WorldWideScience

Sample records for human pharmacogenomic variations

  1. Systems genetics analysis of pharmacogenomics variation during antidepressant treatment

    DEFF Research Database (Denmark)

    Madsen, Majbritt Busk; Kogelman, L J A; Kadarmideen, H N

    2016-01-01

    Selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants, but the efficacy of the treatment varies significantly among individuals. It is believed that complex genetic mechanisms play a part in this variation. We have used a network based approach to unravel the in...... genes involved in calcium homeostasis. In conclusion, we suggest a difference in genetic interaction networks between initial and subsequent SSRI response.The Pharmacogenomics Journal advance online publication, 18 October 2016; doi:10.1038/tpj.2016.68....

  2. Implementing genomics and pharmacogenomics in the clinic: The National Human Genome Research Institute's genomic medicine portfolio.

    Science.gov (United States)

    Manolio, Teri A

    2016-10-01

    Increasing knowledge about the influence of genetic variation on human health and growing availability of reliable, cost-effective genetic testing have spurred the implementation of genomic medicine in the clinic. As defined by the National Human Genome Research Institute (NHGRI), genomic medicine uses an individual's genetic information in his or her clinical care, and has begun to be applied effectively in areas such as cancer genomics, pharmacogenomics, and rare and undiagnosed diseases. In 2011 NHGRI published its strategic vision for the future of genomic research, including an ambitious research agenda to facilitate and promote the implementation of genomic medicine. To realize this agenda, NHGRI is consulting and facilitating collaborations with the external research community through a series of "Genomic Medicine Meetings," under the guidance and leadership of the National Advisory Council on Human Genome Research. These meetings have identified and begun to address significant obstacles to implementation, such as lack of evidence of efficacy, limited availability of genomics expertise and testing, lack of standards, and difficulties in integrating genomic results into electronic medical records. The six research and dissemination initiatives comprising NHGRI's genomic research portfolio are designed to speed the evaluation and incorporation, where appropriate, of genomic technologies and findings into routine clinical care. Actual adoption of successful approaches in clinical care will depend upon the willingness, interest, and energy of professional societies, practitioners, patients, and payers to promote their responsible use and share their experiences in doing so. Published by Elsevier Ireland Ltd.

  3. Progress of pharmacogenomic research related to minerals and trace elements.

    Science.gov (United States)

    Zeng, Mei-Zi; Tang, Jie; Liu, Zhao-Qian; Zhou, Hong-Hao; Zhang, Wei

    2015-10-01

    Pharmacogenomics explores the variations in both the benefits and the adverse effects of a drug among patients in a target population by analyzing genomic profiles of individual patients. Minerals and trace elements, which can be found in human tissues and maintain normal physiological functions, are also in the focus of pharmacogenomic research. Single-nucleotide polymorphisms (SNPs) affect the metabolism, disposition and efficacy of minerals and trace elements in humans, resulting in changes of body function. This review describes some of the recent progress in pharmacogenomic research related to minerals and trace elements.

  4. Pharmacogenomic Biomarkers

    Directory of Open Access Journals (Sweden)

    Sandra C. Kirkwood

    2002-01-01

    Full Text Available Pharmacogenomic biomarkers hold great promise for the future of medicine and have been touted as a means to personalize prescriptions. Genetic biomarkers for disease susceptibility including both Mendelian and complex disease promise to result in improved understanding of the pathophysiology of disease, identification of new potential therapeutic targets, and improved molecular classification of disease. However essential to fulfilling the promise of individualized therapeutic intervention is the identification of drug activity biomarkers that stratify individuals based on likely response to a particular therapeutic, both positive response, efficacy, and negative response, development of side effect or toxicity. Prior to the widespread clinical application of a genetic biomarker multiple scientific studies must be completed to identify the genetic variants and delineate their functional significance in the pathophysiology of a carefully defined phenotype. The applicability of the genetic biomarker in the human population must then be verified through both retrospective studies utilizing stored or clinical trial samples, and through clinical trials prospectively stratifying patients based on the biomarker. The risk conferred by the polymorphism and the applicability in the general population must be clearly understood. Thus, the development and widespread application of a pharmacogenomic biomarker is an involved process and for most disease states we are just at the beginning of the journey towards individualized therapy and improved clinical outcome.

  5. Implementing genomics and pharmacogenomics in the clinic: The National Human Genome Research Institute’s genomic medicine portfolio

    Science.gov (United States)

    Manolio, Teri A.

    2016-01-01

    Increasing knowledge about the influence of genetic variation on human health and growing availability of reliable, cost-effective genetic testing have spurred the implementation of genomic medicine in the clinic. As defined by the National Human Genome Research Institute (NHGRI), genomic medicine uses an individual’s genetic information in his or her clinical care, and has begun to be applied effectively in areas such as cancer genomics, pharmacogenomics, and rare and undiagnosed diseases. In 2011 NHGRI published its strategic vision for the future of genomic research, including an ambitious research agenda to facilitate and promote the implementation of genomic medicine. To realize this agenda, NHGRI is consulting and facilitating collaborations with the external research community through a series of “Genomic Medicine Meetings,” under the guidance and leadership of the National Advisory Council on Human Genome Research. These meetings have identified and begun to address significant obstacles to implementation, such as lack of evidence of efficacy, limited availability of genomics expertise and testing, lack of standards, and diffficulties in integrating genomic results into electronic medical records. The six research and dissemination initiatives comprising NHGRI’s genomic research portfolio are designed to speed the evaluation and incorporation, where appropriate, of genomic technologies and findings into routine clinical care. Actual adoption of successful approaches in clinical care will depend upon the willingness, interest, and energy of professional societies, practitioners, patients, and payers to promote their responsible use and share their experiences in doing so. PMID:27612677

  6. Pharmacogenomics and cardiovascular disease

    DEFF Research Database (Denmark)

    Weeke, Peter; Roden, Dan M

    2013-01-01

    Variability in drug responsiveness is a sine qua non of modern therapeutics, and the contribution of genomic variation is increasingly recognized. Investigating the genomic basis for variable responses to cardiovascular therapies has been a model for pharmacogenomics in general and has established...... resulted in changes to the product labels but also have led to development of initial clinical guidelines that consider how to facilitate incorporating genetic information to the bedside. This review summarizes the state of knowledge in cardiovascular pharmacogenomics and considers how variants described...

  7. Asymmetry in scientific method and limits to cross-disciplinary dialogue: toward a shared language and science policy in pharmacogenomics and human disease genetics.

    Science.gov (United States)

    Ozdemir, Vural; Williams-Jones, Bryn; Graham, Janice E; Preskorn, Sheldon H; Gripeos, Dimitrios; Glatt, Stephen J; Friis, Robert H; Reist, Christopher; Szabo, Sandor; Lohr, James B; Someya, Toshiyuki

    2007-04-01

    Pharmacogenomics is a hybrid field of experimental science at the intersection of human disease genetics and clinical pharmacology sharing applications of the new genomic technologies. But this hybrid field is not yet stable or fully integrated, nor is science policy in pharmacogenomics fully equipped to resolve the challenges of this emerging hybrid field. The disciplines of human disease genetics and clinical pharmacology contain significant differences in their scientific practices. Whereas clinical pharmacology originates as an experimental science, human disease genetics is primarily observational in nature. The result is a significant asymmetry in scientific method that can differentially impact the degree to which gene-environment interactions are discerned and, by extension, the study sample size required in each discipline. Because the number of subjects enrolled in observational genetic studies of diseases is characteristically viewed as an important criterion of scientific validity and reliability, failure to recognize discipline-specific requirements for sample size may lead to inappropriate dismissal or silencing of meritorious, although smaller-scale, craft-based pharmacogenomic investigations using an experimental study design. Importantly, the recognition that pharmacogenomics is an experimental science creates an avenue for systematic policy response to the ethical imperative to prospectively pursue genetically customized therapies before regulatory approval of pharmaceuticals. To this end, we discuss the critical role of interdisciplinary engagement between medical sciences, policy, and social science. We emphasize the need for development of shared standards across scientific, methodologic, and socioethical epistemologic divides in the hybrid field of pharmacogenomics to best serve the interests of public health.

  8. Pharmacogenomics in the newborn

    Directory of Open Access Journals (Sweden)

    Mirta Corsello

    2013-06-01

    Full Text Available Genetic variation is an important determinant affecting the individual response to drugs. Considering the high variability in each individual genotype, the development of individualized therapies, according to the intrinsic features of the single patient, represents one of the most challenging problems in pharmacology. Pharmacogenetics analyzes the relationship between drug response and individual genetic differences, while pharmacogenomics analyzes the effect of genetic variations in patients’ response to different drugs. The aim of these two research fields is to predict either drug response or the potential for the development of drug-related side effects. In particular, an important endpoint of pharmacogenomics should be to identify which group of patients responds positively, which patients are nonresponders and who will develop adverse reactions for the same drug and dose. Nevertheless, the utility of the pharmacogenetic and pharmacogenomic information as predictor of the activity of a specific drug-metabolizing enzyme or transporter should be cautiously limited to those developmental periods in which genotype-phenotype concordance is known. This means that in the perinatal period a special attention on the peculiar pharmacokinetic properties typical of this life period should be guaranteed. This means that effective and safe drug administration during fetal and neonatal life should consider the interindividual genotypic variability leading to different expression and activity of various enzymes. Both pharmacogenetics and pharmacogenomics may have a crucial role in the achievement of an individualized medicine. Prospective clinical trials analyzing the utility, safety, and cost-effectiveness of an individualized medicine based on the individual genotype are required.Proceedings of the 9th International Workshop on Neonatology · Cagliari (Italy · October 23rd-26th, 2013 · Learned lessons, changing practice and cutting-edge research

  9. Significance of Pharmacogenetics and Pharmacogenomics Research in Current Medical Practice.

    Science.gov (United States)

    Prakash, Swayam; Agrawal, Suraksha

    2016-01-01

    Human genome sequencing highlights the involvement of genetic variation towards differential risk of human diseases, presence of different phenotypes, and response to pharmacological elements. This brings the field of personalized medicine to forefront in the era of modern health care. Numerous recent approaches have shown that how variation in the genome at single nucleotide level can be used in pharmacological research. The two broad aspects that deal with pharmacological research are pharmacogenetics and pharmacogenomics. This review encompasses how these variations have created the basis of pharmacogenetics and pharmacogenomics research and important milestones accomplished in these two fields in different diseases. It further discusses at length their importance in disease diagnosis, response of drugs, and various treatment modalities on the basis of genetic determinants.

  10. European Medicines Agency initiatives and perspectives on pharmacogenomics

    Science.gov (United States)

    Ehmann, Falk; Caneva, Laura; Papaluca, Marisa

    2014-01-01

    Pharmacogenomics, the study of variations of DNA and RNA characteristics as related to drug response, has become an integral part of drug development and pharmacovigilance, as reflected by the incorporation of pharmacogenomic data in EU product information. In this short review article, we describe recent European Medicines Agency initiatives intended to support further the implementation of pharmacogenomics in drug development and surveillance so that patients and the public can benefit from advances in genomic science and technology. PMID:24433361

  11. 4th Annual Pharmacogenomics and Medicine Lectures.

    Science.gov (United States)

    Oestreicher, P

    2001-08-01

    In the future, pharmacogenomics will play an important role in the treatment of patients by making it possible to predict drug response based on an individual's genetic make-up. Similarly, pharmacogenomics may be used to reduce the probability that adverse effects will occur. The use of a patient's genetic information will lead to greater predictability in clinical outcomes and personalisation of medical care. Pharmacogenomic information can also aid in drug development by helping to select individuals that are likely to respond to a medication for participation in clinical trials. Integration of pharmacogenomics into the healthcare system has a number of potential economic benefits, including reduced costs of healthcare and drug discovery. The FDA has no specific plans to regulate therapy-guiding pharmacogenomic tests, which are different from diagnostic genetic tests. There are a number of ethical issues related to pharmacogenomics, including the credibility of the system for protecting the rights and welfare of human research subjects, general concerns about genetic research, privacy issues and equitable distribution of the technology. To ensure integration of pharmacogenomics into the healthcare system it will be important to obtain public support through education about the benefits and risks of this technology.

  12. The fallacy of racial pharmacogenomics

    Directory of Open Access Journals (Sweden)

    S.D.J. Pena

    2011-04-01

    Full Text Available Personalized pharmacogenomics aims to use individual genotypes to direct medical treatment. Unfortunately, the loci relevant for the pharmacokinetics and especially the pharmacodynamics of most drugs are still unknown. Moreover, we still do not understand the role that individual genotypes play in modulating the pathogenesis, the clinical course and the susceptibility to drugs of human diseases which, although appearing homogeneous on the surface, may vary from patient to patient. To try to deal with this situation, it has been proposed to use interpopulational variability as a reference for drug development and prescription, leading to the development of "race-targeted drugs". Given the present limitations of genomic knowledge and of the tools needed to fully implement it today, some investigators have proposed to use racial criteria as a palliative measure until personalized pharmacogenomics is fully developed. This was the rationale for the FDA approval of BiDil for treatment of heart failure in African Americans. I will evaluate the efficacy and safety of racial pharmacogenomics here and conclude that it fails on both counts. Next I shall review the perspectives and the predicted rate of development of clinical genomic studies. The conclusion is that "next-generation" genomic sequencing is advancing at a tremendous rate and that true personalized pharmacogenomics, based on individual genotyping, should soon become a clinical reality.

  13. Pharmspresso: a text mining tool for extraction of pharmacogenomic concepts and relationships from full text.

    Science.gov (United States)

    Garten, Yael; Altman, Russ B

    2009-02-05

    Pharmacogenomics studies the relationship between genetic variation and the variation in drug response phenotypes. The field is rapidly gaining importance: it promises drugs targeted to particular subpopulations based on genetic background. The pharmacogenomics literature has expanded rapidly, but is dispersed in many journals. It is challenging, therefore, to identify important associations between drugs and molecular entities--particularly genes and gene variants, and thus these critical connections are often lost. Text mining techniques can allow us to convert the free-style text to a computable, searchable format in which pharmacogenomic concepts (such as genes, drugs, polymorphisms, and diseases) are identified, and important links between these concepts are recorded. Availability of full text articles as input into text mining engines is key, as literature abstracts often do not contain sufficient information to identify these pharmacogenomic associations. Thus, building on a tool called Textpresso, we have created the Pharmspresso tool to assist in identifying important pharmacogenomic facts in full text articles. Pharmspresso parses text to find references to human genes, polymorphisms, drugs and diseases and their relationships. It presents these as a series of marked-up text fragments, in which key concepts are visually highlighted. To evaluate Pharmspresso, we used a gold standard of 45 human-curated articles. Pharmspresso identified 78%, 61%, and 74% of target gene, polymorphism, and drug concepts, respectively. Pharmspresso is a text analysis tool that extracts pharmacogenomic concepts from the literature automatically and thus captures our current understanding of gene-drug interactions in a computable form. We have made Pharmspresso available at http://pharmspresso.stanford.edu.

  14. Current clinical evidence on pioglitazone pharmacogenomics

    Directory of Open Access Journals (Sweden)

    Marina eKawaguchi-Suzuki

    2013-11-01

    Full Text Available Pioglitazone is the most widely used thiazolidinedione and acts as an insulin-sensitizer through activation of the Peroxisome Proliferator-Activated Receptor-γ (PPARγ. Pioglitazone is approved for use in the management of type 2 diabetes mellitus, but its use in other therapeutic areas is increasing due to pleiotropic effects. In this hypothesis article, the current clinical evidence on pioglitazone pharmacogenomics is summarized and related to variability in pioglitazone response. How genetic variation in the human genome affects the pharmacokinetics and pharmacodynamics of pioglitazone was examined. For pharmacodynamic effects, hypoglycemic and anti-atherosclerotic effects, risks of fracture or edema, and the increase in body mass index in response to pioglitazone based on genotype were examined. The genes CYP2C8 and PPARG are the most extensively studied to date and selected polymorphisms contribute to respective variability in pioglitazone pharmacokinetics and pharmacodynamics. We hypothesized that genetic variation in pioglitazone pathway genes contributes meaningfully to the clinically observed variability in drug response. To test the hypothesis that genetic variation in PPARG associates with variability in pioglitazone response, we conducted a meta-analysis to synthesize the currently available data on the PPARG p.Pro12Ala polymorphism. The results showed that PPARG 12Ala carriers had a more favorable change in fasting blood glucose from baseline as compared to patients with the wild-type Pro12Pro genotype (p=0.018. Unfortunately, findings for many other genes lack replication in independent cohorts to confirm association; further studies are needed. Also, the biological functionality of these polymorphisms is unknown. Based on current evidence, we propose that pharmacogenomics may provide an important tool to individualize pioglitazone therapy and better optimize therapy in patients with T2DM or other conditions for which pioglitazone

  15. Pharmacogenomics and its potential impact on drug and formulation development.

    Science.gov (United States)

    Regnstrom, Karin; Burgess, Diane J

    2005-01-01

    Recent advances in genomic research have provided the basis for new insights into the importance of genetic and genomic markers during the different stages of drug development. A new field of research, pharmacogenomics, which studies the relationship between drug effects and the genome, has emerged. Structural pharmacogenomics maps the complete DNA sequences of whole genomes (genotypes) including individual variations, and functional pharmacogenomics assesses the expression levels of thousands of genes in one single experiment. Together, these two areas of pharmacogenomics have generated massive databases, which have become a challenge for the research field of informatics and have fostered a new branch of research, bioinformatics. If skillfully used, the databases generated by pharmacogenomics together with data mining on the Web promise to improve the drug development process in a variety of areas: identification of drug targets, evaluation of toxicity, classification of diseases, evaluation of formulations, assessment of drug response and treatment, post-marketing applications, and development of personalized medicines.

  16. Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design

    Science.gov (United States)

    Ishikawa, Toshihisa; Tamura, Ai; Saito, Hikaru; Wakabayashi, Kanako; Nakagawa, Hiroshi

    2005-10-01

    In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug-drug interactions. We recently developed methods for high-speed functional screening and quantitative structure-activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.

  17. Pharmacogenomics in Oncology Care

    Directory of Open Access Journals (Sweden)

    Kelly K Filipski

    2014-04-01

    Full Text Available Cancer pharmacogenomics have contributed a number of important discoveries to current cancer treatment, changing the paradigm of treatment decisions. Both somatic and germline mutations are utilized to better understand the underlying biology of cancer growth and treatment response. The level of evidence required to fully translate pharmacogenomic discoveries into the clinic has relied heavily on randomized clinical trials. In this review, the use of observational studies, as well as, the use of adaptive trials and next generation sequencing to develop the required level of evidence for clinical implementation are discussed.

  18. Progress towards the integration of pharmacogenomics in practice.

    Science.gov (United States)

    Mooney, Sean D

    2015-05-01

    Understanding the role genes and genetic variants play in clinical treatment response continues to be an active area of research with the goal of common clinical use. This goal has developed into today's industry of pharmacogenomics, where new drug-gene relationships are discovered and further characterized, published and then curated into national and international resources for use by researchers and clinicians. These efforts have given us insight into what a pharmacogenomic variant is, and how it differs from human disease variants and common polymorphisms. While publications continue to reveal pharmacogenomic relationships between genes and specific classes of drugs, many challenges remain toward the goal of widespread use clinically. First, the clinical guidelines for pharmacogenomic testing are still in their infancy. Second, sequencing technologies are changing rapidly making it somewhat unclear what genetic data will be available to the clinician at the time of care. Finally, what and when to return data to a patient is an area under constant debate. New innovations such as PheWAS approaches and whole genome sequencing studies are enabling a tsunami of new findings. In this review, pharmacogenomic variants, pharmacogenomic resources, interpretation clinical guidelines and challenges, such as WGS approaches, and the impact of pharmacogenomics on drug development and regulatory approval are reviewed.

  19. Ethiopian health care professionals' knowledge, attitude, and interests toward pharmacogenomics.

    Science.gov (United States)

    Abdela, Ousman Abubeker; Bhagavathula, Akshaya Srikanth; Gebreyohannes, Eyob Alemayehu; Tegegn, Henok Getachew

    2017-01-01

    Pharmacogenomics is a field of science which studies the impact of inheritance on individual variation in medication therapy response. We assessed healthcare professionals' knowledge, attitude, and interest toward pharmacogenomics. A cross-sectional survey was conducted using a 32-item questionnaire among physicians, nurses, and pharmacists who were working at the University of Gondar Referral and Teaching Hospital in northwest Ethiopia. Descriptive statistics was applied, and the categorical variables were summarized as frequency and percentages. An analysis of variance (ANOVA) test was performed to compare mean scores among health professionals. A p -value of much as 95% of the variability in drug disposition and effects. The ability to accurately apply their knowledge to drug therapy selection, dosing, or monitoring parameter was reported by 35.3% of the participants. More than two-thirds (69.2%) of participants thought that pharmacogenomic testing will allow the identification of the right drug with less side effects. Most of the participants (83.2%) also requested to have training on pharmacogenomics. Participants showed limited knowledge, but they had positive attitude toward pharmacogenomics. Educational programs focusing on pharmacogenomic testing and its clinical application need to be emphasized.

  20. Integrating pharmacogenomics into pharmacy practice via medication therapy management.

    Science.gov (United States)

    Reiss, Susan M

    2011-01-01

    To explore the application and integration of pharmacogenomics in pharmacy clinical practice via medication therapy management (MTM) to improve patient care. Department of Health & Human Services (HHS) Personalized Health Care Initiative, Food and Drug Administration (FDA) pharmacogenomics activity, and findings from the Utilizing E-Prescribing Technologies to Integrate Pharmacogenomics into Prescribing and Dispensing Practices Stakeholder Workshop, convened by the American Pharmacists Association (APhA) on March 5, 2009. Participants at the Stakeholder Workshop included diverse representatives from pharmacy, medicine, pathology, health information technology (HIT), standards, science, academia, government, and others with a key interest in the clinical application of pharmacogenomics. In 2006, HHS initiated the Personalized Health Care Initiative with the goal of building the foundation for the delivery of gene-based care, which may prove to be more effective for large patient subpopulations. In the years since the initiative was launched, drug manufacturers and FDA have begun to incorporate pharmacogenomic data and applications of this information into the drug development, labeling, and approval processes. New applications and processes for using this emerging pharmacogenomics data are needed to effectively integrate this information into clinical practice. Building from the findings of a stakeholder workshop convened by APhA and the advancement of the pharmacist's collaborative role in patient care through MTM, emerging roles for pharmacists using pharmacogenomic information to improve patient care are taking hold. Realizing the potential role of the pharmacist in pharmacogenomics through MTM will require connectivity of pharmacists into the electronic health record infrastructure to permit the exchange of pertinent health information among all members of a patient's health care team. Addressing current barriers, concerns, and system limitations and developing

  1. Pharmacogenomics in diabetes mellitus

    DEFF Research Database (Denmark)

    Zhou, Kaixin; Pedersen, Helle Krogh; Dawed, Adem Y.

    2016-01-01

    . We highlight mechanistic insights from the study of adverse effects and the efficacy of antidiabetic drugs. The identification of extreme sulfonylurea sensitivity in patients with diabetes mellitus owing to heterozygous mutations in HNF1A represents a clear example of how pharmacogenetics can direct...... patient care. However, pharmacogenomic studies of response to antidiabetic drugs in T2DM has yet to be translated into clinical practice, although some moderate genetic effects have now been described that merit follow-up in trials in which patients are selected according to genotype. We also discuss how...

  2. Physicians' pharmacogenomics information needs and seeking behavior: a study with case vignettes.

    Science.gov (United States)

    Heale, Bret S E; Khalifa, Aly; Stone, Bryan L; Nelson, Scott; Del Fiol, Guilherme

    2017-08-01

    Genetic testing, especially in pharmacogenomics, can have a major impact on patient care. However, most physicians do not feel that they have sufficient knowledge to apply pharmacogenomics to patient care. Online information resources can help address this gap. We investigated physicians' pharmacogenomics information needs and information-seeking behavior, in order to guide the design of pharmacogenomics information resources that effectively meet clinical information needs. We performed a formative, mixed-method assessment of physicians' information-seeking process in three pharmacogenomics case vignettes. Interactions of 6 physicians' with online pharmacogenomics resources were recorded, transcribed, and analyzed for prominent themes. Quantitative data included information-seeking duration, page navigations, and number of searches entered. We found that participants searched an average of 8 min per case vignette, spent less than 30 s reviewing specific content, and rarely refined search terms. Participants' information needs included a need for clinically meaningful descriptions of test interpretations, a molecular basis for the clinical effect of drug variation, information on the logistics of carrying out a genetic test (including questions related to cost, availability, test turn-around time, insurance coverage, and accessibility of expert support).Also, participants sought alternative therapies that would not require genetic testing. This study of pharmacogenomics information-seeking behavior indicates that content to support their information needs is dispersed and hard to find. Our results reveal a set of themes that information resources can use to help physicians find and apply pharmacogenomics information to the care of their patients.

  3. Understanding human DNA sequence variation.

    Science.gov (United States)

    Kidd, K K; Pakstis, A J; Speed, W C; Kidd, J R

    2004-01-01

    Over the past century researchers have identified normal genetic variation and studied that variation in diverse human populations to determine the amounts and distributions of that variation. That information is being used to develop an understanding of the demographic histories of the different populations and the species as a whole, among other studies. With the advent of DNA-based markers in the last quarter century, these studies have accelerated. One of the challenges for the next century is to understand that variation. One component of that understanding will be population genetics. We present here examples of many of the ways these new data can be analyzed from a population perspective using results from our laboratory on multiple individual DNA-based polymorphisms, many clustered in haplotypes, studied in multiple populations representing all major geographic regions of the world. These data support an "out of Africa" hypothesis for human dispersal around the world and begin to refine the understanding of population structures and genetic relationships. We are also developing baseline information against which we can compare findings at different loci to aid in the identification of loci subject, now and in the past, to selection (directional or balancing). We do not yet have a comprehensive understanding of the extensive variation in the human genome, but some of that understanding is coming from population genetics.

  4. Pharmacogenomics and migraine: possible implications

    DEFF Research Database (Denmark)

    Tfelt-Hansen, P.; Brosen, K.

    2008-01-01

    Pharmacogenomics is the science about how inherited factors influence the effects of drugs. Drug response is always a result of mutually interacting genes with important modifications from environmental and constitutional factors. Based on the genetic variability of pharmacokinetic and in some...... cases pharmacodynamic variability we mention possible implications for the acute and preventive treatment of migraine. Pharmacogenomics will most likely in the future be one part of our therapeutic armamentarium and will provide a stronger scientific basis for optimizing drug therapy on the basis...

  5. Pharmacogenomics and the challenge of health disparities.

    Science.gov (United States)

    Lee, S S

    2009-01-01

    This paper examines emerging technologies and recent research on population differences in pharmacogenomics and the perspectives of scientists, community advocates, policymakers, and social critics on the use of race as a proxy for genetic variation. The discussion focuses on how recent developments in genomic science impact social understandings of racial difference and the public health goal to eliminate ongoing health disparities among racially identified groups. This paper examines how factors such as governmental policies--requiring the use of racial and ethnic categories in genetic research and increasing interest in identifying untapped racial market niches by the pharmaceutical and biotechnology industries--and weak governmental oversight of race-based therapeutics converge to create an 'infrastructure of racialization' that may alter the vision of personalized medicine that has been so highly anticipated. This paper argues that significant public investment in pharmacogenomics requires careful consideration of the emerging discourse that tethers racial justice to notions of racial biology and discusses the social and ethical implications for the pendulum shift towards a geneticization of race in drug development. Copyright 2009 S. Karger AG, Basel.

  6. Metformin Pharmacogenomics: Current Status and Future Directions

    Science.gov (United States)

    Pawlyk, Aaron C.; Giacomini, Kathleen M.; McKeon, Catherine; Shuldiner, Alan R.

    2014-01-01

    The incidence of type 2 diabetes (T2D) and its costs to the health care system continue to rise. Despite the availability of at least 10 drug classes for the treatment of T2D, metformin remains the most widely used first-line pharmacotherapy for its treatment; however, marked interindividual variability in response and few clinical or biomarker predictors of response reduce its optimal use. As clinical care moves toward precision medicine, a variety of broad discovery-based “omics” approaches will be required. Technical innovation, decreasing sequencing cost, and routine sample storage and processing has made pharmacogenomics the most widely applied discovery-based approach to date. This opens up the opportunity to understand the genetics underlying the interindividual variation in metformin responses in order for clinicians to prescribe specific treatments to given individuals for better efficacy and safety: metformin for those predicted to respond and alternative therapies for those predicted to be nonresponders or who are at increased risk for adverse side effects. Furthermore, understanding of the genetic determinants of metformin response may lead to the identification of novel targets and development of more effective agents for diabetes treatment. The goals of this workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases were to review the state of research on metformin pharmacogenomics, discuss the scientific and clinical hurdles to furthering our knowledge of the variability in patient responses to metformin, and consider how to effectively use this increased understanding to improve patient outcomes. PMID:25060887

  7. Pharmacogenetics and pharmacogenomics as tools in cancer therapy.

    Science.gov (United States)

    Rodríguez-Vicente, Ana E; Lumbreras, Eva; Hernández, Jesus M; Martín, Miguel; Calles, Antonio; Otín, Carlos López; Algarra, Salvador Martín; Páez, David; Taron, Miquel

    2016-03-01

    Pharmacogenetics and pharmacogenomics (PGx) are rapidly growing fields that aim to elucidate the genetic basis for the interindividual differences in drug response. PGx approaches have been applied to many anticancer drugs in an effort to identify relevant inherited or acquired genetic variations that may predict patient response to chemotherapy and targeted therapies. In this article, we discuss the advances in the field of cancer pharmacogenetics and pharmacogenomics, driven by the recent technological advances and new revolutionary massive sequencing technologies and their application to elucidate the genetic bases for interindividual drug response and the development of biomarkers able to personalize drug treatments. Specifically, we present recent progress in breast cancer molecular classifiers, cell-free circulating DNA as a prognostic and predictive biomarker in cancer, patient-derived tumor xenograft models, chronic lymphocytic leukemia genomic landscape, and current pharmacogenetic advances in colorectal cancer. This review is based on the lectures presented by the speakers of the symposium "Pharmacogenetics and Pharmacogenomics as Tools in Cancer Therapy" from the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society (SEFF), held in Madrid (Spain) on April 21, 2015.

  8. Ethiopian health care professionals’ knowledge, attitude, and interests toward pharmacogenomics

    Directory of Open Access Journals (Sweden)

    Abdela OA

    2017-12-01

    Full Text Available Ousman Abubeker Abdela, Akshaya Srikanth Bhagavathula, Eyob Alemayehu Gebreyohannes, Henok Getachew Tegegn Department of Clinical Pharmacy, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia Background: Pharmacogenomics is a field of science which studies the impact of inheritance on individual variation in medication therapy response.Aim: We assessed healthcare professionals’ knowledge, attitude, and interest toward pharmacogenomics.Methods: A cross-sectional survey was conducted using a 32-item questionnaire among physicians, nurses, and pharmacists who were working at the University of Gondar Referral and Teaching Hospital in northwest Ethiopia. Descriptive statistics was applied, and the categorical variables were summarized as frequency and percentages. An analysis of variance (ANOVA test was performed to compare mean scores among health professionals. A p-value of <0.05 was considered as statistically significant.Results: Of 292 health professionals who responded, the majority were male (60% and the mean age of study participants was 27.00 (±4.85 SD years. The mean knowledge scores of all participants, pharmacists, physicians, and nurses were 2.343±1.109, 2.671±1.059, 2.375±1.093, and 2.173±1.110, respectively. Based on the ANOVA test, a statistically significant difference was noted in mean knowledge score between pharmacists and nurses (p=0.002. More than two-thirds (67.33% of nurses, 42.86% of pharmacists, and 40.27% of physicians who participated did not know that genetic variations can account for as much as 95% of the variability in drug disposition and effects. The ability to accurately apply their knowledge to drug therapy selection, dosing, or monitoring parameter was reported by 35.3% of the participants. More than two-thirds (69.2% of participants thought that pharmacogenomic testing will allow the identification of the right drug with less side effects. Most of the

  9. Inconsistency in large pharmacogenomic studies

    DEFF Research Database (Denmark)

    Haibe-Kains, Benjamin; El-Hachem, Nehme; Birkbak, Nicolai Juul

    2013-01-01

    Two large-scale pharmacogenomic studies were published recently in this journal. Genomic data are well correlated between studies; however, the measured drug response data are highly discordant. Although the source of inconsistencies remains uncertain, it has potential implications for using...

  10. Stakeholder views on pharmacogenomic testing.

    Science.gov (United States)

    Patel, Haridarshan N; Ursan, Iulia D; Zueger, Patrick M; Cavallari, Larisa H; Pickard, A Simon

    2014-02-01

    Pharmacogenomics has an important role in the evolution of personalized medicine, and its widespread uptake may ultimately depend on the interests and perspectives of key players in health care. Our aim was to summarize studies on stakeholder perspectives and attitudes toward pharmacogenomic testing. Thus, we conducted a review of original research studies that reported stakeholder views on pharmacogenomic testing using a structured approach in PubMed, International Pharmaceutical Abstracts, Cumulative Index to Nursing and Allied Health Literature, and EMBASE. A standardized data abstraction form was developed that included stakeholder group of interest-patients, general public, providers, and payers. Stakeholder views regarding barriers to pharmacogenetic implementation were organized into the following themes: ancillary information-related, clinical, economic, educational, ethical or legal, medical mistrust, and practicality. Of 34 studies that met our inclusion criteria, 37 perspectives were reported (15 on providers, 9 on the general public, 9 on patients, and 4 on payers). The most common topics that arose in studies of providers related to clinical usefulness of genetic data (n=11) and educational needs (n=11). Among the general public, the most common concerns were medical mistrust (n=5), insufficient education (n=5), and practicality (n=5). The most prevalent issues from the patient perspective were ethical or legal (n=6) and economic (n=5) issues. Among payers, leading issues were practicality (n=4) and clinical usefulness (n=3). There was overlap in the topics and concerns across stakeholder perspectives, including lack of knowledge about pharmacogenomic testing. Views on issues related to privacy, cost, and test result dissemination varied by stakeholder perspective. Limited research had been conducted in underrepresented groups. Efforts to address the issues raised by stakeholders may facilitate the implementation of pharmacogenomic testing into

  11. Pharmacometabolomics-aided Pharmacogenomics in Autoimmune Disease

    Directory of Open Access Journals (Sweden)

    Theodora Katsila

    2016-03-01

    Full Text Available Inter-individual variability has been a major hurdle to optimize disease management. Precision medicine holds promise for improving health and healthcare via tailor-made therapeutic strategies. Herein, we outline the paradigm of “pharmacometabolomics-aided pharmacogenomics” in autoimmune diseases. We envisage merging pharmacometabolomic and pharmacogenomic data (to address the interplay of genomic and environmental influences with information technologies to facilitate data analysis as well as sense- and decision-making on the basis of synergy between artificial and human intelligence. Humans can detect patterns, which computer algorithms may fail to do so, whereas data-intensive and cognitively complex settings and processes limit human ability. We propose that better-informed, rapid and cost-effective omics studies need the implementation of holistic and multidisciplinary approaches.

  12. Size variation in Middle Pleistocene humans.

    Science.gov (United States)

    Arsuaga, J L; Carretero, J M; Lorenzo, C; Gracia, A; Martínez, I; Bermúdez de Castro, J M; Carbonell, E

    1997-08-22

    It has been suggested that European Middle Pleistocene humans, Neandertals, and prehistoric modern humans had a greater sexual dimorphism than modern humans. Analysis of body size variation and cranial capacity variation in the large sample from the Sima de los Huesos site in Spain showed instead that the sexual dimorphism is comparable in Middle Pleistocene and modern populations.

  13. Anatomy, Medical Education, and Human Ancestral Variation

    Science.gov (United States)

    Strkalj, Goran; Spocter, Muhammad A.; Wilkinson, A. Tracey

    2011-01-01

    It is argued in this article that the human body both in health and disease cannot be fully understood without adequately accounting for the different levels of human variation. The article focuses on variation due to ancestry, arguing that the inclusion of information pertaining to ancestry in human anatomy teaching materials and courses should…

  14. MicroRNA pharmacogenomics

    DEFF Research Database (Denmark)

    Rukov, Jakob Lewin; Shomron, Noam

    2011-01-01

    polymorphisms, copy number variations or differences in gene expression levels of drug metabolizing or transporting genes and drug targets. In this review paper, we focus instead on microRNAs (miRNAs): small noncoding RNAs, prevalent in metazoans, that negatively regulate gene expression in many cellular...

  15. Warfarin Pharmacogenomics in Diverse Populations.

    Science.gov (United States)

    Kaye, Justin B; Schultz, Lauren E; Steiner, Heidi E; Kittles, Rick A; Cavallari, Larisa H; Karnes, Jason H

    2017-09-01

    Genotype-guided warfarin dosing algorithms are a rational approach to optimize warfarin dosing and potentially reduce adverse drug events. Diverse populations, such as African Americans and Latinos, have greater variability in warfarin dose requirements and are at greater risk for experiencing warfarin-related adverse events compared with individuals of European ancestry. Although these data suggest that patients of diverse populations may benefit from improved warfarin dose estimation, the vast majority of literature on genotype-guided warfarin dosing, including data from prospective randomized trials, is in populations of European ancestry. Despite differing frequencies of variants by race/ethnicity, most evidence in diverse populations evaluates variants that are most common in populations of European ancestry. Algorithms that do not include variants important across race/ethnic groups are unlikely to benefit diverse populations. In some race/ethnic groups, development of race-specific or admixture-based algorithms may facilitate improved genotype-guided warfarin dosing algorithms above and beyond that seen in individuals of European ancestry. These observations should be considered in the interpretation of literature evaluating the clinical utility of genotype-guided warfarin dosing. Careful consideration of race/ethnicity and additional evidence focused on improving warfarin dosing algorithms across race/ethnic groups will be necessary for successful clinical implementation of warfarin pharmacogenomics. The evidence for warfarin pharmacogenomics has a broad significance for pharmacogenomic testing, emphasizing the consideration of race/ethnicity in discovery of gene-drug pairs and development of clinical recommendations for pharmacogenetic testing. © 2017 Pharmacotherapy Publications, Inc.

  16. Pharmacogenomics in epilepsy.

    Science.gov (United States)

    Balestrini, Simona; Sisodiya, Sanjay M

    2018-02-22

    There is high variability in the response to antiepileptic treatment across people with epilepsy. Genetic factors significantly contribute to such variability. Recent advances in the genetics and neurobiology of the epilepsies are establishing the basis for a new era in the treatment of epilepsy, focused on each individual and their specific epilepsy. Variation in response to antiepileptic drug treatment may arise from genetic variation in a range of gene categories, including genes affecting drug pharmacokinetics, and drug pharmacodynamics, but also genes held to actually cause the epilepsy itself. From a purely pharmacogenetic perspective, there are few robust genetic findings with established evidence in epilepsy. Many findings are still controversial with anecdotal or less secure evidence and need further validation, e.g. variation in genes for transporter systems and antiepileptic drug targets. The increasing use of genetic sequencing and the results of large-scale collaborative projects may soon expand the established evidence. Precision medicine treatments represent a growing area of interest, focussing on reversing or circumventing the pathophysiological effects of specific gene mutations. This could lead to a dramatic improvement of the effectiveness and safety of epilepsy treatments, by targeting the biological mechanisms responsible for epilepsy in each specific individual. Whilst much has been written about epilepsy pharmacogenetics, there does now seem to be building momentum that promises to deliver results of use in clinic. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  17. HGVA: the Human Genome Variation Archive

    OpenAIRE

    Lopez, Javier; Coll, Jacobo; Haimel, Matthias; Kandasamy, Swaathi; Tarraga, Joaquin; Furio-Tari, Pedro; Bari, Wasim; Bleda, Marta; Rueda, Antonio; Gr?f, Stefan; Rendon, Augusto; Dopazo, Joaquin; Medina, Ignacio

    2017-01-01

    Abstract High-profile genomic variation projects like the 1000 Genomes project or the Exome Aggregation Consortium, are generating a wealth of human genomic variation knowledge which can be used as an essential reference for identifying disease-causing genotypes. However, accessing these data, contrasting the various studies and integrating those data in downstream analyses remains cumbersome. The Human Genome Variation Archive (HGVA) tackles these challenges and facilitates access to genomic...

  18. Pharmacogenomics of GPCR Drug Targets

    DEFF Research Database (Denmark)

    Hauser, Alexander Sebastian; Chavali, Sreenivas; Masuho, Ikuo

    2018-01-01

    Natural genetic variation in the human genome is a cause of individual differences in responses to medications and is an underappreciated burden on public health. Although 108 G-protein-coupled receptors (GPCRs) are the targets of 475 (∼34%) Food and Drug Administration (FDA)-approved drugs...... and account for a global sales volume of over 180 billion US dollars annually, the prevalence of genetic variation among GPCRs targeted by drugs is unknown. By analyzing data from 68,496 individuals, we find that GPCRs targeted by drugs show genetic variation within functional regions such as drug......- and effector-binding sites in the human population. We experimentally show that certain variants of μ-opioid and Cholecystokinin-A receptors could lead to altered or adverse drug response. By analyzing UK National Health Service drug prescription and sales data, we suggest that characterizing GPCR variants...

  19. Pharmacogenomics of GPCR Drug Targets

    DEFF Research Database (Denmark)

    Hauser, Alexander Sebastian; Chavali, Sreenivas; Masuho, Ikuo

    2018-01-01

    Natural genetic variation in the human genome is a cause of individual differences in responses to medications and is an underappreciated burden on public health. Although 108 G-protein-coupled receptors (GPCRs) are the targets of 475 (∼34%) Food and Drug Administration (FDA)-approved drugs and a...

  20. Pharmacogenomics education: International Society of Pharmacogenomics recommendations for medical, pharmaceutical, and health schools deans of education

    NARCIS (Netherlands)

    Gurwitz, D.; Lunshof, J.E.; Dedoussis, G.; Flordellis, C.S.; Fuhr, U.; Kirchheiner, J.; Licinio, J.; Llerena, A.; Manolopoulos, V.G.; Sheffield, L.J.; Siest, G.; Torricelli, F.; Vasiliou, V.; Wong, S

    2005-01-01

    Pharmacogenomics would be instrumental for the realization of personalized medicine in coming decades. Efforts are evident to clarify the potential bioethical, societal, and legal implications of key pharmacogenomics-based technologies projected to be soon introduced into the core practice of

  1. Extensive Variation in Chromatin States Across Humans

    KAUST Repository

    Kasowski, M.

    2013-10-17

    The majority of disease-associated variants lie outside protein-coding regions, suggesting a link between variation in regulatory regions and disease predisposition. We studied differences in chromatin states using five histone modifications, cohesin, and CTCF in lymphoblastoid lines from 19 individuals of diverse ancestry. We found extensive signal variation in regulatory regions, which often switch between active and repressed states across individuals. Enhancer activity is particularly diverse among individuals, whereas gene expression remains relatively stable. Chromatin variability shows genetic inheritance in trios, correlates with genetic variation and population divergence, and is associated with disruptions of transcription factor binding motifs. Overall, our results provide insights into chromatin variation among humans.

  2. Extensive Variation in Chromatin States Across Humans

    KAUST Repository

    Kasowski, M.; Kyriazopoulou-Panagiotopoulou, S.; Grubert, F.; Zaugg, J. B.; Kundaje, A.; Liu, Y.; Boyle, A. P.; Zhang, Q. C.; Zakharia, F.; Spacek, D. V.; Li, J.; Xie, D.; Olarerin-George, A.; Steinmetz, L. M.; Hogenesch, J. B.; Kellis, M.; Batzoglou, S.; Snyder, M.

    2013-01-01

    The majority of disease-associated variants lie outside protein-coding regions, suggesting a link between variation in regulatory regions and disease predisposition. We studied differences in chromatin states using five histone modifications, cohesin, and CTCF in lymphoblastoid lines from 19 individuals of diverse ancestry. We found extensive signal variation in regulatory regions, which often switch between active and repressed states across individuals. Enhancer activity is particularly diverse among individuals, whereas gene expression remains relatively stable. Chromatin variability shows genetic inheritance in trios, correlates with genetic variation and population divergence, and is associated with disruptions of transcription factor binding motifs. Overall, our results provide insights into chromatin variation among humans.

  3. Pharmacogenomics in cardiovascular disorders: Steps in approaching personalized medicine in cardiovascular medicine

    Directory of Open Access Journals (Sweden)

    Christopher Barone

    2009-09-01

    Full Text Available Christopher Barone, Shaymaa S Mousa, Shaker A MousaThe Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USAAbstract: Some of the most commonly prescribed medications are those for cardiovascular maladies. The beneficial effects of these medications have been well documented. However, there can be substantial variation in response to these medications among patients, which may be due to genetic variation. For this reason pharmacogenomic studies are emerging across all aspects of cardiovascular medicine. The goal of pharmacogenomics is to tailor treatment to an individual’s genetic makeup in order to improve the benefit-to-risk ratio. This review examines the potential pharmacogenomic parameters which may lead to a future of personalized medicine. For example, it has been found that patients with CYP2C9 and VKORC1 gene variations have a different response to warfarin. Other studies looking at β-blockers, ACE inhibitors, ARBs, diuretics and statins have shown some results linking genetic variations to pharmacologic response. However these studies have not impacted clinical use yet, unlike warfarin findings, as the small retrospective studies need to be followed up by larger prospective studies for definitive results.Keywords: cardiovascular, pharmacogenomics, genetics, cardiovascular medicine, personalized medicine, polymorphism

  4. A global reference for human genetic variation

    DEFF Research Database (Denmark)

    Auton, Adam; Abecasis, Goncalo R.; M. Altshuler, David

    2015-01-01

    The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals ...

  5. Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis

    DEFF Research Database (Denmark)

    Zielinski, Daniel C.; Filipp, F. V.; Bordbar, A.

    2015-01-01

    Drug side effects cause a significant clinical and economic burden. However, mechanisms of drug action underlying side effect pathogenesis remain largely unknown. Here, we integrate pharmacogenomic and clinical data with a human metabolic network and find that non-pharmacokinetic metabolic pathways...

  6. A lay prescription for tailor-made drugs--focus group reflections on pharmacogenomics

    DEFF Research Database (Denmark)

    Almarsdóttir, Anna Birna; Björnsdóttir, Ingunn; Traulsen, Janine Morgall

    2005-01-01

    the consequences of the Human Genome Project over the next 40 years, and asked to give advice to politicians and the pharmaceutical industry. A dominating theme in the focus groups was the expectation that drugs developed based on pharmacogenomics will be more expensive than conventional mass produced drugs...

  7. Big Data Analysis of Human Genome Variations

    KAUST Repository

    Gojobori, Takashi

    2016-01-25

    Since the human genome draft sequence was in public for the first time in 2000, genomic analyses have been intensively extended to the population level. The following three international projects are good examples for large-scale studies of human genome variations: 1) HapMap Data (1,417 individuals) (http://hapmap.ncbi.nlm.nih.gov/downloads/genotypes/2010-08_phaseII+III/forward/), 2) HGDP (Human Genome Diversity Project) Data (940 individuals) (http://www.hagsc.org/hgdp/files.html), 3) 1000 genomes Data (2,504 individuals) http://ftp.1000genomes.ebi.ac.uk/vol1/ftp/release/20130502/ If we can integrate all three data into a single volume of data, we should be able to conduct a more detailed analysis of human genome variations for a total number of 4,861 individuals (= 1,417+940+2,504 individuals). In fact, we successfully integrated these three data sets by use of information on the reference human genome sequence, and we conducted the big data analysis. In particular, we constructed a phylogenetic tree of about 5,000 human individuals at the genome level. As a result, we were able to identify clusters of ethnic groups, with detectable admixture, that were not possible by an analysis of each of the three data sets. Here, we report the outcome of this kind of big data analyses and discuss evolutionary significance of human genomic variations. Note that the present study was conducted in collaboration with Katsuhiko Mineta and Kosuke Goto at KAUST.

  8. Pharmacogenomics in type II diabetes mellitus management: Steps toward personalized medicine

    Directory of Open Access Journals (Sweden)

    Peter Avery

    2009-09-01

    Full Text Available Peter Avery, Shaymaa S Mousa, Shaker A MousaThe Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USAAbstract: Advances in genotype technology in the last decade have put the pharmacogenomics revolution at the forefront of future medicine in clinical practice. Discovery of novel gene variations in drug transporters, drug targets, effector proteins and metabolizing enzymes in the form of single-nucleotide polymorphisms (SNPs continue to provide insight into the biological phenomena that govern drug efficacy and toxicity. To date, novel gene discoveries extracted from genome-wide association scans and candidate gene studies in at least four antidiabetic drug classes have helped illuminate possible causes of interindividual variability in response. Inadequate protocol guidelines for pharmacogenomics studies often leads to poorly designed studies, making it hard to formulate a definitive conclusion regarding the clinical relevance of the information at hand. These issues, along with the ethical, social, political, legislative, technological, and economic challenges associated with pharmacogenomics have only delayed its entry to mainstream clinical practice. On the other hand, these issues are being actively pursued and rapid progress is being made in each area which assures the possibility of gaining widespread acceptance in clinical practice.Keywords: pharmacogenomics, genetics, pharmacokinetics, pharmacodynamics, personalized medicine, type 2 diabetes, pharmacotherapy, antidiabetic drugs, efficacy, and safety

  9. Seasonal variation in human reproduction: environmental factors.

    Science.gov (United States)

    Bronson, F H

    1995-06-01

    Almost all human populations exhibit seasonal variation in births, owing mostly to seasonal variation in the frequency of conception. This review focuses on the degree to which environmental factors like nutrition, temperature and photoperiod contribute to these seasonal patterns by acting directly on the reproductive axis. The reproductive strategy of humans is basically that of the apes: Humans have the capacity to reproduce continuously, albeit slowly, unless inhibited by environmental influences. Two, and perhaps three, environmental factors probably act routinely as seasonal inhibitors in some human populations. First, it seems likely that ovulation is regulated seasonally in populations experiencing seasonal variation in food availability. More specifically, it seems likely that inadequate food intake or the increased energy expenditure required to obtain food, or both, can delay menarche, suppress the frequency of ovulation in the nonlactating adult, and prolong lactational amenorrhea in these populations on a seasonal basis. This action is most easily seen in tropical subsistence societies where food availability often varies greatly owing to seasonal variation in rainfall; hence births in these populations often correlate with rainfall. Second, it seems likely that seasonally high temperatures suppress spermatogenesis enough to influence the incidence of fertilization in hotter latitudes, but possibly only in males wearing clothing that diminishes scrotal cooling. Since most of our knowledge about this phenomenon comes from temperate latitudes, the sensitivity of spermatogenesis in both human and nonhuman primates to heat in the tropics needs further study. It is quite possible that high temperatures suppress ovulation and early embryo survival seasonally in some of these same populations. Since we know less than desired about the effect of heat stress on ovulation and early pregnancy in nonhuman mammals, and nothing at all about it in humans or any of the

  10. Genetic variation in an individual human exome.

    Directory of Open Access Journals (Sweden)

    Pauline C Ng

    2008-08-01

    Full Text Available There is much interest in characterizing the variation in a human individual, because this may elucidate what contributes significantly to a person's phenotype, thereby enabling personalized genomics. We focus here on the variants in a person's 'exome,' which is the set of exons in a genome, because the exome is believed to harbor much of the functional variation. We provide an analysis of the approximately 12,500 variants that affect the protein coding portion of an individual's genome. We identified approximately 10,400 nonsynonymous single nucleotide polymorphisms (nsSNPs in this individual, of which approximately 15-20% are rare in the human population. We predict approximately 1,500 nsSNPs affect protein function and these tend be heterozygous, rare, or novel. Of the approximately 700 coding indels, approximately half tend to have lengths that are a multiple of three, which causes insertions/deletions of amino acids in the corresponding protein, rather than introducing frameshifts. Coding indels also occur frequently at the termini of genes, so even if an indel causes a frameshift, an alternative start or stop site in the gene can still be used to make a functional protein. In summary, we reduced the set of approximately 12,500 nonsilent coding variants by approximately 8-fold to a set of variants that are most likely to have major effects on their proteins' functions. This is our first glimpse of an individual's exome and a snapshot of the current state of personalized genomics. The majority of coding variants in this individual are common and appear to be functionally neutral. Our results also indicate that some variants can be used to improve the current NCBI human reference genome. As more genomes are sequenced, many rare variants and non-SNP variants will be discovered. We present an approach to analyze the coding variation in humans by proposing multiple bioinformatic methods to hone in on possible functional variation.

  11. Pharmacogenomics and Nanotechnology Toward Advancing Personalized Medicine

    Science.gov (United States)

    Vizirianakis, Ioannis S.; Amanatiadou, Elsa P.

    The target of personalized medicine to achieve major benefits for all patients in terms of diagnosis and drug delivery can be facilitated by creating a sincere multidisciplinary information-based infrastructure in health care. To this end, nanotechnology, pharmacogenomics, and informatics can advance the utility of personalized medicine, enable clinical translation of genomic knowledge, empower healthcare environment, and finally improve clinical outcomes.

  12. Genetics and pharmacogenomics of diffuse gliomas

    NARCIS (Netherlands)

    van Thuijl, H. F.; Ylstra, B.; Würdinger, T.; van Nieuwenhuizen, D.; Heimans, J. J.; Wesseling, P.; Reijneveld, J. C.

    2013-01-01

    Rapidly evolving techniques for analysis of the genome provide new opportunities for cancer therapy. For diffuse gliomas this has resulted in molecular markers with potential for personalized therapy. Some drugs that utilize pharmacogenomics are currently being tested in clinical trials. In

  13. HGVA: the Human Genome Variation Archive.

    Science.gov (United States)

    Lopez, Javier; Coll, Jacobo; Haimel, Matthias; Kandasamy, Swaathi; Tarraga, Joaquin; Furio-Tari, Pedro; Bari, Wasim; Bleda, Marta; Rueda, Antonio; Gräf, Stefan; Rendon, Augusto; Dopazo, Joaquin; Medina, Ignacio

    2017-07-03

    High-profile genomic variation projects like the 1000 Genomes project or the Exome Aggregation Consortium, are generating a wealth of human genomic variation knowledge which can be used as an essential reference for identifying disease-causing genotypes. However, accessing these data, contrasting the various studies and integrating those data in downstream analyses remains cumbersome. The Human Genome Variation Archive (HGVA) tackles these challenges and facilitates access to genomic data for key reference projects in a clean, fast and integrated fashion. HGVA provides an efficient and intuitive web-interface for easy data mining, a comprehensive RESTful API and client libraries in Python, Java and JavaScript for fast programmatic access to its knowledge base. HGVA calculates population frequencies for these projects and enriches their data with variant annotation provided by CellBase, a rich and fast annotation solution. HGVA serves as a proof-of-concept of the genome analysis developments being carried out by the University of Cambridge together with UK's 100 000 genomes project and the National Institute for Health Research BioResource Rare-Diseases, in particular, deploying open-source for Computational Biology (OpenCB) software platform for storing and analyzing massive genomic datasets. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  14. Translating pharmacogenomics: challenges on the road to the clinic.

    Directory of Open Access Journals (Sweden)

    Jesse J Swen

    2007-08-01

    Full Text Available Pharmacogenomics is one of the first clinical applications of the postgenomic era. It promises personalized medicine rather than the established "one size fits all" approach to drugs and dosages. The expected reduction in trial and error should ultimately lead to more efficient and safer drug therapy. In recent years, commercially available pharmacogenomic tests have been approved by the Food and Drug Administration (FDA, but their application in patient care remains very limited. More generally, the implementation of pharmacogenomics in routine clinical practice presents significant challenges. This article presents specific clinical examples of such challenges and discusses how obstacles to implementation of pharmacogenomic testing can be addressed.

  15. The applications of pharmacogenomics to neurological disorders.

    Science.gov (United States)

    Gilman, C; McSweeney, C; Mao, Y

    2014-01-01

    The most common neurological disorders, including neurodegenerative diseases and psychiatric disorders, have received recent attention with regards to pharmacogenomics and personalized medicine. Here, we will focus on a neglected neurodegenerative disorder, cerebral ischemic stroke (CIS), and highlight recent advances in two disorders, Parkinson's disease (PD) and Alzheimer's diseases (AD), that possess both similar and distinct mechanisms in regards to potential therapeutic targets. In the first part of this review, we will focus primarily on mechanisms that are somewhat specific to each disorder which are involved in neurodegeneration (i.e., protease pathways, calcium homeostasis, reactive oxygen species regulation, DNA repair mechanisms, neurogenesis regulation, mitochondrial function, etc.). In the second part of this review, we will discuss the applications of the genome-wide technology on pharmacogenomics of mental illnesses including schizophrenia (SCZ), autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD).

  16. Personalized Medicine: Pharmacogenomics and Drug Development

    Directory of Open Access Journals (Sweden)

    Somayeh Mirsadeghi

    2017-03-01

    Full Text Available Personalized medicine aims is to supply the proper drug to the proper patient within the right dose. Pharmacogenomics (PGx is to recognize genetic variants that may influence drug efficacy and toxicity. All things considered, the fields cover a wide area, including basic drug discovery researches, the genetic origin of pharmacokinetics and pharmacodynamics, novel drug improvement, patient genetic assessment and clinical patient administration. At last, the objective of Pharmacogenomics is to anticipate a patient’s genetic response to a particular drug as a way of presenting the best possible medical treatment. By predicting the drug response of an individual, it will be possible to increase the success of therapies and decrease the incidence of adverse side effect.

  17. Statistical Analysis of Big Data on Pharmacogenomics

    Science.gov (United States)

    Fan, Jianqing; Liu, Han

    2013-01-01

    This paper discusses statistical methods for estimating complex correlation structure from large pharmacogenomic datasets. We selectively review several prominent statistical methods for estimating large covariance matrix for understanding correlation structure, inverse covariance matrix for network modeling, large-scale simultaneous tests for selecting significantly differently expressed genes and proteins and genetic markers for complex diseases, and high dimensional variable selection for identifying important molecules for understanding molecule mechanisms in pharmacogenomics. Their applications to gene network estimation and biomarker selection are used to illustrate the methodological power. Several new challenges of Big data analysis, including complex data distribution, missing data, measurement error, spurious correlation, endogeneity, and the need for robust statistical methods, are also discussed. PMID:23602905

  18. Development and evaluation of a pharmacogenomics educational program for pharmacists.

    Science.gov (United States)

    Formea, Christine M; Nicholson, Wayne T; McCullough, Kristen B; Berg, Kevin D; Berg, Melody L; Cunningham, Julie L; Merten, Julianna A; Ou, Narith N; Stollings, Joanna L

    2013-02-12

    Objectives. To evaluate hospital and outpatient pharmacists' pharmacogenomics knowledge before and 2 months after participating in a targeted, case-based pharmacogenomics continuing education program.Design. As part of a continuing education program accredited by the Accreditation Council for Pharmacy Education (ACPE), pharmacists were provided with a fundamental pharmacogenomics education program.Evaluation. An 11-question, multiple-choice, electronic survey instrument was distributed to 272 eligible pharmacists at a single campus of a large, academic healthcare system. Pharmacists improved their pharmacogenomics test scores by 0.7 questions (pretest average 46%; posttest average 53%, p=0.0003).Conclusions. Although pharmacists demonstrated improvement, overall retention of educational goals and objectives was marginal. These results suggest that the complex topic of pharmacogenomics requires a large educational effort in order to increase pharmacists' knowledge and comfort level with this emerging therapeutic opportunity.

  19. Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics

    NARCIS (Netherlands)

    Becquemont, Laurent; Alfirevic, Ana; Amstutz, Ursula; Brauch, Hiltrud; Jacqz-Aigrain, Evelyne; Laurent-Puig, Pierre; Molina, Miguel A.; Niemi, Mikko; Schwab, Matthias; Somogyi, Andrew A.; Thervet, Eric; Maitland-van der Zee, Anke-Hilse; van Kuilenburg, André B. P.; van Schaik, Ron H. N.; Verstuyft, Céline; Wadelius, Mia; Daly, Ann K.

    2011-01-01

    The present article summarizes the discussions of the 3rd European Science Foundation University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, which was held in June 2010 in Spain. It was focused on practical applications in routine medical practice. We

  20. Modeling Individual Cyclic Variation in Human Behavior.

    Science.gov (United States)

    Pierson, Emma; Althoff, Tim; Leskovec, Jure

    2018-04-01

    Cycles are fundamental to human health and behavior. Examples include mood cycles, circadian rhythms, and the menstrual cycle. However, modeling cycles in time series data is challenging because in most cases the cycles are not labeled or directly observed and need to be inferred from multidimensional measurements taken over time. Here, we present Cyclic Hidden Markov Models (CyH-MMs) for detecting and modeling cycles in a collection of multidimensional heterogeneous time series data. In contrast to previous cycle modeling methods, CyHMMs deal with a number of challenges encountered in modeling real-world cycles: they can model multivariate data with both discrete and continuous dimensions; they explicitly model and are robust to missing data; and they can share information across individuals to accommodate variation both within and between individual time series. Experiments on synthetic and real-world health-tracking data demonstrate that CyHMMs infer cycle lengths more accurately than existing methods, with 58% lower error on simulated data and 63% lower error on real-world data compared to the best-performing baseline. CyHMMs can also perform functions which baselines cannot: they can model the progression of individual features/symptoms over the course of the cycle, identify the most variable features, and cluster individual time series into groups with distinct characteristics. Applying CyHMMs to two real-world health-tracking datasets-of human menstrual cycle symptoms and physical activity tracking data-yields important insights including which symptoms to expect at each point during the cycle. We also find that people fall into several groups with distinct cycle patterns, and that these groups differ along dimensions not provided to the model. For example, by modeling missing data in the menstrual cycles dataset, we are able to discover a medically relevant group of birth control users even though information on birth control is not given to the model.

  1. Frequently Asked Questions about Pharmacogenomics

    Science.gov (United States)

    ... Care Genomic Medicine Working Group New Horizons and Research Patient Management Policy and Ethics Issues Quick Links for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for ...

  2. Genetic polymorphisms of pharmacogenomic VIP variants in the Kyrgyz population from northwest China.

    Science.gov (United States)

    Yunus, Zulfiya; Liu, Lijun; Wang, Hong; Zhang, Le; Li, Xiaolan; Geng, Tingting; Kang, Longli; Jin, Tianbo; Chen, Chao

    2013-10-15

    Pharmacogenomic variant information is well known for major human populations; however, this information is less commonly studied in minorities. In the present study, we genotyped 85 very important pharmacogenetic (VIP) variants (selected from the PharmGKB database) in the Kyrgyz population and compared our data with other four major human populations including Han Chinese in Beijing, China (CHB), the Japanese in Tokyo, Japan (JPT), a northern and western Europe population (CEU), and the Yoruba in Ibadan, Nigeria (YRI). There were 13, 12 and 16 of the selected VIP variant genotype frequencies in the Kyrgyz which differed from those of the CHB, JPT and CEU, respectively (p<0.005). In the YRI, there were 32 different variants, compared to the Kyrgyz (p<0.005). Genotype frequencies of ADH1B, AHR, CYP3A5, PTGS2, VDR, and VKORC1 in the Kyrgyz differed widely from those in the four populations. Haplotype analyses also showed differences among the Kyrgyz and the other four populations. Our results complement the information provided by the database of pharmacogenomics on Kyrgyz. We provide a theoretical basis for safer drug administration and individualized treatment plans for the Kyrgyz. We also provide a template for the study of pharmacogenomics in various ethnic minority groups in China. © 2013 Elsevier B.V. All rights reserved.

  3. Genomic variation landscape of the human gut microbiome

    DEFF Research Database (Denmark)

    Schloissnig, Siegfried; Arumugam, Manimozhiyan; Sunagawa, Shinichi

    2013-01-01

    Whereas large-scale efforts have rapidly advanced the understanding and practical impact of human genomic variation, the practical impact of variation is largely unexplored in the human microbiome. We therefore developed a framework for metagenomic variation analysis and applied it to 252 faecal...... polymorphism rates of 0.11 was more variable between gut microbial species than across human hosts. Subjects sampled at varying time intervals exhibited individuality and temporal stability of SNP variation patterns, despite considerable composition changes of their gut microbiota. This indicates...

  4. Child Development and Structural Variation in the Human Genome

    Science.gov (United States)

    Zhang, Ying; Haraksingh, Rajini; Grubert, Fabian; Abyzov, Alexej; Gerstein, Mark; Weissman, Sherman; Urban, Alexander E.

    2013-01-01

    Structural variation of the human genome sequence is the insertion, deletion, or rearrangement of stretches of DNA sequence sized from around 1,000 to millions of base pairs. Over the past few years, structural variation has been shown to be far more common in human genomes than previously thought. Very little is currently known about the effects…

  5. Pharmacogenomics of alcohol addiction: Personalizing pharmacologic treatment of alcohol dependence

    Directory of Open Access Journals (Sweden)

    Ragia Georgia

    2014-01-01

    Full Text Available Alcohol dependence is a serious psychiatric disorder with harmful physical, mental and social consequences, and a high probability of a chronic relapsing course. The field of pharmacologic treatment of alcohol dependence and craving is expanding rapidly; the drugs that have been found to reduce relapse rates or drinking in alcohol-dependent patients and are approved for treatment of alcohol dependence are naltrexone, acamprosate and disulfiram, whereas also topiramate appears as a promising therapy. For many patients, however, these treatments are not effective. Evidence from a number of different studies suggests that genetic variation is a significant contributor to interindividual variation of clinical presentation of alcohol problems and response to a given treatment. The aim of the present review is to summarize and discuss the findings on the association between gene polymorphisms and the response to alcohol dependence treatment medications. It is anticipated that future implementation of pharmacogenomics in clinical practice will help personalize alcohol dependence drug treatment, and development personalized hospital pharmacology.

  6. Big Data Analysis of Human Genome Variations

    KAUST Repository

    Gojobori, Takashi

    2016-01-01

    Since the human genome draft sequence was in public for the first time in 2000, genomic analyses have been intensively extended to the population level. The following three international projects are good examples for large-scale studies of human

  7. Pharmacogenomics of inhaled corticosteroids and leukotriene modifiers : a systematic review

    NARCIS (Netherlands)

    Farzan, N.|info:eu-repo/dai/nl/412501929; Vijverberg, S.J.H.|info:eu-repo/dai/nl/325847460; Arets, H.G.M.; Raaijmakers, J.A.M.|info:eu-repo/dai/nl/072763299; van der Zee, A.H.|info:eu-repo/dai/nl/255164688

    BACKGROUND Pharmacogenetics studies of anti-inflammatory medication of asthma have expanded rapidly in recent decades, but the clinical value of their findings remains limited. OBJECTIVE To perform a systematic review of pharmacogenomics and pharmacogenetics of inhaled corticosteroids (ICS) and

  8. Pharmacogenomics and pharmacogenetics for the intensive care unit: a narrative review.

    Science.gov (United States)

    MacKenzie, Meghan; Hall, Richard

    2017-01-01

    Knowledge of how alterations in pharmacogenomics and pharmacogenetics may affect drug therapy in the intensive care unit (ICU) has received little study. We review the clinically relevant application of pharmacogenetics and pharmacogenomics to drugs and conditions encountered in the ICU. We selected relevant literature to illustrate the important concepts contained within. Two main approaches have been used to identify genetic abnormalities - the candidate gene approach and the genome-wide approach. Genetic variability in response to drugs may occur as a result of alterations of drug-metabolizing (cytochrome P [CYP]) enzymes, receptors, and transport proteins leading to enhancement or delay in the therapeutic response. Of relevance to the ICU, genetic variation in CYP-450 isoenzymes results in altered effects of midazolam, fentanyl, morphine, codeine, phenytoin, clopidogrel, warfarin, carvedilol, metoprolol, HMG-CoA reductase inhibitors, calcineurin inhibitors, non-steroidal anti-inflammatory agents, proton pump inhibitors, and ondansetron. Changes in cholinesterase enzyme function may affect the disposition of succinylcholine, benzylisoquinoline muscle relaxants, remifentanil, and hydralazine. Genetic variation in transport proteins leads to differences in the response to opioids and clopidogrel. Polymorphisms in drug receptors result in altered effects of β-blockers, catecholamines, antipsychotic agents, and opioids. Genetic variation also contributes to the diversity and incidence of diseases and conditions such as sepsis, malignant hyperthermia, drug-induced hypersensitivity reactions, cardiac channelopathies, thromboembolic disease, and congestive heart failure. Application of pharmacogenetics and pharmacogenomics has seen improvements in drug therapy. Ongoing study and incorporation of these concepts into clinical decision making in the ICU has the potential to affect patient outcomes.

  9. Pharmacogenomics and epilepsy: the road ahead.

    LENUS (Irish Health Repository)

    Cavalleri, Gianpiero L

    2011-10-01

    Epilepsy is one of the most common, serious neurological disorders, affecting an estimated 50 million people worldwide. The condition is typically treated using antiepileptic drugs of which there are 16 in widespread use. However, there are many different syndrome and seizure types within epilepsy and information guiding clinicians on the most effective drug and dose for individual patients is lacking. Further, all of the antiepileptic drugs have associated adverse reactions, some of which are severe and life-threatening. Here, we review the pharmacogenomic work to date in the context of these issues and comment on key aspects of study design that are required to speed up the identification of clinically relevant genetic factors.

  10. Pharmacogenomic knowledge gaps and educational resource needs among physicians in selected specialties

    Directory of Open Access Journals (Sweden)

    Johansen Taber KA

    2014-07-01

    Full Text Available Katherine A Johansen Taber, Barry D Dickinson Department of Science and Biotechnology, American Medical Association, Chicago, IL, USA Background: The use of pharmacogenomic testing in the clinical setting has the potential to improve the safety and effectiveness of drug therapy, yet studies have revealed that physicians lack knowledge about the topic of pharmacogenomics, and are not prepared to implement it in the clinical setting. This study further explores the pharmacogenomic knowledge deficit and educational resource needs among physicians. Materials and methods: Surveys of primary care physicians, cardiologists, and psychiatrists were conducted. Results: Few physicians reported familiarity with the topic of pharmacogenomics, but more reported confidence in their knowledge about the influence of genetics on drug therapy. Only a small minority had undergone formal training in pharmacogenomics, and a majority reported being unsure what type of pharmacogenomic tests were appropriate to order for the clinical situation. Respondents indicated that an ideal pharmacogenomic educational resource should be electronic and include such components as how to interpret pharmacogenomic test results, recommendations for prescribing, population subgroups most likely to be affected, and contact information for laboratories offering pharmacogenomic testing. Conclusion: Physicians continue to demonstrate pharmacogenomic knowledge gaps, and are unsure about how to use pharmacogenomic testing in clinical practice. Educational resources that are clinically oriented and easily accessible are preferred by physicians, and may best support appropriate clinical implementation of pharmacogenomics. Keywords: pharmacogenomics, knowledge gap, drug response, educational resource

  11. Evolutionary perspectives on human height variation

    NARCIS (Netherlands)

    Stulp, Gert; Barrett, Louise

    Human height is a highly variable trait, both within and between populations, has a high heritability, and influences the manner in which people behave and are treated in society. Although we know much about human height, this information has rarely been brought together in a comprehensive,

  12. Cyclic Variations in Sustained Human Performance

    Science.gov (United States)

    Aue, William R.; Arruda, James E.; Kass, Steven J.; Stanny, Claudia J.

    2009-01-01

    Biological rhythms play a prominent role in the modulation of human physiology and behavior. [Smith, K., Valentino, D., & Arruda, J. (2003). "Rhythmic oscillations in the performance of a sustained attention task." "Journal of Clinical and Experimental Neuropsychology," 25, 561-570] suggested that sustained human performance may systematically…

  13. Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium

    DEFF Research Database (Denmark)

    Farzan, Niloufar; Vijverberg, Susanne J; Andiappan, Anand K

    2017-01-01

    AIM: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium. MATERIALS & METHODS: Investigators of each study participating in PiCA provided data...... corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center...

  14. Variation in alternative splicing across human tissues

    OpenAIRE

    Yeo, Gene; Holste, Dirk; Kreiman, Gabriel; Burge, Christopher B

    2004-01-01

    Background: Alternative pre-mRNA splicing (AS) is widely used by higher eukaryotes to generate different protein isoforms in specific cell or tissue types. To compare AS events across human tissues, we analyzed the splicing patterns of genomically aligned expressed sequence tags (ESTs) derived from libraries of cDNAs from different tissues. Results: Controlling for differences in EST coverage among tissues, we found that the brain and testis had the highest levels of exon skipping. The most p...

