human sample, for which shallow TruSeq read cloud sequencing data are available, and on an invasive breast carcinoma genome that we sequenced using the same method. We demonstrate that RFA facilitates accurate recovery of variation in 155 Mb of the human genome, including 94% of 67 Mb of segmental duplication sequence and 96% of 11 Mb of transcribed sequence, that are currently hidden from short-read technologies.

  1. In vitro production and characterization of partly assembled human CD3 complexes

    DEFF Research Database (Denmark)

    Kastrup, J; Pedersen, L Ø; Dietrich, J

    2002-01-01

    in Golgi apparatus before the fully assembled T-cell receptor is transported to the cell surface. To study the structural properties of the human CD3 chains, we have developed new methods to produce and fold the extracellular domains of CD3 gamma, CD3 delta and CD3 epsilon. Proteins were expressed...

  2. Global spatio-temporal patterns in human migration: a complex network perspective.

    Directory of Open Access Journals (Sweden)

    Kyle F Davis

    Full Text Available Migration is a powerful adaptive strategy for humans to navigate hardship and pursue a better quality of life. As a universal vehicle facilitating exchanges of ideas, culture, money and goods, international migration is a major contributor to globalization. Consisting of countries linked by multiple connections of human movements, global migration constitutes a network. Despite the important role of human migration in connecting various communities in different parts of the world, the topology and behavior of the international migration network and its changes through time remain poorly understood. Here we show that the global human migration network became more interconnected during the latter half of the twentieth century and that migrant destination choice partly reflects colonial and postcolonial histories, language, religion, and distances. From 1960 to 2000 we found a steady increase in network transitivity (i.e. connectivity between nodes connected to the same node, a decrease in average path length and an upward shift in degree distribution, all of which strengthened the 'small-world' behavior of the migration network. Furthermore, we found that distinct groups of countries preferentially interact to form migration communities based largely on historical, cultural and economic factors.

  3. Ionization of tyrosine residues in human serum albumin and in its complexes with bilirubin and laurate

    DEFF Research Database (Denmark)

    Honoré, B; Brodersen, R

    1992-01-01

    Spectrophotometric titration of human serum albumin indicates that ionization of the 18 tyrosine residues takes place between pH 9 and 12.7. A Hill plot indicates that protons dissociate co-operatively from tyrosine residues, in pure albumin between pH 11.0 and 11.4 with a Hill coefficient 1.7, a...

  4. A complex selection signature at the human AVPR1B gene

    Directory of Open Access Journals (Sweden)

    Cagliani Rachele

    2009-06-01

    Full Text Available Abstract Background The vasopressin receptor type 1b (AVPR1B is mainly expressed by pituitary corticotropes and it mediates the stimulatory effects of AVP on ACTH release; common AVPR1B haplotypes have been involved in mood and anxiety disorders in humans, while rodents lacking a functional receptor gene display behavioral defects and altered stress responses. Results Here we have analyzed the two exons of the gene and the data we present suggest that AVPR1B has been subjected to natural selection in humans. In particular, analysis of exon 2 strongly suggests the action of balancing selection in African populations and Europeans: the region displays high nucleotide diversity, an excess of intermediate-frequency alleles, a higher level of within-species diversity compared to interspecific divergence and a genealogy with common haplotypes separated by deep branches. This relatively unambiguous situation coexists with unusual features across exon 1, raising the possibility that a nonsynonymous variant (Gly191Arg in this region has been subjected to directional selection. Conclusion Although the underlying selective pressure(s remains to be identified, we consider this to be among the first documented examples of a gene involved in mood disorders and subjected to natural selection in humans; this observation might add support to the long-debated idea that depression/low mood might have played an adaptive role during human evolution.

  5. The effects of syntactic complexity on the human-computer interaction

    Science.gov (United States)

    Chechile, R. A.; Fleischman, R. N.; Sadoski, D. M.

    1986-01-01

    Three divided-attention experiments were performed to evaluate the effectiveness of a syntactic analysis of the primary task of editing flight route-way-point information. For all editing conditions, a formal syntactic expression was developed for the operator's interaction with the computer. In terms of the syntactic expression, four measures of syntactic were examined. Increased syntactic complexity did increase the time to train operators, but once the operators were trained, syntactic complexity did not influence the divided-attention performance. However, the number of memory retrievals required of the operator significantly accounted for the variation in the accuracy, workload, and task completion time found on the different editing tasks under attention-sharing conditions.

  6. Spectro-temporal analysis of complex sounds in the human auditory system

    DEFF Research Database (Denmark)

    Piechowiak, Tobias

    2009-01-01

    Most sounds encountered in our everyday life carry information in terms of temporal variations of their envelopes. These envelope variations, or amplitude modulations, shape the basic building blocks for speech, music, and other complex sounds. Often a mixture of such sounds occurs in natural...... acoustic scenes, with each of the sounds having its own characteristic pattern of amplitude modulations. Complex sounds, such as speech, share the same amplitude modulations across a wide range of frequencies. This "comodulation" is an important characteristic of these sounds since it can enhance...... in conditions which are sensitive to cochlear suppression. The fourth chapter examines the role of cognitive processing in different stimulus paradigms: CMR, binaural masking level differences and modulation detection interference are investigated in contexts of auditory grouping. It is shown that auditory...

  7. A Scalable Genome-Editing-Based Approach for Mapping Multiprotein Complexes in Human Cells

    Directory of Open Access Journals (Sweden)

    Mathieu Dalvai

    2015-10-01

    Full Text Available Conventional affinity purification followed by mass spectrometry (AP-MS analysis is a broadly applicable method used to decipher molecular interaction networks and infer protein function. However, it is sensitive to perturbations induced by ectopically overexpressed target proteins and does not reflect multilevel physiological regulation in response to diverse stimuli. Here, we developed an interface between genome editing and proteomics to isolate native protein complexes produced from their natural genomic contexts. We used CRISPR/Cas9 and TAL effector nucleases (TALENs to tag endogenous genes and purified several DNA repair and chromatin-modifying holoenzymes to near homogeneity. We uncovered subunits and interactions among well-characterized complexes and report the isolation of MCM8/9, highlighting the efficiency and robustness of the approach. These methods improve and simplify both small- and large-scale explorations of protein interactions as well as the study of biochemical activities and structure-function relationships.

  8. Beyond description. Comment on "Approaching human language with complex networks" by Cong and Liu

    Science.gov (United States)

    Ferrer-i-Cancho, R.

    2014-12-01

    In their historical overview, Cong & Liu highlight Sausurre as the father of modern linguistics [1]. They apparently miss G.K. Zipf as a pioneer of the view of language as a complex system. His idea of a balance between unification and diversification forces in the organization of natural systems, e.g., vocabularies [2], can be seen as a precursor of the view of complexity as a balance between order (unification) and disorder (diversification) near the edge of chaos [3]. Although not mentioned by Cong & Liu somewhere else, trade-offs between hearer and speaker needs are very important in Zipf's view, which has inspired research on the optimal networks mapping words into meanings [4-6]. Quantitative linguists regard G.K. Zipf as the funder of modern quantitative linguistics [7], a discipline where statistics plays a central role as in network science. Interestingly, that centrality of statistics is missing Saussure's work and that of many of his successors.

