Integrated PK-PD and agent-based modeling in oncology.

PubMed

Wang, Zhihui; Butner, Joseph D; Cristini, Vittorio; Deisboeck, Thomas S

2015-04-01

Mathematical modeling has become a valuable tool that strives to complement conventional biomedical research modalities in order to predict experimental outcome, generate new medical hypotheses, and optimize clinical therapies. Two specific approaches, pharmacokinetic-pharmacodynamic (PK-PD) modeling, and agent-based modeling (ABM), have been widely applied in cancer research. While they have made important contributions on their own (e.g., PK-PD in examining chemotherapy drug efficacy and resistance, and ABM in describing and predicting tumor growth and metastasis), only a few groups have started to combine both approaches together in an effort to gain more insights into the details of drug dynamics and the resulting impact on tumor growth. In this review, we focus our discussion on some of the most recent modeling studies building on a combined PK-PD and ABM approach that have generated experimentally testable hypotheses. Some future directions are also discussed.

Integrated PK-PD and Agent-Based Modeling in Oncology

PubMed Central

Wang, Zhihui; Butner, Joseph D.; Cristini, Vittorio

2016-01-01

Mathematical modeling has become a valuable tool that strives to complement conventional biomedical research modalities in order to predict experimental outcome, generate new medical hypotheses, and optimize clinical therapies. Two specific approaches, pharmacokinetic-pharmacodynamic (PK-PD) modeling, and agent-based modeling (ABM), have been widely applied in cancer research. While they have made important contributions on their own (e.g., PK-PD in examining chemotherapy drug efficacy and resistance, and ABM in describing and predicting tumor growth and metastasis), only a few groups have started to combine both approaches together in an effort to gain more insights into the details of drug dynamics and the resulting impact on tumor growth. In this review, we focus our discussion on some of the most recent modeling studies building on a combined PK-PD and ABM approach that have generated experimentally testable hypotheses. Some future directions are also discussed. PMID:25588379

A systems framework for identifying candidate microbial assemblages for disease management

USDA-ARS?s Scientific Manuscript database

Network models of soil and plant microbiomes present new opportunities for enhancing disease management, but also challenges for interpretation. We present a framework for interpreting microbiome networks, illustrating how the observed structure of networks can be used to generate testable hypothese...

Evidence-based Sensor Tasking for Space Domain Awareness

NASA Astrophysics Data System (ADS)

Jaunzemis, A.; Holzinger, M.; Jah, M.

2016-09-01

Space Domain Awareness (SDA) is the actionable knowledge required to predict, avoid, deter, operate through, recover from, and/or attribute cause to the loss and/or degradation of space capabilities and services. A main purpose for SDA is to provide decision-making processes with a quantifiable and timely body of evidence of behavior(s) attributable to specific space threats and/or hazards. To fulfill the promise of SDA, it is necessary for decision makers and analysts to pose specific hypotheses that may be supported or refuted by evidence, some of which may only be collected using sensor networks. While Bayesian inference may support some of these decision making needs, it does not adequately capture ambiguity in supporting evidence; i.e., it struggles to rigorously quantify 'known unknowns' for decision makers. Over the past 40 years, evidential reasoning approaches such as Dempster Shafer theory have been developed to address problems with ambiguous bodies of evidence. This paper applies mathematical theories of evidence using Dempster Shafer expert systems to address the following critical issues: 1) How decision makers can pose critical decision criteria as rigorous, testable hypotheses, 2) How to interrogate these hypotheses to reduce ambiguity, and 3) How to task a network of sensors to gather evidence for multiple competing hypotheses. This theory is tested using a simulated sensor tasking scenario balancing search versus track responsibilities.

Leveraging Rigorous Local Evaluations to Understand Contradictory Findings

ERIC Educational Resources Information Center

Boulay, Beth; Martin, Carlos; Zief, Susan; Granger, Robert

2013-01-01

Contradictory findings from "well-implemented" rigorous evaluations invite researchers to identify the differences that might explain the contradictions, helping to generate testable hypotheses for new research. This panel will examine efforts to ensure that the large number of local evaluations being conducted as part of four…

The Process of Mentoring Pregnant Adolescents: An Exploratory Study.