  15. Variation of Human Salivary O-Glycome.

    Directory of Open Access Journals (Sweden)

    Radoslaw P Kozak

    Full Text Available The study of saliva O-glycosylation is receiving increasing attention due to the potential of glycans for disease biomarkers, but also due to easy access and non-invasive collection of saliva as biological fluid. Saliva is rich in glycoproteins which are secreted from the bloodstream or produced by salivary glands. Mucins, which are highly O-glycosylated proteins, are particularly abundant in human saliva. Their glycosylation is associated with blood group and secretor status, and represents a reservoir of potential disease biomarkers. This study aims to analyse and compare O-glycans released from whole human mouth saliva collected 3 times a day from a healthy individual over a 5 days period. O-linked glycans were released by hydrazinolysis, labelled with procainamide and analysed by ultra-high performance liquid chromatography with fluorescence detection (UHPLC-FLR coupled to electrospray ionization mass spectrometry (ESI-MS/MS. The sample preparation method showed excellent reproducibility and can therefore be used for biomarker discovery. Our data demonstrates that the O-glycosylation in human saliva changes significantly during the day. These changes may be related to changes in the salivary concentrations of specific proteins.

  16. Host genetic variation impacts microbiome composition across human body sites.

    Science.gov (United States)

    Blekhman, Ran; Goodrich, Julia K; Huang, Katherine; Sun, Qi; Bukowski, Robert; Bell, Jordana T; Spector, Timothy D; Keinan, Alon; Ley, Ruth E; Gevers, Dirk; Clark, Andrew G

    2015-09-15

    The composition of bacteria in and on the human body varies widely across human individuals, and has been associated with multiple health conditions. While microbial communities are influenced by environmental factors, some degree of genetic influence of the host on the microbiome is also expected. This study is part of an expanding effort to comprehensively profile the interactions between human genetic variation and the composition of this microbial ecosystem on a genome- and microbiome-wide scale. Here, we jointly analyze the composition of the human microbiome and host genetic variation. By mining the shotgun metagenomic data from the Human Microbiome Project for host DNA reads, we gathered information on host genetic variation for 93 individuals for whom bacterial abundance data are also available. Using this dataset, we identify significant associations between host genetic variation and microbiome composition in 10 of the 15 body sites tested. These associations are driven by host genetic variation in immunity-related pathways, and are especially enriched in host genes that have been previously associated with microbiome-related complex diseases, such as inflammatory bowel disease and obesity-related disorders. Lastly, we show that host genomic regions associated with the microbiome have high levels of genetic differentiation among human populations, possibly indicating host genomic adaptation to environment-specific microbiomes. Our results highlight the role of host genetic variation in shaping the composition of the human microbiome, and provide a starting point toward understanding the complex interaction between human genetics and the microbiome in the context of human evolution and disease.

  17. Pharmacogenomics to Revive Drug Development in Cardiovascular Disease.

    Science.gov (United States)

    Dubé, Marie-Pierre; de Denus, Simon; Tardif, Jean-Claude

    2016-02-01

    Investment in cardiovascular drug development is on the decline as large cardiovascular outcomes trials require considerable investments in time, efforts and financial resources. Pharmacogenomics has the potential to help revive the cardiovascular drug development pipeline by providing new and better drug targets at an earlier stage and by enabling more efficient outcomes trials. This article will review some of the recent developments highlighting the value of pharmacogenomics for drug development. We discuss how genetic biomarkers can enable the conduct of more efficient clinical outcomes trials by enriching patient populations for good responders to the medication. In addition, we assess past drug development programs which support the added value of selecting drug targets that have established genetic evidence supporting the targeted mechanism of disease. Finally, we discuss how pharmacogenomics can provide valuable evidence linking a drug target to clinically relevant outcomes, enabling novel drug discovery and drug repositioning opportunities.

  18. Analytical strategies for discovery and replication of genetic effects in pharmacogenomic studies

    Directory of Open Access Journals (Sweden)

    Kohler JR

    2014-08-01

    Full Text Available Jared R Kohler, Tobias Guennel, Scott L MarshallBioStat Solutions, Inc., Frederick, MD, USAAbstract: In the past decade, the pharmaceutical industry and biomedical research sector have devoted considerable resources to pharmacogenomics (PGx with the hope that understanding genetic variation in patients would deliver on the promise of personalized medicine. With the advent of new technologies and the improved collection of DNA samples, the roadblock to advancements in PGx discovery is no longer the lack of high-density genetic information captured on patient populations, but rather the development, adaptation, and tailoring of analytical strategies to effectively harness this wealth of information. The current analytical paradigm in PGx considers the single-nucleotide polymorphism (SNP as the genomic feature of interest and performs single SNP association tests to discover PGx effects – ie, genetic effects impacting drug response. While it can be straightforward to process single SNP results and to consider how this information may be extended for use in downstream patient stratification, the rate of replication for single SNP associations has been low and the desired success of producing clinically and commercially viable biomarkers has not been realized. This may be due to the fact that single SNP association testing is suboptimal given the complexities of PGx discovery in the clinical trial setting, including: 1 relatively small sample sizes; 2 diverse clinical cohorts within and across trials due to genetic ancestry (potentially impacting the ability to replicate findings; and 3 the potential polygenic nature of a drug response. Subsequently, a shift in the current paradigm is proposed: to consider the gene as the genomic feature of interest in PGx discovery. The proof-of-concept study presented in this manuscript demonstrates that genomic region-based association testing has the potential to improve the power of detecting single SNP or

  19. Functional characterization of genetic enzyme variations in human lipoxygenases

    Directory of Open Access Journals (Sweden)

    Thomas Horn

    2013-01-01

    Full Text Available Mammalian lipoxygenases play a role in normal cell development and differentiation but they have also been implicated in the pathogenesis of cardiovascular, hyperproliferative and neurodegenerative diseases. As lipid peroxidizing enzymes they are involved in the regulation of cellular redox homeostasis since they produce lipid hydroperoxides, which serve as an efficient source for free radicals. There are various epidemiological correlation studies relating naturally occurring variations in the six human lipoxygenase genes (SNPs or rare mutations to the frequency for various diseases in these individuals, but for most of the described variations no functional data are available. Employing a combined bioinformatical and enzymological strategy, which included structural modeling and experimental site-directed mutagenesis, we systematically explored the structural and functional consequences of non-synonymous genetic variations in four different human lipoxygenase genes (ALOX5, ALOX12, ALOX15, and ALOX15B that have been identified in the human 1000 genome project. Due to a lack of a functional expression system we resigned to analyze the functionality of genetic variations in the hALOX12B and hALOXE3 gene. We found that most of the frequent non-synonymous coding SNPs are located at the enzyme surface and hardly alter the enzyme functionality. In contrast, genetic variations which affect functional important amino acid residues or lead to truncated enzyme variations (nonsense mutations are usually rare with a global allele frequency<0.1%. This data suggest that there appears to be an evolutionary pressure on the coding regions of the lipoxygenase genes preventing the accumulation of loss-of-function variations in the human population.

  20. Implementing pharmacogenomics decision support across seven European countries: The Ubiquitous Pharmacogenomics (U-PGx) project.

    Science.gov (United States)

    Blagec, Kathrin; Koopmann, Rudolf; Crommentuijn-van Rhenen, Mandy; Holsappel, Inge; van der Wouden, Cathelijne H; Konta, Lidija; Xu, Hong; Steinberger, Daniela; Just, Enrico; Swen, Jesse J; Guchelaar, Henk-Jan; Samwald, Matthias

    2018-02-09

    Clinical pharmacogenomics (PGx) has the potential to make pharmacotherapy safer and more effective by utilizing genetic patient data for drug dosing and selection. However, widespread adoption of PGx depends on its successful integration into routine clinical care through clinical decision support tools, which is often hampered by insufficient or fragmented infrastructures. This paper describes the setup and implementation of a unique multimodal, multilingual clinical decision support intervention consisting of digital, paper-, and mobile-based tools that are deployed across implementation sites in seven European countries participating in the Ubiquitous PGx (U-PGx) project. © The Author(s) 2018. Published by Oxford University Press on behalf of the American Medical Informatics Association.

  1. Biotechnology, nanotechnology, and pharmacogenomics and pharmaceutical compounding, Part 1.

    Science.gov (United States)

    Allen, Loyd V

    2015-01-01

    The world of pharmaceuticals is changing rapidly as biotechnology continues to grow and nanotechnology appears on the horizon. Biotechnology is gaining in importance in extemporaneous pharmaceutical compounding, and nanotechnology and pharmacogenomics could drastically change the practice of pharmacy. This article discusses biotechnology and the factors to consider when compounding biotechnology drugs.

  2. The pharmacogenomics of escitalopram in the treatment of neuropathic pain

    DEFF Research Database (Denmark)

    Andersen, Charlotte Brasch; Møller, Malik U; Sindrup, Søren Hein

    and the non-responders, which led to a pharmacogenomic study investigating genetic differences between the two groups for functional variants in genes involved in the signaling pathway for serotonin.  We tested the serotonin receptor subunits 5-HTR2C G68C (rs6318) and 5-HTR2A C1354T (rs6314) both giving rise...

  3. Translating pharmacogenomics : Challenges on the road to the clinic

    NARCIS (Netherlands)

    Swen, Jesse J.; Huizinga, Tom W.; Gelderblom, Hans; de Vries, Elisabeth G. E.; Assendelft, Willem J. J.; Kirchheiner, Julia; Guchelaar, Henk-Jan

    2007-01-01

    Pharmacogenomics is one of the first clinical applications of the postgenomic era. It promises personalized medicine rather than the established "one size fits all" approach to drugs and dosages. The expected reduction in trial and error should ultimately lead to more efficient and safer drug

  4. Generating Genome-Scale Candidate Gene Lists for Pharmacogenomics

    DEFF Research Database (Denmark)

    Hansen, Niclas Tue; Brunak, Søren; Altman, R. B.

    2009-01-01

    A critical task in pharmacogenomics is identifying genes that may be important modulators of drug response. High-throughput experimental methods are often plagued by false positives and do not take advantage of existing knowledge. Candidate gene lists can usefully summarize existing knowledge...

  5. Pharmacogenomics genes show varying perceptibility to microRNA regulation

    DEFF Research Database (Denmark)

    Rukov, Jakob Lewin; Vinther, Jeppe; Shomron, Noam

    2011-01-01

    The aim of pharmacogenomics is to identify individual differences in genome and transcriptome composition and their effect on drug efficacy. MicroRNAs (miRNAs) are short noncoding RNAs that negatively regulate expression of the majority of animal genes, including many genes involved in drug...

  6. Anatomical variation of human thoracic rib in dry bone.

    Directory of Open Access Journals (Sweden)

    Dr. Nalini Konkani

    2017-12-01

    Full Text Available Introduction: The Ribs are essential structure of osseous thorax and provide information that aids in the interpretation of radiologic images. The purpose of this study to investigate variations in thoracic rib and its morphological & clinical importance. So, In present study attempted to find out additional intercostal spaces due to bifurcation of ribs, less intercostal space due to fusion of ribs, variation of the normal ribs like, gap in the rib, fusion of one rib to another at a shaft of rib. Congenital abnormalities of the ribs are usually asymptomatic, often discovered incidentally on chest X-ray. Effects of this neuroskeletal anomaly can include respiratory difficulties and neurological limitations.Material & Method: The study was carried out in Bone Store of Department of Anatomy, B. J. Medical College, Ahmedabad, Gujarat. Study was carried out on 500 human dried ribs. And the variations in the ribs are studied. We got variation in the human ribs and studied. Result : Variations were seen like out of 500 ribs, Bifid rib having two ends 9(1.8%, rib having bifid space 2(0.4%, fusion rib at the level of shaft 1(0.2%, fusion of first rib and second rib 1(0.2%,first rib having two ends 1(0.2%. Conclusion: Bifid rib is an anatomical variant where the sternal end of the rib is cleaved into two. So we can rule out mesodermal abnormalities, parenchymal lung disease, chest wall tumor or costal fracture.

  7. Implementation of a pharmacogenomics service in a community pharmacy.

    Science.gov (United States)

    Ferreri, Stefanie P; Greco, Angelo J; Michaels, Natasha M; O'Connor, Shanna K; Chater, Rebecca W; Viera, Anthony J; Faruki, Hawazin; McLeod, Howard L; Roederer, Mary W

    2014-01-01

    OBJECTIVE To determine the feasibility of implementing a pharmacogenomics service in a community pharmacy. SETTING A single community pharmacy that is part of a regional chain known for offering innovative pharmacy services. PRACTICE DESCRIPTION Community pharmacists at the project site routinely provide clinical pharmacy services, including medication therapy management, immunizations, point-of-care testing, blood pressure monitoring, and diabetes education. PRACTICE INNOVATION The implementation of a pharmacogenomic testing and interpretation service for the liver isoenzyme cytochrome P450 2C19. PARTICIPANTS 18 patients taking clopidogrel, a drug metabolized by CYP2C19. MAIN OUTCOME MEASURES Rate of patient participation, rate of prescriber acceptance of pharmacist recommendation, time to perform genetic testing service, and number of claims submitted to and paid by insurance. RESULTS Of 41 patients taking clopidogrel and meeting project criteria, 18 (43.9%) enrolled and completed testing and interpretation of pharmacogenomic results. The mean time pharmacists spent completing all stages of the project with each participant was 76.6 minutes. The mean time to complete participation in the project (time between person's first and second visit) was 30.1 days. Nine patients had wild-type alleles, and pharmacists recommended continuation of therapy as ordered. Genetic variants were found in the other nine patients, and all pharmacist recommendations for modifications in therapy were ultimately accepted by prescribers. Overall, 17 patients consented to filing of reimbursement claims with their insurers. Five were not able to be billed due to submission difficulties. Of the remaining 12, none was paid. CONCLUSION A pharmacogenomics service can be an extension of medication therapy management services in a community pharmacy. Prescribers are receptive to having community pharmacists conduct pharmacogenomics testing, but reimbursement is a challenge.

  8. DNA methylation-based variation between human populations.

    Science.gov (United States)

    Kader, Farzeen; Ghai, Meenu

    2017-02-01

    Several studies have proved that DNA methylation affects regulation of gene expression and development. Epigenome-wide studies have reported variation in methylation patterns between populations, including Caucasians, non-Caucasians (Blacks), Hispanics, Arabs, and numerous populations of the African continent. Not only has DNA methylation differences shown to impact externally visible characteristics, but is also a potential biomarker for underlying racial health disparities between human populations. Ethnicity-related methylation differences set their mark during early embryonic development. Genetic variations, such as single-nucleotide polymorphisms and environmental factors, such as age, dietary folate, socioeconomic status, and smoking, impacts DNA methylation levels, which reciprocally impacts expression of phenotypes. Studies show that it is necessary to address these external influences when attempting to differentiate between populations since the relative impacts of these factors on the human methylome remain uncertain. The present review summarises several reported attempts to establish the contribution of differential DNA methylation to natural human variation, and shows that DNA methylation could represent new opportunities for risk stratification and prevention of several diseases amongst populations world-wide. Variation of methylation patterns between human populations is an exciting prospect which inspires further valuable research to apply the concept in routine medical and forensic casework. However, trans-generational inheritance needs to be quantified to decipher the proportion of variation contributed by DNA methylation. The future holds thorough evaluation of the epigenome to understand quantification, heritability, and the effect of DNA methylation on phenotypes. In addition, methylation profiling of the same ethnic groups across geographical locations will shed light on conserved methylation differences in populations.

  9. [Proper antibiotic therapy. From penicillin to pharmacogenomic].

    Science.gov (United States)

    Caramia, G; Ruffini, E

    2012-04-01

    judgment, and clinical discretion is always required in their application. Genome studies have identified hundreds of genetic polymorphism important determinants of the efficacy of therapy and several trial demonstrated the successful use of pharmacogenomic testing to reduce the incidence of hypersensitivity reactions in patients. Knowing the phenotype of a patient prior to therapy, optimal dose and type drugs can be prescribed to achieve better management of patients.

  10. Genetic polymorphisms in very important pharmacogenomic variants in the Zhuang ethnic group of Southwestern China: A cohort study in the Zhuang population.

    Science.gov (United States)

    Li, Jing; Guo, Chenghao; Yan, Mengdan; Niu, Fanglin; Chen, Peng; Li, Bin; Jin, Tianbo

    2018-04-01

    Pharmacogenomics, the study of the role of genetics in drug response, has recently become a focal point of research. Previous studies showed that genes associated with drug detoxification vary among different populations. However, pharmacogenomic information of the Zhuang ethnic group is scarce. The aim of the present study was to screen members of the Zhuang ethnicity in southwestern China for genotype frequencies of very important pharmacogenomic (VIP) variants and to determine the differences between the Zhuang ethnicity and other human populations.We genotyped 80 variants of VIP genes in 100 unrelated healthy Zhuang adults from the Yunnan province of China. Next, we analyzed the genotyping data with Structure and F-statistics (Fst).We compared our data with those of other populations using the HapMap data set, and observed that the frequency distribution of Zhuang population in Yunnan closely resembles that of JPT. Furthermore, population structure and Fst analysis showed that the Zhuang population is closely related to the Shaanxi Han population with respect to genetic background.Our study supplements existing information on Zhuang population pharmacogenomics and provides an extensive overview for developing personalized medicine.

  11. Pharmacogenomics and Global Precision Medicine in the Context of Adverse Drug Reactions: Top 10 Opportunities and Challenges for the Next Decade.

    Science.gov (United States)

    Alessandrini, Marco; Chaudhry, Mamoonah; Dodgen, Tyren M; Pepper, Michael S

    2016-10-01

    In a move indicative of the enthusiastic support of precision medicine, the U.S. President Barack Obama announced the Precision Medicine Initiative in January 2015. The global precision medicine ecosystem is, thus, receiving generous support from the United States ($215 million), and numerous other governments have followed suit. In the context of precision medicine, drug treatment and prediction of its outcomes have been important for nearly six decades in the field of pharmacogenomics. The field offers an elegant solution for minimizing the effects and occurrence of adverse drug reactions (ADRs). The Clinical Pharmacogenetics Implementation Consortium (CPIC) plays an important role in this context, and it aims at specifically guiding the translation of clinically relevant and evidence-based pharmacogenomics research. In this forward-looking analysis, we make particular reference to several of the CPIC guidelines and their role in guiding the treatment of highly relevant diseases, namely cardiovascular disease, major depressive disorder, cancer, and human immunodeficiency virus, with a view to predicting and managing ADRs. In addition, we provide a list of the top 10 crosscutting opportunities and challenges facing the fields of precision medicine and pharmacogenomics, which have broad applicability independent of the drug class involved. Many of these opportunities and challenges pertain to infrastructure, study design, policy, and science culture in the early 21st century. Ultimately, rational pharmacogenomics study design and the acquisition of comprehensive phenotypic data that proportionately match the genomics data should be an imperative as we move forward toward global precision medicine.

  12. Understanding human genetic variation in the era of high-throughput sequencing

    OpenAIRE

    Knight, Julian C.

    2010-01-01

    The EMBO/EMBL symposium ‘Human Variation: Cause and Consequence' highlighted advances in understanding the molecular basis of human genetic variation and its myriad implications for biology, human origins and disease.

  13. Variation in human recombination rates and its genetic determinants.

    Directory of Open Access Journals (Sweden)

    Adi Fledel-Alon

    Full Text Available Despite the fundamental role of crossing-over in the pairing and segregation of chromosomes during human meiosis, the rates and placements of events vary markedly among individuals. Characterizing this variation and identifying its determinants are essential steps in our understanding of the human recombination process and its evolution.Using three large sets of European-American pedigrees, we examined variation in five recombination phenotypes that capture distinct aspects of crossing-over patterns. We found that the mean recombination rate in males and females and the historical hotspot usage are significantly heritable and are uncorrelated with one another. We then conducted a genome-wide association study in order to identify loci that influence them. We replicated associations of RNF212 with the mean rate in males and in females as well as the association of Inversion 17q21.31 with the female mean rate. We also replicated the association of PRDM9 with historical hotspot usage, finding that it explains most of the genetic variance in this phenotype. In addition, we identified a set of new candidate regions for further validation.These findings suggest that variation at broad and fine scales is largely separable and that, beyond three known loci, there is no evidence for common variation with large effects on recombination phenotypes.

  14. Human footprint variation while performing load bearing tasks.

    Directory of Open Access Journals (Sweden)

    Cara M Wall-Scheffler

    Full Text Available Human footprint fossils have provided essential evidence about the evolution of human bipedalism as well as the social dynamics of the footprint makers, including estimates of speed, sex and group composition. Generally such estimates are made by comparing footprint evidence with modern controls; however, previous studies have not accounted for the variation in footprint dimensions coming from load bearing activities. It is likely that a portion of the hominins who created these fossil footprints were carrying a significant load, such as offspring or foraging loads, which caused variation in the footprint which could extend to variation in any estimations concerning the footprint's maker. To identify significant variation in footprints due to load-bearing tasks, we had participants (N = 30, 15 males and 15 females walk at a series of speeds carrying a 20kg pack on their back, side and front. Paint was applied to the bare feet of each participant to create footprints that were compared in terms of foot length, foot width and foot area. Female foot length and width increased during multiple loaded conditions. An appreciation of footprint variability associated with carrying loads adds an additional layer to our understanding of the behavior and morphology of extinct hominin populations.

  15. The study of human Y chromosome variation through ancient DNA.

    Science.gov (United States)

    Kivisild, Toomas

    2017-05-01

    High throughput sequencing methods have completely transformed the study of human Y chromosome variation by offering a genome-scale view on genetic variation retrieved from ancient human remains in context of a growing number of high coverage whole Y chromosome sequence data from living populations from across the world. The ancient Y chromosome sequences are providing us the first exciting glimpses into the past variation of male-specific compartment of the genome and the opportunity to evaluate models based on previously made inferences from patterns of genetic variation in living populations. Analyses of the ancient Y chromosome sequences are challenging not only because of issues generally related to ancient DNA work, such as DNA damage-induced mutations and low content of endogenous DNA in most human remains, but also because of specific properties of the Y chromosome, such as its highly repetitive nature and high homology with the X chromosome. Shotgun sequencing of uniquely mapping regions of the Y chromosomes to sufficiently high coverage is still challenging and costly in poorly preserved samples. To increase the coverage of specific target SNPs capture-based methods have been developed and used in recent years to generate Y chromosome sequence data from hundreds of prehistoric skeletal remains. Besides the prospects of testing directly as how much genetic change in a given time period has accompanied changes in material culture the sequencing of ancient Y chromosomes allows us also to better understand the rate at which mutations accumulate and get fixed over time. This review considers genome-scale evidence on ancient Y chromosome diversity that has recently started to accumulate in geographic areas favourable to DNA preservation. More specifically the review focuses on examples of regional continuity and change of the Y chromosome haplogroups in North Eurasia and in the New World.

  16. Genome-wide associations of gene expression variation in humans.

    Directory of Open Access Journals (Sweden)

    Barbara E Stranger

    2005-12-01

    Full Text Available The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis- to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

  17. Genome-Wide Associations of Gene Expression Variation in Humans.

    Directory of Open Access Journals (Sweden)

    2005-12-01

    Full Text Available The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis- to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

  18. Systematic evaluation of clinical practice guidelines for pharmacogenomics.

    Science.gov (United States)

    Beckett, Robert D; Kisor, David F; Smith, Thomas; Vonada, Brooke

    2018-06-01

    To systematically assess methodological quality of pharmacogenomics clinical practice guidelines. Guidelines published through 2017 were reviewed by at least three independent reviewers using the AGREE II instrument, which consists of 23 items grouped into 6 domains and 2 items representing an overall assessment. Items were assessed on a seven-point rating scale, and aggregate quality scores were calculated. 31 articles were included. All guidelines were published as peer-reviewed articles and 90% (n = 28) were endorsed by professional organizations. Mean AGREE II domain scores (maximum score 100%) ranged from 46.6 ± 11.5% ('applicability') to 78.9 ± 11.4% ('clarity of presentation'). Median overall quality score was 72.2% (IQR: 61.1-77.8%). Quality of pharmacogenomics guidelines was generally high, but variable, for most AGREE II domains.

  19. Racializing drug design: implications of pharmacogenomics for health disparities.

    Science.gov (United States)

    Lee, Sandra Soo-Jin

    2005-12-01

    Current practices of using "race" in pharmacogenomics research demands consideration of the ethical and social implications for understandings of group difference and for efforts to eliminate health disparities. This discussion focuses on an "infrastructure of racialization" created by current trajectories of research on genetic differences among racially identified groups, the use of race as a proxy for risk in clinical practice, and increasing interest in new market niches by the pharmaceutical industry. The confluence of these factors has resulted in the conflation of genes, disease, and race. I argue that public investment in pharmacogenomics requires careful consideration of current inequities in health status and social and ethical concerns over reifying race and issues of distributive justice.

  20. Integrating common and rare genetic variation in diverse human populations.

    Science.gov (United States)

    Altshuler, David M; Gibbs, Richard A; Peltonen, Leena; Altshuler, David M; Gibbs, Richard A; Peltonen, Leena; Dermitzakis, Emmanouil; Schaffner, Stephen F; Yu, Fuli; Peltonen, Leena; Dermitzakis, Emmanouil; Bonnen, Penelope E; Altshuler, David M; Gibbs, Richard A; de Bakker, Paul I W; Deloukas, Panos; Gabriel, Stacey B; Gwilliam, Rhian; Hunt, Sarah; Inouye, Michael; Jia, Xiaoming; Palotie, Aarno; Parkin, Melissa; Whittaker, Pamela; Yu, Fuli; Chang, Kyle; Hawes, Alicia; Lewis, Lora R; Ren, Yanru; Wheeler, David; Gibbs, Richard A; Muzny, Donna Marie; Barnes, Chris; Darvishi, Katayoon; Hurles, Matthew; Korn, Joshua M; Kristiansson, Kati; Lee, Charles; McCarrol, Steven A; Nemesh, James; Dermitzakis, Emmanouil; Keinan, Alon; Montgomery, Stephen B; Pollack, Samuela; Price, Alkes L; Soranzo, Nicole; Bonnen, Penelope E; Gibbs, Richard A; Gonzaga-Jauregui, Claudia; Keinan, Alon; Price, Alkes L; Yu, Fuli; Anttila, Verneri; Brodeur, Wendy; Daly, Mark J; Leslie, Stephen; McVean, Gil; Moutsianas, Loukas; Nguyen, Huy; Schaffner, Stephen F; Zhang, Qingrun; Ghori, Mohammed J R; McGinnis, Ralph; McLaren, William; Pollack, Samuela; Price, Alkes L; Schaffner, Stephen F; Takeuchi, Fumihiko; Grossman, Sharon R; Shlyakhter, Ilya; Hostetter, Elizabeth B; Sabeti, Pardis C; Adebamowo, Clement A; Foster, Morris W; Gordon, Deborah R; Licinio, Julio; Manca, Maria Cristina; Marshall, Patricia A; Matsuda, Ichiro; Ngare, Duncan; Wang, Vivian Ota; Reddy, Deepa; Rotimi, Charles N; Royal, Charmaine D; Sharp, Richard R; Zeng, Changqing; Brooks, Lisa D; McEwen, Jean E

    2010-09-02

    Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called 'HapMap 3', includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of variation and its role in human disease, and serves as a step towards a high-resolution map of the landscape of human genetic variation.

  1. Pharmacogenomics and Efficacy of Risperidone Long-Term Treatment in Thai Autistic Children and Adolescents.

    Science.gov (United States)

    Nuntamool, Nopphadol; Ngamsamut, Nattawat; Vanwong, Natchaya; Puangpetch, Apichaya; Chamnanphon, Monpat; Hongkaew, Yaowaluck; Limsila, Penkhae; Suthisisang, Chuthamanee; Wilffert, Bob; Sukasem, Chonlaphat

    2017-10-01

    The purpose of this study was to evaluate the association of pharmacogenomic factors and clinical outcome in autistic children and adolescents who were treated with risperidone for long periods. Eighty-two autistic subjects diagnosed with DSM-IV and who were treated with risperidone for more than 1 year were recruited. Pharmacogenomics and clinical outcome (CGI-I, aggressive, overactivity and repetitive score) were evaluated. Almost all patients showed stable symptoms on aggressive behaviour (89.02%), overactivity (71.95%), repetitive (70.89%) behaviour and all clinical symptoms (81.71%). Only 4.48% of patients showed minimally worse CGI-I score. Patients in the non-stable symptom group had DRD2 Taq1A non-wild-type (TT and CT) frequencies higher than the clinically stable group (p = 0.04), whereas other gene polymorphisms showed no significant association. Haplotype ACCTCAT (rs6311, rs1045642, rs1128503, rs1800497, rs4436578, rs1799978, rs6280) showed a significant association with non-stable clinical outcome (χ 2  = 6.642, p = 0.010). Risperidone levels showed no association with any clinical outcome. On the other hand, risperidone dose, 9-OH risperidone levels and prolactin levels were significantly higher in the non-stable compared to the stable symptom group (p = 0.013, p = 0.044, p = 0.030). Increased appetite was the most common adverse drug reaction and associated with higher body-weight, whereas it was not significantly associated with genetic variations and non-genetic information. In conclusion, risperidone showed efficacy to control autism, especially aggressive symptoms in long-term treatment. However, Taq1A T - carrier of dopamine 2 receptor gene - is associated with non-stable response in risperidone-treated patients. This study supports pharmacogenomics testing for personalized therapy with risperidone in autistic children and adolescents. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  2. Host genome variations and risk of infections during induction treatment for childhood acute lymphoblastic leukaemia

    DEFF Research Database (Denmark)

    Lund, Bendik; Wesolowska-Andersen, Agata; Lausen, Birgitte

    2014-01-01

    Objectives: To investigate association of host genomic variation and risk of infections during treatment for childhood acute lymphoblastic leukaemia (ALL). Methods: We explored association of 34 000 singlenucleotide polymorphisms (SNPs) related primarily to pharmacogenomics and immune function...

  3. Genome Architecture and Its Roles in Human Copy Number Variation

    Directory of Open Access Journals (Sweden)

    Lu Chen

    2014-12-01

    Full Text Available Besides single-nucleotide variants in the human genome, large-scale genomic variants, such as copy number variations (CNVs, are being increasingly discovered as a genetic source of human diversity and the pathogenic factors of diseases. Recent experimental findings have shed light on the links between different genome architectures and CNV mutagenesis. In this review, we summarize various genomic features and discuss their contributions to CNV formation. Genomic repeats, including both low-copy and high-copy repeats, play important roles in CNV instability, which was initially known as DNA recombination events. Furthermore, it has been found that human genomic repeats can also induce DNA replication errors and consequently result in CNV mutations. Some recent studies showed that DNA replication timing, which reflects the high-order information of genomic organization, is involved in human CNV mutations. Our review highlights that genome architecture, from DNA sequence to high-order genomic organization, is an important molecular factor in CNV mutagenesis and human genomic instability.

  4. Analysis of pharmacogenomic variants associated with population differentiation.

    Directory of Open Access Journals (Sweden)

    Bora Yeon

    Full Text Available In the present study, we systematically investigated population differentiation of drug-related (DR genes in order to identify common genetic features underlying population-specific responses to drugs. To do so, we used the International HapMap project release 27 Data and Pharmacogenomics Knowledge Base (PharmGKB database. First, we compared four measures for assessing population differentiation: the chi-square test, the analysis of variance (ANOVA F-test, Fst, and Nearest Shrunken Centroid Method (NSCM. Fst showed high sensitivity with stable specificity among varying sample sizes; thus, we selected Fst for determining population differentiation. Second, we divided DR genes from PharmGKB into two groups based on the degree of population differentiation as assessed by Fst: genes with a high level of differentiation (HD gene group and genes with a low level of differentiation (LD gene group. Last, we conducted a gene ontology (GO analysis and pathway analysis. Using all genes in the human genome as the background, the GO analysis and pathway analysis of the HD genes identified terms related to cell communication. "Cell communication" and "cell-cell signaling" had the lowest Benjamini-Hochberg's q-values (0.0002 and 0.0006, respectively, and "drug binding" was highly enriched (16.51 despite its relatively high q-value (0.0142. Among the 17 genes related to cell communication identified in the HD gene group, five genes (STX4, PPARD, DCK, GRIK4, and DRD3 contained single nucleotide polymorphisms with Fst values greater than 0.5. Specifically, the Fst values for rs10871454, rs6922548, rs3775289, rs1954787, and rs167771 were 0.682, 0.620, 0.573, 0.531, and 0.510, respectively. In the analysis using DR genes as the background, the HD gene group contained six significant terms. Five were related to reproduction, and one was "Wnt signaling pathway," which has been implicated in cancer. Our analysis suggests that the HD gene group from PharmGKB is

  5. Analysis of pharmacogenomic variants associated with population differentiation.

    Science.gov (United States)

    Yeon, Bora; Ahn, Eunyong; Kim, Kyung-Im; Kim, In-Wha; Oh, Jung Mi; Park, Taesung

    2015-01-01

    In the present study, we systematically investigated population differentiation of drug-related (DR) genes in order to identify common genetic features underlying population-specific responses to drugs. To do so, we used the International HapMap project release 27 Data and Pharmacogenomics Knowledge Base (PharmGKB) database. First, we compared four measures for assessing population differentiation: the chi-square test, the analysis of variance (ANOVA) F-test, Fst, and Nearest Shrunken Centroid Method (NSCM). Fst showed high sensitivity with stable specificity among varying sample sizes; thus, we selected Fst for determining population differentiation. Second, we divided DR genes from PharmGKB into two groups based on the degree of population differentiation as assessed by Fst: genes with a high level of differentiation (HD gene group) and genes with a low level of differentiation (LD gene group). Last, we conducted a gene ontology (GO) analysis and pathway analysis. Using all genes in the human genome as the background, the GO analysis and pathway analysis of the HD genes identified terms related to cell communication. "Cell communication" and "cell-cell signaling" had the lowest Benjamini-Hochberg's q-values (0.0002 and 0.0006, respectively), and "drug binding" was highly enriched (16.51) despite its relatively high q-value (0.0142). Among the 17 genes related to cell communication identified in the HD gene group, five genes (STX4, PPARD, DCK, GRIK4, and DRD3) contained single nucleotide polymorphisms with Fst values greater than 0.5. Specifically, the Fst values for rs10871454, rs6922548, rs3775289, rs1954787, and rs167771 were 0.682, 0.620, 0.573, 0.531, and 0.510, respectively. In the analysis using DR genes as the background, the HD gene group contained six significant terms. Five were related to reproduction, and one was "Wnt signaling pathway," which has been implicated in cancer. Our analysis suggests that the HD gene group from PharmGKB is associated with

  6. Human feeding biomechanics: performance, variation, and functional constraints

    Directory of Open Access Journals (Sweden)

    Justin A. Ledogar

    2016-07-01

    Full Text Available The evolution of the modern human (Homo sapiens cranium is characterized by a reduction in the size of the feeding system, including reductions in the size of the facial skeleton, postcanine teeth, and the muscles involved in biting and chewing. The conventional view hypothesizes that gracilization of the human feeding system is related to a shift toward eating foods that were less mechanically challenging to consume and/or foods that were processed using tools before being ingested. This hypothesis predicts that human feeding systems should not be well-configured to produce forceful bites and that the cranium should be structurally weak. An alternate hypothesis, based on the observation that humans have mechanically efficient jaw adductors, states that the modern human face is adapted to generate and withstand high biting forces. We used finite element analysis (FEA to test two opposing mechanical hypotheses: that compared to our closest living relative, chimpanzees (Pan troglodytes, the modern human craniofacial skeleton is (1 less well configured, or (2 better configured to generate and withstand high magnitude bite forces. We considered intraspecific variation in our examination of human feeding biomechanics by examining a sample of geographically diverse crania that differed notably in shape. We found that our biomechanical models of human crania had broadly similar mechanical behavior despite their shape variation and were, on average, less structurally stiff than the crania of chimpanzees during unilateral biting when loaded with physiologically-scaled muscle loads. Our results also show that modern humans are efficient producers of bite force, consistent with previous analyses. However, highly tensile reaction forces were generated at the working (biting side jaw joint during unilateral molar bites in which the chewing muscles were recruited with bilateral symmetry. In life, such a configuration would have increased the risk of joint

  7. Human feeding biomechanics: performance, variation, and functional constraints

    Science.gov (United States)

    Dechow, Paul C.; Wang, Qian; Gharpure, Poorva H.; Baab, Karen L.; Smith, Amanda L.; Weber, Gerhard W.; Grosse, Ian R.; Ross, Callum F.; Richmond, Brian G.; Wright, Barth W.; Byron, Craig; Wroe, Stephen; Strait, David S.

    2016-01-01

    The evolution of the modern human (Homo sapiens) cranium is characterized by a reduction in the size of the feeding system, including reductions in the size of the facial skeleton, postcanine teeth, and the muscles involved in biting and chewing. The conventional view hypothesizes that gracilization of the human feeding system is related to a shift toward eating foods that were less mechanically challenging to consume and/or foods that were processed using tools before being ingested. This hypothesis predicts that human feeding systems should not be well-configured to produce forceful bites and that the cranium should be structurally weak. An alternate hypothesis, based on the observation that humans have mechanically efficient jaw adductors, states that the modern human face is adapted to generate and withstand high biting forces. We used finite element analysis (FEA) to test two opposing mechanical hypotheses: that compared to our closest living relative, chimpanzees (Pan troglodytes), the modern human craniofacial skeleton is (1) less well configured, or (2) better configured to generate and withstand high magnitude bite forces. We considered intraspecific variation in our examination of human feeding biomechanics by examining a sample of geographically diverse crania that differed notably in shape. We found that our biomechanical models of human crania had broadly similar mechanical behavior despite their shape variation and were, on average, less structurally stiff than the crania of chimpanzees during unilateral biting when loaded with physiologically-scaled muscle loads. Our results also show that modern humans are efficient producers of bite force, consistent with previous analyses. However, highly tensile reaction forces were generated at the working (biting) side jaw joint during unilateral molar bites in which the chewing muscles were recruited with bilateral symmetry. In life, such a configuration would have increased the risk of joint dislocation and

  8. Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium

    NARCIS (Netherlands)

    Farzan, Niloufar; Vijverberg, Susanne J.; Andiappan, Anand K.; Arianto, Lambang; Berce, Vojko; Blanca-López, Natalia; Bisgaard, Hans; Bønnelykke, Klaus; Burchard, Esteban G.; Campo, Paloma; Canino, Glorisa; Carleton, Bruce; Celedón, Juan C.; Chew, Fook Tim; Chiang, Wen Chin; Cloutier, Michelle M.; Daley, Denis; den Dekker, Herman T.; Dijk, F. Nicole; Duijts, Liesbeth; Flores, Carlos; Forno, Erick; Hawcutt, Daniel B.; Hernandez-Pacheco, Natalia; de Jongste, Johan C.; Kabesch, Michael; Koppelman, Gerard H.; Manolopoulos, Vangelis G.; Melén, Erik; Mukhopadhyay, Somnath; Nilsson, Sara; Palmer, Colin N.; Pino-Yanes, Maria; Pirmohamed, Munir; Potočnik, Uros; Raaijmakers, Jan A.; Repnik, Katja; Schieck, Maximilian; Sio, Yang Yie; Smyth, Rosalind L.; Szalai, Csaba; Tantisira, Kelan G.; Turner, Steve; van der Schee, Marc P.; Verhamme, Katia M.; Maitland-van der Zee, Anke H.

    2017-01-01

    Aim: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium. Materials & methods: Investigators of each study participating in PiCA provided data on the study

  9. Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium

    NARCIS (Netherlands)

    Farzan, Niloufar; Vijverberg, Susanne J.; Andiappan, Anand K.; Arianto, Lambang; Berce, Vojko; Blanca-Lopez, Natalia; Bisgaard, Hans; Bonnelykke, Klaus; Burchard, Esteban G.; Campo, Paloma; Canino, Glorisa; Carleton, Bruce; Celedon, Juan C.; Chew, Fook Tim; Chiang, Wen Chin; Cloutier, Michelle M.; Daley, Denis; Den Dekker, Herman T.; Dijk, Nicole F.; Duijts, Liesbeth; Flores, Carlos; Forno, Erick; Hawcutt, Daniel B.; Hernandez-Pacheco, Natalia; de Jongste, Johan C.; Kabesch, Michael; Koppelman, Gerard H.; Manolopoulos, Vangelis G.; Melen, Erik; Mukhopadhyay, Somnath; Nilsson, Sara; Palmer, Colin N.; Pino-Yanes, Maria; Pirmohamed, Munir; Potocnki, Uros; Raaijmakers, Jan A.; Repnik, Katja; Schieck, Maximilian; Sio, Yang Yie; Smyth, Rosalind L.; Szalai, Csaba; Tantisira, Kelan G.; Turner, Steve; van der Schee, Marc P.; Verhamme, Katia M.; Maitland-van der Zee, Anke H.

    2017-01-01

    Aim: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium.  Materials & methods: Investigators of each study participating in PiCA provided data on the

  10. Clinical practice guidelines for translating pharmacogenomic knowledge to bedside. Focus on anticancer drugs.

    Directory of Open Access Journals (Sweden)

    José A G Agúndez

    2014-08-01

    Full Text Available The development of clinical practice recommendations or guidelines for the clinical use of pharmacogenomics data is an essential issue for improving drug therapy, particularly for drugs with high toxicity and/or narrow therapeutic index such as anticancer drugs. Although pharmacogenomic-based recommendations have been formulated for over 40 anticancer drugs, the number of clinical practice guidelines available is very low. The guidelines already published indicate that pharmacogenomic testing is useful for patient selection, but final dosing adjustment should be carried out on the basis of clinical or analytical parameters rather than on pharmacogenomic information.Patient selection may seem a modest objective, but it constitutes a crucial improvement with regard to the pre-pharmacogenomics situation and it saves patients’ lives. However we should not overstate the current power of pharmacogenomics. At present the pharmacogenomics of anticancer drugs is not sufficiently developed for dose adjustments based on pharmacogenomics only, and no current guidelines recommend such adjustments without considering clinical and/or analytical parameters.

  11. Fast and frugal trees: translating population-based pharmacogenomics to medication prioritization

    NARCIS (Netherlands)

    Rooij, T. van; Roederer, M.; Wareham, H.T.; Rooij, I.J.E.I. van; McLeod, H.L.; Marsh, S.

    2015-01-01

    Aim: Fast and frugal decision trees (FFTs) can simplify clinical decision making by providing a heuristic approach to contextual guidance. We wanted to use FFTs for pharmacogenomic knowledge translation at point-of-care. Materials & Methods: The Pharmacogenomics for Every Nation Initiative (PGENI),

  12. Is variation in human radiosensitivity real or artifactual?

    International Nuclear Information System (INIS)

    Nakamura, Nori; Kushiro, Jun-ichi; Sposto, R.; Akiyama, Mitoshi.

    1989-12-01

    Two methods of producing human T-lymphocyte colonies in vitro are described, as well as dose-survival experiments using these methods for the investigation of possible differential radiosensitivity among individuals. In one method, the cloning efficiency (CE) of nonirradiated lymphocytes was between 10 % and 40 % (method 1), whereas subsequent improvement in assay conditions (method 2) resulted in a CE greater than 30 %. In vitro X-irradiation of colonies produced using method 1 revealed that the dose required to kill 90 % of the cells (D 10 ) was 2.87±0.28 Gy (mean ±SD, n = 18) for repeated examinations of lymphocytes from one reference individual. Using method 2, the D 10 values were greater, viz., 3.66±0.21 Gy for 28 repeated tests of the same reference individual and 3.58±0.19 Gy for 31 different individuals. Analysis of variance to compare the data from repeated examinations of one person versus data from single examinations of different persons showed that variation in the D 10 value was not significantly greater in the latter group. These results support the hypothesis that individual variation in human radiosensitivity is quite small, if it exists at all, as far as can be determined by the loss of colony-forming ability of irradiated G 0 lymphocytes. (author)

  13. Patterns of cis regulatory variation in diverse human populations.

    Directory of Open Access Journals (Sweden)

    Barbara E Stranger

    Full Text Available The genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation and elucidation of disease signals. To date, many studies have looked in specific tissues and population-based samples, but there has been limited assessment of the degree of inter-population variability in regulatory variation. We analyzed genome-wide gene expression in lymphoblastoid cell lines from a total of 726 individuals from 8 global populations from the HapMap3 project and correlated gene expression levels with HapMap3 SNPs located in cis to the genes. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We further dissect the specific functional pathways differentiated between populations. We also identify 5,691 expression quantitative trait loci (eQTLs after controlling for both non-genetic factors and population admixture and observe that half of the cis-eQTLs are replicated in one or more of the populations. We highlight patterns of eQTL-sharing between populations, which are partially determined by population genetic relatedness, and discover significant sharing of eQTL effects between Asians, European-admixed, and African subpopulations. Specifically, we observe that both the effect size and the direction of effect for eQTLs are highly conserved across populations. We observe an increasing proximity of eQTLs toward the transcription start site as sharing of eQTLs among populations increases, highlighting that variants close to TSS have stronger effects and therefore are more likely to be detected across a wider panel of populations. Together these results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation and provide an estimate for

  14. Genome-environment interactions and prospective technology assessment: evolution from pharmacogenomics to nutrigenomics and ecogenomics.

    Science.gov (United States)

    Ozdemir, Vural; Motulsky, Arno G; Kolker, Eugene; Godard, Béatrice

    2009-02-01

    The relationships between food, nutrition science, and health outcomes have been mapped over the past century. Genomic variation among individuals and populations is a new factor that enriches and challenges our understanding of these complex relationships. Hence, the confluence of nutritional science and genomics-nutrigenomics--was the focus of the OMICS: A Journal of Integrative Biology in December 2008 (Part 1). The 2009 Special Issue (Part 2) concludes the analysis of nutrigenomics research and innovations. Together, these two issues expand the scope and depth of critical scholarship in nutrigenomics, in keeping with an integrated multidisciplinary analysis across the bioscience, omics technology, social, ethical, intellectual property and policy dimensions. Historically, the field of pharmacogenetics provided the first examples of specifically identifiable gene variants predisposing to unexpected responses to drugs since the 1950s. Brewer coined the term ecogenetics in 1971 to broaden the concept of gene-environment interactions from drugs and nutrition to include environmental agents in general. In the mid-1990s, introduction of high-throughput technologies led to the terms pharmacogenomics, nutrigenomics and ecogenomics to describe, respectively, the contribution of genomic variability to differential responses to drugs, food, and environment defined in the broadest sense. The distinctions, if any, between these newer fields (e.g., nutrigenomics) and their predecessors (e.g., nutrigenetics) remain to be delineated. For nutrigenomics, its reliance on genome-wide analyses may lead to detection of new biological mechanisms governing host response to food. Recognizing "genome-environment interactions" as the conceptual thread that connects and runs through pharmacogenomics, nutrigenomics, and ecogenomics may contribute toward anticipatory governance and prospective real-time analysis of these omics fields. Such real-time analysis of omics technologies and

  15. Pharmacogenomics-guided policy in opioid use disorder (OUD management: An ethnically-diverse case-based approach

    Directory of Open Access Journals (Sweden)

    Earl B. Ettienne

    2017-12-01

    Full Text Available Introduction: Opioid use disorder (OUD is characterized by a problematic pattern of opioid use leading to clinically-significant impairment or distress. Opioid agonist treatment is an integral component of OUD management, and buprenorphine is often utilized in OUD management due to strong clinical evidence for efficacy. However, interindividual genetic differences in buprenorphine metabolism may result in variable treatment response, leaving some patients undertreated and at increased risk for relapse. Clinical pharmacogenomics studies the effect that inherited genetic variations have on drug response. Our objective is to demonstrate the impact of pharmacogenetic testing on OUD management outcomes. Methods: We analyzed a patient who reported discomfort at daily buprenorphine dose of 24mg, which was a mandated daily maximum by the pharmacy benefits manager. Regular urine screenings were conducted to detect the presence of unauthorized substances, and pharmacogenetic testing was used to determine the appropriate dose of buprenorphine for OUD management. Results: At the 24mg buprenorphine daily dose, the patient had multiple relapses with unauthorized substances. Pharmacogenetic testing revealed that the patient exhibited a cytochrome P450 3A4 ultrarapid metabolizer phenotype, which necessitated a higher than recommended daily dose of buprenorphine (32mg for adequate OUD management. The patient exhibited a reduction in the number of relapses on the pharmacogenetic-based dose recommendation compared to standard dosing. Conclusion: Pharmacogenomic testing as clinical decision support helped to individualize OUD management. Collaboration by key stakeholders is essential to establishing pharmacogenetic testing as standard of care in OUD management. Keywords: Opioid use disorder, Opioid agonist treatment, Buprenorphine, Pharmacogenomics, Policy

  16. Variation in heterozygosity predicts variation in human substitution rates between populations, individuals and genomic regions.

    Directory of Open Access Journals (Sweden)

    William Amos

    Full Text Available The "heterozygote instability" (HI hypothesis suggests that gene conversion events focused on heterozygous sites during meiosis locally increase the mutation rate, but this hypothesis remains largely untested. As humans left Africa they lost variability, which, if HI operates, should have reduced the mutation rate in non-Africans. Relative substitution rates were quantified in diverse humans using aligned whole genome sequences from the 1,000 genomes project. Substitution rate is consistently greater in Africans than in non-Africans, but only in diploid regions of the genome, consistent with a role for heterozygosity. Analysing the same data partitioned into a series of non-overlapping 2 Mb windows reveals a strong, non-linear correlation between the amount of heterozygosity lost "out of Africa" and the difference in substitution rate between Africans and non-Africans. Putative recent mutations, derived variants that occur only once among the 80 human chromosomes sampled, occur preferentially at the centre of 2 Kb windows that have elevated heterozygosity compared both with the same region in a closely related population and with an immediately adjacent region in the same population. More than half of all substitutions appear attributable to variation in heterozygosity. This observation provides strong support for HI with implications for many branches of evolutionary biology.

  17. Frequency variations of discrete cranial traits in major human populations. III. Hyperostotic variations.

    Science.gov (United States)

    Hanihara, T; Ishida, H

    2001-09-01

    Seven discrete cranial traits usually categorised as hyperostotic characters, the medial palatine canal, hypoglossal canal bridging, precondylar tubercle, condylus tertius, jugular foramen bridging, auditory exostosis, and mylohyoid bridging were investigated in 81 major human population samples from around the world. Significant asymmetric occurrences of the bilateral traits were detected in the medial palatine canal and jugular foramen bridging in several samples. Significant intertrait associations were found between some pairs of the traits, but not consistently across the large geographical samples. The auditory exostosis showed a predominant occurrence in males. With the exception of the auditory exostosis and mylohyoid bridging in a few samples, significant sex differences were slight. The frequency distributions of the traits (except for the auditory exostosis) showed some interregional clinality and intraregional discontinuity, suggesting that genetic drift could have contributed to the observed pattern of variation.

  18. Religious influences on human capital variations in imperial Russia

    Directory of Open Access Journals (Sweden)

    Tomila Lankina

    2012-01-01

    Full Text Available Historical legacies, particularly imperial tutelage and religion, have featured prominently in recent scholarship on political regime variations in post-communist settings, challenging earlier temporally proximate explanations. The overlap between tutelage, geography, and religion has complicated the uncovering of the spatially uneven effects of the various legacies. The author addresses this challenge by conducting sub-national analysis of religious influences within one imperial domain, Russia. In particular, the paper traces how European settlement in imperial Russia has had a bearing on human development in the imperial periphery. The causal mechanism that the paper proposes to account for this influence is the Western communities’ impact on literacy, which is in turn linked in the analysis to the Western Christian, particularly Protestant, roots, of settler populations. The author makes this case by constructing an original dataset based on sub-national data from the hitherto underutilised first imperial census of 1897.

  19. Age variations in the properties of human tibial trabecular bone

    DEFF Research Database (Denmark)

    Ding, Ming; Dalstra, M; Danielsen, CC

    1997-01-01

    We tested in compression specimens of human proximal tibial trabecular bone from 31 normal donors aged from 16 to 83 years and determined the mechanical properties, density and mineral and collagen content. Young's modulus and ultimate stress were highest between 40 and 50 years, whereas ultimate...... strain and failure energy showed maxima at younger ages. These age-related variations (except for failure energy) were non-linear. Tissue density and mineral concentration were constant throughout life, whereas apparent density (the amount of bone) varied with ultimate stress. Collagen density (the...... amount of collagen) varied with failure energy. Collagen concentration was maximal at younger ages but varied little with age. Our results suggest that the decrease in mechanical properties of trabecular bone such as Young's modulus and ultimate stress is mainly a consequence of the loss of trabecular...

  20. Human Variome Project Quality Assessment Criteria for Variation Databases.

    Science.gov (United States)

    Vihinen, Mauno; Hancock, John M; Maglott, Donna R; Landrum, Melissa J; Schaafsma, Gerard C P; Taschner, Peter

    2016-06-01

    Numerous databases containing information about DNA, RNA, and protein variations are available. Gene-specific variant databases (locus-specific variation databases, LSDBs) are typically curated and maintained for single genes or groups of genes for a certain disease(s). These databases are widely considered as the most reliable information source for a particular gene/protein/disease, but it should also be made clear they may have widely varying contents, infrastructure, and quality. Quality is very important to evaluate because these databases may affect health decision-making, research, and clinical practice. The Human Variome Project (HVP) established a Working Group for Variant Database Quality Assessment. The basic principle was to develop a simple system that nevertheless provides a good overview of the quality of a database. The HVP quality evaluation criteria that resulted are divided into four main components: data quality, technical quality, accessibility, and timeliness. This report elaborates on the developed quality criteria and how implementation of the quality scheme can be achieved. Examples are provided for the current status of the quality items in two different databases, BTKbase, an LSDB, and ClinVar, a central archive of submissions about variants and their clinical significance. © 2016 WILEY PERIODICALS, INC.

  1. Human midsagittal brain shape variation: patterns, allometry and integration

    Science.gov (United States)

    Bruner, Emiliano; Martin-Loeches, Manuel; Colom, Roberto

    2010-01-01

    Midsagittal cerebral morphology provides a homologous geometrical reference for brain shape and cortical vs. subcortical spatial relationships. In this study, midsagittal brain shape variation is investigated in a sample of 102 humans, in order to describe and quantify the major patterns of correlation between morphological features, the effect of size and sex on general anatomy, and the degree of integration between different cortical and subcortical areas. The only evident pattern of covariation was associated with fronto-parietal cortical bulging. The allometric component was weak for the cortical profile, but more robust for the posterior subcortical areas. Apparent sex differences were evidenced in size but not in brain shape. Cortical and subcortical elements displayed scarcely integrated changes, suggesting a modular separation between these two areas. However, a certain correlation was found between posterior subcortical and parietal cortical variations. These results should be directly integrated with information ranging from functional craniology to wiring organization, and with hypotheses linking brain shape and the mechanical properties of neurons during morphogenesis. PMID:20345859

  2. Estimating mobility using sparse data: Application to human genetic variation.

    Science.gov (United States)

    Loog, Liisa; Mirazón Lahr, Marta; Kovacevic, Mirna; Manica, Andrea; Eriksson, Anders; Thomas, Mark G

    2017-11-14

    Mobility is one of the most important processes shaping spatiotemporal patterns of variation in genetic, morphological, and cultural traits. However, current approaches for inferring past migration episodes in the fields of archaeology and population genetics lack either temporal resolution or formal quantification of the underlying mobility, are poorly suited to spatially and temporally sparsely sampled data, and permit only limited systematic comparison between different time periods or geographic regions. Here we present an estimator of past mobility that addresses these issues by explicitly linking trait differentiation in space and time. We demonstrate the efficacy of this estimator using spatiotemporally explicit simulations and apply it to a large set of ancient genomic data from Western Eurasia. We identify a sequence of changes in human mobility from the Late Pleistocene to the Iron Age. We find that mobility among European Holocene farmers was significantly higher than among European hunter-gatherers both pre- and postdating the Last Glacial Maximum. We also infer that this Holocene rise in mobility occurred in at least three distinct stages: the first centering on the well-known population expansion at the beginning of the Neolithic, and the second and third centering on the beginning of the Bronze Age and the late Iron Age, respectively. These findings suggest a strong link between technological change and human mobility in Holocene Western Eurasia and demonstrate the utility of this framework for exploring changes in mobility through space and time. Copyright © 2017 the Author(s). Published by PNAS.

  3. Midsagittal Brain Variation among Non-Human Primates: Insights into Evolutionary Expansion of the Human Precuneus.

    Science.gov (United States)

    Pereira-Pedro, Ana Sofia; Rilling, James K; Chen, Xu; Preuss, Todd M; Bruner, Emiliano

    2017-01-01

    The precuneus is a major element of the superior parietal lobule, positioned on the medial side of the hemisphere and reaching the dorsal surface of the brain. It is a crucial functional region for visuospatial integration, visual imagery, and body coordination. Previously, we argued that the precuneus expanded in recent human evolution, based on a combination of paleontological, comparative, and intraspecific evidence from fossil and modern human endocasts as well as from human and chimpanzee brains. The longitudinal proportions of this region are a major source of anatomical variation among adult humans and, being much larger in Homo sapiens, is the main characteristic differentiating human midsagittal brain morphology from that of our closest living primate relative, the chimpanzee. In the current shape analysis, we examine precuneus variation in non-human primates through landmark-based models, to evaluate the general pattern of variability in non-human primates, and to test whether precuneus proportions are influenced by allometric effects of brain size. Results show that precuneus proportions do not covary with brain size, and that the main difference between monkeys and apes involves a vertical expansion of the frontal and occipital regions in apes. Such differences might reflect differences in brain proportions or differences in cranial architecture. In this sample, precuneus variation is apparently not influenced by phylogenetic or allometric factors, but does vary consistently within species, at least in chimpanzees and macaques. This result further supports the hypothesis that precuneus expansion in modern humans is not merely a consequence of increasing brain size or of allometric scaling, but rather represents a species-specific morphological change in our lineage. © 2017 S. Karger AG, Basel.

  4. Pharmacogenomics-guided policy in opioid use disorder (OUD) management: An ethnically-diverse case-based approach.

    Science.gov (United States)

    Ettienne, Earl B; Chapman, Edwin; Maneno, Mary; Ofoegbu, Adaku; Wilson, Bradford; Settles-Reaves, Beverlyn; Clarke, Melissa; Dunston, Georgia; Rosenblatt, Kevin

    2017-12-01

    Opioid use disorder (OUD) is characterized by a problematic pattern of opioid use leading to clinically-significant impairment or distress. Opioid agonist treatment is an integral component of OUD management, and buprenorphine is often utilized in OUD management due to strong clinical evidence for efficacy. However, interindividual genetic differences in buprenorphine metabolism may result in variable treatment response, leaving some patients undertreated and at increased risk for relapse. Clinical pharmacogenomics studies the effect that inherited genetic variations have on drug response. Our objective is to demonstrate the impact of pharmacogenetic testing on OUD management outcomes. We analyzed a patient who reported discomfort at daily buprenorphine dose of 24 mg, which was a mandated daily maximum by the pharmacy benefits manager. Regular urine screenings were conducted to detect the presence of unauthorized substances, and pharmacogenetic testing was used to determine the appropriate dose of buprenorphine for OUD management. At the 24 mg buprenorphine daily dose, the patient had multiple relapses with unauthorized substances. Pharmacogenetic testing revealed that the patient exhibited a cytochrome P450 3A4 ultrarapid metabolizer phenotype, which necessitated a higher than recommended daily dose of buprenorphine (32 mg) for adequate OUD management. The patient exhibited a reduction in the number of relapses on the pharmacogenetic-based dose recommendation compared to standard dosing. Pharmacogenomic testing as clinical decision support helped to individualize OUD management. Collaboration by key stakeholders is essential to establishing pharmacogenetic testing as standard of care in OUD management.

  5. Race, pharmacogenomics, and marketing: putting BiDil in context.

    Science.gov (United States)

    Kahn, Jonathan

    2006-01-01

    This article endeavors to place into context recent developments surrounding the United States Food and Drug Administration recent approval of BiDil (isosorbide dinitrate/hydralazine hydrochloride) (NitroMed, Inc., Lexington, MA) as the first ever race-specific drug--in this case to treat heart failure in African Americans. It focuses in particular on both commercial incentives and statistical manipulation of medical data as framing the drive to bring BiDil to market as a race-specific drug. In current discourse about pharmacogenomics, targeting a racial audience is perceived as necessary because at this point the technology and resources do not exist to scan efficiently every individual's genetic profile. The article argues that medical researchers may say they are using race as a surrogate to target biology in drug development, but corporations are using biology as a surrogate to target race in drug marketing. Pharmacogenomics may hold great promise, but on our way to that Promised Land, it is imperative to review such short cuts with a critical eye.

  6. Variation in ovarian follicle density during human fetal development.

    Science.gov (United States)

    Geber, Selmo; Megale, Rodrigo; Vale, Fabiene; Lanna, Ana Maria Arruda; Cabral, Antônio Carlos Vieira

    2012-09-01

    To obtain a precise estimate of ovarian follicle density and variation in the number of follicles at several gestational ages during human fetal development. Twelve necropsied ovaries from 9 fetuses (gestational age: 24 to 36 weeks) and 3 neonates (who died within the first hours of life) were studied. Ovaries were fixed with 4 % formaldehyde and embedded in paraffin. Serial, 7 mm thick sections of the ovaries were cut and evaluated at every 50 cuts. Follicles were counted in 10 regions (each measuring 625 μm(2)) of the ovarian cortex and the number of follicles per mm³ was calculated. The number of follicles per 0.25 mm² ranged from 10.9 (± 4.8) in a neonate to 34.7 (± 10.6) also in a neonate. Among fetuses, follicle density was lowest at 36 weeks of gestation (11.1 ± 6.2) and highest at 26 weeks (32 ± 8.9). The total number of follicles ranged from 500,000 at the age of 22 weeks to > 1,000,000 at the age of 39 weeks. Our results show a peak in the number of follicles during intrauterine life at approximately 26 weeks, followed by a rapid reduction in this number before birth, providing a step forward towards the understanding of primordial follicular assembly in humans and, ultimately, the identification of the determinants of reproductive capacity.

  7. Variations in the formation of the human caudal spinal cord.

    Science.gov (United States)

    Saraga-Babić, M; Sapunar, D; Wartiovaara, J

    1995-01-01

    Collection of 15 human embryos between 4-8 developmental weeks was used to histologically investigate variations in the development of the caudal part of the spinal cord and the neighboring axial organs (notochord and vertebral column). In the 4-week embryo, two types of neurulation were parallelly observed along the anteroposterior body axis: primary in the areas cranial to the neuroporus caudalis and secondary in the more caudal tail regions. In the 5-week embryos, both parts of the neural tube fused, forming only one continuous lumen in the developing spinal cord. In the three examined embryos we found anomalous pattern of spinal cord formation. Caudal parts of these spinal cords displayed division of their central canal into two or three separate lumina, each surrounded by neuroepithelial layer. In the caudal area of the spinal cord, derived by secondary neurulation, formation of separate lumina was neither connected to any anomalous notochord or vertebral column formation, nor the appearance of any major axial disturbances. We suggest that development of the caudal part of the spinal cord differs from its cranial region not only in the type of neurulation, but also in the destiny of its derivatives and possible modes of abnormality formation.

  8. HSP90 Shapes the Consequences of Human Genetic Variation.

    Science.gov (United States)

    Karras, Georgios I; Yi, Song; Sahni, Nidhi; Fischer, Máté; Xie, Jenny; Vidal, Marc; D'Andrea, Alan D; Whitesell, Luke; Lindquist, Susan

    2017-02-23

    HSP90 acts as a protein-folding buffer that shapes the manifestations of genetic variation in model organisms. Whether HSP90 influences the consequences of mutations in humans, potentially modifying the clinical course of genetic diseases, remains unknown. By mining data for >1,500 disease-causing mutants, we found a strong correlation between reduced phenotypic severity and a dominant (HSP90 ≥ HSP70) increase in mutant engagement by HSP90. Examining the cancer predisposition syndrome Fanconi anemia in depth revealed that mutant FANCA proteins engaged predominantly by HSP70 had severely compromised function. In contrast, the function of less severe mutants was preserved by a dominant increase in HSP90 binding. Reducing HSP90's buffering capacity with inhibitors or febrile temperatures destabilized HSP90-buffered mutants, exacerbating FA-related chemosensitivities. Strikingly, a compensatory FANCA somatic mutation from an "experiment of nature" in monozygotic twins both prevented anemia and reduced HSP90 binding. These findings provide one plausible mechanism for the variable expressivity and environmental sensitivity of genetic diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. PHARMACOGENOMICS OF PROSTAGLANDIN AND LEUKOTRIENE RECEPTORS

    Directory of Open Access Journals (Sweden)

    José Antonio Cornejo-García

    2016-09-01

    Full Text Available Individual genetic background together with environmental effects are thought to be behind many human complex diseases. A number of genetic variants, mainly single nucleotide polymorphisms (SNPs, have been shown to be associated with various pathological and inflammatory conditions, representing potential therapeutic targets. Prostaglandins (PTGs and leukotrienes (LTs are eicosanoids derived from arachidonic acid and related polyunsaturated fatty acids that participate in both normal homeostasis and inflammatory conditions. These bioactive lipid mediators are synthesised through two major multistep enzymatic pathways: PTGs by cyclooxygenase and LTs by 5-lipoxygenase. The main physiological effects of PTGs include vasodilation and vascular leakage (PTGE2; mast cell maturation, eosinophil recruitment and allergic responses (PTGD2; vascular and respiratory smooth muscle contraction (PTGF2, and inhibition of platelet aggregation (PTGI2. LTB4 is mainly involved in neutrophil recruitment, vascular leakage, and epithelial barrier function, whereas cysteinyl LTs (CysLTs (LTC4, LTD4 and LTE4 induce bronchoconstriction and neutrophil extravasation, and also participate in vascular leakage. PTGs and LTs exert their biological functions by binding to cognate receptors, which belong to the seven transmembrane, G protein-coupled receptor superfamily. SNPs in genes encoding these receptors may influence their functionality and have a role in disease susceptibility and drug treatment response. In this review we summarize SNPs in PTGs and LTs receptors and their relevance in human diseases. We also provide information on gene expression. Finally, we speculate on future directions for this topic.

  10. Japan PGx Data Science Consortium Database: SNPs and HLA genotype data from 2994 Japanese healthy individuals for pharmacogenomics studies.

    Science.gov (United States)

    Kamitsuji, Shigeo; Matsuda, Takashi; Nishimura, Koichi; Endo, Seiko; Wada, Chisa; Watanabe, Kenji; Hasegawa, Koichi; Hishigaki, Haretsugu; Masuda, Masatoshi; Kuwahara, Yusuke; Tsuritani, Katsuki; Sugiura, Kenkichi; Kubota, Tomoko; Miyoshi, Shinji; Okada, Kinya; Nakazono, Kazuyuki; Sugaya, Yuki; Yang, Woosung; Sawamoto, Taiji; Uchida, Wataru; Shinagawa, Akira; Fujiwara, Tsutomu; Yamada, Hisaharu; Suematsu, Koji; Tsutsui, Naohisa; Kamatani, Naoyuki; Liou, Shyh-Yuh

    2015-06-01

    Japan Pharmacogenomics Data Science Consortium (JPDSC) has assembled a database for conducting pharmacogenomics (PGx) studies in Japanese subjects. The database contains the genotypes of 2.5 million single-nucleotide polymorphisms (SNPs) and 5 human leukocyte antigen loci from 2994 Japanese healthy volunteers, as well as 121 kinds of clinical information, including self-reports, physiological data, hematological data and biochemical data. In this article, the reliability of our data was evaluated by principal component analysis (PCA) and association analysis for hematological and biochemical traits by using genome-wide SNP data. PCA of the SNPs showed that all the samples were collected from the Japanese population and that the samples were separated into two major clusters by birthplace, Okinawa and other than Okinawa, as had been previously reported. Among 87 SNPs that have been reported to be associated with 18 hematological and biochemical traits in genome-wide association studies (GWAS), the associations of 56 SNPs were replicated using our data base. Statistical power simulations showed that the sample size of the JPDSC control database is large enough to detect genetic markers having a relatively strong association even when the case sample size is small. The JPDSC database will be useful as control data for conducting PGx studies to explore genetic markers to improve the safety and efficacy of drugs either during clinical development or in post-marketing.

  11. Overcoming regulatory and economic challenges facing pharmacogenomics.

    Science.gov (United States)

    Cohen, Joshua P

    2012-09-15

    The number of personalized medicines and companion diagnostics in use in the United States has gradually increased over the past decade, from a handful of medicines and tests in 2001 to several dozen in 2011. However, the numbers have not reached the potential hoped for when the human genome project was completed in 2001. Significant clinical, regulatory, and economic barriers exist and persist. From a regulatory perspective, therapeutics and companion diagnostics are ideally developed simultaneously, with the clinical significance of the diagnostic established using data from the clinical development program of the corresponding therapeutic. Nevertheless, this is not (yet) happening. Most personalized medicines are personalized post hoc, that is, a companion diagnostic is developed separately and approved after the therapeutic. This is due in part to a separate and more complex regulatory process for diagnostics coupled with a lack of clear regulatory guidance. More importantly, payers have placed restrictions on reimbursement of personalized medicines and their companion diagnostics, given the lack of evidence on the clinical utility of many tests. To achieve increased clinical adoption of diagnostics and targeted therapies through more favorable reimbursement and incorporation in clinical practice guidelines, regulators will need to provide unambiguous guidance and manufacturers will need to bring more and better clinical evidence to the market place. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. Benefits of and Barriers to Pharmacogenomics-Guided Treatment for Major Depressive Disorder.

    Science.gov (United States)

    Ahmed, Ahmed T; Weinshilboum, Richard; Frye, Mark A

    2018-05-01

    Antidepressants have reduced the symptom burden for many Major Depressive Disorder (MDD) patients, but drug-related side effects and treatment resistance continue to present major challenges. Pharmacogenomics represents one approach to enhance antidepressant efficacy and avoid adverse reactions, but concerns remain with regard to the overall "value equation," and several barriers must be overcome to achieve the full potential of MDD pharmacogenomics. © 2018 American Society for Clinical Pharmacology and Therapeutics.

  13. Anatomical Variations of the Circulus Arteriosus in Cadaveric Human Brains

    Science.gov (United States)

    Gunnal, S. A.; Farooqui, M. S.; Wabale, R. N.

    2014-01-01

    Objective. Circulus arteriosus/circle of Willis (CW) is a polygonal anastomotic channel at the base of the brain which unites the internal carotid and vertebrobasilar system. It maintains the steady and constant supply to the brain. The variations of CW are seen often. The Aim of the present work is to find out the percentage of normal pattern of CW, and the frequency of variations of the CW and to study the morphological and morphometric aspects of all components of CW. Methods. Circulus arteriosus of 150 formalin preserved brains were dissected. Dimensions of all the components forming circles were measured. Variations of all the segments were noted and well photographed. The variations such as aplasia, hypoplasia, duplication, fenestrations, and difference in dimensions with opposite segments were noted. The data collected in the study was analyzed. Results. Twenty-one different types of CW were found in the present study. Normal and complete CW was found in 60%. CW with gross morphological variations was seen in 40%. Maximum variations were seen in the PCoA followed by the ACoA in 50% and 40%, respectively. Conclusion. As it confirms high percentage of variations, all surgical interventions should be preceded by angiography. Awareness of these anatomical variations is important in neurovascular procedures. PMID:24891951

  14. Pharmacogenomics Bias - Systematic distortion of study results by genetic heterogeneity

    Directory of Open Access Journals (Sweden)

    Zietemann, Vera

    2008-04-01

    Full Text Available Background: Decision analyses of drug treatments in chronic diseases require modeling the progression of disease and treatment response beyond the time horizon of clinical or epidemiological studies. In many such models, progression and drug effect have been applied uniformly to all patients; heterogeneity in progression, including pharmacogenomic effects, has been ignored. Objective: We sought to systematically evaluate the existence, direction and relative magnitude of a pharmacogenomics bias (PGX-Bias resulting from failure to adjust for genetic heterogeneity in both treatment response (HT and heterogeneity in progression of disease (HP in decision-analytic studies based on clinical study data. Methods: We performed a systematic literature search in electronic databases for studies regarding the effect of genetic heterogeneity on the validity of study results. Included studies have been summarized in evidence tables. In the case of lacking evidence from published studies we sought to perform our own simulation considering both HT and HP. We constructed two simple Markov models with three basic health states (early-stage disease, late-stage disease, dead, one adjusting and the other not adjusting for genetic heterogeneity. Adjustment was done by creating different disease states for presence (G+ and absence (G- of a dichotomous genetic factor. We compared the life expectancy gains attributable to treatment resulting from both models and defined pharmacogenomics bias as percent deviation of treatment-related life expectancy gains in the unadjusted model from those in the adjusted model. We calculated the bias as a function of underlying model parameters to create generic results. We then applied our model to lipid-lowering therapy with pravastatin in patients with coronary atherosclerosis, incorporating the influence of two TaqIB polymorphism variants (B1 and B2 on progression and drug efficacy as reported in the DNA substudy of the REGRESS

  15. Deep learning in pharmacogenomics: from gene regulation to patient stratification.

    Science.gov (United States)

    Kalinin, Alexandr A; Higgins, Gerald A; Reamaroon, Narathip; Soroushmehr, Sayedmohammadreza; Allyn-Feuer, Ari; Dinov, Ivo D; Najarian, Kayvan; Athey, Brian D

    2018-05-01

    This Perspective provides examples of current and future applications of deep learning in pharmacogenomics, including: identification of novel regulatory variants located in noncoding domains of the genome and their function as applied to pharmacoepigenomics; patient stratification from medical records; and the mechanistic prediction of drug response, targets and their interactions. Deep learning encapsulates a family of machine learning algorithms that has transformed many important subfields of artificial intelligence over the last decade, and has demonstrated breakthrough performance improvements on a wide range of tasks in biomedicine. We anticipate that in the future, deep learning will be widely used to predict personalized drug response and optimize medication selection and dosing, using knowledge extracted from large and complex molecular, epidemiological, clinical and demographic datasets.