  9. Fractal analysis of the structural complexity of the connective tissue in human carotid bodies

    Directory of Open Access Journals (Sweden)

    Diego eGuidolin

    2014-11-01

    Full Text Available The carotid body may undergo different structural changes during perinatal development, aging, or in response to environmental stimuli. In the previous literature, morphometric approaches to evaluate these changes have considered quantitative first order parameters, such as volumes or densities, while changes in spatial disposition and/or complexity of structural components have not yet been considered. In the present study, different strategies for addressing morphological complexity of carotid body, apart from the overall amount of each tissue component, were evaluated and compared. In particular, we considered the spatial distribution of connective tissue in the carotid bodies of young control subjects, young opiate-related deaths and aged subjects, through analysis of dispersion (Morisita’s index, gray level co-occurrence matrix (entropy, angular second moment, variance, correlation, and fractal analysis (fractal dimension, lacunarity. Opiate-related deaths and aged subjects showed a comparable increase in connective tissue with respect to young controls. However, the Morisita’s index (p<0.05, angular second moment (p<0.05, fractal dimension (p<0.01 and lacunarity (p<0.01 permitted to identify significant differences in the disposition of the connective tissue between these two series. A receiver operating characteristic (ROC curve was also calculated to evaluate the efficiency of each parameter. The fractal dimension and lacunarity, with areas under the ROC curve of 0.9651 (excellent accuracy and 0.8835 (good accuracy, respectively, showed the highest discriminatory power. They evidenced higher level of structural complexity in the carotid bodies of opiate-related deaths than old controls, due to more complex branching of intralobular connective tissue. Further analyses will have to consider the suitability of these approaches to address other morphological features of the carotid body, such as different cell populations

  10. Methodological issues in analyzing human communication – the complexities of multimodality

    DEFF Research Database (Denmark)

    Høegh, Tina

    2017-01-01

    This chapter develops a multimodal method for transcribing speech, communication, and performance. The chapter discusses the methodological solutions to the complex translation of speech, language rhythm and gesture in time and space into the two-dimensional format of a piece of paper. The focus...... is on orally performed literature and its pedagogical implications. The chapter thoroughly examines relevant theories and discusses methodological issues of research in language, literature, and cultural performance. Current themes within social semiotics, metrical studies, ethnography of speaking, narratology...

  11. The view from linguistics. Comment on "Approaching human language with complex networks" by Cong and Liu

    Science.gov (United States)

    Hudson, Richard

    2014-12-01

    The study of language as a complex network (as described by Cong and Liu [3]) comes at a good time for a theoretical linguist such as me, because it coincides with a number of other developments which it complements well. On the other hand, it also presents important new challenges for our research, not least Cong and Liu's challenge of providing the 'much deeper explanation' for the network properties that this new research reveals.

  12. Introduction to the special issue on organizational dynamics within substance abuse treatment: a complex human activity system.

    Science.gov (United States)

    Flynn, Patrick M; Knight, Danica K; Godley, Mark D; Knudsen, Hannah K

    2012-03-01

    Substance abuse treatment programs represent complex human activity systems in which multiple actors, including clients, counselors, and managers, are nested. Furthermore, treatment programs are nested within the broader environmental context of resource allocation and regulatory enforcement. This special issue of the Journal of Substance Abuse Treatment presents 12 empirical papers that address organizational dynamics within specialty treatment programs. In this introduction to the special issue, the guest editors describe a conceptual framework of organizational dynamics, offer an overview of the articles within this issue, and discuss future prospects for research.

  13. Crystallization and preliminary X-ray crystallographic studies of recombinant human leukotriene A4 hydrolase complexed with bestatin.

    Science.gov (United States)

    Tsuge, H; Ago, H; Aoki, M; Furuno, M; Noma, M; Miyano, M; Minami, M; Izumi, T; Shimizu, T

    1994-05-20

    Recombinant human leukotriene A4 hydrolase complexed with bestatin, an inhibitor of metalloprotease, has been crystallized by the hanging drop vapor diffusion method using 0.1 M phosphate buffer (pH 6.5) and 50 to 54% saturated ammonium sulfate. The orthorhombic crystals belong to the space group I222 or I2(1)2(1)2(1) with unit cell dimensions of a = 273.6 A, b = 261.3 A and c = 52.9 A. They diffract beyond 2.5 A resolution and a native data set up to 3 A resolution has been collected on an imaging plate Weissenberg camera using synchrotron radiation.

  14. FEATURES OF HUMAN RESOURCES IN THE OLTENIA ENERGY COMPLEX IMPORTANT PART OF THE COUNTY'S LABOR MARKET RESOURCES GORJ COUNTY

    Directory of Open Access Journals (Sweden)

    Păunescu Alberto Nicolae

    2013-06-01

    Full Text Available Currently the company Oltenia Energy Complex is in a comprehensive reorganization but not completed. This project implies also the restructuring the workforce including labor force county level. Due to increased production from renewable resources (due to legislation that lead to low price sale by manufacturers and high income by selling green certificates allocated requires a shift in market strategy and the unit with powerful implications on human resources both in the manufacturing sector, energy, heat mining sector, as well as TESA(economic, technical, service, administrative. This implies at least retraining and reducing staff in compliance with the new realities of Energy.

  15. Crystal structure of a human rhinovirus neutralizing antibody complexed with a peptide derived from viral capsid protein VP2.

    OpenAIRE

    1994-01-01

    The three-dimensional structure of the complex between the Fab fragment of an anti-human rhinovirus neutralizing antibody (8F5) and a cross-reactive synthetic peptide from the viral capsid protein VP2 has been determined at 2.5 A resolution by crystallographic methods. The refinement is presently at an R factor of 0.18 and the antigen-binding site and viral peptide are well defined. The peptide antigen adopts a compact fold by two tight turns and interacts through hydrogen bonds, some with io...

  16. CR2-mediated activation of the complement alternative pathway results in formation of membrane attack complexes on human B lymphocytes

    DEFF Research Database (Denmark)

    Nielsen, C H; Marquart, H V; Prodinger, W M;

    2001-01-01

    Normal human B lymphocytes activate the alternative pathway of complement via complement receptor type 2 (CR2, CD21), that binds hydrolysed C3 (iC3) and thereby promotes the formation of a membrane-bound C3 convertase. We have investigated whether this might lead to the generation of a C5...... convertase and consequent formation of membrane attack complexes (MAC). Deposition of C3 fragments and MAC was assessed on human peripheral B lymphocytes in the presence of 30% autologous serum containing 4.4 mM MgCl2/20 mM EGTA, which abrogates the classical pathway of complement without affecting...... the alternative pathway. Blockade of the CR2 ligand-binding site with the monoclonal antibody FE8 resulted in 56 +/- 13% and 71 +/- 9% inhibition of the C3-fragment and MAC deposition, respectively, whereas the monoclonal antibody HB135, directed against an irrelevant CR2 epitope, had no effect. Blockade...

  17. Characteristics of the three ligaments of human spring ligament complex from a viewpoint of elements.

    Science.gov (United States)

    Tohno, Yoshiyuki; Tohno, Setsuko; Taniguchi, Akira; Azuma, Cho; Minami, Takeshi; Mahakkanukrauh, Pasuk

    2012-06-01

    To elucidate characteristics of the three ligaments constituting the spring ligament complex from a viewpoint of elements, the authors investigated age-related changes of elements, relationships among their elements, relationships among ligaments in the elements, and gender differences in the three ligaments of the spring ligament complex, the superomedial calcaneonavicular (SMCN), inferoplantar longitudinal calcaneonavicular (ICN), and third or medioplantar oblique calcaneonavicular (TCN) ligaments. After ordinary dissection at Nara Medical University was finished, the SMCN, ICN, and TCN ligaments of the spring ligament complex were removed from the subjects. The subjects consisted of 10 men and 12 women, ranging in age from 62 to 99 years (average age = 80.5 ± 9.7 years). After incineration with nitric acid and perchloric acid, the element contents were determined by inductively coupled plasma-atomic emission spectrometry. It was found that although the Ca and P content hardly changed in the SMCN ligament with aging, the Ca and P content in the ICN ligament increased to about three and five times higher in the 80s in comparison with the 60s, respectively, whereas in the TCN ligament, it increased about 40% and 90% higher in the 80s compared with the 60s, respectively. Regarding the relationships among elements, significant direct correlations were found among the contents of Ca, P, and Mg in all the three ligaments of the spring ligament complex. This finding was in agreement with the previous finding obtained with the three ligaments of the anterior cruciate ligament, posterior longitudinal ligament, and ligamentum capitis femoris. Whether there were significant correlations among the three ligaments of the spring ligament complex with regard to the Ca, P, S, Mg, Zn, and Fe contents was examined using Pearson's correlation. It was found that there were significant direct correlations between the SMCN and TCN ligaments in all the Ca, P, Mg, and Zn contents and