ERIC Educational Resources Information Center

Blinn-Pike, Lynn; Kuschel, Diane; McDaniel, Annette; Mingus, Suzanne; Mutti, Megan Poole

1998-01-01

The process that occurs in relationships between volunteer adult mentors and pregnant adolescent "mentees" is described empirically; testable hypotheses based on findings concerning the mentor role are proposed. Case records from 20 mentors are analyzed; findings regarding mentors' roles are discussed. Criteria for conceptualizing quasi-parenting…

Researching the Study Abroad Experience

ERIC Educational Resources Information Center

McLeod, Mark; Wainwright, Philip

2009-01-01

The authors propose a paradigm for rigorous scientific assessment of study abroad programs, with the focus being on how study abroad experiences affect psychological constructs as opposed to looking solely at study-abroad-related outcomes. Social learning theory is used as a possible theoretical basis for making testable hypotheses and guiding…

A THEORY OF WORK ADJUSTMENT. MINNESOTA STUDIES IN VOCATIONAL REHABILITATION, 15.

ERIC Educational Resources Information Center

DAWIS, RENE V.; AND OTHERS

A THEORY OF WORK ADJUSTMENT WHICH MAY CONTRIBUTE TO THE DEVELOPMENT OF A SCIENCE OF THE PSYCHOLOGY OF OCCUPATIONAL BEHAVIOR IS PROPOSED. IT BUILDS ON THE BASIC PSYCHOLOGICAL CONCEPTS OF STIMULUS, RESPONSE, AND REINFORCEMENT, AND PROVIDES A RESEARCH PARADIGM FOR GENERATING TESTABLE HYPOTHESES. IT WAS DERIVED FROM EARLY RESEARCH EFFORTS OF THE…

Learning Progressions, Vertical Scales, and Testable Hypotheses: Promising Intuitions and Points for Clarification

ERIC Educational Resources Information Center

Maul, Andrew

2015-01-01

Briggs and Peck [in "Using Learning Progressions to Design Vertical Scales That Support Coherent Inferences about Student Growth"] call for greater care in the conceptualization of the target attributes of students, or "what it is that is growing from grade to grade." In particular, they argue that learning progressions can…

Phases in the Adoption of Educational Innovations in Teacher Training Institutions.

ERIC Educational Resources Information Center

Hall, Gene E.

An attempt has been made to categorize phenomena observed as 20 teacher training institutions have adopted innovations and to extrapolate from these findings key concepts and principles that could form the basis for developing empirically testable hypotheses and could be of some immediate utility to those involved in innovation adoption. The…

Thinking about Evolution: Combinatorial Play as a Strategy for Exercising Scientific Creativity

ERIC Educational Resources Information Center

Wingate, Richard J. T.

2011-01-01

An enduring focus in education on how scientists formulate experiments and "do science" in the laboratory has excluded a vital element of scientific practice: the creative and imaginative thinking that generates models and testable hypotheses. In this case study, final-year biomedical sciences university students were invited to create and justify…

How Do Structure and Charge Affect Metal-Complex Binding to DNA? An Upper-Division Integrated Laboratory Project Using Cyclic Voltammetry

ERIC Educational Resources Information Center

Kulczynska, Agnieszka; Johnson, Reed; Frost, Tony; Margerum, Lawrence D.

2011-01-01

An advanced undergraduate laboratory project is described that integrates inorganic, analytical, physical, and biochemical techniques to reveal differences in binding between cationic metal complexes and anionic DNA (herring testes). Students were guided to formulate testable hypotheses based on the title question and a list of different metal…

The part of cognitive science that is philosophy.

PubMed

Dennett, Daniel C

2009-04-01

There is much good work for philosophers to do in cognitive science if they adopt the constructive attitude that prevails in science, work toward testable hypotheses, and take on the task of clarifying the relationship between the scientific concepts and the everyday concepts with which we conduct our moral lives. Copyright © 2009 Cognitive Science Society, Inc.

Evolutionary biology of plant defenses against herbivory and their predictive implications for endocrine disruptor susceptibility in vertebrates.

PubMed Central

Wynne-Edwards, K E

2001-01-01

Hormone disruption is a major, underappreciated component of the plant chemical arsenal, and the historical coevolution between hormone-disrupting plants and herbivores will have both increased the susceptibility of carnivores and diversified the sensitivities of herbivores to man-made endocrine disruptors. Here I review diverse evidence of the influence of plant secondary compounds on vertebrate reproduction, including human reproduction. Three of the testable hypotheses about the evolutionary responses of vertebrate herbivores to hormone-disrupting challenges from their diet are developed. Specifically, the hypotheses are that a) vertebrate herbivores will express steroid hormone receptors in the buccal cavity and/or the vomeronasal organ; b) absolute sex steroid concentrations will be lower in carnivores than in herbivores; and c) herbivore steroid receptors should be more diverse in their binding affinities than carnivore lineages. The argument developed in this review, if empirically validated by support for the specific hypotheses, suggests that a) carnivores will be more susceptible than herbivores to endocrine-disrupting compounds of anthropogenic origin entering their bodies, and b) diverse herbivore lineages will be variably susceptible to any given natural or synthetic contaminant. As screening methods for hormone-disrupting potential are compared and adopted, comparative endocrine physiology research is urgently needed to develop models that predict the broad applicability of those screening results in diverse vertebrate species. PMID:11401754