  16. State of Art of Cancer Pharmacogenomics in Latin American Populations

    Directory of Open Access Journals (Sweden)

    Andrés López-Cortés

    2017-05-01

    Full Text Available Over the past decades, several studies have shown that tumor-related somatic and germline alterations predicts tumor prognosis, drug response and toxicity. Latin American populations present a vast geno-phenotypic diversity due to the great interethnic and interracial mixing. This genetic flow leads to the appearance of complex characteristics that allow individuals to adapt to endemic environments, such as high altitude or extreme tropical weather. These genetic changes, most of them subtle and unexplored, could establish a mutational profile to develop new pharmacogenomic therapies specific for Latin American populations. In this review, we present the current status of research on somatic and germline alterations in Latin America compared to those found in Caucasian and Asian populations.

  17. Errors in data interpretation from genetic variation of human analytes

    OpenAIRE

    Howie, Heather L.; Delaney, Meghan; Wang, Xiaohong; Er, Lay See; Kapp, Linda; Lebedev, Jenna N.; Zimring, James C.

    2017-01-01

    In recent years, the extent of our vulnerability to misinterpretation due to poorly characterized reagents has become an issue of great concern. Antibody reagents have been identified as a major source of error, contributing to the ?reproducibility crisis.? In the current report, we define an additional dimension of the crisis; in particular, we define variation of the targets being analyzed. We report that natural variation in the immunoglobulin ?constant? region alters the reactivity with c...

  18. Examining perceptions of the usefulness and usability of a mobile-based system for pharmacogenomics clinical decision support: a mixed methods study

    Directory of Open Access Journals (Sweden)

    Kathrin Blagec

    2016-02-01

    Full Text Available Background. Pharmacogenomic testing has the potential to improve the safety and efficacy of pharmacotherapy, but clinical application of pharmacogenetic knowledge has remained uncommon. Clinical Decision Support (CDS systems could help overcome some of the barriers to clinical implementation. The aim of this study was to evaluate the perception and usability of a web- and mobile-enabled CDS system for pharmacogenetics-guided drug therapy–the Medication Safety Code (MSC system–among potential users (i.e., physicians and pharmacists. Furthermore, this study sought to collect data on the practicability and comprehensibility of potential layouts of a proposed personalized pocket card that is intended to not only contain the machine-readable data for use with the MSC system but also human-readable data on the patient’s pharmacogenomic profile. Methods. We deployed an emergent mixed methods design encompassing (1 qualitative interviews with pharmacists and pharmacy students, (2 a survey among pharmacogenomics experts that included both qualitative and quantitative elements and (3 a quantitative survey among physicians and pharmacists. The interviews followed a semi-structured guide including a hypothetical patient scenario that had to be solved by using the MSC system. The survey among pharmacogenomics experts focused on what information should be printed on the card and how this information should be arranged. Furthermore, the MSC system was evaluated based on two hypothetical patient scenarios and four follow-up questions on the perceived usability. The second survey assessed physicians’ and pharmacists’ attitude towards the MSC system. Results. In total, 101 physicians, pharmacists and PGx experts coming from various relevant fields evaluated the MSC system. Overall, the reaction to the MSC system was positive across all investigated parameters and among all user groups. The majority of participants were able to solve the patient

  19. Frequency variations of discrete cranial traits in major human populations. I. Supernumerary ossicle variations.

    Science.gov (United States)

    Hanihara, T; Ishida, H

    2001-06-01

    Four supernumerary ossicle variations-the ossicle at the lambda, the parietal notch bone, the asterionic bone, and the occipitomastoid bone-were examined for laterality differences, intertrait correlations, sex differences, and between group variations in the samples from around the world. Significant laterality differences were not detected in almost all samples. In some pairs of traits, significant association of occurrence were found. Several geographic samples were sexually dimorphic with respect to the asterionic bone and to a lesser extent for the parietal notch bone. East/Northeast Asians including the Arctic populations in general had lower frequencies of the 4 accessory ossicles. Australians, Melanesians and the majority of the New World peoples, on the other hand, generally had high frequencies. In the western hemisphere of the Old World, Subsaharan Africans had relatively high frequencies. Except for the ossicle at the lambda, the distribution pattern in incidence showed clinal variation from south to north. Any identifiable adaptive value related to environmental or subsistence factors may be expressed in such clinal variation. This may allow us to hypothesise that not only mechanical factors but a founder effect, genetic drift, and population structure could have been the underlying causes for interregional variation and possible clines in the incidences of the accessory ossicles.

  20. A Rare Variation of the Human Median Nerve Direction

    Directory of Open Access Journals (Sweden)

    Barfi

    2016-04-01

    Full Text Available Introduction The brachial plexus, a complex network of nerves, innervates to the upper limbs. Variation in the course of the nerves in the upper limb is common. Case Presentation This paper describes two cases of upper limb variations in a cadaver dissected at Lorestan University of Medical Sciences. In the first variation, the median nerve in the arm has a different route, so that the median moves deep into the brachialis muscle. In the latter case, after piercing the coracobrachialis muscle a musculocutaneous nerve exists between the brachialis and biceps and goes to the lateral region of the forearm. This is known as the lateral cutaneous nerve of the forearm nerve, and innervates the skin of the lateral part of the forearm and the dorsal part of the hand. Conclusions Because of the possibility of damage to the brachial plexus branches is high in upper limb injuries and surgeries, full knowledge of normal anatomy and variations of these branches is essential for orthopedic specialists, neurosurgeons, radiologists, and anatomists.

  1. Human genetics: international projects and personalized medicine.

    Science.gov (United States)

    Apellaniz-Ruiz, Maria; Gallego, Cristina; Ruiz-Pinto, Sara; Carracedo, Angel; Rodríguez-Antona, Cristina

    2016-03-01

    In this article, we present the progress driven by the recent technological advances and new revolutionary massive sequencing technologies in the field of human genetics. We discuss this knowledge in relation with drug response prediction, from the germline genetic variation compiled in the 1000 Genomes Project or in the Genotype-Tissue Expression project, to the phenome-genome archives, the international cancer projects, such as The Cancer Genome Atlas or the International Cancer Genome Consortium, and the epigenetic variation and its influence in gene expression, including the regulation of drug metabolism. This review is based on the lectures presented by the speakers of the Symposium "Human Genetics: International Projects & New Technologies" from the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society, held on the 20th and 21st of April 2015.

  2. Time-related patient data retrieval for the case studies from the pharmacogenomics research network

    Science.gov (United States)

    Zhu, Qian; Tao, Cui; Ding, Ying; Chute, Christopher G.

    2012-01-01

    There are lots of question-based data elements from the pharmacogenomics research network (PGRN) studies. Many data elements contain temporal information. To semantically represent these elements so that they can be machine processiable is a challenging problem for the following reasons: (1) the designers of these studies usually do not have the knowledge of any computer modeling and query languages, so that the original data elements usually are represented in spreadsheets in human languages; and (2) the time aspects in these data elements can be too complex to be represented faithfully in a machine-understandable way. In this paper, we introduce our efforts on representing these data elements using semantic web technologies. We have developed an ontology, CNTRO, for representing clinical events and their temporal relations in the web ontology language (OWL). Here we use CNTRO to represent the time aspects in the data elements. We have evaluated 720 time-related data elements from PGRN studies. We adapted and extended the knowledge representation requirements for EliXR-TIME to categorize our data elements. A CNTRO-based SPARQL query builder has been developed to customize users’ own SPARQL queries for each knowledge representation requirement. The SPARQL query builder has been evaluated with a simulated EHR triple store to ensure its functionalities. PMID:23076712

  3. Time-related patient data retrieval for the case studies from the pharmacogenomics research network.

    Science.gov (United States)

    Zhu, Qian; Tao, Cui; Ding, Ying; Chute, Christopher G

    2012-11-01

    There are lots of question-based data elements from the pharmacogenomics research network (PGRN) studies. Many data elements contain temporal information. To semantically represent these elements so that they can be machine processiable is a challenging problem for the following reasons: (1) the designers of these studies usually do not have the knowledge of any computer modeling and query languages, so that the original data elements usually are represented in spreadsheets in human languages; and (2) the time aspects in these data elements can be too complex to be represented faithfully in a machine-understandable way. In this paper, we introduce our efforts on representing these data elements using semantic web technologies. We have developed an ontology, CNTRO, for representing clinical events and their temporal relations in the web ontology language (OWL). Here we use CNTRO to represent the time aspects in the data elements. We have evaluated 720 time-related data elements from PGRN studies. We adapted and extended the knowledge representation requirements for EliXR-TIME to categorize our data elements. A CNTRO-based SPARQL query builder has been developed to customize users' own SPARQL queries for each knowledge representation requirement. The SPARQL query builder has been evaluated with a simulated EHR triple store to ensure its functionalities.

  4. Clinical pharmacogenomics testing in the era of next generation sequencing: challenges and opportunities for precision medicine.

    Science.gov (United States)

    Ji, Yuan; Si, Yue; McMillin, Gwendolyn A; Lyon, Elaine

    2018-04-23

    The rapid development and dramatic decrease in cost of sequencing techniques have ushered the implementation of genomic testing in patient care. Next generation DNA sequencing (NGS) techniques have been used increasingly in clinical laboratories to scan the whole or part of the human genome in order to facilitate diagnosis and/or prognostics of genetic disease. Despite many hurdles and debates, pharmacogenomics (PGx) is believed to be an area of genomic medicine where precision medicine could have immediate impact in the near future. Areas covered: This review focuses on lessons learned through early attempts of clinically implementing PGx testing; the challenges and opportunities that PGx testing brings to precision medicine in the era of NGS. Expert commentary: Replacing targeted analysis approach with NGS for PGx testing is neither technically feasible nor necessary currently due to several technical limitations and uncertainty involved in interpreting variants of uncertain significance for PGx variants. However, reporting PGx variants out of clinical whole exome or whole genome sequencing (WES/WGS) might represent additional benefits for patients who are tested by WES/WGS.

  5. Pharmacogenomics Implications of Using Herbal Medicinal Plants on African Populations in Health Transition

    Science.gov (United States)

    Thomford, Nicholas E.; Dzobo, Kevin; Chopera, Denis; Wonkam, Ambroise; Skelton, Michelle; Blackhurst, Dee; Chirikure, Shadreck; Dandara, Collet

    2015-01-01

    The most accessible points of call for most African populations with respect to primary health care are traditional health systems that include spiritual, religious, and herbal medicine. This review focusses only on the use of herbal medicines. Most African people accept herbal medicines as generally safe with no serious adverse effects. However, the overlap between conventional medicine and herbal medicine is a reality among countries in health systems transition. Patients often simultaneously seek treatment from both conventional and traditional health systems for the same condition. Commonly encountered conditions/diseases include malaria, HIV/AIDS, hypertension, tuberculosis, and bleeding disorders. It is therefore imperative to understand the modes of interaction between different drugs from conventional and traditional health care systems when used in treatment combinations. Both conventional and traditional drug entities are metabolized by the same enzyme systems in the human body, resulting in both pharmacokinetics and pharmacodynamics interactions, whose properties remain unknown/unquantified. Thus, it is important that profiles of interaction between different herbal and conventional medicines be evaluated. This review evaluates herbal and conventional drugs in a few African countries and their potential interaction at the pharmacogenomics level. PMID:26402689

  6. Genetic analysis of variation in human meiotic recombination.

    Directory of Open Access Journals (Sweden)

    Reshmi Chowdhury

    2009-09-01

    Full Text Available The number of recombination events per meiosis varies extensively among individuals. This recombination phenotype differs between female and male, and also among individuals of each gender. In this study, we used high-density SNP genotypes of over 2,300 individuals and their offspring in two datasets to characterize recombination landscape and to map the genetic variants that contribute to variation in recombination phenotypes. We found six genetic loci that are associated with recombination phenotypes. Two of these (RNF212 and an inversion on chromosome 17q21.31 were previously reported in the Icelandic population, and this is the first replication in any other population. Of the four newly identified loci (KIAA1462, PDZK1, UGCG, NUB1, results from expression studies provide support for their roles in meiosis. Each of the variants that we identified explains only a small fraction of the individual variation in recombination. Notably, we found different sequence variants associated with female and male recombination phenotypes, suggesting that they are regulated by different genes. Characterization of genetic variants that influence natural variation in meiotic recombination will lead to a better understanding of normal meiotic events as well as of non-disjunction, the primary cause of pregnancy loss.

  7. Genetic variation in a member of the laminin gene family affects variation in body composition in Drosophila and humans

    Directory of Open Access Journals (Sweden)

    Hunter Gary R

    2008-08-01

    Full Text Available Abstract Background The objective of the present study was to map candidate loci influencing naturally occurring variation in triacylglycerol (TAG storage using quantitative complementation procedures in Drosophila melanogaster. Based on our results from Drosophila, we performed a human population-based association study to investigate the effect of natural variation in LAMA5 gene on body composition in humans. Results We identified four candidate genes that contributed to differences in TAG storage between two strains of D. melanogaster, including Laminin A (LanA, which is a member of the α subfamily of laminin chains. We confirmed the effects of this gene using a viable LanA mutant and showed that female flies homozygous for the mutation had significantly lower TAG storage, body weight, and total protein content than control flies. Drosophila LanA is closely related to human LAMA5 gene, which maps to the well-replicated obesity-linkage region on chromosome 20q13.2-q13.3. We tested for association between three common single nucleotide polymorphisms (SNPs in the human LAMA5 gene and variation in body composition and lipid profile traits in a cohort of unrelated women of European American (EA and African American (AA descent. In both ethnic groups, we found that SNP rs659822 was associated with weight (EA: P = 0.008; AA: P = 0.05 and lean mass (EA: P= 0.003; AA: P = 0.03. We also found this SNP to be associated with height (P = 0.01, total fat mass (P = 0.01, and HDL-cholesterol (P = 0.003 but only in EA women. Finally, significant associations of SNP rs944895 with serum TAG levels (P = 0.02 and HDL-cholesterol (P = 0.03 were observed in AA women. Conclusion Our results suggest an evolutionarily conserved role of a member of the laminin gene family in contributing to variation in weight and body composition.

  8. Use of combinatorial pharmacogenomic testing in two cases from community psychiatry

    Directory of Open Access Journals (Sweden)

    Fields ES

    2016-08-01

    Full Text Available Eve S Fields,1 Raymond A Lorenz,2 Joel G Winner2 1Northwest Center for Community Mental Health, Reston, VA, USA; 2Assurex Health, Mason, OH, USA Abstract: This report describes two cases in which pharmacogenomic testing was utilized to guide medication selection for difficult to treat patients. The first patient is a 29-year old male with bipolar disorder who had severe akathisia due to his long acting injectable antipsychotic. The second patient is a 59-year old female with major depressive disorder who was not ­responding to her medication. In both cases, a proprietary combinatorial pharmacogenomic test was used to inform medication changes and improve patient outcomes. The first patient was switched to a long acting injectable that was not affected by his genetic profile and his adverse effects abated. The second patient had her medications discontinued due to the results of the genetic testing and more intense psychotherapy initiated. While pharmacogenomic testing may be ­helpful in cases such as these presented here, it should never serve as a proxy for a comprehensive biopsychosocial approach. The pharmacogenomic information may be selectively added to this comprehensive approach to support medication treatment. Keywords: pharmacogenomics, adverse effects, risperidone, nortriptyline, paliperidone

  9. Normal human bone marrow and its variations in MRI

    International Nuclear Information System (INIS)

    Vahlensieck, M.; Schmidt, H.M.

    2000-01-01

    Physiology and age dependant changes of human bone marrow are described. The resulting normal distribution patterns of active and inactive bone marrow including the various contrasts on different MR-sequences are discussed. (orig.) [de

  10. Evidence used in model-based economic evaluations for evaluating pharmacogenetic and pharmacogenomic tests: a systematic review protocol.

    Science.gov (United States)

    Peters, Jaime L; Cooper, Chris; Buchanan, James

    2015-11-11

    Decision models can be used to conduct economic evaluations of new pharmacogenetic and pharmacogenomic tests to ensure they offer value for money to healthcare systems. These models require a great deal of evidence, yet research suggests the evidence used is diverse and of uncertain quality. By conducting a systematic review, we aim to investigate the test-related evidence used to inform decision models developed for the economic evaluation of genetic tests. We will search electronic databases including MEDLINE, EMBASE and NHS EEDs to identify model-based economic evaluations of pharmacogenetic and pharmacogenomic tests. The search will not be limited by language or date. Title and abstract screening will be conducted independently by 2 reviewers, with screening of full texts and data extraction conducted by 1 reviewer, and checked by another. Characteristics of the decision problem, the decision model and the test evidence used to inform the model will be extracted. Specifically, we will identify the reported evidence sources for the test-related evidence used, describe the study design and how the evidence was identified. A checklist developed specifically for decision analytic models will be used to critically appraise the models described in these studies. Variations in the test evidence used in the decision models will be explored across the included studies, and we will identify gaps in the evidence in terms of both quantity and quality. The findings of this work will be disseminated via a peer-reviewed journal publication and at national and international conferences. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  11. Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome

    NARCIS (Netherlands)

    Collins, Ryan L; Brand, Harrison; Redin, Claire E.; Hanscom, Carrie; Antolik, Caroline; Stone, Matthew R; Glessner, Joseph T.; Mason, Tamara; Pregno, Giulia; Dorrani, Naghmeh; Mandrile, Giorgia; Giachino, Daniela; Perrin, Danielle; Walsh, Cole; Cipicchio, Michelle; Costello, Maura; Stortchevoi, Alexei; An, Joon Yong; Currall, Benjamin B; Seabra, Catarina M; Ragavendran, Ashok; Margolin, Lauren; Martinez-Agosto, Julian A.; Lucente, Diane; Levy, Brynn; Sanders, Jan-Stephan; Wapner, Ronald J.; Quintero-Rivera, Fabiola; Kloosterman, Wigard; Talkowski, Michael E.

    2017-01-01

    Background: Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies. Results: We sequenced 689 participants with autism spectrum disorder (ASD) and other

  12. The Body as a Substrate of Differentiation. Shifting the Focus from Race Science to Life Scientists' Research on Human Variation

    OpenAIRE

    Lipphardt, Veronika

    2017-01-01

    Abstract This article suggests to focus on the history of human variation instead of focussing on the history of race science. It views the latter as a subset of the former, hence views race science as embedded into the larger field of life scientists' investigations into human variation. This paper explores why human variation is such an attractive and productive object particularly for the life sciences. It proposes that knowledge about human variation is incomplete in a promising way, and ...

  13. Characterization and potential functional significance of human-chimpanzee large INDEL variation

    Directory of Open Access Journals (Sweden)

    Polavarapu Nalini

    2011-10-01

    Full Text Available Abstract Background Although humans and chimpanzees have accumulated significant differences in a number of phenotypic traits since diverging from a common ancestor about six million years ago, their genomes are more than 98.5% identical at protein-coding loci. This modest degree of nucleotide divergence is not sufficient to explain the extensive phenotypic differences between the two species. It has been hypothesized that the genetic basis of the phenotypic differences lies at the level of gene regulation and is associated with the extensive insertion and deletion (INDEL variation between the two species. To test the hypothesis that large INDELs (80 to 12,000 bp may have contributed significantly to differences in gene regulation between the two species, we categorized human-chimpanzee INDEL variation mapping in or around genes and determined whether this variation is significantly correlated with previously determined differences in gene expression. Results Extensive, large INDEL variation exists between the human and chimpanzee genomes. This variation is primarily attributable to retrotransposon insertions within the human lineage. There is a significant correlation between differences in gene expression and large human-chimpanzee INDEL variation mapping in genes or in proximity to them. Conclusions The results presented herein are consistent with the hypothesis that large INDELs, particularly those associated with retrotransposons, have played a significant role in human-chimpanzee regulatory evolution.

  14. Inter-specific variation in avian responses to human disturbance

    Science.gov (United States)

    Daniel T. Blumstein; Esteban Fernandez-Juricic; Patrick A. Zollner; Susan C. Garity

    2005-01-01

    1. Increasing urbanization and recreational activities around and within biodiversity hotspots require an understanding of how to reduce the impacts of human disturbance on more than a single species; however, we lack a general framework to study multiple species. One approach is to expand on knowledge about the theory of anti-predator behaviour to understand and...

  15. Original article Temperamental variation in learned irrelevance in humans

    Directory of Open Access Journals (Sweden)

    Aleksandra Gruszka

    2015-07-01

    Full Text Available Background Learned irrelevance (LIRR represents one of the mechanisms of attentional set-shifting and refers to the inability to attend to, or to learn about, any aspect of a stimulus previously experienced as irrelevant. Although it has been extensively studied in the context of clinical populations, not much is known about LIRR effects in relation to normal variation in individual differences. The present study was designed to assess how temperamental factors may modulate LIRR. Participants and procedures Sixty-eight healthy volunteers performed a visual discrimination learning task modelled after Wisconsin Card Sorting Test. To test the susceptibility to learned irrelevance, participants were expected to shift their attention either to a dimension that prior to the extra-dimensional shift was completely irrelevant, or to a dimension that was previously partly correlated with reinforcement. Temperamental traits were assessed using the Formal Characteristics of Behaviour-Temperament Inventory (Zawadzki & Strelau, 1997. Intelligence level was stratified according to Raven’s Advanced Progressive Matrices (Raven, Raven, & Court, 2003. Results Low level of Briskness and high level of Perseverance were related to enhanced susceptibility to LIRR. High levels of Activity and Emotional Reactivity were related to the poorer performance on the extra-dimensional set-shifting. No effects of other temperament characteristics or intelligence on LIRR were observed. Conclusions The results confirm a strong variation in LIRR related to individual differences in temperament, which appears to be unrelated to DA function. Our results highlight the importance of considering individual differences in studies on cognitive control.

  16. Anatomical-clinical investigations of variations of the human coronary arteries

    OpenAIRE

    Aida Hasanović; Faruk Dilberović; Fehim Ovčina

    2003-01-01

    Variations of the human coronary arteries have always attracted the attention of many researchers. A review of the literature shows that variations can cause ischemic heart disease or sudden cardiac death. The aim of the investigations was to examine the existence and clinical significance of variations of the human coronary arteries. Special attention has been focused on myocardial bridging of the coronary arteries and coronary arteriovenous fistula. Our investigations were carried out on th...

  17. Qualitative and quantitative estimations of the effect of geomagnetic field variations on human brain functional state

    International Nuclear Information System (INIS)

    Belisheva, N.K.; Popov, A.N.; Petukhova, N.V.; Pavlova, L.P.; Osipov, K.S.; Tkachenko, S.Eh.; Baranova, T.I.

    1995-01-01

    The comparison of functional dynamics of human brain with reference to qualitative and quantitative characteristics of local geomagnetic field (GMF) variations was conducted. Steady and unsteady states of human brain can be determined: by geomagnetic disturbances before the observation period; by structure and doses of GMF variations; by different combinations of qualitative and quantitative characteristics of GMF variations. Decrease of optimal GMF activity level and the appearance of aperiodic disturbances of GMF can be a reason of unsteady brain's state. 18 refs.; 3 figs

  18. Non-codingRNA sequence variations in human chronic lymphocytic leukemia and colorectal cancer.

    Science.gov (United States)

    Wojcik, Sylwia E; Rossi, Simona; Shimizu, Masayoshi; Nicoloso, Milena S; Cimmino, Amelia; Alder, Hansjuerg; Herlea, Vlad; Rassenti, Laura Z; Rai, Kanti R; Kipps, Thomas J; Keating, Michael J; Croce, Carlo M; Calin, George A

    2010-02-01

    Cancer is a genetic disease in which the interplay between alterations in protein-coding genes and non-coding RNAs (ncRNAs) plays a fundamental role. In recent years, the full coding component of the human genome was sequenced in various cancers, whereas such attempts related to ncRNAs are still fragmentary. We screened genomic DNAs for sequence variations in 148 microRNAs (miRNAs) and ultraconserved regions (UCRs) loci in patients with chronic lymphocytic leukemia (CLL) or colorectal cancer (CRC) by Sanger technique and further tried to elucidate the functional consequences of some of these variations. We found sequence variations in miRNAs in both sporadic and familial CLL cases, mutations of UCRs in CLLs and CRCs and, in certain instances, detected functional effects of these variations. Furthermore, by integrating our data with previously published data on miRNA sequence variations, we have created a catalog of DNA sequence variations in miRNAs/ultraconserved genes in human cancers. These findings argue that ncRNAs are targeted by both germ line and somatic mutations as well as by single-nucleotide polymorphisms with functional significance for human tumorigenesis. Sequence variations in ncRNA loci are frequent and some have functional and biological significance. Such information can be exploited to further investigate on a genome-wide scale the frequency of genetic variations in ncRNAs and their functional meaning, as well as for the development of new diagnostic and prognostic markers for leukemias and carcinomas.

  19. Copy number variation of human AMY1 is a minor contributor to variation in salivary amylase expression and activity.

    Science.gov (United States)

    Carpenter, Danielle; Mitchell, Laura M; Armour, John A L

    2017-02-20

    Salivary amylase in humans is encoded by the copy variable gene AMY1 in the amylase gene cluster on chromosome 1. Although the role of salivary amylase is well established, the consequences of the copy number variation (CNV) at AMY1 on salivary amylase protein production are less well understood. The amylase gene cluster is highly structured with a fundamental difference between odd and even AMY1 copy number haplotypes. In this study, we aimed to explore, in samples from 119 unrelated individuals, not only the effects of AMY1 CNV on salivary amylase protein expression and amylase enzyme activity but also whether there is any evidence for underlying difference between the common haplotypes containing odd numbers of AMY1 and even copy number haplotypes. AMY1 copy number was significantly correlated with the variation observed in salivary amylase production (11.7% of variance, P structure may affect expression, but this was not significant in our data.

  20. Continental synchronicity of human influenza virus epidemics despite climactic variation.

    Science.gov (United States)

    Geoghegan, Jemma L; Saavedra, Aldo F; Duchêne, Sebastián; Sullivan, Sheena; Barr, Ian; Holmes, Edward C

    2018-01-01

    The factors that determine the pattern and rate of spread of influenza virus at a continental-scale are uncertain. Although recent work suggests that influenza epidemics in the United States exhibit a strong geographical correlation, the spatiotemporal dynamics of influenza in Australia, a country and continent of approximately similar size and climate complexity but with a far smaller population, are not known. Using a unique combination of large-scale laboratory-confirmed influenza surveillance comprising >450,000 entries and genomic sequence data we determined the local-level spatial diffusion of this important human pathogen nationwide in Australia. We used laboratory-confirmed influenza data to characterize the spread of influenza virus across Australia during 2007-2016. The onset of established epidemics varied across seasons, with highly synchronized epidemics coinciding with the emergence of antigenically distinct viruses, particularly during the 2009 A/H1N1 pandemic. The onset of epidemics was largely synchronized between the most populous cities, even those separated by distances of >3000 km and those that experience vastly diverse climates. In addition, by analyzing global phylogeographic patterns we show that the synchronized dissemination of influenza across Australian cities involved multiple introductions from the global influenza population, coupled with strong domestic connectivity, rather than through the distinct radial patterns of geographic dispersal that are driven by work-flow transmission as observed in the United States. In addition, by comparing the spatial structure of influenza A and B, we found that these viruses tended to occupy different geographic regions, and peak in different seasons, perhaps indicative of moderate cross-protective immunity or viral interference effects. The highly synchronized outbreaks of influenza virus at a continental-scale revealed here highlight the importance of coordinated public health responses in the

  1. Human alteration of the rural landscape: Variations in visual perception

    International Nuclear Information System (INIS)

    Cloquell-Ballester, Vicente-Agustín; Carmen Torres-Sibille, Ana del; Cloquell-Ballester, Víctor-Andrés; Santamarina-Siurana, María Cristina

    2012-01-01

    The objective of this investigation is to evaluate how visual perception varies as the rural landscape is altered by human interventions of varying character. An experiment is carried out using Semantic Differential Analysis to analyse the effect of the character and the type of the intervention on perception. Interventions are divided into elements of “permanent industrial character”, “elements of permanent rural character” and “elements of temporary character”, and these categories are sub-divided into smaller groups according to the type of development. To increase the reliability of the results, the Intraclass Correlation Coefficient tool, is applied to validate the semantic space of the perceptual responses and to determine the number of subjects required for a reliable evaluation of the scenes.

  2. Human alteration of the rural landscape: Variations in visual perception

    Energy Technology Data Exchange (ETDEWEB)

    Cloquell-Ballester, Vicente-Agustin, E-mail: cloquell@dpi.upv.es; Carmen Torres-Sibille, Ana del; Cloquell-Ballester, Victor-Andres; Santamarina-Siurana, Maria Cristina

    2012-01-15

    The objective of this investigation is to evaluate how visual perception varies as the rural landscape is altered by human interventions of varying character. An experiment is carried out using Semantic Differential Analysis to analyse the effect of the character and the type of the intervention on perception. Interventions are divided into elements of 'permanent industrial character', 'elements of permanent rural character' and 'elements of temporary character', and these categories are sub-divided into smaller groups according to the type of development. To increase the reliability of the results, the Intraclass Correlation Coefficient tool, is applied to validate the semantic space of the perceptual responses and to determine the number of subjects required for a reliable evaluation of the scenes.

  3. Variation in macronutrients in human bank milk: Influencing factors and implications for human milk banking

    DEFF Research Database (Denmark)

    Michaelsen, K F; Skafte, Ester Lis; Badsberg, Jens Henrik

    1990-01-01

    . There was a large variation in the concentration of energy-yielding macronutrients. The contents of P, F, C, and E in the samples with the highest values (97.5 percentile) were 2.3-, 4.8-, 1.2-, and 2.3-fold, respectively, above the contents in the samples with the lowest values (2.5 percentile). The P content...... decreased exponentially during the 1st 8 months, followed by an increase during the following months. The F content decreased during the 1st 4 months, followed by an almost linear increase. The possible influence of different maternal characteristics on the macronutrient content of the milk was examined...... with a high P content, we have developed a "high-protein" milk with a P content of about 12 g/L (true protein) and an E content of about 725 kcal/L. Thus, by continuous monitoring of macronutrient content in human bank milk it is possible to develop a "high-protein" milk with sufficient P and E content...

  4. Seasonal variations in health-related human physical activity.

    Science.gov (United States)

    Reilly, Thomas; Peiser, Benny

    2006-01-01

    There are profound fluctuations in climate that occur within the annual cycle of seasonal changes. The severity of these changes depends on latitude of location and prevailing topography. Living creatures have evolved means of coping with seasonal extremes. Endogenous circannual cycles, at least in humans, appear to have been masked by mechanisms employed to cope with environmental changes. Physical activity levels tend to be lower in winter than in summer, mediating effects on health-related fitness. In athletes, seasonal changes are dictated by requirements of the annual programme of competitive engagements rather than an inherent circannual rhythm. Injury rates are influenced by seasonal environmental factors, notably in field sports. Season of birth has been related to susceptibility to selected morbidities, including mental ill-health. In age-restricted sports, there is a date-of-birth bias favouring those individuals born early in the competitive year. Trainers and selectors should acknowledge this trend if they are to avoid omitting gifted individuals, born later in the year, from talent development programmes.

  5. Temporal and spatial variation of the human microbiota during pregnancy.

    Science.gov (United States)

    DiGiulio, Daniel B; Callahan, Benjamin J; McMurdie, Paul J; Costello, Elizabeth K; Lyell, Deirdre J; Robaczewska, Anna; Sun, Christine L; Goltsman, Daniela S A; Wong, Ronald J; Shaw, Gary; Stevenson, David K; Holmes, Susan P; Relman, David A

    2015-09-01

    Despite the critical role of the human microbiota in health, our understanding of microbiota compositional dynamics during and after pregnancy is incomplete. We conducted a case-control study of 49 pregnant women, 15 of whom delivered preterm. From 40 of these women, we analyzed bacterial taxonomic composition of 3,767 specimens collected prospectively and weekly during gestation and monthly after delivery from the vagina, distal gut, saliva, and tooth/gum. Linear mixed-effects modeling, medoid-based clustering, and Markov chain modeling were used to analyze community temporal trends, community structure, and vaginal community state transitions. Microbiota community taxonomic composition and diversity remained remarkably stable at all four body sites during pregnancy (P > 0.05 for trends over time). Prevalence of a Lactobacillus-poor vaginal community state type (CST 4) was inversely correlated with gestational age at delivery (P = 0.0039). Risk for preterm birth was more pronounced for subjects with CST 4 accompanied by elevated Gardnerella or Ureaplasma abundances. This finding was validated with a set of 246 vaginal specimens from nine women (four of whom delivered preterm). Most women experienced a postdelivery disturbance in the vaginal community characterized by a decrease in Lactobacillus species and an increase in diverse anaerobes such as Peptoniphilus, Prevotella, and Anaerococcus species. This disturbance was unrelated to gestational age at delivery and persisted for up to 1 y. These findings have important implications for predicting premature labor, a major global health problem, and for understanding the potential impact of a persistent, altered postpartum microbiota on maternal health, including outcomes of pregnancies following short interpregnancy intervals.

  6. Genomic Sequence Variation Markup Language (GSVML).

    Science.gov (United States)

    Nakaya, Jun; Kimura, Michio; Hiroi, Kaei; Ido, Keisuke; Yang, Woosung; Tanaka, Hiroshi

    2010-02-01

    With the aim of making good use of internationally accumulated genomic sequence variation data, which is increasing rapidly due to the explosive amount of genomic research at present, the development of an interoperable data exchange format and its international standardization are necessary. Genomic Sequence Variation Markup Language (GSVML) will focus on genomic sequence variation data and human health applications, such as gene based medicine or pharmacogenomics. We developed GSVML through eight steps, based on case analysis and domain investigations. By focusing on the design scope to human health applications and genomic sequence variation, we attempted to eliminate ambiguity and to ensure practicability. We intended to satisfy the requirements derived from the use case analysis of human-based clinical genomic applications. Based on database investigations, we attempted to minimize the redundancy of the data format, while maximizing the data covering range. We also attempted to ensure communication and interface ability with other Markup Languages, for exchange of omics data among various omics researchers or facilities. The interface ability with developing clinical standards, such as the Health Level Seven Genotype Information model, was analyzed. We developed the human health-oriented GSVML comprising variation data, direct annotation, and indirect annotation categories; the variation data category is required, while the direct and indirect annotation categories are optional. The annotation categories contain omics and clinical information, and have internal relationships. For designing, we examined 6 cases for three criteria as human health application and 15 data elements for three criteria as data formats for genomic sequence variation data exchange. The data format of five international SNP databases and six Markup Languages and the interface ability to the Health Level Seven Genotype Model in terms of 317 items were investigated. GSVML was developed as

  7. Pharmacogenomics and Efficacy of Risperidone Long-Term Treatment in Thai Autistic Children and Adolescents

    NARCIS (Netherlands)

    Nuntamool, Nopphadol; Ngamsamut, Nattawat; Vanwong, Natchaya; Puangpetch, Apichaya; Chamnanphon, Monpat; Hongkaew, Yaowaluck; Limsila, Penkhae; Suthisisang, Chuthamanee; Wilffert, Bob; Sukasem, Chonlaphat

    2017-01-01

    The purpose of this study was to evaluate the association of pharmacogenomic factors and clinical outcome in autistic children and adolescents who were treated with risperidone for long periods. Eighty-two autistic subjects diagnosed with DSM-IV and who were treated with risperidone for more than

  8. Early health technology assessments in pharmacogenomics: a case example in cardiovascular drugs

    NARCIS (Netherlands)

    Geenen, Joost W.; Baranova, Ekaterina V.; Asselbergs, Folkert W.; de Boer, Anthonius; Vreman, Rick A.; Palmer, Colin Na; Maitland-van der Zee, Anke H.; Hövels, Anke M.

    2017-01-01

    Aim: To assess the required characteristics (cost, sensitivity and specificity) of a pharmacogenomic test for being a cost-effective prevention of angiotensin-converting enzyme inhibitors induced angioedema. Furthermore, we assessed the influence of only testing high-risk populations. Materials &

  9. Landscape and variation of RNA secondary structure across the human transcriptome.

    OpenAIRE

    Wan, Y; Qu, K; Zhang, QC; Flynn, RA; Manor, O; Ouyang, Z; Zhang, J; Spitale, RC; Snyder, MP; Segal, E; Chang, HY

    2014-01-01

    In parallel to the genetic code for protein synthesis, a second layer of information is embedded in all RNA transcripts in the form of RNA structure. RNA structure influences practically every step in the gene expression program. However, the nature of most RNA structures or effects of sequence variation on structure are not known. Here we report the initial landscape and variation of RNA secondary structures (RSSs) in a human family trio (mother, father and their child). This provides a comp...

  10. Identification of species and genetic variation in Taenia isolates from human and swine of North India.

    Science.gov (United States)

    Singh, Satyendra K; Prasad, Kashi N; Singh, Aloukick K; Gupta, Kamlesh K; Chauhan, Ranjeet S; Singh, Amrita; Singh, Avinash; Rai, Ravi P; Pati, Binod K

    2016-10-01

    Taenia solium is the major cause of taeniasis and cysticercosis/neurocysticercosis (NCC) in the developing countries including India, but the existence of other Taenia species and genetic variation have not been studied in India. So, we studied the existence of different Taenia species, and sequence variation in Taenia isolates from human (proglottids and cysticerci) and swine (cysticerci) in North India. Amplification of cytochrome c oxidase subunit 1 gene (cox1) was done by polymerase chain reaction (PCR) followed by sequencing and phylogenetic analysis. We identified two species of Taenia i.e. T. solium and Taenia asiatica in our isolates. T. solium isolates showed similarity with Asian genotype and nucleotide variations from 0.25 to 1.01 %, whereas T. asiatica displayed nucleotide variations ranged from 0.25 to 0.5 %. These findings displayed the minimal genetic variations in North Indian isolates of T. solium and T. asiatica.

  11. Humans and Deep Networks Largely Agree on Which Kinds of Variation Make Object Recognition Harder.

    Science.gov (United States)

    Kheradpisheh, Saeed R; Ghodrati, Masoud; Ganjtabesh, Mohammad; Masquelier, Timothée

    2016-01-01

    View-invariant object recognition is a challenging problem that has attracted much attention among the psychology, neuroscience, and computer vision communities. Humans are notoriously good at it, even if some variations are presumably more difficult to handle than others (e.g., 3D rotations). Humans are thought to solve the problem through hierarchical processing along the ventral stream, which progressively extracts more and more invariant visual features. This feed-forward architecture has inspired a new generation of bio-inspired computer vision systems called deep convolutional neural networks (DCNN), which are currently the best models for object recognition in natural images. Here, for the first time, we systematically compared human feed-forward vision and DCNNs at view-invariant object recognition task using the same set of images and controlling the kinds of transformation (position, scale, rotation in plane, and rotation in depth) as well as their magnitude, which we call "variation level." We used four object categories: car, ship, motorcycle, and animal. In total, 89 human subjects participated in 10 experiments in which they had to discriminate between two or four categories after rapid presentation with backward masking. We also tested two recent DCNNs (proposed respectively by Hinton's group and Zisserman's group) on the same tasks. We found that humans and DCNNs largely agreed on the relative difficulties of each kind of variation: rotation in depth is by far the hardest transformation to handle, followed by scale, then rotation in plane, and finally position (much easier). This suggests that DCNNs would be reasonable models of human feed-forward vision. In addition, our results show that the variation levels in rotation in depth and scale strongly modulate both humans' and DCNNs' recognition performances. We thus argue that these variations should be controlled in the image datasets used in vision research.

  12. Humans and deep networks largely agree on which kinds of variation make object recognition harder

    Directory of Open Access Journals (Sweden)

    Saeed Reza Kheradpisheh

    2016-08-01

    Full Text Available View-invariant object recognition is a challenging problem that has attracted much attention among the psychology, neuroscience, and computer vision communities. Humans are notoriously good at it, even if some variations are presumably more difficult to handle than others (e.g. 3D rotations. Humans are thought to solve the problem through hierarchical processing along the ventral stream, which progressively extracts more and more invariant visual features. This feed-forward architecture has inspired a new generation of bio-inspired computer vision systems called deep convolutional neural networks (DCNN, which are currently the best models for object recognition in natural images. Here, for the first time, we systematically compared human feed-forward vision and DCNNs at view-invariant object recognition task using the same set of images and controlling the kinds of transformation (position, scale, rotation in plane, and rotation in depth as well as their magnitude, which we call variation level. We used four object categories: car, ship, motorcycle, and animal. In total, 89 human subjects participated in 10 experiments in which they had to discriminate between two or four categories after rapid presentation with backward masking. We also tested two recent DCNNs (proposed respectively by Hinton's group and Zisserman's group on the same tasks. We found that humans and DCNNs largely agreed on the relative difficulties of each kind of variation: rotation in depth is by far the hardest transformation to handle, followed by scale, then rotation in plane, and finally position (much easier. This suggests that DCNNs would be reasonable models of human feed-forward vision. In addition, our results show that the variation levels in rotation in depth and scale strongly modulate both humans' and DCNNs' recognition performances. We thus argue that these variations should be controlled in the image datasets used in vision research.

  13. Cardiovascular Pharmacogenomics and Cognitive Function in Patients with Schizophrenia.

    Science.gov (United States)

    Ward, Kristen M; Kraal, A Zarina; Flowers, Stephanie A; Ellingrod, Vicki L

    2017-09-01

    The authors sought to examine the impact of multiple risk alleles for cognitive dysfunction and cardiovascular disease risk on cognitive function and to determine if these relationships varied by cognitive reserve (CR) or concomitant medication use in patients with schizophrenia. They conducted a cross-sectional study in ambulatory mental health centers. A total of 122 adults with a schizophrenia spectrum diagnosis who were maintained on a stable antipsychotic regimen for at least 6 months before study enrollment were included. Patients were divided into three CR groups based on years of formal education: no high school completion or equivalent (low-education group [18 patients]), completion of high school or equivalent (moderate-education group [36 patients], or any degree of post-high school education (high-education group [68 patients]). The following pharmacogenomic variants were genotyped for each patient: AGT M268T (rs699), ACE insertion/deletion (or ACE I/D, rs1799752), and APOE ε2, ε3, and ε4 (rs429358 and rs7412). Risk allele carrier status (identified per gene as AGT M268 T carriers, ACE D carriers, and APOE ε4 carriers) was not significantly different among CR groups. The Brief Assessment of Cognition in Schizophrenia (BACS) scale was used to assess cognitive function. The mean ± SD patient age was 43.9 ± 11.6 years. Cardiovascular risk factors such as hypertension and hyperlipidemia diagnoses, and use of antihypertensive and lipid-lowering agents, did not significantly differ among CR groups. Mixed modeling revealed that risk allele carrier status was significantly associated with lower verbal memory scores for ACE D and APOE ε4 carriers, but AGT T carrier status was significantly associated with higher verbal memory scores (p=0.0188, p=0.0055, and p=0.0058, respectively). These results were only significant in the low-education group. In addition, medication-gene interactions were not significant predictors of BACS scores. ACE D and APOE ε4

  14. Genetic Variation and Adaptation in Africa: Implications for Human Evolution and Disease

    Science.gov (United States)

    Gomez, Felicia; Hirbo, Jibril; Tishkoff, Sarah A.

    2014-01-01

    Because modern humans originated in Africa and have adapted to diverse environments, African populations have high levels of genetic and phenotypic diversity. Thus, genomic studies of diverse African ethnic groups are essential for understanding human evolutionary history and how this leads to differential disease risk in all humans. Comparative studies of genetic diversity within and between African ethnic groups creates an opportunity to reconstruct some of the earliest events in human population history and are useful for identifying patterns of genetic variation that have been influenced by recent natural selection. Here we describe what is currently known about genetic variation and evolutionary history of diverse African ethnic groups. We also describe examples of recent natural selection in African genomes and how these data are informative for understanding the frequency of many genetic traits, including those that cause disease susceptibility in African populations and populations of recent African descent. PMID:24984772

  15. Human-specific HERV-K insertion causes genomic variations in the human genome.

    Directory of Open Access Journals (Sweden)

    Wonseok Shin

    Full Text Available Human endogenous retroviruses (HERV sequences account for about 8% of the human genome. Through comparative genomics and literature mining, we identified a total of 29 human-specific HERV-K insertions. We characterized them focusing on their structure and flanking sequence. The results showed that four of the human-specific HERV-K insertions deleted human genomic sequences via non-classical insertion mechanisms. Interestingly, two of the human-specific HERV-K insertion loci contained two HERV-K internals and three LTR elements, a pattern which could be explained by LTR-LTR ectopic recombination or template switching. In addition, we conducted a polymorphic test and observed that twelve out of the 29 elements are polymorphic in the human population. In conclusion, human-specific HERV-K elements have inserted into human genome since the divergence of human and chimpanzee, causing human genomic changes. Thus, we believe that human-specific HERV-K activity has contributed to the genomic divergence between humans and chimpanzees, as well as within the human population.

  16. Human fertility variation, size-related obstetrical performance and the evolution of sexual stature dimorphism

    OpenAIRE

    Guégan, Jean-François; Teriokhin, A.T.; Thomas, F.

    2000-01-01

    In several animal species, change in sexual size dimorphism is a correlated response to selection on fecundity. In humans, different hypotheses have been proposed to explain the variation of sexual dimorphism in stature, but no consensus has yet emerged. In this paper, we evaluate from a theoretical and an empirical point of view the hypothesis that the extent of sexual dimorphism in human populations results from the interaction between fertility and size-related obstetric complications. We ...

  17. Feedforward Object-Vision Models Only Tolerate Small Image Variations Compared to Human

    Directory of Open Access Journals (Sweden)

    Masoud eGhodrati

    2014-07-01

    Full Text Available Invariant object recognition is a remarkable ability of primates' visual system that its underlying mechanism has constantly been under intense investigations. Computational modelling is a valuable tool toward understanding the processes involved in invariant object recognition. Although recent computational models have shown outstanding performances on challenging image databases, they fail to perform well when images with more complex variations of the same object are applied to them. Studies have shown that making sparse representation of objects by extracting more informative visual features through a feedforward sweep can lead to higher recognition performances. Here, however, we show that when the complexity of image variations is high, even this approach results in poor performance compared to humans. To assess the performance of models and humans in invariant object recognition tasks, we built a parametrically controlled image database consisting of several object categories varied in different dimensions and levels, rendered from 3D planes. Comparing the performance of several object recognition models with human observers shows that only in low-level image variations the models perform similar to humans in categorization tasks. Furthermore, the results of our behavioral experiments demonstrate that, even under difficult experimental conditions (i.e. briefly presented masked stimuli with complex image variations, human observers performed outstandingly well, suggesting that the models are still far from resembling humans in invariant object recognition. Taken together, we suggest that learning sparse informative visual features, although desirable, is not a complete solution for future progresses in object-vision modelling. We show that this approach is not of significant help in solving the computational crux of object recognition (that is invariant object recognition when the identity-preserving image variations become more complex.

  18. Institutional Profile: University of California San Diego Pharmacogenomics Education Program (PharmGenEd™): bridging the gap between science and practice.

    Science.gov (United States)

    Kuo, Grace M; Ma, Joseph D; Lee, Kelly C; Halpert, James R; Bourne, Philip E; Ganiats, Theodore G; Taylor, Palmer

    2011-02-01

    Clinical application of evidence-based pharmacogenomics information has the potential to help healthcare professionals provide safe and effective medication management to patients. However, there is a gap between the advances of pharmacogenomics discovery and the health professionals' knowledge regarding pharmacogenomics testing and therapeutic uses. Furthermore, pharmacogenomics education materials for healthcare professionals have not been readily available or accessible. Pharmacogenomics Education Program (PharmGenEd™) is an evidence-based pharmacogenomics education program developed at the University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences and the School of Medicine (CA, USA), with funding support from the Centers for Disease Control and Prevention. Program components include continuing education modules, train-the-trainer materials and shared curriculum modules based on therapeutic topics, and virtual communities with online resources.

  19. Patterns of genic intolerance of rare copy number variation in 59,898 human exomes

    Science.gov (United States)

    Ruderfer, Douglas M.; Hamamsy, Tymor; Lek, Monkol; Karczewski, Konrad J.; Kavanagh, David; Samocha, Kaitlin E.; Daly, Mark J.; MacArthur, Daniel G.; Fromer, Menachem; Purcell, Shaun M.

    2016-01-01

    Copy number variation (CNV) impacting protein-coding genes contributes significantly to human diversity and disease. Here we characterized the rates and properties of rare genic CNV (intolerance to CNVs that demonstrated moderate correlation with measures of genic constraint based on single-nucleotide variation (SNV) and was independently correlated with measures of evolutionary conservation. For individuals with schizophrenia, genes impacted by CNVs were more intolerant than in controls. ExAC CNV data constitutes a critical component of an integrated database spanning the spectrum of human genetic variation, aiding the interpretation of personal genomes as well as population-based disease studies. These data are freely available for download and visualization online. PMID:27533299

  20. Integrative analysis of RNA, translation, and protein levels reveals distinct regulatory variation across humans.

    Science.gov (United States)

    Cenik, Can; Cenik, Elif Sarinay; Byeon, Gun W; Grubert, Fabian; Candille, Sophie I; Spacek, Damek; Alsallakh, Bilal; Tilgner, Hagen; Araya, Carlos L; Tang, Hua; Ricci, Emiliano; Snyder, Michael P

    2015-11-01

    Elucidating the consequences of genetic differences between humans is essential for understanding phenotypic diversity and personalized medicine. Although variation in RNA levels, transcription factor binding, and chromatin have been explored, little is known about global variation in translation and its genetic determinants. We used ribosome profiling, RNA sequencing, and mass spectrometry to perform an integrated analysis in lymphoblastoid cell lines from a diverse group of individuals. We find significant differences in RNA, translation, and protein levels suggesting diverse mechanisms of personalized gene expression control. Combined analysis of RNA expression and ribosome occupancy improves the identification of individual protein level differences. Finally, we identify genetic differences that specifically modulate ribosome occupancy--many of these differences lie close to start codons and upstream ORFs. Our results reveal a new level of gene expression variation among humans and indicate that genetic variants can cause changes in protein levels through effects on translation. © 2015 Cenik et al.; Published by Cold Spring Harbor Laboratory Press.

  1. Analysis of indel variations in the human disease-associated genes ...

    Indian Academy of Sciences (India)

    Keywords. insertion–deletion variations; haematological disease; tumours; human genetics. Journal of Genetics ... domly selected healthy Korean individuals using a blood genomic DNA ... Bioinformatics annotation and 3-D protein structure analysis. In this study ..... 2009 A genome-wide meta-analysis identifies. Journal of ...

  2. New Regions of the Human Genome Linked to Skin Color Variation in Some African Populations

    Science.gov (United States)

    In the first study of its kind, an international team of genomics researchers has identified new regions of the human genome that are associated with skin color variation in some African populations, opening new avenues for research on skin diseases and cancer in all populations.

  3. An integrated map of genetic variation from 1.092 human genomes

    DEFF Research Database (Denmark)

    Abecasis, Goncalo R.; Auton, Adam; Brooks, Lisa D.

    2012-01-01

    By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination ...

  4. Diffusion tensor imaging of the human calf : Variation of inter- and intramuscle-specific diffusion parameters

    NARCIS (Netherlands)

    Schlaffke, Lara; Rehmann, Robert; Froeling, Martijn; Kley, Rudolf; Tegenthoff, Martin; Vorgerd, Matthias; Schmidt-Wilcke, Tobias

    2017-01-01

    Purpose: To investigate to what extent inter- and intramuscular variations of diffusion parameters of human calf muscles can be explained by age, gender, muscle location, and body mass index (BMI) in a specific age group (20-35 years). Materials and Methods: Whole calf muscles of 18 healthy

  5. Metabolism of styrene in the human liver in vitro: interindividual variation and enantioselectivity

    NARCIS (Netherlands)

    Wenker, M. A.; Kezić, S.; Monster, A. C.; de Wolff, F. A.

    2001-01-01

    1. The interindividual variation and enantioselectivity of the in vitro styrene oxidation by cytochrome P450 have been investigated in 20 human microsomal liver samples. Liver samples were genotyped for the CYP2E1*6 and CYP2E1*5B alleles. 2. Kinetic analysis indicated the presence of at least two

  6. Lack of influence of GTP cyclohydrolase gene (GCH1 variations on pain sensitivity in humans

    Directory of Open Access Journals (Sweden)

    Dionne Raymond A

    2007-03-01

    Full Text Available Abstract Objectives To assess the effect of variations in GTP cyclohydrolase gene (GCH1 on pain sensitivity in humans. Methods Thermal and cold pain sensitivity were evaluated in a cohort of 735 healthy volunteers. Among this cohort, the clinical pain responses of 221 subjects after the surgical removal of impacted third molars were evaluated. Genotyping was done for 38 single nucleotide polymorphisms (SNPs whose heterozygosity > 0.2 in GCH1. Influence of the genetic variations including SNPs and haplotypes on pain sensitivity were analyzed. Results Minor allele frequencies and linkage disequilibrium show significant differences in European Americans, African Americans, Hispanic Americans and Asian Americans. Association analyses in European Americans do not replicate the previously reported important influence of GCH1 variations on pain sensitivity. Conclusion Considering population stratification, previously reported associations between GCH1 genetic variations and pain sensitivity appear weak or negligible in this well characterized model of pain.

  7. Intrapopulational body size variation and cranial capacity variation in Middle Pleistocene humans: the Sima de los Huesos sample (Sierra de Atapuerca, Spain).

    Science.gov (United States)

    Lorenzo, C; Carretero, J M; Arsuaga, J L; Gracia, A; Martínez, I

    1998-05-01

    A sexual dimorphism more marked than in living humans has been claimed for European Middle Pleistocene humans, Neandertals and prehistoric modern humans. In this paper, body size and cranial capacity variation are studied in the Sima de los Huesos Middle Pleistocene sample. This is the largest sample of non-modern humans found to date from one single site, and with all skeletal elements represented. Since the techniques available to estimate the degree of sexual dimorphism in small palaeontological samples are all unsatisfactory, we have used the bootstraping method to asses the magnitude of the variation in the Sima de los Huesos sample compared to modern human intrapopulational variation. We analyze size variation without attempting to sex the specimens a priori. Anatomical regions investigated are scapular glenoid fossa; acetabulum; humeral proximal and distal epiphyses; ulnar proximal epiphysis; radial neck; proximal femur; humeral, femoral, ulnar and tibial shaft; lumbosacral joint; patella; calcaneum; and talar trochlea. In the Sima de los Huesos sample only the humeral midshaft perimeter shows an unusual high variation (only when it is expressed by the maximum ratio, not by the coefficient of variation). In spite of that the cranial capacity range at Sima de los Huesos almost spans the rest of the European and African Middle Pleistocene range. The maximum ratio is in the central part of the distribution of modern human samples. Thus, the hypothesis of a greater sexual dimorphism in Middle Pleistocene populations than in modern populations is not supported by either cranial or postcranial evidence from Sima de los Huesos.

  8. An ontology-based, mobile-optimized system for pharmacogenomic decision support at the point-of-care.

    Directory of Open Access Journals (Sweden)

    Jose Antonio Miñarro-Giménez

    Full Text Available The development of genotyping and genetic sequencing techniques and their evolution towards low costs and quick turnaround have encouraged a wide range of applications. One of the most promising applications is pharmacogenomics, where genetic profiles are used to predict the most suitable drugs and drug dosages for the individual patient. This approach aims to ensure appropriate medical treatment and avoid, or properly manage, undesired side effects.We developed the Medicine Safety Code (MSC service, a novel pharmacogenomics decision support system, to provide physicians and patients with the ability to represent pharmacogenomic data in computable form and to provide pharmacogenomic guidance at the point-of-care. Pharmacogenomic data of individual patients are encoded as Quick Response (QR codes and can be decoded and interpreted with common mobile devices without requiring a centralized repository for storing genetic patient data. In this paper, we present the first fully functional release of this system and describe its architecture, which utilizes Web Ontology Language 2 (OWL 2 ontologies to formalize pharmacogenomic knowledge and to provide clinical decision support functionalities.The MSC system provides a novel approach for enabling the implementation of personalized medicine in clinical routine.

  9. Systematic documentation and analysis of human genetic variation using the microattribution approach

    Science.gov (United States)

    Giardine, Belinda; Borg, Joseph; Higgs, Douglas R.; Peterson, Kenneth R.; Maglott, Donna; Basak, A. Nazli; Clark, Barnaby; Faustino, Paula; Felice, Alex E.; Francina, Alain; Gallivan, Monica V. E.; Georgitsi, Marianthi; Gibbons, Richard J.; Giordano, Piero C.; Harteveld, Cornelis L.; Joly, Philippe; Kanavakis, Emmanuel; Kollia, Panagoula; Menzel, Stephan; Miller, Webb; Moradkhani, Kamran; Old, John; Papachatzopoulou, Adamantia; Papadakis, Manoussos N.; Papadopoulos, Petros; Pavlovic, Sonja; Philipsen, Sjaak; Radmilovic, Milena; Riemer, Cathy; Schrijver, Iris; Stojiljkovic, Maja; Thein, Swee Lay; Traeger-Synodinos, Jan; Tully, Ray; Wada, Takahito; Waye, John; Wiemann, Claudia; Zukic, Branka; Chui, David H. K.; Wajcman, Henri; Hardison, Ross C.; Patrinos, George P.

    2013-01-01

    We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to these disorders, and then implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories 1. A total of 1,941 unique genetic variants in 37 genes, encoding globins (HBA2, HBA1, HBG2, HBG1, HBD, HBB) and other erythroid proteins (ALOX5AP, AQP9, ARG2, ASS1, ATRX, BCL11A, CNTNAP2, CSNK2A1, EPAS1, ERCC2, FLT1, GATA1, GPM6B, HAO2, HBS1L, KDR, KL, KLF1, MAP2K1, MAP3K5, MAP3K7, MYB, NOS1, NOS2, NOS3, NOX3, NUP133, PDE7B, SMAD3, SMAD6, and TOX) are currently documented in these databases with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants and now provides a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The large repository of previously reported data, together with more recent data, acquired by microattribution, demonstrates how the comprehensive documentation of human variation will provide key insights into normal biological processes and how these are perturbed in human genetic disease. Using the microattribution process set out here, datasets which took decades to accumulate for the globin genes could be assembled rapidly for other genes and disease systems. The principles established here for the globin gene system will serve as a model for other systems and the analysis of other common and/or complex human genetic diseases. PMID:21423179

  10. Demographic and spatio-temporal variation in human plague at a persistent focus in Tanzania

    DEFF Research Database (Denmark)

    Davis, S; Makundi, R H; Machang'u, R S

    2006-01-01

    Human plague in the Western Usambara Mountains in Tanzania has been a public health problem since the first outbreak in 1980. The wildlife reservoir is unknown and eradication measures that have proved effective elsewhere in Tanzania appear to fail in this region. We use census data from 2002...... and hospital records kept since 1986 to describe the temporal, spatial and demographic variation in human plague. A seasonal peak in cases occurs from December to February with the numbers of cases during this peak varying between 0 and 1150. Variation in incidence, calculated for each village as the mean...... number of cases per thousand inhabitants per year, indicates that human plague is concentrated around a group of three neighbouring, relatively isolated, high-altitude villages; Nywelo, Madala and Gologolo. However, there was no evidence that these villages were acting as a source of infection...

  11. Genetic variation in lipid desaturases and its impact on the development of human disease.

    Science.gov (United States)

    Merino, Diana M; Ma, David W L; Mutch, David M

    2010-06-18

    Perturbations in lipid metabolism characterize many of the chronic diseases currently plaguing our society, such as obesity, diabetes, and cardiovascular disease. Thus interventions that target plasma lipid levels remain a primary goal to manage these diseases. The determinants of plasma lipid levels are multi-factorial, consisting of both genetic and lifestyle components. Recent evidence indicates that fatty acid desaturases have an important role in defining plasma and tissue lipid profiles. This review will highlight the current state-of-knowledge regarding three desaturases (Scd-1, Fads1 and Fads2) and their potential roles in disease onset and development. Although research in rodent models has provided invaluable insight into the regulation and functions of these desaturases, the extent to which murine research can be translated to humans remains unclear. Evidence emerging from human-based research demonstrates that genetic variation in human desaturase genes affects enzyme activity and, consequently, disease risk factors. Moreover, this genetic variation may have a trans-generational effect via breastfeeding. Therefore inter-individual variation in desaturase function is attributed to both genetic and lifestyle components. As such, population-based research regarding the role of desaturases on disease risk is challenged by this complex gene-lifestyle paradigm. Unravelling the contribution of each component is paramount for understanding the inter-individual variation that exists in plasma lipid profiles, and will provide crucial information to develop personalized strategies to improve health management.

  12. Meiotic gene-conversion rate and tract length variation in the human genome.

    Science.gov (United States)

    Padhukasahasram, Badri; Rannala, Bruce

    2013-02-27

    Meiotic recombination occurs in the form of two different mechanisms called crossing-over and gene-conversion and both processes have an important role in shaping genetic variation in populations. Although variation in crossing-over rates has been studied extensively using sperm-typing experiments, pedigree studies and population genetic approaches, our knowledge of variation in gene-conversion parameters (ie, rates and mean tract lengths) remains far from complete. To explore variability in population gene-conversion rates and its relationship to crossing-over rate variation patterns, we have developed and validated using coalescent simulations a comprehensive Bayesian full-likelihood method that can jointly infer crossing-over and gene-conversion rates as well as tract lengths from population genomic data under general variable rate models with recombination hotspots. Here, we apply this new method to SNP data from multiple human populations and attempt to characterize for the first time the fine-scale variation in gene-conversion parameters along the human genome. We find that the estimated ratio of gene-conversion to crossing-over rates varies considerably across genomic regions as well as between populations. However, there is a great degree of uncertainty associated with such estimates. We also find substantial evidence for variation in the mean conversion tract length. The estimated tract lengths did not show any negative relationship with the local heterozygosity levels in our analysis.European Journal of Human Genetics advance online publication, 27 February 2013; doi:10.1038/ejhg.2013.30.

  13. Public involvement in pharmacogenomics research: a national survey on public attitudes towards pharmacogenomics research and the willingness to donate DNA samples to a DNA bank in Japan.

    Science.gov (United States)

    Kobayashi, Eriko; Satoh, Nobunori

    2009-11-01

    To assess the attitudes of the Japanese general public towards pharmacogenomics research and a DNA bank for identifying genomic markers associated with ADRs and their willingness to donate DNA samples, we conducted a national survey for 1,103 Japanese adults from the general public, not a patient population. The response rate was 36.8%. The majority of the respondents showed a positive attitude towards pharmacogenomics research (81.0%) and a DNA bank (70.4%). Considering fictitious clinical situations such as taking medications and experiencing ADRs, the willingness to donate DNA samples when experiencing ADRs (61.7%) was higher than when taking medications (45.3%). Older generations were significantly associated with a decreased willingness to donate (OR = 0.45, CI 0.28-0.72 in 50s. OR = 0.49, CI: 0.31-0.77 in 60s). Positive attitudes towards pharmacogenomics research, a DNA bank, blood/bone marrow/organ donation were significantly associated with an increased willingness. However, the respondents had the following concerns regarding a DNA bank: the confidentiality of their personal information, the manner by which research results were utilized and simply the use of their own DNA for research. In order to attain public understanding to overcome these concerns, a process of public awareness should be put into place to emphasize the beneficial aspects of identifying genomic markers associated with ADRs and to address these concerns raised in our study. Further study is needed to assess the willingness of actual patients taking medications in real situations, since the respondents in our study were from the general public, not a patient population, and their willingness was assessed on the condition of assuming that they were patients taking medications.

  14. The variation field of the radiosensitivity in the human population: hypersensitivity and hypo sensitivity

    International Nuclear Information System (INIS)

    Bouffler, S.

    2009-01-01

    It is generally admitted in the radiotherapy practice that 5% of patients will present serious reactions of normal tissues. Studies made on human population confirm it exists variations of cell radiosensitivity and genetic factors contribute in a significant manner to the observed variations. The researches of markers able to predict the reactions of normal tissues to the therapy focussed on the identification of sensitive sub-group. It is however obvious that exists also a part of the population relatively hypo sensitive. It would be interesting to make studies on the genome to find genes associated to serious reactions of normal tissues to radiotherapy. (N.C.)

  15. Variations in Humanized and Defined Culture Conditions Supporting Derivation of New Human Embryonic Stem Cell Lines

    DEFF Research Database (Denmark)

    Fletcher, Judy M; Ferrier, Patricia M; Gardner, John O

    2006-01-01

    matrix substrate of purified human laminin (Ln) with transitional reliance on mitotically inactivated human fibroblast (HDF) feeder cells. With this integrated system hESC lines were isolated using either HDF conditioned medium supplemented with a bovine-sourced serum replacement (bSRM), or a defined...

  16. Variation in calculated human exposure. Comparison of calculations with seven European human exposure models

    NARCIS (Netherlands)

    Swartjes F; ECO

    2003-01-01

    Twenty scenarios, differing with respect to land use, soil type and contaminant, formed the basis for calculating human exposure from soil contaminants with the use of models contributed by seven European countries (one model per country). Here, the human exposures to children and children

  17. The offspring quantity–quality trade-off and human fertility variation

    Science.gov (United States)

    Lawson, David W.; Borgerhoff Mulder, Monique

    2016-01-01

    The idea that trade-offs between offspring quantity and quality shape reproductive behaviour has long been central to economic perspectives on fertility. It also has a parallel and richer theoretical foundation in evolutionary ecology. We review the application of the quantity–quality trade-off concept to human reproduction, emphasizing distinctions between clutch size and lifetime fertility, and the wider set of forces contributing to fertility variation in iteroparous and sexually reproducing species like our own. We then argue that in settings approximating human evolutionary history, several factors limit costly sibling competition. Consequently, while the optimization of quantity–quality trade-offs undoubtedly shaped the evolution of human physiology setting the upper limits of reproduction, we argue it plays a modest role in accounting for socio-ecological and individual variation in fertility. Only upon entering the demographic transition can fertility limitation be clearly interpreted as strategically orientated to advancing offspring quality via increased parental investment per child, with low fertility increasing descendant socio-economic success, although not reproductive success. We conclude that existing economic and evolutionary literature has often overemphasized the centrality of quantity–quality trade-offs to human fertility variation and advocate for the development of more holistic frameworks encompassing alternative life-history trade-offs and the evolved mechanisms guiding their resolution. PMID:27022072

  18. Regulatory perspective on remaining challenges for utilization of pharmacogenomics-guided drug developments.

    Science.gov (United States)

    Otsubo, Yasuto; Ishiguro, Akihiro; Uyama, Yoshiaki

    2013-01-01

    Pharmacogenomics-guided drug development has been implemented in practice in the last decade, resulting in increased labeling of drugs with pharmacogenomic information. However, there are still many challenges remaining in utilizing this process. Here, we describe such remaining challenges from the regulatory perspective, specifically focusing on sample collection, biomarker qualification, ethnic factors, codevelopment of companion diagnostics and means to provide drugs for off-target patients. To improve the situation, it is important to strengthen international harmonization and collaboration among academia, industries and regulatory agencies, followed by the establishment of an international guideline on this topic. Communication with a regulatory agency from an early stage of drug development is also a key to success.

  19. The emerging science of precision medicine and pharmacogenomics for Parkinson's disease.

    Science.gov (United States)

    Payami, Haydeh

    2017-08-01

    Current therapies for Parkinson's disease are problematic because they are symptomatic and have adverse effects. New drugs have failed in clinical trials because of inadequate efficacy. At the core of the problem is trying to make one drug work for all Parkinson's disease patients, when we know this premise is wrong because (1) Parkinson's disease is not a single disease, and (2) no two individuals have the same biological makeup. Precision medicine is the goal to strive for, but we are only at the beginning stages of building the infrastructure for one of the most complex projects in the history of science, and it will be a long time before Parkinson's disease reaps the benefits. Pharmacogenomics, a cornerstone of precision medicine, has already proven successful for many conditions and could also propel drug discovery and improve treatment for Parkinson's disease. To make progress in the pharmacogenomics of Parkinson's disease, we need to change course from small inconclusive candidate gene studies to large-scale rigorously planned genome-wide studies that capture the nuclear genome and the microbiome. Pharmacogenomic studies must use homogenous subtypes of Parkinson's disease or apply the brute force of statistical power to overcome heterogeneity, which will require large sample sizes achievable only via internet-based methods and electronic databases. Large-scale pharmacogenomic studies, together with biomarker discovery efforts, will yield the knowledge necessary to design clinical trials with precision to alleviate confounding by disease heterogeneity and interindividual variability in drug response, two of the major impediments to successful drug discovery and effective treatment. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  20. The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Overcoming Challenges of Real-World Implementation

    Science.gov (United States)

    Shuldiner, AR; Relling, MV; Peterson, JF; Hicks, JK; Freimuth, RR; Sadee, W; Pereira, NL; Roden, DM; Johnson, JA; Klein, TE

    2013-01-01

    The pace of discovery of potentially actionable pharmacogenetic variants has increased dramatically in recent years. However, the implementation of this new knowledge for individualized patient care has been slow. The Pharmacogenomics Research Network (PGRN) Translational Pharmacogenetics Program seeks to identify barriers and develop real-world solutions to implementation of evidence-based pharmacogenetic tests in diverse health-care settings. Dissemination of the resulting toolbox of “implementation best practices” will prove useful to a broad audience. PMID:23588301

  1. Balancing selection on a regulatory region exhibiting ancient variation that predates human-neandertal divergence.

    Directory of Open Access Journals (Sweden)

    Omer Gokcumen

    2013-04-01

    Full Text Available Ancient population structure shaping contemporary genetic variation has been recently appreciated and has important implications regarding our understanding of the structure of modern human genomes. We identified a ∼36-kb DNA segment in the human genome that displays an ancient substructure. The variation at this locus exists primarily as two highly divergent haplogroups. One of these haplogroups (the NE1 haplogroup aligns with the Neandertal haplotype and contains a 4.6-kb deletion polymorphism in perfect linkage disequilibrium with 12 single nucleotide polymorphisms (SNPs across diverse populations. The other haplogroup, which does not contain the 4.6-kb deletion, aligns with the chimpanzee haplotype and is likely ancestral. Africans have higher overall pairwise differences with the Neandertal haplotype than Eurasians do for this NE1 locus (p<10⁻¹⁵. Moreover, the nucleotide diversity at this locus is higher in Eurasians than in Africans. These results mimic signatures of recent Neandertal admixture contributing to this locus. However, an in-depth assessment of the variation in this region across multiple populations reveals that African NE1 haplotypes, albeit rare, harbor more sequence variation than NE1 haplotypes found in Europeans, indicating an ancient African origin of this haplogroup and refuting recent Neandertal admixture. Population genetic analyses of the SNPs within each of these haplogroups, along with genome-wide comparisons revealed significant FST (p = 0.00003 and positive Tajima's D (p = 0.00285 statistics, pointing to non-neutral evolution of this locus. The NE1 locus harbors no protein-coding genes, but contains transcribed sequences as well as sequences with putative regulatory function based on bioinformatic predictions and in vitro experiments. We postulate that the variation observed at this locus predates Human-Neandertal divergence and is evolving under balancing selection, especially among European

  2. Genomic Features That Predict Allelic Imbalance in Humans Suggest Patterns of Constraint on Gene Expression Variation

    Science.gov (United States)

    Fédrigo, Olivier; Haygood, Ralph; Mukherjee, Sayan; Wray, Gregory A.