  18. Analysis of Complexity Evolution Management and Human Performance Issues in Commercial Aircraft Automation Systems

    Science.gov (United States)

    Vakil, Sanjay S.; Hansman, R. John

    2000-01-01

    Autoflight systems in the current generation of aircraft have been implicated in several recent incidents and accidents. A contributory aspect to these incidents may be the manner in which aircraft transition between differing behaviours or 'modes.' The current state of aircraft automation was investigated and the incremental development of the autoflight system was tracked through a set of aircraft to gain insight into how these systems developed. This process appears to have resulted in a system without a consistent global representation. In order to evaluate and examine autoflight systems, a 'Hybrid Automation Representation' (HAR) was developed. This representation was used to examine several specific problems known to exist in aircraft systems. Cyclomatic complexity is an analysis tool from computer science which counts the number of linearly independent paths through a program graph. This approach was extended to examine autoflight mode transitions modelled with the HAR. A survey was conducted of pilots to identify those autoflight mode transitions which airline pilots find difficult. The transitions identified in this survey were analyzed using cyclomatic complexity to gain insight into the apparent complexity of the autoflight system from the perspective of the pilot. Mode transitions which had been identified as complex by pilots were found to have a high cyclomatic complexity. Further examination was made into a set of specific problems identified in aircraft: the lack of a consistent representation of automation, concern regarding appropriate feedback from the automation, and the implications of physical limitations on the autoflight systems. Mode transitions involved in changing to and leveling at a new altitude were identified across multiple aircraft by numerous pilots. Where possible, evaluation and verification of the behaviour of these autoflight mode transitions was investigated via aircraft-specific high fidelity simulators. Three solution

  19. Complexity of bioindicator selection for ecological, human, and cultural health: Chinook salmon and red knot as case studies

    Science.gov (United States)

    Burger, Joanna; Gochfeld, Michael; Niles, Lawrence; Powers, Charles; Brown, Kevin; Clarke, James; Dey, Amanda; Kosson, David

    2015-01-01

    There is considerable interest in developing bioindicators of ecological health that are also useful indicators for human health. Yet, human health assessment usually encompasses physical/chemical exposures and not cultural well-being. In this paper, we propose that bioindicators can be selected for all three purposes. We use Chinook or king salmon (Oncorhynchus tshawytscha) and red knot (Calidris canutus rufa, a sandpiper) as examples of indicators that can be used to assess human, ecological, and cultural health. Even so, selecting endpoints or metrics for each indicator species is complex and is explored in this paper. We suggest that there are several endpoint types to examine for a given species, including physical environment, environmental stressors, habitat, life history, demography, population counts, and cultural/societal aspects. Usually cultural endpoints are economic indicators (e.g., number of days fished, number of hunting licenses), rather than the importance of a fishing culture. Development of cultural/societal endpoints must include the perceptions of local communities, cultural groups, and tribal nations, as well as governmental and regulatory communities (although not usually so defined, the latter have cultures as well). Endpoint selection in this category is difficult because the underlying issues need to be identified and used to develop endpoints that tribes and stakeholders themselves see as reasonable surrogates of the qualities they value. We describe several endpoints for salmon and knots that can be used for ecological, human, and cultural/societal health. PMID:25666646

  20. A model of human physiology and comfort for assessing complex thermal environments

    Energy Technology Data Exchange (ETDEWEB)

    Huizenga, C.; Zhang Hui; Arens, E. [University of California, Berkeley, CA (United States). Center for Environmental Design Research

    2001-07-01

    The Berkeley Comfort Model is based on the Stolwijk model of human thermal regulation but includes several significant improvements. Our new model allows an unlimited body segment (compared to six in the Stolwijk model). Each segment is modeled as four body layers (core, muscle, fat, and skin tissues) and a clothing layer. Physiological mechanisms such as vasodilation, vasoconstriction, sweating, and metabolic heat production are explicitly considered. Convection, conduction (such as to a car seat or other surface in contact with any part of the body) and radiation between the body and the environment are treated independently. The model is capable of predicting human physiological response to transient, non-uniform thermal environments. This paper describes the physiological algorithms as well as the implementation of the model. (author)

  1. The Complexity of a Dengue Vaccine: A Review of the Human Antibody Response.

    Directory of Open Access Journals (Sweden)

    Jacky Flipse

    Full Text Available Dengue is the most prevalent mosquito-borne viral disease worldwide. Yet, there are no vaccines or specific antivirals available to prevent or treat the disease. Several dengue vaccines are currently in clinical or preclinical stages. The most advanced vaccine is the chimeric tetravalent CYD-TDV vaccine of Sanofi Pasteur. This vaccine has recently cleared Phase III, and efficacy results have been published. Excellent tetravalent seroconversion was seen, yet the protective efficacy against infection was surprisingly low. Here, we will describe the complicating factors involved in the generation of a safe and efficacious dengue vaccine. Furthermore, we will discuss the human antibody responses during infection, including the epitopes targeted in humans. Also, we will discuss the current understanding of the assays used to evaluate antibody response. We hope this review will aid future dengue vaccine development as well as fundamental research related to the phenomenon of antibody-dependent enhancement of dengue virus infection.

  2. The Complexity of a Dengue Vaccine: A Review of the Human Antibody Response.

    Science.gov (United States)

    Flipse, Jacky; Smit, Jolanda M

    2015-01-01

    Dengue is the most prevalent mosquito-borne viral disease worldwide. Yet, there are no vaccines or specific antivirals available to prevent or treat the disease. Several dengue vaccines are currently in clinical or preclinical stages. The most advanced vaccine is the chimeric tetravalent CYD-TDV vaccine of Sanofi Pasteur. This vaccine has recently cleared Phase III, and efficacy results have been published. Excellent tetravalent seroconversion was seen, yet the protective efficacy against infection was surprisingly low. Here, we will describe the complicating factors involved in the generation of a safe and efficacious dengue vaccine. Furthermore, we will discuss the human antibody responses during infection, including the epitopes targeted in humans. Also, we will discuss the current understanding of the assays used to evaluate antibody response. We hope this review will aid future dengue vaccine development as well as fundamental research related to the phenomenon of antibody-dependent enhancement of dengue virus infection.

  3. Toward unraveling the complexity of simple epithelial keratins in human disease.

    Science.gov (United States)

    Omary, M Bishr; Ku, Nam-On; Strnad, Pavel; Hanada, Shinichiro

    2009-07-01

    Simple epithelial keratins (SEKs) are found primarily in single-layered simple epithelia and include keratin 7 (K7), K8, K18-K20, and K23. Genetically engineered mice that lack SEKs or overexpress mutant SEKs have helped illuminate several keratin functions and served as important disease models. Insight into the contribution of SEKs to human disease has indicated that K8 and K18 are the major constituents of Mallory-Denk bodies, hepatic inclusions associated with several liver diseases, and are essential for inclusion formation. Furthermore, mutations in the genes encoding K8, K18, and K19 predispose individuals to a variety of liver diseases. Hence, as we discuss here, the SEK cytoskeleton is involved in the orchestration of several important cellular functions and contributes to the pathogenesis of human liver disease.

  4. Complexity of the influence of gangliosides on histamine release from human basophils and rat mast cells

    DEFF Research Database (Denmark)

    Jensen, C; Svendsen, U G; Thastrup, Ole;

    1987-01-01

    The influence of exogenous addition of gangliosides on histamine release from human basophils and rat mast cells was examined in vitro. Gangliosides dose-dependently inhibited histamine release, and this inhibition was dependent on the ganglioside sialic acid content, since GT1b, having 3 sialic...... was reflected in the sensitivity of the cells to extracellular calcium, since inhibition of the release could be counteracted by increasing the extracellular concentration of calcium....