Mirror neurons in the tree of life: mosaic evolution, plasticity and exaptation of sensorimotor matching responses.

PubMed

Tramacere, Antonella; Pievani, Telmo; Ferrari, Pier F

2017-08-01

Considering the properties of mirror neurons (MNs) in terms of development and phylogeny, we offer a novel, unifying, and testable account of their evolution according to the available data and try to unify apparently discordant research, including the plasticity of MNs during development, their adaptive value and their phylogenetic relationships and continuity. We hypothesize that the MN system reflects a set of interrelated traits, each with an independent natural history due to unique selective pressures, and propose that there are at least three evolutionarily significant trends that gave raise to three subtypes: hand visuomotor, mouth visuomotor, and audio-vocal. Specifically, we put forward a mosaic evolution hypothesis, which posits that different types of MNs may have evolved at different rates within and among species. This evolutionary hypothesis represents an alternative to both adaptationist and associative models. Finally, the review offers a strong heuristic potential in predicting the circumstances under which specific variations and properties of MNs are expected. Such predictive value is critical to test new hypotheses about MN activity and its plastic changes, depending on the species, the neuroanatomical substrates, and the ecological niche. © 2016 Cambridge Philosophical Society.

A systematic survey of lipids across mouse tissues

PubMed Central

Jain, Mohit; Ngoy, Soeun; Sheth, Sunil A.; Swanson, Raymond A.; Rhee, Eugene P.; Liao, Ronglih; Clish, Clary B.; Mootha, Vamsi K.

2014-01-01

Lipids are a diverse collection of macromolecules essential for normal physiology, but the tissue distribution and function for many individual lipid species remain unclear. Here, we report a mass spectrometry survey of lipid abundance across 18 mouse tissues, detecting ∼1,000 mass spectrometry features, of which we identify 179 lipids from the glycerolipids, glycerophospholipids, lysophospholipids, acylcarnitines, sphingolipids, and cholesteryl ester classes. Our data reveal tissue-specific organization of lipids and can be used to generate testable hypotheses. For example, our data indicate that circulating triglycerides positively and negatively associated with future diabetes in humans are enriched in mouse adipose tissue and liver, respectively, raising hypotheses regarding the tissue origins of these diabetes-associated lipids. We also integrate our tissue lipid data with gene expression profiles to predict a number of substrates of lipid-metabolizing enzymes, highlighting choline phosphotransferases and sterol O-acyltransferases. Finally, we identify several tissue-specific lipids not present in plasma under normal conditions that may be of interest as biomarkers of tissue injury, and we show that two of these lipids are released into blood following ischemic brain injury in mice. This resource complements existing compendia of tissue gene expression and may be useful for integrative physiology and lipid biology. PMID:24518676

Assisted reproduction with gametes and embryos: what research is needed and fundable?

PubMed

Seidel, George E

2016-01-01

Principles for selecting future research projects include interests of investigators, fundability, potential applications, ethical considerations, being able to formulate testable hypotheses and choosing the best models, including selection of the most appropriate species. The following 10 areas of assisted reproduction seem especially appropriate for further research: efficacious capacitation of bovine spermatozoa in vitro; improved in vitro bovine oocyte maturation; decreasing variability and increasing efficacy of bovine superovulation; improved fertility of sexed semen; improving equine IVF; improving cryopreservation of rooster spermatozoa; understanding differences between males in success of sperm cryopreservation and reasons for success in competitive fertilisation; mechanisms of reprogramming somatic cell nuclei after nuclear transfer; regulation of differentiation of ovarian primordial follicles; and means by which spermatozoa maintain fertility during storage in the epididymis. Issues are species specific for several of these topics, in most cases because the biology is species specific.

LSI/VLSI design for testability analysis and general approach

NASA Technical Reports Server (NTRS)

Lam, A. Y.