    2009-01-01

    Variation in gene expression is an important contributor to phenotypic diversity within and between species. Although this variation often has a genetic component, identification of the genetic variants driving this relationship remains challenging. In particular, measurements of gene expression usually do not reveal whether the genetic basis for any observed variation lies in cis or in trans to the gene, a distinction that has direct relevance to the physical location of the underlying genetic variant, and which may also impact its evolutionary trajectory. Allelic imbalance measurements identify cis-acting genetic effects by assaying the relative contribution of the two alleles of a cis-regulatory region to gene expression within individuals. Identification of patterns that predict commonly imbalanced genes could therefore serve as a useful tool and also shed light on the evolution of cis-regulatory variation itself. Here, we show that sequence motifs, polymorphism levels, and divergence levels around a gene can be used to predict commonly imbalanced genes in a human data set. Reduction of this feature set to four factors revealed that only one factor significantly differentiated between commonly imbalanced and nonimbalanced genes. We demonstrate that these results are consistent between the original data set and a second published data set in humans obtained using different technical and statistical methods. Finally, we show that variation in the single allelic imbalance-associated factor is partially explained by the density of genes in the region of a target gene (allelic imbalance is less probable for genes in gene-dense regions), and, to a lesser extent, the evenness of expression of the gene across tissues and the magnitude of negative selection on putative regulatory regions of the gene. These results suggest that the genomic distribution of functional cis-regulatory variants in the human genome is nonrandom, perhaps due to local differences in evolutionary

  3. Global and disease-associated genetic variation in the human Fanconi anemia gene family.

    Science.gov (United States)

    Rogers, Kai J; Fu, Wenqing; Akey, Joshua M; Monnat, Raymond J

    2014-12-20

    Fanconi anemia (FA) is a human recessive genetic disease resulting from inactivating mutations in any of 16 FANC (Fanconi) genes. Individuals with FA are at high risk of developmental abnormalities, early bone marrow failure and leukemia. These are followed in the second and subsequent decades by a very high risk of carcinomas of the head and neck and anogenital region, and a small continuing risk of leukemia. In order to characterize base pair-level disease-associated (DA) and population genetic variation in FANC genes and the segregation of this variation in the human population, we identified 2948 unique FANC gene variants including 493 FA DA variants across 57,240 potential base pair variation sites in the 16 FANC genes. We then analyzed the segregation of this variation in the 7578 subjects included in the Exome Sequencing Project (ESP) and the 1000 Genomes Project (1KGP). There was a remarkably high frequency of FA DA variants in ESP/1KGP subjects: at least 1 FA DA variant was identified in 78.5% (5950 of 7578) individuals included in these two studies. Six widely used functional prediction algorithms correctly identified only a third of the known, DA FANC missense variants. We also identified FA DA variants that may be good candidates for different types of mutation-specific therapies. Our results demonstrate the power of direct DNA sequencing to detect, estimate the frequency of and follow the segregation of deleterious genetic variation in human populations. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. Researchers' perceptions of the ethical implications of pharmacogenomics research with children.

    Science.gov (United States)

    Avard, D; Silverstein, T; Sillon, G; Joly, Y

    2009-01-01

    This paper presents the results of an exploratory qualitative study that assesses Canadian pediatric researchers' perceptions of a pre-selected group of ethical issues raised by pharmacogenomics research with children. As a pilot study, we conducted semi-structured telephone interviews with Canadian pediatric pharmacogenomic researchers. The interviews were guided by the following themes: (1) benefits and risks of inclusion, (2) the consent/assent process, and (3) the return of research results. Issues about assent, consent, risks and benefits, as well as the communication of results were addressed by the respondents. Some issues, such as the unique vulnerability of children, the long term privacy concerns associated with biobanking, additional core elements that need to be discussed and included in the consent/assent forms, as well as the challenges of communicating research results in a pediatric research were not explicitly identified by the respondents. Further consideration should be given to address the ethical challenges of including children in pharmacogenomics research. This exploratory study indicates that further guidance is needed if children are to be protected and yet benefit from such research. Copyright 2009 S. Karger AG, Basel.

  5. Comparison of organ doses in human phantoms: variations due to body size and posture

    International Nuclear Information System (INIS)

    Feng, Xu; Xiang-Hong, Jia; Xue-Jun, Yu; Zhan-Chun, Pan; Qian, Liu; Chun-Xin, Yang

    2017-01-01

    Organ dose calculations performed using human phantoms can provide estimates of astronauts' health risks due to cosmic radiation. However, the characteristics of such phantoms strongly affect the estimation precision. To investigate organ dose variations with body size and posture in human phantoms, a non-uniform rational B-spline boundary surfaces model was constructed based on cryo-section images. This model was used to establish four phantoms with different body size and posture parameters, whose organs parameters were changed simultaneously and which were voxelised with 4x4x4 mm"3 resolution. Then, using Monte Carlo transport code, the organ doses caused by ≤500 MeV isotropic incident protons were calculated. The dose variations due to body size differences within a certain range were negligible, and the doses received in crouching and standing-up postures were similar. Therefore, a standard Chinese phantom could be established, and posture changes cannot effectively protect astronauts during solar particle events. (authors)

  6. Transcriptome variations among human embryonic stem cell lines are associated with their differentiation propensity.

    Directory of Open Access Journals (Sweden)

    Changbin Sun

    Full Text Available Human embryonic stem cells (hESCs have the potential to form any cell type in the body, making them attractive cell sources in drug screening, regenerative medicine, disease and developmental processes modeling. However, not all hESC lines have the equal potency to generate desired cell types in vitro. Significant variations have been observed for the differentiation efficiency of various human ESC lines. The precise underpinning molecular mechanisms are still unclear. In this work, we compared transcriptome variations of four hESC lines H7, HUES1, HUES8 and HUES9. We found that hESC lines have different gene expression profiles, and these differentially expressed genes (DEGs are significantly enriched in developmental processes, such as ectodermal, mesodermal and endodermal development. The enrichment difference between hESC lines was consistent with its lineage bias. Among these DEGs, some pluripotency factors and genes involved in signaling transduction showed great variations as well. The pleiotropic functions of these genes in controlling hESC identity and early lineage specification, implicated that different hESC lines may utilize distinct balance mechanisms to maintain pluripotent state. When the balance is broken in a certain environment, gene expression variation between them could impact on their different lineage specification behavior.

  7. A survey on the awareness and attitude of pharmacists and doctors towards the application of pharmacogenomics and its challenges in Qatar.

    Science.gov (United States)

    Elewa, Hazem; Alkhiyami, Dania; Alsahan, Dima; Abdel-Aziz, Ahmed

    2015-08-01

    Pharmacists are expected to play an important role in applying pharmacogenomics discoveries to patient care. Despite the increased attention to genetic research in Qatar, clinicians' attitudes towards the application of pharmacogenomics are not yet explored. The aim of this study was to assess the awareness and attitude of pharmacists compared with doctors towards pharmacogenomics and its implications by submitting an electronic-based survey to all pharmacists and doctors currently working in a large medical corporation in Qatar. A cross-sectional survey instrument was developed based on literature review. Eligible participants were pharmacists and doctors currently practicing in Hamad Medical Corporation hospitals in Qatar. The survey comprised questions on demographic and professional characteristics. It also evaluated the awareness, attitudes and challenges towards pharmacogenomics and its application. We collected 202 surveys, 108 (53.2%) of which were pharmacists and the remaining 94 (46.5%) were doctors. The overall participants' mean total awareness score percentage was low (39% ± 22) and there were no difference between the mean score achieved by pharmacists and doctors. Pharmacists had significantly more positive attitudes than doctors towards: (i) taking the responsibility of applying pharmacogenomics to drug therapy selection, dosing and monitoring; (ii) perceiving a positive role of pharmacogenomics testing on the control of drug expenditure; and (iii) their willingness to participate in pharmacogenomics-related training sessions. Both pharmacists and doctors perceived lack of knowledge and guidelines as major challenges towards the application of pharmacogenomics in Qatar. Despite doctors' and pharmacists' low level of awareness towards pharmacogenomics, they both have positive attitudes towards the clinical implications of pharmacogenomics. Pharmacists are more motivated to learn about pharmacogenomics and are more willing to take initiatives in

  8. Brief communication: human cranial variation fits iterative founder effect model with African origin.

    Science.gov (United States)

    von Cramon-Taubadel, Noreen; Lycett, Stephen J

    2008-05-01

    Recent studies comparing craniometric and neutral genetic affinity matrices have concluded that, on average, human cranial variation fits a model of neutral expectation. While human craniometric and genetic data fit a model of isolation by geographic distance, it is not yet clear whether this is due to geographically mediated gene flow or human dispersal events. Recently, human genetic data have been shown to fit an iterative founder effect model of dispersal with an African origin, in line with the out-of-Africa replacement model for modern human origins, and Manica et al. (Nature 448 (2007) 346-349) have demonstrated that human craniometric data also fit this model. However, in contrast with the neutral model of cranial evolution suggested by previous studies, Manica et al. (2007) made the a priori assumption that cranial form has been subject to climatically driven natural selection and therefore correct for climate prior to conducting their analyses. Here we employ a modified theoretical and methodological approach to test whether human cranial variability fits the iterative founder effect model. In contrast with Manica et al. (2007) we employ size-adjusted craniometric variables, since climatic factors such as temperature have been shown to correlate with aspects of cranial size. Despite these differences, we obtain similar results to those of Manica et al. (2007), with up to 26% of global within-population craniometric variation being explained by geographic distance from sub-Saharan Africa. Comparative analyses using non-African origins do not yield significant results. The implications of these results are discussed in the light of the modern human origins debate. (c) 2007 Wiley-Liss, Inc.

  9. Genetic determination of human facial morphology: links between cleft-lips and normal variation.

    Science.gov (United States)

    Boehringer, Stefan; van der Lijn, Fedde; Liu, Fan; Günther, Manuel; Sinigerova, Stella; Nowak, Stefanie; Ludwig, Kerstin U; Herberz, Ruth; Klein, Stefan; Hofman, Albert; Uitterlinden, Andre G; Niessen, Wiro J; Breteler, Monique M B; van der Lugt, Aad; Würtz, Rolf P; Nöthen, Markus M; Horsthemke, Bernhard; Wieczorek, Dagmar; Mangold, Elisabeth; Kayser, Manfred

    2011-11-01

    Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and other previous studies showed distinctly differing facial distance measurements when comparing unaffected relatives of NSCL/P patients with normal controls. Here, we test the hypothesis that genetic loci involved in NSCL/P also influence normal variation in facial morphology. We tested 11 SNPs from 10 genomic regions previously showing replicated evidence of association with NSCL/P for association with normal variation of nose width and bizygomatic distance in two cohorts from Germany (N=529) and the Netherlands (N=2497). The two most significant associations found were between nose width and SNP rs1258763 near the GREM1 gene in the German cohort (P=6 × 10(-4)), and between bizygomatic distance and SNP rs987525 at 8q24.21 near the CCDC26 gene (P=0.017) in the Dutch sample. A genetic prediction model explained 2% of phenotype variation in nose width in the German and 0.5% of bizygomatic distance variation in the Dutch cohort. Although preliminary, our data provide a first link between genetic loci involved in a pathological facial trait such as NSCL/P and variation of normal facial morphology. Moreover, we present a first approach for understanding the genetic basis of human facial appearance, a highly intriguing trait with implications on clinical practice, clinical genetics, forensic intelligence, social interactions and personal identity.

  10. Understanding variation in human fertility: what can we learn from evolutionary demography?

    Science.gov (United States)

    Sear, Rebecca; Lawson, David W; Kaplan, Hillard; Shenk, Mary K

    2016-04-19

    Decades of research on human fertility has presented a clear picture of how fertility varies, including its dramatic decline over the last two centuries in most parts of the world. Why fertility varies, both between and within populations, is not nearly so well understood. Fertility is a complex phenomenon, partly physiologically and partly behaviourally determined, thus an interdisciplinary approach is required to understand it. Evolutionary demographers have focused on human fertility since the 1980s. The first wave of evolutionary demographic research made major theoretical and empirical advances, investigating variation in fertility primarily in terms of fitness maximization. Research focused particularly on variation within high-fertility populations and small-scale subsistence societies and also yielded a number of hypotheses for why fitness maximization seems to break down as fertility declines during the demographic transition. A second wave of evolutionary demography research on fertility is now underway, paying much more attention to the cultural and psychological mechanisms underpinning fertility. It is also engaging with the complex, multi-causal nature of fertility variation, and with understanding fertility in complex modern and transitioning societies. Here, we summarize the history of evolutionary demographic work on human fertility, describe the current state of the field, and suggest future directions. © 2016 The Author(s).

  11. NDVI-Based analysis on the influence of human activities on vegetation variation on Hainan Island

    Science.gov (United States)

    Luo, Hongxia; Dai, Shengpei; Xie, Zhenghui; Fang, Jihua

    2018-02-01

    Using the Moderate Resolution Imaging Spectroradiometer-normalized difference vegetation index (NDVI) dataset, we analyzed the predicted NDVI values variation and the influence of human activities on vegetation on Hainan Island during 2001-2015. We investigated the roles of human activities in vegetation variation, particularly from 2002 when implemented the Grain-for-Greenprogram on Hainan Island. The trend analysis, linear regression model and residual analysis were used to analyze the data. The results of the study showed that (1) The predicted vegetation on Hainan Island showed an general upward trend with a linear growth rate of 0.0025/10y (phuman activities. (3) In general, human activities had played a positive role in the vegetation increase on Hainan Island, and the residual NDVI trend of this region showed positive outcomes for vegetation variation after implementing ecological engineering projects. However, it indicated a growing risk of vegetation degradation in the coastal region of Hainan Island as a result of rapid urbanization, land reclamation.

  12. Analysis of temporal variation in human masticatory cycles during gum chewing.

    Science.gov (United States)

    Crane, Elizabeth A; Rothman, Edward D; Childers, David; Gerstner, Geoffrey E

    2013-10-01

    The study investigated modulation of fast and slow opening (FO, SO) and closing (FC, SC) chewing cycle phases using gum-chewing sequences in humans. Twenty-two healthy adult subjects participated by chewing gum for at least 20s on the right side and at least 20s on the left side while jaw movements were tracked with a 3D motion analysis system. Jaw movement data were digitized, and chewing cycle phases were identified and analysed for all chewing cycles in a complete sequence. All four chewing cycle phase durations were more variant than total cycle durations, a result found in other non-human primates. Significant negative correlations existed between the opening phases, SO and FO, and between the closing phases, SC and FC; however, there was less consistency in terms of which phases were negatively correlated both between subjects, and between chewing sides within subjects, compared with results reported in other species. The coordination of intra-cycle phases appears to be flexible and to follow complex rules during gum-chewing in humans. Alternatively, the observed intra-cycle phase relationships could simply reflect: (1) variation in jaw kinematics due to variation in how gum was handled by the tongue on a chew-by-chew basis in our experimental design or (2) by variation due to data sampling noise and/or how phases were defined and identified. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. Comparison of inter- and intraspecies variation in humans and fruit flies

    Directory of Open Access Journals (Sweden)

    Juliann Shih

    2015-03-01

    Full Text Available Variation is essential to species survival and adaptation during evolution. This variation is conferred by the imperfection of biochemical processes, such as mutations and alterations in DNA sequences, and can also be seen within genomes through processes such as the generation of antibodies. Recent sequencing projects have produced multiple versions of the genomes of humans and fruit flies (Drosophila melanogaster. These give us a chance to study how individual gene sequences vary within and between species. Here we arranged human and fly genes in orthologous pairs and compared such within-species variability with their degree of conservation between flies and humans. We observed that a significant number of proteins associated with mRNA translation are highly conserved between species and yet are highly variable within each species. The fact that we observe this in two species whose lineages separated more than 700 million years ago suggests that this is the result of a very ancient process. We hypothesize that this effect might be attributed to a positive selection for variability of virus-interacting proteins that confers a general resistance to viral hijacking of the mRNA translation machinery within populations. Our analysis points to this and to other processes resulting in positive selection for gene variation.

  14. Public involvement in pharmacogenomics research: a national survey on patients' attitudes towards pharmacogenomics research and the willingness to donate DNA samples to a DNA bank in Japan.

    Science.gov (United States)

    Kobayashi, Eriko; Sakurada, Tomoya; Ueda, Shiro; Satoh, Nobunori

    2011-05-01

    To assess the attitude of Japanese patients towards pharmacogenomics research and a DNA bank for identifying genomic markers associated with adverse drug reactions (ADRs) and their willingness to donate DNA samples, we conducted a survey of 550 male and female patients. The majority of the respondents showed a positive attitude towards pharmacogenomics research (87.6%) and a DNA bank (75.1%). The willingness to donate DNA samples when experiencing severe ADRs (55.8%) was higher than when taking medications (40.4%). Positive attitudes towards a DNA bank and organ donation were significantly associated with an increased willingness to donate. Though the level of positive attitude in the patient population was higher than that in the general public in our former study (81.0 and 70.4%, respectively), the level of the willingness of patients to donate was 40.4% when taking medications and 55.8% when experiencing severe ADRs which was lower than that of the general public in our former study (45.3 and 61.7%). The results suggested that the level of true willingness in the patient population was lower than that of the general public considering the fictitious situation presented to the public (to suppose that they were patients receiving medication). It is important to assess the willingness of patients who are true potential donors, not the general public.

  15. Population genetic inference from personal genome data: impact of ancestry and admixture on human genomic variation.

    Science.gov (United States)

    Kidd, Jeffrey M; Gravel, Simon; Byrnes, Jake; Moreno-Estrada, Andres; Musharoff, Shaila; Bryc, Katarzyna; Degenhardt, Jeremiah D; Brisbin, Abra; Sheth, Vrunda; Chen, Rong; McLaughlin, Stephen F; Peckham, Heather E; Omberg, Larsson; Bormann Chung, Christina A; Stanley, Sarah; Pearlstein, Kevin; Levandowsky, Elizabeth; Acevedo-Acevedo, Suehelay; Auton, Adam; Keinan, Alon; Acuña-Alonzo, Victor; Barquera-Lozano, Rodrigo; Canizales-Quinteros, Samuel; Eng, Celeste; Burchard, Esteban G; Russell, Archie; Reynolds, Andy; Clark, Andrew G; Reese, Martin G; Lincoln, Stephen E; Butte, Atul J; De La Vega, Francisco M; Bustamante, Carlos D

    2012-10-05

    Full sequencing of individual human genomes has greatly expanded our understanding of human genetic variation and population history. Here, we present a systematic analysis of 50 human genomes from 11 diverse global populations sequenced at high coverage. Our sample includes 12 individuals who have admixed ancestry and who have varying degrees of recent (within the last 500 years) African, Native American, and European ancestry. We found over 21 million single-nucleotide variants that contribute to a 1.75-fold range in nucleotide heterozygosity across diverse human genomes. This heterozygosity ranged from a high of one heterozygous site per kilobase in west African genomes to a low of 0.57 heterozygous sites per kilobase in segments inferred to have diploid Native American ancestry from the genomes of Mexican and Puerto Rican individuals. We show evidence of all three continental ancestries in the genomes of Mexican, Puerto Rican, and African American populations, and the genome-wide statistics are highly consistent across individuals from a population once ancestry proportions have been accounted for. Using a generalized linear model, we identified subtle variations across populations in the proportion of neutral versus deleterious variation and found that genome-wide statistics vary in admixed populations even once ancestry proportions have been factored in. We further infer that multiple periods of gene flow shaped the diversity of admixed populations in the Americas-70% of the European ancestry in today's African Americans dates back to European gene flow happening only 7-8 generations ago. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  16. Inter-chromosomal variation in the pattern of human population genetic structure

    Directory of Open Access Journals (Sweden)

    Baye Tesfaye M

    2011-05-01

    Full Text Available Abstract Emerging technologies now make it possible to genotype hundreds of thousands of genetic variations in individuals, across the genome. The study of loci at finer scales will facilitate the understanding of genetic variation at genomic and geographic levels. We examined global and chromosomal variations across HapMap populations using 3.7 million single nucleotide polymorphisms to search for the most stratified genomic regions of human populations and linked these regions to ontological annotation and functional network analysis. To achieve this, we used five complementary statistical and genetic network procedures: principal component (PC, cluster, discriminant, fixation index (FST and network/pathway analyses. At the global level, the first two PC scores were sufficient to account for major population structure; however, chromosomal level analysis detected subtle forms of population structure within continental populations, and as many as 31 PCs were required to classify individuals into homogeneous groups. Using recommended population ancestry differentiation measures, a total of 126 regions of the genome were catalogued. Gene ontology and networks analyses revealed that these regions included the genes encoding oculocutaneous albinism II (OCA2, hect domain and RLD 2 (HERC2, ectodysplasin A receptor (EDAR and solute carrier family 45, member 2 (SLC45A2. These genes are associated with melanin production, which is involved in the development of skin and hair colour, skin cancer and eye pigmentation. We also identified the genes encoding interferon-γ (IFNG and death-associated protein kinase 1 (DAPK1, which are associated with cell death, inflammatory and immunological diseases. An in-depth understanding of these genomic regions may help to explain variations in adaptation to different environments. Our approach offers a comprehensive strategy for analysing chromosome-based population structure and differentiation, and demonstrates the

  17. Topographic variation in redifferentiation capacity of chondrocytes in the adult human knee joint.

    Science.gov (United States)

    Stenhamre, H; Slynarski, K; Petrén, C; Tallheden, T; Lindahl, A

    2008-11-01

    The aim of this study was to investigate the topographic variation in matrix production and cell density in the adult human knee joint. Additionally, we have examined the redifferentiation potential of chondrocytes expanded in vitro from the different locations. Full thickness cartilage-bone biopsies were harvested from seven separate anatomical locations of healthy knee joints from deceased adult human donors. Chondrocytes were isolated, expanded in vitro and redifferentiated in a pellet mass culture. Biochemical analysis of total collagen, proteoglycans and cellular content as well as histology and immunohistochemistry were performed on biopsies and pellets. In the biochemical analysis of the biopsies, we found lower proteoglycan to collagen (GAG/HP) ratio in the non-weight bearing (NWB) areas compared to the weight bearing (WB) areas. The chondrocytes harvested from different locations in femur showed a significantly better attachment and proliferation ability as well as good post-expansion chondrogenic capacity in pellet mass culture compared with the cells harvested from tibia. These results demonstrate that there are differences in extra cellular content within the adult human knee in respect to GAG/HP ratio. Additionally, the data show that clear differences between chondrocytes harvested from femur and tibia from healthy human knee joints exist and that the differences are not completely abolished during the process of de- and redifferentiation. These findings emphasize the importance of the understanding of topographic variation in articular cartilage biology when approaching new cartilage repair strategies.

  18. PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans.

    Science.gov (United States)

    Berg, Ingrid L; Neumann, Rita; Lam, Kwan-Wood G; Sarbajna, Shriparna; Odenthal-Hesse, Linda; May, Celia A; Jeffreys, Alec J

    2010-10-01

    PRDM9 has recently been identified as a likely trans regulator of meiotic recombination hot spots in humans and mice. PRDM9 contains a zinc finger array that, in humans, can recognize a short sequence motif associated with hot spots, with binding to this motif possibly triggering hot-spot activity via chromatin remodeling. We now report that human genetic variation at the PRDM9 locus has a strong effect on sperm hot-spot activity, even at hot spots lacking the sequence motif. Subtle changes within the zinc finger array can create hot-spot nonactivating or enhancing variants and can even trigger the appearance of a new hot spot, suggesting that PRDM9 is a major global regulator of hot spots in humans. Variation at the PRDM9 locus also influences aspects of genome instability-specifically, a megabase-scale rearrangement underlying two genomic disorders as well as minisatellite instability-implicating PRDM9 as a risk factor for some pathological genome rearrangements.

  19. Natural selection affects multiple aspects of genetic variation at putatively peutral sites across the human genome

    DEFF Research Database (Denmark)

    Lohmueller, Kirk E; Albrechtsen, Anders; Li, Yingrui

    2011-01-01

    A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries...... these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination...... and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations...

  20. Mutation Rate Variation is a Primary Determinant of the Distribution of Allele Frequencies in Humans.

    Directory of Open Access Journals (Sweden)

    Arbel Harpak

    2016-12-01

    Full Text Available The site frequency spectrum (SFS has long been used to study demographic history and natural selection. Here, we extend this summary by examining the SFS conditional on the alleles found at the same site in other species. We refer to this extension as the "phylogenetically-conditioned SFS" or cSFS. Using recent large-sample data from the Exome Aggregation Consortium (ExAC, combined with primate genome sequences, we find that human variants that occurred independently in closely related primate lineages are at higher frequencies in humans than variants with parallel substitutions in more distant primates. We show that this effect is largely due to sites with elevated mutation rates causing significant departures from the widely-used infinite sites mutation model. Our analysis also suggests substantial variation in mutation rates even among mutations involving the same nucleotide changes. In summary, we show that variable mutation rates are key determinants of the SFS in humans.

  1. Natural selection affects multiple aspects of genetic variation at putatively neutral sites across the human genome.

    Science.gov (United States)

    Lohmueller, Kirk E; Albrechtsen, Anders; Li, Yingrui; Kim, Su Yeon; Korneliussen, Thorfinn; Vinckenbosch, Nicolas; Tian, Geng; Huerta-Sanchez, Emilia; Feder, Alison F; Grarup, Niels; Jørgensen, Torben; Jiang, Tao; Witte, Daniel R; Sandbæk, Annelli; Hellmann, Ines; Lauritzen, Torsten; Hansen, Torben; Pedersen, Oluf; Wang, Jun; Nielsen, Rasmus

    2011-10-01

    A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations.

  2. Geography, Ethnicity or Subsistence-Specific Variations in Human Microbiome Composition and Diversity

    Directory of Open Access Journals (Sweden)

    Vinod K. Gupta

    2017-06-01

    Full Text Available One of the fundamental issues in the microbiome research is characterization of the healthy human microbiota. Recent studies have elucidated substantial divergences in the microbiome structure between healthy individuals from different race and ethnicity. This review provides a comprehensive account of such geography, ethnicity or life-style-specific variations in healthy microbiome at five major body habitats—Gut, Oral-cavity, Respiratory Tract, Skin, and Urogenital Tract (UGT. The review focuses on the general trend in the human microbiome evolution—a gradual transition in the gross compositional structure along with a continual decrease in diversity of the microbiome, especially of the gut microbiome, as the human populations passed through three stages of subsistence like foraging, rural farming and industrialized urban western life. In general, gut microbiome of the hunter-gatherer populations is highly abundant with Prevotella, Proteobacteria, Spirochaetes, Clostridiales, Ruminobacter etc., while those of the urban communities are often enriched in Bacteroides, Bifidobacterium, and Firmicutes. The oral and skin microbiome are the next most diverse among different populations, while respiratory tract and UGT microbiome show lesser variations. Higher microbiome diversity is observed for oral-cavity in hunter-gatherer group with higher prevalence of Haemophilus than agricultural group. In case of skin microbiome, rural and urban Chinese populations show variation in abundance of Trabulsiella and Propionibacterium. On the basis of published data, we have characterized the core microbiota—the set of genera commonly found in all populations, irrespective of their geographic locations, ethnicity or mode of subsistence. We have also identified the major factors responsible for geography-based alterations in microbiota; though it is not yet clear which factor plays a dominant role in shaping the microbiome—nature or nurture, host genetics

  3. Landscape and variation of RNA secondary structure across the human transcriptome.

    Science.gov (United States)

    Wan, Yue; Qu, Kun; Zhang, Qiangfeng Cliff; Flynn, Ryan A; Manor, Ohad; Ouyang, Zhengqing; Zhang, Jiajing; Spitale, Robert C; Snyder, Michael P; Segal, Eran; Chang, Howard Y

    2014-01-30

    In parallel to the genetic code for protein synthesis, a second layer of information is embedded in all RNA transcripts in the form of RNA structure. RNA structure influences practically every step in the gene expression program. However, the nature of most RNA structures or effects of sequence variation on structure are not known. Here we report the initial landscape and variation of RNA secondary structures (RSSs) in a human family trio (mother, father and their child). This provides a comprehensive RSS map of human coding and non-coding RNAs. We identify unique RSS signatures that demarcate open reading frames and splicing junctions, and define authentic microRNA-binding sites. Comparison of native deproteinized RNA isolated from cells versus refolded purified RNA suggests that the majority of the RSS information is encoded within RNA sequence. Over 1,900 transcribed single nucleotide variants (approximately 15% of all transcribed single nucleotide variants) alter local RNA structure. We discover simple sequence and spacing rules that determine the ability of point mutations to impact RSSs. Selective depletion of 'riboSNitches' versus structurally synonymous variants at precise locations suggests selection for specific RNA shapes at thousands of sites, including 3' untranslated regions, binding sites of microRNAs and RNA-binding proteins genome-wide. These results highlight the potentially broad contribution of RNA structure and its variation to gene regulation.

  4. Effect of speech-intrinsic variations on human and automatic recognition of spoken phonemes.

    Science.gov (United States)

    Meyer, Bernd T; Brand, Thomas; Kollmeier, Birger

    2011-01-01

    The aim of this study is to quantify the gap between the recognition performance of human listeners and an automatic speech recognition (ASR) system with special focus on intrinsic variations of speech, such as speaking rate and effort, altered pitch, and the presence of dialect and accent. Second, it is investigated if the most common ASR features contain all information required to recognize speech in noisy environments by using resynthesized ASR features in listening experiments. For the phoneme recognition task, the ASR system achieved the human performance level only when the signal-to-noise ratio (SNR) was increased by 15 dB, which is an estimate for the human-machine gap in terms of the SNR. The major part of this gap is attributed to the feature extraction stage, since human listeners achieve comparable recognition scores when the SNR difference between unaltered and resynthesized utterances is 10 dB. Intrinsic variabilities result in strong increases of error rates, both in human speech recognition (HSR) and ASR (with a relative increase of up to 120%). An analysis of phoneme duration and recognition rates indicates that human listeners are better able to identify temporal cues than the machine at low SNRs, which suggests incorporating information about the temporal dynamics of speech into ASR systems.

  5. Evaluating variation in human gut microbiota profiles due to DNA extraction method and inter-subject differences.

    Science.gov (United States)

    Wagner Mackenzie, Brett; Waite, David W; Taylor, Michael W

    2015-01-01

    The human gut contains dense and diverse microbial communities which have profound influences on human health. Gaining meaningful insights into these communities requires provision of high quality microbial nucleic acids from human fecal samples, as well as an understanding of the sources of variation and their impacts on the experimental model. We present here a systematic analysis of commonly used microbial DNA extraction methods, and identify significant sources of variation. Five extraction methods (Human Microbiome Project protocol, MoBio PowerSoil DNA Isolation Kit, QIAamp DNA Stool Mini Kit, ZR Fecal DNA MiniPrep, phenol:chloroform-based DNA isolation) were evaluated based on the following criteria: DNA yield, quality and integrity, and microbial community structure based on Illumina amplicon sequencing of the V4 region of bacterial and archaeal 16S rRNA genes. Our results indicate that the largest portion of variation within the model was attributed to differences between subjects (biological variation), with a smaller proportion of variation associated with DNA extraction method (technical variation) and intra-subject variation. A comprehensive understanding of the potential impact of technical variation on the human gut microbiota will help limit preventable bias, enabling more accurate diversity estimates.

  6. Evaluating variation in human gut microbiota profiles due to DNA extraction method and inter-subject differences

    Directory of Open Access Journals (Sweden)

    Brett eWagner Mackenzie

    2015-02-01

    Full Text Available The human gut contains dense and diverse microbial communities which have profound influences on human health. Gaining meaningful insights into these communities requires provision of high quality microbial nucleic acids from human fecal samples, as well as an understanding of the sources of variation and their impacts on the experimental model. We present here a systematic analysis of commonly used microbial DNA extraction methods, and identify significant sources of variation. Five extraction methods (Human Microbiome Project protocol, MoBio PowerSoil DNA Isolation Kit, QIAamp DNA Stool Mini Kit, ZR Fecal DNA MiniPrep, phenol:chloroform-based DNA isolation were evaluated based on the following criteria: DNA yield, quality and integrity, and microbial community structure based on Illumina amplicon sequencing of the V4 region of bacterial and archaeal 16S rRNA genes. Our results indicate that the largest portion of variation within the model was attributed to differences between subjects (biological variation, with a smaller proportion of variation associated with DNA extraction method (technical variation and intra-subject variation. A comprehensive understanding of the potential impact of technical variation on the human gut microbiota will help limit preventable bias, enabling more accurate diversity estimates.

  7. Simultaneous inference of selection and population growth from patterns of variation in the human genome

    DEFF Research Database (Denmark)

    Williamson, Scott H.; Hernandez, Ryan; Fledel-Alon, Adi

    2005-01-01

    Natural selection and demographic forces can have similar effects on patterns of DNA polymorphism. Therefore, to infer selection from samples of DNA sequences, one must simultaneously account for demographic effects. Here we take a model-based approach to this problem by developing predictions fo......-specific methods, and (iii) strong evidence for very recent population growth....... for patterns of polymorphism in the presence of both population size change and natural selection. If data are available from different functional classes of variation, and a priori information suggests that mutations in one of those classes are selectively neutral, then the putatively neutral class can...... this method to a large polymorphism data set from 301 human genes and find (i) widespread negative selection acting on standing nonsynonymous variation, (ii) that the fitness effects of nonsynonymous mutations are well predicted by several measures of amino acid exchangeability, especially site...

  8. Severity of infection and seasonal variation of non-typhoid Salmonelle occurence in humans

    DEFF Research Database (Denmark)

    Gradel, K.O.; Dethlefsen, Claus; Schønheyder, H.C.

    2007-01-01

    Non-typhoid Salmonella infections may present as severe gastroenteritis necessitatinghospitalization and some patients become septic with bacteraemia. We hypothesized that theseasonal variation of non-typhoid Salmonella occurrence in humans diminishes with increasedseverity of infection. We...... examined the seasonal variation of non-typhoid Salmonella infections inthree patient groups with differing severity of infection: outpatients treated for gastroenteritis(n=1490); in-patients treated for gastroenteritis (n=492); and in-patients treated for bacteraemia(n=113). The study was population......-based and included all non-typhoid Salmonella patients ina Danish county from 1994 to 2003. A periodic regression model was used to compute thepeak-to-trough ratio for the three patient groups. The peak-to-trough ratios were 4·3 [95%confidence interval (CI) 3·6–5.0] for outpatients with gastroenteritis, 3·2 (95% CI...

  9. Genetics in endocrinology: genetic variation in deiodinases: a systematic review of potential clinical effects in humans.

    Science.gov (United States)

    Verloop, Herman; Dekkers, Olaf M; Peeters, Robin P; Schoones, Jan W; Smit, Johannes W A

    2014-09-01

    Iodothyronine deiodinases represent a family of selenoproteins involved in peripheral and local homeostasis of thyroid hormone action. Deiodinases are expressed in multiple organs and thyroid hormone affects numerous biological systems, thus genetic variation in deiodinases may affect multiple clinical endpoints. Interest in clinical effects of genetic variation in deiodinases has clearly increased. We aimed to provide an overview for the role of deiodinase polymorphisms in human physiology and morbidity. In this systematic review, studies evaluating the relationship between deiodinase polymorphisms and clinical parameters in humans were eligible. No restrictions on publication date were imposed. The following databases were searched up to August 2013: Pubmed, EMBASE (OVID-version), Web of Science, COCHRANE Library, CINAHL (EbscoHOST-version), Academic Search Premier (EbscoHOST-version), and ScienceDirect. Deiodinase physiology at molecular and tissue level is described, and finally the role of these polymorphisms in pathophysiological conditions is reviewed. Deiodinase type 1 (D1) polymorphisms particularly show moderate-to-strong relationships with thyroid hormone parameters, IGF1 production, and risk for depression. D2 variants correlate with thyroid hormone levels, insulin resistance, bipolar mood disorder, psychological well-being, mental retardation, hypertension, and risk for osteoarthritis. D3 polymorphisms showed no relationship with inter-individual variation in serum thyroid hormone parameters. One D3 polymorphism was associated with risk for osteoarthritis. Genetic deiodinase profiles only explain a small proportion of inter-individual variations in serum thyroid hormone levels. Evidence suggests a role of genetic deiodinase variants in certain pathophysiological conditions. The value for determination of deiodinase polymorphism in clinical practice needs further investigation. © 2014 European Society of Endocrinology.

  10. Microgeographic variation in locomotor traits among lizards in a human-built environment

    Directory of Open Access Journals (Sweden)

    Colin Donihue

    2016-03-01

    Full Text Available Microgeographic variation in fitness-relevant traits may be more common than previously appreciated. The fitness of many vertebrates is directly related to their locomotor capacity, a whole-organism trait integrating behavior, morphology, and physiology. Because locomotion is inextricably related to context, I hypothesized that it might vary with habitat structure in a wide-ranging lizard, Podarcis erhardii, found in the Greek Cyclade Islands. I compared lizard populations living on human-built rock walls, a novel habitat with complex vertical structure, with nearby lizard populations that are naive to human-built infrastructure and live in flat, loose-substrate habitat. I tested for differences in morphology, behavior, and performance. Lizards from built sites were larger and had significantly (and relatively longer forelimbs and hindlimbs. The differences in hindlimb morphology were especially pronounced for distal components—the foot and longest toe. These morphologies facilitated a significant behavioral shift in jumping propensity across a rocky experimental substrate. I found no difference in maximum velocity between these populations; however, females originating from wall sites potentially accelerated faster over the rocky experimental substrate. The variation between these closely neighboring populations suggests that the lizards inhabiting walls have experienced a suite of trait changes enabling them to take advantage of the novel habitat structure created by humans.

  11. Premolar root and canal variation in extant non-human hominoidea.

    Science.gov (United States)

    Moore, N Collin; Hublin, Jean-Jacques; Skinner, Matthew M

    2015-08-11

    The premolar sub-cervical region in four non-human extant ape genera are examined to: 1) define a classification scheme for the premolar root system in order to rigorously characterize, quantify and document variation in root and canal, form, number and configuration; 2) compare this variation within and between genera; and 3) test the hypotheses that sex and size (i.e., the "size/number continuum," Shields, ) of the premolar are determinants of root/canal form and/or number. Microtomography and 3D visualization software are utilized to examine a large sample of Hylobates, Pan, Gorilla, and Pongo (n = 951 teeth). Each premolar root system is examined to ascertain the expected level of variability for each taxon. Cervical surface area (mm 2 ) serves as a metric proxy for tooth size. A Chi-square test of independence is used to assess for variability differences between and within each taxon, and Mann-Whitney U tests are employed to assess the predicted relationship between tooth size and variation within each taxon. Our findings indicate that root and canal configurations, non-metric root traits and tooth size can distinguish between extant ape genera. Within the four ape taxa, premolar size variation is generally, but not always, correlated with canal/root number. Our results indicate that males and females within genera differ in tooth size but not in canal/root form and number. We report previously undocumented variation in the study taxa. Our results are discussed within the context of Miocene Apes as well as the developmental and systematic implications. Am J Phys Anthropol, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  12. Circadian Macronutrients Variations over the First 7 Weeks of Human Milk Feeding of Preterm Infants.

    Science.gov (United States)

    Moran-Lev, Hadar; Mimouni, Francis B; Ovental, Amit; Mangel, Laurence; Mandel, Dror; Lubetzky, Ronit

    2015-09-01

    Little is known about circadian variations of macronutrients content of expressed preterm human milk (HM). This study evaluated diurnal variations of macronutrients and energy content of preterm HM over the first 7 weeks of lactation and tested the hypothesis that values obtained during a morning sample are predictive of those obtained from an evening sample. Expressed HM was obtained from 32 mothers of preterm infants (26-33 weeks in gestational age), who routinely expressed all their milk every 3 hours from the beginning of the second to the seventh week after delivery. One aliquot was obtained from the first morning expression and the second from the evening expression. Energy and macronutrients contents were measured using an HM analyzer. Mean fat and energy contents of all samples obtained during the whole period were significantly higher in evening samples (p < 0.0001). There were no significant differences between morning and evening carbohydrates and protein contents. Concentrations of protein, carbohydrates, and fat from morning samples were predictive of evening concentrations to different extents (R(2) = 0.720, R(2) = 0.663, and R(2) = 0.20, respectively; p < 0.02). The predictability of evening values by morning values was not influenced by the week of lactation at sampling or by individual patients. In repeated-measures analysis of variance performed on 11 patients who completed the whole 7-week period, over time, there was a significant decrease in fat, energy, and protein contents, whereas carbohydrates content remained unchanged. Day-night differences remained significant only for fat content. Circadian variations in fat and energy concentrations of HM are consistent over the first 7 weeks of lactation. There are no consistent circadian variations in HM protein and carbohydrates. Over a given day, there are little variations in protein and carbohydrates content, but fat concentrations are more variable, and evening values are less well predicted by

  13. Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics.

    Science.gov (United States)

    ElRakaiby, Marwa; Dutilh, Bas E; Rizkallah, Mariam R; Boleij, Annemarie; Cole, Jason N; Aziz, Ramy K

    2014-07-01

    The Human Microbiome Project (HMP) is a global initiative undertaken to identify and characterize the collection of human-associated microorganisms at multiple anatomic sites (skin, mouth, nose, colon, vagina), and to determine how intra-individual and inter-individual alterations in the microbiome influence human health, immunity, and different disease states. In this review article, we summarize the key findings and applications of the HMP that may impact pharmacology and personalized therapeutics. We propose a microbiome cloud model, reflecting the temporal and spatial uncertainty of defining an individual's microbiome composition, with examples of how intra-individual variations (such as age and mode of delivery) shape the microbiome structure. Additionally, we discuss how this microbiome cloud concept explains the difficulty to define a core human microbiome and to classify individuals according to their biome types. Detailed examples are presented on microbiome changes related to colorectal cancer, antibiotic administration, and pharmacomicrobiomics, or drug-microbiome interactions, highlighting how an improved understanding of the human microbiome, and alterations thereof, may lead to the development of novel therapeutic agents, the modification of antibiotic policies and implementation, and improved health outcomes. Finally, the prospects of a collaborative computational microbiome research initiative in Africa are discussed.

  14. Regional variations of cell surface carbohydrates in human oral stratified epithelium

    DEFF Research Database (Denmark)

    Vedtofte, P; Dabelsteen, Erik; Hakomori, S

    1984-01-01

    The distribution of blood group carbohydrate chains with antigen A, B, H type 2 chain (A and B precursor), and N-acetyllactosamine (H type 2 precursor) specificity was studied in human oral epithelium from different anatomical regions. These represented various epithelial differentiation patterns...... epithelium from nine blood group A, two blood group B, and nine blood group O individuals. The blood group carbohydrate chains were examined in tissue sections by immunofluorescence microscopy. The A and B blood group antigens were detected by human blood group sera, and antigen H type 2 chains and N...... antigen H type 2 chains in metaplastically keratinized buccal epithelium was found to differ significantly from that seen in normal non-keratinized buccal epithelium. The regional variations demonstrated in cell surface carbohydrates are suggested to reflect differences in tissue differentiation....

  15. Designing a post-genomics knowledge ecosystem to translate pharmacogenomics into public health action.

    Science.gov (United States)

    Dove, Edward S; Faraj, Samer A; Kolker, Eugene; Ozdemir, Vural

    2012-01-01

    Translation of pharmacogenomics to public health action is at the epicenter of the life sciences agenda. Post-genomics knowledge is simultaneously co-produced at multiple scales and locales by scientists, crowd-sourcing and biological citizens. The latter are entrepreneurial citizens who are autonomous, self-governing and increasingly conceptualizing themselves in biological terms, ostensibly taking responsibility for their own health, and engaging in patient advocacy and health activism. By studying these heterogeneous 'scientific cultures', we can locate innovative parameters of collective action to move pharmacogenomics to practice (personalized therapeutics). To this end, we reconceptualize knowledge-based innovation as a complex ecosystem comprising 'actors' and 'narrators'. For robust knowledge translation, we require a nested post-genomics technology governance system composed of first-order narrators (for example, social scientists, philosophers, bioethicists) situated at arm's length from innovation actors (for example, pharmacogenomics scientists). Yet, second-order narrators (for example, an independent and possibly crowd-funded think-tank of citizen scholars, marginalized groups and knowledge end-users) are crucial to prevent first-order narrators from gaining excessive power that can be misused in the course of steering innovations. To operate such 'self-calibrating' and nested innovation ecosystems, we introduce the concept of 'wiki-governance' to enable mutual and iterative learning among innovation actors and first- and second-order narrators. '[A] scientific expert is someone who knows more and more about less and less, until finally knowing (almost) everything about (almost) nothing.' [1] 'Ubuntu: I am because you are.' [2].

  16. ALDH1A2 (RALDH2 genetic variation in human congenital heart disease

    Directory of Open Access Journals (Sweden)

    Mesquita Sonia MF

    2009-11-01

    ALDH1A2 genetic variation is present in TOF patients, suggesting a possible causal role for this gene in rare cases of human CHD, but does not support the hypothesis that variation at the ALDH1A2 locus is a significant modifier of the risk for CHD in humans.

  17. Current trend of annotating single nucleotide variation in humans--A case study on SNVrap.

    Science.gov (United States)

    Li, Mulin Jun; Wang, Junwen

    2015-06-01

    As high throughput methods, such as whole genome genotyping arrays, whole exome sequencing (WES) and whole genome sequencing (WGS), have detected huge amounts of genetic variants associated with human diseases, function annotation of these variants is an indispensable step in understanding disease etiology. Large-scale functional genomics projects, such as The ENCODE Project and Roadmap Epigenomics Project, provide genome-wide profiling of functional elements across different human cell types and tissues. With the urgent demands for identification of disease-causal variants, comprehensive and easy-to-use annotation tool is highly in demand. Here we review and discuss current progress and trend of the variant annotation field. Furthermore, we introduce a comprehensive web portal for annotating human genetic variants. We use gene-based features and the latest functional genomics datasets to annotate single nucleotide variation (SNVs) in human, at whole genome scale. We further apply several function prediction algorithms to annotate SNVs that might affect different biological processes, including transcriptional gene regulation, alternative splicing, post-transcriptional regulation, translation and post-translational modifications. The SNVrap web portal is freely available at http://jjwanglab.org/snvrap. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. STUDY ON NORTHERN AND SOUTHERN INDIA VARIATIONS OF HUMAN SKULL- A SECONDARY RESEARCH

    Directory of Open Access Journals (Sweden)

    Jameskutty Baby Jacob Kaithackal

    2016-12-01

    Full Text Available BACKGROUND Identity of a human being with regard to sex, race, age etc. can be revealed if the skull is suitably examined. The general concept of ethnic and geographic variations being reflected in the body as variations in size, shape, etc. can be checked for in the case of skeleton also. This article is formed out of a term paper study submitted by myself in 2016 to the Yenepoya University, Mangalore, Karnataka, as part of the postgraduate diploma course in Forensic Anthropology. The research was based on a question whether there is a significant difference between human skulls from North and South India. The aims/objectives were bi-fold: to analyse the difference in male and female skull from North Indian and South Indian regions from review of scholarly literature and to explore the possibility identification of individuals from cranial features unique to North and South India. MATERIALS AND METHODS The original articles available on this type of work were extensively reviewed to recognise any traits that differentiated the skulls with regard to their regional variation. RESULTS At the end of the scrutiny of such papers, a summary of the features that distinguished skulls as belonging to northern or southern parts of India was tried. The Indian cranial series, though varied widely in shape, the absence of any statistically significant difference between them made it unreliable to predict skull as male or female by morphometric estimation. The studies by different scholars did not propose for a uniform distinctiveness between north and south Indian skulls. CONCLUSION It was concluded that analysing a single specimen to be of a distinct geographic origin should be done more cautiously when compared to a setting of series analysis where variability might be there of course.

  19. A map of human genome variation from population-scale sequencing.

    Science.gov (United States)

    Abecasis, Gonçalo R; Altshuler, David; Auton, Adam; Brooks, Lisa D; Durbin, Richard M; Gibbs, Richard A; Hurles, Matt E; McVean, Gil A

    2010-10-28

    The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.

  20. Association of common genetic variants with human skin color variation in Indian populations.

    Science.gov (United States)

    Sarkar, Anujit; Nandineni, Madhusudan R

    2018-01-01

    Human skin color is one of the most conspicuously variable physical traits that has attracted the attention of physical anthropologists, social scientists and human geneticists. Although several studies have established the underlying genes and their variants affecting human skin color, they were mostly confined to Europeans and Africans and similar studies in Indian populations have been scanty. Studying the association between candidate genetic variants and skin color will help to validate previous findings and to better understand the molecular mechanism of skin color variation. In this study, 22 candidate SNPs from 12 genes were tested for association with skin color in 299 unrelated samples sourced from nine geographical locations in India. Our study establishes the association of 9 SNPs with the phenotype in Indian populations and could explain ∼31% of the variance in skin color. Haplotype analysis of chromosome 15 revealed a significant association of alleles G, A and C of SNPs rs1426654, rs11070627, and rs12913316, respectively, to the phenotype, and accounted for 17% of the variance. Latitude of the sampling location was also a significant factor, contributing to ∼19% of the variation observed in the samples. These observations support the findings that rs1426654 and rs4775730 located in SLC24A5, and rs11070627 and rs12913316 located in MYEF2 and CTXN2 genes respectively, are major contributors toward skin pigmentation and would aid in further unraveling the genotype-phenotype association in Indian populations. These findings can be utilized in forensic DNA applications for criminal investigations. © 2017 Wiley Periodicals, Inc.

  1. HLA DNA sequence variation among human populations: molecular signatures of demographic and selective events.

    Directory of Open Access Journals (Sweden)

    Stéphane Buhler

    2011-02-01

    Full Text Available Molecular differences between HLA alleles vary up to 57 nucleotides within the peptide binding coding region of human Major Histocompatibility Complex (MHC genes, but it is still unclear whether this variation results from a stochastic process or from selective constraints related to functional differences among HLA molecules. Although HLA alleles are generally treated as equidistant molecular units in population genetic studies, DNA sequence diversity among populations is also crucial to interpret the observed HLA polymorphism. In this study, we used a large dataset of 2,062 DNA sequences defined for the different HLA alleles to analyze nucleotide diversity of seven HLA genes in 23,500 individuals of about 200 populations spread worldwide. We first analyzed the HLA molecular structure and diversity of these populations in relation to geographic variation and we further investigated possible departures from selective neutrality through Tajima's tests and mismatch distributions. All results were compared to those obtained by classical approaches applied to HLA allele frequencies.Our study shows that the global patterns of HLA nucleotide diversity among populations are significantly correlated to geography, although in some specific cases the molecular information reveals unexpected genetic relationships. At all loci except HLA-DPB1, populations have accumulated a high proportion of very divergent alleles, suggesting an advantage of heterozygotes expressing molecularly distant HLA molecules (asymmetric overdominant selection model. However, both different intensities of selection and unequal levels of gene conversion may explain the heterogeneous mismatch distributions observed among the loci. Also, distinctive patterns of sequence divergence observed at the HLA-DPB1 locus suggest current neutrality but old selective pressures on this gene. We conclude that HLA DNA sequences advantageously complement HLA allele frequencies as a source of data used

  2. Size variation in early human mandibles and molars from Klasies River, South Africa: comparison with other middle and late Pleistocene assemblages and with modern humans.

    Science.gov (United States)

    Royer, Danielle F; Lockwood, Charles A; Scott, Jeremiah E; Grine, Frederick E

    2009-10-01

    Previous studies of the Middle Stone Age human remains from Klasies River have concluded that they exhibited more sexual dimorphism than extant populations, but these claims have not been assessed statistically. We evaluate these claims by comparing size variation in the best-represented elements at the site, namely the mandibular corpora and M(2)s, to that in samples from three recent human populations using resampling methods. We also examine size variation in these same elements from seven additional middle and late Pleistocene sites: Skhūl, Dolní Vestonice, Sima de los Huesos, Arago, Krapina, Shanidar, and Vindija. Our results demonstrate that size variation in the Klasies assemblage was greater than in recent humans, consistent with arguments that the Klasies people were more dimorphic than living humans. Variation in the Skhūl, Dolní Vestonice, and Sima de los Huesos mandibular samples is also higher than in the recent human samples, indicating that the Klasies sample was not unusual among middle and late Pleistocene hominins. In contrast, the Neandertal samples (Krapina, Shanidar, and Vindija) do not evince relatively high mandibular and molar variation, which may indicate that the level of dimorphism in Neandertals was similar to that observed in extant humans. These results suggest that the reduced levels of dimorphism in Neandertals and living humans may have developed independently, though larger fossil samples are needed to test this hypothesis.

  3. Mechanisms of Surface Antigenic Variation in the Human Pathogenic Fungus Pneumocystis jirovecii.

    Science.gov (United States)

    Schmid-Siegert, Emanuel; Richard, Sophie; Luraschi, Amanda; Mühlethaler, Konrad; Pagni, Marco; Hauser, Philippe M

    2017-11-07

    Microbial pathogens commonly escape the human immune system by varying surface proteins. We investigated the mechanisms used for that purpose by Pneumocystis jirovecii This uncultivable fungus is an obligate pulmonary pathogen that in immunocompromised individuals causes pneumonia, a major life-threatening infection. Long-read PacBio sequencing was used to assemble a core of subtelomeres of a single P. jirovecii strain from a bronchoalveolar lavage fluid specimen from a single patient. A total of 113 genes encoding surface proteins were identified, including 28 pseudogenes. These genes formed a subtelomeric gene superfamily, which included five families encoding adhesive glycosylphosphatidylinositol (GPI)-anchored glycoproteins and one family encoding excreted glycoproteins. Numerical analyses suggested that diversification of the glycoproteins relies on mosaic genes created by ectopic recombination and occurs only within each family. DNA motifs suggested that all genes are expressed independently, except those of the family encoding the most abundant surface glycoproteins, which are subject to mutually exclusive expression. PCR analyses showed that exchange of the expressed gene of the latter family occurs frequently, possibly favored by the location of the genes proximal to the telomere because this allows concomitant telomere exchange. Our observations suggest that (i) the P. jirovecii cell surface is made of a complex mixture of different surface proteins, with a majority of a single isoform of the most abundant glycoprotein, (ii) genetic mosaicism within each family ensures variation of the glycoproteins, and (iii) the strategy of the fungus consists of the continuous production of new subpopulations composed of cells that are antigenically different. IMPORTANCE Pneumocystis jirovecii is a fungus causing severe pneumonia in immunocompromised individuals. It is the second most frequent life-threatening invasive fungal infection. We have studied the mechanisms

  4. Variability in the efficacy of psychopharmaceuticals: contributions from pharmacogenomics, ethnopsychopharmacology, and psychological and psychiatric anthropologies.

    Science.gov (United States)

    Ninnemann, Kristi M

    2012-03-01

    Psychological and psychiatric anthropology have long questioned the universality of psychiatric diagnoses, bringing to light the fluidity of mental disorder, and recognizing that the experience and expression of psychopathology is influenced by complex and interacting genetic, environmental, and cultural factors. The majority of our discussions, however, have remained centered around the role of culture in shaping mental illness: drawing attention to subjective experiences of mental illness and culturally patterned modes of symptom presentation, and interrogating the cogency of universal diagnostic rubrics. Psychological and psychiatric anthropology have yet to robustly engage the broadly assumed universal validity of psychiatric medications and the ways in which they are prescribed and experienced. This article provides an introduction into the fields of pharmacogenomics and ethnopsychopharmacology, areas of inquiry seeking to understand the ways in which genetic variability occurring between, and within, large population groups influences individual ability to metabolize psychotropic medications. This piece further addresses the complex issue of psychopharmaceutical efficacy, stressing the ways in which, just as with psychopathology, medications and their outcomes are likewise influenced by the complex interactions of genes, environment, and culture. Lastly, ways in which anthropology can and should engage with the growing fields of pharmacogenomics and ethnopsychopharmacology are suggested.

  5. The Promise of Pharmacogenomics in Reducing Toxicity During Acute Lymphoblastic Leukemia Maintenance Treatment

    Directory of Open Access Journals (Sweden)

    Shoshana Rudin

    2017-04-01

    Full Text Available Pediatric acute lymphoblastic leukemia (ALL affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2–3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP and methotrexate (MTX, are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment. 6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase (TPMT, nudix hydrolase 15 (NUDT15, and potentially inosine triphosphatase (ITPA, which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1 and dihydrofolate reductase (DHFR. Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1 (SLC19A1 and thymidylate synthetase (TYMS, but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.

  6. Pharmacogenetics and pharmacogenomics in psoriasis treatment: current challenges and future prospects.

    Science.gov (United States)

    Sutherland, Alison; Power, Rebecca J; Rahman, Proton; O'Rielly, Darren D

    2016-08-01

    Topical, systemic, oral disease modifying, and biologic agents are part of the armamentarium to manage psoriatic disease. The choice of therapy depends upon disease severity, relevant co-morbidities and patient preference. There is great variability in patient response with these agents, and there is still no clear method of selecting the preferred therapeutic agent for efficacy or lack of adverse events. This article will review the pharmacogenetic and pharmacogenomic targets that are currently known with respect to psoriasis vulgaris, and the most frequent co-morbidity of psoriasis, psoriatic arthritis. Presently, no clinically actionable biomarker exists for any therapeutic agent used to treat psoriasis or psoriatic arthritis. The lack of validated outcome measures and conflicting results of open-label studies conducted may be attributed to a multitude of issues that confound discovery. Consequently, studies have been underpowered to identify genes or genetic variants worth translating to clinical practice. In order to achieve a pharmacogenetic/pharmacogenomic signature, improvements in study design of future investigations are required, including carefully designed prospective studies. It is imperative to combine known clinical, serological, and molecular markers with consistent outcomes and an adequate health economic evaluation before they can be adopted widely in clinical practice.

  7. Orion: Detecting regions of the human non-coding genome that are intolerant to variation using population genetics.

    Science.gov (United States)

    Gussow, Ayal B; Copeland, Brett R; Dhindsa, Ryan S; Wang, Quanli; Petrovski, Slavé; Majoros, William H; Allen, Andrew S; Goldstein, David B

    2017-01-01

    There is broad agreement that genetic mutations occurring outside of the protein-coding regions play a key role in human disease. Despite this consensus, we are not yet capable of discerning which portions of non-coding sequence are important in the context of human disease. Here, we present Orion, an approach that detects regions of the non-coding genome that are depleted of variation, suggesting that the regions are intolerant of mutations and subject to purifying selection in the human lineage. We show that Orion is highly correlated with known intolerant regions as well as regions that harbor putatively pathogenic variation. This approach provides a mechanism to identify pathogenic variation in the human non-coding genome and will have immediate utility in the diagnostic interpretation of patient genomes and in large case control studies using whole-genome sequences.

  8. Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.

    Science.gov (United States)

    Alvarez, Monica I; Glover, Luke C; Luo, Peter; Wang, Liuyang; Theusch, Elizabeth; Oehlers, Stefan H; Walton, Eric M; Tram, Trinh Thi Bich; Kuang, Yu-Lin; Rotter, Jerome I; McClean, Colleen M; Chinh, Nguyen Tran; Medina, Marisa W; Tobin, David M; Dunstan, Sarah J; Ko, Dennis C

    2017-09-12

    Risk, severity, and outcome of infection depend on the interplay of pathogen virulence and host susceptibility. Systematic identification of genetic susceptibility to infection is being undertaken through genome-wide association studies, but how to expeditiously move from genetic differences to functional mechanisms is unclear. Here, we use genetic association of molecular, cellular, and human disease traits and experimental validation to demonstrate that genetic variation affects expression of VAC14, a phosphoinositide-regulating protein, to influence susceptibility to Salmonella enterica serovar Typhi ( S Typhi) infection. Decreased VAC14 expression increased plasma membrane cholesterol, facilitating Salmonella docking and invasion. This increased susceptibility at the cellular level manifests as increased susceptibility to typhoid fever in a Vietnamese population. Furthermore, treating zebrafish with a cholesterol-lowering agent, ezetimibe, reduced susceptibility to S Typhi. Thus, coupling multiple genetic association studies with mechanistic dissection revealed how VAC14 regulates Salmonella invasion and typhoid fever susceptibility and may open doors to new prophylactic/therapeutic approaches.

  9. Variation in population exposure in China as a result of differing human activities

    Energy Technology Data Exchange (ETDEWEB)

    Pan, Z.Q. [China Atomic Energy Authority, Beijing (China). Bureau of Safety, Protection and Health; Guo, M.Q. [China Nuclear Industry Huaqing Company, Beijing (China)

    1995-08-01

    The necessity of studying the variations in radiation levels dispassionately is discussed. Human activities may increase, but can also decrease, radiation dose to the population. Travel by air may cause a rise in population collective dose by 3.6 x 10 man.Sv, and travel by ship, train and vehicle may lead to a drop of 5.36 x 10{sup 2} man.Sv. Dwellings of coal cinder brick may increase collective dose by 3.5 x 10{sup 3} man.Sv, and buildings of reinforced concrete may decrease collective dose by 3.7 x 10{sup 3} man.Sv. It is inadequate to study only those activities which may increase radiation levels. (author).

  10. Unleashing the power of human genetic variation knowledge: New Zealand stakeholder perspectives.

    Science.gov (United States)

    Gu, Yulong; Warren, James Roy; Day, Karen Jean

    2011-01-01

    This study aimed to characterize the challenges in using genetic information in health care and to identify opportunities for improvement. Taking a grounded theory approach, semistructured interviews were conducted with 48 participants to collect multiple stakeholder perspectives on genetic services in New Zealand. Three themes emerged from the data: (1) four service delivery models were identified in operation, including both those expected models involving genetic counselors and variations that do not route through the formal genetic service program; (2) multiple barriers to sharing and using genetic information were perceived, including technological, organizational, institutional, legal, ethical, and social issues; and (3) impediments to wider use of genetic testing technology, including variable understanding of genetic test utilities among clinicians and the limited capacity of clinical genetic services. Targeting these problems, information technologies and knowledge management tools have the potential to support key tasks in genetic services delivery, improve knowledge processes, and enhance knowledge networks. Because of the effect of issues in genetic information and knowledge management, the potential of human genetic variation knowledge to enhance health care delivery has been put on a "leash."

  11. Genetic variations in the DNA replication origins of human papillomavirus family correlate with their oncogenic potential.

    Science.gov (United States)

    Yilmaz, Gulden; Biswas-Fiss, Esther E; Biswas, Subhasis B

    2018-04-01

    Human papillomaviruses (HPVs) encompass a large family of viruses that range from benign to highly carcinogenic. The crucial differences between benign and carcinogenic types of HPV remain unknown, except that the two HPV types differ in the frequency of DNA replication. We have systematically analyzed the mechanism of HPV DNA replication initiation in low-risk and high-risk HPVs. Our results demonstrate that HPV-encoded E2 initiator protein and its four binding sites in the replication origin play pivotal roles in determining the destiny of the HPV-infected cell. We have identified strain-specific single nucleotide variations in E2 binding sites found only in the high-risk HPVs. We have demonstrated that these variations result in attenuated formation of the E2-DNA complex. E2 binding to these sites is linked to the activation of the DNA replication origin as well as initiation of DNA replication. Both electrophoretic mobility shift assay and atomic force microscopy studies demonstrated that binding of E2 from either low- or high-risk HPVs with variant binding sequences lacked multimeric E2-DNA complex formation in vitro. These results provided a molecular basis of differential DNA replication in the two types of HPVs and pointed to a correlation with the development of cancer. Copyright © 2017. Published by Elsevier B.V.

  12. Apparent Transition in the Human Height Distribution Caused by Age-Dependent Variation during Puberty Period

    Science.gov (United States)

    Iwata, Takaki; Yamazaki, Yoshihiro; Kuninaka, Hiroto

    2013-08-01

    In this study, we examine the validity of the transition of the human height distribution from the log-normal distribution to the normal distribution during puberty, as suggested in an earlier study [Kuninaka et al.: J. Phys. Soc. Jpn. 78 (2009) 125001]. Our data analysis reveals that, in late puberty, the variation in height decreases as children grow. Thus, the classification of a height dataset by age at this stage leads us to analyze a mixture of distributions with larger means and smaller variations. This mixture distribution has a negative skewness and is consequently closer to the normal distribution than to the log-normal distribution. The opposite case occurs in early puberty and the mixture distribution is positively skewed, which resembles the log-normal distribution rather than the normal distribution. Thus, this scenario mimics the transition during puberty. Additionally, our scenario is realized through a numerical simulation based on a statistical model. The present study does not support the transition suggested by the earlier study.

  13. Common Variation in the DOPA Decarboxylase (DDC) Gene and Human Striatal DDC Activity In Vivo.

    Science.gov (United States)

    Eisenberg, Daniel P; Kohn, Philip D; Hegarty, Catherine E; Ianni, Angela M; Kolachana, Bhaskar; Gregory, Michael D; Masdeu, Joseph C; Berman, Karen F

    2016-08-01

    The synthesis of multiple amine neurotransmitters, such as dopamine, norepinephrine, serotonin, and trace amines, relies in part on DOPA decarboxylase (DDC, AADC), an enzyme that is required for normative neural operations. Because rare, loss-of-function mutations in the DDC gene result in severe enzymatic deficiency and devastating autonomic, motor, and cognitive impairment, DDC common genetic polymorphisms have been proposed as a source of more moderate, but clinically important, alterations in DDC function that may contribute to risk, course, or treatment response in complex, heritable neuropsychiatric illnesses. However, a direct link between common genetic variation in DDC and DDC activity in the living human brain has never been established. We therefore tested for this association by conducting extensive genotyping across the DDC gene in a large cohort of 120 healthy individuals, for whom DDC activity was then quantified with [(18)F]-FDOPA positron emission tomography (PET). The specific uptake constant, Ki, a measure of DDC activity, was estimated for striatal regions of interest and found to be predicted by one of five tested haplotypes, particularly in the ventral striatum. These data provide evidence for cis-acting, functional common polymorphisms in the DDC gene and support future work to determine whether such variation might meaningfully contribute to DDC-mediated neural processes relevant to neuropsychiatric illness and treatment.

  14. Analysis of Long-Term Temperature Variations in the Human Body.

    Science.gov (United States)

    Dakappa, Pradeepa Hoskeri; Mahabala, Chakrapani

    2015-01-01

    Body temperature is a continuous physiological variable. In normal healthy adults, oral temperature is estimated to vary between 36.1°C and 37.2°C. Fever is a complex host response to many external and internal agents and is a potential contributor to many clinical conditions. Despite being one of the foremost vital signs, temperature and its analysis and variations during many pathological conditions has yet to be examined in detail using mathematical techniques. Classical fever patterns based on recordings obtained every 8-12 h have been developed. However, such patterns do not provide meaningful information in diagnosing diseases. Because fever is a host response, it is likely that there could be a unique response to specific etiologies. Continuous long-term temperature monitoring and pattern analysis using specific analytical methods developed in engineering and physics could aid in revealing unique fever responses of hosts and in different clinical conditions. Furthermore, such analysis can potentially be used as a novel diagnostic tool and to study the effect of pharmaceutical agents and other therapeutic protocols. Thus, the goal of our article is to present a comprehensive review of the recent relevant literature and analyze the current state of research regarding temperature variations in the human body.

  15. Novel association strategy with copy number variation for identifying new risk Loci of human diseases.

    Directory of Open Access Journals (Sweden)

    Xianfeng Chen

    2010-08-01

    Full Text Available Copy number variations (CNV are important causal genetic variations for human disease; however, the lack of a statistical model has impeded the systematic testing of CNVs associated with disease in large-scale cohort.Here, we developed a novel integrated strategy to test CNV-association in genome-wide case-control studies. We converted the single-nucleotide polymorphism (SNP signal to copy number states using a well-trained hidden Markov model. We mapped the susceptible CNV-loci through SNP site-specific testing to cope with the physiological complexity of CNVs. We also ensured the credibility of the associated CNVs through further window-based CNV-pattern clustering. Genome-wide data with seven diseases were used to test our strategy and, in total, we identified 36 new susceptible loci that are associated with CNVs for the seven diseases: 5 with bipolar disorder, 4 with coronary artery disease, 1 with Crohn's disease, 7 with hypertension, 9 with rheumatoid arthritis, 7 with type 1 diabetes and 3 with type 2 diabetes. Fifteen of these identified loci were validated through genotype-association and physiological function from previous studies, which provide further confidence for our results. Notably, the genes associated with bipolar disorder converged in the phosphoinositide/calcium signaling, a well-known affected pathway in bipolar disorder, which further supports that CNVs have impact on bipolar disorder.Our results demonstrated the effectiveness and robustness of our CNV-association analysis and provided an alternative avenue for discovering new associated loci of human diseases.

  16. Striatal dopamine release and genetic variation of the serotonin 2C receptor in humans.

    Science.gov (United States)

    Mickey, Brian J; Sanford, Benjamin J; Love, Tiffany M; Shen, Pei-Hong; Hodgkinson, Colin A; Stohler, Christian S; Goldman, David; Zubieta, Jon-Kar

    2012-07-04

    Mesoaccumbal and nigrostriatal projections are sensitive to stress, and heightened stress sensitivity is thought to confer risk for neuropsychiatric disorders. Serotonin 2C (5-HT(2C)) receptors mediate the inhibitory effects of serotonin on dopaminergic circuitry in experimental animals, and preclinical findings have implicated 5-HT(2C) receptors in motivated behaviors and psychotropic drug mechanisms. In humans, a common missense single-nucleotide change (rs6318, Cys23Ser) in the 5-HT(2C) receptor gene (HTR2C) has been associated with altered activity in vitro and with clinical mood disorders. We hypothesized that dopaminergic circuitry would be more sensitive to stress in humans carrying the Ser23 variant. To test this hypothesis, we studied 54 healthy humans using positron emission tomography and the displaceable D(2)/D(3) receptor radiotracer [(11)C]raclopride. Binding potential (BP(ND)) was quantified before and after a standardized stress challenge consisting of 20 min of moderate deep muscular pain, and reduction in BP(ND) served as an index of dopamine release. The Cys23Ser variant was genotyped on a custom array, and ancestry informative markers were used to control for population stratification. We found greater dopamine release in the nucleus accumbens, caudate nucleus, and putamen among Ser23 carriers, after controlling for sex, age, and ancestry. Genotype accounted for 12% of the variance in dopamine release in the nucleus accumbens. There was no association of Cys23Ser with baseline BP(ND). These findings indicate that a putatively functional HTR2C variant (Ser23) is associated with greater striatal dopamine release during pain in healthy humans. Mesoaccumbal stress sensitivity may mediate the effects of HTR2C variation on risk of neuropsychiatric disorders.

  17. Rethinking the starch digestion hypothesis for AMY1 copy number variation in humans.

    Science.gov (United States)

    Fernández, Catalina I; Wiley, Andrea S

    2017-08-01

    Alpha-amylase exists across taxonomic kingdoms with a deep evolutionary history of gene duplications that resulted in several α-amylase paralogs. Copy number variation (CNV) in the salivary α-amylase gene (AMY1) exists in many taxa, but among primates, humans appear to have higher average AMY1 copies than nonhuman primates. Additionally, AMY1 CNV in humans has been associated with starch content of diets, and one known function of α-amylase is its involvement in starch digestion. Thus high AMY1 CNV is considered to result from selection favoring more efficient starch digestion in the Homo lineage. Here, we present several lines of evidence that challenge the hypothesis that increased AMY1 CNV is an adaptation to starch consumption. We observe that α- amylase plays a very limited role in starch digestion, with additional steps required for starch digestion and glucose metabolism. Specifically, we note that α-amylase hydrolysis only produces a minute amount of free glucose with further enzymatic digestion and glucose absorption being rate-limiting steps for glucose availability. Indeed α-amylase is nonessential for starch digestion since sucrase-isomaltase and maltase-glucoamylase can hydrolyze whole starch granules while releasing glucose. While higher AMY1 CN and CNV among human populations may result from natural selection, existing evidence does not support starch digestion as the major selective force. We report that in humans α-amylase is expressed in several other tissues where it may have potential roles of evolutionary significance. © 2017 Wiley Periodicals, Inc.

  18. Pharmacogenomic study using bio- and nanobioelectrochemistry: Drug-DNA interaction.

    Science.gov (United States)

    Hasanzadeh, Mohammad; Shadjou, Nasrin

    2016-04-01

    Small molecules that bind genomic DNA have proven that they can be effective anticancer, antibiotic and antiviral therapeutic agents that affect the well-being of millions of people worldwide. Drug-DNA interaction affects DNA replication and division; causes strand breaks, and mutations. Therefore, the investigation of drug-DNA interaction is needed to understand the mechanism of drug action as well as in designing DNA-targeted drugs. On the other hand, the interaction between DNA and drugs can cause chemical and conformational modifications and, thus, variation of the electrochemical properties of nucleobases. For this purpose, electrochemical methods/biosensors can be used toward detection of drug-DNA interactions. The present paper reviews the drug-DNA interactions, their types and applications of electrochemical techniques used to study interactions between DNA and drugs or small ligand molecules that are potentially of pharmaceutical interest. The results are used to determine drug binding sites and sequence preference, as well as conformational changes due to drug-DNA interactions. Also, the intention of this review is to give an overview of the present state of the drug-DNA interaction cognition. The applications of electrochemical techniques for investigation of drug-DNA interaction were reviewed and we have discussed the type of qualitative or quantitative information that can be obtained from the use of each technique. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Application of Method of Variation to Analyze and Predict Human Induced Modifications of Water Resource Systems

    Science.gov (United States)

    Dessu, S. B.; Melesse, A. M.; Mahadev, B.; McClain, M.