  5. Structural analysis of a series of antiviral agents complexed with human rhinovirus 14.

    OpenAIRE

    1988-01-01

    The binding to human rhinovirus 14 of a series of eight antiviral agents that inhibit picornaviral uncoating after entry into host cells has been characterized crystallographically. All of these bind into the same hydrophobic pocket within the viral protein VP1 beta-barrel structure, although the orientation and position of each compound within the pocket was found to differ. The compounds cause the protein shell to be less flexible, thereby inhibiting disassembly. Although the antiviral pote...

  6. Complex origins of breadfruit (Artocarpus altilis, Moraceae): implications for human migrations in Oceania.

    Science.gov (United States)

    Zerega, Nyree J C; Ragone, Diane; Motley, Timothy J

    2004-05-01

    Breadfruit (Artocarpus altilis, Moraceae), a traditional starch crop in Oceania, has enjoyed legendary status ever since its role in the infamous mutiny aboard the H.M.S. Bounty in 1789, yet its origins remain unclear. Breadfruit's closest relatives are A. camansi and A. mariannensis. DNA fingerprinting data (AFLP, amplified fragment length polymorphisms) from over 200 breadfruit cultivars, 30 A. camansi, and 24 A. mariannensis individuals were used to investigate the relationships among these species. Multivariate analyses and the identification of species-specific AFLP markers indicate at least two origins of breadfruit. Most Melanesian and Polynesian cultivars appear to have arisen over generations of vegetative propagation and selection from A. camansi. In contrast, most Micronesian breadfruit cultivars appear to be the result of hybridization between A. camansi-derived breadfruit and A. mariannensis. Because breadfruit depends on humans for dispersal, the data were compared to theories on the human colonization of Oceania. The results agree with the well-supported theory that humans settled Polynesia via Melanesia. Additionally, a long-distance migration from eastern Melanesia into Micronesia is supported.

  7. Design considerations for massively parallel sequencing studies of complex human disease.

    Directory of Open Access Journals (Sweden)

    Bing-Jian Feng

    Full Text Available Massively Parallel Sequencing (MPS allows sequencing of entire exomes and genomes to now be done at reasonable cost, and its utility for identifying genes responsible for rare Mendelian disorders has been demonstrated. However, for a complex disease, study designs need to accommodate substantial degrees of locus, allelic, and phenotypic heterogeneity, as well as complex relationships between genotype and phenotype. Such considerations include careful selection of samples for sequencing and a well-developed strategy for identifying the few "true" disease susceptibility genes from among the many irrelevant genes that will be found to harbor rare variants. To examine these issues we have performed simulation-based analyses in order to compare several strategies for MPS sequencing in complex disease. Factors examined include genetic architecture, sample size, number and relationship of individuals selected for sequencing, and a variety of filters based on variant type, multiple observations of genes and concordance of genetic variants within pedigrees. A two-stage design was assumed where genes from the MPS analysis of high-risk families are evaluated in a secondary screening phase of a larger set of probands with more modest family histories. Designs were evaluated using a cost function that assumes the cost of sequencing the whole exome is 400 times that of sequencing a single candidate gene. Results indicate that while requiring variants to be identified in multiple pedigrees and/or in multiple individuals in the same pedigree are effective strategies for reducing false positives, there is a danger of over-filtering so that most true susceptibility genes are missed. In most cases, sequencing more than two individuals per pedigree results in reduced power without any benefit in terms of reduced overall cost. Further, our results suggest that although no single strategy is optimal, simulations can provide important guidelines for study design.

  8. Cobinding of bilirubin and laurate to human serum albumin: spectroscopic characterization of stoichiometric complexes

    DEFF Research Database (Denmark)

    Honoré, B; Sato, H; Brodersen, R

    1988-01-01

    Light absorption and CD spectra of bound bilirubin and albumin fluorescence spectra have been recorded from mixtures containing albumin, A, bilirubin, B, and laurate, L, in Tris-NaCl buffer at pH 8.2, 25 degrees C. Concentrations of the corresponding stoichiometric complexes, ABiLj, for i = 0....... Brodersen et al. (1987) Eur. J. Biochem. 169, 487-495). The results were utilized at the microscopic level to investigate ligand-induced conformational changes. When laurate was bound to AB, a decrease of the distance between Trp-214 and the bound bilirubin occurred, as measured according to Förster...

  9. A standardized method for quantitating the complement-mediated immune complex solubilizing capacity of human serum

    DEFF Research Database (Denmark)

    Baatrup, G; Peterson, I; Svehag, S E;

    1983-01-01

    A standardized radioassay for measuring the complement-mediated immune complex solubilizing capacity (CMSC) and the initial kinetics of the solubilization (IKS) reaction is described. The total complement (C)-mediated solubilizing capacity was determined after incubation of diluted serum and 125I......-BSA-anti-BSA. Percentage C-mediated solubilization (CMS) was measured after centrifugation by determining the distribution of radioactivity. The dependency of CMSC upon factors such as serum dilution and buffer system used, amount of IC added to serum, serum storage conditions and centrifugation conditions...

  10. Reversal of multidrug resistance phenotype in human breast cancer cells using doxorubicin-liposome-microbubble complexes assisted by ultrasound.

    Science.gov (United States)

    Deng, Zhiting; Yan, Fei; Jin, Qiaofeng; Li, Fei; Wu, Junru; Liu, Xin; Zheng, Hairong

    2014-01-28

    The circumvention of multidrug resistance (MDR) plays a critically important role in the success of chemotherapy. The aim of this work is to investigate the effectiveness and possible mechanisms of the reversal of MDR phenotype in human breast cancer cells by using doxorubicin-liposome-microbubble complexes (DLMC) assisted by ultrasound (US). DLMC is fabricated through conjugating doxorubicin (DOX)-liposome (DL) to the surface of microbubbles (MBs) via the biotin-avidin linkage. The resulting drug-loaded complexes are then characterized and incubated with MCF-7/ADR human breast cancer cells and followed by US exposure. Our results show the more rapid cellular uptake, evident enhancement of nuclear accumulation and less drug efflux in the resistant cells treated by DLMC+US than those treated by DL, DL+verapamil under the same US treatment or DLMC without US. The enhanced drug delivery and cellular uptake also associated with the increase of cytotoxicity against MCF-7/ADR cells, lower MCF-7/ADR cell viability and higher apoptotic cells. Mechanism investigations further disclose a significant increase of reactive oxygen species (ROS) level, enhanced DNA damage and obvious reduction of P-glycoprotein expression in the resistant cells treated with DLMC+US compared with the control cases of cells treated by DLMC, DL+US or DL+verapamil+US. In conclusion, our study demonstrates that DLMC in combination with US may provide an effective delivery of drug to sensitize cells to circumvent MDR and to enhance the therapeutic index of the chemotherapy.

  11. FRK inhibits migration and invasion of human glioma cells by promoting N-cadherin/β-catenin complex formation.

    Science.gov (United States)

    Shi, Qiong; Song, Xu; Wang, Jun; Gu, Jia; Zhang, Weijian; Hu, Jinxia; Zhou, Xiuping; Yu, Rutong

    2015-01-01

    Fyn-related kinase (FRK), a member of Src-related tyrosine kinases, is recently reported to function as a potent tumor suppressor in several cancer types. Our previous study has also shown that FRK over-expression inhibited the migration and invasion of glioma cells. However, the mechanism of FRK effect on glioma cell migration and invasion, a feature of human malignant gliomas, is still not clear. In this study, we found that FRK over-expression increased the protein level of N-cadherin, but not E-cadherin. Meanwhile, FRK over-expression promoted β-catenin translocation to the plasma membrane, where it formed complex with N-cadherin, while decreased β-catenin level in the nuclear fraction. In addition, down-regulation of N-cadherin by siRNA promoted the migration and invasion of glioma U251 and U87 cells and abolished the inhibitory effect of FRK on glioma cell migration and invasion. In summary, these results indicate that FRK inhibits migration and invasion of human glioma cells by promoting N-cadherin/β-catenin complex formation.