1982-01-01

The incorporation of testability characteristics into large scale digital design is not only necessary for, but also pertinent to effective device testing and enhancement of device reliability. There are at least three major DFT techniques, namely, the self checking, the LSSD, and the partitioning techniques, each of which can be incorporated into a logic design to achieve a specific set of testability and reliability requirements. Detailed analysis of the design theory, implementation, fault coverage, hardware requirements, application limitations, etc., of each of these techniques are also presented.

Surface fire effects on conifer and hardwood crowns--applications of an integral plume model

Treesearch

Matthew Dickinson; Anthony Bova; Kathleen Kavanagh; Antoine Randolph; Lawrence Band

2009-01-01

An integral plume model was applied to the problems of tree death from canopy injury in dormant-season hardwoods and branch embolism in Douglas fir (Pseudotsuga menziesii) crowns. Our purpose was to generate testable hypotheses. We used the integral plume models to relate crown injury to bole injury and to explore the effects of variation in fire...

Objections to routine clinical outcomes measurement in mental health services: any evidence so far?

PubMed

MacDonald, Alastair J D; Trauer, Tom

2010-12-01

Routine clinical outcomes measurement (RCOM) is gaining importance in mental health services. To examine whether criticisms published in advance of the development of RCOM have been borne out by data now available from such a programme. This was an observational study of routine ratings using HoNOS65+ at inception/admission and again at discharge in an old age psychiatry service from 1997 to 2008. Testable hypotheses were generated from each criticism amenable to empirical examination. Inter-rater reliability estimates were applied to observed differences between scores between community and ward patients using resampling. Five thousand one hundred eighty community inceptions and 862 admissions had HoNOS65+ ratings at referral/admission and discharge. We could find no evidence of gaming (artificially worse scores at inception and better at discharge), selection, attrition or detection bias, and ratings were consistent with diagnosis and level of service. Anticipated low levels of inter-rater reliability did not vitiate differences between levels of service. Although only hypotheses testable from within RCOM data were examined, and only 46% of eligible episodes had complete outcomes data, no evidence of the alleged biases were found. RCOM seems valid and practical in mental health services.

The evolutionary psychology of hunger.

PubMed

Al-Shawaf, Laith

2016-10-01

An evolutionary psychological perspective suggests that emotions can be understood as coordinating mechanisms whose job is to regulate various psychological and physiological programs in the service of solving an adaptive problem. This paper suggests that it may also be fruitful to approach hunger from this coordinating mechanism perspective. To this end, I put forward an evolutionary task analysis of hunger, generating novel a priori hypotheses about the coordinating effects of hunger on psychological processes such as perception, attention, categorization, and memory. This approach appears empirically fruitful in that it yields a bounty of testable new hypotheses. Copyright © 2016 Elsevier Ltd. All rights reserved.

Causes and consequences of reduced blood volume in space flight - A multi-discipline modeling study

NASA Technical Reports Server (NTRS)

Leonard, J. I.

1983-01-01

A group of mathematical models of various physiological systems have been developed and applied to studying problems associated with adaptation to weightlessness. One biomedical issue which could be addressed by at least three of these models from varying perspectives was the reduction in blood volume that universally occurs in astronauts. Accordingly, models of fluid-electrolyte, erythropoiesis, and cardiovascular regulation were employed to study the causes and consequences of blood volume loss during space flight. This analysis confirms the notion that alterations of blood volume are central to an understanding of adaptation to prolonged space flight. More importantly, the modeling studies resulted in specific hypotheses accounting for plasma volume and red cell mass losses and testable predictions concerning the behavior of the circulatory system.

A Framework for Evidence-Based Licensure of Adaptive Autonomous Systems

DTIC Science & Technology

2016-03-01

insights gleaned to DoD. The autonomy community has identified significant challenges associated with test, evaluation verification and validation of...licensure as a test, evaluation, verification , and validation (TEVV) framework that can address these challenges. IDA found that traditional...language requirements to testable (preferably machine testable) specifications • Design of architectures that treat development and verification of

Structural Genomics of Bacterial Virulence Factors

DTIC Science & Technology

2006-05-01

positioned in the unit cell by Molecular Replacement (Protein Data Bank ( PDB ) ID code 1acc)6 using MOLREP, and refined with REFMAC version 5.0 (ref. 24...increase our understanding of the molecular mechanisms of pathogenicity, putting us in a stronger position to anticipate and react to emerging...term, the accumulated structural information will generate important and testable hypotheses that will increase our understanding of the molecular