    2010-12-01

    Water resource systems have often used gravitational surface and subsurface flows because of their practicality in hydrological modeling and prediction. Activities such as inter/intra-basin water transfer, the use of small pumps and the construction of micro-ponds challenge the tradition of natural rivers as water resource management unit. On the contrary, precipitation is barely affected by topography and plot harvesting in wet regions can be more manageable than diverting from rivers. Therefore, it is indicative to attend to systems where precipitation drives the dynamics while the internal mechanics constitutes spectrum of human activity and decision in a network of plots. The trade-in volume and path of harvested precipitation depends on water balance, energy balance and the kinematics of supply and demand. Method of variation can be used to understand and predict the implication of local excess precipitation harvest and exchange on the natural water system. A system model was developed using the variational form of Euler-Bernoulli’s equation for the Kenyan Mara River basin. Satellite derived digital elevation models, precipitation estimates, and surface properties such as fractional impervious surface area, are used to estimate the available water resource. Four management conditions are imposed in the model: gravitational flow, open water extraction and high water use investment at upstream and downstream respectively. According to the model, the first management maintains the basin status quo while the open source management could induce externality. The high water market at the upstream in the third management offers more than 50% of the basin-wide total revenue to the upper third section of the basin thus may promote more harvesting. The open source and upstream exploitation suggest potential drop of water availability to downstream. The model exposed the latent potential of economic gradient to reconfigure the flow network along the direction where the

  20. Within-Host Variations of Human Papillomavirus Reveal APOBEC-Signature Mutagenesis in the Viral Genome.

    Science.gov (United States)

    Hirose, Yusuke; Onuki, Mamiko; Tenjimbayashi, Yuri; Mori, Seiichiro; Ishii, Yoshiyuki; Takeuchi, Takamasa; Tasaka, Nobutaka; Satoh, Toyomi; Morisada, Tohru; Iwata, Takashi; Miyamoto, Shingo; Matsumoto, Koji; Sekizawa, Akihiko; Kukimoto, Iwao

    2018-03-28

    Persistent infection with oncogenic human papillomaviruses (HPVs) causes cervical cancer, accompanied with the accumulation of somatic mutations into the host genome. There are concomitant genetic changes in the HPV genome during viral infection; however, their relevance to cervical carcinogenesis is poorly understood. Here we explored within-host genetic diversity of HPV by performing deep sequencing analyses of viral whole-genome sequences in clinical specimens. The whole genomes of HPV types 16, 52 and 58 were amplified by type-specific PCR from total cellular DNA of cervical exfoliated cells collected from patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC), and were deep-sequenced. After constructing a reference vial genome sequence for each specimen, nucleotide positions showing changes with > 0.5% frequencies compared to the reference sequence were determined for individual samples. In total, 1,052 positions of nucleotide variations were detected in HPV genomes from 151 samples (CIN1, n = 56; CIN2/3, n = 68; ICC, n = 27), with varying numbers per sample. Overall, C-to-T and C-to-A substitutions were the dominant changes observed across all histological grades. While C-to-T transitions were predominantly detected in CIN1, their prevalence was decreased in CIN2/3 and fell below that of C-to-A transversions in ICC. Analysis of the tri-nucleotides context encompassing substituted bases revealed that Tp C pN, a preferred target sequence for cellular APOBEC cytosine deaminases, was a primary site for C-to-T substitutions in the HPV genome. These results strongly imply that the APOBEC proteins are drivers of HPV genome mutation, particularly in CIN1 lesions. IMPORTANCE HPVs exhibit surprisingly high levels of genetic diversity, including a large repertoire of minor genomic variants in each viral genotype. Here, by conducting deep sequencing analyses, we show for the first time a comprehensive snapshot of the "within

  1. Stochastic variation in telomere shortening rate causes heterogeneity of human fibroblast replicative life span.

    Science.gov (United States)

    Martin-Ruiz, Carmen; Saretzki, Gabriele; Petrie, Joanne; Ladhoff, Juliane; Jeyapalan, Jessie; Wei, Wenyi; Sedivy, John; von Zglinicki, Thomas

    2004-04-23

    The replicative life span of human fibroblasts is heterogeneous, with a fraction of cells senescing at every population doubling. To find out whether this heterogeneity is due to premature senescence, i.e. driven by a nontelomeric mechanism, fibroblasts with a senescent phenotype were isolated from growing cultures and clones by flow cytometry. These senescent cells had shorter telomeres than their cycling counterparts at all population doubling levels and both in mass cultures and in individual subclones, indicating heterogeneity in the rate of telomere shortening. Ectopic expression of telomerase stabilized telomere length in the majority of cells and rescued them from early senescence, suggesting a causal role of telomere shortening. Under standard cell culture conditions, there was a minor fraction of cells that showed a senescent phenotype and short telomeres despite active telomerase. This fraction increased under chronic mild oxidative stress, which is known to accelerate telomere shortening. It is possible that even high telomerase activity cannot fully compensate for telomere shortening in all cells. The data show that heterogeneity of the human fibroblast replicative life span can be caused by significant stochastic cell-to-cell variation in telomere shortening.

  2. Distinct Contributions of Replication and Transcription to Mutation Rate Variation of Human Genomes

    KAUST Repository

    Cui, Peng; Ding, Feng; Lin, Qiang; Zhang, Lingfang; Li, Ang; Zhang, Zhang; Hu, Songnian; Yu, Jun

    2012-01-01

    Here, we evaluate the contribution of two major biological processes—DNA replication and transcription—to mutation rate variation in human genomes. Based on analysis of the public human tissue transcriptomics data, high-resolution replicating map of Hela cells and dbSNP data, we present significant correlations between expression breadth, replication time in local regions and SNP density. SNP density of tissue-specific (TS) genes is significantly higher than that of housekeeping (HK) genes. TS genes tend to locate in late-replicating genomic regions and genes in such regions have a higher SNP density compared to those in early-replication regions. In addition, SNP density is found to be positively correlated with expression level among HK genes. We conclude that the process of DNA replication generates stronger mutational pressure than transcription-associated biological processes do, resulting in an increase of mutation rate in TS genes while having weaker effects on HK genes. In contrast, transcription-associated processes are mainly responsible for the accumulation of mutations in highly-expressed HK genes.

  3. Human Y chromosome copy number variation in the next generation sequencing era and beyond.

    Science.gov (United States)

    Massaia, Andrea; Xue, Yali

    2017-05-01

    The human Y chromosome provides a fertile ground for structural rearrangements owing to its haploidy and high content of repeated sequences. The methodologies used for copy number variation (CNV) studies have developed over the years. Low-throughput techniques based on direct observation of rearrangements were developed early on, and are still used, often to complement array-based or sequencing approaches which have limited power in regions with high repeat content and specifically in the presence of long, identical repeats, such as those found in human sex chromosomes. Some specific rearrangements have been investigated for decades; because of their effects on fertility, or their outstanding evolutionary features, the interest in these has not diminished. However, following the flourishing of large-scale genomics, several studies have investigated CNVs across the whole chromosome. These studies sometimes employ data generated within large genomic projects such as the DDD study or the 1000 Genomes Project, and often survey large samples of healthy individuals without any prior selection. Novel technologies based on sequencing long molecules and combinations of technologies, promise to stimulate the study of Y-CNVs in the immediate future.

  4. Distinct Contributions of Replication and Transcription to Mutation Rate Variation of Human Genomes

    KAUST Repository

    Cui, Peng

    2012-03-23

    Here, we evaluate the contribution of two major biological processes—DNA replication and transcription—to mutation rate variation in human genomes. Based on analysis of the public human tissue transcriptomics data, high-resolution replicating map of Hela cells and dbSNP data, we present significant correlations between expression breadth, replication time in local regions and SNP density. SNP density of tissue-specific (TS) genes is significantly higher than that of housekeeping (HK) genes. TS genes tend to locate in late-replicating genomic regions and genes in such regions have a higher SNP density compared to those in early-replication regions. In addition, SNP density is found to be positively correlated with expression level among HK genes. We conclude that the process of DNA replication generates stronger mutational pressure than transcription-associated biological processes do, resulting in an increase of mutation rate in TS genes while having weaker effects on HK genes. In contrast, transcription-associated processes are mainly responsible for the accumulation of mutations in highly-expressed HK genes.

  5. Inter- and Intraspecific Variations in the Pectoral Muscles of Common Chimpanzees (Pan troglodytes), Bonobos (Pan paniscus), and Humans (Homo sapiens)

    OpenAIRE

    Potau, J. M.; Arias-Martorell, J.; Bello-Hellegouarch, G.; Casado, A.; Pastor, J. F.; de Paz, F.; Diogo, R.

    2018-01-01

    We have analyzed anatomic variations in the pectoralis major and pectoralis minor muscles of common chimpanzees (Pan\\ud troglodytes) and bonobos(Pan paniscus) and compared them to anatomic variations in these muscles in humans(Homo sapiens). We\\ud have macroscopically dissected these muscles in six adult Pan troglodytes, five Pan paniscus of ages ranging from fetus to adult, and\\ud five adult Homo sapiens. Although Pan troglodytes are thought to lack a separate pectoralis abdominis muscle, we...

  6. Human-Induced Climate Variations Linked to Urbanization: From Observations to Modeling

    Science.gov (United States)

    Shepherd, J. Marshall; Jin, Menglin

    2004-01-01

    The goal of this session is to bring together scientists from interdisciplinary backgrounds to discuss the data, scientific approaches and recent results focusing on the impact of urbanization on the climate. The discussion will highlight current observational and modeling capabilities being employed for investigating the urban environment and its linkage to the change in the Earth's climate system. The goal of the session is to identify our current stand and the future direction on the topic. Urbanization is one of the extreme cases of land use change. Most of population of the world has moved to urban areas. By 1995, more than 70% of population of North America and Europe were living in cities. By 2025, the United Nations estimates that 60% of the worlds population will live in cities. Although currently only 1.2% of the land is urban, better understanding of how the atmosphere-ocean-land-biosphere components interact as a coupled system and the influence of human activities on this system is critical. Our understanding of urbanization effect is incomplete, partly because human activities induce new changes on climate in addition to the original natural variations, and partly because previously few data available for study urban effect globally. Urban construction changes surface roughness, albedo, heat capacity and vegetation coverage. Traffic and industry increase atmospheric aerosol. It is suggested that urbanization may modify rainfall processes through aerosol-cloud interactions or dynamic feedbacks. Because urbanization effect on climate is determined by many factors including land cover, the city's microscale features, population density, and human lifestyle patterns, it is necessary to study urban areas over globe.

  7. Genetic variation of the RASGRF1 regulatory region affects human hippocampus-dependent memory

    Directory of Open Access Journals (Sweden)

    Adriana eBarman

    2014-04-01

    Full Text Available The guanine nucleotide exchange factor RASGRF1 is an important regulator of intracellular signaling and neural plasticity in the brain. RASGRF1-deficient mice exhibit a complex phenotype with learning deficits and ocular abnormalities. Also in humans, a genome-wide association study has identified the single nucleotide polymorphism (SNP rs8027411 in the putative transcription regulatory region of RASGRF1 as a risk variant of myopia. Here we aimed to assess whether, in line with the RASGRF1 knockout mouse phenotype, rs8027411 might also be associated with human memory function. We performed computer-based neuropsychological learning experiments in two independent cohorts of young, healthy participants. Tests included the Verbal Learning and Memory Test (VLMT and the logical memory section of the Wechsler Memory Scale (WMS. Two sub-cohorts additionally participated in functional magnetic resonance imaging (fMRI studies of hippocampus function. 119 participants performed a novelty encoding task that had previously been shown to engage the hippocampus, and 63 subjects participated in a reward-related memory encoding study. RASGRF1 rs8027411 genotype was indeed associated with memory performance in an allele dosage-dependent manner, with carriers of the T allele (i.e. the myopia risk allele showing better memory performance in the early encoding phase of the VLMT and in the recall phase of the WMS logical memory section. In fMRI, T allele carriers exhibited increased hippocampal activation during presentation of novel images and during encoding of pictures associated with monetary reward. Taken together, our results provide evidence for a role of the RASGRF1 gene locus in hippocampus-dependent memory and, along with the previous association with myopia, point towards pleitropic effects of RASGRF1 genetic variations on complex neural function in humans.

  8. An Analytic Equation Partitioning Climate Variation and Human Impacts on River Sediment Load

    Science.gov (United States)

    Zhang, J.; Gao, G.; Fu, B.

    2017-12-01

    Spatial or temporal patterns and process-based equations could co-exist in hydrologic model. Yet, existing approaches quantifying the impacts of those variables on river sediment load (RSL) changes are found to be severely limited, and new ways to evaluate the contribution of these variables are thus needed. Actually, the Newtonian modeling is hardly achievable for this process due to the limitation of both observations and knowledge of mechanisms, whereas laws based on the Darwinian approach could provide one component of a developed hydrologic model. Since that streamflow is the carrier of suspended sediment, sediment load changes are documented in changes of streamflow and suspended sediment concentration (SSC) - water discharge relationships. Consequently, an analytic equation for river sediment load changes are proposed to explicitly quantify the relative contributions of climate variation and direct human impacts on river sediment load changes. Initially, the sediment rating curve, which is of great significance in RSL changes analysis, was decomposed as probability distribution of streamflow and the corresponding SSC - water discharge relationships at equally spaced discharge classes. Furthermore, a proposed segmentation algorithm based on the fractal theory was used to decompose RSL changes attributed to these two portions. Additionally, the water balance framework was utilized and the corresponding elastic parameters were calculated. Finally, changes in climate variables (i.e. precipitation and potential evapotranspiration) and direct human impacts on river sediment load could be figured out. By data simulation, the efficiency of the segmentation algorithm was verified. The analytic equation provides a superior Darwinian approach partitioning climate and human impacts on RSL changes, as only data series of precipitation, potential evapotranspiration and SSC - water discharge are demanded.

  9. Variations in Glycogen Synthesis in Human Pluripotent Stem Cells with Altered Pluripotent States

    Science.gov (United States)

    Chen, Richard J.; Zhang, Guofeng; Garfield, Susan H.; Shi, Yi-Jun; Chen, Kevin G.; Robey, Pamela G.; Leapman, Richard D.

    2015-01-01

    Human pluripotent stem cells (hPSCs) represent very promising resources for cell-based regenerative medicine. It is essential to determine the biological implications of some fundamental physiological processes (such as glycogen metabolism) in these stem cells. In this report, we employ electron, immunofluorescence microscopy, and biochemical methods to study glycogen synthesis in hPSCs. Our results indicate that there is a high level of glycogen synthesis (0.28 to 0.62 μg/μg proteins) in undifferentiated human embryonic stem cells (hESCs) compared with the glycogen levels (0 to 0.25 μg/μg proteins) reported in human cancer cell lines. Moreover, we found that glycogen synthesis was regulated by bone morphogenetic protein 4 (BMP-4) and the glycogen synthase kinase 3 (GSK-3) pathway. Our observation of glycogen bodies and sustained expression of the pluripotent factor Oct-4 mediated by the potent GSK-3 inhibitor CHIR-99021 reveals an altered pluripotent state in hPSC culture. We further confirmed glycogen variations under different naïve pluripotent cell growth conditions based on the addition of the GSK-3 inhibitor BIO. Our data suggest that primed hPSCs treated with naïve growth conditions acquire altered pluripotent states, similar to those naïve-like hPSCs, with increased glycogen synthesis. Furthermore, we found that suppression of phosphorylated glycogen synthase was an underlying mechanism responsible for altered glycogen synthesis. Thus, our novel findings regarding the dynamic changes in glycogen metabolism provide new markers to assess the energetic and various pluripotent states in hPSCs. The components of glycogen metabolic pathways offer new assays to delineate previously unrecognized properties of hPSCs under different growth conditions. PMID:26565809

  10. Evaluation of the interindividual human variation in bioactivation of methyleugenol using physiologically based kinetic modeling and Monte Carlo simulations

    Energy Technology Data Exchange (ETDEWEB)

    Al-Subeihi, Ala' A.A., E-mail: subeihi@yahoo.com [Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen (Netherlands); BEN-HAYYAN-Aqaba International Laboratories, Aqaba Special Economic Zone Authority (ASEZA), P. O. Box 2565, Aqaba 77110 (Jordan); Alhusainy, Wasma; Kiwamoto, Reiko; Spenkelink, Bert [Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen (Netherlands); Bladeren, Peter J. van [Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen (Netherlands); Nestec S.A., Avenue Nestlé 55, 1800 Vevey (Switzerland); Rietjens, Ivonne M.C.M.; Punt, Ans [Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen (Netherlands)

    2015-03-01

    The present study aims at predicting the level of formation of the ultimate carcinogenic metabolite of methyleugenol, 1′-sulfooxymethyleugenol, in the human population by taking variability in key bioactivation and detoxification reactions into account using Monte Carlo simulations. Depending on the metabolic route, variation was simulated based on kinetic constants obtained from incubations with a range of individual human liver fractions or by combining kinetic constants obtained for specific isoenzymes with literature reported human variation in the activity of these enzymes. The results of the study indicate that formation of 1′-sulfooxymethyleugenol is predominantly affected by variation in i) P450 1A2-catalyzed bioactivation of methyleugenol to 1′-hydroxymethyleugenol, ii) P450 2B6-catalyzed epoxidation of methyleugenol, iii) the apparent kinetic constants for oxidation of 1′-hydroxymethyleugenol, and iv) the apparent kinetic constants for sulfation of 1′-hydroxymethyleugenol. Based on the Monte Carlo simulations a so-called chemical-specific adjustment factor (CSAF) for intraspecies variation could be derived by dividing different percentiles by the 50th percentile of the predicted population distribution for 1′-sulfooxymethyleugenol formation. The obtained CSAF value at the 90th percentile was 3.2, indicating that the default uncertainty factor of 3.16 for human variability in kinetics may adequately cover the variation within 90% of the population. Covering 99% of the population requires a larger uncertainty factor of 6.4. In conclusion, the results showed that adequate predictions on interindividual human variation can be made with Monte Carlo-based PBK modeling. For methyleugenol this variation was observed to be in line with the default variation generally assumed in risk assessment. - Highlights: • Interindividual human differences in methyleugenol bioactivation were simulated. • This was done using in vitro incubations, PBK modeling

  11. Evaluation of the interindividual human variation in bioactivation of methyleugenol using physiologically based kinetic modeling and Monte Carlo simulations

    International Nuclear Information System (INIS)

    Al-Subeihi, Ala' A.A.; Alhusainy, Wasma; Kiwamoto, Reiko; Spenkelink, Bert; Bladeren, Peter J. van; Rietjens, Ivonne M.C.M.; Punt, Ans

    2015-01-01

    The present study aims at predicting the level of formation of the ultimate carcinogenic metabolite of methyleugenol, 1′-sulfooxymethyleugenol, in the human population by taking variability in key bioactivation and detoxification reactions into account using Monte Carlo simulations. Depending on the metabolic route, variation was simulated based on kinetic constants obtained from incubations with a range of individual human liver fractions or by combining kinetic constants obtained for specific isoenzymes with literature reported human variation in the activity of these enzymes. The results of the study indicate that formation of 1′-sulfooxymethyleugenol is predominantly affected by variation in i) P450 1A2-catalyzed bioactivation of methyleugenol to 1′-hydroxymethyleugenol, ii) P450 2B6-catalyzed epoxidation of methyleugenol, iii) the apparent kinetic constants for oxidation of 1′-hydroxymethyleugenol, and iv) the apparent kinetic constants for sulfation of 1′-hydroxymethyleugenol. Based on the Monte Carlo simulations a so-called chemical-specific adjustment factor (CSAF) for intraspecies variation could be derived by dividing different percentiles by the 50th percentile of the predicted population distribution for 1′-sulfooxymethyleugenol formation. The obtained CSAF value at the 90th percentile was 3.2, indicating that the default uncertainty factor of 3.16 for human variability in kinetics may adequately cover the variation within 90% of the population. Covering 99% of the population requires a larger uncertainty factor of 6.4. In conclusion, the results showed that adequate predictions on interindividual human variation can be made with Monte Carlo-based PBK modeling. For methyleugenol this variation was observed to be in line with the default variation generally assumed in risk assessment. - Highlights: • Interindividual human differences in methyleugenol bioactivation were simulated. • This was done using in vitro incubations, PBK modeling

  12. Quantitative variation in obesity-related traits and insulin precursors linked to the OB gene region on human chromosome 7

    Energy Technology Data Exchange (ETDEWEB)

    Duggirala, R.; Stern, M.P.; Reinhart, L.J. [Univ. of Texas Health Science Center, San Antonio, TX (United States)] [and others

    1996-09-01

    Despite the evidence that human obesity has strong genetic determinants, efforts at identifying specific genes that influence human obesity have largely been unsuccessful. Using the sibship data obtained from 32 low-income Mexican American pedigrees ascertained on a type II diabetic proband and a multipoint variance-components method, we tested for linkage between various obesity-related traits plus associated metabolic traits and 15 markers on human chromosome 7. We found evidence for linkage between markers in the OB gene region and various traits, as follows: D7S514 and extremity skinfolds (LOD = 3.1), human carboxypeptidase A1 (HCPA1) and 32,33-split proinsulin level (LOD = 4.2), and HCPA1 and proinsulin level (LOD = 3.2). A putative susceptibility locus linked to the marker D7S514 explained 56% of the total phenotypic variation in extremity skinfolds. Variation at the HCPA1 locus explained 64% of phenotypic variation in proinsulin level and {approximately}73% of phenotypic variation in split proinsulin concentration, respectively. Weaker evidence for linkage to several other obesity-related traits (e.g., waist circumference, body-mass index, fat mass by bioimpedance, etc.) was observed for a genetic location, which is {approximately}15 cM telomeric to OB. In conclusion, our study reveals that the OB region plays a significant role in determining the phenotypic variation of both insulin precursors and obesity-related traits, at least in Mexican Americans. 66 refs., 3 figs., 4 tabs.

  13. Genetic polymorphisms of pharmacogenomic VIP variants in the Yi population from China.

    Science.gov (United States)

    Yan, Mengdan; Li, Dianzhen; Zhao, Guige; Li, Jing; Niu, Fanglin; Li, Bin; Chen, Peng; Jin, Tianbo

    2018-03-30

    Drug response and target therapeutic dosage are different among individuals. The variability is largely genetically determined. With the development of pharmacogenetics and pharmacogenomics, widespread research have provided us a wealth of information on drug-related genetic polymorphisms, and the very important pharmacogenetic (VIP) variants have been identified for the major populations around the world whereas less is known regarding minorities in China, including the Yi ethnic group. Our research aims to screen the potential genetic variants in Yi population on pharmacogenomics and provide a theoretical basis for future medication guidance. In the present study, 80 VIP variants (selected from the PharmGKB database) were genotyped in 100 unrelated and healthy Yi adults recruited for our research. Through statistical analysis, we made a comparison between the Yi and other 11 populations listed in the HapMap database for significant SNPs detection. Two specific SNPs were subsequently enrolled in an observation on global allele distribution with the frequencies downloaded from ALlele FREquency Database. Moreover, F-statistics (Fst), genetic structure and phylogenetic tree analyses were conducted for determination of genetic similarity between the 12 ethnic groups. Using the χ2 tests, rs1128503 (ABCB1), rs7294 (VKORC1), rs9934438 (VKORC1), rs1540339 (VDR) and rs689466 (PTGS2) were identified as the significantly different loci for further analysis. The global allele distribution revealed that the allele "A" of rs1540339 and rs9934438 were more frequent in Yi people, which was consistent with the most populations in East Asia. F-statistics (Fst), genetic structure and phylogenetic tree analyses demonstrated that the Yi and CHD shared a closest relationship on their genetic backgrounds. Additionally, Yi was considered similar to the Han people from Shaanxi province among the domestic ethnic populations in China. Our results demonstrated significant differences on

  14. Application of low background liquid scintillation counting method to pharmacy. Variation of endogenous 14C in human urine

    International Nuclear Information System (INIS)

    Horie, Masanobu; Yanagi, Mashiho; Baba, Shigeo; Kato, Yuka; Yoshimura, Tomoyuki

    2010-01-01

    The intra-day, inter-day and individual variations in endogenous 14 C radioactivity of human urine were studied by use of 5 mL urine. The endogenous 14 C radioactivity of human urine is relatively constant (approximately 1.5 dpm/mL urine). In order to eliminate the effect of endogenous 40 K it is of the greatest importance to count 14 C signal with the optimal window. Since these variations are relatively small, we can estimate correctly the net 14 C activity from the BG value of the same time zone of the day before dosing. (author)

  15. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.

    Directory of Open Access Journals (Sweden)

    Alexandra C Nica

    2011-02-01

    Full Text Available While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL, skin, and fat. The samples (156 LCL, 160 skin, 166 fat were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes. In addition, we apply factor analysis (FA to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes. The unique study design (Matched Co-Twin Analysis--MCTA permits immediate replication of eQTLs using co-twins (93%-98% and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20% have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.

  16. Diffusion tensor imaging of the human calf: Variation of inter- and intramuscle-specific diffusion parameters.

    Science.gov (United States)

    Schlaffke, Lara; Rehmann, Robert; Froeling, Martijn; Kley, Rudolf; Tegenthoff, Martin; Vorgerd, Matthias; Schmidt-Wilcke, Tobias

    2017-10-01

    To investigate to what extent inter- and intramuscular variations of diffusion parameters of human calf muscles can be explained by age, gender, muscle location, and body mass index (BMI) in a specific age group (20-35 years). Whole calf muscles of 18 healthy volunteers were evaluated. Magnetic resonance imaging (MRI) was performed using a 3T scanner and a 16-channel Torso XL coil. Diffusion-weighted images were acquired to perform fiber tractography and diffusion tensor imaging (DTI) analysis for each muscle of both legs. Fiber tractography was used to separate seven lower leg muscles. Associations between DTI parameters and confounds were evaluated. All muscles were additionally separated in seven identical segments along the z-axis to evaluate intramuscular differences in diffusion parameters. Fractional anisotropy (FA) and mean diffusivity (MD) were obtained for each muscle with low standard deviations (SDs) (SD FA : 0.01-0.02; SD MD : 0.07-0.14(10 -3 )). We found significant differences in FA values of the tibialis anterior muscle (AT) and extensor digitorum longus (EDL) muscles between men and women for whole muscle FA (two-sample t-tests; AT: P = 0.0014; EDL: P = 0.0004). We showed significant intramuscular differences in diffusion parameters between adjacent segments in most calf muscles (P < 0.001). Whereas muscle insertions showed higher (SD 0.03-0.06) than muscle bellies (SD 0.01-0.03), no relationships between FA or MD with age or BMI were found. Inter- and intramuscular variations in diffusion parameters of the calf were shown, which are not related to age or BMI in this age group. Differences between muscle belly and insertion should be considered when interpreting datasets not including whole muscles. 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1137-1148. © 2017 International Society for Magnetic Resonance in Medicine.

  17. Chondrocyte heterogeneity: immunohistologically defined variation of integrin expression at different sites in human fetal knees.

    Science.gov (United States)

    Salter, D M; Godolphin, J L; Gourlay, M S

    1995-04-01

    During development and at maturity different forms of cartilage vary in morphology and macromolecular content. This reflects heterogeneity of chondrocyte activity, in part involving differential interactions with the adjacent extracellular matrix via specialized cell surface receptors such as integrins. We undertook an immunohistological study on a series of human fetal knee joints to assess variation in the expression of integrins by chondrocytes and potential matrix ligands in articular, epiphyseal, growth plate, and meniscal cartilage. The results show that articular chondrocytes (beta 1+, beta 5 alpha V+, alpha 1+, alpha 2+/-, alpha 5+, weakly alpha 6+, alpha V+) differed from epiphyseal (beta 1+, beta 5 alpha V+, alpha 1+/-, alpha 2+/-, alpha 5+, alpha 6+, alpha V+) growth plate (beta 1+, beta 5 alpha V+, alpha 1-, alpha 2-, alpha 5+, alpha 6+, alpha V+), and meniscal cells (beta 1+, beta 5 alpha V+, alpha 1+, strongly alpha 2+, alpha 5+, alpha 6+, alpha V+ in expression of integrin subunits. There was no expression of beta 3, beta 4, beta 6, or alpha 3 by chondrocytes. These results differ from previous reports on the expression of integrins by adult articular cartilage, where alpha 2 and alpha 6 are not seen. Variation in distribution of matrix ligands was also seen. Fibronectin, laminin and Type VI collagen were expressed in all cartilages but there was restricted expression of tenascin, ED-A and ED-B fibronectin isoforms (articular cartilage and meniscus), and vitronectin (absent from growth plate cartilage). Regulated expression of integrins by chondrocytes, associated with changes in the pericellular matrix composition, is of potential importance in control of cartilage differentiation and function in health and disease.

  18. Cultural variation is part of human nature : Literary universals, context-sensitivity, and "shakespeare in the bush".

    Science.gov (United States)

    Sugiyama, Michelle Scalise

    2003-12-01

    In 1966, Laura Bohannan wrote her classic essay challenging the supposition that great literary works speak to universal human concerns and conditions and, by extension, that human nature is the same everywhere. Her evidence: the Tiv of West Africa interpret Hamlet differently from Westerners. While Bohannan's essay implies that cognitive universality and cultural variation are mutually exclusive phenomena, adaptationist theory suggests otherwise. Adaptive problems ("the human condition") and cognitive adaptations ("human nature") are constant across cultures. What differs between cultures is habitat: owing to environmental variation, the means and information relevant to solving adaptive problems differ from place to place. Thus, we find differences between cultures not because human minds differ in design but largely because human habitats differ in resources and history. On this view, we would expect world literature to express both human universals and cultural particularities. Specifically, we should expect to find literary universality at the macro level (e.g., adaptive problems, cognitive adaptations) and literary variation at the micro level (e.g., local solutions to adaptive problems).

  19. Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach

    NARCIS (Netherlands)

    B. Giardine (Belinda); J. Borg (Joseph); D.R. Higgs (Douglas); K.R. Peterson (Kenneth R.); J.N.J. Philipsen (Sjaak); D. Maglott (Donna); B.K. Singleton (Belinda K.); D.J. Anstee (David J.); A.N. Basak (Nazli); B.H. Clark (Bruce); F.C. Costa (Flavia C.); P. Faustino (Paula); H. Fedosyuk (Halyna); A.E. Felice (Alex); A. Francina (Alain); R. Galanello (Renzo); M.V.E. Gallivan (Monica V. E.); M. Georgitsi (Marianthi); R.J. Gibbons (Richard J.); P.C. Giordano (Piero Carlo); C.L. Harteveld (Cornelis); J.D. Hoyer (James D.); M. Jarvis (Martin); P. Joly (Philippe); E. Kanavakis (Emmanuel); P. Kollia (Panagoula); S. Menzel (Stephan); W.G. Miller (William); K. Moradkhani (Kamran); J. Old (John); A. Papachatzpoulou (Adamantia); M.N. Papadakis (Manoussos); P. Papadopoulos (Petros); S. Pavlovic (Sonja); L. Perseu (Lucia); M. Radmilovic (Milena); C. Riemer (Cathy); S. Satta (Stefania); I.A. Schrijver (Ingrid); M. Stojiljkovic (Maja); S.L. Thein; J. Traeger-Synodinos (Joanne); R. Tully (Ray); T. Wada (Takahito); J.S. Waye (John); C. Wiemann (Claudia); B. Zukic (Branka); D.H.K. Chui (David H. K.); H. Wajcman (Henri); R. Hardison (Ross); G.P. Patrinos (George)

    2011-01-01

    textabstractWe developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public

  20. Micro RNA, A Review: Pharmacogenomic drug targets for complex diseases

    Directory of Open Access Journals (Sweden)

    Sandhya Bawa

    2010-01-01

    Full Text Available

    Micro RNAs (miRNAs are non-coding RNAs that can regulate gene expression to target several mRNAs in a gene regulatory network. MiRNA related Single Nucleotide Polymorphisms (S.N.P.s represent a newly identified type of genetic variability that can be of influence to the risk of certain human diseases and also affect how drugs can be activated and metabolized by patients. This will help in personalized medicines which are used for administrating the correct dosage of drug and drug efficacy. miRNA deregulated expression has been extensively described in a variety of diseases such as Cancer, Obesity , Diabetes, Schizophrenia and control and self renewal of stem cells. MiRNA can function as oncogenes and/or tumor suppressors. MiRNAs may act as key regulators of processes as diverse as early development, cell proliferation and cell death, apoptosis and fat metabolism and cell differentiation .miRNA expression have shown their role in brain development chronic lymphocytic leukemia, colonic adeno carcinoma, Burkiff’s lymphoma and viral infection. These show their links with viral disease, neurodevelopment and cancer. It has been shown that they play a key role in melanoma metastasis. These may be

    1. Combined approach with therapeutic drug monitoring and pharmacogenomics in renal transplant recipients

      Directory of Open Access Journals (Sweden)

      S Manvizhi

      2013-01-01

      Full Text Available In patients undergoing renal transplantation, dose individualization for tacrolimus is routinely achieved with therapeutic drug monitoring (TDM. The patient started on 5.5 mg/day of tacrolimus had a significantly elevated tacrolimus trough concentration. The tacrolimus dose was regularly reduced following TDM at many time periods in the post transplant period but the tacrolimus concentration was consistently elevated. Genomic analysis done after four years revealed mutations in the genes encoding for CYP3A5 and MDR1 (2677G > T. Pharmacogenomics alongside TDM, will soon emerge as the backbone of dose individualization. But for genomics to be beneficial, it should be advocated in the pre-transplant or early post transplant period.

    2. Variations in riboflavin binding by human plasma: identification of immunoglobulins as the major proteins responsible

      International Nuclear Information System (INIS)

      Innis, W.S.; McCormick, D.B.; Merrill, A.H. Jr.

      1985-01-01

      Riboflavin binding by plasma proteins from healthy human subjects was examined by equilibrium dialysis using a physiological concentration of [2-14C]riboflavin (0.04 microM). Binding ranged from 0.080 to 0.917 pmole of riboflavin/mg of protein (with a mean +/- SD of 0.274 +/- 0.206), which corresponded to 4.14 to 49.4 pmole/ml of plasma (15.5 +/- 11.0) (N = 34). Males and females yielded similar results. Upon fractionation of plasma by gel filtration, the major riboflavin-binding components eluted with albumin and gamma-globulins. Albumin was purified and found to bind riboflavin only very weakly (Kd = 3.8 to 10.4 mM), although FMN and photochemical degradation products (e.g., lumiflavine and lumichrome) were more tightly bound. Binding in the gamma-globulin fraction was attributed to IgG and IGA because the binding protein(s) and immunoglobulins copurified using various methods were removed by treatment of plasma with protein A-agarose, and were coincident upon immunoelectrophoresis followed by autoradiography to detect [2-14C]riboflavin. Differences among the plasma samples correlated with the binding recovered with the immunoglobulins. Binding was not directly related to the total IgG or IgA levels of subjects. Hence, it appears that the binding is due to a subfraction of these proteins. These findings suggest that riboflavin-binding immunoglobulins are a major cause of variations in riboflavin binding in human circulation, and may therefore affect the utilization of this micronutrient

    3. Assessment of Pharmacogenomic Panel Assay for Prediction of Taxane Toxicities: Preliminary Results

      Directory of Open Access Journals (Sweden)

      Raffaele Di Francia

      2017-11-01

      Full Text Available Backbone: Paclitaxel and docetaxel are the primary taxane anticancer drugs regularly used to treat, breast, gastric, ovarian, head/neck, lung, and genitourinary neoplasm. Suspension of taxane treatments compromising patient benefits is more frequently caused by peripheral neuropathy and allergy, than to tumor progression. Several strategies for preventing toxicity have been investigated so far. Recently, findings on the genetic variants associated with toxicity and resistance to taxane-based chemotherapy have been reported.Methods: An extensive panel of five polymorphisms on four candidate genes (ABCB1, CYP2C8*3, CYP3A4*1B, XRCC3, previously validated as significant markers related to paclitaxel and Docetaxel toxicity, are analyzed and discussed. We genotyped 76 cancer patients, and 35 of them received paclitaxel or docetaxel-based therapy. What is more, an early outline evaluation of the genotyping costs and benefit was assessed.Results: Out of 35 patients treated with a taxane, six (17.1% had adverse neuropathy events. Pharmacogenomics analysis showed no correlation between candidate gene polymorphisms and toxicity, except for the XRCC3 AG+GG allele [OR 2.61 (95% CI: 0.91–7.61] which showed a weak significant trend of risk of neurotoxicities vs. the AG allele [OR 1.52 (95% CI: 0.51–4.91] P = 0.03.Summary: Based on our experimental results and data from the literature, we propose a useful and low-cost genotyping panel assay for the prevention of toxicity in patients undergoing taxane-based therapy. With the individual pharmacogenomics profile, clinicians will have additional information to plan the better treatment for their patients to minimize toxicity and maximize benefits, including determining cost-effectiveness for national healthcare sustainability.

    4. Human Genetic Variation and Yellow Fever Mortality during 19th Century U.S. Epidemics

      Science.gov (United States)

      2014-01-01

      ABSTRACT We calculated the incidence, mortality, and case fatality rates for Caucasians and non-Caucasians during 19th century yellow fever (YF) epidemics in the United States and determined statistical significance for differences in the rates in different populations. We evaluated nongenetic host factors, including socioeconomic, environmental, cultural, demographic, and acquired immunity status that could have influenced these differences. While differences in incidence rates were not significant between Caucasians and non-Caucasians, differences in mortality and case fatality rates were statistically significant for all epidemics tested (P < 0.01). Caucasians diagnosed with YF were 6.8 times more likely to succumb than non-Caucasians with the disease. No other major causes of death during the 19th century demonstrated a similar mortality skew toward Caucasians. Nongenetic host factors were examined and could not explain these large differences. We propose that the remarkably lower case mortality rates for individuals of non-Caucasian ancestry is the result of human genetic variation in loci encoding innate immune mediators. PMID:24895309

    5. Rare and common regulatory variation in population-scale sequenced human genomes.

      Directory of Open Access Journals (Sweden)

      Stephen B Montgomery

      2011-07-01

      Full Text Available Population-scale genome sequencing allows the characterization of functional effects of a broad spectrum of genetic variants underlying human phenotypic variation. Here, we investigate the influence of rare and common genetic variants on gene expression patterns, using variants identified from sequencing data from the 1000 genomes project in an African and European population sample and gene expression data from lymphoblastoid cell lines. We detect comparable numbers of expression quantitative trait loci (eQTLs when compared to genotypes obtained from HapMap 3, but as many as 80% of the top expression quantitative trait variants (eQTVs discovered from 1000 genomes data are novel. The properties of the newly discovered variants suggest that mapping common causal regulatory variants is challenging even with full resequencing data; however, we observe significant enrichment of regulatory effects in splice-site and nonsense variants. Using RNA sequencing data, we show that 46.2% of nonsynonymous variants are differentially expressed in at least one individual in our sample, creating widespread potential for interactions between functional protein-coding and regulatory variants. We also use allele-specific expression to identify putative rare causal regulatory variants. Furthermore, we demonstrate that outlier expression values can be due to rare variant effects, and we approximate the number of such effects harboured in an individual by effect size. Our results demonstrate that integration of genomic and RNA sequencing analyses allows for the joint assessment of genome sequence and genome function.

    6. Few single nucleotide variations in exomes of human cord blood induced pluripotent stem cells.

      Directory of Open Access Journals (Sweden)

      Rui-Jun Su

      Full Text Available The effect of the cellular reprogramming process per se on mutation load remains unclear. To address this issue, we performed whole exome sequencing analysis of induced pluripotent stem cells (iPSCs reprogrammed from human cord blood (CB CD34(+ cells. Cells from a single donor and improved lentiviral vectors for high-efficiency (2-14% reprogramming were used to examine the effects of three different combinations of reprogramming factors: OCT4 and SOX2 (OS, OS and ZSCAN4 (OSZ, OS and MYC and KLF4 (OSMK. Five clones from each group were subject to whole exome sequencing analysis. We identified 14, 11, and 9 single nucleotide variations (SNVs, in exomes, including untranslated regions (UTR, in the five clones of OSMK, OS, and OSZ iPSC lines. Only 8, 7, and 4 of these, respectively, were protein-coding mutations. An average of 1.3 coding mutations per CB iPSC line is remarkably lower than previous studies using fibroblasts and low-efficiency reprogramming approaches. These data demonstrate that point nucleotide mutations during cord blood reprogramming are negligible and that the inclusion of genome stabilizers like ZSCAN4 during reprogramming may further decrease reprogramming-associated mutations. Our findings provide evidence that CB is a superior source of cells for iPSC banking.

    7. Quantitative Susceptibility Mapping of Human Brain Reflects Spatial Variation in Tissue Composition

      Science.gov (United States)

      Li, Wei; Wu, Bing; Liu, Chunlei

      2011-01-01

      Image phase from gradient echo MRI provides a unique contrast that reflects brain tissue composition variations, such as iron and myelin distribution. Phase imaging is emerging as a powerful tool for the investigation of functional brain anatomy and disease diagnosis. However, the quantitative value of phase is compromised by its nonlocal and orientation dependent properties. There is an increasing need for reliable quantification of magnetic susceptibility, the intrinsic property of tissue. In this study, we developed a novel and accurate susceptibility mapping method that is also phase-wrap insensitive. The proposed susceptibility mapping method utilized two complementary equations: (1) the Fourier relationship of phase and magnetic susceptibility; and (2) the first-order partial derivative of the first equation in the spatial frequency domain. In numerical simulation, this method reconstructed the susceptibility map almost free of streaking artifact. Further, the iterative implementation of this method allowed for high quality reconstruction of susceptibility maps of human brain in vivo. The reconstructed susceptibility map provided excellent contrast of iron-rich deep nuclei and white matter bundles from surrounding tissues. Further, it also revealed anisotropic magnetic susceptibility in brain white matter. Hence, the proposed susceptibility mapping method may provide a powerful tool for the study of brain physiology and pathophysiology. Further elucidation of anisotropic magnetic susceptibility in vivo may allow us to gain more insight into the white matter microarchitectures. PMID:21224002

    8. Promise and Capability of NASA's Earth Observing System to Monitor Human-Induced Climate Variations

      Science.gov (United States)

      King, M. D.

      2003-01-01

      The Earth Observing System (EOS) is a space-based observing system comprised of a series of satellite sensors by which scientists can monitor the Earth, a Data and Information System (EOSDIS) enabling researchers worldwide to access the satellite data, and an interdisciplinary science research program to interpret the satellite data. The Moderate Resolution Imaging Spectroradiometer (MODIS), developed as part of the Earth Observing System (EOS) and launched on Terra in December 1999 and Aqua in May 2002, is designed to meet the scientific needs for satellite remote sensing of clouds, aerosols, water vapor, and land and ocean surface properties. This sensor and multi-platform observing system is especially well suited to observing detailed interdisciplinary components of the Earth s surface and atmosphere in and around urban environments, including aerosol optical properties, cloud optical and microphysical properties of both liquid water and ice clouds, land surface reflectance, fire occurrence, and many other properties that influence the urban environment and are influenced by them. In this presentation I will summarize the current capabilities of MODIS and other EOS sensors currently in orbit to study human-induced climate variations.

    9. Blood flow variation in human muscle during electrically stimulated exercise bouts.

      Science.gov (United States)

      Vanderthommen, Marc; Depresseux, Jean-Claude; Dauchat, Luc; Degueldre, Christian; Croisier, Jean-Louis; Crielaard, Jean-Michel

      2002-07-01

      To evaluate, with a high spatial resolution, the blood flow variations in human skeletal muscle during neuromuscular electric stimulation (NMES) and hence to gain better understanding of the mechanisms of muscle spatial recruitment during NMES. One thigh was submitted to 3 stimulation bouts of different durations (S1=4min, S2=8min, S3=12min) with a workload corresponding to 10% of quadriceps maximal isometric voluntary torque. A cyclotron research center at a Belgian university. Ten healthy male volunteers. Not applicable. Participants were studied with positron emission tomography and H(2)(15)O. Tissue blood flow was evaluated during the last 4 minutes of each stimulation bout in multiple regions of interest (ROIs) selected in the transverse section of the stimulated thigh. Mean tissue blood flow was significantly lower during S1 (5.9+/-1.3mL. min(-1). 100g(-1)) than during S2 (10.6+/-3.4mL. min(-1). 100g(-1)) and S3 (11.6+/-3.7mL. min(-1). 100g(-1)) (Precruited ROIs were preferentially located far from the electrode. During NMES, new muscular regions situated far from the stimulation site are recruited. These recruitment mechanisms are particular and contrast with the recruitment of motor units seen during voluntary contraction. Copyright 2002 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

    10. Initial studies on the variations of load-displacement curves of in vivo human healthy heel pads

      DEFF Research Database (Denmark)

      Matteoli, Sara; Wilhjelm, Jens E.; Virga, Antonio

      2011-01-01

      The aim of this study was to quantify on the measurement variation of in vivo load-displacement curves by using a group of human healthy heel pads. The recordings were done with a compression device measuring force and displacement. Twenty three heel pads, one from each of 23 subjects aged 20...

    11. Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation

      NARCIS (Netherlands)

      Homburger, J.R. (Julian R.); Green, E.M. (Eric M.); Caleshu, C. (Colleen); Sunitha, M.S. (Margaret S.); Taylor, R.E. (Rebecca E.); Ruppel, K.M. (Kathleen M.); Metpally, R.P.R. (Raghu Prasad Rao); S.D. Colan (Steven); M. Michels (Michelle); Day, S.M. (Sharlene M.); I. Olivotto (Iacopo); Bustamante, C.D. (Carlos D.); Dewey, F.E. (Frederick E.); Ho, C.Y. (Carolyn Y.); Spudich, J.A. (James A.); Ashley, E.A. (Euan A.)

      2016-01-01

      textabstractMyosin motors are the fundamental force-generating elements of muscle contraction. Variation in the human β-cardiac myosin heavy chain gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac

    12. Pharmacogenomic Testing

      Science.gov (United States)

      ... your family Plan for the future Insurance and financial planning Transition for children Emergency preparedness Testing & Services Testing ... Support Genetic Disease Information Find a Support Group Financial Planning Who Should I Tell? Genetic Testing & Counseling Compensation ...

    13. Vascular Smooth Muscle Cells From Hypertensive Patient-Derived Induced Pluripotent Stem Cells to Advance Hypertension Pharmacogenomics.

      Science.gov (United States)

      Biel, Nikolett M; Santostefano, Katherine E; DiVita, Bayli B; El Rouby, Nihal; Carrasquilla, Santiago D; Simmons, Chelsey; Nakanishi, Mahito; Cooper-DeHoff, Rhonda M; Johnson, Julie A; Terada, Naohiro

      2015-12-01

      Studies in hypertension (HTN) pharmacogenomics seek to identify genetic sources of variable antihypertensive drug response. Genetic association studies have detected single-nucleotide polymorphisms (SNPs) that link to drug responses; however, to understand mechanisms underlying how genetic traits alter drug responses, a biological interface is needed. Patient-derived induced pluripotent stem cells (iPSCs) provide a potential source for studying otherwise inaccessible tissues that may be important to antihypertensive drug response. The present study established multiple iPSC lines from an HTN pharmacogenomics cohort. We demonstrated that established HTN iPSCs can robustly and reproducibly differentiate into functional vascular smooth muscle cells (VSMCs), a cell type most relevant to vasculature tone control. Moreover, a sensitive traction force microscopy assay demonstrated that iPSC-derived VSMCs show a quantitative contractile response on physiological stimulus of endothelin-1. Furthermore, the inflammatory chemokine tumor necrosis factor α induced a typical VSMC response in iPSC-derived VSMCs. These studies pave the way for a large research initiative to decode biological significance of identified SNPs in hypertension pharmacogenomics. Treatment of hypertension remains suboptimal, and a pharmacogenomics approach seeks to identify genetic biomarkers that could be used to guide treatment decisions; however, it is important to understand the biological underpinnings of genetic associations. Mouse models do not accurately recapitulate individual patient responses based on their genetics, and hypertension-relevant cells are difficult to obtain from patients. Induced pluripotent stem cell (iPSC) technology provides a great interface to bring patient cells with their genomic data into the laboratory and to study hypertensive responses. As an initial step, the present study established an iPSC bank from patients with primary hypertension and demonstrated an effective

    14. Circadian variations of interferon-induced enhancement of human natural killer (NK) cell activity.

      Science.gov (United States)

      Gatti, G; Cavallo, R; Sartori, M L; Carignola, R; Masera, R; Delponte, D; Salvadori, A; Angeli, A

      1988-01-01

      We searched for circadian changes in the enhancement of the NK activity after exposure to IFN-gamma of peripheral blood mononuclear (PBM) cells obtained serially throughout the 24-h cycle. In August-October 1986, blood was drawn from 7 healthy, diurnally active and nocturnally resting male volunteers (22-34 yr) at 4-h intervals for 24 h starting at 08:00. PBM cells were immediately separated and assayed for NK cell activity, using K 562 cultured cells as a target in a 4-h 51Cr release assay after prior incubation for 20 h with buffer or 300 IU rIFN-gamma. Circadian variations of the spontaneous NK cell cytotoxicity were apparent; the activity was at its maximum at the end of the night or in the early morning and then declined in the afternoon. The 24-h rhythmic pattern was validated with statistical significance by the Cosinor method (p less than 0.02; acrophase 04:22). Maximum enhancement by IFN-gamma was attained in the second part of the night or in the early morning, i.e. in phase with the peak of the spontaneous NK cell activity. A significant circadian rhythm of the percent increase above control levels was validated by the Cosinor method (p less than 0.01; acrophase 04:03). Our findings may be of relevance to a better understanding of the mechanisms of control of human NK activity and warrant consideration as an approach to improve the effectiveness of time-qualified immunotherapy.

    15. Diurnal Variations of Human Circulating Cell-Free Micro-RNA.

      Directory of Open Access Journals (Sweden)

      Niels H H Heegaard

      Full Text Available A 24-hour light and dark cycle-dependent rhythmicity pervades physiological processes in virtually all living organisms including humans. These regular oscillations are caused by external cues to endogenous, independent biological time-keeping systems (clocks. The rhythm is reflected by gene expression that varies in a circadian and specific fashion in different organs and tissues and is regulated largely by dynamic epigenetic and post-transcriptional mechanisms. This leads to well-documented oscillations of specific electrolytes, hormones, metabolites, and plasma proteins in blood samples. An emerging, important class of gene regulators is short single-stranded RNA (micro-RNA, miRNA that interferes post-transcriptionally with gene expression and thus may play a role in the circadian variation of gene expression. MiRNAs are promising biomarkers by virtue of their disease-specific tissue expression and because of their presence as stable entities in the circulation. However, no studies have addressed the putative circadian rhythmicity of circulating, cell-free miRNAs. This question is important both for using miRNAs as biological markers and for clues to miRNA function in the regulation of circadian gene expression. Here, we investigate 92 miRNAs in plasma samples from 24 young male, healthy volunteers repeatedly sampled 9 times during a 24-hour stay in a regulated environment. We demonstrate that a third (26/79 of the measurable plasma miRNAs (using RT-qPCR on a microfluidic system exhibit a rhythmic behavior and are distributed in two main phase patterns. Some of these miRNAs weakly target known clock genes and many have strong targets in intracellular MAPK signaling pathways. These novel findings highlight the importance of considering bio-oscillations in miRNA biomarker studies and suggest the further study of a set of specific circulating miRNAs in the regulation and functioning of biological clocks.

    16. Diurnal variation of the human adipose transcriptome and the link to metabolic disease

      Directory of Open Access Journals (Sweden)

      Lamb John

      2009-02-01

      Full Text Available Abstract Background Circadian (diurnal rhythm is an integral part of the physiology of the body; specifically, sleep, feeding behavior and metabolism are tightly linked to the light-dark cycle dictated by earth's rotation. Methods The present study examines the effect of diurnal rhythm on gene expression in the subcutaneous adipose tissue of overweight to mildly obese, healthy individuals. In this well-controlled clinical study, adipose biopsies were taken in the morning, afternoon and evening from individuals in three study arms: treatment with the weight loss drug sibutramine/fasted, placebo/fed and placebo/fasted. Results The results indicated that diurnal rhythm was the most significant driver of gene expression variation in the human adipose tissue, with at least 25% of the genes having had significant changes in their expression levels during the course of the day. The mRNA expression levels of core clock genes at a specific time of day were consistent across multiple subjects on different days in all three arms, indicating robust diurnal regulation irrespective of potential confounding factors. The genes essential for energy metabolism and tissue physiology were part of the diurnal signature. We hypothesize that the diurnal transition of the expression of energy metabolism genes reflects the shift in the adipose tissue from an energy-expending state in the morning to an energy-storing state in the evening. Consistent with this hypothesis, the diurnal transition was delayed by fasting and treatment with sibutramine. Finally, an in silico comparison of the diurnal signature with data from the publicly-available Connectivity Map demonstrated a significant association with transcripts that were repressed by mTOR inhibitors, suggesting a possible link between mTOR signaling, diurnal gene expression and metabolic regulation. Conclusion Diurnal rhythm plays an important role in the physiology and regulation of energy metabolism in the adipose

    17. Loss of variation of state detected in soybean metabolic and human myelomonocytic leukaemia cell transcriptional networks under external stimuli

      KAUST Repository

      Sakata, Katsumi

      2016-10-24

      Soybean (Glycine max) is sensitive to flooding stress, and flood damage at the seedling stage is a barrier to growth. We constructed two mathematical models of the soybean metabolic network, a control model and a flooded model, from metabolic profiles in soybean plants. We simulated the metabolic profiles with perturbations before and after the flooding stimulus using the two models. We measured the variation of state that the system could maintain from a state–space description of the simulated profiles. The results showed a loss of variation of state during the flooding response in the soybean plants. Loss of variation of state was also observed in a human myelomonocytic leukaemia cell transcriptional network in response to a phorbol-ester stimulus. Thus, we detected a loss of variation of state under external stimuli in two biological systems, regardless of the regulation and stimulus types. Our results suggest that a loss of robustness may occur concurrently with the loss of variation of state in biological systems. We describe the possible applications of the quantity of variation of state in plant genetic engineering and cell biology. Finally, we present a hypothetical “external stimulus-induced information loss” model of biological systems.

    18. Loss of variation of state detected in soybean metabolic and human myelomonocytic leukaemia cell transcriptional networks under external stimuli

      KAUST Repository

      Sakata, Katsumi; Saito, Toshiyuki; Ohyanagi, Hajime; Okumura, Jun; Ishige, Kentaro; Suzuki, Harukazu; Nakamura, Takuji; Komatsu, Setsuko

      2016-01-01

      Soybean (Glycine max) is sensitive to flooding stress, and flood damage at the seedling stage is a barrier to growth. We constructed two mathematical models of the soybean metabolic network, a control model and a flooded model, from metabolic profiles in soybean plants. We simulated the metabolic profiles with perturbations before and after the flooding stimulus using the two models. We measured the variation of state that the system could maintain from a state–space description of the simulated profiles. The results showed a loss of variation of state during the flooding response in the soybean plants. Loss of variation of state was also observed in a human myelomonocytic leukaemia cell transcriptional network in response to a phorbol-ester stimulus. Thus, we detected a loss of variation of state under external stimuli in two biological systems, regardless of the regulation and stimulus types. Our results suggest that a loss of robustness may occur concurrently with the loss of variation of state in biological systems. We describe the possible applications of the quantity of variation of state in plant genetic engineering and cell biology. Finally, we present a hypothetical “external stimulus-induced information loss” model of biological systems.

    19. Genetics in endocrinology: genetic variation in deiodinases: a systematic review of potential clinical effects in humans

      NARCIS (Netherlands)

      Verloop, H.; Dekkers, O.M.; Peeters, R.P.; Schoones, J.W.; Smit, J.W.

      2014-01-01

      Iodothyronine deiodinases represent a family of selenoproteins involved in peripheral and local homeostasis of thyroid hormone action. Deiodinases are expressed in multiple organs and thyroid hormone affects numerous biological systems, thus genetic variation in deiodinases may affect multiple

    20. Circle of willis and its variations; morphometric study in adult human cadavers

      OpenAIRE

      Raghavendra, Shirol VS, Daksha Dixit, Anil Kumar Reddy Y, Desai SP

      2014-01-01

      Background and Objectives: Circle of Willis plays a vital role in collateral circulation and redistribution of blood to all areas of the brain. Variation in circle of Willis is known to cause grave disorders like cerebrovascular disorders, subarachnoid haemorrhage, cerebral aneurysm and schizophrenia. The objectives of the present study are to study the formation and branching pattern of circle of Willis and also to study the distribution of variations. MATERIALS & Methods: The study was cond...

    1. Inter-individual and inter-cell type variation in residual DNA damage after in vivo irradiation of human skin

      International Nuclear Information System (INIS)

      Chua, Melvin Lee Kiang; Somaiah, Navita; Bourne, Sara; Daley, Frances; A'Hern, Roger; Nuta, Otilia; Davies, Sue; Herskind, Carsten; Pearson, Ann; Warrington, Jim; Helyer, Sarah; Owen, Roger; Yarnold, John; Rothkamm, Kai

      2011-01-01

      Purpose: The aim of this study was to compare inter-individual and inter-cell type variation in DNA double-strand break (DSB) repair following in vivo irradiation of human skin. Materials and methods: Duplicate 4 mm core biopsies of irradiated and unirradiated skin were collected from 35 patients 24 h after 4 Gy exposure using 6 MeV electrons. Residual DSB were quantified by scoring 53BP1 foci in dermal fibroblasts, endothelial cells, superficial keratinocytes and basal epidermal cells. Results: Coefficients of inter-individual variation for levels of residual foci 24 h after in vivo irradiation of skin were 39.9% in dermal fibroblasts, 44.3% in endothelial cells, 32.9% in superficial keratinocytes and 46.4% in basal epidermal cells (p < 0.001, ANOVA). In contrast, the coefficient of inter-cell type variation for residual foci levels was only 11.3% in human skin between the different epidermal and dermal cells (p = 0.034, ANOVA). Foci levels between the different skin cell types were correlated (Pearson's R = 0.855-0.955, p < 0.001). Conclusions: Patient-specific factors appear to be more important than cell type-specific factors in determining residual foci levels following in vivo irradiation of human skin.

    2. Circle of willis and its variations; morphometric study in adult human cadavers

      Directory of Open Access Journals (Sweden)

      Raghavendra, Shirol VS, Daksha Dixit, Anil Kumar Reddy Y, Desai SP

      2014-04-01

      Full Text Available Background and Objectives: Circle of Willis plays a vital role in collateral circulation and redistribution of blood to all areas of the brain. Variation in circle of Willis is known to cause grave disorders like cerebrovascular disorders, subarachnoid haemorrhage, cerebral aneurysm and schizophrenia. The objectives of the present study are to study the formation and branching pattern of circle of Willis and also to study the distribution of variations. MATERIALS & Methods: The study was conducted on 50 adult brain specimens. Each brain was removed in one piece by dissection and the circle of Willis was observed for its formation, pattern and variations. Results: Among the 50 specimens studied, 28 cases (56% had a normal pattern of circle of Willis and variations were observed in the remaining 22 cases (44%. More number of variations was observed on the right side than on the left side. The most common variation observed was hypoplastic posterior communicating artery (7 cases, 31.8%. Posterior communicating artery was found to be the most variable vessel while middle cerebral artery was the least variable vessel. Interpretation and Conclusion: The results with respect to the circle of Willis and all its component arteries were consistent with the results in the available literature. The only exception was the increased incidence of absence of both the anterior and posterior communicating arteries. This finding is of clinical significance to neurologists and neurosurgeons in this geographical location of north Karnataka. A higher incidence of variations in the communicating arteries is likely to manifest as a higher incidence in disorders like migraine, schizophrenia and cerebrovascular disorders due to compromised collateral circulation and poor redistribution of blood.

    3. mtDNA variation predicts population size in humans and reveals a major Southern Asian chapter in human prehistory.

      Science.gov (United States)

      Atkinson, Quentin D; Gray, Russell D; Drummond, Alexei J

      2008-02-01

      The relative timing and size of regional human population growth following our expansion from Africa remain unknown. Human mitochondrial DNA (mtDNA) diversity carries a legacy of our population history. Given a set of sequences, we can use coalescent theory to estimate past population size through time and draw inferences about human population history. However, recent work has challenged the validity of using mtDNA diversity to infer species population sizes. Here we use Bayesian coalescent inference methods, together with a global data set of 357 human mtDNA coding-region sequences, to infer human population sizes through time across 8 major geographic regions. Our estimates of relative population sizes show remarkable concordance with the contemporary regional distribution of humans across Africa, Eurasia, and the Americas, indicating that mtDNA diversity is a good predictor of population size in humans. Plots of population size through time show slow growth in sub-Saharan Africa beginning 143-193 kya, followed by a rapid expansion into Eurasia after the emergence of the first non-African mtDNA lineages 50-70 kya. Outside Africa, the earliest and fastest growth is inferred in Southern Asia approximately 52 kya, followed by a succession of growth phases in Northern and Central Asia (approximately 49 kya), Australia (approximately 48 kya), Europe (approximately 42 kya), the Middle East and North Africa (approximately 40 kya), New Guinea (approximately 39 kya), the Americas (approximately 18 kya), and a second expansion in Europe (approximately 10-15 kya). Comparisons of relative regional population sizes through time suggest that between approximately 45 and 20 kya most of humanity lived in Southern Asia. These findings not only support the use of mtDNA data for estimating human population size but also provide a unique picture of human prehistory and demonstrate the importance of Southern Asia to our recent evolutionary past.

    4. Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects

      Science.gov (United States)

      Meier-Ewert, H. K.; Ridker, P. M.; Rifai, N.; Price, N.; Dinges, D. F.; Mullington, J. M.

      2001-01-01

      BACKGROUND: The concentration of C-reactive protein (CRP) in otherwise healthy subjects has been shown to predict future risk of myocardial infarction and stroke. CRP is synthesized by the liver in response to interleukin-6, the serum concentration of which is subject to diurnal variation. METHODS: To examine the existence of a time-of-day effect for baseline CRP values, we determined CRP concentrations in hourly blood samples drawn from healthy subjects (10 males, 3 females; age range, 21-35 years) during a baseline day in a controlled environment (8 h of nighttime sleep). RESULTS: Overall CRP concentrations were low, with only three subjects having CRP concentrations >2 mg/L. Comparison of raw data showed stability of CRP concentrations throughout the 24 h studied. When compared with cutoff values of CRP quintile derived from population-based studies, misclassification of greater than one quintile did not occur as a result of diurnal variation in any of the subjects studied. Nonparametric ANOVA comparing different time points showed no significant differences for both raw and z-transformed data. Analysis for rhythmic diurnal variation using a method fitting a cosine curve to the group data was negative. CONCLUSIONS: Our data show that baseline CRP concentrations are not subject to time-of-day variation and thus help to explain why CRP concentrations are a better predictor of vascular risk than interleukin-6. Determination of CRP for cardiovascular risk prediction may be performed without concern for diurnal variation.

    5. Weight Gain, Schizophrenia and Antipsychotics: New Findings from Animal Model and Pharmacogenomic Studies

      Directory of Open Access Journals (Sweden)

      Fabio Panariello

      2011-01-01

      Full Text Available Excess body weight is one of the most common physical health problems among patients with schizophrenia that increases the risk for many medical problems, including type 2 diabetes mellitus, coronary heart disease, osteoarthritis, and hypertension, and accounts in part for 20% shorter life expectancy than in general population. Among patients with severe mental illness, obesity can be attributed to an unhealthy lifestyle, personal genetic profile, as well as the effects of psychotropic medications, above all antipsychotic drugs. Novel “atypical” antipsychotic drugs represent a substantial improvement on older “typical” drugs. However, clinical experience has shown that some, but not all, of these drugs can induce substantial weight gain. Animal models of antipsychotic-related weight gain and animal transgenic models of knockout or overexpressed genes of antipsychotic receptors have been largely evaluated by scientific community for changes in obesity-related gene expression or phenotypes. Moreover, pharmacogenomic approaches have allowed to detect more than 300 possible candidate genes for antipsychotics-induced body weight gain. In this paper, we summarize current thinking on: (1 the role of polymorphisms in several candidate genes, (2 the possible roles of various neurotransmitters and neuropeptides in this adverse drug reaction, and (3 the state of development of animal models in this matter. We also outline major areas for future research.

    6. Prognostic, predictive and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer.

      Science.gov (United States)

      Bruun, Jarle; Sveen, Anita; Barros, Rita; Eide, Peter W; Eilertsen, Ina; Kolberg, Matthias; Pellinen, Teijo; David, Leonor; Svindland, Aud; Kallioniemi, Olli; Guren, Marianne G; Nesbakken, Arild; Almeida, Raquel; Lothe, Ragnhild A

      2018-06-14

      We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I-IV primary CRCs by gene expression (n=403) or immunohistochemistry (n=642) and in relation to 5-year relapse-free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX2 was prognostic only in stage IV, independent of chemotherapy. Among stage I-III patients not treated in an adjuvant setting, CDX2 loss was associated with a particularly poor survival in the BRAF-mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes In stage III, the 5-year RFS rate was higher among patients with loss of CDX2 who received adjuvant chemotherapy than among patients who did not. The CDX2-negative cell lines were significantly more sensitive to chemotherapeutics than CDX2-positive cells, and the multidrug resistance genes MDR1 and CFTR were significantly downregulated both in CDX2-negative cells and patient tumors. Molecular Oncology (2018) © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

    7. Pharmacogenomics of Hypertension and Preeclampsia: Focus on Gene–Gene Interactions

      Directory of Open Access Journals (Sweden)

      Marcelo R. Luizon

      2018-02-01

      Full Text Available Hypertension is a leading cause of cardiovascular mortality, but only about half of patients on antihypertensive therapy achieve blood pressure control. Preeclampsia is defined as pregnancy-induced hypertension and proteinuria, and is associated with increased maternal and perinatal mortality and morbidity. Similarly, a large number of patients with preeclampsia are non-responsive to antihypertensive therapy. Pharmacogenomics may help to guide the personalized treatment for non-responsive hypertensive patients. There is evidence for the association of genetic variants with variable response to the most commonly used antihypertensive drugs. However, further replication is needed to confirm these associations in different populations. The failure to replicate findings from single-locus association studies has prompted the search for novel statistical methods for data analysis, which are required to detect the complex effects from multiple genes to drug response phenotypes. Notably, gene–gene interaction analyses have been applied to pharmacogenetic studies, including antihypertensive drug response. In this perspective article, we present advances of considering the interactions among genetic polymorphisms of different candidate genes within pathways relevant to antihypertensive drug response, and we highlight recent findings related to gene–gene interactions on pharmacogenetics of hypertension and preeclampsia. Finally, we discuss the future directions that are needed to unravel additional genes and variants involved in the responsiveness to antihypertensive drugs.

    8. Mixed effects modeling of proliferation rates in cell-based models: consequence for pharmacogenomics and cancer.

      Directory of Open Access Journals (Sweden)

      Hae Kyung Im

      2012-02-01

      Full Text Available The International HapMap project has made publicly available extensive genotypic data on a number of lymphoblastoid cell lines (LCLs. Building on this resource, many research groups have generated a large amount of phenotypic data on these cell lines to facilitate genetic studies of disease risk or drug response. However, one problem that may reduce the usefulness of these resources is the biological noise inherent to cellular phenotypes. We developed a novel method, termed Mixed Effects Model Averaging (MEM, which pools data from multiple sources and generates an intrinsic cellular growth rate phenotype. This intrinsic growth rate was estimated for each of over 500 HapMap cell lines. We then examined the association of this intrinsic growth rate with gene expression levels and found that almost 30% (2,967 out of 10,748 of the genes tested were significant with FDR less than 10%. We probed further to demonstrate evidence of a genetic effect on intrinsic growth rate by determining a significant enrichment in growth-associated genes among genes targeted by top growth-associated SNPs (as eQTLs. The estimated intrinsic growth rate as well as the strength of the association with genetic variants and gene expression traits are made publicly available through a cell-based pharmacogenomics database, PACdb. This resource should enable researchers to explore the mediating effects of proliferation rate on other phenotypes.

    9. Applications of pharmacogenomics in regulatory science: a product life cycle review.

      Science.gov (United States)

      Tan-Koi, W C; Leow, P C; Teo, Y Y

      2018-05-22

      With rapid developments of pharmacogenomics (PGx) and regulatory science, it is important to understand the current PGx integration in product life cycle, impact on clinical practice thus far and opportunities ahead. We conducted a cross-sectional review on PGx-related regulatory documents and implementation guidelines in the United States and Europe. Our review found that although PGx-related guidance in both markets span across the entire product life cycle, the scope of implementation guidelines varies across two continents. Approximately one-third of Food and Drug Administration (FDA)-approved drugs with PGx information in drug labels and half of the European labels posted on PharmGKB website contain recommendations on genetic testing. The drugs affected 19 and 15 World Health Organization Anatomical Therapeutic Chemical drug classes (fourth level) in the United States and Europe, respectively, with protein kinase inhibitors (13 drugs in the United States and 16 drugs in Europe) being most prevalent. Topics of emerging interest were novel technologies, adaptive design in clinical trial and sample collection.

    10. Circadian variation of EEG power spectra in NREM and REM sleep in humans: dissociation from body temperature

      Science.gov (United States)

      Dijk, D. J.

      1999-01-01

      In humans, EEG power spectra in REM and NREM sleep, as well as characteristics of sleep spindles such as their duration, amplitude, frequency and incidence, vary with circadian phase. Recently it has been hypothesized that circadian variations in EEG spectra in humans are caused by variations in brain or body temperature and may not represent phenomena relevant to sleep regulatory processes. To test this directly, a further analysis of EEG power spectra - collected in a forced desynchrony protocol in which sleep episodes were scheduled to a 28-h period while the rhythms of body temperature and plasma melatonin were oscillating at their near 24-h period - was carried out. EEG power spectra were computed for NREM and REM sleep occurring between 90-120 and 270-300 degrees of the circadian melatonin rhythm, i.e. just after the clearance of melatonin from plasma in the 'morning' and just after the 'evening' increase in melatonin secretion. Average body temperatures during scheduled sleep at these two circadian phases were identical (36.72 degrees C). Despite identical body temperatures, the power spectra in NREM sleep were very different at these two circadian phases. EEG activity in the low frequency spindle range was significantly and markedly enhanced after the evening increase in plasma melatonin as compared to the morning phase. For REM sleep, significant differences in power spectra during these two circadian phases, in particular in the alpha range, were also observed. The results confirm that EEG power spectra in NREM and REM sleep vary with circadian phase, suggesting that the direct contribution of temperature to the circadian variation in EEG power spectra is absent or only minor, and are at variance with the hypothesis that circadian variations in EEG power spectra are caused by variations in temperature.

    11. Plasmodium falciparum CS protein - prime malaria vaccine candidate: definition of the human CTL domain and analysis of its variation

      Directory of Open Access Journals (Sweden)

      Denise L. Doolan

      1992-01-01

      Full Text Available Studies in mice have shown that immunity to malaria sporozoites is mediated primarily by citotoxic T lymphocytes (CTL specific for epitopes within the circumsporozoite (CS protein. Humans, had never been shown to generate CTL against any malaria or other parasite protein. The design of a sub-unit vaccine for humans ralies on the epitopes recognized by CTL being identified and polymorphisms therein being defined. We have developed a novel technique using an entire series of overlapping synthetic peptides to define the epitopes of the Plasmodium falciparum CS protein recognized by human CTL and have analyzed the sequence variation of the protein with respect to the identified CTL epitopic domain. We have demonstrated that some humans can indeed generate CTL. against the P. falciparum CS protein. Furthermore, the extent of variation observed for the CTL recognition domain is finite and the combination of peptides necessary for inclusion in a polyvalent vaccine may be small. If ways can be found to increase immune responsiveness, then a vaccine designed to stimulate CS protein-specific CTL activity may prevent malaria.

    12. Assessing vegetation response to climatic variations and human activities: spatiotemporal NDVI variations in the Hexi Corridor and surrounding areas from 2000 to 2010

      Science.gov (United States)

      Guan, Qingyu; Yang, Liqin; Guan, Wenqian; Wang, Feifei; Liu, Zeyu; Xu, Chuanqi

      2018-03-01

      Vegetation cover is a commonly used indicator for evaluating terrestrial environmental conditions, and for revealing environmental evolution and transitions. Spatiotemporal variations in the vegetation cover of the Hexi Corridor and surrounding areas from 2000 to 2010 were investigated using MODIS NDVI data, and the causes of vegetation cover changes were analyzed, considering both climatic variability and human activities. The vegetation cover of the study area increased during 2000-2010. The greenness of the vegetation showed a significant increase from the northwest to the southeast, which was similar to the spatial distribution of the annual precipitation. Variations in vegetation have a close relationship with those in precipitation within the Qilian Mountains region, but the NDVI is negatively correlated with precipitation in oasis areas. Increasing temperatures led to drought, inhibiting vegetation growth in summer; however, increasing temperatures may have also advanced and prolonged the growing periods in spring and autumn. The NDVI showed a slight degradation in March and July, primarily in the Qilian Mountains, and especially the Wushao Mountains. In March, due to low temperatures, the metabolism rate of vegetation was too slow to enable strong plant growth in high elevations of the Qilian Mountains. In July, increasing temperatures enhanced the intensity of transpiration and decreasing precipitation reduced the moisture available to plants, producing a slight degradation of vegetation in the Qilian Mountains. In May and August, the NDVI showed a significant improvement, primarily in the artificial oases and the Qilian Mountains. Abundant precipitation provided the necessary water for plant growth, and suitable temperatures increased the efficiency of photosynthesis, resulting in a significant improvement of vegetation in the Qilian Mountains. The improvement of production technologies, especially in irrigation, has been beneficial to the growth of

    13. Pharmacomicrobiomics: The Impact of Human Microbiome Variations on Systems Pharmacology and Personalized Therapeutics

      OpenAIRE

      ElRakaiby, Marwa; Dutilh, Bas E.; Rizkallah, Mariam R.; Boleij, Annemarie; Cole, Jason N.; Aziz, Ramy K.