  12. Structure of a membrane-attack complex/perforin (MACPF) family protein from the human gut symbiont Bacteroides thetaiotaomicron.

    Science.gov (United States)

    Xu, Qingping; Abdubek, Polat; Astakhova, Tamara; Axelrod, Herbert L; Bakolitsa, Constantina; Cai, Xiaohui; Carlton, Dennis; Chen, Connie; Chiu, Hsiu Ju; Clayton, Thomas; Das, Debanu; Deller, Marc C; Duan, Lian; Ellrott, Kyle; Farr, Carol L; Feuerhelm, Julie; Grant, Joanna C; Grzechnik, Anna; Han, Gye Won; Jaroszewski, Lukasz; Jin, Kevin K; Klock, Heath E; Knuth, Mark W; Kozbial, Piotr; Krishna, S Sri; Kumar, Abhinav; Lam, Winnie W; Marciano, David; Miller, Mitchell D; Morse, Andrew T; Nigoghossian, Edward; Nopakun, Amanda; Okach, Linda; Puckett, Christina; Reyes, Ron; Tien, Henry J; Trame, Christine B; van den Bedem, Henry; Weekes, Dana; Wooten, Tiffany; Yeh, Andrew; Zhou, Jiadong; Hodgson, Keith O; Wooley, John; Elsliger, Marc André; Deacon, Ashley M; Godzik, Adam; Lesley, Scott A; Wilson, Ian A

    2010-10-01

    Membrane-attack complex/perforin (MACPF) proteins are transmembrane pore-forming proteins that are important in both human immunity and the virulence of pathogens. Bacterial MACPFs are found in diverse bacterial species, including most human gut-associated Bacteroides species. The crystal structure of a bacterial MACPF-domain-containing protein BT_3439 (Bth-MACPF) from B. thetaiotaomicron, a predominant member of the mammalian intestinal microbiota, has been determined. Bth-MACPF contains a membrane-attack complex/perforin (MACPF) domain and two novel C-terminal domains that resemble ribonuclease H and interleukin 8, respectively. The entire protein adopts a flat crescent shape, characteristic of other MACPF proteins, that may be important for oligomerization. This Bth-MACPF structure provides new features and insights not observed in two previous MACPF structures. Genomic context analysis infers that Bth-MACPF may be involved in a novel protein-transport or nutrient-uptake system, suggesting an important role for these MACPF proteins, which were likely to have been inherited from eukaryotes via horizontal gene transfer, in the adaptation of commensal bacteria to the host environment.

  13. Complex nanominerals and ultrafine particles assemblages in phosphogypsum of the fertilizer industry and implications on human exposure

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Luis F.O., E-mail: felipeqma@yahoo.com.br [Catarinense Institute of Environmental Research and Human Development-IPADHC, Capivari de Baixo, Santa Catarina (Brazil); Hower, James C. [University of Kentucky Center for Applied Energy Research, Lexington, KY, 40511 (United States); Izquierdo, Maria; Querol, Xavier [Institute of Environmental Assessment and Water Research (IDAEA-CSIC) C/Lluis Sole y Sabaris s/n, 08028 Barcelona (Spain)

    2010-10-01

    Phosphogypsum (CaSO{sub 4}.2H{sub 2}O), a by-product of phosphate-rock processing, contains high amounts of impurities such P{sub 2}O{sub 5}, F, radioactive elements, organic substances, secondary nanominerals, and ultrafine particles (UFP) enriched in metals and metalloids. In this study, we examine phosphogypsum (PG) collected from abandoned fertilizer industry facility in south Brazil (Santa Catarina state). The fragile nature of nanominerals and UFP assemblages from fertilizer industry systems required novel techniques and experimental approaches. The investigation of the geochemistry of complex nanominerals and UFP assemblages was a prerequisite to accurately assess the environmental and human health risks of contaminants and cost-effective chemical and biogeological remediation strategies. Particular emphasis was placed on the study and characterization of the complex mixed nanominerals and UFP containing potentially toxic elements. Nanometer-sized phases in PG were characterized using energy-dispersive X-ray spectrometer (EDS), field-emission scanning electron microscope (FE-SEM), and high-resolution transmission electron microscopy (HR-TEM) images. The chemical composition and possible correlations with morphology of nanominerals and UFP, as well as aspects of nanominerals and UFP, are discussed in the context of human health exposure, as well as in relation to management of the nanominerals and UFP in PG environments.

  14. Complex nanominerals and ultrafine particles assemblages in phosphogypsum of the fertilizer industry and implications on human exposure.

    Science.gov (United States)

    Silva, Luis F O; Hower, James C; Izquierdo, Maria; Querol, Xavier

    2010-10-01

    Phosphogypsum (CaSO(4).2H(2)O), a by-product of phosphate-rock processing, contains high amounts of impurities such P(2)O(5), F, radioactive elements, organic substances, secondary nanominerals, and ultrafine particles (UFP) enriched in metals and metalloids. In this study, we examine phosphogypsum (PG) collected from abandoned fertilizer industry facility in south Brazil (Santa Catarina state). The fragile nature of nanominerals and UFP assemblages from fertilizer industry systems required novel techniques and experimental approaches. The investigation of the geochemistry of complex nanominerals and UFP assemblages was a prerequisite to accurately assess the environmental and human health risks of contaminants and cost-effective chemical and biogeological remediation strategies. Particular emphasis was placed on the study and characterization of the complex mixed nanominerals and UFP containing potentially toxic elements. Nanometer-sized phases in PG were characterized using energy-dispersive X-ray spectrometer (EDS), field-emission scanning electron microscope (FE-SEM), and high-resolution transmission electron microscopy (HR-TEM) images. The chemical composition and possible correlations with morphology of nanominerals and UFP, as well as aspects of nanominerals and UFP, are discussed in the context of human health exposure, as well as in relation to management of the nanominerals and UFP in PG environments.

  15. Three-Dimensional Architecture of the Human BRCA1-A Histone Deubiquitinase Core Complex

    Directory of Open Access Journals (Sweden)

    Otto J.P. Kyrieleis

    2016-12-01

    Full Text Available BRCA1 is a tumor suppressor found to be mutated in hereditary breast and ovarian cancer and plays key roles in the maintenance of genomic stability by homologous recombination repair. It is recruited to damaged chromatin as a component of the BRCA1-A deubiquitinase, which cleaves K63-linked ubiquitin chains attached to histone H2A and H2AX. BRCA1-A contributes to checkpoint regulation, repair pathway choice, and HR repair efficiency through molecular mechanisms that remain largely obscure. The structure of an active core complex comprising two Abraxas/BRCC36/BRCC45/MERIT40 tetramers determined by negative-stain electron microscopy (EM reveals a distorted V-shape architecture in which a dimer of Abraxas/BRCC36 heterodimers sits at the base, with BRCC45/Merit40 pairs occupying each arm. The location and ubiquitin-binding activity of BRCC45 suggest that it may provide accessory interactions with nucleosome-linked ubiquitin chains that contribute to their efficient processing. Our data also suggest how ataxia telangiectasia mutated (ATM-dependent BRCA1 dimerization may stabilize self-association of the entire BRCA1-A complex.

  16. Crystallization and preliminary neutron diffraction experiment of human farnesyl pyrophosphate synthase complexed with risedronate.

    Science.gov (United States)

    Yokoyama, Takeshi; Ostermann, Andreas; Mizuguchi, Mineyuki; Niimura, Nobuo; Schrader, Tobias E; Tanaka, Ichiro

    2014-04-01

    Nitrogen-containing bisphosphonates (N-BPs), such as risedronate and zoledronate, are currently used as a clinical drug for bone-resorption diseases and are potent inhibitors of farnesyl pyrophosphate synthase (FPPS). X-ray crystallographic analyses of FPPS with N-BPs have revealed that N-BPs bind to FPPS with three magnesium ions and several water molecules. To understand the structural characteristics of N-BPs bound to FPPS, including H atoms and hydration by water, neutron diffraction studies were initiated using BIODIFF at the Heinz Maier-Leibnitz Zentrum (MLZ). FPPS-risedronate complex crystals of approximate dimensions 2.8 × 2.5 × 1.5 mm (∼3.5 mm(3)) were obtained by repeated macro-seeding. Monochromatic neutron diffraction data were collected to 2.4 Å resolution with 98.4% overall completeness. Here, the first successful neutron data collection from FPPS in complex with N-BPs is reported.

  17. The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease.

    Science.gov (United States)

    Astle, William J; Elding, Heather; Jiang, Tao; Allen, Dave; Ruklisa, Dace; Mann, Alice L; Mead, Daniel; Bouman, Heleen; Riveros-Mckay, Fernando; Kostadima, Myrto A; Lambourne, John J; Sivapalaratnam, Suthesh; Downes, Kate; Kundu, Kousik; Bomba, Lorenzo; Berentsen, Kim; Bradley, John R; Daugherty, Louise C; Delaneau, Olivier; Freson, Kathleen; Garner, Stephen F; Grassi, Luigi; Guerrero, Jose; Haimel, Matthias; Janssen-Megens, Eva M; Kaan, Anita; Kamat, Mihir; Kim, Bowon; Mandoli, Amit; Marchini, Jonathan; Martens, Joost H A; Meacham, Stuart; Megy, Karyn; O'Connell, Jared; Petersen, Romina; Sharifi, Nilofar; Sheard, Simon M; Staley, James R; Tuna, Salih; van der Ent, Martijn; Walter, Klaudia; Wang, Shuang-Yin; Wheeler, Eleanor; Wilder, Steven P; Iotchkova, Valentina; Moore, Carmel; Sambrook, Jennifer; Stunnenberg, Hendrik G; Di Angelantonio, Emanuele; Kaptoge, Stephen; Kuijpers, Taco W; Carrillo-de-Santa-Pau, Enrique; Juan, David; Rico, Daniel; Valencia, Alfonso; Chen, Lu; Ge, Bing; Vasquez, Louella; Kwan, Tony; Garrido-Martín, Diego; Watt, Stephen; Yang, Ying; Guigo, Roderic; Beck, Stephan; Paul, Dirk S; Pastinen, Tomi; Bujold, David; Bourque, Guillaume; Frontini, Mattia; Danesh, John; Roberts, David J; Ouwehand, Willem H; Butterworth, Adam S; Soranzo, Nicole

    2016-11-17

    Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Final LDRD report human interaction with complex systems: advances in hybrid reachability and control.

    Energy Technology Data Exchange (ETDEWEB)

    Oishi, Meeko M.

    2006-08-01

    This document describes new advances in hybrid reachability techniques accomplished during the course of a one-year Truman Postdoctoral Fellowship. These techniques provide guarantees of safety in complex systems, which is especially important in high-risk, expensive, or safety-critical systems. My work focused on new approaches to two specific problems motivated by real-world issues in complex systems: (1) multi-objective controller synthesis, and (2) control for recovery from error. Regarding the first problem, a novel application of reachability analysis allowed controller synthesis in a single step to achieve (a) safety, (b) stability, and (c) prevent input saturation. By extending the state to include the input parameters, constraints for stability, saturation, and envelope protection are incorporated into a single reachability analysis. Regarding the second problem, a new approach to the problem of recovery provides (a) states from which recovery is possible, and (b) controllers to guide the system during a recovery maneuver from an error state to a safe state in minimal time. Results are computed in both problems on nonlinear models of single longitudinal aircraft dynamics and two-aircraft lateral collision avoidance dynamics.

  19. Phagocytosis of IgA Immune Complexes by Human U937 Cells

    Institute of Scientific and Technical Information of China (English)

    郭彩云; 崔薇; 张伟

    2003-01-01

    In order to study FcαR Ⅰ mediated phagocytosis ot lgA immune complexes by U937 cells, antigen 8.9NIP/BSA was labeled with FITC and reacted with anti-NIP IgA or anti-NIP IgG antibody to form immune complexes (ICs). They were then incubated with phorbol 12-myristate B-acetate (PMA) stimulated U937 cells. The phagocytosed ICs were quantified by flow cytometry. The results was that the expression of FcαR Ⅰ on U937 cells was higher than that of FcγR Ⅰ , FcyR Ⅱ and FcγR Ⅲ. After stimulation by PMA, expression of FcαR Ⅰ on U937 cells was markedly upregulated and the phagocytosis of IgA ICs was enhanced. FcαR Ⅰ mediated specific IgA phagocytosis was stronger than FcγR Ⅰ and FcγR Ⅱ mediated IgG phagocytosis. Complement receptors, CR1 and CR3, enhanced U937 cell phagocytosis of IgA ICs. It concludes that FcγR Ⅰ mediated strong phagocytosis of IgA ICs.

  20. Functional Insights into Human HMG-CoA Lyase from Structures of Acyl-CoA-containing Ternary Complexes

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Zhuji; Runquist, Jennifer A.; Montgomery, Christa; Miziorko, Henry M.; Kim, Jung-Ja P. (MCW); (UMKC)

    2010-08-16

    HMG-CoA lyase (HMGCL) is crucial to ketogenesis, and inherited human mutations are potentially lethal. Detailed understanding of the HMGCL reaction mechanism and the molecular basis for correlating human mutations with enzyme deficiency have been limited by the lack of structural information for enzyme liganded to an acyl-CoA substrate or inhibitor. Crystal structures of ternary complexes of WT HMGCL with the competitive inhibitor 3-hydroxyglutaryl-CoA and of the catalytically deficient HMGCL R41M mutant with substrate HMG-CoA have been determined to 2.4 and 2.2 {angstrom}, respectively. Comparison of these {beta}/{alpha}-barrel structures with those of unliganded HMGCL and R41M reveals substantial differences for Mg{sup 2+} coordination and positioning of the flexible loop containing the conserved HMGCL 'signature' sequence. In the R41M-Mg{sup 2+}-substrate ternary complex, loop residue Cys{sup 266} (implicated in active-site function by mechanistic and mutagenesis observations) is more closely juxtaposed to the catalytic site than in the case of unliganded enzyme or the WT enzyme-Mg{sup 2+}-3-hydroxyglutaryl-CoA inhibitor complex. In both ternary complexes, the S-stereoisomer of substrate or inhibitor is specifically bound, in accord with the observed Mg{sup 2+} liganding of both C3 hydroxyl and C5 carboxyl oxygens. In addition to His{sup 233} and His{sup 235} imidazoles, other Mg{sup 2+} ligands are the Asp{sup 42} carboxyl oxygen and an ordered water molecule. This water, positioned between Asp{sup 42} and the C3 hydroxyl of bound substrate/inhibitor, may function as a proton shuttle. The observed interaction of Arg{sup 41} with the acyl-CoA C1 carbonyl oxygen explains the effects of Arg{sup 41} mutation on reaction product enolization and explains why human Arg{sup 41} mutations cause drastic enzyme deficiency.

  1. SYT associates with human SNF/SWI complexes and the C-terminal region of its fusion partner SSX1 targets histones.

    NARCIS (Netherlands)

    Kato, H.; Tjernberg, A.; Zhang, W.; Krutchinsky, A.N.; An, W.; Takeuchi, T.; Ohtsuki, Y.; Sugano, S.; Bruijn, D.R.H. de; Chait, B.T.; Roeder, R.G.

    2002-01-01

    A global transcriptional co-activator, the SNF/SWI complex, has been characterized as a chromatin remodeling factor that enhances accessibility of the transcriptional machinery to DNA within a repressive chromatin structure. On the other hand, mutations in some human SNF/SWI complex components have

  2. IgG and complement deposition and neuronal loss in cats and humans with epilepsy and voltage-gated potassium channel complex antibodies.