      2014-01-01

      The Human Microbiome Project (HMP) is a global initiative undertaken to identify and characterize the collection of human-associated microorganisms at multiple anatomic sites (skin, mouth, nose, colon, vagina), and to determine how intra-individual and inter-individual alterations in the microbiome influence human health, immunity, and different disease states. In this review article, we summarize the key findings and applications of the HMP that may impact pharmacology and personalized thera...

    14. Cosmic ray variations of solar origin in relation to human physiological state during the December 2006 solar extreme events

      Science.gov (United States)

      Papailiou, M.; Mavromichalaki, H.; Vassilaki, A.; Kelesidis, K. M.; Mertzanos, G. A.; Petropoulos, B.

      2009-02-01

      There is an increasing amount of evidence linking biological effects to solar and geomagnetic disturbances. A series of studies is published referring to the changes in human physiological responses at different levels of geomagnetic activity. In this study, the possible relation between the daily variations of cosmic ray intensity, measured by the Neutron Monitor at the Cosmic Ray Station of the University of Athens (http://cosray.phys.uoa.gr) and the average daily and hourly heart rate variations of persons, with no symptoms or hospital admission, monitored by Holter electrocardiogram, is considered. This work refers to a group of persons admitted to the cardiological clinic of the KAT Hospital in Athens during the time period from 4th to 24th December 2006 that is characterized by extreme solar and geomagnetic activity. A series of Forbush decreases started on 6th December and lasted until the end of the month and a great solar proton event causing a Ground Level Enhancement (GLE) of the cosmic ray intensity on 13th December occurred. A sudden decrease of the cosmic ray intensity on 15th December, when a geomagnetic storm was registered, was also recorded in Athens Neutron Monitor station (cut-off rigidity 8.53 GV) with amplitude of 4%. It is noticed that during geomagnetically quiet days the heart rate and the cosmic ray intensity variations are positively correlated. When intense cosmic ray variations, like Forbush decreases and relativistic proton events produced by strong solar phenomena occur, cosmic ray intensity and heart rate get minimum values and their variations, also, coincide. During these events the correlation coefficient of these two parameters changes and follows the behavior of the cosmic ray intensity variations. This is only a small part of an extended investigation, which has begun using data from the year 2002 and is still in progress.

    15. Nocturnal variations in subcutaneous blood flow rate in lower leg of normal human subjects

      DEFF Research Database (Denmark)

      Sindrup, J H; Kastrup, J; Jørgensen, B

      1991-01-01

      in central and local postural sympathetic vasoconstrictor activity. During sleep, characteristic variations in subcutaneous blood flow were disclosed. The 133Xe washout curve could be divided into three segments with significantly different slopes. Approximately 90 min after the subject went to sleep...

    16. Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes

      NARCIS (Netherlands)

      Jetten, M.J.A.; Blanco Garcia, Ainhoa; Coonen, M.L.J.; Claessen, Sandra; Herwijnen, van M.H.M.; Lommen, Arjen; Delft, van J.H.M.; Peijnenburg, A.A.C.M.; Kleinjans, J.C.S.

      2016-01-01

      Acetaminophen (APAP) is a readily available over-the-counter drug and is one of the most commonly used analgesics/antipyretics worldwide. Large interindividual variation in susceptibility toward APAP-induced liver failure has been reported. However, the exact underlying factors causing this

    17. Pleistocene-Holocene boundary in Southern Arabia from the perspective of human mtDNA variation

      Czech Academy of Sciences Publication Activity Database

      Al-Abri, A.-R.; Podgorná, E.; Rose, J. I.; Pereira, L.; Mulligan, C. J.; Silva, N. M.; Bayoumi, R.; Soares, P.; Černý, Viktor

      2012-01-01

      Roč. 149, č. 2 (2012), s. 291-298 ISSN 0002-9483 R&D Projects: GA MŠk ME 917 Institutional research plan: CEZ:AV0Z80020508 Keywords : mtDNA variation * Arabian Peninsula * migrations Subject RIV: AC - Archeology, Anthropology, Ethnology Impact factor: 2.481, year: 2012

    18. Husbands' and Wives' Relative Earnings: Exploring Variation by Race, Human Capital, Labor Supply, and Life Stage

      Science.gov (United States)

      Winslow-Bowe, Sarah

      2009-01-01

      Whereas much research has explored the causes and consequences of the gender wage gap, far less has examined earnings differentials within marriage. This article contributes to this literature by utilizing the 2000 wave of the 1979 National Longitudinal Survey of Youth to examine variation in husbands' and wives' relative income by race/ethnicity,…

    19. Variation in tissue outcome of ovine and human engineered heart valve constructs : relevance for tissue engineering

      NARCIS (Netherlands)

      Geemen, van D.; Driessen - Mol, A.; Grootzwagers, L.G.M.; Soekhradj - Soechit, R.S.; Riem Vis, P.W.; Baaijens, F.P.T.; Bouten, C.V.C.

      AIM: Clinical application of tissue engineered heart valves requires precise control of the tissue culture process to predict tissue composition and mechanical properties prior to implantation, and to understand the variation in tissue outcome. To this end we investigated cellular phenotype and

    20. Chloroplast DNA variation of oaks in western Central Europe and genetic consequences of human influences

      NARCIS (Netherlands)

      König, A.O.; Ziegenhagen, B.; Dam, van B.C.; Csaikl, U.M.; Coart, E.; Degen, B.; Burg, K.; Vries, de S.M.G.; Petit, R.J.

      2002-01-01

      Oak chloroplast DNA (cpDNA) variation was studied in a grid-based inventory in western Central Europe, including Belgium, The Netherlands, Luxembourg, Germany, the Czech Republic, and the northern parts of Upper and Lower Austria. A total of 2155 trees representing 426 populations of Quercus robur

    1. Sources of variation in hair cortisol in wild and captive non-human primates.

      Science.gov (United States)

      Fourie, Nicolaas H; Brown, Janine L; Jolly, Clifford J; Phillips-Conroy, Jane E; Rogers, Jeffrey; Bernstein, Robin M

      2016-04-01

      Hair cortisol analysis is a potentially powerful tool for evaluating adrenal function and chronic stress. However, the technique has only recently been applied widely to studies of wildlife, including primates, and there are numerous practical and technical factors that should be considered to ensure good quality data and the validity of results and conclusions. Here we report on various intrinsic and extrinsic sources of variation in hair cortisol measurements in wild and captive primates. Hair samples from both wild and captive primates revealed that age and sex can affect hair cortisol concentrations; these effects need to be controlled for when making comparisons between individual animals or populations. Hair growth rates also showed considerable inter-specific variation among a number of primate species. We describe technical limitations of hair analyses and variation in cortisol concentrations as a function of asynchronous hair growth, anatomical site of collection, and the amount and numbers of hair/s used for cortisol extraction. We discuss these sources of variation and their implications for proper study design and interpretation of results. Published by Elsevier GmbH.

    2. New generation pharmacogenomic tools: a SNP linkage disequilibrium Map, validated SNP assay resource, and high-throughput instrumentation system for large-scale genetic studies.

      Science.gov (United States)

      De La Vega, Francisco M; Dailey, David; Ziegle, Janet; Williams, Julie; Madden, Dawn; Gilbert, Dennis A

      2002-06-01

      Since public and private efforts announced the first draft of the human genome last year, researchers have reported great numbers of single nucleotide polymorphisms (SNPs). We believe that the availability of well-mapped, quality SNP markers constitutes the gateway to a revolution in genetics and personalized medicine that will lead to better diagnosis and treatment of common complex disorders. A new generation of tools and public SNP resources for pharmacogenomic and genetic studies--specifically for candidate-gene, candidate-region, and whole-genome association studies--will form part of the new scientific landscape. This will only be possible through the greater accessibility of SNP resources and superior high-throughput instrumentation-assay systems that enable affordable, highly productive large-scale genetic studies. We are contributing to this effort by developing a high-quality linkage disequilibrium SNP marker map and an accompanying set of ready-to-use, validated SNP assays across every gene in the human genome. This effort incorporates both the public sequence and SNP data sources, and Celera Genomics' human genome assembly and enormous resource ofphysically mapped SNPs (approximately 4,000,000 unique records). This article discusses our approach and methodology for designing the map, choosing quality SNPs, designing and validating these assays, and obtaining population frequency ofthe polymorphisms. We also discuss an advanced, high-performance SNP assay chemisty--a new generation of the TaqMan probe-based, 5' nuclease assay-and high-throughput instrumentation-software system for large-scale genotyping. We provide the new SNP map and validation information, validated SNP assays and reagents, and instrumentation systems as a novel resource for genetic discoveries.

    3. Inter- and Intraspecific Variations in the Pectoral Muscles of Common Chimpanzees (Pan troglodytes, Bonobos (Pan paniscus, and Humans (Homo sapiens

      Directory of Open Access Journals (Sweden)

      J. M. Potau

      2018-01-01

      Full Text Available We have analyzed anatomic variations in the pectoralis major and pectoralis minor muscles of common chimpanzees (Pan troglodytes and bonobos (Pan paniscus and compared them to anatomic variations in these muscles in humans (Homo sapiens. We have macroscopically dissected these muscles in six adult Pan troglodytes, five Pan paniscus of ages ranging from fetus to adult, and five adult Homo sapiens. Although Pan troglodytes are thought to lack a separate pectoralis abdominis muscle, we have identified this muscle in three of the Pan troglodytes; none of the Pan paniscus, however, had this muscle. We have also found deep supernumerary fascicles in the pectoralis major of two Pan troglodytes and all five Pan paniscus. In all six Pan troglodytes, the pectoralis minor was inserted at the supraspinatus tendon, while, in Pan paniscus and Homo sapiens, it was inserted at the coracoid process of the scapula. Some of the anatomic features and variations of these muscles in common chimpanzees and bonobos are similar to those found in humans, therefore enhancing our knowledge of primate comparative anatomy and evolution and also shedding light on several clinical issues.

    4. Inter- and Intraspecific Variations in the Pectoral Muscles of Common Chimpanzees (Pan troglodytes), Bonobos (Pan paniscus), and Humans (Homo sapiens).

      Science.gov (United States)

      Potau, J M; Arias-Martorell, J; Bello-Hellegouarch, G; Casado, A; Pastor, J F; de Paz, F; Diogo, R

      2018-01-01

      We have analyzed anatomic variations in the pectoralis major and pectoralis minor muscles of common chimpanzees (Pan troglodytes) and bonobos (Pan paniscus) and compared them to anatomic variations in these muscles in humans (Homo sapiens) . We have macroscopically dissected these muscles in six adult Pan troglodytes , five Pan paniscus of ages ranging from fetus to adult, and five adult Homo sapiens . Although Pan troglodytes are thought to lack a separate pectoralis abdominis muscle, we have identified this muscle in three of the Pan troglodytes ; none of the Pan paniscus , however, had this muscle. We have also found deep supernumerary fascicles in the pectoralis major of two Pan troglodytes and all five Pan paniscus . In all six Pan troglodytes , the pectoralis minor was inserted at the supraspinatus tendon, while, in Pan paniscus and Homo sapiens , it was inserted at the coracoid process of the scapula. Some of the anatomic features and variations of these muscles in common chimpanzees and bonobos are similar to those found in humans, therefore enhancing our knowledge of primate comparative anatomy and evolution and also shedding light on several clinical issues.

    5. Pharmacomicrobiomics : the impact of human microbiome variations on systems pharmacology and personalized therapeutics

      NARCIS (Netherlands)

      ElRakaiby, Marwa; Dutilh, Bas E; Rizkallah, Mariam R; Boleij, Annemarie; Cole, Jason N; Aziz, Ramy K

      The Human Microbiome Project (HMP) is a global initiative undertaken to identify and characterize the collection of human-associated microorganisms at multiple anatomic sites (skin, mouth, nose, colon, vagina), and to determine how intra-individual and inter-individual alterations in the microbiome

    6. Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics

      NARCIS (Netherlands)

      ElRakaiby, M.; Dutilh, B.E.; Rizkallah, M.R.; Boleij, A.; Cole, J.N.; Aziz, R.K.

      2014-01-01

      The Human Microbiome Project (HMP) is a global initiative undertaken to identify and characterize the collection of human-associated microorganisms at multiple anatomic sites (skin, mouth, nose, colon, vagina), and to determine how intra-individual and inter-individual alterations in the microbiome

    7. Evolutionary developmental pathology and anthropology: A new field linking development, comparative anatomy, human evolution, morphological variations and defects, and medicine.

      Science.gov (United States)

      Diogo, Rui; Smith, Christopher M; Ziermann, Janine M

      2015-11-01

      We introduce a new subfield of the recently created field of Evolutionary-Developmental-Anthropology (Evo-Devo-Anth): Evolutionary-Developmental-Pathology-and-Anthropology (Evo-Devo-P'Anth). This subfield combines experimental and developmental studies of nonhuman model organisms, biological anthropology, chordate comparative anatomy and evolution, and the study of normal and pathological human development. Instead of focusing on other organisms to try to better understand human development, evolution, anatomy, and pathology, it places humans as the central case study, i.e., as truly model organism themselves. We summarize the results of our recent Evo-Devo-P'Anth studies and discuss long-standing questions in each of the broader biological fields combined in this subfield, paying special attention to the links between: (1) Human anomalies and variations, nonpentadactyly, homeotic transformations, and "nearest neighbor" vs. "find and seek" muscle-skeleton associations in limb+facial muscles vs. other head muscles; (2) Developmental constraints, the notion of "phylotypic stage," internalism vs. externalism, and the "logic of monsters" vs. "lack of homeostasis" views about human birth defects; (3) Human evolution, reversions, atavisms, paedomorphosis, and peromorphosis; (4) Scala naturae, Haeckelian recapitulation, von Baer's laws, and parallelism between phylogeny and development, here formally defined as "Phylo-Devo parallelism"; and (5) Patau, Edwards, and Down syndrome (trisomies 13, 18, 21), atavisms, apoptosis, heart malformations, and medical implications. © 2015 Wiley Periodicals, Inc.

    8. Bridging two scholarly islands enriches both: COI DNA barcodes for species identification versus human mitochondrial variation for the study of migrations and pathologies.

      Science.gov (United States)

      Thaler, David S; Stoeckle, Mark Y

      2016-10-01

      DNA barcodes for species identification and the analysis of human mitochondrial variation have developed as independent fields even though both are based on sequences from animal mitochondria. This study finds questions within each field that can be addressed by reference to the other. DNA barcodes are based on a 648-bp segment of the mitochondrially encoded cytochrome oxidase I. From most species, this segment is the only sequence available. It is impossible to know whether it fairly represents overall mitochondrial variation. For modern humans, the entire mitochondrial genome is available from thousands of healthy individuals. SNPs in the human mitochondrial genome are evenly distributed across all protein-encoding regions arguing that COI DNA barcode is representative. Barcode variation among related species is largely based on synonymous codons. Data on human mitochondrial variation support the interpretation that most - possibly all - synonymous substitutions in mitochondria are selectively neutral. DNA barcodes confirm reports of a low variance in modern humans compared to nonhuman primates. In addition, DNA barcodes allow the comparison of modern human variance to many other extant animal species. Birds are a well-curated group in which DNA barcodes are coupled with census and geographic data. Putting modern human variation in the context of intraspecies variation among birds shows humans to be a single breeding population of average variance.

    9. Composition and Variation of Macronutrients, Immune Proteins, and Human Milk Oligosaccharides in Human Milk From Nonprofit and Commercial Milk Banks.

      Science.gov (United States)

      Meredith-Dennis, Laura; Xu, Gege; Goonatilleke, Elisha; Lebrilla, Carlito B; Underwood, Mark A; Smilowitz, Jennifer T

      2018-02-01

      When human milk is unavailable, banked milk is recommended for feeding premature infants. Milk banks use processes to eliminate pathogens; however, variability among methods exists. Research aim: The aim of this study was to compare the macronutrient (protein, carbohydrate, fat, energy), immune-protective protein, and human milk oligosaccharide (HMO) content of human milk from three independent milk banks that use pasteurization (Holder vs. vat techniques) or retort sterilization. Randomly acquired human milk samples from three different milk banks ( n = 3 from each bank) were analyzed for macronutrient concentrations using a Fourier transform mid-infrared spectroscopy human milk analyzer. The concentrations of IgA, IgM, IgG, lactoferrin, lysozyme, α-lactalbumin, α antitrypsin, casein, and HMO were analyzed by mass spectrometry. The concentrations of protein and fat were significantly ( p < .05) less in the retort sterilized compared with the Holder and vat pasteurized samples, respectively. The concentrations of all immune-modulating proteins were significantly ( p < .05) less in the retort sterilized samples compared with vat and/or Holder pasteurized samples. The total HMO concentration and HMOs containing fucose, sialic acid, and nonfucosylated neutral sugars were significantly ( p < .05) less in retort sterilized compared with Holder pasteurized samples. Random milk samples that had undergone retort sterilization had significantly less immune-protective proteins and total and specific HMOs compared with samples that had undergone Holder and vat pasteurization. These data suggest that further analysis of the effect of retort sterilization on human milk components is needed prior to widespread adoption of this process.

    10. Noninvasive monitoring local variations of fever and edema on human: potential for point-of-care inflammation assessment

      Science.gov (United States)

      Li, Zebin; Li, Xianglin; Li, Ting

      2018-02-01

      Tissue inflammation is often accompanied by fever and edema, which are common and troublesome problems that probably trigger disability, lymphangitis, cosmetic deformity and cellulitis. Here we developed a device, which can measure concentration and temperature variations of water in local human body by extended near infrared spectroscopy in 900 1000 nm wavelength range. An experiment of four steps incremental cycling exercise was designed to change tissue water concentration and temperature of subjects. Body temperature was also estimated by tympanic thermometer and surface thermometer as comparisons during the experiment. In the stage of recovery after exercise, the signal detected by custom device is similar to tympanic thermometer at the beginning, but it is closer to the temperature of surface later. In particular, this signal shows a better linearity, and a significant change when the exercise was suspended. This study demonstrated the potential of optical touch-sensing for inflammation severity monitoring by measuring water concentration and temperature variations in local lesions.

    11. Characterising the variations in ethnic skin colours: a new calibrated data base for human skin.

      Science.gov (United States)

      Xiao, K; Yates, J M; Zardawi, F; Sueeprasan, S; Liao, N; Gill, L; Li, C; Wuerger, S

      2017-02-01

      Accurate skin colour measurements are important for numerous medical applications including the diagnosis and treatment of cutaneous disorders and the provision of maxillofacial soft tissue prostheses. In this study, we obtained accurate skin colour measurements from four different ethnic groups (Caucasian, Chinese, Kurdish, Thai) and at four different body locations (Forehead, cheek, inner arm, back of hand) with a view of establishing a new skin colour database for medical and cosmetic applications. Skin colours are measured using a spectrophotometer and converted to a device-independent standard colour appearance space (CIELAB) where skin colour is expressed as values along the three dimensions: Lightness L*, Redness a* and Yellowness b*. Skin colour differences and variation are then evaluated as a function of ethnicity and body location. We report three main results: (1) When plotted in a standard colour appearance space (CIELAB), skin colour distributions for the four ethnic groups overlap significantly, although there are systematic mean differences. Between ethnicities, the most significant skin colour differences occur along the yellowness dimension, with Thai skin exhibiting the highest yellowness (b*) value and Caucasian skin the lowest value. Facial redness (a*) is invariant across the four ethnic groups. (2) Between different body locations, there are significant variations in redness (a*), with the forehead showing the highest redness value and the inner arm the lowest. (3) The colour gamut is smallest in the Chinese sample and largest in the Caucasian sample, with the Chinese gamut lying entirely the Caucasian gamut. Similarly, the largest variability in skin tones is found in the Caucasian group, and the smallest in the Chinese group. Broadly speaking, skin colour variation can be explained by two main factors: individual differences in lightness and yellowness are mostly due to ethnicity, whereas differences in redness are primarily due to

    12. Variations of the attachment of the superior head of human lateral pterygoid muscle.

      Science.gov (United States)

      Antonopoulou, Maria; Iatrou, Ioannis; Paraschos, Alexandros; Anagnostopoulou, Sophia

      2013-09-01

      The superior head of the lateral pterygoid muscle (LPM), is closely related to the temporomandibular joint (TMJ) and plays a role in the aetiology of temporomandibular disorders. Increased activity of this muscle has been implicated in the anterior displacement of the TMJ disc. However, there is uncertainty about the manner of the LPM attachment to the disc-condyle complex. The aim of this study was to investigate the exact anatomy of the attachment of the superior head of the LPM (SLPM) to the disc-condyle complex of the TMJ. Thirty-six TMJs were examined - both sides of 18 Greek cadavers (eight males and 10 females, mean age 79.6 years). Examination of the attachment of the SLPM was undertaken viewed under the dissecting microscope. Variation in the attachment of the SLPM was categorized into three types: in type I, the SLPM inserted into the condyle and the disc-capsule complex (55.5%). In type II, the SLPM only inserted into the condyle (27.8%). In type III, the SLPM inserted purely into the disc-capsule complex (16.7%). This study demonstrates that there are three different attachment types of the SLPM to the disc-condyle complex. The type III variation could be involved in the TMJ pathology. The knowledge of the variations of the SLPM attachment could be useful for precise surgical and pharmaceutical approaches. Copyright © 2012 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

    13. Variation in sister chromatid exchange frequencies between human and pig whole blood, plasma leukocyte, and mononuclear leukocyte cultures

      International Nuclear Information System (INIS)

      Larramendy, M.L.; Reigosa, M.A.

      1986-01-01

      Sister chromatid exchange (SCE) induction by ultraviolet (UV) light was studied in both human and pig whole blood cultures (WBC) and plasma leukocyte cultures (PLC). No variation in SCE frequency was observed between pig WBC and PLC in control as well as in treated cells. Conversely, SCE frequencies of human PLC were consistently higher than those of WBC in control and UV-exposed cells. Thus, red blood cells (RBCs) do not influence the sensitivity of lymphocytes to UV LIGHT exposure, and there must be some different culture condition(s) in the inducation of SCEs between human WBC and PLC but not in swine lymphocyte cultures. Since the BrdUrd/lymphocyte ratio of WBC was halved in PLC, the effect of BrdUrd concentration in inducing the SCE baseline frequency of PLC may be ruled out. Neither the cell separation technique nor polymorphonuclear leukocytes had a significant role in the elevated SCE frequency of human PLC or MLC. Experiments where human RBCs were titrated into human PLC showed that the induction of an elevated SCE frequency of PLC was suppressed in a dose-dependent manner by the presence of RBCs in the culture medium. Since the incorporation of pig or human RBCs into human PLC as well as into MLC reduced the SCE frequency to that of WBC, a common component and/or function existing in these cells is suggested. Analysis of different RBC components showed that RBCs, specifically RBC ghosts, release a diffusible but not dialyzable corrective factor into culture medium that is able to reduce the SCE frequencies of PLC

    14. Human activities as a driver of spatial variation in the trophic structure of fish communities on Pacific coral reefs.

      Science.gov (United States)

      Ruppert, Jonathan L W; Vigliola, Laurent; Kulbicki, Michel; Labrosse, Pierre; Fortin, Marie-Josée; Meekan, Mark G

      2018-01-01

      Anthropogenic activities such as land-use change, pollution and fishing impact the trophic structure of coral reef fishes, which can influence ecosystem health and function. Although these impacts may be ubiquitous, they are not consistent across the tropical Pacific Ocean. Using an extensive database of fish biomass sampled using underwater visual transects on coral reefs, we modelled the impact of human activities on food webs at Pacific-wide and regional (1,000s-10,000s km) scales. We found significantly lower biomass of sharks and carnivores, where there were higher densities of human populations (hereafter referred to as human activity); however, these patterns were not spatially consistent as there were significant differences in the trophic structures of fishes among biogeographic regions. Additionally, we found significant changes in the benthic structure of reef environments, notably a decline in coral cover where there was more human activity. Direct human impacts were the strongest in the upper part of the food web, where we found that in a majority of the Pacific, the biomass of reef sharks and carnivores were significantly and negatively associated with human activity. Finally, although human-induced stressors varied in strength and significance throughout the coral reef food web across the Pacific, socioeconomic variables explained more variation in reef fish trophic structure than habitat variables in a majority of the biogeographic regions. Notably, economic development (measured as GDP per capita) did not guarantee healthy reef ecosystems (high coral cover and greater fish biomass). Our results indicate that human activities are significantly shaping patterns of trophic structure of reef fishes in a spatially nonuniform manner across the Pacific Ocean, by altering processes that organize communities in both "top-down" (fishing of predators) and "bottom-up" (degradation of benthic communities) contexts. © 2017 John Wiley & Sons Ltd.

    15. Geographic variation in nasal cavity form among three human groups from the Japanese Archipelago: Ecogeographic and functional implications.

      Science.gov (United States)

      Fukase, Hitoshi; Ito, Tsuyoshi; Ishida, Hajime

      2016-05-01

      Geographic variation in human nasal form has often been interpreted as a climatic adaptation, owing to the nasal air-conditioning function. The aim of this study was to further address morphofunctional issues of the nasal cavity, using three human groups from subarctic, temperate, and subtropical regions of the Japanese Archipelago: prehistoric Okhotsk, early-modern Honshu and Okinawa groups. Using three-dimensional coordinates of craniometric landmarks surrounding the nasal cavity, we compared linear measurements regarding nasal cavity form among the three groups and also conducted 3D geometric morphometrics. Both linear measurements and morphometric analyses corroborate the previously reported covariation pattern of nasal cavity shape with climate, where humans from a cold/dry climate tend to possess a relatively tall, narrow, and deep nasal cavity compared with those from a warm/humid environment. The northern Okhotsk group had overall larger cranial airways, which may be attributable to their large facial skeleton. However, the ratio of nasal/bimaxillary breadth was significantly lower in the Okhotsk group, indicating that maxillary size does not necessarily constrain the nasal breadth. In addition, despite the presence of obvious geographic clines in anterior nasal shape, posterior choanal shape lacked the north-south geographic cline. This suggests a certain level of morphofunctional independence between the anterior and posterior nasal openings. The observed geographic variations must, however, be partly considered as a reflection of different ancestral traits and population histories of the three groups. Nevertheless, the results indicate that intergroup variations in nasal cavity morphology can be largely explained by climatic conditions. Am. J. Hum. Biol. 28:343-351, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

    16. Evolution of the auditory ossicles in extant hominids: metric variation in African apes and humans

      Science.gov (United States)

      Quam, Rolf M; Coleman, Mark N; Martínez, Ignacio

      2014-01-01

      The auditory ossicles in primates have proven to be a reliable source of phylogenetic information. Nevertheless, to date, very little data have been published on the metric dimensions of the ear ossicles in African apes and humans. The present study relies on the largest samples of African ape ear ossicles studied to date to address questions of taxonomic differences and the evolutionary transformation of the ossicles in gorillas, chimpanzees and humans. Both African ape taxa show a malleus that is characterized by a long and slender manubrium and relatively short corpus, whereas humans show the opposite constellation of a short and thick manubrium and relatively long corpus. These changes in the manubrium are plausibly linked with changes in the size of the tympanic membrane. The main difference between the incus in African apes and humans seems to be related to changes in the functional length. Compared with chimpanzees, human incudes are larger in nearly all dimensions, except articular facet height, and show a more open angle between the axes. The gorilla incus resembles humans more closely in its metric dimensions, including functional length, perhaps as a result of the dramatically larger body size compared with chimpanzees. The differences between the stapedes of humans and African apes are primarily size-related, with humans being larger in nearly all dimensions. Nevertheless, some distinctions between the African apes were found in the obturator foramen and head height. Although correlations between metric variables in different ossicles were generally lower than those between variables in the same bone, variables of the malleus/incus complex appear to be more strongly correlated than those of the incus/stapes complex, perhaps reflecting the different embryological and evolutionary origins of the ossicles. The middle ear lever ratio for the African apes is similar to other haplorhines, but humans show the lowest lever ratio within primates. Very low levels

    17. High-confidence assessment of functional impact of human mitochondrial non-synonymous genome variations by APOGEE.

      Directory of Open Access Journals (Sweden)

      Stefano Castellana

      2017-06-01

      Full Text Available 24,189 are all the possible non-synonymous amino acid changes potentially affecting the human mitochondrial DNA. Only a tiny subset was functionally evaluated with certainty so far, while the pathogenicity of the vast majority was only assessed in-silico by software predictors. Since these tools proved to be rather incongruent, we have designed and implemented APOGEE, a machine-learning algorithm that outperforms all existing prediction methods in estimating the harmfulness of mitochondrial non-synonymous genome variations. We provide a detailed description of the underlying algorithm, of the selected and manually curated training and test sets of variants, as well as of its classification ability.

    18. High-resolution copy-number variation map reflects human olfactory receptor diversity and evolution.

      Directory of Open Access Journals (Sweden)

      Yehudit Hasin

      2008-11-01

      Full Text Available Olfactory receptors (ORs, which are involved in odorant recognition, form the largest mammalian protein superfamily. The genomic content of OR genes is considerably reduced in humans, as reflected by the relatively small repertoire size and the high fraction ( approximately 55% of human pseudogenes. Since several recent low-resolution surveys suggested that OR genomic loci are frequently affected by copy-number variants (CNVs, we hypothesized that CNVs may play an important role in the evolution of the human olfactory repertoire. We used high-resolution oligonucleotide tiling microarrays to detect CNVs across 851 OR gene and pseudogene loci. Examining genomic DNA from 25 individuals with ancestry from three populations, we identified 93 OR gene loci and 151 pseudogene loci affected by CNVs, generating a mosaic of OR dosages across persons. Our data suggest that approximately 50% of the CNVs involve more than one OR, with the largest CNV spanning 11 loci. In contrast to earlier reports, we observe that CNVs are more frequent among OR pseudogenes than among intact genes, presumably due to both selective constraints and CNV formation biases. Furthermore, our results show an enrichment of CNVs among ORs with a close human paralog or lacking a one-to-one ortholog in chimpanzee. Interestingly, among the latter we observed an enrichment in CNV losses over gains, a finding potentially related to the known diminution of the human OR repertoire. Quantitative PCR experiments performed for 122 sampled ORs agreed well with the microarray results and uncovered 23 additional CNVs. Importantly, these experiments allowed us to uncover nine common deletion alleles that affect 15 OR genes and five pseudogenes. Comparison to the chimpanzee reference genome revealed that all of the deletion alleles are human derived, therefore indicating a profound effect of human-specific deletions on the individual OR gene content. Furthermore, these deletion alleles may be used

    19. Economic Evaluations of Pharmacogenetic and Pharmacogenomic Screening Tests: A Systematic Review. Second Update of the Literature.

      Directory of Open Access Journals (Sweden)

      Elizabeth J J Berm

      Full Text Available Due to extended application of pharmacogenetic and pharmacogenomic screening (PGx tests it is important to assess whether they provide good value for money. This review provides an update of the literature.A literature search was performed in PubMed and papers published between August 2010 and September 2014, investigating the cost-effectiveness of PGx screening tests, were included. Papers from 2000 until July 2010 were included via two previous systematic reviews. Studies' overall quality was assessed with the Quality of Health Economic Studies (QHES instrument.We found 38 studies, which combined with the previous 42 studies resulted in a total of 80 included studies. An average QHES score of 76 was found. Since 2010, more studies were funded by pharmaceutical companies. Most recent studies performed cost-utility analysis, univariate and probabilistic sensitivity analyses, and discussed limitations of their economic evaluations. Most studies indicated favorable cost-effectiveness. Majority of evaluations did not provide information regarding the intrinsic value of the PGx test. There were considerable differences in the costs for PGx testing. Reporting of the direction and magnitude of bias on the cost-effectiveness estimates as well as motivation for the chosen economic model and perspective were frequently missing.Application of PGx tests was mostly found to be a cost-effective or cost-saving strategy. We found that only the minority of recent pharmacoeconomic evaluations assessed the intrinsic value of the PGx tests. There was an increase in the number of studies and in the reporting of quality associated characteristics. To improve future evaluations, scenario analysis including a broad range of PGx tests costs and equal costs of comparator drugs to assess the intrinsic value of the PGx tests, are recommended. In addition, robust clinical evidence regarding PGx tests' efficacy remains of utmost importance.

    20. Evaluation of prescriber responses to pharmacogenomics clinical decision support for thiopurine S-methyltransferase testing.

      Science.gov (United States)

      Ubanyionwu, Samuel; Formea, Christine M; Anderson, Benjamin; Wix, Kelly; Dierkhising, Ross; Caraballo, Pedro J

      2018-02-15

      Results of a study of prescribers' responses to a pharmacogenomics-based clinical decision support (CDS) alert designed to prompt thiopurine S -methyltransferase (TPMT) status testing are reported. A single-center, retrospective, chart review-based study was conducted to evaluate prescriber compliance with a pretest CDS alert that warned of potential thiopurine drug toxicity resulting from deficient TPMT activity due to TPMT gene polymorphism. The CDS alert was triggered when prescribers ordered thiopurine drugs for patients whose records did not indicate TPMT status or when historical thiopurine use was documented in the electronic health record. The alert pop-up also provided a link to online educational resources to guide thiopurine dosing calculations. During the 9-month study period, 500 CDS alerts were generated: in 101 cases (20%), TPMT phenotyping or TPMT genotyping was ordered; in 399 cases (80%), testing was not ordered. Multivariable regression analysis indicated that documentation of historical thiopurine use was the only independent predictor of test ordering. Among the 99 patients tested subsequent to CDS alerts, 70 (71%) had normal TPMT activity, 29 (29%) had intermediate activity, and none had deficient activity. The online resources provided thiopurine dosing recommendations applicable to 24 patients, but only 3 were prescribed guideline-supported doses after CDS alerts. The pretest CDS rule resulted in a large proportion of neglected alerts due to poor alerting accuracy and consequent alert fatigue. Prescriber usage of online thiopurine dosing resources was low. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

    1. Pharmacogenomic diversity among Brazilians: Influence of ancestry, self-reported Color and geographical origin

      Directory of Open Access Journals (Sweden)

      Guilherme eSuarez-Kurtz

      2012-11-01

      Full Text Available By virtue of being the product of the genetic admixture of three ancestral roots: Europeans, Africans and Amerindians, the present day Brazilian population displays very high levels of genomic diversity, which have important pharmacogenetic/-genomic (PGx implications. Recognition of this fact has prompted the creation of the Brazilian Pharmacogenomics Network (Refargen, a nationwide consortium of research groups, with the mission to provide leadership in PGx research and education in Brazil, with a population heath impact. Here, we present original data and review published results from a Refargen comprehensive study of the distribution of PGx polymorphisms in a representative cohort of the Brazilian people, comprising 1,034 healthy, unrelated adults, self-identified as white, brown or black, according to the Color categories adopted by the Brazilian Census. Multinomial log-linear regression analysis was applied to infer the statistical association between allele, genotype and haplotype distributions among Brazilians (response variables and self-reported Color, geographical region and biogeographical ancestry (explanatory variables, whereas Wright´s FST statistics was used to assess the extent of PGx divergence among different strata of the Brazilian population. Major PGx implications of these findings are: first, extrapolation of data from relatively well-defined ethnic groups is clearly not applicable to the majority of Brazilians; second, the frequency distribution of polymorphisms in several pharmacogenes of clinical relevance (e.g. ABCB1, CYP3A5, CYP2C9, VKORC varies continuously among Brazilians and is not captured by race/Color self-identification; third, the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of PGx studies in order to avoid spurious conclusions based on improper matching of study cohorts.

    2. Human Capital Versus Income Variations: Are They Linked in OECD Countries?

      Directory of Open Access Journals (Sweden)

      Jakub Bartak

      2016-03-01

      Full Text Available Purpose: The theory of endogenous growth suggests a number of relations between income inequality and human capital. However, empirical evidence in this field is scarce. Therefore, in this paper we aim to demonstrate the existence of interdependencies between income inequality and human capital across OECD countries.Methodology: We present findings of the endogenous growth theory on the mechanisms linking inequality with human capital. Subsequently, we attempt to verify these links empirically using the regression function estimated by means of the generalized method of moments (GMM. The empirical analysis is based on panel data from 1995–2010.Findings: The results of the study reveal the existence of a negative relationship between income inequality and health indicators (infant mortality and maternal mortality. However, we did not reach an authoritative conclusion about the relationship between income inequality and quantitative indicators of educational achievement.Research limitations: Research is limited to the sample of OECD countries. Interdependencies between income inequality and human capital could be captured more clearly using a broader sample.Originality: This paper presents one of few studies testing the relation between human capital and income inequality. The use of high-quality empirical data on inequality (SWIID data and the generalized method of moments made it possible to contribute new arguments to the discussion of empirical analyses of these economic categories.

    3. Inducible nitric oxide synthase (iNOS) regulatory region variation in non-human primates.

      Science.gov (United States)

      Roodgar, Morteza; Ross, Cody T; Kenyon, Nicholas J; Marcelino, Gretchen; Smith, David Glenn

      2015-04-01

      Inducible nitric oxide synthase (iNOS) is an enzyme that plays a key role in intracellular immune response against respiratory infections. Since various species of nonhuman primates exhibit different levels of susceptibility to infectious respiratory diseases, and since variation in regulatory regions of genes is thought to play a key role in expression levels of genes, two candidate regulatory regions of iNOS were mapped, sequenced, and compared across five species of nonhuman primates: African green monkeys (Chlorocebus sabaeus), pig-tailed macaques (Macaca nemestrina), cynomolgus macaques (Macaca fascicularis), Indian rhesus macaques (Macaca mulatta), and Chinese rhesus macaques (M. mulatta). In addition, we conducted an in silico analysis of the transcription factor binding sites associated with genetic variation in these two candidate regulatory regions across species. We found that only one of the two candidate regions showed strong evidence of involvement in iNOS regulation. Specifically, we found evidence of 13 conserved binding site candidates linked to iNOS regulation: AP-1, C/EBPB, CREB, GATA-1, GATA-3, NF-AT, NF-AT5, NF-κB, KLF4, Oct-1, PEA3, SMAD3, and TCF11. Additionally, we found evidence of interspecies variation in binding sites for several regulatory elements linked to iNOS (GATA-3, GATA-4, KLF6, SRF, STAT-1, STAT-3, OLF-1 and HIF-1) across species, especially in African green monkeys relative to other species. Given the key role of iNOS in respiratory immune response, the findings of this study might help guide the direction of future studies aimed to uncover the molecular mechanisms underlying the increased susceptibility of African green monkeys to several viral and bacterial respiratory infections. Copyright © 2015 Elsevier B.V. All rights reserved.

    4. Inter-individual variations of human mercury exposure biomarkers: a cross-sectional assessment

      Directory of Open Access Journals (Sweden)

      Einarsson Östen

      2005-10-01

      Full Text Available Abstract Background Biomarkers for mercury (Hg exposure have frequently been used to assess exposure and risk in various groups of the general population. We have evaluated the most frequently used biomarkers and the physiology on which they are based, to explore the inter-individual variations and their suitability for exposure assessment. Methods Concentrations of total Hg (THg, inorganic Hg (IHg and organic Hg (OHg, assumed to be methylmercury; MeHg were determined in whole blood, red blood cells, plasma, hair and urine from Swedish men and women. An automated multiple injection cold vapour atomic fluorescence spectrophotometry analytical system for Hg analysis was developed, which provided high sensitivity, accuracy, and precision. The distribution of the various mercury forms in the different biological media was explored. Results About 90% of the mercury found in the red blood cells was in the form of MeHg with small inter-individual variations, and part of the IHg found in the red blood cells could be attributed to demethylated MeHg. THg in plasma was associated with both IHg and MeHg, with large inter-individual variations in the distribution between red blood cells and plasma. THg in hair reflects MeHg exposure at all exposure levels, and not IHg exposure. The small fraction of IHg in hair is most probably emanating from demethylated MeHg. The inter-individual variation in the blood to hair ratio was very large. The variability seemed to decrease with increasing OHg in blood, most probably due to more frequent fish consumption and thereby blood concentrations approaching steady state. THg in urine reflected IHg exposure, also at very low IHg exposure levels. Conclusion The use of THg concentration in whole blood as a proxy for MeHg exposure will give rise to an overestimation of the MeHg exposure depending on the degree of IHg exposure, why speciation of mercury forms is needed. THg in RBC and hair are suitable proxies for MeHg exposure

    5. Validation of the 17-item Hamilton Depression Rating Scale definition of response for adults with major depressive disorder using equipercentile linking to Clinical Global Impression scale ratings: analysis of Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) data.

      Science.gov (United States)

      Bobo, William V; Angleró, Gabriela C; Jenkins, Gregory; Hall-Flavin, Daniel K; Weinshilboum, Richard; Biernacka, Joanna M

      2016-05-01

      The study aimed to define thresholds of clinically significant change in 17-item Hamilton Depression Rating Scale (HDRS-17) scores using the Clinical Global Impression-Improvement (CGI-I) Scale as a gold standard. We conducted a secondary analysis of individual patient data from the Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study, an 8-week, single-arm clinical trial of citalopram or escitalopram treatment of adults with major depression. We used equipercentile linking to identify levels of absolute and percent change in HDRS-17 scores that equated with scores on the CGI-I at 4 and 8 weeks. Additional analyses equated changes in the HDRS-7 and Bech-6 scale scores with CGI-I scores. A CGI-I score of 2 (much improved) corresponded to an absolute decrease (improvement) in HDRS-17 total score of 11 points and a percent decrease of 50-57%, from baseline values. Similar results were observed for percent change in HDRS-7 and Bech-6 scores. Larger absolute (but not percent) decreases in HDRS-17 scores equated with CGI-I scores of 2 in persons with higher baseline depression severity. Our results support the consensus definition of response based on HDRS-17 scores (>50% decrease from baseline). A similar definition of response may apply to the HDRS-7 and Bech-6. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

    6. Perspectives on Human Variation through the Lens of Diversity and Race.

      Science.gov (United States)

      Chakravarti, Aravinda

      2015-09-01

      Human populations, however defined, differ in the distribution and frequency of traits they display and diseases to which individuals are susceptible. These need to be understood with respect to three recent advances. First, these differences are multicausal and a result of not only genetic but also epigenetic and environmental factors. Second, the actions of genes, although crucial, turn out to be quite dynamic and modifiable, which contrasts with the classical view that they are inflexible machines. Third, the diverse human populations across the globe have spent too little time apart from our common origin 50,000 years ago to have developed many individually adapted traits. Human trait and disease differences by continental ancestry are thus as much the result of nongenetic as genetic forces. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

    7. Obesity and Bariatric Surgery Drive Epigenetic Variation of Spermatozoa in Humans

      DEFF Research Database (Denmark)

      Donkin, Ida; Versteyhe, Soetkin; Ingerslev, Lars R.

      2016-01-01

      Obesity is a heritable disorder, with children of obese fathers at higher risk of developing obesity. Environmental factors epigenetically influence somatic tissues, but the contribution of these factors to the establishment of epigenetic patterns in human gametes is unknown. Here, we hypothesized...... of morbidly obese men, surgery-induced weight loss was associated with a dramatic remodeling of sperm DNA methylation, notably at genetic locations implicated in the central control of appetite. Our data provide evidence that the epigenome of human spermatozoa dynamically changes under environmental pressure...

    8. In silico assessment of genetic variation in KCNA5 reveals multiple mechanisms of human atrial arrhythmogenesis

      DEFF Research Database (Denmark)

      Colman, Michael A; Ni, Haibo; Liang, Bo

      2017-01-01

      and quantify the functional impact of these KCNA5 mutations on atrial electrical activity. A multi-scale model of the human atria was updated to incorporate detailed experimental data on IKur from both wild-type and mutants. The effects of the mutations on human atrial action potential and rate dependence were...... provides new insights into understanding the mechanisms by which mutant IKur contributes to atrial arrhythmias. In addition, as IKur is an atrial-specific channel and a number of IKur-selective blockers have been developed as anti-AF agents, this study also helps to understand some contradictory results...

    9. Variations in the ultrastructure of human nasal cilia including abnormalities found in retinitis pigmentosa.

      Science.gov (United States)

      Fox, B; Bull, T B; Arden, G B

      1980-01-01

      The electron microscopic structure of cilia from the inferior turbinate of the nose was studied in 12 adults, four with chronic sinusitis, one with allergic rhinitis, two with bronchiectasis, three with deviated nasal septum, and two normals. The changes are compared with those found in nasal cilia in 14 patients with retinitis pigmentosa. There were compound cilia in the seven cases with chronic sinusitis, allergic rhinitis, and bronchiectasis but, apart from this, the structure of the cilia was similar in all 12 cases. There were variations in the microtubular pattern in about 4% of cilia, dynein arms were not seen in 4%, and in the rest an average of 5-6 dynein arms were seen in each cilium. The orientation of the cilia was 0 to 90 degrees. In the retinitis pigmentosa patients there was a highly significant increase in cilial abnormalities. The establishment on a quantitative basis of the variations in normal structure of nasal cilila facilitated the recognition of an association between cilial abnormalities and retinitis pigmentosa and should help in the identification of associations that may exist between cilial abnormalities and other diseases. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 7 Fig. 8 PMID:7400333

    10. Intra- and interhemispheric variations of diffusivity in subcortical white matter in normal human brain

      International Nuclear Information System (INIS)

      Yoshiura, Takashi; Noguchi, Tomoyuki; Hiwatashi, Akio; Togao, Osamu; Yamashita, Koji; Nagao, Eiki; Kamano, Hironori; Honda, Hiroshi

      2010-01-01

      Our purpose was to reveal potential regional variations in water molecular diffusivity within each cerebral hemisphere and across the right and left hemispheres. Diffusion-weighted images of 44 healthy right-handed adult male subjects were obtained using a diffusion tensor imaging sequence. Mean diffusivity (MD) values in subcortical white matter (WM) within 39 regions in each hemisphere were measured using an automated method. Intrahemispheric comparisons of MDs in subcortical WM were performed among six brain regions (frontal, parietal, occipital and temporal lobes and pre- and postcentral gyri). Interhemispheric comparisons of MDs were performed between the right and left counterparts of the 39 regions. In both hemispheres, diffusivity in the precentral gyrus was lower than those in other regions, while diffusivity in the parietal lobe was higher than others. MD asymmetry in which the left was lower than the right was found in the parietal lobe, middle occipital gyrus, and medial and orbital aspects of the frontal lobe. The converse asymmetry was revealed in the frontal operculum, supplementary motor cortex, temporal lobe, limbic cortices, precuneus and cuneus. Our results revealed significant intra- and interhemispheric regional variations in MD in subcortical WM, which may be related to different densities of axons and myelin sheaths. (orig.)

    11. Intra- and interhemispheric variations of diffusivity in subcortical white matter in normal human brain

      Energy Technology Data Exchange (ETDEWEB)

      Yoshiura, Takashi; Noguchi, Tomoyuki; Hiwatashi, Akio; Togao, Osamu; Yamashita, Koji; Nagao, Eiki; Kamano, Hironori; Honda, Hiroshi [Kyushu University, Department of Clinical Radiology, Graduate School of Medical Sciences, Fukuoka (Japan)

      2010-01-15

      Our purpose was to reveal potential regional variations in water molecular diffusivity within each cerebral hemisphere and across the right and left hemispheres. Diffusion-weighted images of 44 healthy right-handed adult male subjects were obtained using a diffusion tensor imaging sequence. Mean diffusivity (MD) values in subcortical white matter (WM) within 39 regions in each hemisphere were measured using an automated method. Intrahemispheric comparisons of MDs in subcortical WM were performed among six brain regions (frontal, parietal, occipital and temporal lobes and pre- and postcentral gyri). Interhemispheric comparisons of MDs were performed between the right and left counterparts of the 39 regions. In both hemispheres, diffusivity in the precentral gyrus was lower than those in other regions, while diffusivity in the parietal lobe was higher than others. MD asymmetry in which the left was lower than the right was found in the parietal lobe, middle occipital gyrus, and medial and orbital aspects of the frontal lobe. The converse asymmetry was revealed in the frontal operculum, supplementary motor cortex, temporal lobe, limbic cortices, precuneus and cuneus. Our results revealed significant intra- and interhemispheric regional variations in MD in subcortical WM, which may be related to different densities of axons and myelin sheaths. (orig.)

    12. Common variation in ISL1 confers genetic susceptibility for human congenital heart disease.

      Directory of Open Access Journals (Sweden)

      Kristen N Stevens

      Full Text Available Congenital heart disease (CHD is the most common birth abnormality and the etiology is unknown in the overwhelming majority of cases. ISLET1 (ISL1 is a transcription factor that marks cardiac progenitor cells and generates diverse multipotent cardiovascular cell lineages. The fundamental role of ISL1 in cardiac morphogenesis makes this an exceptional candidate gene to consider as a cause of complex congenital heart disease. We evaluated whether genetic variation in ISL1 fits the common variant-common disease hypothesis. A 2-stage case-control study examined 27 polymorphisms mapping to the ISL1 locus in 300 patients with complex congenital heart disease and 2,201 healthy pediatric controls. Eight genic and flanking ISL1 SNPs were significantly associated with complex congenital heart disease. A replication study analyzed these candidate SNPs in 1,044 new cases and 3,934 independent controls and confirmed that genetic variation in ISL1 is associated with risk of non-syndromic congenital heart disease. Our results demonstrate that two different ISL1 haplotypes contribute to risk of CHD in white and black/African American populations.

    13. Experimental and analytical variation in human urine in 1H NMR spectroscopy-based metabolic phenotyping studies.

      Science.gov (United States)

      Maher, Anthony D; Zirah, Séverine F M; Holmes, Elaine; Nicholson, Jeremy K

      2007-07-15

      1H NMR spectroscopy potentially provides a robust approach for high-throughput metabolic screening of biofluids such as urine and plasma, but sample handling and preparation need careful optimization to ensure that spectra accurately report biological status or disease state. We have investigated the effects of storage temperature and time on the 1H NMR spectral profiles of human urine from two participants, collected three times a day on four different days. These were analyzed using modern chemometric methods. Analytical and preparation variation (tested between -40 degrees C and room temperature) and time of storage (to 24 h) were found to be much less influential than biological variation in sample classification. Statistical total correlation spectroscopy and discriminant function methods were used to identify the specific metabolites that were hypervariable due to preparation and biology. Significant intraindividual variation in metabolite profiles were observed even for urine collected on the same day and after at least 6 h fasting. The effect of long-term storage at different temperatures was also investigated, showing urine is stable if frozen for at least 3 months and that storage at room temperature for long periods (1-3 months) results in a metabolic profile explained by bacterial activity. Presampling (e.g., previous day) intake of food and medicine can also strongly influence the urinary metabolic profiles indicating that collective detailed participant historical meta data are important for interpretation of metabolic phenotypes and for avoiding false biomarker discovery.

    14. Recon3D enables a three-dimensional view of gene variation in human metabolism

      DEFF Research Database (Denmark)

      Brunk, Elizabeth; Sahoo, Swagatika; Zielinski, Daniel C.

      2018-01-01

      Genome-scale network reconstructions have helped uncover the molecular basis of metabolism. Here we present Recon3D, a computational resource that includes three-dimensional (3D) metabolite and protein structure data and enables integrated analyses of metabolic functions in humans. We use Recon3D...

    15. Finding the molecular basis of complex genetic variation in humans and mice

      OpenAIRE

      Mott, Richard

      2006-01-01

      I survey the state of the art in complex trait analysis, including the use of new experimental and computational technologies and resources becoming available, and the challenges facing us. I also discuss how the prospects of rodent model systems compare with association mapping in humans.

    16. Variations of Human DNA Polymerase Genes as Biomarkers of Prostate Cancer Progression

      Science.gov (United States)

      2011-07-01

      Pesche S, Latil A, Muzeau F, Cussenot O, Fournier G, Longy M, Eng C, Lidereau R. 1998. PTEN/MMAC1/TEP1 involvement in primary prostate cancers. Oncogene 16...skin fibroblasts from heterozygotes for the Lesch-Nyhan syndrome : a sensitive marker for carrier detection. Hum Hered 29:64–68. 48 HUMAN MUTATION, Vol

    17. Evidence for genetic variation in human mate preferences for sexually dimorphic physical traits

      NARCIS (Netherlands)

      Verweij, K.J.H.; Burri, A.V.; Zietsch, B.P.

      2012-01-01

      Intersexual selection has been proposed as an important force in shaping a number of morphological traits that differ between human populations and/or between the sexes. Important to these accounts is the source of mate preferences for such traits, but this has not been investigated. In a large

    18. Defining the role of common variation in the genomic and biological architecture of adult human height

      DEFF Research Database (Denmark)

      Wood, Andrew R.; Esko, Tonu; Yang, Jian

      2014-01-01

      to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR...

    19. Genetic Variations in the Human Cannabinoid Receptor Gene Are Associated with Happiness

      Science.gov (United States)

      Matsunaga, Masahiro; Isowa, Tokiko; Yamakawa, Kaori; Fukuyama, Seisuke; Shinoda, Jun; Yamada, Jitsuhiro; Ohira, Hideki

      2014-01-01

      Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a relatively stable state of being happy (subjective happiness level). As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude

    20. Genetic variations in the human cannabinoid receptor gene are associated with happiness.

      Directory of Open Access Journals (Sweden)

      Masahiro Matsunaga

      Full Text Available Happiness has been viewed as a temporary emotional state (e.g., pleasure and a relatively stable state of being happy (subjective happiness level. As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater

    1. Genetic variations in the human cannabinoid receptor gene are associated with happiness.

      Science.gov (United States)

      Matsunaga, Masahiro; Isowa, Tokiko; Yamakawa, Kaori; Fukuyama, Seisuke; Shinoda, Jun; Yamada, Jitsuhiro; Ohira, Hideki

      2014-01-01

      Happiness has been viewed as a temporary emotional state (e.g., pleasure) and a relatively stable state of being happy (subjective happiness level). As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated. According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness. In Experiment 1, 198 healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers. Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers. Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude

    2. Effect of genetic variation in a Drosophila model of diabetes-associated misfolded human proinsulin.

      Science.gov (United States)

      He, Bin Z; Ludwig, Michael Z; Dickerson, Desiree A; Barse, Levi; Arun, Bharath; Vilhjálmsson, Bjarni J; Jiang, Pengyao; Park, Soo-Young; Tamarina, Natalia A; Selleck, Scott B; Wittkopp, Patricia J; Bell, Graeme I; Kreitman, Martin

      2014-02-01

      The identification and validation of gene-gene interactions is a major challenge in human studies. Here, we explore an approach for studying epistasis in humans using a Drosophila melanogaster model of neonatal diabetes mellitus. Expression of the mutant preproinsulin (hINS(C96Y)) in the eye imaginal disc mimics the human disease: it activates conserved stress-response pathways and leads to cell death (reduction in eye area). Dominant-acting variants in wild-derived inbred lines from the Drosophila Genetics Reference Panel produce a continuous, highly heritable distribution of eye-degeneration phenotypes in a hINS(C96Y) background. A genome-wide association study (GWAS) in 154 sequenced lines identified a sharp peak on chromosome 3L, which mapped to a 400-bp linkage block within an intron of the gene sulfateless (sfl). RNAi knockdown of sfl enhanced the eye-degeneration phenotype in a mutant-hINS-dependent manner. RNAi against two additional genes in the heparan sulfate (HS) biosynthetic pathway (ttv and botv), in which sfl acts, also modified the eye phenotype in a hINS(C96Y)-dependent manner, strongly suggesting a novel link between HS-modified proteins and cellular responses to misfolded proteins. Finally, we evaluated allele-specific expression difference between the two major sfl-intronic haplotypes in heterozygtes. The results showed significant heterogeneity in marker-associated gene expression, thereby leaving the causal mutation(s) and its mechanism unidentified. In conclusion, the ability to create a model of human genetic disease, map a QTL by GWAS to a specific gene, and validate its contribution to disease with available genetic resources and the potential to experimentally link the variant to a molecular mechanism demonstrate the many advantages Drosophila holds in determining the genetic underpinnings of human disease.

    3. Quantitative historical analysis uncovers a single dimension of complexity that structures global variation in human social organization

      Science.gov (United States)

      Turchin, Peter; Currie, Thomas E.; Whitehouse, Harvey; François, Pieter; Feeney, Kevin; Mullins, Daniel; Hoyer, Daniel; Collins, Christina; Grohmann, Stephanie; Mendel-Gleason, Gavin; Turner, Edward; Dupeyron, Agathe; Cioni, Enrico; Reddish, Jenny; Levine, Jill; Jordan, Greine; Brandl, Eva; Williams, Alice; Cesaretti, Rudolf; Krueger, Marta; Ceccarelli, Alessandro; Figliulo-Rosswurm, Joe; Tuan, Po-Ju; Peregrine, Peter; Marciniak, Arkadiusz; Preiser-Kapeller, Johannes; Kradin, Nikolay; Korotayev, Andrey; Palmisano, Alessio; Baker, David; Bidmead, Julye; Bol, Peter; Christian, David; Cook, Connie; Covey, Alan; Feinman, Gary; Júlíusson, Árni Daníel; Kristinsson, Axel; Miksic, John; Mostern, Ruth; Petrie, Cameron; Rudiak-Gould, Peter; ter Haar, Barend; Wallace, Vesna; Mair, Victor; Xie, Liye; Baines, John; Bridges, Elizabeth; Manning, Joseph; Lockhart, Bruce; Bogaard, Amy; Spencer, Charles

      2018-01-01

      Do human societies from around the world exhibit similarities in the way that they are structured, and show commonalities in the ways that they have evolved? These are long-standing questions that have proven difficult to answer. To test between competing hypotheses, we constructed a massive repository of historical and archaeological information known as “Seshat: Global History Databank.” We systematically coded data on 414 societies from 30 regions around the world spanning the last 10,000 years. We were able to capture information on 51 variables reflecting nine characteristics of human societies, such as social scale, economy, features of governance, and information systems. Our analyses revealed that these different characteristics show strong relationships with each other and that a single principal component captures around three-quarters of the observed variation. Furthermore, we found that different characteristics of social complexity are highly predictable across different world regions. These results suggest that key aspects of social organization are functionally related and do indeed coevolve in predictable ways. Our findings highlight the power of the sciences and humanities working together to rigorously test hypotheses about general rules that may have shaped human history. PMID:29269395

    4. Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: pharmacometabolomics-informed pharmacogenomics.

      Science.gov (United States)

      Ji, Y; Hebbring, S; Zhu, H; Jenkins, G D; Biernacka, J; Snyder, K; Drews, M; Fiehn, O; Zeng, Z; Schaid, D; Mrazek, D A; Kaddurah-Daouk, R; Weinshilboum, R M

      2011-01-01

      Major depressive disorder (MDD) is a common psychiatric disease. Selective serotonin reuptake inhibitors (SSRIs) are an important class of drugs used in the treatment of MDD. However, many patients do not respond adequately to SSRI therapy. We used a pharmacometabolomics-informed pharmacogenomic research strategy to identify citalopram/escitalopram treatment outcome biomarkers. Metabolomic assay of plasma samples from 20 escitalopram remitters and 20 nonremitters showed that glycine was negatively associated with treatment outcome (P = 0.0054). This observation was pursued by genotyping tag single-nucleotide polymorphisms (SNPs) for genes encoding glycine synthesis and degradation enzymes, using 529 DNA samples from SSRI-treated MDD patients. The rs10975641 SNP in the glycine dehydrogenase (GLDC) gene was associated with treatment outcome phenotypes. Genotyping for rs10975641 was carried out in 1,245 MDD patients in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, and its presence was significant (P = 0.02) in DNA taken from these patients. These results highlight a possible role for glycine in SSRI response and illustrate the use of pharmacometabolomics to "inform" pharmacogenomics.

    5. Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans.

      Science.gov (United States)

      Rodrigues, Sarina M; Saslow, Laura R; Garcia, Natalia; John, Oliver P; Keltner, Dacher

      2009-12-15

      Oxytocin, a peptide that functions as both a hormone and neurotransmitter, has broad influences on social and emotional processing throughout the body and the brain. In this study, we tested how a polymorphism (rs53576) of the oxytocin receptor relates to two key social processes related to oxytocin: empathy and stress reactivity. Compared with individuals homozygous for the G allele of rs53576 (GG), individuals with one or two copies of the A allele (AG/AA) exhibited lower behavioral and dispositional empathy, as measured by the "Reading the Mind in the Eyes" Test and an other-oriented empathy scale. Furthermore, AA/AG individuals displayed higher physiological and dispositional stress reactivity than GG individuals, as determined by heart rate response during a startle anticipation task and an affective reactivity scale. Our results provide evidence of how a naturally occurring genetic variation of the oxytocin receptor relates to both empathy and stress profiles.

    6. Population-genetic nature of copy number variations in the human genome.

      Science.gov (United States)

      Kato, Mamoru; Kawaguchi, Takahisa; Ishikawa, Shumpei; Umeda, Takayoshi; Nakamichi, Reiichiro; Shapero, Michael H; Jones, Keith W; Nakamura, Yusuke; Aburatani, Hiroyuki; Tsunoda, Tatsuhiko

      2010-03-01

      Copy number variations (CNVs) are universal genetic variations, and their association with disease has been increasingly recognized. We designed high-density microarrays for CNVs, and detected 3000-4000 CNVs (4-6% of the genomic sequence) per population that included CNVs previously missed because of smaller sizes and residing in segmental duplications. The patterns of CNVs across individuals were surprisingly simple at the kilo-base scale, suggesting the applicability of a simple genetic analysis for these genetic loci. We utilized the probabilistic theory to determine integer copy numbers of CNVs and employed a recently developed phasing tool to estimate the population frequencies of integer copy number alleles and CNV-SNP haplotypes. The results showed a tendency toward a lower frequency of CNV alleles and that most of our CNVs were explained only by zero-, one- and two-copy alleles. Using the estimated population frequencies, we found several CNV regions with exceptionally high population differentiation. Investigation of CNV-SNP linkage disequilibrium (LD) for 500-900 bi- and multi-allelic CNVs per population revealed that previous conflicting reports on bi-allelic LD were unexpectedly consistent and explained by an LD increase correlated with deletion-allele frequencies. Typically, the bi-allelic LD was lower than SNP-SNP LD, whereas the multi-allelic LD was somewhat stronger than the bi-allelic LD. After further investigation of tag SNPs for CNVs, we conclude that the customary tagging strategy for disease association studies can be applicable for common deletion CNVs, but direct interrogation is needed for other types of CNVs.

    7. Human cerebral cortices: signal variation on diffusion-weighted MR imaging

      Energy Technology Data Exchange (ETDEWEB)

      Asao, Chiaki [Kumamoto Regional Medical Center, Department of Radiology, Kumamoto (Japan); National Hospital Organization Kumamoto Medical Center, Department of Radiology, Kumamoto (Japan); Hirai, Toshinori; Yamashita, Yasuyuki [Kumamoto University Graduate School of Medical Sciences, Department of Diagnostic Radiology, Kumamoto (Japan); Yoshimatsu, Shunji [National Hospital Organization Kumamoto Medical Center, Department of Radiology, Kumamoto (Japan); Matsukawa, Tetsuya; Imuta, Masanori [Kumamoto Regional Medical Center, Department of Radiology, Kumamoto (Japan); Sagara, Katsuro [Kumamoto Regional Medical Center, Department of Internal Medicine, Kumamoto (Japan)

      2008-03-15

      We have often encountered high signal intensity (SI) of the cingulate gyrus and insula during diffusion-weighted magnetic resonance imaging (DW-MRI) on neurologically healthy adults. To date, cortical signal heterogeneity on DW images has not been investigated systematically. The purpose of our study was to determine whether there is regional signal variation in the brain cortices of neurologically healthy adults on DW-MR images. The SI of the cerebral cortices on DW-MR images at 1.5 T was evaluated in 50 neurologically healthy subjects (34 men, 16 women; age range 33-84 years; mean age 57.6 years). The cortical SI in the cingulate gyrus, insula, and temporal, occipital, and parietal lobes was graded relative to the SI of the frontal lobe. Contrast-to-noise ratios (CNRs) on DW-MR images were compared for each cortical area. Diffusion changes were analyzed by visually assessment of the differences in appearance among the cortices on apparent diffusion coefficient (ADC) maps. Increased SI was frequently seen in the cingulate gyrus and insula regardless of patient age. There were no significant gender- or laterality-related differences. The CNR was significantly higher in the cingulate gyrus and insula than in the other cortices (p <.01), and significant differences existed among the cortical regions (p <.001). There were no apparent ADC differences among the cortices on ADC maps. Regional signal variation of the brain cortices was observed on DW-MR images of healthy subjects, and the cingulate gyrus and insula frequently manifested high SI. These findings may help in the recognition of cortical signal abnormalities as visualized on DW-MR images. (orig.)

    8. Human cerebral cortices: signal variation on diffusion-weighted MR imaging

      International Nuclear Information System (INIS)

      Asao, Chiaki; Hirai, Toshinori; Yamashita, Yasuyuki; Yoshimatsu, Shunji; Matsukawa, Tetsuya; Imuta, Masanori; Sagara, Katsuro

      2008-01-01

      We have often encountered high signal intensity (SI) of the cingulate gyrus and insula during diffusion-weighted magnetic resonance imaging (DW-MRI) on neurologically healthy adults. To date, cortical signal heterogeneity on DW images has not been investigated systematically. The purpose of our study was to determine whether there is regional signal variation in the brain cortices of neurologically healthy adults on DW-MR images. The SI of the cerebral cortices on DW-MR images at 1.5 T was evaluated in 50 neurologically healthy subjects (34 men, 16 women; age range 33-84 years; mean age 57.6 years). The cortical SI in the cingulate gyrus, insula, and temporal, occipital, and parietal lobes was graded relative to the SI of the frontal lobe. Contrast-to-noise ratios (CNRs) on DW-MR images were compared for each cortical area. Diffusion changes were analyzed by visually assessment of the differences in appearance among the cortices on apparent diffusion coefficient (ADC) maps. Increased SI was frequently seen in the cingulate gyrus and insula regardless of patient age. There were no significant gender- or laterality-related differences. The CNR was significantly higher in the cingulate gyrus and insula than in the other cortices (p <.01), and significant differences existed among the cortical regions (p <.001). There were no apparent ADC differences among the cortices on ADC maps. Regional signal variation of the brain cortices was observed on DW-MR images of healthy subjects, and the cingulate gyrus and insula frequently manifested high SI. These findings may help in the recognition of cortical signal abnormalities as visualized on DW-MR images. (orig.)

    9. Investigation of the daily variation in iodine and creatinine excretion in human urine

      International Nuclear Information System (INIS)

      Aabech, H.S.

      1975-08-01

      Continuing earlier investigations of the level of iodine intake in Norway, the excretion of iodine in 24-hour samples of urine over 7 days has been measured for 23 persons. Three of them collected 24-hour samples of urine during continuous periods of 21, 22 and 54 days. The main aim of the investigation was to study the diurnal variation of iodine excretion , and to correlate it with diet components when connection was suspected. To this end the persons had to keep record of the diet, especially with respect to fish and fish products. The variation from day to day of the iodine excretion was much greater than expected, and the highest values were always preceded by meals of sea-fish. Mean 24-hour iodine excretion from 13 males was 266 μg/24h (range 54-2272), from 8 females 154 μg/24h (range 58-627), and from 2 children 74 μg/24h (range 33-129). Large fluctuations were present, as indicated by standard deviations that varied from 12 to 119% of the mean. None of the persons had a mean 24-hour excretion lower than the advised minimum of 1 μg iodine/kg b w. The excretion of creatinine has also been measured, and the excretion from day to day showed large fluctuations for some of the persons. In 13 males the mean 24-hour excretion of creatinine was 1.88 gram (range 0.81-2.93), and in 8 females 1.17 gram (range 0.47-1.74). In one person, who collected urine during a period of 54 days, the mean excretion of creatinine was 1.80 gram (range 1.19-2.75). (auth.)

    10. Age variations in the properties of human tibial trabecular bone and cartilage

      DEFF Research Database (Denmark)

      Ding, Ming

      2000-01-01

      , such as apparent, apparent ash and collagen densities of human tibial trabecular bone have significant relationships with age. Tissue density and mineral concentration remain constant throughout life. Trabecular bone is tougher in the younger age, i.e. fracture requires more energy. Collagen density was the single......Initiated and motivated by clinical and scientific problems such as age-related bone fracture, prosthetic loosening, bone remodeling, and degenerative bone diseases, much significant research on the properties of trabecular bone has been carried out over the last two decades. This work has mainly...... focused on the central vertebral trabecular bone, while little is known about age-related changes in the properties of human peripheral (tibial) trabecular bone. Knowledge of the properties of peripheral (tibial) trabecular bone is of major importance for the understanding of degenerative diseases...

    11. Human upper limb manipulator mass center motion and mass moments of inertia variation

      Directory of Open Access Journals (Sweden)

      Nikolova Gergana

      2018-01-01

      Full Text Available Motion control is complicated for people having traumas or neurological diseases. An underlying assumption in our work is that the motion of healthy people is optimal with respect to positioning accuracy, movement response, and energy expenditure. In this paper, a new approach for determination of the human upper limb mass-inertial characteristics is presented by using the 3D geometrical mathematical modeling analysis approach. Two examples will be given to illustrate the main features and advantages of the proposed design concepts. The objective of the work presented in this paper is a determination of the mass properties of a two joints human upper limb manipulator. Results are aimed to have application in an exoskeleton design, the design of manipulation system and external manipulation system, serving people with some motion difficulties, as well as in sport and rehabilitation.

    12. Transferrin receptors on human reticulocytes: variation in site number in hematologic disorders

      International Nuclear Information System (INIS)

      Shumak, K.H.; Rachkewich, R.A.

      1984-01-01

      Assays of binding of 125iodine-labeled ( 125 I) human transferrin were used to study transferrin receptor sites on reticulocytes from 15 normal subjects and from 66 patients with various hematologic disorders. In normal subjects, few or no transferrin receptors were detected whereas the average number of receptors per reticulocyte varied greatly from patient to patient, ranging from 0 to 67,700 in samples, from 35 patients, on which Scatchard analysis of binding of [ 125 I]-transferrin was done. Marked heterogeneity in the number of reticulocyte transferrin receptors in different hematologic disorders was also found in assays with [ 125 I]-OKT9 (monoclonal antibody to the human transferrin receptor). The number of receptors was not correlated with either the reticulocyte count or the hemoglobin

    13. Nocturnal variations in peripheral blood flow, systemic blood pressure, and heart rate in humans

      DEFF Research Database (Denmark)

      Sindrup, J H; Kastrup, J; Christensen, H

      1991-01-01

      Subcutaneous adipose tissue blood flow rate, together with systemic arterial blood pressure and heart rate under ambulatory conditions, was measured in the lower legs of 15 normal human subjects for 12-20 h. The 133Xe-washout technique, portable CdTe(Cl) detectors, and a portable data storage uni.......0001). The synchronism of the nocturnal subcutaneous hyperemia and the decrease in systemic mean arterial blood pressure point to a common, possibly central nervous or humoral, eliciting mechanism.......Subcutaneous adipose tissue blood flow rate, together with systemic arterial blood pressure and heart rate under ambulatory conditions, was measured in the lower legs of 15 normal human subjects for 12-20 h. The 133Xe-washout technique, portable CdTe(Cl) detectors, and a portable data storage unit...

    14. Striatal dopamine release and genetic variation of the serotonin 2C receptor in humans

      OpenAIRE

      Mickey, Brian J; Sanford, Benjamin J; Love, Tiffany M; Shen, Pei-Hong; Hodgkinson, Colin; Stohler, Christian S; Goldman, David; Zubieta, Jon-Kar

      2012-01-01

      Mesoaccumbal and nigrostriatal projections are sensitive to stress, and heightened stress sensitivity is thought to confer risk for neuropsychiatric disorders. Serotonin 2C (5-HT2C) receptors mediate the inhibitory effects of serotonin on dopaminergic circuitry in experimental animals, and preclinical findings have implicated 5-HT2C receptors in motivated behaviors and psychotropic drug mechanisms. In humans, a common missense single-nucleotide change (rs6318, Cys23Ser) in the 5-HT2C receptor...