    Science.gov (United States)

    Klang, Andrea; Schmidt, Peter; Kneissl, Sibylle; Bagó, Zoltán; Vincent, Angela; Lang, Bethan; Moloney, Teresa; Bien, Christian G; Halász, Péter; Bauer, Jan; Pákozdy, Akos

    2014-05-01

    Voltage-gated potassium channel complex (VGKC-complex) antibody (Ab) encephalitis is a well-recognized form of limbic encephalitis in humans, usually occurring in the absence of an underlying tumor. The patients have a subacute onset of seizures, magnetic resonance imaging findings suggestive of hippocampal inflammation, and high serum titers of Abs against proteins of the VGKC-complex, particularly leucine-rich, glioma-inactivated 1 (LGI1). Most patients are diagnosed promptly and recover substantially with immunotherapies; consequently, neuropathological data are limited. We have recently shown that feline complex partial cluster seizures with orofacial involvement (FEPSO) in cats can also be associated with Abs against VGKC-complexes/LGI1. Here we examined the brains of cats with FEPSO and compared the neuropathological findings with those in a human with VGKC-complex-Ab limbic encephalitis. Similar to humans, cats with VGKC-complex-Ab and FEPSO have hippocampal lesions with only moderate T-cell infiltrates but with marked IgG infiltration and complement C9neo deposition on hippocampal neurons, associated with neuronal loss. These findings provide further evidence that FEPSO is a feline form of VGKC-complex-Ab limbic encephalitis and provide a model for increasing understanding of the human disease.

  3. The valence state of technetium-99 in its complexes with bleomycin, 1-hydroxy-ethylidene-1,1-diphosphonate and human serum albumin

    NARCIS (Netherlands)

    Korteland, J.; Dekker, B.G.; Ligny, C.L. de

    1980-01-01

    The valence state of technetium-99 in its complexes with bleomycin, 1-hydroxy-ethylidene-1,1-diphosphonate and human serum albumin was determined by titration of 99TcO4− with Sn(II) in the presence of these complexing agents. Both direct titration, and addition of an excess of Sn(II) and back-titrat

  4. The valence state of technetium-99 in its complexes with bleomycin, 1-hydroxy-ethylidene-1,1-diphosphonate and human serum albumin

    NARCIS (Netherlands)

    Korteland, J.; Dekker, B.G.; Ligny, C.L. de

    1980-01-01

    The valence state of technetium-99 in its complexes with bleomycin, 1-hydroxy-ethylidene-1,1-diphosphonate and human serum albumin was determined by titration of 99TcO4− with Sn(II) in the presence of these complexing agents. Both direct titration, and addition of an excess of Sn(II) and back-titrat

  5. Human NK Cell Subsets in Pregnancy and Disease: Toward a New Biological Complexity

    Science.gov (United States)

    Cristiani, Costanza Maria; Palella, Eleonora; Sottile, Rosa; Tallerico, Rossana; Garofalo, Cinzia; Carbone, Ennio

    2016-01-01

    In humans, NK cells are mainly identified by the surface expression levels of CD56 and CD16, which differentiate between five functionally different NK cell subsets. However, nowadays NK cells are considered as a more heterogeneous population formed by various subsets differing in function, surface phenotype, and anatomic localization. In human CMV- and hantaviruses-infected subjects, an increased frequency of a NKG2A−CD57+NKG2C+ NK cell subset has been observed, while the phenotype of the NK cell subpopulation associated with cancer may vary according to the specific kind of tumor and its anatomical location. The healthy human lymph nodes contain mainly the CD56bright NK cell subset while in melanoma metastatic lymph nodes the CD56dimCD57+KIR+CCR7+ NK cell subpopulation prevails. The five NK cell subpopulations are found in breast cancer patients, where they differ for expression pattern of chemokine receptors, maturation stage, functional capabilities. In pregnancy, uterine NK cells show a prevalence of the CD56brightCD16− NK cell compartment, whose activity is influenced by KIRs repertoire. This NK cell subset’s super specialization could be explained by (i) the expansion of single mature CD56dim clones, (ii) the recruitment and maturation of CD56bright NK cells through specific stimuli, and (iii) the in situ development of tumor-resident NK cells from tissue-resident CD56bright NK cells independently of the circulating NK cell compartment. This new and unexpected biological feature of the NK cell compartment could be an important source of new biomarkers to improve patients’ diagnosis. PMID:28082990

  6. Monitoring human parvovirus B19 virus-like particles and antibody complexes in solution by fluorescence correlation spectroscopy.

    Science.gov (United States)

    Toivola, Jouni; Michel, Patrik O; Gilbert, Leona; Lahtinen, Tomi; Marjomäki, Varpu; Hedman, Klaus; Vuento, Matti; Oker-Blom, Christian

    2004-01-01

    Fluorescence correlation spectroscopy (FCS) was used in monitoring human parvovirus B19 virus-like particle (VLP) antibody complexes from acute phase and past-immunity serum samples. The Oregon Green 488-labeled VLPs gave an average diffusion coefficient of 1.7 x 10(-7) cm2 s(-1) with an apparent hydrodynamic radius of 14 nm. After incubation of the fluorescent VLPs with an acute phase serum sample, the mobility information obtained from the fluorescence intensity fluctuation by autocorrelation analysis showed an average diffusion coefficient of 1.5 x 10(-8) cm2 s(-1), corresponding to an average radius of 157 nm. In contrast, incubation of the fluorescent VLPs with a past-immunity serum sample gave an average diffusion coefficient of 3.5 x 10(-8) cm2 s(-1) and a radius of 69 nm. A control serum devoid of B19 antibodies caused a change in the diffusion coefficient from 1.7 x 10(-7) to 1.6 x 10(-7) cm2 s(-1), which is much smaller than that observed with acute phase or past-immunity sera. Thus, VLP-antibody complexes with different diffusion coefficients could be identified for the acute phase and past-immunity sera. FCS measurement of VLP-immune complexes could be useful in distinguishing between antibodies present in acute phase or past-immunity sera as well as in titration of the VLPs.

  7. Molecular characterization and mutational analysis of the human B17 subunit of the mitochondrial respiratory chain complex I.

    Science.gov (United States)

    Smeitink, J; Loeffen, J; Smeets, R; Triepels, R; Ruitenbeek, W; Trijbels, F; van den Heuvel, L

    1998-08-01

    Bovine NADH:ubiquinone oxidoreductase (complex 1) of the mitochondrial respiratory chain consists of about 36 nuclear-encoded subunits. We review the current knowledge of the 15 human complex I subunits cloned so far, and report the 598-bp cDNA sequence, the chromosomal localization and the tissue expression of an additional subunit, the B17 subunit. The cDNA open reading frame of B17 comprises 387 bp and encodes a protein of 128 amino acids (calculated Mr 15.5 kDa). There is 82.7% and 78.1% homology, respectively, at the cDNA and amino acid level with the bovine counterpart. The gene of the B17 subunit has been mapped to chromosome 2. Multiple-tissue dot-blots showed ubiquitous expression of the mRNA with relatively higher expression in tissues known for their high energy demand. Of these, kidney showed the highest expression. Mutational analysis of the subunit revealed no mutations or polymorphisms in 20 patients with isolated enzymatic complex I deficiency in cultured skin fibroblasts.