    15. Human Immunodeficiency Virus (HIV) Infections; Strain and Type Variations; Diagnosis and Prevention.

      Science.gov (United States)

      1992-10-26

      Scarlatti et al. 1992 (41) 1 1 Arendrup et al. 1992 (42) SIVsm/monkey 7 0 Zhang et al. manuscript (43) B) Sequential samples: serum collected >6 months...983-990. 1991. 12. Scarlatti , G, Lombardi, V, Plebani, A, Principi, N, Chiara, V, Ferraris, G, Bucceri, A, Feny6, E M, Wigzell, H, Rossi, P, and...envelope glycoprotein gp125 of human immunodeficiency virus type2. Manuscript. M2. Scarlatti , G, Albert, J, Rossi, P, Hodara, V, Biraghi, P, Muggiasca

    16. Global and disease-associated genetic variation in the human Fanconi anemia gene family

      OpenAIRE

      Rogers, Kai J.; Fu, Wenqing; Akey, Joshua M.; Monnat, Raymond J.

      2014-01-01

      Fanconi anemia (FA) is a human recessive genetic disease resulting from inactivating mutations in any of 16 FANC (Fanconi) genes. Individuals with FA are at high risk of developmental abnormalities, early bone marrow failure and leukemia. These are followed in the second and subsequent decades by a very high risk of carcinomas of the head and neck and anogenital region, and a small continuing risk of leukemia. In order to characterize base pair-level disease-associated (DA) and population gen...

    17. Age-related variations in the microstructure of human tibial cancellous bone

      DEFF Research Database (Denmark)

      Ding, M.; Odgaard, A.; Linde, F.

      2002-01-01

      -related changes in the three-dimensional (3D) microstructure of human tibial cancellous bone. One hundred and sixty cylindrical cancellous bone specimens were produced from 40 normal proximal tibiae from 40 donors, aged 16-85 years. These specimens were micro-computed tomography (micro-CT) scanned......, and microstructural properties were determined. The specimens were then tested in compression to obtain Young's modulus. The degree of anisotropy, mean marrow space volume, and bone surface-to-volume ratio increased significantly with age. Bone volume fraction, mean trabecular volume, and bone surface density...

    18. Diurnal Variations of Human Circulating Cell-Free Micro-RNA

      DEFF Research Database (Denmark)

      Heegaard, Niels H H; Carlsen, Anting Liu; Lilje, Berit

      2016-01-01

      A 24-hour light and dark cycle-dependent rhythmicity pervades physiological processes in virtually all living organisms including humans. These regular oscillations are caused by external cues to endogenous, independent biological time-keeping systems (clocks). The rhythm is reflected by gene...... expression that varies in a circadian and specific fashion in different organs and tissues and is regulated largely by dynamic epigenetic and post-transcriptional mechanisms. This leads to well-documented oscillations of specific electrolytes, hormones, metabolites, and plasma proteins in blood samples...

    19. Variations and voids: the regulation of human cloning around the world.

      Science.gov (United States)

      Pattinson, Shaun D; Caulfield, Timothy

      2004-12-13

      No two countries have adopted identical regulatory measures on cloning. Understanding the complexity of these regulatory variations is essential. It highlights the challenges associated with the regulation of a controversial and rapidly evolving area of science and sheds light on a regulatory framework that can accommodate this reality. Using the most reliable information available, we have performed a survey of the regulatory position of thirty countries around the world regarding the creation and use of cloned embryos (see Table 1). We have relied on original and translated legislation, as well as published sources and personal communications. We have examined the regulation of both reproductive cloning (RC) and non-reproductive cloning (NRC). While most of the countries studied have enacted national legislation, the absence of legislation in seven of these countries should not be equated with the absence of regulation. Senator Morin was not correct in stating that the majority of recent legislation bans both RC and NRC. Recent regulatory moves are united only with regard to the banning of RC. While NRC is not permitted in seventeen of the countries examined, it could be permitted in up to thirteen countries. There is little consensus on the various approaches to cloning laws and policies, and the regulatory position in many countries remains uncertain.

    20. Variations and voids: the regulation of human cloning around the world

      Directory of Open Access Journals (Sweden)

      Caulfield Timothy

      2004-12-01

      Full Text Available Abstract Background No two countries have adopted identical regulatory measures on cloning. Understanding the complexity of these regulatory variations is essential. It highlights the challenges associated with the regulation of a controversial and rapidly evolving area of science and sheds light on a regulatory framework that can accommodate this reality. Methods Using the most reliable information available, we have performed a survey of the regulatory position of thirty countries around the world regarding the creation and use of cloned embryos (see Table 1. We have relied on original and translated legislation, as well as published sources and personal communications. We have examined the regulation of both reproductive cloning (RC and non-reproductive cloning (NRC. Results While most of the countries studied have enacted national legislation, the absence of legislation in seven of these countries should not be equated with the absence of regulation. Senator Morin was not correct in stating that the majority of recent legislation bans both RC and NRC. Recent regulatory moves are united only with regard to the banning of RC. While NRC is not permitted in seventeen of the countries examined, it could be permitted in up to thirteen countries. Conclusions There is little consensus on the various approaches to cloning laws and policies, and the regulatory position in many countries remains uncertain.

    1. Brief communication: Population variation in human maxillary premolar accessory ridges (MxPAR).

      Science.gov (United States)

      Burnett, Scott E; Hawkey, Diane E; Turner, Christy G

      2010-02-01

      The purpose of this brief communication is to report the results of an analysis of maxillary premolar accessory ridges (MxPAR), a common but understudied accessory ridge that may occur both mesial and distal to the central ridge of the buccal cusp of upper premolars. We developed a new five-grade scoring plaque to better categorize MxPAR variation. Subsequently, we conducted a population analysis of MxPAR frequency in 749 dental casts of South African Indian, American Chinese, Alaskan Eskimo, Tohono O'odham (Papago), Akimel O'odham (Pima), Solomon Islander, South African Bantu, and both American and South African Whites. Northeast Asian and Asian-derived populations exhibited the highest MxPAR frequencies while Indo-European samples (South African Indians, American and South African Whites) exhibited relatively low frequencies. The Solomon Islanders and South African Bantu samples exhibited intermediate frequencies. Our analysis indicates that statistically significant differences in MxPAR frequency exist between major geographic populations. As a result, the MxPAR plaque has now been added to the Arizona State University Dental Anthropology System, an important contribution as maxillary premolar traits are underrepresented in analyses of dental morphology. 2009 Wiley-Liss, Inc.

    2. Changes in radiation dose with variations in human anatomy: moderately and severely obese adults.

      Science.gov (United States)

      Clark, Landon D; Stabin, Michael G; Fernald, Michael J; Brill, Aaron B

      2010-06-01

      The phantoms used in standardized dose assessment are based on a median (i.e., 50th percentile) individual of a large population, for example, adult males or females or children of a particular age. Here we describe phantoms that model instead the influence of obesity on specific absorbed fractions (SAFs) and dose factors in adults. The literature was reviewed to evaluate how individual organ sizes change with variations in body weight in mildly and severely obese adult men and women. On the basis of the literature evaluation, changes were made to our deformable reference adult male and female total-body models. Monte Carlo simulations of radiation transport were performed. SAFs for photons were generated for mildly and severely obese adults, and comparisons were made to the reference (50th) percentile SAF values. SAFs studied between the obese phantoms and the 50th percentile reference phantoms were not significantly different from the reference 50th percentile individual, with the exception of intestines irradiating some abdominal organs, because of an increase in separation between folds caused by an increase in mesenteric adipose deposits. Some low-energy values for certain organ pairs were different, possibly due only to the statistical variability of the data at these low energies. The effect of obesity on dose calculations for internal emitters is minor and may be neglected in the routine use of standardized dose estimates.

    3. Defining the role of common variation in the genomic and biological architecture of adult human height.

      Science.gov (United States)

      Wood, Andrew R; Esko, Tonu; Yang, Jian; Vedantam, Sailaja; Pers, Tune H; Gustafsson, Stefan; Chu, Audrey Y; Estrada, Karol; Luan, Jian'an; Kutalik, Zoltán; Amin, Najaf; Buchkovich, Martin L; Croteau-Chonka, Damien C; Day, Felix R; Duan, Yanan; Fall, Tove; Fehrmann, Rudolf; Ferreira, Teresa; Jackson, Anne U; Karjalainen, Juha; Lo, Ken Sin; Locke, Adam E; Mägi, Reedik; Mihailov, Evelin; Porcu, Eleonora; Randall, Joshua C; Scherag, André; Vinkhuyzen, Anna A E; Westra, Harm-Jan; Winkler, Thomas W; Workalemahu, Tsegaselassie; Zhao, Jing Hua; Absher, Devin; Albrecht, Eva; Anderson, Denise; Baron, Jeffrey; Beekman, Marian; Demirkan, Ayse; Ehret, Georg B; Feenstra, Bjarke; Feitosa, Mary F; Fischer, Krista; Fraser, Ross M; Goel, Anuj; Gong, Jian; Justice, Anne E; Kanoni, Stavroula; Kleber, Marcus E; Kristiansson, Kati; Lim, Unhee; Lotay, Vaneet; Lui, Julian C; Mangino, Massimo; Mateo Leach, Irene; Medina-Gomez, Carolina; Nalls, Michael A; Nyholt, Dale R; Palmer, Cameron D; Pasko, Dorota; Pechlivanis, Sonali; Prokopenko, Inga; Ried, Janina S; Ripke, Stephan; Shungin, Dmitry; Stancáková, Alena; Strawbridge, Rona J; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Trompet, Stella; van der Laan, Sander W; van Setten, Jessica; Van Vliet-Ostaptchouk, Jana V; Wang, Zhaoming; Yengo, Loïc; Zhang, Weihua; Afzal, Uzma; Arnlöv, Johan; Arscott, Gillian M; Bandinelli, Stefania; Barrett, Amy; Bellis, Claire; Bennett, Amanda J; Berne, Christian; Blüher, Matthias; Bolton, Jennifer L; Böttcher, Yvonne; Boyd, Heather A; Bruinenberg, Marcel; Buckley, Brendan M; Buyske, Steven; Caspersen, Ida H; Chines, Peter S; Clarke, Robert; Claudi-Boehm, Simone; Cooper, Matthew; Daw, E Warwick; De Jong, Pim A; Deelen, Joris; Delgado, Graciela; Denny, Josh C; Dhonukshe-Rutten, Rosalie; Dimitriou, Maria; Doney, Alex S F; Dörr, Marcus; Eklund, Niina; Eury, Elodie; Folkersen, Lasse; Garcia, Melissa E; Geller, Frank; Giedraitis, Vilmantas; Go, Alan S; Grallert, Harald; Grammer, Tanja B; Gräßler, Jürgen; Grönberg, Henrik; de Groot, Lisette C P G M; Groves, Christopher J; Haessler, Jeffrey; Hall, Per; Haller, Toomas; Hallmans, Goran; Hannemann, Anke; Hartman, Catharina A; Hassinen, Maija; Hayward, Caroline; Heard-Costa, Nancy L; Helmer, Quinta; Hemani, Gibran; Henders, Anjali K; Hillege, Hans L; Hlatky, Mark A; Hoffmann, Wolfgang; Hoffmann, Per; Holmen, Oddgeir; Houwing-Duistermaat, Jeanine J; Illig, Thomas; Isaacs, Aaron; James, Alan L; Jeff, Janina; Johansen, Berit; Johansson, Åsa; Jolley, Jennifer; Juliusdottir, Thorhildur; Junttila, Juhani; Kho, Abel N; Kinnunen, Leena; Klopp, Norman; Kocher, Thomas; Kratzer, Wolfgang; Lichtner, Peter; Lind, Lars; Lindström, Jaana; Lobbens, Stéphane; Lorentzon, Mattias; Lu, Yingchang; Lyssenko, Valeriya; Magnusson, Patrik K E; Mahajan, Anubha; Maillard, Marc; McArdle, Wendy L; McKenzie, Colin A; McLachlan, Stela; McLaren, Paul J; Menni, Cristina; Merger, Sigrun; Milani, Lili; Moayyeri, Alireza; Monda, Keri L; Morken, Mario A; Müller, Gabriele; Müller-Nurasyid, Martina; Musk, Arthur W; Narisu, Narisu; Nauck, Matthias; Nolte, Ilja M; Nöthen, Markus M; Oozageer, Laticia; Pilz, Stefan; Rayner, Nigel W; Renstrom, Frida; Robertson, Neil R; Rose, Lynda M; Roussel, Ronan; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Schumacher, Fredrick R; Schunkert, Heribert; Scott, Robert A; Sehmi, Joban; Seufferlein, Thomas; Shi, Jianxin; Silventoinen, Karri; Smit, Johannes H; Smith, Albert Vernon; Smolonska, Joanna; Stanton, Alice V; Stirrups, Kathleen; Stott, David J; Stringham, Heather M; Sundström, Johan; Swertz, Morris A; Syvänen, Ann-Christine; Tayo, Bamidele O; Thorleifsson, Gudmar; Tyrer, Jonathan P; van Dijk, Suzanne; van Schoor, Natasja M; van der Velde, Nathalie; van Heemst, Diana; van Oort, Floor V A; Vermeulen, Sita H; Verweij, Niek; Vonk, Judith M; Waite, Lindsay L; Waldenberger, Melanie; Wennauer, Roman; Wilkens, Lynne R; Willenborg, Christina; Wilsgaard, Tom; Wojczynski, Mary K; Wong, Andrew; Wright, Alan F; Zhang, Qunyuan; Arveiler, Dominique; Bakker, Stephan J L; Beilby, John; Bergman, Richard N; Bergmann, Sven; Biffar, Reiner; Blangero, John; Boomsma, Dorret I; Bornstein, Stefan R; Bovet, Pascal; Brambilla, Paolo; Brown, Morris J; Campbell, Harry; Caulfield, Mark J; Chakravarti, Aravinda; Collins, Rory; Collins, Francis S; Crawford, Dana C; Cupples, L Adrienne; Danesh, John; de Faire, Ulf; den Ruijter, Hester M; Erbel, Raimund; Erdmann, Jeanette; Eriksson, Johan G; Farrall, Martin; Ferrannini, Ele; Ferrières, Jean; Ford, Ian; Forouhi, Nita G; Forrester, Terrence; Gansevoort, Ron T; Gejman, Pablo V; Gieger, Christian; Golay, Alain; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Haas, David W; Hall, Alistair S; Harris, Tamara B; Hattersley, Andrew T; Heath, Andrew C; Hengstenberg, Christian; Hicks, Andrew A; Hindorff, Lucia A; Hingorani, Aroon D; Hofman, Albert; Hovingh, G Kees; Humphries, Steve E; Hunt, Steven C; Hypponen, Elina; Jacobs, Kevin B; Jarvelin, Marjo-Riitta; Jousilahti, Pekka; Jula, Antti M; Kaprio, Jaakko; Kastelein, John J P; Kayser, Manfred; Kee, Frank; Keinanen-Kiukaanniemi, Sirkka M; Kiemeney, Lambertus A; Kooner, Jaspal S; Kooperberg, Charles; Koskinen, Seppo; Kovacs, Peter; Kraja, Aldi T; Kumari, Meena; Kuusisto, Johanna; Lakka, Timo A; Langenberg, Claudia; Le Marchand, Loic; Lehtimäki, Terho; Lupoli, Sara; Madden, Pamela A F; Männistö, Satu; Manunta, Paolo; Marette, André; Matise, Tara C; McKnight, Barbara; Meitinger, Thomas; Moll, Frans L; Montgomery, Grant W; Morris, Andrew D; Morris, Andrew P; Murray, Jeffrey C; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J; Ong, Ken K; Ouwehand, Willem H; Pasterkamp, Gerard; Peters, Annette; Pramstaller, Peter P; Price, Jackie F; Qi, Lu; Raitakari, Olli T; Rankinen, Tuomo; Rao, D C; Rice, Treva K; Ritchie, Marylyn; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Saramies, Jouko; Sarzynski, Mark A; Schwarz, Peter E H; Sebert, Sylvain; Sever, Peter; Shuldiner, Alan R; Sinisalo, Juha; Steinthorsdottir, Valgerdur; Stolk, Ronald P; Tardif, Jean-Claude; Tönjes, Anke; Tremblay, Angelo; Tremoli, Elena; Virtamo, Jarmo; Vohl, Marie-Claude; Amouyel, Philippe; Asselbergs, Folkert W; Assimes, Themistocles L; Bochud, Murielle; Boehm, Bernhard O; Boerwinkle, Eric; Bottinger, Erwin P; Bouchard, Claude; Cauchi, Stéphane; Chambers, John C; Chanock, Stephen J; Cooper, Richard S; de Bakker, Paul I W; Dedoussis, George; Ferrucci, Luigi; Franks, Paul W; Froguel, Philippe; Groop, Leif C; Haiman, Christopher A; Hamsten, Anders; Hayes, M Geoffrey; Hui, Jennie; Hunter, David J; Hveem, Kristian; Jukema, J Wouter; Kaplan, Robert C; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; Martin, Nicholas G; März, Winfried; Melbye, Mads; Moebus, Susanne; Munroe, Patricia B; Njølstad, Inger; Oostra, Ben A; Palmer, Colin N A; Pedersen, Nancy L; Perola, Markus; Pérusse, Louis; Peters, Ulrike; Powell, Joseph E; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Reinmaa, Eva; Ridker, Paul M; Rivadeneira, Fernando; Rotter, Jerome I; Saaristo, Timo E; Saleheen, Danish; Schlessinger, David; Slagboom, P Eline; Snieder, Harold; Spector, Tim D; Strauch, Konstantin; Stumvoll, Michael; Tuomilehto, Jaakko; Uusitupa, Matti; van der Harst, Pim; Völzke, Henry; Walker, Mark; Wareham, Nicholas J; Watkins, Hugh; Wichmann, H-Erich; Wilson, James F; Zanen, Pieter; Deloukas, Panos; Heid, Iris M; Lindgren, Cecilia M; Mohlke, Karen L; Speliotes, Elizabeth K; Thorsteinsdottir, Unnur; Barroso, Inês; Fox, Caroline S; North, Kari E; Strachan, David P; Beckmann, Jacques S; Berndt, Sonja I; Boehnke, Michael; Borecki, Ingrid B; McCarthy, Mark I; Metspalu, Andres; Stefansson, Kari; Uitterlinden, André G; van Duijn, Cornelia M; Franke, Lude; Willer, Cristen J; Price, Alkes L; Lettre, Guillaume; Loos, Ruth J F; Weedon, Michael N; Ingelsson, Erik; O'Connell, Jeffrey R; Abecasis, Goncalo R; Chasman, Daniel I; Goddard, Michael E; Visscher, Peter M; Hirschhorn, Joel N; Frayling, Timothy M

      2014-11-01

      Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

    4. Defining the role of common variation in the genomic and biological architecture of adult human height

      Science.gov (United States)

      Chu, Audrey Y; Estrada, Karol; Luan, Jian’an; Kutalik, Zoltán; Amin, Najaf; Buchkovich, Martin L; Croteau-Chonka, Damien C; Day, Felix R; Duan, Yanan; Fall, Tove; Fehrmann, Rudolf; Ferreira, Teresa; Jackson, Anne U; Karjalainen, Juha; Lo, Ken Sin; Locke, Adam E; Mägi, Reedik; Mihailov, Evelin; Porcu, Eleonora; Randall, Joshua C; Scherag, André; Vinkhuyzen, Anna AE; Westra, Harm-Jan; Winkler, Thomas W; Workalemahu, Tsegaselassie; Zhao, Jing Hua; Absher, Devin; Albrecht, Eva; Anderson, Denise; Baron, Jeffrey; Beekman, Marian; Demirkan, Ayse; Ehret, Georg B; Feenstra, Bjarke; Feitosa, Mary F; Fischer, Krista; Fraser, Ross M; Goel, Anuj; Gong, Jian; Justice, Anne E; Kanoni, Stavroula; Kleber, Marcus E; Kristiansson, Kati; Lim, Unhee; Lotay, Vaneet; Lui, Julian C; Mangino, Massimo; Leach, Irene Mateo; Medina-Gomez, Carolina; Nalls, Michael A; Nyholt, Dale R; Palmer, Cameron D; Pasko, Dorota; Pechlivanis, Sonali; Prokopenko, Inga; Ried, Janina S; Ripke, Stephan; Shungin, Dmitry; Stancáková, Alena; Strawbridge, Rona J; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Trompet, Stella; van der Laan, Sander W; van Setten, Jessica; Van Vliet-Ostaptchouk, Jana V; Wang, Zhaoming; Yengo, Loïc; Zhang, Weihua; Afzal, Uzma; Ärnlöv, Johan; Arscott, Gillian M; Bandinelli, Stefania; Barrett, Amy; Bellis, Claire; Bennett, Amanda J; Berne, Christian; Blüher, Matthias; Bolton, Jennifer L; Böttcher, Yvonne; Boyd, Heather A; Bruinenberg, Marcel; Buckley, Brendan M; Buyske, Steven; Caspersen, Ida H; Chines, Peter S; Clarke, Robert; Claudi-Boehm, Simone; Cooper, Matthew; Daw, E Warwick; De Jong, Pim A; Deelen, Joris; Delgado, Graciela; Denny, Josh C; Dhonukshe-Rutten, Rosalie; Dimitriou, Maria; Doney, Alex SF; Dörr, Marcus; Eklund, Niina; Eury, Elodie; Folkersen, Lasse; Garcia, Melissa E; Geller, Frank; Giedraitis, Vilmantas; Go, Alan S; Grallert, Harald; Grammer, Tanja B; Gräßler, Jürgen; Grönberg, Henrik; de Groot, Lisette C.P.G.M.; Groves, Christopher J; Haessler, Jeffrey; Hall, Per; Haller, Toomas; Hallmans, Goran; Hannemann, Anke; Hartman, Catharina A; Hassinen, Maija; Hayward, Caroline; Heard-Costa, Nancy L; Helmer, Quinta; Hemani, Gibran; Henders, Anjali K; Hillege, Hans L; Hlatky, Mark A; Hoffmann, Wolfgang; Hoffmann, Per; Holmen, Oddgeir; Houwing-Duistermaat, Jeanine J; Illig, Thomas; Isaacs, Aaron; James, Alan L; Jeff, Janina; Johansen, Berit; Johansson, Åsa; Jolley, Jennifer; Juliusdottir, Thorhildur; Junttila, Juhani; Kho, Abel N; Kinnunen, Leena; Klopp, Norman; Kocher, Thomas; Kratzer, Wolfgang; Lichtner, Peter; Lind, Lars; Lindström, Jaana; Lobbens, Stéphane; Lorentzon, Mattias; Lu, Yingchang; Lyssenko, Valeriya; Magnusson, Patrik KE; Mahajan, Anubha; Maillard, Marc; McArdle, Wendy L; McKenzie, Colin A; McLachlan, Stela; McLaren, Paul J; Menni, Cristina; Merger, Sigrun; Milani, Lili; Moayyeri, Alireza; Monda, Keri L; Morken, Mario A; Müller, Gabriele; Müller-Nurasyid, Martina; Musk, Arthur W; Narisu, Narisu; Nauck, Matthias; Nolte, Ilja M; Nöthen, Markus M; Oozageer, Laticia; Pilz, Stefan; Rayner, Nigel W; Renstrom, Frida; Robertson, Neil R; Rose, Lynda M; Roussel, Ronan; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Schumacher, Fredrick R; Schunkert, Heribert; Scott, Robert A; Sehmi, Joban; Seufferlein, Thomas; Shi, Jianxin; Silventoinen, Karri; Smit, Johannes H; Smith, Albert Vernon; Smolonska, Joanna; Stanton, Alice V; Stirrups, Kathleen; Stott, David J; Stringham, Heather M; Sundström, Johan; Swertz, Morris A; Syvänen, Ann-Christine; Tayo, Bamidele O; Thorleifsson, Gudmar; Tyrer, Jonathan P; van Dijk, Suzanne; van Schoor, Natasja M; van der Velde, Nathalie; van Heemst, Diana; van Oort, Floor VA; Vermeulen, Sita H; Verweij, Niek; Vonk, Judith M; Waite, Lindsay L; Waldenberger, Melanie; Wennauer, Roman; Wilkens, Lynne R; Willenborg, Christina; Wilsgaard, Tom; Wojczynski, Mary K; Wong, Andrew; Wright, Alan F; Zhang, Qunyuan; Arveiler, Dominique; Bakker, Stephan JL; Beilby, John; Bergman, Richard N; Bergmann, Sven; Biffar, Reiner; Blangero, John; Boomsma, Dorret I; Bornstein, Stefan R; Bovet, Pascal; Brambilla, Paolo; Brown, Morris J; Campbell, Harry; Caulfield, Mark J; Chakravarti, Aravinda; Collins, Rory; Collins, Francis S; Crawford, Dana C; Cupples, L Adrienne; Danesh, John; de Faire, Ulf; den Ruijter, Hester M; Erbel, Raimund; Erdmann, Jeanette; Eriksson, Johan G; Farrall, Martin; Ferrannini, Ele; Ferrières, Jean; Ford, Ian; Forouhi, Nita G; Forrester, Terrence; Gansevoort, Ron T; Gejman, Pablo V; Gieger, Christian; Golay, Alain; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Haas, David W; Hall, Alistair S; Harris, Tamara B; Hattersley, Andrew T; Heath, Andrew C; Hengstenberg, Christian; Hicks, Andrew A; Hindorff, Lucia A; Hingorani, Aroon D; Hofman, Albert; Hovingh, G Kees; Humphries, Steve E; Hunt, Steven C; Hypponen, Elina; Jacobs, Kevin B; Jarvelin, Marjo-Riitta; Jousilahti, Pekka; Jula, Antti M; Kaprio, Jaakko; Kastelein, John JP; Kayser, Manfred; Kee, Frank; Keinanen-Kiukaanniemi, Sirkka M; Kiemeney, Lambertus A; Kooner, Jaspal S; Kooperberg, Charles; Koskinen, Seppo; Kovacs, Peter; Kraja, Aldi T; Kumari, Meena; Kuusisto, Johanna; Lakka, Timo A; Langenberg, Claudia; Le Marchand, Loic; Lehtimäki, Terho; Lupoli, Sara; Madden, Pamela AF; Männistö, Satu; Manunta, Paolo; Marette, André; Matise, Tara C; McKnight, Barbara; Meitinger, Thomas; Moll, Frans L; Montgomery, Grant W; Morris, Andrew D; Morris, Andrew P; Murray, Jeffrey C; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J; Ong, Ken K; Ouwehand, Willem H; Pasterkamp, Gerard; Peters, Annette; Pramstaller, Peter P; Price, Jackie F; Qi, Lu; Raitakari, Olli T; Rankinen, Tuomo; Rao, DC; Rice, Treva K; Ritchie, Marylyn; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Saramies, Jouko; Sarzynski, Mark A; Schwarz, Peter EH; Sebert, Sylvain; Sever, Peter; Shuldiner, Alan R; Sinisalo, Juha; Steinthorsdottir, Valgerdur; Stolk, Ronald P; Tardif, Jean-Claude; Tönjes, Anke; Tremblay, Angelo; Tremoli, Elena; Virtamo, Jarmo; Vohl, Marie-Claude; Amouyel, Philippe; Asselbergs, Folkert W; Assimes, Themistocles L; Bochud, Murielle; Boehm, Bernhard O; Boerwinkle, Eric; Bottinger, Erwin P; Bouchard, Claude; Cauchi, Stéphane; Chambers, John C; Chanock, Stephen J; Cooper, Richard S; de Bakker, Paul IW; Dedoussis, George; Ferrucci, Luigi; Franks, Paul W; Froguel, Philippe; Groop, Leif C; Haiman, Christopher A; Hamsten, Anders; Hayes, M Geoffrey; Hui, Jennie; Hunter, David J.; Hveem, Kristian; Jukema, J Wouter; Kaplan, Robert C; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; Martin, Nicholas G; März, Winfried; Melbye, Mads; Moebus, Susanne; Munroe, Patricia B; Njølstad, Inger; Oostra, Ben A; Palmer, Colin NA; Pedersen, Nancy L; Perola, Markus; Pérusse, Louis; Peters, Ulrike; Powell, Joseph E; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Reinmaa, Eva; Ridker, Paul M; Rivadeneira, Fernando; Rotter, Jerome I; Saaristo, Timo E; Saleheen, Danish; Schlessinger, David; Slagboom, P Eline; Snieder, Harold; Spector, Tim D; Strauch, Konstantin; Stumvoll, Michael; Tuomilehto, Jaakko; Uusitupa, Matti; van der Harst, Pim; Völzke, Henry; Walker, Mark; Wareham, Nicholas J; Watkins, Hugh; Wichmann, H-Erich; Wilson, James F; Zanen, Pieter; Deloukas, Panos; Heid, Iris M; Lindgren, Cecilia M; Mohlke, Karen L; Speliotes, Elizabeth K; Thorsteinsdottir, Unnur; Barroso, Inês; Fox, Caroline S; North, Kari E; Strachan, David P; Beckmann, Jacques S.; Berndt, Sonja I; Boehnke, Michael; Borecki, Ingrid B; McCarthy, Mark I; Metspalu, Andres; Stefansson, Kari; Uitterlinden, André G; van Duijn, Cornelia M; Franke, Lude; Willer, Cristen J; Price, Alkes L.; Lettre, Guillaume; Loos, Ruth JF; Weedon, Michael N; Ingelsson, Erik; O’Connell, Jeffrey R; Abecasis, Goncalo R; Chasman, Daniel I; Goddard, Michael E

      2014-01-01

      Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants. PMID:25282103

    5. Normal variations in the isotopic composition of metabolically relevant transition metals in human blood

      Science.gov (United States)

      Van Heghe, L.; Cloquet, C.; Vanhaecke, F.

      2012-04-01

      Cu, Fe and Zn are transition metals with great catalytic, structural and regulating importance in the human body. Hence, an aberrant metabolism of these elements can have serious implications on the health of a person. It is assumed that, due to differences in isotope fractionation, the isotopic composition of these elements in whole blood of patients can be different from that in blood of healthy subjects. Therefore, isotopic analysis of the element affected by the disease can be a promising approach for early diagnosis. A method for isotopic analysis of Cu, Fe and Zn in human whole blood was developed. The simultaneous chromatographic isolation of these elements and the conditions for isotope ratio measurement via multi-collector ICP - mass spectrometry (MC-ICP-MS) were optimized. So far, only whole blood of supposedly healthy volunteers (reference population) was analyzed. Results for Fe confirmed the known differences in isotopic composition between male and female blood. It is also shown that other parameters can have influence as well, e.g., the isotopic composition of Zn seems to be governed by the diet.

    6. Variation of Human Hairiness: A Possible Adaptation to Solar Radiation and Melanin

      Directory of Open Access Journals (Sweden)

      Dhugga Amrita

      2014-07-01

      Full Text Available Many theories have been advanced to explain human hairlessness, however, there is no consensus. This study of 76 males observed that skin reflectance measuring skin colouration and melanin pigmentation correlated with hair size and follicle density. Individuals with a greater concentration of melanin within the superficial layer of the skin had a lower follicle density and smaller sizes of hairs. In contrast, individuals with a lower melanin concentration and lighter skin colour had a full range of hairiness. This leads to the suggestion that over the course of human evolution, high concentrations of melanin in consistently exposed to ultraviolet radiation areas developed first and that hair loss was a consequence of competition in the skin between melanin production and hair growth. Darker pigmented skin and lower follicle density are significantly correlated (R2=0.283; p<0.05. Individuals with darker skin had a mean of 4.91 follicles per cm2 whereas those with lighter skin reflectance had 11.20 follicles per cm2. This suggests that increased concentrations of melanin in the basal layer of the epidermis may limit hairiness by negatively influencing the skin's ability to produce hair.

    7. EFFECTS OF HUMAN IMPACTS AND CLIMATE VARIATION ON FORESTS: THE RIETI BASIN SINCE MEDIEVAL TIME

      Directory of Open Access Journals (Sweden)

      S. Mensing

      2013-03-01

      Full Text Available A number of recent paleoenvironmental studies have argued that abrupt changes in climate have been the primary cause for societal collapse. Many social scientists, including anthropologists and environmental historians, reject environmental explanations as deterministic and overly simplistic. They argue that socio-political decisions contribute to environmental change and that efforts to study societal vulnerability within a human-environment system must include analysis of complex social structures. There is a gap in our understanding of how past societies responded to climate change because there are very few interdisciplinary studies that integrate both physical and behavioral sciences in paleoenvironmental reconstructions. While there is a general sense that modern societies are more insulated than pre-industrial societies from the effects of climate change, this may not prove to be true. A more complete understanding of how both natural and human-caused changes have affected the environment in the past can potentially guide decisions aimed at promoting future sustainability. Here we present a project funded by the United States National Science Foundation that will explicitly integrate paleoenvironmental reconstruction with socioeconomic history in a local context to identify linkages between social and environmental change associated with climate variability.

    8. Genetic variation in polyunsaturated fatty acid metabolism and its potential relevance for human development and health.

      Science.gov (United States)

      Glaser, Claudia; Lattka, Eva; Rzehak, Peter; Steer, Colin; Koletzko, Berthold

      2011-04-01

      Blood and tissue contents of polyunsaturated fatty acid (PUFA) and long-chain PUFA (LC-PUFA) are related to numerous health outcomes including cardiovascular health, allergies, mental health and cognitive development. Evidence has accumulated to show that in addition to diet, common polymorphisms in the fatty acid desaturase (FADS) gene cluster have very marked effects on human PUFA and LC-PUFA status. Recent results suggest that in addition to fatty acid desaturase 1 and fatty acid desaturase 2, the gene product of fatty acid desaturase 3 is associated with desaturating activity. New data have become available to show that FADS single nucleotide polymorphisms (SNPs) also modulate docosahexaenoic acid status in pregnancy as well as LC-PUFA levels in children and in human milk. There are indications that FADS SNPs modulate the risk for allergic disorders and eczema, and the effect of breastfeeding on later cognitive development. Mechanisms by which FADS SNPs modulate PUFA levels in blood, breast milk and tissues should be explored further. More studies are required to explore the effects of FADS gene variants in populations with different ethnic backgrounds, lifestyles and dietary habits, and to investigate in greater depth the interaction of gene variants, diet and clinical end points, including immune response and developmental outcomes. Analyses of FADS gene variants should be included into all sizeable cohort and intervention studies addressing biological effects of PUFA and LC-PUFA in order to consider these important confounders, and to enhance study sensitivity and precision. © 2011 Blackwell Publishing Ltd.

    9. Investigating the sex-related geometric variation of the human cranium.

      Science.gov (United States)

      Bertsatos, Andreas; Papageorgopoulou, Christina; Valakos, Efstratios; Chovalopoulou, Maria-Eleni

      2018-01-29

      Accurate sexing methods are of great importance in forensic anthropology since sex assessment is among the principal tasks when examining human skeletal remains. The present study explores a novel approach in assessing the most accurate metric traits of the human cranium for sex estimation based on 80 ectocranial landmarks from 176 modern individuals of known age and sex from the Athens Collection. The purpose of the study is to identify those distance and angle measurements that can be most effectively used in sex assessment. Three-dimensional landmark coordinates were digitized with a Microscribe 3DX and analyzed in GNU Octave. An iterative linear discriminant analysis of all possible combinations of landmarks was performed for each unique set of the 3160 distances and 246,480 angles. Cross-validated correct classification as well as multivariate DFA on top performing variables reported 13 craniometric distances with over 85% classification accuracy, 7 angles over 78%, as well as certain multivariate combinations yielding over 95%. Linear regression of these variables with the centroid size was used to assess their relation to the size of the cranium. In contrast to the use of generalized procrustes analysis (GPA) and principal component analysis (PCA), which constitute the common analytical work flow for such data, our method, although computational intensive, produced easily applicable discriminant functions of high accuracy, while at the same time explored the maximum of cranial variability.

    10. Intraskeletal variation in human cortical osteocyte lacunar density: Implications for bone quality assessment

      Directory of Open Access Journals (Sweden)

      Randee L. Hunter

      2016-12-01

      Full Text Available Osteocytes and their lacunocanalicular network have been identified as the regulator of bone quality and function by exerting extensive influence over metabolic processes, mechanical adaptation, and mineral homeostasis. Recent research has shown that osteocyte apoptosis leads to a decrease in bone quality and increase in bone fragility mediated through its effects on remodeling. The purpose of this study is to investigate variation in cortical bone osteocyte lacunar density with respect to major factors including sex, age, and intracortical porosity to establish both regional and systemic trends. Samples from the midshaft femur, midshaft rib and distal one-third diaphysis of the radius were recovered from 30 modern cadaveric individuals (15 males and 15 females ranging from 49 to 100 years old. Thick ground undecalcified histological (80 μm cross-sections were made and imaged under bright field microscopy. Osteocyte lacunar density (Ot.Lc.N/B.Ar and intracortical porosity (%Po.Ar were quantified. No significant sex differences in Ot.Lc.N/B.Ar or %Po.Ar were found in any element. Linear regressions demonstrated a significant decrease in osteocyte lacunar density (Ot.Lc.N/B.Ar and increase in intracortical porosity (%Po.Ar with age for the sex-pooled sample in the femur (R2 = 0.208, 0.297 respectively and radius (R2 = 0.108, 0.545 respectively. Age was unable to significantly predict osteocyte lacunar density or intracortical porosity in the rib (R2 = 0.058, 0.114 respectively. Comparisons of regression coefficients demonstrated a systemic trend in the decrease in osteocyte lacunar density (Ot.Lc.N/B.Ar and increase in intracortical porosity (%Po.Ar with age. In each element, intracortical porosity was significantly negatively correlated with lacunar density for which the radius demonstrated the strongest relationship (r = −0.746. Using pore number (Po.N as a proxy for available vascularity to support the osteocyte population, Po

    11. Global pharmacogenomics: distribution of CYP3A5 polymorphisms and phenotypes in the Brazilian population.

      Directory of Open Access Journals (Sweden)

      Guilherme Suarez-Kurtz

      Full Text Available The influence of self-reported "race/color", geographical origin and genetic ancestry on the distribution of three functional CYP3A5 polymorphisms, their imputed haplotypes and inferred phenotypes was examined in 909 healthy, adult Brazilians, self-identified as White, Brown or Black ("race/color" categories of the Brazilian census. The cohort was genotyped for CYP3A5*3 (rs776746, CYP3A5*6 (rs10264272 and CYP3A5*7 (rs41303343, CYP3A5 haplotypes were imputed and CYP3A5 metabolizer phenotypes were inferred according to the number of defective CYP3A5 alleles. Estimates of the individual proportions of Amerindian, African and European ancestry were available for the entire cohort. Multinomial log-linear regression models were applied to infer the statistical association between the distribution of CYP3A5 alleles, haplotypes and phenotypes (response variables, and self-reported Color, geographical region and ancestry (explanatory variables. We found that Color per se or in combination with geographical region associates significantly with the distribution of CYP3A5 variant alleles and CYP3A5 metabolizer phenotypes, whereas geographical region per se influences the frequency distribution of CYP3A5 variant alleles. The odds of having the default CYP3A5*3 allele and the poor metabolizer phenotype increases continuously with the increase of European ancestry and decrease of African ancestry. The opposite trend is observed in relation to CYP3A5*6, CYP3A5*7, the default CYP3A5*1 allele, and both the extensive and intermediate phenotypes. No significant effect of Amerindian ancestry on the distribution of CYP3A5 alleles or phenotypes was observed. In conclusion, this study strongly supports the notion that the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of pharmacogenomic studies, and dealt with as a continuous variable, rather than proportioned in arbitrary categories that do not capture the

    12. Genetics of VEGF serum variation in human isolated populations of cilento: importance of VEGF polymorphisms.

      Directory of Open Access Journals (Sweden)

      Daniela Ruggiero

      Full Text Available Vascular Endothelial Growth Factor (VEGF is the main player in angiogenesis. Because of its crucial role in this process, the study of the genetic factors controlling VEGF variability may be of particular interest for many angiogenesis-associated diseases. Although some polymorphisms in the VEGF gene have been associated with a susceptibility to several disorders, no genome-wide search on VEGF serum levels has been reported so far. We carried out a genome-wide linkage analysis in three isolated populations and we detected a strong linkage between VEGF serum levels and the 6p21.1 VEGF region in all samples. A new locus on chromosome 3p26.3 significantly linked to VEGF serum levels was also detected in a combined population sample. A sequencing of the gene followed by an association study identified three common single nucleotide polymorphisms (SNPs influencing VEGF serum levels in one population (Campora, two already reported in the literature (rs3025039, rs25648 and one new signal (rs3025020. A fourth SNP (rs41282644 was found to affect VEGF serum levels in another population (Cardile. All the identified SNPs contribute to the related population linkages (35% of the linkage explained in Campora and 15% in Cardile. Interestingly, none of the SNPs influencing VEGF serum levels in one population was found to be associated in the two other populations. These results allow us to exclude the hypothesis that the common variants located in the exons, intron-exon junctions, promoter and regulative regions of the VEGF gene may have a causal effect on the VEGF variation. The data support the alternative hypothesis of a multiple rare variant model, possibly consisting in distinct variants in different populations, influencing VEGF serum levels.

    13. Seasonal variation in plasma lipids and lipases in young healthy humans.

      Science.gov (United States)

      Cambras, Trinitat; Baena-Fustegueras, Juan A; Pardina, Eva; Ricart-Jané, David; Rossell, Joana; Díez-Noguera, Antoni; Peinado-Onsurbe, Julia

      2017-01-01

      Although intermediate metabolism is known to follow circadian rhythms, little information is available on the variation in lipase activities (lipoprotein and hepatic lipase, LPL and HL, respectively) and lipids throughout the year. In a cross-sectional study, we collected and analysed blood from 245 healthy students (110 men and 135 women) between 18 and 25 years old from the University of Barcelona throughout the annual campaign (March, May, October and December) of the blood bank. All subjects gave their written informed consent to participate. All blood samples were taken after breakfast at 8:00 and 11:00 am. Plasma glucose, total plasma protein, triacylglycerides (TAG), free fatty acids (FFA), free cholesterol and esterified cholesterol (FC and TC, respectively), cholesterol in low-density lipoproteins (cLDL), cholesterol in high-density lipoproteins (cHDL), phospholipids (PL) and lipase activities (LPL and HL) were determined. Cosinor analysis was used to evaluate the presence (significance of fit cosine curve to data and variance explained by rhythm) and characteristics of possible 12-month rhythms (acrophase, MESOR and amplitude). Statistically significant seasonal rhythms were detected for all the variables studied except proteins, with most of them peaking in the winter season. The lowest value for cLDL and the HL occurs in summer, while for cHDL and the LPL it is in winter. These findings demonstrate for the first time that in physiological conditions, plasma LPL and HL activities and lipids follow seasonal rhythms. The metabolic significance of this pattern is discussed.

    14. Variations in Urine Calcium Isotope: Composition Reflect Changes in Bone Mineral Balance in Humans

      Science.gov (United States)

      Skulan, Joseph; Anbar, Ariel; Bullen, Thomas; Puzas, J. Edward; Shackelford, Linda; Smith, Scott M.

      2004-01-01

      Changes in bone mineral balance cause rapid and systematic changes in the calcium isotope composition of human urine. Urine from subjects in a 17 week bed rest study was analyzed for calcium isotopic composition. Comparison of isotopic data with measurements of bone mineral density and metabolic markers of bone metabolism indicates the calcium isotope composition of urine reflects changes in bone mineral balance. Urine calcium isotope composition probably is affected by both bone metabolism and renal processes. Calcium isotope. analysis of urine and other tissues may provide information on bone mineral balance that is in important respects better than that available from other techniques, and illustrates the usefulness of applying geochemical techniques to biomedical problems.

    15. Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging.

      Science.gov (United States)

      Yokoyama, Jennifer S; Marx, Gabe; Brown, Jesse A; Bonham, Luke W; Wang, Dan; Coppola, Giovanni; Seeley, William W; Rosen, Howard J; Miller, Bruce L; Kramer, Joel H; Dubal, Dena B

      2017-04-01

      Cognitive decline is a major biomedical challenge as the global population ages. Elevated levels of the longevity factor klotho suppress aging, enhance cognition, and promote synaptic plasticity and neural resilience against aging and Alzheimer's disease (AD)-related pathogenic proteins. Here, we examined the relationship between human genetic variants of KLOTHO and systemic klotho levels - and assessed neuroanatomic correlates of serum klotho in a cohort of healthy older adults. Serum klotho levels were increased with KL-VS heterozygosity, as anticipated. We report, for the first time, that serum klotho levels were paradoxically decreased with KL-VS homozygosity. Further, we found that higher serum klotho levels were associated with measures of greater intrinsic connectivity in key functional networks of the brain vulnerable to aging and AD such as the fronto-parietal and default mode networks. Our findings suggest that elevated klotho promotes a resilient brain, possibly through increased network connectivity of critical brain regions.

    16. Phenotype Variation in Human Immunodeficiency virus Type 1 Transmission and Disease Progression

      Directory of Open Access Journals (Sweden)

      Mariangela Cavarelli

      2009-01-01

      Full Text Available Human immunodeficiency virus type I (HIV-1 infects target cells through interaction with the CD4 molecule and chemokine receptors, mainly CCR5 and CXCR4. Viral isolates can be phenotypically classified based on the co-receptor they utilize to infect target cells. Thus, R5 and X4 virus use respectively CCR5 and CXCR4, whereas R5X4 virus can use either CCR5 or CXCR4. This review describes the central role played by co-receptor expression and usage for HIV-1 cell tropism, transmission and pathogenesis. We discuss various hypotheses proposed to explain the preferential transmission of R5 viruses and the mechanisms driving the change of HIV-1 co-receptor usage in the course of infection. Recent insights in the intrinsic variability of R5 viruses and their role in influencing disease progression in both adults and children are also discussed.

    17. Phenotype variation in human immunodeficiency virus type 1 transmission and disease progression.

      Science.gov (United States)

      Cavarelli, Mariangela; Scarlatti, Gabriella

      2009-01-01

      Human immunodeficiency virus type I (HIV-1) infects target cells through interaction with the CD4 molecule and chemokine receptors, mainly CCR5 and CXCR4. Viral isolates can be phenotypically classified based on the co-receptor they utilize to infect target cells. Thus, R5 and X4 virus use respectively CCR5 and CXCR4, whereas R5X4 virus can use either CCR5 or CXCR4. This review describes the central role played by co-receptor expression and usage for HIV-1 cell tropism, transmission and pathogenesis. We discuss various hypotheses proposed to explain the preferential transmission of R5 viruses and the mechanisms driving the change of HIV-1 co-receptor usage in the course of infection. Recent insights in the intrinsic variability of R5 viruses and their role in influencing disease progression in both adults and children are also discussed.

    18. Human insulin polymorphism upon ligand binding and pH variation: the case of 4-ethylresorcinol.

      Science.gov (United States)

      Fili, S; Valmas, A; Norrman, M; Schluckebier, G; Beckers, D; Degen, T; Wright, J; Fitch, A; Gozzo, F; Giannopoulou, A E; Karavassili, F; Margiolaki, I

      2015-09-01

      This study focuses on the effects of the organic ligand 4-ethylresorcinol on the crystal structure of human insulin using powder X-ray crystallography. For this purpose, systematic crystallization experiments have been conducted in the presence of the organic ligand and zinc ions within the pH range 4.50-8.20, while observing crystallization behaviour around the isoelectric point of insulin. High-throughput crystal screening was performed using a laboratory X-ray diffraction system. The most representative samples were selected for synchrotron X-ray diffraction measurements, which took place at the European Synchrotron Radiation Facility (ESRF) and the Swiss Light Source (SLS). Four different crystalline polymorphs have been identified. Among these, two new phases with monoclinic symmetry have been found, which are targets for the future development of microcrystalline insulin drugs.

    19. High-Frequency EEG Variations in Children with Autism Spectrum Disorder during Human Faces Visualization

      Directory of Open Access Journals (Sweden)

      Celina A. Reis Paula

      2017-01-01

      Full Text Available Autism spectrum disorder (ASD is a neuropsychiatric disorder characterized by the impairment in the social reciprocity, interaction/language, and behavior, with stereotypes and signs of sensory function deficits. Electroencephalography (EEG is a well-established and noninvasive tool for neurophysiological characterization and monitoring of the brain electrical activity, able to identify abnormalities related to frequency range, connectivity, and lateralization of brain functions. This research aims to evidence quantitative differences in the frequency spectrum pattern between EEG signals of children with and without ASD during visualization of human faces in three different expressions: neutral, happy, and angry. Quantitative clinical evaluations, neuropsychological evaluation, and EEG of children with and without ASD were analyzed paired by age and gender. The results showed stronger activation in higher frequencies (above 30 Hz in frontal, central, parietal, and occipital regions in the ASD group. This pattern of activation may correlate with developmental characteristics in the children with ASD.

    20. Evidence for genetic variation in human mate preferences for sexually dimorphic physical traits.

      Directory of Open Access Journals (Sweden)

      Karin J H Verweij

      Full Text Available Intersexual selection has been proposed as an important force in shaping a number of morphological traits that differ between human populations and/or between the sexes. Important to these accounts is the source of mate preferences for such traits, but this has not been investigated. In a large sample of twins, we assess forced-choice, dichotomous mate preferences for height, skin colour, hair colour and length, chest hair, facial hair, and breast size. Across the traits, identical twins reported more similar preferences than nonidentical twins, suggesting genetic effects. However, the relative magnitude of estimated genetic and environmental effects differed greatly and significantly between different trait preferences, with heritability estimates ranging from zero to 57%.

    1. Regional fibrocartilage variations in human anterior cruciate ligament tibial insertion: a histological three-dimensional reconstruction.

      Science.gov (United States)

      Dai, Can; Guo, Lin; Yang, Liu; Wu, Yi; Gou, Jingyue; Li, Bangchun

      2015-02-01

      We studied anterior cruciate ligament (ACL) tibial insertion architecture in humans and investigated regional differences that could suggest unequal force transmission from ligament to bone. ACL tibial insertions were processed histologically. With Photoshop software, digital images taken from the histological slides were collaged, contour lines were drawn, and different gray values were filled based on the structure. The data were exported to Amira software for three-dimensional reconstruction. The uncalcified fibrocartilage (UF) layer was divided into three regions: lateral, medial and posterior according to the architecture. The UF zone was significantly thicker laterally than medially or posteriorly (p fibrocartilage (CF) thickness was significantly greater in the lateral part of the enthesis compared to the medial and posterior parts (p < 0.05). The UF quantity (more UF laterally) corresponding to the CF quantity (more CF laterally) at the ACL tibial insertion provides further evidence suggesting that the load transferred from the ACL to the tibia was greater laterally than medially and posteriorly.

    2. Variation in the loss of O6-methylguanine-DNA methyltransferase during immortalization of human fibroblasts.

      Science.gov (United States)

      Green, M H; Karran, P; Lowe, J E; Priestley, A; Arlett, C F; Mayne, L

      1990-01-01

      We have examined O6-methylguanine-DNA methyltransferase (MT) activity in four human fibroblast cell lines during immortalization. Transfection of primary fibroblasts with the plasmid pSV3gpt or pSV3neo, which encode the SV40 large T antigen, confers a transformed phenotype but not immediate immortality. After a period of growth (pre-crisis) the cells enter a quiescent phase (crisis) from which an immortal clone of cells eventually grows out. From measurements of MT activity in extracts of cells taken at different defined stages of the immortalization process, we conclude that the establishment of a Mex- (MT-deficient) cell population is not specifically associated with cellular transformation or with any particular stage of immortalization. It appears that in different cell populations the change from Mex+ to Mex- may occur at different times during the immortalization process and that the change may be very abrupt.

    3. Rapid detection of structural variation in a human genome using nanochannel-based genome mapping technology

      DEFF Research Database (Denmark)

      Cao, Hongzhi; Hastie, Alex R.; Cao, Dandan

      2014-01-01

      mutations; however, none of the current detection methods are comprehensive, and currently available methodologies are incapable of providing sufficient resolution and unambiguous information across complex regions in the human genome. To address these challenges, we applied a high-throughput, cost......-effective genome mapping technology to comprehensively discover genome-wide SVs and characterize complex regions of the YH genome using long single molecules (>150 kb) in a global fashion. RESULTS: Utilizing nanochannel-based genome mapping technology, we obtained 708 insertions/deletions and 17 inversions larger...... fosmid data. Of the remaining 270 SVs, 260 are insertions and 213 overlap known SVs in the Database of Genomic Variants. Overall, 609 out of 666 (90%) variants were supported by experimental orthogonal methods or historical evidence in public databases. At the same time, genome mapping also provides...

    4. Variation in consumption of human milk oligosaccharides by infant gut-associated strains of Bifidobacterium breve.

      Science.gov (United States)

      Ruiz-Moyano, Santiago; Totten, Sarah M; Garrido, Daniel A; Smilowitz, Jennifer T; German, J Bruce; Lebrilla, Carlito B; Mills, David A

      2013-10-01

      Human milk contains a high concentration of complex oligosaccharides that influence the composition of the intestinal microbiota in breast-fed infants. Previous studies have indicated that select species such as Bifidobacterium longum subsp. infantis and Bifidobacterium bifidum can utilize human milk oligosaccharides (HMO) in vitro as the sole carbon source, while the relatively few B. longum subsp. longum and Bifidobacterium breve isolates tested appear less adapted to these substrates. Considering the high frequency at which B. breve is isolated from breast-fed infant feces, we postulated that some B. breve strains can more vigorously consume HMO and thus are enriched in the breast-fed infant gastrointestinal tract. To examine this, a number of B. breve isolates from breast-fed infant feces were characterized for the presence of different glycosyl hydrolases that participate in HMO utilization, as well as by their ability to grow on HMO or specific HMO species such as lacto-N-tetraose (LNT) and fucosyllactose. All B. breve strains showed high levels of growth on LNT and lacto-N-neotetraose (LNnT), and, in general, growth on total HMO was moderate for most of the strains, with several strain differences. Growth and consumption of fucosylated HMO were strain dependent, mostly in isolates possessing a glycosyl hydrolase family 29 α-fucosidase. Glycoprofiling of the spent supernatant after HMO fermentation by select strains revealed that all B. breve strains can utilize sialylated HMO to a certain extent, especially sialyl-lacto-N-tetraose. Interestingly, this specific oligosaccharide was depleted before neutral LNT by strain SC95. In aggregate, this work indicates that the HMO consumption phenotype in B. breve is variable; however, some strains display specific adaptations to these substrates, enabling more vigorous consumption of fucosylated and sialylated HMO. These results provide a rationale for the predominance of this species in breast-fed infant feces and

    5. MitoLSDB: a comprehensive resource to study genotype to phenotype correlations in human mitochondrial DNA variations.

      Directory of Open Access Journals (Sweden)

      Shamnamole K

      Full Text Available Human mitochondrial DNA (mtDNA encodes a set of 37 genes which are essential structural and functional components of the electron transport chain. Variations in these genes have been implicated in a broad spectrum of diseases and are extensively reported in literature and various databases. In this study, we describe MitoLSDB, an integrated platform to catalogue disease association studies on mtDNA (http://mitolsdb.igib.res.in. The main goal of MitoLSDB is to provide a central platform for direct submissions of novel variants that can be curated by the Mitochondrial Research Community. MitoLSDB provides access to standardized and annotated data from literature and databases encompassing information from 5231 individuals, 675 populations and 27 phenotypes. This platform is developed using the Leiden Open (source Variation Database (LOVD software. MitoLSDB houses information on all 37 genes in each population amounting to 132397 variants, 5147 unique variants. For each variant its genomic location as per the Revised Cambridge Reference Sequence, codon and amino acid change for variations in protein-coding regions, frequency, disease/phenotype, population, reference and remarks are also listed. MitoLSDB curators have also reported errors documented in literature which includes 94 phantom mutations, 10 NUMTs, six documentation errors and one artefactual recombination. MitoLSDB is the largest repository of mtDNA variants systematically standardized and presented using the LOVD platform. We believe that this is a good starting resource to curate mtDNA variants and will facilitate direct submissions enhancing data coverage, annotation in context of pathogenesis and quality control by ensuring non-redundancy in reporting novel disease associated variants.

    6. Local variations in {sup 14}C - How is bomb-pulse dating of human tissues and cells affected?

      Energy Technology Data Exchange (ETDEWEB)

      Stenstroem, Kristina, E-mail: Kristina.Stenstrom@nuclear.lu.s [Lund University, Department of Physics, Division of Nuclear Physics, Box 118, SE-221 00 Lund (Sweden); Skog, Goeran [Lund University, GeoBiosphere Science Centre, Geocentrum II, Soelvegatan 12, SE-223 672 Lund (Sweden); Nilsson, Carl Magnus [Lund University, Department of Physics, Division of Nuclear Physics, Box 118, SE-221 00 Lund (Sweden); Lund University, Department of Medical Radiation Physics, Malmoe University Hospital, SE-205 02 Malmoe (Sweden); Hellborg, Ragnar [Lund University, Department of Physics, Division of Nuclear Physics, Box 118, SE-221 00 Lund (Sweden); Svegborn, Sigrid Leide [Lund University, Department of Medical Radiation Physics, Malmoe University Hospital, SE-205 02 Malmoe (Sweden); Georgiadou, Elisavet [Lund University, Department of Physics, Division of Nuclear Physics, Box 118, SE-221 00 Lund (Sweden); Mattsson, Soeren [Lund University, Department of Medical Radiation Physics, Malmoe University Hospital, SE-205 02 Malmoe (Sweden)

      2010-04-15

      Atmospheric nuclear weapons testing in the late 1950s and early 1960s almost doubled the amount of {sup 14}C in the atmosphere. The resulting {sup 14}C 'bomb-pulse' has been shown to provide useful age information in e.g. forensic and environmental sciences, biology and the geosciences. The technique is also currently being used for retrospective cell dating in man, in order to provide insight into the rate of formation of new cells in the human body. Bomb-pulse dating relies on precise measurements of the declining {sup 14}C concentration in atmospheric CO{sub 2} collected at clean-air sites. However, it is not always recognized that the calculations can be complicated in some cases by significant local variations in the specific activity of {sup 14}C in carbon in the air and foodstuff. This paper presents investigations of local {sup 14}C variations in the vicinities of nuclear installations and laboratories using {sup 14}C. Levels of {sup 14}C in workers using this radioisotope are also discussed.

    7. Effect of variation of geometric parameters on the flow within a synthetic models of lower human airways

      Science.gov (United States)

      Espinosa Moreno, Andres Santiago; Duque Daza, Carlos Alberto

      2017-11-01

      The effects of variation of two geometric parameters, such as bifurcation angle and carina rounding radius, during the respiratory inhalation process, are studied numerically using two synthetic models of lower human airways. Laminar flow simulations were performed for six angles and three rounding radius, for 500, 1000, 1500 and 2000 for Reynolds numbers. Numerical results showed the existence of a direct relationship between the deformation of the velocity profiles (effect produced by the bifurcation) and the vortical structures observed through the secondary flow patterns. It is observed that the location of the vortices (and their related saddle point) is associated with the displacement of the velocity peak. On the other hand, increasing the angle and the rounding radius seems to bring about a growth of the pressure drop, which in turn displaces the distribution and peaks of the maximum shear stresses of the carina, that is, of the bifurcation point. Some physiological effects associated with the phenomena produced by these geometric variations are also discussed.

    8. Impact of seasonal variation, age and smoking status on human semen parameters: The Massachusetts General Hospital experience

      Science.gov (United States)

      Chen, Zuying; Godfrey-Bailey, Linda; Schiff, Isaac; Hauser, Russ

      2004-01-01

      Background To investigate the relationship of human semen parameters with season, age and smoking status. Methods The present study used data from subjects recruited into an ongoing cross-sectional study on the relationship between environmental agents and semen characteristics. Our population consisted of 306 patients who presented to the Vincent Memorial Andrology Laboratory of Massachusetts General Hospital for semen evaluation. Sperm concentration and motility were measured with computer aided sperm analysis (CASA). Sperm morphology was scored using Tygerberg Kruger strict criteria. Regression analyses were used to investigate the relationships between semen parameters and season, age and smoking status, adjusting for abstinence interval. Results Sperm concentration in the spring was significantly higher than in winter, fall and summer (p seasons. There were no statistically significant relationships between semen parameters and smoking status, though current smokers tended to have lower sperm concentration. We also did not find a statistically significant relationship between age and semen parameters. Conclusions We found seasonal variations in sperm concentration and suggestive evidence of seasonal variation in sperm motility and percent sperm with normal morphology. Although smoking status was not a significant predictor of semen parameters, this may have been due to the small number of current smokers in the study. PMID:15507127

    9. [Seasonal variations in the myocardial infarction incidence and possible effects of geomagnetic micropulsations on the cardiovascular system in humans].

      Science.gov (United States)

      Kleĭmenova, N G; Kozyreva, O V; Breus, T K; Rapoport, S I

      2007-01-01

      The analysis of the ambulance calls in Moscow, related to myocardial infarction (85.000 events), sudden death (71.700 events), and hypertension crises (165.500 events) over the period of 1979-1981 demonstrated their clear seasonal variations with a profound summer minimum and a winter maximum. The same results were obtained in the analysis of statistical monthly data on sudden death from infarction in Bulgaria over the period of 15 years (1970-1985). However, there are a great number of clinical and statistical studies confirming the rises in the incidence of myocardial infarction, hypertension crise, and sudden death during geomagnetic disturbances, which have maximum occurrence near equinox, not in winter. In order to explain this contradiction, we suggested that one of critical factors that affect the human cardiovascular system is geomagnetic micropulsations Pc1 having the frequency comparable with the frequency of heart rate beatings and winter maximum in their occurrence. The results of a comparative analysis of data of ambulance calls in Moscow related to myocardial infarction and sudden death and the catalog of Pc1 observations at the geophysical observatory "Borok" (Yaroslavl region) are presented. It is shown that in approximately 70% of days with an anomalously large number of ambulance calls related to myocardial infarction, Pc1 micropulsations have been registered. The probability of simultaneous occurrence of myocardial infarction and Pc1 in the winter season was 1.5 times greater than their accidental coincidence. Moreover, it was found that in winter the effects of magnetic storms and Pc1 IM(A) were much higher than in summer. We suggested that one of possible reasons for the seasonal variations in the occurrence of myocardial infarction is an increase in the production of the pineal hormone melatonin in winter which leads to an unstable state of the human organism and an increase in its sensitivity to the effect of geomagnetic pulsations.

    10. Quantifying seasonal and diel variation in Anopheline and Culex human biting rates in Southern Ecuador.

      Science.gov (United States)

      Ryan, Sadie J; Lippi, Catherine A; Boersch-Supan, Philipp H; Heydari, Naveed; Silva, Mercy; Adrian, Jefferson; Noblecilla, Leonardo F; Ayala, Efraín B; Encalada, Mayling D; Larsen, David A; Krisher, Jesse T; Krisher, Lyndsay; Fregosi, Lauren; Stewart-Ibarra, Anna M

      2017-11-22

      Quantifying mosquito biting rates for specific locations enables estimation of mosquito-borne disease risk, and can inform intervention efforts. Measuring biting itself is fraught with ethical concerns, so the landing rate of mosquitoes on humans is often used as a proxy measure. Southern coastal Ecuador was historically endemic for malaria (Plasmodium falciparum and Plasmodium vivax), although successful control efforts in the 2000s eliminated autochthonous transmission (since 2011). This study presents an analysis of data collected during the elimination period. Human landing catch (HLC) data for three mosquito taxa: two malaria vectors, Anopheles albimanus and Anopheles punctimacula, and grouped Culex spp. were examined for this study. These data were collected by the National Vector Control Service of the Ministry of Health over a 5-year time span (2007-2012) in five cities in southern coastal Ecuador, at multiple households, in all months of the year, during dusk-dawn (18:00-6:00) hours, often at both indoor and outdoor locations. Hurdle models were used to determine if biting activity was fundamentally different for the three taxa, and to identify spatial and temporal factors influencing bite rate. Due to the many different approaches to studying and quantifying bite rates in the literature, a glossary of terms was created, to facilitate comparative studies in the future. Biting trends varied significantly with species and time. All taxa exhibited exophagic feeding behavior, and outdoor locations increased both the odds and incidence of bites across taxa. Anopheles albimanus was most frequently observed biting, with an average of 4.7 bites/h. The highest and lowest respective months for significant biting activity were March and July for An. albimanus, July and August for An. punctimacula, and February and July for Culex spp. Fine-scale differences in endophagy and exophagy, and temporal differences among months and hours exist in biting patterns among

    11. Natural variations in calcium isotope composition as a monitor of bone mineral balance in humans.

      Science.gov (United States)

      Skulan, J.; Anbar, A.; Thomas, B.; Smith, S.

      2004-12-01

      The skeleton is the largest reservoir of calcium in the human body and is responsible for the short term control of blood levels of this element. Accurate measurement of changes in bone calcium balance is critical to understanding how calcium metabolism responds to physiological and environmental changes and, more specifically, to diagnosing and evaluating the effectiveness of treatments for osteoporosis and other serious calcium-related disorders. It is very difficult to measure bone calcium balance using current techniques, however, because these techniques rely either on separate estimates of bone resorption and formation that are not quantitatively comparable, or on complex and expensive studies of calcium kinetics using administered isotopic tracers. This difficulty is even more apparent and more severe for measurements of short-term changes in bone calcium balance that do not produce detectable changes in bone mineral density. Calcium isotopes may provide a novel means of addressing this problem. The foundation of this isotope application is the ca. 1.3 per mil fractionation of calcium during bone formation, favoring light calcium in the bone. This fractionation results in a steady-state isotopic offset between calcium in bone and calcium in soft tissues, blood and urine. Perturbations to this steady state due to changes in the net formation or resorption of bone should be reflected in changes in the isotopic composition of soft tissues and fluids. Here we present evidence that easily detectable shifts in the natural calcium isotope composition of human urine rapidly reflect changes in bone calcium balance. Urine from subjects in a 17-week bed rest study was analyzed for calcium isotopic composition. Bed rest promotes net resorption of bone, shifting calcium from bone to soft tissues, blood and urine. The calcium isotope composition of patients in this study shifted toward lighter values during bed rest, consistent with net resorption of isotopically

    12. Dynamic knee alignment and collateral knee laxity and its variations in normal humans

      Directory of Open Access Journals (Sweden)

      Kamal eDeep

      2015-11-01

      Full Text Available Alignment of normal, arthritic and replaced human knees is a much debated subject as is the collateral ligamentous laxity. Traditional quantitative values have been challenged. Methods used to measure these are also not without flaws. Authors review the recent literature and a novel method of measurement of these values has been included. This method includes use of computer navigation technique in clinic setting for assessment of the normal or affected knee before the surgery. Computer navigation has been known for achievement of alignment accuracy during knee surgery. Now its use in clinic setting has added to the inventory of measurement methods. Authors dispel the common myth of straight mechanical axis in normal knees and also look at quantification of amount of collateral knee laxity. Based on the scientific studies it has been shown that the mean alignment is in varus in normal knees. It changes from lying non weight bearing position to standing weight bearing position in both coronal and the sagittal planes. It also varies with gender and race. The collateral laxity is also different for males and females. Further studies are needed to define the ideal alignment and collateral laxity which the surgeon should aim for individual knees.

    13. Human papillomavirus 33 worldwide genetic variation and associated risk of cervical cancer

      Science.gov (United States)

      Chen, Alyce A.; Heideman, Daniëlle A.M.; Boon, Debby; Chen, Zigui; Burk, Robert D.; De Vuyst, Hugo; Gheit, Tarik; Snijders, Peter J.F.; Tommasino, Massimo; Franceschi, Silvia; Clifford, Gary M.

      2014-01-01

      Human papillomavirus (HPV) 33, a member of the HPV16-related alpha-9 species group, is found in approximately 5% of cervical cancers worldwide. The current study aimed to characterize the genetic diversity of HPV33 and to explore the association of HPV33 variants with the risk for cervical cancer. Taking advantage of the International Agency for Research on Cancer biobank, we sequenced the entire E6 and E7 open reading frames of 213 HPV33-positive cervical samples from 30 countries. We identified 28 HPV33 variants that formed 5 phylogenetic groups: the previously identified A1, A2, and B (sub) lineages and the novel A3 and C (sub)lineages. The A1 sublineage was strongly over-represented in cervical cases compared to controls in both Africa and Europe. In conclusion, we provide a classification system for HPV33 variants based on the sequence of E6 and E7 and suggest that the association of HPV33 with cervical cancer may differ by variant (sub)lineage. PMID:24314666

    14. The cross-cultural variation of predictors of human papillomavirus vaccination intentions.

      Science.gov (United States)

      Lechuga, Julia; Swain, Geoffrey R; Weinhardt, Lance S

      2011-02-01

      The influence of health beliefs on human papillomavirus (HPV) vaccine acceptability have been extensively documented in past research. However, studies documenting the generalizability of prior findings to culturally diverse participants are lacking. The importance of generalizability studies is underscored by the immense disparities in cervical cancer rates across ethnicities. Moreover, theory in cultural psychology suggests that beliefs derived from personal expectations may not be the strongest predictors of intentions in individuals socialized in collectivist cultures. The purpose of this research was to investigate the strongest predictors of mothers' intentions to vaccinate their daughters across three cultural groups: Hispanic, non-Hispanic white, and African American. One hundred fifty mothers were recruited from Public Health Department clinics in Milwaukee, Wisconsin. Mothers were asked to answer measures that assessed personal and normative predictors of intentions. Results indicated that predictors of vaccination intentions varied cross-culturally. Specifically, culture moderated the influence of norms on intentions. Interventions designed for Hispanics may be more effective if norms, rather than attitudes, are targeted.

    15. Variation in clinical phenotype of human infection among genetic groups of Blastomyces dermatitidis

      Science.gov (United States)

      Meece, Jennifer K.; Anderson, Jennifer L.; Gruszka, Sarah; Sloss, Brian L.; Sullivan, Bradley; Reed, Kurt D.

      2013-01-01

      Background. Blastomyces dermatitidis, the etiologic agent of blastomycosis, has 2 genetic groups and shows varied clinical presentation, ranging from silent infections to fulminant respiratory disease and dissemination. The objective of this study was to determine whether clinical phenotype and outcomes vary based on the infecting organism's genetic group.Methods. We used microsatellites to genotype 227 clinical isolates of B. dermatitidis from Wisconsin patients. For each isolate, corresponding clinical disease characteristics and patient demographic information were abstracted from electronic health records and Wisconsin Division of Health reportable disease forms and questionnaires.Results. In univariate analysis, group 1 isolates were more likely to be associated with pulmonary-only infections (P 1 month (P smoking status (P = .0001) remained predictors for group 2 infections.Conclusions. This study identified previously unknown associations between clinical phenotype of human infection and genetic groups of B. dermatitidis and provides a framework for further investigations of the genetic basis for virulence in B. dermatitidis.

    16. Genetic Variation among Major Human Geographic Groups Supports a Peculiar Evolutionary Trend in PAX9

      Science.gov (United States)

      Paixão-Côrtes, Vanessa R.; Meyer, Diogo; Pereira, Tiago V.; Mazières, Stéphane; Elion, Jacques; Krishnamoorthy, Rajagopal; Zago, Marco A.; Silva, Wilson A.; Salzano, Francisco M.; Bortolini, Maria Cátira

      2011-01-01

      A total of 172 persons from nine South Amerindian, three African and one Eskimo populations were studied in relation to the Paired box gene 9 (PAX9) exon 3 (138 base pairs) as well as its 5′and 3′flanking intronic segments (232 bp and 220 bp, respectively) and integrated with the information available for the same genetic region from individuals of different geographical origins. Nine mutations were scored in exon 3 and six in its flanking regions; four of them are new South American tribe-specific singletons. Exon3 nucleotide diversity is several orders of magnitude higher than its intronic regions. Additionally, a set of variants in the PAX9 and 101 other genes related with dentition can define at least some dental morphological differences between Sub-Saharan Africans and non-Africans, probably associated with adaptations after the modern human exodus from Africa. Exon 3 of PAX9 could be a good molecular example of how evolvability works. PMID:21298044

    17. Genetic variation among major human geographic groups supports a peculiar evolutionary trend in PAX9.

      Directory of Open Access Journals (Sweden)

      Vanessa R Paixão-Côrtes

      Full Text Available A total of 172 persons from nine South Amerindian, three African and one Eskimo populations were studied in relation to the Paired box gene 9 (PAX9 exon 3 (138 base pairs as well as its 5'and 3'flanking intronic segments (232 bp and 220 bp, respectively and integrated with the information available for the same genetic region from individuals of different geographical origins. Nine mutations were scored in exon 3 and six in its flanking regions; four of them are new South American tribe-specific singletons. Exon3 nucleotide diversity is several orders of magnitude higher than its intronic regions. Additionally, a set of variants in the PAX9 and 101 other genes related with dentition can define at least some dental morphological differences between Sub-Saharan Africans and non-Africans, probably associated with adaptations after the modern human exodus from Africa. Exon 3 of PAX9 could be a good molecular example of how evolvability works.

    18. Global Variation of Human Papillomavirus Genotypes and Selected Genes Involved in Cervical Malignancies.

      Science.gov (United States)

      Husain, R S Akram; Ramakrishnan, V

      2015-01-01

      Carcinoma of the cervix is ranked second among the top 5 cancers affecting women globally. Parallel to other cancers, it is also a complex disease involving numerous factors such as human papillomavirus (HPV) infection followed by the activity of oncogenes and environmental factors. The incidence rate of the disease remains high in developing countries due to lack of awareness, followed by mass screening programs, various socioeconomic issues, and low usage of preventive vaccines. Over the past 3 decades, extensive research has taken place in cervical malignancy to elucidate the role of host genes in the pathogenesis of the disease, yet it remains one of the most prevalent diseases. It is imperative that recent genome-wide techniques be used to determine whether carcinogenesis of oncogenes is associated with cervical cancer at the molecular level and to translate that knowledge into developing diagnostic and therapeutic tools. The aim of this study was to discuss HPV predominance with their genotype distribution worldwide, and in India, as well as to discuss the newly identified oncogenes related to cervical cancer in current scenario. Using data from various databases and robust technologies, oncogenes associated with cervical malignancies were identified and are explained in concise manner. Due to the advent of recent technologies, new candidate genes are explored and can be used as precise biomarkers for screening and developing drug targets. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

    19. Variation in sensitizing effect of caffeine in human tumour cell lines after γ-irradiation

      International Nuclear Information System (INIS)

      Valenzuela, M.T.; Almodovar, M.R. de; Mateos, S.; McMillan, T.J.

      2000-01-01

      We have investigated whether the protective role of the G2 checkpoint has increasing importance when the p53-dependent G1 checkpoint is inactivated. We have studied the differential effect of caffeine by clonogenic assays and flow cytometry in three human tumour cell lines with different functionality of p53 protein. The radiosensitizing effect of caffeine (2 mM) expressed itself as a significant decrease in surviving fraction at 2 Gy and a significant increase in α-values in RT112 and TE671, both with non-functional p53. However, no radiosensitizing effect was seen in cells with a normal p53 function (MCF-7 BUS). Two millimoles of caffeine also caused important changes in the cell cycle progression after irradiation. MCF-7 BUS showed a G1 arrest after irradiation and an early G2 arrest but those cells that reached the second G2 did not arrest significantly. In contrast, TE671 exhibited radiosensitization by caffeine, no G1 arrest, a G2 arrest in those cells irradiated in G2, no significant accumulation in the second G2 but an overall delay in release from the first cell cycle, which could be abrogated by caffeine. RT112 was similar to TE671 except that the emphasis in a G2 arrest was shifted from the block in cells irradiated in G2 to those irradiated at other cell cycle phases. The data presented confirm that p53 status can be a significant determinant of the efficacy of caffeine as radiosensitizer in these tumour cell lines, and document the importance of the G2 checkpoint in this effect. (author)

    20. Relationship between human physiological parameters and geomagnetic variations of solar origin

      Science.gov (United States)

      Dimitrova, S.

      Results presented concern influence of increased geomagnetic activity on some human physiological parameters. The blood pressure and heart rate of 86 volunteers were measured on working days in autumn 2001 (01/10 09/11) and in spring 2002 (08/04 28/05). These periods were chosen because of maximal expected geomagnetic activity. Altogether 2799 recordings were obtained and analysed. Questionnaire information about subjective psycho-physiological complaints was also gathered. MANOVA was employed to check the significance of the influence of three factors on the physiological parameters under consideration. The factors were the following: (1) planetary geomagnetic activity level estimated by Ap-index and divided into five levels; (2) gender males and females; (3) blood pressure degree persons in the group examined were divided into hypotensive, normotensive and hypertensive. Post hoc analysis was performed to elicit the significance of differences in the factors’ levels. The average arterial blood pressure of the group was found to increase significantly with the increase of geomagnetic activity level. The average increment of systolic and diastolic blood pressure of the group examined reached 9%. This effect was present irrespectively of gender. Results obtained suppose that hypertensive persons have the highest sensitivity and the hypotensive persons have the lowest sensitivity of the arterial blood pressure to increase of geomagnetic activity. The results did not show significant changes in the heart rate. The percentage of the persons who reported subjective psycho-physiological complaints was also found to increase significantly with the geomagnetic activity increase and the highest sensitivity was revealed for the hypertensive females.

    1. Human longevity and common variations in the LMNA gene: a meta-analysis

      Science.gov (United States)

      Conneely, Karen N.; Capell, Brian C.; Erdos, Michael R.; Sebastiani, Paola; Solovieff, Nadia; Swift, Amy J.; Baldwin, Clinton T.; Budagov, Temuri; Barzilai, Nir; Atzmon, Gil; Puca, Annibale A.; Perls, Thomas T.; Geesaman, Bard J.; Boehnke, Michael; Collins, Francis S.

      2012-01-01

      Summary A mutation in the LMNA gene is responsible for the most dramatic form of premature aging, Hutchinson-Gilford progeria syndrome (HGPS). Several recent studies have suggested that protein products of this gene might have a role in normal physiological cellular senescence. To explore further LMNA's possible role in normal aging, we genotyped 16 SNPs over a span of 75.4 kb of the LMNA gene on a sample of long-lived individuals (US Caucasians with age ≥95 years, N=873) and genetically matched younger controls (N=443). We tested all common non-redundant haplotypes (frequency ≥ 0.05) based on subgroups of these 16 SNPs for association with longevity. The most significant haplotype, based on 4 SNPs, remained significant after adjustment for multiple testing (OR = 1.56, P=2.5×10−5, multiple-testing-adjusted P=0.0045). To attempt to replicate these results, we genotyped 3448 subjects from four independent samples of long-lived individuals and control subjects from 1) the New England Centenarian Study (NECS) (N=738), 2) the Southern Italian Centenarian Study (SICS) (N=905), 3) France (N=1103), and 4) the Einstein Ashkenazi Longevity Study (N=702). We replicated the association with the most significant haplotype from our initial analysis in the NECS sample (OR = 1.60, P=0.0023), but not in the other three samples (P>.15). In a meta-analysis combining all five samples, the best haplotype remained significantly associated with longevity after adjustment for multiple testing in the initial and follow-up samples (OR = 1.18, P=7.5×10−4, multiple-testing-adjusted P=0.037). These results suggest that LMNA variants may play a role in human lifespan. PMID:22340368

    2. Global analysis of genetic variation in human arsenic (+ 3 oxidation state) methyltransferase (AS3MT)

      International Nuclear Information System (INIS)

      Fujihara, Junko; Soejima, Mikiko; Yasuda, Toshihiro; Koda, Yoshiro; Agusa, Tetsuro; Kunito, Takashi; Tongu, Miki; Yamada, Takaya; Takeshita, Haruo

      2010-01-01

      Human arsenic (+ 3 oxidation state) methyltransferase (AS3MT) is known to catalyze the methylation of arsenite. The objective of this study was to investigate the diversity of the AS3MT gene at the global level. The distribution of 18 single nucleotide polymorphisms (SNPs) in AS3MT was performed in 827 individuals from 10 populations (Japanese, Korean, Chinese, Mongolian, Tibetans, Sri Lankan Tamils, Sri Lankan Sinhalese, Nepal Tamangs, Ovambo, and Ghanaian). In the African populations, the A allele in A6144T was not observed; the allele frequencies of C35587 were much lower than those in other populations; the allele frequencies of A37616 and C37950 were relatively higher than those in other populations. Among Asian populations, Mongolians showed a different genotype distribution pattern. A lower C3963 and T6144 frequencies were observed, and, in the C37616A and T37950C polymorphism, the Mongolian population showed higher A37616 and C37950 allele frequencies than other Asian populations, similarly to the African populations. A total of 66 haplotypes were observed in the Ovambo, 48, in the Ghanaian, 99, in the Japanese, 103, in the Korean, 103, in the South Chinese, 20, in the Sri Lankan Tamil, 12, in the Sri Lankan Sinhalese, 21, in the Nepal Tamang, 50, in the Tibetan, and 45, in the Mongolian populations. The D' values between the SNP pairs were extremely high in the Sri Lankan Sinhalese population. Relatively higher D' values were observed in Mongolian and Sri Lankan Tamil populations. Network analysis showed two clusters that may have different origins, African and Asians (Chinese and/or Japanese). The present study is the first to demonstrate the existence of genetic heterogeneity in a world wide distribution of 18 SNPs in AS3MT.

    3. Ethnic Variations in Perception of Human Papillomavirus and its Vaccination among Young Women in Nepal .

      Science.gov (United States)

      Sathian, Brijesh; Babu, M G Ramesh; van Teijlingen, Edwin R; Banerjee, Indrajit; Roy, Bedanta; Subramanya, Supram Hosuru; Rajesh, Elayedath; Devkota, Suresh

      2017-03-01

      The Human Papillomavirus (HPV) is strongly associated with cervical and other cancers. In women, cervical cancer is the third most common cancer. HPV infection can be largely prevented through vaccination of (adolescent) girls. At the same time, Nepal is a low-income country experiencing a cultural change in attitudes towards sex and sexual behaviour. However, in the adolescent population knowledge about HPV, factors associated with an increased risk of HPV and the existence of the vaccination is often low. This was a cross-sectional study with female students enrolled in health and non-health science courses in Pokhara, Nepal. The questionnaire included demographic details, knowledge and attitude questions related to HPV, associated risk behaviour and its vaccination. Descriptive statistics, including Chi-Square test, were used to identify statistically significant relationships. Ethical approval was granted by the relevant authority in Nepal. Hindu religion (75.0 %; 95% CI: 70.9, 78.6) and Newari caste (75.5%; CI: 61.1, 86.7) were more aware about HPV, HPV vaccination. Hindus religion (55.6%; 95% CI: 51.2, 60.0) and Dalit caste (61.6%, 95% CI: 53.3, 69.4) more willing to be vaccinated than other religions and other castes, respectively. Not unsurprisingly, students on health-related courses had a greater awareness of HPV, HPV vaccination and were more willing to be vaccinated than students on other courses. Similar patterns of association arose for knowledge related to those sexually active at an early age; HPV risk and multiple sex partners; and fact that condoms cannot fully prevent the transmission of HPV. Knowledge about the link between HPV and (a) early sexual initiation, (b) having multiple sexual partners, and (c) the limited protection of condoms and other birth control measures was poor in our study compared to similar research conducted in other parts of the world. One key implication is the need for education campaigns in Nepal to educate young women

    4. Ethnic Variations in Perception of Human Papillomavirus and its Vaccination among Young Women in Nepal .

      Science.gov (United States)

      Babu, M G Ramesh; van Teijlingen, Edwin R.; Banerjee, Indrajit; Roy, Bedanta; Subramanya, Supram Hosuru; Rajesh, Elayedath; Devkota, Suresh

      2017-01-01

      Background: The Human Papillomavirus (HPV) is strongly associated with cervical and other cancers. In women, cervical cancer is the third most common cancer. HPV infection can be largely prevented through vaccination of (adolescent) girls. At the same time, Nepal is a low-income country experiencing a cultural change in attitudes towards sex and sexual behaviour. However, in the adolescent population knowledge about HPV, factors associated with an increased risk of HPV and the existence of the vaccination is often low. Materials and Methods: This was a cross-sectional study with female students enrolled in health and non-health science courses in Pokhara, Nepal. The questionnaire included demographic details, knowledge and attitude questions related to HPV, associated risk behaviour and its vaccination. Descriptive statistics, including Chi-Square test, were used to identify statistically significant relationships. Ethical approval was granted by the relevant authority in Nepal. Results: Hindu religion (75.0 %; 95% CI: 70.9, 78.6) and Newari caste (75.5%; CI: 61.1, 86.7) were more aware about HPV, HPV vaccination. Hindus religion (55.6%; 95% CI: 51.2, 60.0) and Dalit caste (61.6%, 95% CI: 53.3, 69.4) more willing to be vaccinated than other religions and other castes, respectively. Not unsurprisingly, students on health-related courses had a greater awareness of HPV, HPV vaccination and were more willing to be vaccinated than students on other courses. Similar patterns of association arose for knowledge related to those sexually active at an early age; HPV risk and multiple sex partners; and fact that condoms cannot fully prevent the transmission of HPV. Conclusion: Knowledge about the link between HPV and (a) early sexual initiation, (b) having multiple sexual partners, and (c) the limited protection of condoms and other birth control measures was poor in our study compared to similar research conducted in other parts of the world. One key implication is the need

    5. 3D variations in human crown dentin tubule orientation: a phase-contrast microtomography study.

      Science.gov (United States)

      Zaslansky, Paul; Zabler, Simon; Fratzl, Peter

      2010-01-01

      Tubules dominate the microstructure of dentin, and in crowns of human teeth they are surrounded by thick mineralized peritubular cuffs of high stiffness. Here we examine the three-dimensional (3D) arrangement of tubules in relation to enamel on the buccal and lingual aspects of intact premolars and molars. Specifically we investigate the angular orientation of tubules relative to the plane of the junction of dentin with enamel (DEJ) by means of wet, non-destructive and high-resolution phase-contrast (coherent) tomography. Enamel capped dentin samples (n=16), cut from the buccal and lingual surfaces of upper and lower premolar and molar teeth, were imaged in water by high-resolution synchrotron-based phase-contrast X-ray radiography. Reconstructed 3D virtual images were co-aligned with respect to the DEJ plane. The average tubule orientation was determined at increasing distances from the DEJ, based on integrated projections onto orthogonal virtual planes. The angle and curl of the tubules were determined every 100 microm to a depth of 1.4mm beneath the DEJ. Most tubules do not extend at right angles from the DEJ. Even when they do, tubules always change their orientations substantially within the first half-millimeter zone beneath the DEJ, both on the buccal and lingual aspects of premolar and molar teeth. Tubules also tend to curl and twist within this zone. Student t-tests indicate that lower teeth seem to have greater tilts in the tubule orientations relative to the DEJ normal with an average angle of 42 degrees (+/-2.0 degrees), whereas upper teeth exhibit a smaller change of orientation, with an average of 32 degrees (+/-2.1 degrees). Tubules are a central characteristic of dentin, with important implications on how it is arranged and what the properties are. Knowing about the path that tubules follow is important for various reasons, ranging form improving control over restorative procedures to understanding or simulating the mechanical properties of teeth

    6. Variations in the post-weaning human gut metagenome profile as result of Bifidobacterium acquisition in the Western microbiome

      Directory of Open Access Journals (Sweden)

      Matteo Soverini

      2016-07-01

      Full Text Available Studies of the gut microbiome variation among human populations revealed the existence of robust compositional and functional layouts matching the three subsistence strategies that describe a trajectory of changes across our recent evolutionary history: hunting and gathering, rural agriculture, and urban post-industrialized agriculture. In particular, beside the overall reduction of ecosystem diversity, the gut microbiome of Western industrial populations is typically characterized by the loss of Treponema and the acquisition of Bifidobacterium as an abundant inhabitant of the post-weaning gut microbial ecosystem. In order to advance the hypothesis about the possible adaptive nature of this exchange, here we explore specific functional attributes that correspond to the mutually exclusive presence of Treponema and Bifidobacterium using publically available gut metagenomic data from Hadza hunter-gatherers and urban industrial Italians. According to our findings, Bifidobacterium provides the enteric ecosystem with a diverse panel of saccharolytic functions, well suited to the array of gluco- and galacto-based saccharides that abound in the Western diet. On the other hand, the metagenomic functions assigned to Treponema are more predictive of a capacity to incorporate complex polysaccharides, such as those found in unrefined plant foods, which are consistently incorporated in the Hadza diet. Finally, unlike Treponema, the Bifidobacterium metagenome functions include genes that permit the establishment of microbe-host immunological cross-talk, suggesting recent co-evolutionary events between the human immune system and Bifidobacterium that are adaptive in the context of agricultural subsistence and sedentary societies.

    7. Variation in the human ribs geometrical properties and mechanical response based on X-ray computed tomography images resolution.

      Science.gov (United States)

      Perz, Rafał; Toczyski, Jacek; Subit, Damien

      2015-01-01

      Computational models of the human body are commonly used for injury prediction in automobile safety research. To create these models, the geometry of the human body is typically obtained from segmentation of medical images such as computed tomography (CT) images that have a resolution between 0.2 and 1mm/pixel. While the accuracy of the geometrical and structural information obtained from these images depend greatly on their resolution, the effect of image resolution on the estimation of the ribs geometrical properties has yet to be established. To do so, each of the thirty-four sections of ribs obtained from a Post Mortem Human Surrogate (PMHS) was imaged using three different CT modalities: standard clinical CT (clinCT), high resolution clinical CT (HRclinCT), and microCT. The images were processed to estimate the rib cross-section geometry and mechanical properties, and the results were compared to those obtained from the microCT images by computing the 'deviation factor', a metric that quantifies the relative difference between results obtained from clinCT and HRclinCT to those obtained from microCT. Overall, clinCT images gave a deviation greater than 100%, and were therefore deemed inadequate for the purpose of this study. HRclinCT overestimated the rib cross-sectional area by 7.6%, the moments of inertia by about 50%, and the cortical shell area by 40.2%, while underestimating the trabecular area by 14.7%. Next, a parametric analysis was performed to quantify how the variations in the estimate of the geometrical properties affected the rib predicted mechanical response under antero-posterior loading. A variation of up to 45% for the predicted peak force and up to 50% for the predicted stiffness was observed. These results provide a quantitative estimate of the sensitivity of the response of the FE model to the resolution of the images used to generate it. They also suggest that a correction factor could be derived from the comparison between microCT and

    8. Using Workflow Modeling to Identify Areas to Improve Genetic Test Processes in the University of Maryland Translational Pharmacogenomics Project.

      Science.gov (United States)

      Cutting, Elizabeth M; Overby, Casey L; Banchero, Meghan; Pollin, Toni; Kelemen, Mark; Shuldiner, Alan R; Beitelshees, Amber L

      Delivering genetic test results to clinicians is a complex process. It involves many actors and multiple steps, requiring all of these to work together in order to create an optimal course of treatment for the patient. We used information gained from focus groups in order to illustrate the current process of delivering genetic test results to clinicians. We propose a business process model and notation (BPMN) representation of this process for a Translational Pharmacogenomics Project being implemented at the University of Maryland Medical Center, so that personalized medicine program implementers can identify areas to improve genetic testing processes. We found that the current process could be improved to reduce input errors, better inform and notify clinicians about the implications of certain genetic tests, and make results more easily understood. We demonstrate our use of BPMN to improve this important clinical process for CYP2C19 genetic testing in patients undergoing invasive treatment of coronary heart disease.

    9. The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems.

      Science.gov (United States)

      Luzum, J A; Pakyz, R E; Elsey, A R; Haidar, C E; Peterson, J F; Whirl-Carrillo, M; Handelman, S K; Palmer, K; Pulley, J M; Beller, M; Schildcrout, J S; Field, J R; Weitzel, K W; Cooper-DeHoff, R M; Cavallari, L H; O'Donnell, P H; Altman, R B; Pereira, N; Ratain, M J; Roden, D M; Embi, P J; Sadee, W; Klein, T E; Johnson, J A; Relling, M V; Wang, L; Weinshilboum, R M; Shuldiner, A R; Freimuth, R R

      2017-09-01

      Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs. © 2017, The American Society for Clinical Pharmacology and Therapeutics.

    10. Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome.

      Science.gov (United States)

      Collins, Ryan L; Brand, Harrison; Redin, Claire E; Hanscom, Carrie; Antolik, Caroline; Stone, Matthew R; Glessner, Joseph T; Mason, Tamara; Pregno, Giulia; Dorrani, Naghmeh; Mandrile, Giorgia; Giachino, Daniela; Perrin, Danielle; Walsh, Cole; Cipicchio, Michelle; Costello, Maura; Stortchevoi, Alexei; An, Joon-Yong; Currall, Benjamin B; Seabra, Catarina M; Ragavendran, Ashok; Margolin, Lauren; Martinez-Agosto, Julian A; Lucente, Diane; Levy, Brynn; Sanders, Stephan J; Wapner, Ronald J; Quintero-Rivera, Fabiola; Kloosterman, Wigard; Talkowski, Michael E

      2017-03-06

      Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies. We sequenced 689 participants with autism spectrum disorder (ASD) and other developmental abnormalities to construct a genome-wide map of large SV. Using long-insert jumping libraries at 105X mean physical coverage and linked-read whole-genome sequencing from 10X Genomics, we document seven major SV classes at ~5 kb SV resolution. Our results encompass 11,735 distinct large SV sites, 38.1% of which are novel and 16.8% of which are balanced or complex. We characterize 16 recurrent subclasses of complex SV (cxSV), revealing that: (1) cxSV are larger and rarer than canonical SV; (2) each genome harbors 14 large cxSV on average; (3) 84.4% of large cxSVs involve inversion; and (4) most large cxSV (93.8%) have not been delineated in previous studies. Rare SVs are more likely to disrupt coding and regulatory non-coding loci, particularly when truncating constrained and disease-associated genes. We also identify multiple cases of catastrophic chromosomal rearrangements known as chromoanagenesis, including somatic chromoanasynthesis, and extreme balanced germline chromothripsis events involving up to 65 breakpoints and 60.6 Mb across four chromosomes, further defining rare categories of extreme cxSV. These data provide a foundational map of large SV in the morbid human genome and demonstrate a previously underappreciated abundance and diversity of cxSV that should be considered in genomic studies of human disease.

    11. Hepatitis C virus pharmacogenomics in Latin American populations: implications in the era of direct-acting antivirals

      Directory of Open Access Journals (Sweden)

      Trinks J

      2017-03-01

      Full Text Available Julieta Trinks,1,2 Mariela Caputo,2,3 María L Hulaniuk,1 Daniel Corach,2,3 Diego Flichman2,4 1Basic Science and Experimental Medicine Institute (ICBME, University Institute of the Italian Hospital of Buenos Aires, 2Scientific and Technological National Research Council (CONICET, 3Servicio de Huellas Digitales Genéticas, Facultad de Farmacia y Bioquímica, 4Cátedra de Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina Abstract: In recent years, great progress has been made in the field of new therapeutic options for hepatitis C virus (HCV infection. The new direct-acting antiviral agents (DAAs represent a great hope for millions of chronically infected individuals because their use may lead to excellent cure rates with fewer side effects. In Latin America, the high prevalence of HCV genotype 1 infection and the significant association of Native American ancestry with risk predictive single-nucleotide polymorphisms (SNPs in IFNL4 and ITPA genes highlight the need to implement new treatment regimens in these populations. However, the universal accessibility to DAAs is still not a reality in the region as their high cost is one of the major, although not the only, limiting factors for their broad implementation. Therefore, under these circumstances, could the assessment of host genetic markers be a useful tool to prioritize DAA treatment until global access to these new drugs can be achieved? This review will summarize the scientific evidences and the potential implications of HCV pharmacogenomics in this rapidly evolving era of anti-HCV drug development. Keywords: hepatitis C virus, pharmacogenomics, PEG-IFN/RBV, DAAs, Latin America

    12. Pharmacogenomics and Patient Treatment Parameters to Opioid Treatment in Chronic Pain: A Focus on Morphine, Oxycodone, Tramadol, and Fentanyl.

      Science.gov (United States)

      Lloyd, Renae A; Hotham, Elizabeth; Hall, Catherine; Williams, Marie; Suppiah, Vijayaprakash

      2017-12-01

      Opioids are one of the most commonly prescribed medicines for chronic pain. However, their use for chronic pain has been controversial. The objective of this literature review was to identify the role of genetic polymorphisms on patient treatment parameters (opioid dose requirements, response, and adverse effects) for opioids used in malignant and nonmalignant chronic pain. The opioids that this review focuses on are codeine, morphine, oxycodone, tramadol, and fentanyl. A literature search of databases Medline and Embase was carried out, and studies up to April 2016 were included in this review. Studies were included based on a combination of key words: chronic pain and related terms, pharmacogenetics and related terms, and opioids and related terms. Among the 1,408 individual papers retrieved from the search in Medline and Embase, 32 original articles were included in this review, with none related to codeine. The 32 papers reported various study designs, opioids, and polymorphisms being studied for associations with treatment outcomes. This literature review reveals that variants in ABCB1, OPRM1, and COMT have been replicated for opioid dosing and variants in ABCB1 have been replicated for both treatment response and adverse effects. Currently, there are few validated studies to form a strong evidence base to support pharmacogenomics testing when initiating opioid therapy. However, the field of pharmacogenomics in chronic pain is likely to expand over the coming years, with the increasing number of treatment options available and larger cohorts being assembled in order to identify true associations. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

    13. Preanalytical and analytical variation of surface-enhanced laser desorption-ionization time-of-flight mass spectrometry of human serum

      DEFF Research Database (Denmark)

      Albrethsen, Jakob; Bøgebo, Rikke; Olsen, Jesper

      2006-01-01

      BACKGROUND: Surface-enhanced laser desorption-ionization time-of-flight (SELDI-TOF) mass spectrometry of human serum is a potential diagnostic tool in human diseases. In the present study, the preanalytical and analytical variation of SELDI-TOF mass spectrometry of serum was assessed in healthy...... was 18% (6%-34%, n=4) for 16 peaks, and inter-individual CV was 38% (16%-56%, n=16) for 20 peaks. CONCLUSIONS: The pre-analytical and analytical conditions of SELDI-TOF mass spectrometry of serum have a significant impact on the protein peaks, with the number of peaks low and the assay variation high...

    14. Human- Versus System-Level Factors and Their Effect on Electronic Work List Variation: Challenging Radiology's Fundamental Attribution Error.

      Science.gov (United States)

      Davenport, Matthew S; Khalatbari, Shokoufeh; Platt, Joel F

      2015-09-01

      The aim of this study was to analyze sources of variation influencing the unread volume on an electronic abdominopelvic CT work list and to compare those results with blinded radiologist perception. The requirement for institutional review board approval was waived for this HIPAA-compliant quality improvement effort. Data pertaining to an electronic abdominopelvic CT work list were analyzed retrospectively from July 1, 2013, to June 30, 2014, and modeled with respect to the unread case total at 6 pm (Monday through Friday, excluding holidays). Eighteen system-level factors outside individual control (eg, number of workers, workload) and 7 human-level factors within individual control (eg, individual productivity) were studied. Attending radiologist perception was assessed with a blinded anonymous survey (n = 12 of 15 surveys completed). The mean daily unread total was 24 (range, 3-72). The upper control limit (48 CT studies [3 SDs above the mean]) was exceeded 10 times. Multivariate analysis revealed that the rate of unread CT studies was affected principally by system-level factors, including the number of experienced trainees on service (postgraduate year 5 residents [odds ratio, 0.83; 95% confidence interval, 0.74-0.92; P = .0008] and fellows [odds ratio, 0.84; 95% confidence interval, 0.74-0.95; P = .005]) and the daily workload (P = .02 to P level factors best predict the variation in unread CT examinations, but blinded faculty radiologists believe that it relates most strongly to variable individual effort. Copyright © 2015 American College of Radiology. Published by Elsevier Inc. All rights reserved.

    15. Variation of gunshot injury patterns in mortality associated with human rights abuses and armed conflict: an exploratory study.

      Science.gov (United States)

      Baraybar, Jose Pablo

      2015-09-01

      -insurgency operations, a careful analysis of gunshot injury patterns could serve as an indicator that in fact murder, rather than combat, took place and the intention was to kill rather than to maim or render people unfit for battle. To compare the variation of gunshot injury patterns between mortality associated with human rights abuses and armed conflict in selected samples from different countries. Literature review and case analysis. Original statistical analysis of gunshot injuries on human remains (n=777) recovered from mass or clandestine graves associated with human rights abuses in countries in Somaliland, the Balkans and Peru (1983-1995) and literature review of mortality caused by armed conflicts. Mechanism of gunshot injury and wound distribution pattern in geographically diverse samples of human rights abuse. Copyright © 2015 The Chartered Society of Forensic Sciences. Published by Elsevier Ireland Ltd. All rights reserved.

    16. Ethical, Political and Societal Implications of the Open Access Journal Movement in the Era of Economic Crisis, with Emphasis on Public Health Pharmacogenomics.

      Science.gov (United States)

      Bragazzi, Nicola Luigi

      2013-12-01

      Publication of the research outputs is a vital step of the research processes and a gateway between the laboratory and the global society. Open Access is revolutionizing the dissemination of scientific ideas, particularly in the field of public health pharmacogenomics that examines the ways in which pharmacogenomics impacts health systems and services at a societal level, rather than a narrow bench to bedside model of translation science. This manuscript argues that despite some limitations and drawbacks, open access has profound ethical, political and societal implications especially on underdeveloped and developing countries, and that it provides opportunities for science to grow in these resource-limited countries, particularly in the era of a severe economic and financial crisis that is imposing cuts and restrictions to research.

    17. The Daniel K. Inouye College of Pharmacy Scripts: Precision Medicine Through the Use of Pharmacogenomics: Current Status and Barriers to Implementation.

      Science.gov (United States)

      Ciarleglio, Anita E; Ma, Carolyn

      2017-09-01

      The precision medicine initiative brought forth by President Barack Obama in 2015 is an important step on the journey to truly personalized medicine. A broad knowledge and understanding of the implications of the pharmacogenomic literature will be critical to the achievement of this goal. While a great amount of data has been published in the areas of pharmacogenomics and pharmacogenetics, there are still relatively few instances in which the need for clinical intervention can be stated without doubt, and which are widely accepted and practiced by the medical community. As our knowledge base rapidly expands, issues such as insurance reimbursement for genetic testing and education of the health care workforce will be paramount to achieving the goal of precision medicine for all patients.

    18. Intra-individual metameric variation expressed at the enamel-dentine junction of lower post-canine dentition of South African fossil hominins and modern humans.

      Science.gov (United States)

      Pan, Lei; Thackeray, John Francis; Dumoncel, Jean; Zanolli, Clément; Oettlé, Anna; de Beer, Frikkie; Hoffman, Jakobus; Duployer, Benjamin; Tenailleau, Christophe; Braga, José

      2017-08-01

      The aim of this study is to compare the degree and patterning of inter- and intra-individual metameric variation in South African australopiths, early Homo and modern humans. Metameric variation likely reflects developmental and taxonomical issues, and could also be used to infer ecological and functional adaptations. However, its patterning along the early hominin postcanine dentition, particularly among South African fossil hominins, remains unexplored. Using microfocus X-ray computed tomography (µXCT) and geometric morphometric tools, we studied the enamel-dentine junction (EDJ) morphology and we investigated the intra- and inter-individual EDJ metameric variation among eight australopiths and two early Homo specimens from South Africa, as well as 32 modern humans. Along post-canine dentition, shape changes between metameres represented by relative positions and height of dentine horns, outlines of the EDJ occlusal table are reported in modern and fossil taxa. Comparisons of EDJ mean shapes and multivariate analyses reveal substantial variation in the direction and magnitude of metameric shape changes among taxa, but some common trends can be found. In modern humans, both the direction and magnitude of metameric shape change show increased variability in M 2 -M 3 compared to M 1 -M 2 . Fossil specimens are clustered together showing similar magnitudes of shape change. Along M 2 -M 3 , the lengths of their metameric vectors are not as variable as those of modern humans, but they display considerable variability in the direction of shape change. The distalward increase of metameric variation along the modern human molar row is consistent with the odontogenetic models of molar row structure (inhibitory cascade model). Though much remains to be tested, the variable trends and magnitudes in metamerism in fossil hominins reported here, together with differences in the scale of shape change between modern humans and fossil hominins may provide valuable information

    19. Variations of the candidate SEZ6L2 gene on Chromosome 16p11.2 in patients with autism spectrum disorders and in human populations.

      Directory of Open Access Journals (Sweden)

      Marina Konyukh

      Full Text Available BACKGROUND: Autism spectrum disorders (ASD are a group of severe childhood neurodevelopmental disorders with still unknown etiology. One of the most frequently reported associations is the presence of recurrent de novo or inherited microdeletions and microduplications on chromosome 16p11.2. The analysis of rare variations of 8 candidate genes among the 27 genes located in this region suggested SEZ6L2 as a compelling candidate. METHODOLOGY/PRINCIPAL FINDINGS: We further explored the role of SEZ6L2 variations by screening its coding part in a group of 452 individuals, including 170 patients with ASD and 282 individuals from different ethnic backgrounds of the Human Genome Diversity Panel (HGDP, complementing the previously reported screening. We detected 7 previously unidentified non-synonymous variations of SEZ6L2 in ASD patients. We also identified 6 non-synonymous variations present only in HGDP. When we merged our results with the previously published, no enrichment of non-synonymous variation in SEZ6L2 was observed in the ASD group compared with controls. CONCLUSIONS/SIGNIFICANCE: Our results provide an extensive ascertainment of the genetic variability of SEZ6L2 in human populations and do not support a major role for SEZ6L2 sequence variations in the susceptibility to ASD.

    20. Rapid evidence review of the comparative effectiveness, harms, and cost-effectiveness of pharmacogenomics-guided antidepressant treatment versus usual care for major depressive disorder.

      Science.gov (United States)

      Peterson, Kimberly; Dieperink, Eric; Anderson, Johanna; Boundy, Erin; Ferguson, Lauren; Helfand, Mark

      2017-06-01

      This study aims to conduct an evidence review of the effectiveness, harms, and cost-effectiveness of pharmacogenomics-guided antidepressant treatment for major depressive disorder. We searched MEDLINE®, the Cochrane Central Registry of Controlled Trials, and PsycINFO through February 2017. We used prespecified criteria to select studies, abstract data, and rate internal validity and strength of the evidence (PROSPERO number CRD42016036358). We included two randomized trials (RCT), five controlled cohort studies, and six modeling studies of mostly women in their mid-40s with few comorbidities. CNSDose (ABCB1, ABCC1, CYP2C19, CYP2D6, UGT1A1) is the only pharmacogenomics test that significantly improved remission (one additional remitting patient in 12 weeks per three genotyped, 95% CI 1.7 to 3.5) and reduced intolerability in an RCT. ABCB1 genotyping leads to one additional remitting patient in 5 weeks per three genotyped (95% CI 3 to 20), but tolerability was not reported. In an RCT, GeneSight (CYP2D6, CYPC19, CYP1A2, SLC6A4, HTR2A) did not statistically significantly improve remission, and evidence is inconclusive about its tolerability. Evidence is generally low strength because RCTs were few and underpowered. Cost-effectiveness is unclear due to lack of directly observed cost-effectiveness outcomes. We found no studies that evaluated whether pharmacogenomics shortens time to optimal treatment, whether improvements were due to switches to genetically congruent medication, or whether effectiveness varies based on test and patient characteristics. Certain pharmacogenomics tools show promise of improving short-term remission rates in women in their mid-40s with few comorbidities. But, important evidence limitations preclude recommending their widespread use and indicate a need for further research.

    1. Genomic and transcriptome profiling identified both human and HBV genetic variations and their interactions in Chinese hepatocellular carcinoma

      Directory of Open Access Journals (Sweden)

      Hua Dong

      2015-12-01

      Full Text Available Interaction between HBV and host genome integrations in hepatocellular carcinoma (HCC development is a complex process and the mechanism is still unclear. Here we described in details the quality controls and data mining of aCGH and transcriptome sequencing data on 50 HCC samples from the Chinese patients, published by Dong et al. (2015 (GEO#: GSE65486. In additional to the HBV-MLL4 integration discovered, we also investigated the genetic aberrations of HBV and host genes as well as their genetic interactions. We reported human genome copy number changes and frequent transcriptome variations (e.g. TP53, CTNNB1 mutation, especially MLL family mutations in this cohort of the patients. For HBV genotype C, we identified a novel linkage disequilibrium region covering HBV replication regulatory elements, including basal core promoter, DR1, epsilon and poly-A regions, which is associated with HBV core antigen over-expression and almost exclusive to HBV-MLL4 integration.

    2. The rhesus macaque is three times as diverse but more closely equivalent in damaging coding variation as compared to the human

      Directory of Open Access Journals (Sweden)

      Yuan Qiaoping

      2012-06-01

      Full Text Available Abstract Background As a model organism in biomedicine, the rhesus macaque (Macaca mulatta is the most widely used nonhuman primate. Although a draft genome sequence was completed in 2007, there has been no systematic genome-wide comparison of genetic variation of this species to humans. Comparative analysis of functional and nonfunctional diversity in this highly abundant and adaptable non-human primate could inform its use as a model for human biology, and could reveal how variation in population history and size alters patterns and levels of sequence variation in primates. Results We sequenced the mRNA transcriptome and H3K4me3-marked DNA regions in hippocampus from 14 humans and 14 rhesus macaques. Using equivalent methodology and sampling spaces, we identified 462,802 macaque SNPs, most of which were novel and disproportionately located in the functionally important genomic regions we had targeted in the sequencing. At least one SNP was identified in each of 16,797 annotated macaque genes. Accuracy of macaque SNP identification was conservatively estimated to be >90%. Comparative analyses using SNPs equivalently identified in the two species revealed that rhesus macaque has approximately three times higher SNP density and average nucleotide diversity as compared to the human. Based on this level of diversity, the effective population size of the rhesus macaque is approximately 80,000 which contrasts with an effective population size of less than 10,000 for humans. Across five categories of genomic regions, intergenic regions had the highest SNP density and average nucleotide diversity and CDS (coding sequences the lowest, in both humans and macaques. Although there are more coding SNPs (cSNPs per individual in macaques than in humans, the ratio of dN/dS is significantly lower in the macaque. Furthermore, the number of damaging nonsynonymous cSNPs (have damaging effects on protein functions from PolyPhen-2 prediction in the macaque is more

    3. Estimation of Geographic Variation in Human Papillomavirus Vaccine Uptake in Men and Women: An Online Survey Using Facebook Recruitment

      Science.gov (United States)

      Hughes, John; Oakes, J Michael; Pankow, James S; Kulasingam, Shalini L

      2014-01-01

      Background Federally funded surveys of human papillomavirus (HPV) vaccine uptake are important for pinpointing geographically based health disparities. Although national and state level data are available, local (ie, county and postal code level) data are not due to small sample sizes, confidentiality concerns, and cost. Local level HPV vaccine uptake data may be feasible to obtain by targeting specific geographic areas through social media advertising and recruitment strategies, in combination with online surveys. Objective Our goal was to use Facebook-based recruitment and online surveys to estimate local variation in HPV vaccine uptake among young men and women in Minnesota. Methods From November 2012 to January 2013, men and women were recruited via a targeted Facebook advertisement campaign to complete an online survey about HPV vaccination practices. The Facebook advertisements were targeted to recruit men and women by location (25 mile radius of Minneapolis, Minnesota, United States), age (18-30 years), and language (English). Results Of the 2079 men and women who responded to the Facebook advertisements and visited the study website, 1003 (48.2%) enrolled in the study and completed the survey. The average advertising cost per completed survey was US $1.36. Among those who reported their postal code, 90.6% (881/972) of the participants lived within the previously defined geographic study area. Receipt of 1 dose or more of HPV vaccine was reported by 65.6% women (351/535), and 13.0% (45/347) of men. These results differ from previously reported Minnesota state level estimates (53.8% for young women and 20.8% for young men) and from national estimates (34.5% for women and 2.3% for men). Conclusions This study shows that recruiting a representative sample of young men and women based on county and postal code location to complete a survey on HPV vaccination uptake via the Internet is a cost-effective and feasible strategy. This study also highlights the need

    4. Estimation of geographic variation in human papillomavirus vaccine uptake in men and women: an online survey using facebook recruitment.

      Science.gov (United States)

      Nelson, Erik J; Hughes, John; Oakes, J Michael; Pankow, James S; Kulasingam, Shalini L

      2014-09-01

      Federally funded surveys of human papillomavirus (HPV) vaccine uptake are important for pinpointing geographically based health disparities. Although national and state level data are available, local (ie, county and postal code level) data are not due to small sample sizes, confidentiality concerns, and cost. Local level HPV vaccine uptake data may be feasible to obtain by targeting specific geographic areas through social media advertising and recruitment strategies, in combination with online surveys. Our goal was to use Facebook-based recruitment and online surveys to estimate local variation in HPV vaccine uptake among young men and women in Minnesota. From November 2012 to January 2013, men and women were recruited via a targeted Facebook advertisement campaign to complete an online survey about HPV vaccination practices. The Facebook advertisements were targeted to recruit men and women by location (25 mile radius of Minneapolis, Minnesota, United States), age (18-30 years), and language (English). Of the 2079 men and women who responded to the Facebook advertisements and visited the study website, 1003 (48.2%) enrolled in the study and completed the survey. The average advertising cost per completed survey was US $1.36. Among those who reported their postal code, 90.6% (881/972) of the participants lived within the previously defined geographic study area. Receipt of 1 dose or more of HPV vaccine was reported by 65.6% women (351/535), and 13.0% (45/347) of men. These results differ from previously reported Minnesota state level estimates (53.8% for young women and 20.8% for young men) and from national estimates (34.5% for women and 2.3% for men). This study shows that recruiting a representative sample of young men and women based on county and postal code location to complete a survey on HPV vaccination uptake via the Internet is a cost-effective and feasible strategy. This study also highlights the need for local estimates to assess the variation in HPV

    5. A combination of PhP typing and β-d-glucuronidase gene sequence variation analysis for differentiation of Escherichia coli from humans and animals.

      Science.gov (United States)

      Masters, N; Christie, M; Katouli, M; Stratton, H

      2015-06-01

      We investigated the usefulness of the β-d-glucuronidase gene variance in Escherichia coli as a microbial source tracking tool using a novel algorithm for comparison of sequences from a prescreened set of host-specific isolates using a high-resolution PhP typing method. A total of 65 common biochemical phenotypes belonging to 318 E. coli strains isolated from humans and domestic and wild animals were analysed for nucleotide variations at 10 loci along a 518 bp fragment of the 1812 bp β-d-glucuronidase gene. Neighbour-joining analysis of loci variations revealed 86 (76.8%) human isolates and 91.2% of animal isolates were correctly identified. Pairwise hierarchical clustering improved assignment; where 92 (82.1%) human and 204 (99%) animal strains were assigned to their respective cluster. Our data show that initial typing of isolates and selection of common types from different hosts prior to analysis of the β-d-glucuronidase gene sequence improves source identification. We also concluded that numerical profiling of the nucleotide variations can be used as a valuable approach to differentiate human from animal E. coli. This study signifies the usefulness of the β-d-glucuronidase gene as a marker for differentiating human faecal pollution from animal sources.

    6. Development of a Combined In Vitro Physiologically Based Kinetic (PBK) and Monte Carlo Modelling Approach to Predict Interindividual Human Variation in Phenol-Induced Developmental Toxicity.

      Science.gov (United States)

      Strikwold, Marije; Spenkelink, Bert; Woutersen, Ruud A; Rietjens, Ivonne M C M; Punt, Ans

      2017-06-01

      With our recently developed in vitro physiologically based kinetic (PBK) modelling approach, we could extrapolate in vitro toxicity data to human toxicity values applying PBK-based reverse dosimetry. Ideally information on kinetic differences among human individuals within a population should be considered. In the present study, we demonstrated a modelling approach that integrated in vitro toxicity data, PBK modelling and Monte Carlo simulations to obtain insight in interindividual human kinetic variation and derive chemical specific adjustment factors (CSAFs) for phenol-induced developmental toxicity. The present study revealed that UGT1A6 is the primary enzyme responsible for the glucuronidation of phenol in humans followed by UGT1A9. Monte Carlo simulations were performed taking into account interindividual variation in glucuronidation by these specific UGTs and in the oral absorption coefficient. Linking Monte Carlo simulations with PBK modelling, population variability in the maximum plasma concentration of phenol for the human population could be predicted. This approach provided a CSAF for interindividual variation of 2.0 which covers the 99th percentile of the population, which is lower than the default safety factor of 3.16 for interindividual human kinetic differences. Dividing the dose-response curve data obtained with in vitro PBK-based reverse dosimetry, with the CSAF provided a dose-response curve that reflects the consequences of the interindividual variability in phenol kinetics for the developmental toxicity of phenol. The strength of the presented approach is that it provides insight in the effect of interindividual variation in kinetics for phenol-induced developmental toxicity, based on only in vitro and in silico testing. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

    7. Observed changes of temperature extremes during 1960-2005 in China: natural or human-induced variations?

      Science.gov (United States)

      Zhang, Qiang; Li, Jianfeng; David Chen, Yongqin; Chen, Xiaohong

      2011-12-01

      The purpose of this study was to statistically examine changes of surface air temperature in time and space and to analyze two factors potentially influencing air temperature changes in China, i.e., urbanization and net solar radiation. Trends within the temperature series were detected by using Mann-Kendall trend test technique. The scientific problem this study expected to address was that what could be the role of human activities in the changes of temperature extremes. Other influencing factors such as net solar radiation were also discussed. The results of this study indicated that: (1) increasing temperature was observed mainly in the northeast and northwest China; (2) different behaviors were identified in the changes of maximum and minimum temperature respectively. Maximum temperature seemed to be more influenced by urbanization, which could be due to increasing urban albedo, aerosol, and air pollutions in the urbanized areas. Minimum temperature was subject to influences of variations of net solar radiation; (3) not significant increasing and even decreasing temperature extremes in the Yangtze River basin and the regions south to the Yangtze River basin could be the consequences of higher relative humidity as a result of increasing precipitation; (4) the entire China was dominated by increasing minimum temperature. Thus, we can say that the warming process of China was reflected mainly by increasing minimum temperature. In addition, consistently increasing temperature was found in the upper reaches of the Yellow River basin, the Yangtze River basin, which have the potential to enhance the melting of permafrost in these areas. This may trigger new ecological problems and raise new challenges for the river basin scale water resource management.

    8. Comparative sensitivity to environmental variation and human disturbance of Asian tapirs (Tapirus indicus) and other wild ungulates in Thailand.

      Science.gov (United States)

      Lynam, Antony J; Tantipisanuh, Naruemon; Chutipong, Wanlop; Ngoprasert, Dusit; Baker, Megan C; Cutter, Passanan; Gale, George; Kitamura, Shumpei; Steinmetz, Robert; Sukmasuang, Ronglarp; Thunhikorn, Somying

      2012-12-01

      Southeast Asia's tropical forests suffer the highest rates of deforestation and disturbance of any on Earth, with poorly understood impacts on native fauna. Asian tapirs (Tapirus indicus) are among the least studied of the large mammals in these forests. Using records from 9 camera trap surveys in 7 of the largest (>1000 km(2) ) protected area complexes, we assessed the influence of environmental variation and human-induced disturbance on tapir occurrence. Tapirs were detected at 13% of locations sampled, significantly associated with evergreen forest (P tapir presence 87% of the time. According to this model, tapir occurrence was positively influenced by annual rainfall and proximity to the forest edge. However, tapirs may not avoid edges but instead prefer wetter evergreen forest, a habitat type that tended to occur further from the forest edge at higher elevations in our particular study sites (P tapirs showed a range of differing responses. Tapirs are expected to be less sensitive to disturbance because they are not targets for hunting and trade, and are almost entirely active at night, so avoid peak traffic periods in parks. Tapir populations in Thailand may be more stable than in other parts of their global range because rates of forest loss have decreased >40% over the past 20 years. We recommend surveys to fill gaps in the understanding of the status in lesser-known protected areas, research to better understand the fine-scale environmental influences on behavior and habitats of tapirs, and other forest ungulates, and continued legal status for tapirs in the highest category of protection. © 2012 Wiley Publishing Asia Pty Ltd, ISZS and IOZ/CAS.

    9. Cell type-specific variations in the induction of hsp70 in human leukocytes by feverlike whole body hyperthermia.

      Science.gov (United States)

      Oehler, R; Pusch, E; Zellner, M; Dungel, P; Hergovics, N; Homoncik, M; Eliasen, M M; Brabec, M; Roth, E

      2001-10-01

      Fever has been associated with shortened duration and improved survival in infectious disease. The mechanism of this beneficial response is still poorly understood. The heat-inducible 70-kDa heat shock protein (Hsp70) has been associated with protection of leukocytes against the cytotoxicity of inflammatory mediators and with improved survival of severe infections. This study characterizes the induction of Hsp70 by feverlike temperatures in human leukocytes in vitro and in vivo. Using flow cytometry, Hsp70 expression was determined in whole blood samples. This approach eliminated cell isolation procedures that would greatly affect the results. Heat treatment of whole blood in vitro for 2 hours at different temperatures revealed that Hsp70 expression depends on temperature and cell type; up to 41 degrees C, Hsp70 increased only slightly in lymphocytes and polymorphonuclear leukocytes. However, in monocytes a strong induction was already seen at 39 degrees C, and Hsp70 levels at 41 degrees C were 10-fold higher than in the 37 degrees C control. To be as close as possible to the physiological situation during fever, we immersed healthy volunteers in a hot water bath, inducing whole body hyperthermia (39 degrees C), and measured leukocyte Hsp70 expression. Hsp70 was induced in all leukocytes with comparable but less pronounced cell type-specific variations as observed in vitro. Thus, a systemic increase of body temperature as triggered by fever stimulates Hsp70 expression in peripheral leukocytes, especially in monocytes. This fever-induced Hsp70 expression may protect monocytes when confronted with cytotoxic inflammatory mediators, thereby improving the course of the disease.

    10. Ureaplasma Species Multiple Banded Antigen (MBA) Variation Is Associated with the Severity of Inflammation In vivo and In vitro in Human Placentae.

      Science.gov (United States)

      Sweeney, Emma L; Kallapur, Suhas G; Meawad, Simone; Gisslen, Tate; Stephenson, Sally-Anne; Jobe, Alan H; Knox, Christine L

      2017-01-01

      Background: The multiple banded antigen (MBA), a surface-exposed lipoprotein, is a proposed virulence factor of Ureaplasma spp. We previously demonstrated that the number of Ureaplasma parvum MBA size variants in amniotic fluid was inversely proportional to the severity of chorioamnionitis in experimentally infected pregnant sheep. However, the effect of ureaplasma MBA size variation on inflammation in human pregnancies has not been reported. Methods: Ureaplasmas isolated from the chorioamnion of pregnant women from a previous study ( n = 42) were speciated/serotyped and MBA size variation was demonstrated by PCR and western blot. Results were correlated with the severity of chorioamnionitis and cord blood cytokines. In vitro , THP-1-derived macrophages were exposed to recombinant-MBA proteins of differing sizes and NF-κB activation and cytokine responses were determined. Results: MBA size variation was identified in 21/32 (65.6%) clinical isolates (in 10 clinical isolates MBA size variation was unable to be determined). Any size variation (increase/decrease) of the MBA (regardless of Ureaplasma species or serovar) was associated with mild or absent chorioamnionitis ( P = 0.023) and lower concentrations of cord blood cytokines IL-8 ( P = 0.04) and G-CSF ( P = 0.008). In vitro , recombinant-MBA variants elicited different cytokine responses and altered expression of NF-κB p65. Conclusion: This study demonstrates that size variation of the ureaplasma MBA protein modulates the host immune response in vivo and in vitro .

    11. Genetic variation in the Cytb gene of human cerebral Taenia solium cysticerci recovered from clinically and radiologically heterogeneous patients with neurocysticercosis

      Directory of Open Access Journals (Sweden)

      Hector Palafox-Fonseca

      2013-11-01

      Full Text Available Neurocysticercosis (NC is a clinically and radiologically heterogeneous parasitic disease caused by the establishment of larval Taenia solium in the human central nervous system. Host and/or parasite variations may be related to this observed heterogeneity. Genetic differences between pig and human-derived T. solium cysticerci have been reported previously. In this study, 28 cysticerci were surgically removed from 12 human NC patients, the mitochondrial gene that encodes cytochrome b was amplified from the cysticerci and genetic variations that may be related to NC heterogeneity were characterised. Nine different haplotypes (Ht, which were clustered in four haplogroups (Hg, were identified. Hg 3 and 4 exhibited a tendency to associate with age and gender, respectively. However, no significant associations were found between NC heterogeneity and the different T. solium cysticerci Ht or Hg. Parasite variants obtained from patients with similar NC clinical or radiological features were genetically closer than those found in groups of patients with a different NC profile when using the Mantel test. Overall, this study establishes the presence of genetic differences in the Cytb gene of T. solium isolated from human cysticerci and suggests that parasite variation could contribute to NC heterogeneity.

    12. Gender-based differences in the shape of the human corpus callosum are associated with allometric variations

      Science.gov (United States)

      Bruner, Emiliano; de la Cuétara, José Manuel; Colom, Roberto; Martin-Loeches, Manuel

      2012-01-01

      The corpus callosum displays considerable morphological variability between individuals. Although some characteristics are thought to differ between male and female brains, there is no agreement regarding the source of this variation. Biomedical imaging and geometric morphometrics have provided tools to investigate shape and size variation in terms of integration and correlation. Here we analyze variations at the midsagittal outline of the corpus callosum in a sample of 102 young adults in order to describe and quantify the pattern of covariation associated with its morphology. Our results suggest that the shape of the corpus callosum is characterized by low levels of morphological integration, which explains the large variability. In larger brains, a minor allometric component involves a relative reduction of the splenium. Small differences between males and?females are associated with this allometric pattern, induced primarily by size variation rather than gender-specific characteristics. PMID:22296183

    13. Improved physiologically based pharmacokinetic model for oral exposures to chromium in mice, rats, and humans to address temporal variation and sensitive populations.

      Science.gov (United States)

      Kirman, C R; Suh, M; Proctor, D M; Hays, S M

      2017-06-15

      A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations. Important species differences, sources of non-linear toxicokinetics, and human variation are identified and discussed within the context of human health risk assessment. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

    14. Association of 5' end neuregulin-1 (NRG1) gene variation with subcortical medial frontal microstructure in humans.

      Science.gov (United States)

      Winterer, Georg; Konrad, Andreas; Vucurevic, Goran; Musso, Francesco; Stoeter, Peter; Dahmen, Norbert

      2008-04-01

      ., Lemke, G., Sainz, J., Johannesson, G., Andresson, T., Gudbjartsson, D., Manolescu, A., Frigge, M.L., Gurney, M.E., Kong, A., Gulcher, J.R., Petursson, H., Stefansson, K. 2002. Neuregulin-1 and susceptibility to schizophrenia. Am. J. Hum. Genet. 71, 877-892). As predicted, we found medial frontal FA to be significantly associated with this NRG1 gene variation. Using voxel-based morphometry (VBM), we could largely exclude the possibility that this genotype effect is indirectly caused by genotype-dependent effects on brain volume. This is the first demonstration that SNP8NRG221533 of the NRG1 gene affects medial frontal white matter microstructure in humans. As the degree of neuronal myelination contributes to structural integrity, our finding further supports a potential role of NRG1 in neuronal myelination in the human brain. By extension, our findings suggest that SNP8NRG221533 may contribute to the risk for the complex polygenic illness schizophrenia via its impact on myelination in frontal lobe white matter.

    15. Genome-wide association studies on HIV susceptibility, pathogenesis and pharmacogenomics

      NARCIS (Netherlands)

      van Manen, Daniëlle; van 't Wout, Angélique B.; Schuitemaker, Hanneke

      2012-01-01

      Susceptibility to HIV-1 and the clinical course after infection show a substantial heterogeneity between individuals. Part of this variability can be attributed to host genetic variation. Initial candidate gene studies have revealed interesting host factors that influence HIV infection, replication

    16. Assessing the impacts of human activities and climate variations on grassland productivity by partial least squares structural equation modeling (PLS-SEM)

      Institute of Scientific and Technical Information of China (English)

      SHA Zongyao; XIE Yichun; TAN Xicheng; BAI Yongfei; LI Jonathan; LIU Xuefeng

      2017-01-01

      The cause-effect associations between geographical phenomena are an important focus in ecological research.Recent studies in structural equation modeling (SEM) demonstrated the potential for analyzing such associations.We applied the variance-based partial least squares SEM (PLS-SEM) and geographically-weighted regression (GWR) modeling to assess the human-climate impact on grassland productivity represented by above-ground biomass (AGB).The human and climate factors and their interaction were taken to explain the AGB variance by a PLS-SEM developed for the grassland ecosystem in Inner Mongolia,China.Results indicated that 65.5% of the AGB variance could be explained by the human and climate factors and their interaction.The case study showed that the human and climate factors imposed a significant and negative impact on the AGB and that their interaction alleviated to some extent the threat from the intensified human-climate pressure.The alleviation may be attributable to vegetation adaptation to high human-climate stresses,to human adaptation to climate conditions or/and to recent vegetation restoration programs in the highly degraded areas.Furthermore,the AGB response to the human and climate factors modeled by GWR exhibited significant spatial variations.This study demonstrated that the combination of PLS-SEM and GWR model is feasible to investigate the cause-effect relation in socio-ecological systems.

    17. On the Use of Biomineral Oxygen Isotope Data to Identify Human Migrants in the Archaeological Record: Intra-Sample Variation, Statistical Methods and Geographical Considerations.

      Directory of Open Access Journals (Sweden)

      Emma Lightfoot

      Full Text Available Oxygen isotope analysis of archaeological skeletal remains is an increasingly popular tool to study past human migrations. It is based on the assumption that human body chemistry preserves the δ18O of precipitation in such a way as to be a useful technique for identifying migrants and, potentially, their homelands. In this study, the first such global survey, we draw on published human tooth enamel and bone bioapatite data to explore the validity of using oxygen isotope analyses to identify migrants in the archaeological record. We use human δ18O results to show that there are large variations in human oxygen isotope values within a population sample. This may relate to physiological factors influencing the preservation of the primary isotope signal, or due to human activities (such as brewing, boiling, stewing, differential access to water sources and so on causing variation in ingested water and food isotope values. We compare the number of outliers identified using various statistical methods. We determine that the most appropriate method for identifying migrants is dependent on the data but is likely to be the IQR or median absolute deviation from the median under most archaeological circumstances. Finally, through a spatial assessment of the dataset, we show that the degree of overlap in human isotope values from different locations across Europe is such that identifying individuals' homelands on the basis of oxygen isotope analysis alone is not possible for the regions analysed to date. Oxygen isotope analysis is a valid method for identifying first-generation migrants from an archaeological site when used appropriately, however it is difficult to identify migrants using statistical methods for a sample size of less than c. 25 individuals. In the absence of local previous analyses, each sample should be treated as an individual dataset and statistical techniques can be used to identify migrants, but in most cases pinpointing a specific

    18. New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation.

      Science.gov (United States)

      Fabbri, C; Tansey, K E; Perlis, R H; Hauser, J; Henigsberg, N; Maier, W; Mors, O; Placentino, A; Rietschel, M; Souery, D; Breen, G; Curtis, C; Sang-Hyuk, L; Newhouse, S; Patel, H; Guipponi, M; Perroud, N; Bondolfi, G; O'Donovan, M; Lewis, G; Biernacka, J M; Weinshilboum, R M; Farmer, A; Aitchison, K J; Craig, I; McGuffin, P; Uher, R; Lewis, C M

      2017-11-21

      Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (P=1.80e-08, ITGA9 (integrin α9)) and rs76191705 (P=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P=0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying

    19. Accounting for regional variation in both natural environment and human disturbance to improve performance of multimetric indices of lotic benthic diatoms.

      Science.gov (United States)

      Tang, Tao; Stevenson, R Jan; Infante, Dana M

      2016-10-15

      Regional variation in both natural environment and human disturbance can influence performance of ecological assessments. In this study we calculated 5 types of benthic diatom multimetric indices (MMIs) with 3 different approaches to account for variation in ecological assessments. We used: site groups defined by ecoregions or diatom typologies; the same or different sets of metrics among site groups; and unmodeled or modeled MMIs, where models accounted for natural variation in metrics within site groups by calculating an expected reference condition for each metric and each site. We used data from the USEPA's National Rivers and Streams Assessment to calculate the MMIs and evaluate changes in MMI performance. MMI performance was evaluated with indices of precision, bias, responsiveness, sensitivity and relevancy which were respectively measured as MMI variation among reference sites, effects of natural variables on MMIs, difference between MMIs at reference and highly disturbed sites, percent of highly disturbed sites properly classified, and relation of MMIs to human disturbance and stressors. All 5 types of MMIs showed considerable discrimination ability. Using different metrics among ecoregions sometimes reduced precision, but it consistently increased responsiveness, sensitivity, and relevancy. Site specific metric modeling reduced bias and increased responsiveness. Combined use of different metrics among site groups and site specific modeling significantly improved MMI performance irrespective of site grouping approach. Compared to ecoregion site classification, grouping sites based on diatom typologies improved precision, but did not improve overall performance of MMIs if we accounted for natural variation in metrics with site specific models. We conclude that using different metrics among ecoregions and site specific metric modeling improve MMI performance, particularly when used together. Applications of these MMI approaches in ecological assessments

    20. HSC extrinsic sex-related and intrinsic autoimmune disease-related human B-cell variation is recapitulated in humanized mice.

      Science.gov (United States)

      Borsotti, Chiara; Danzl, Nichole M; Nauman, Grace; Hölzl, Markus A; French, Clare; Chavez, Estefania; Khosravi-Maharlooei, Mohsen; Glauzy, Salome; Delmotte, Fabien R; Meffre, Eric; Savage, David G; Campbell, Sean R; Goland, Robin; Greenberg, Ellen; Bi, Jing; Satwani, Prakash; Yang, Suxiao; Bathon, Joan; Winchester, Robert; Sykes, Megan

      2017-10-24

      B cells play a major role in antigen presentation and antibody production in the development of autoimmune diseases, and some of these diseases disproportionally occur in females. Moreover, immune responses tend to be stronger in female vs male humans and mice. Because it is challenging to distinguish intrinsic from extrinsic influences on human immune responses, we used a personalized immune (PI) humanized mouse model, in which immune systems were generated de novo from adult human hematopoietic stem cells (HSCs) in immunodeficient mice. We assessed the effect of recipient sex and of donor autoimmune diseases (type 1 diabetes [T1D] and rheumatoid arthritis [RA]) on human B-cell development in PI mice. We observed that human B-cell levels were increased in female recipients regardless of the source of human HSCs or the strain of immunodeficient recipient mice. Moreover, mice injected with T1D- or RA-derived HSCs displayed B-cell abnormalities compared with healthy control HSC-derived mice, including altered B-cell levels, increased proportions of mature B cells and reduced CD19 expression. Our study revealed an HSC-extrinsic effect of recipient sex on human B-cell reconstitution. Moreover, the PI humanized mouse model revealed HSC-intrinsic defects in central B-cell tolerance that recapitulated those in patients with autoimmune diseases. These results demonstrate the utility of humanized mouse models as a tool to better understand human immune cell development and regulation.

    1. In normal human fibroblasts variation in DSB repair capacity cannot be ascribed to radiation-induced changes in the localisation, expression or activity of major NHEJ proteins

      DEFF Research Database (Denmark)

      Kasten-Pisula, Ulla; Vronskaja, Svetlana; Overgaard, Jens

      2008-01-01

      in the activity of the DNA-PK complex induced upon irradiation. CONCLUSIONS: For normal human fibroblasts, the level or activity of NHEJ proteins measured prior to or after irradiation cannot be used to predict the DSB repair capacity or cellular radiosensitivity. Udgivelsesdato: 2008-Mar......BACKGROUND AND PURPOSE: The aim of the present study was to test whether for normal human fibroblasts the variation in double-strand break (DSB) repair capacity results from radiation-induced differences in localisation, expression or activity of major non-homologous end-joining (NHEJ) proteins....... MATERIALS AND METHODS: Experiments were performed with 11 normal human fibroblast strains AF01-11. NHEJ proteins were determined by Western blot and DNA-PK activity by pulldown-assay. RESULTS: The four NHEJ proteins tested (Ku70, Ku80, XRCC4 and DNA-PKcs) were found to be localised almost exclusively...

    2. CpDNA haplotype variation reveals strong human influence on oak stands of the Veluwe forest in the Netherlands

      NARCIS (Netherlands)

      Buiteveld, J.; Koelewijn, H.P.

      2006-01-01

      We examined chloroplast DNA (cpDNA) variation in 78 oak stands of an important forest complex (the Veluwe) in The Netherlands. Based on historical maps and information oak stands were classified as planted or autochthonous. A genetic study by means of cpDNA haplotype characterisation was carried out

    3. Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels

      DEFF Research Database (Denmark)

      Nossent, Anne Yaël; Robben, J H; Deen, P M T

      2010-01-01

      SUMMARY OBJECTIVES: Stimulation of arginine vasopressin 2 receptor (V2R) with arginine vasopressin (AVP) results in a rise in von Willebrand factor (VWF) and factor VIII plasma levels. We hypothesized that gain-of-function variations in the V2R gene (AVPR2) would lead to higher plasma levels of V...

    4. Structural variation in two human genomes mapped at single-nucleotide resolution by whole genome de novo assembly

      DEFF Research Database (Denmark)

      Li, Yingrui; Zheng, Hancheng; Luo, Ruibang

      2011-01-01

      Here we use whole-genome de novo assembly of second-generation sequencing reads to map structural variation (SV) in an Asian genome and an African genome. Our approach identifies small- and intermediate-size homozygous variants (1-50 kb) including insertions, deletions, inversions and their precise...

    5. Genetic regulation of the variation of circulating insulin-like growth factors and leptin in human pedigrees.

      Science.gov (United States)

      Pantsulaia, Ia; Pantsulaia, I; Trofimov, Svetlana; Kobyliansky, Eugene; Livshits, Gregory

      2005-07-01

      Recent literature has shown that circulating levels of insulin-like growth factor I (IGF-I) and/or IGF binding proteins (IGF-BPs) may be of importance in the risk assessment of several chronic diseases including cancer, cardiovascular disease, diabetes mellitus and so on. The present study examined the extent of genetic and environmental influences on the populational variation of circulating IGF-I and IGF-BP-1 in apparently healthy and ethnically homogeneous white families. The plasma levels of each of the studied biochemical indices were determined by enzyme-linked immunoassay in 563 individuals aged 18 to 80 years. Quantitative genetic analysis showed that the IGF-I variation was appreciably attributable to genetic effects (47.1% +/- 9.0%), whereas for IGF-BP-1, only 23.3% +/- 7.8% of the interindividual variation was explained by genetic determinants. Common familial environment factors contributed significantly only to IGF-BP-1 variation (23.3% +/- 7.8%). In addition, we examined the covariations between these molecules and between them and IGF-BP-3 and leptin that were previously studied in the same sample. The analysis revealed that the pleiotropic genetic effects were significant for 2 pairs of traits, namely for IGF-I and IGF-BP-3, and for IGF-BP-1 and leptin. The bivariate heritability estimates were 0.21 +/- 0.04 and 0.15 +/- 0.05. The common environmental factors were consistently a significant source of correlation between all pairs (barring IGF-I and leptin) of the studied molecules; they were the sole predictors of correlation between IGF-I and IGF-BP-1, and between IGF-BP-1 and IGF-BP-3. Our results affirm the existence of specific and common genetic pathways that in combination determine a substantial proportion of the circulating variation of these molecules.

    6. Identification of stiffness variations in supporting substances of a human canine tooth with a bracket-beam-piezoelectric sensor and its electromechanical impedance

      Directory of Open Access Journals (Sweden)

      Hector A. Tinoco

      2017-06-01

      Full Text Available In this paper, an experimental method is described to identify the stiffness variations produced by drillings done in different supporting substances of a human canine tooth. To measure the supporting substances parameters through of a canine, a sensor-actuator system was developed. The sensor-actuator device was composed of a stainless steel bracket bonded to a steel wire attached to two piezoelectric transducers, with a concentrated mass attached to the end of the wire. To excite the device, high frequency voltage (between 5 and 10 KHz was applied through the piezo-transducers, which affects the tooth by means of the vibration of the wire. High frequency mechanical vibrations allowed the appraisal of the mechanical response from the supporting substances. Mechanical responses associated with the stiffness of the support were quantified with the electrical impedance of the piezo-transducers. The device was coupled to the crown of a canine tooth simulating a condition of fixing as in the bone, the tooth was fastened by the root portion inside the supporting substance. Four supporting substances were characterized for the tests. After establishing base values of the stiffness of each supporting substance, the stiffness variations were assessed in two stages (two drillings; these were made perpendicularly to the longitudinal axis of the tooth, Results show that it is possible to assess stiffness variations with the proposed methodology as well as to quantify the stiffness differences, by means of variation indexes.

    7. A review of barriers to effective asthma management in Puerto Ricans: cultural, healthcare system and pharmacogenomic issues.

      Science.gov (United States)

      Alicea-Alvarez, Norma; Swanson-Biearman, Brenda; Kelsen, Steven G

      2014-02-01

      , hence, asthma outcomes. Finally, given ethnically based differences in pharmacogenomics, clinical trials targeting the Puerto Rican population may help to better define optimal asthma medication regimens in this ethnic group.

    8. The Norwegian human milk study HUMIS variations in levels of chlorinated pesticides, PCBs and PBDEs in Norwegian breast milk

      Energy Technology Data Exchange (ETDEWEB)

      Polder, A.; Loeken, K. [The Norwegian School of Veterinary Science, Oslo (Norway); Thomsen, C.; Becher, G.; Eggesboe, M. [Norwegian Inst. of Public Health, Oslo (Norway); Skaare, J.U. [National Veterinary Inst., Oslo (Norway)

      2004-09-15

      Organochlorine pesticides (OCPs), polychlorinated, -dibenzo-pdioxins (PCDDs), -dibenzofurans (PCDFs), -biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are among the persistent organic pollutants (POPs) that have been found to accumulate in human breast milk. Because nursing children are exposed to these chemicals through the contaminated breast milk, health authorities worldwide are concerned for the infants' intake and therefore human milk monitoring programs are performed in many countries. While restrictions and bans resulted in a decline of organochlorines (OCs) in human milk during the last decades, an increasing trend has been found for PBDEs. The main goals of ''The Norwegian Human Milk Study, HUMIS'' are: to elucidate the human exposure in Norway to POPs, to identify dietary habits and other lifestyle factors that are associated with high levels of POPs in human milk, and to study the impact of exposure to the these contaminants on child health. This study reports preliminary results of recent levels of POPs in human milk in 4 different counties in Norway.

    9. Generation of Variations on Theme Music Based on Impressions of Story Scenes Considering Human's Feeling of Music and Stories

      Directory of Open Access Journals (Sweden)

      Kenkichi Ishizuka

      2008-01-01

      Full Text Available This paper describes a system which generates variations on theme music fitting to story scenes represented by texts and/or pictures. Inputs to the present system are original theme music and numerical information on given story scenes. The present system varies melodies, tempos, tones, tonalities, and accompaniments of given theme music based on impressions of story scenes. Genetic algorithms (GAs using modular neural network (MNN models as fitness functions are applied to music generation in order to reflect user's feeling of music and stories. The present system adjusts MNN models for each user on line. This paper also describes the evaluation experiments to confirm whether the generated variations on theme music reflect impressions of story scenes appropriately or not.

    10. Age- and gender-related regional variations of human brain cortical thickness, complexity, and gradient in the third decade.

      Science.gov (United States)

      Creze, Maud; Versheure, Leslie; Besson, Pierre; Sauvage, Chloe; Leclerc, Xavier; Jissendi-Tchofo, Patrice

      2014-06-01

      Brain functional and cytoarchitectural maturation continue until adulthood, but little is known about the evolution of the regional pattern of cortical thickness (CT), complexity (CC), and intensity or gradient (CG) in young adults. We attempted to detect global and regional age- and gender-related variations of brain CT, CC, and CG, in 28 healthy young adults (19-33 years) using a three-dimensional T1 -weighted magnetic resonance imaging sequence and surface-based methods. Whole brain interindividual variations of CT and CG were similar to that in the literature. As a new finding, age- and gender-related variations significantly affected brain complexity (P gender), all in the right hemisphere. Regions of interest analyses showed age and gender significant interaction (P left inferior parietal. In addition, we found significant inverse correlations between CT and CC and between CT and CG over the whole brain and markedly in precentral and occipital areas. Our findings differ in details from previous reports and may correlate with late brain maturation and learning plasticity in young adults' brain in the third decade. Copyright © 2013 Wiley Periodicals, Inc.

    11. Genome-wide association studies on HIV susceptibility, pathogenesis and pharmacogenomics

      Directory of Open Access Journals (Sweden)

      van Manen Daniëlle

      2012-08-01

      Full Text Available Abstract Susceptibility to HIV-1 and the clinical course after infection show a substantial heterogeneity between individuals. Part of this variability can be attributed to host genetic variation. Initial candidate gene studies have revealed interesting host factors that influence HIV infection, replication and pathogenesis. Recently, genome-wide association studies (GWAS were utilized for unbiased searches at a genome-wide level to discover novel genetic factors and pathways involved in HIV-1 infection. This review gives an overview of findings from the GWAS performed on HIV infection, within different cohorts, with variable patient and phenotype selection. Furthermore, novel techniques and strategies in research that might contribute to the complete understanding of virus-host interactions and its role on the pathogenesis of HIV infection are discussed.

    12. Variation in the h