  8. Structural Basis for Fc[gamma]RIIa Recognition of Human IgG and Formation of Inflammatory Signaling Complexes

    Energy Technology Data Exchange (ETDEWEB)

    Ramsland, Paul A.; Farrugia, William; Bradford, Tessa M.; Sardjono, Caroline Tan; Esparon, Sandra; Trist, Halina M.; Powell, Maree S.; Tan, Peck Szee; Cendron, Angela C.; Wines, Bruce D.; Scott, Andrew M.; Hogarth, P. Mark (Burnet); (Monash); (LICR); (Melbourne)

    2011-09-20

    The interaction of Abs with their specific FcRs is of primary importance in host immune effector systems involved in infection and inflammation, and are the target for immune evasion by pathogens. Fc{gamma}RIIa is a unique and the most widespread activating FcR in humans that through avid binding of immune complexes potently triggers inflammation. Polymorphisms of Fc{gamma}RIIa (high responder/low responder [HR/LR]) are linked to susceptibility to infections, autoimmune diseases, and the efficacy of therapeutic Abs. In this article, we define the three-dimensional structure of the complex between the HR (arginine, R134) allele of Fc{gamma}RIIa (Fc{gamma}RIIa-HR) and the Fc region of a humanized IgG1 Ab, hu3S193. The structure suggests how the HR/LR polymorphism may influence Fc{gamma}RIIa interactions with different IgG subclasses and glycoforms. In addition, mutagenesis defined the basis of the epitopes detected by FcR blocking mAbs specific for Fc{gamma}RIIa (IV.3), Fc{gamma}RIIb (X63-21), and a pan Fc{gamma}RII Ab (8.7). The epitopes detected by these Abs are distinct, but all overlap with residues defined by crystallography to contact IgG. Finally, crystal structures of LR (histidine, H134) allele of Fc{gamma}RIIa and Fc{gamma}RIIa-HR reveal two distinct receptor dimers that may represent quaternary states on the cell surface. A model is presented whereby a dimer of Fc{gamma}RIIa-HR binds Ag-Ab complexes in an arrangement that possibly occurs on the cell membrane as part of a larger signaling assembly.

  9. Characterization of a [open quotes]kissing[close quotes] hairpin complex derived from the human immunodeficiency virus genome

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Kung-Yao; Tinoco, Ignacio Jr. (Lawrence Berkeley Lab., CA (United States))

    1994-08-30

    Base-pair formation between hairpin loops-a [open quotes]kissing[close quotes] complex-is an RNA-folding motif that links two elements of RNA secondary structure. It is also a unique protein recognition site involved in regulation of ColE1 plasmid DNA replication. The trans-activation response element (TAR), a hairpin and bulge at the 5[prime] end of the untranslated leader region of the human immunodeficiency virus 1 mRNA, enhances the transcription of the virus and is necessary for viral replication. Gel electrophoresis and absorbance melting curves indicate that a synthesized RNA hairpin (Tar*-16) with a loop sequence complementary to the TAR loop sequence (CUGGGA) associates specifically with a 16-nucleotide TAR hairpin (Tar-16) to form a stable complex. RNase T1 probing indicates that the three guanines in the Tar-16 loop become inaccessible in the complex. NMR imino proton spectra reveal that 5 base pairs are formed between the two hairpin loops (Tar-16 and Tar*-16); only the adenine at the 3[prime] terminus of the TAR loop does not form a base pair with the 5[prime]-terminal uracil of the complementary loop. A 14-nucleotide hairpin [CCUA-(UCCCAG)UAGG] with a loop sequence complementary to the TAR loop is conserved within the gag gene of human immunodeficiency virus 1. A synthesized RNA hairpin corresponding to this conserved sequence also binds to the Tar-16 hairpin with high affinity. It is possible that the same RNA loop-loop interaction occurs during the viral life cycle. 40 refs., 7 figs.

  10. Dynamics in enzymatic protein complexes offer a novel principle for the regulation of melatonin synthesis in the human pineal gland.

    Science.gov (United States)

    Maronde, Erik; Saade, Anastasia; Ackermann, Katrin; Goubran-Botros, Hany; Pagan, Cecile; Bux, Roman; Bourgeron, Thomas; Dehghani, Faramarz; Stehle, Jörg H

    2011-08-01

    Time of day is communicated to the body through rhythmic cues, including pineal gland melatonin synthesis, which is restricted to nighttime. Whereas in most rodents transcriptional regulation of the arylalkylamine N-acetyltransferase (Aanat) gene is essential for rhythmic melatonin synthesis, investigations into nonrodent mammalian species have shown post-transcriptional regulation to be of central importance, with molecular mechanisms still elusive. Therefore, human pineal tissues, taken from routine autopsies were allocated to four time-of-death groups (night/dawn/day/dusk) and analyzed for daytime-dependent changes in phosphorylated AANAT (p31T-AANAT) and in acetyl-serotonin-methyltransferase (ASMT) expression and activity. Protein content, intracellular localization, and colocalization of p31T-AANAT and ASMT were assessed, using immunoblotting, immunofluorescence, and immunoprecipitation techniques. Fresh sheep pineal gland preparations were used for comparative purposes. The amount of p31T-AANAT and ASMT proteins as well as their intracellular localization showed no diurnal variation in autoptic human and fresh sheep pineal glands. Moreover, in human and sheep pineal extracts, AANAT could not be dephosphorylated, which was at variance to data derived from rat pineal extracts. P31T-AANAT and ASMT were often found to colocalize in cellular rod-like structures that were also partly immunoreactive for the pinealocyte process-specific marker S-antigen (arrestin) in both, human and sheep pinealocytes. Protein-protein interaction studies with p31T-AANAT, ASMT, and S-antigen demonstrated a direct association and formation of robust complexes, involving also 14-3-3. This work provides evidence for a regulation principle for AANAT activity in the human pineal gland, which may not be based on a p31T-AANAT phosphorylation/dephosphorylation switch, as described for other mammalian species.

  11. Latent physiological factors of complex human diseases revealed by independent component analysis of clinarrays

    Directory of Open Access Journals (Sweden)

    Chen David P

    2010-10-01

    Full Text Available Abstract Background Diagnosis and treatment of patients in the clinical setting is often driven by known symptomatic factors that distinguish one particular condition from another. Treatment based on noticeable symptoms, however, is limited to the types of clinical biomarkers collected, and is prone to overlooking dysfunctions in physiological factors not easily evident to medical practitioners. We used a vector-based representation of patient clinical biomarkers, or clinarrays, to search for latent physiological factors that underlie human diseases directly from clinical laboratory data. Knowledge of these factors could be used to improve assessment of disease severity and help to refine strategies for diagnosis and monitoring disease progression. Results Applying Independent Component Analysis on clinarrays built from patient laboratory measurements revealed both known and novel concomitant physiological factors for asthma, types 1 and 2 diabetes, cystic fibrosis, and Duchenne muscular dystrophy. Serum sodium was found to be the most significant factor for both type 1 and type 2 diabetes, and was also significant in asthma. TSH3, a measure of thyroid function, and blood urea nitrogen, indicative of kidney function, were factors unique to type 1 diabetes respective to type 2 diabetes. Platelet count was significant across all the diseases analyzed. Conclusions The results demonstrate that large-scale analyses of clinical biomarkers using unsupervised methods can offer novel insights into the pathophysiological basis of human disease, and suggest novel clinical utility of established laboratory measurements.

  12. Predicting human preferences using the block structure of complex social networks

    CERN Document Server

    Guimera, Roger; Moro, Esteban; Sales-Pardo, Marta; 10.1371/journal.pone.0044620

    2012-01-01

    With ever-increasing available data, predicting individuals' preferences and helping them locate the most relevant information has become a pressing need. Understanding and predicting preferences is also important from a fundamental point of view, as part of what has been called a "new" computational social science. Here, we propose a novel approach based on stochastic block models, which have been developed by sociologists as plausible models of complex networks of social interactions. Our model is in the spirit of predicting individuals' preferences based on the preferences of others but, rather than fitting a particular model, we rely on a Bayesian approach that samples over the ensemble of all possible models. We show that our approach is considerably more accurate than leading recommender algorithms, with major relative improvements between 38% and 99% over industry-level algorithms. Besides, our approach sheds light on decision-making processes by identifying groups of individuals that have consistently...

  13. Conformational changes in the bilirubin-human serum albumin complex at extreme alkaline pH

    DEFF Research Database (Denmark)

    Honoré, B; Frandsen, P C

    1986-01-01

    Light-absorption, c.d. and fluorescence of the bilirubin-albumin complex were investigated at extreme alkaline pH. Above pH 11.1 albumin binds the bilirubin