On the Importance of Comparative Research for the Understanding of Human Behavior and Development: A Reply to Gottlieb & Lickliter (2004)

ERIC Educational Resources Information Center

Maestripieri, Dario

2005-01-01

Comparative behavioral research is important for a number of reasons and can contribute to the understanding of human behavior and development in many different ways. Research with animal models of human behavior and development can be a source not only of general principles and testable hypotheses but also of empirical information that may be…

Debates—Hypothesis testing in hydrology: Introduction

NASA Astrophysics Data System (ADS)

Blöschl, Günter

2017-03-01

This paper introduces the papers in the "Debates—Hypothesis testing in hydrology" series. The four articles in the series discuss whether and how the process of testing hypotheses leads to progress in hydrology. Repeated experiments with controlled boundary conditions are rarely feasible in hydrology. Research is therefore not easily aligned with the classical scientific method of testing hypotheses. Hypotheses in hydrology are often enshrined in computer models which are tested against observed data. Testability may be limited due to model complexity and data uncertainty. All four articles suggest that hypothesis testing has contributed to progress in hydrology and is needed in the future. However, the procedure is usually not as systematic as the philosophy of science suggests. A greater emphasis on a creative reasoning process on the basis of clues and explorative analyses is therefore needed.

It takes two to talk: a second-person neuroscience approach to language learning.

PubMed

Syal, Supriya; Anderson, Adam K

2013-08-01

Language is a social act. We have previously argued that language remains embedded in sociality because the motivation to communicate exists only within a social context. Schilbach et al. underscore the importance of studying linguistic behavior from within the motivated, socially interactive frame in which it is learnt and used, as well as provide testable hypotheses for a participatory, second-person neuroscience approach to language learning.

Empirical approaches to the study of language evolution.

PubMed

Fitch, W Tecumseh

2017-02-01

The study of language evolution, and human cognitive evolution more generally, has often been ridiculed as unscientific, but in fact it differs little from many other disciplines that investigate past events, such as geology or cosmology. Well-crafted models of language evolution make numerous testable hypotheses, and if the principles of strong inference (simultaneous testing of multiple plausible hypotheses) are adopted, there is an increasing amount of relevant data allowing empirical evaluation of such models. The articles in this special issue provide a concise overview of current models of language evolution, emphasizing the testable predictions that they make, along with overviews of the many sources of data available to test them (emphasizing comparative, neural, and genetic data). The key challenge facing the study of language evolution is not a lack of data, but rather a weak commitment to hypothesis-testing approaches and strong inference, exacerbated by the broad and highly interdisciplinary nature of the relevant data. This introduction offers an overview of the field, and a summary of what needed to evolve to provide our species with language-ready brains. It then briefly discusses different contemporary models of language evolution, followed by an overview of different sources of data to test these models. I conclude with my own multistage model of how different components of language could have evolved.

Creation of a Mouse with Stress-Induced Dystonia: Control of an ATPase Chaperone

DTIC Science & Technology

2013-04-01

was successful, and a mouse with the desired dystonic symptoms was obtained. It has two mutations , one a dominantly inherited gene with 100...the hallmark of dystonia. 15. SUBJECT TERMS Dystonia, genetically modified mice, stress, gene mutations , animal model of disease. 16...there are a variety of hypotheses that should be testable if there were a realistic animal model. Mice with mutations in genes known to cause dystonia

Systems analysis of transcriptome data provides new hypotheses about Arabidopsis root response to nitrate treatments

PubMed Central

Canales, Javier; Moyano, Tomás C.; Villarroel, Eva; Gutiérrez, Rodrigo A.

2014-01-01

Nitrogen (N) is an essential macronutrient for plant growth and development. Plants adapt to changes in N availability partly by changes in global gene expression. We integrated publicly available root microarray data under contrasting nitrate conditions to identify new genes and functions important for adaptive nitrate responses in Arabidopsis thaliana roots. Overall, more than 2000 genes exhibited changes in expression in response to nitrate treatments in Arabidopsis thaliana root organs. Global regulation of gene expression by nitrate depends largely on the experimental context. However, despite significant differences from experiment to experiment in the identity of regulated genes, there is a robust nitrate response of specific biological functions. Integrative gene network analysis uncovered relationships between nitrate-responsive genes and 11 highly co-expressed gene clusters (modules). Four of these gene network modules have robust nitrate responsive functions such as transport, signaling, and metabolism. Network analysis hypothesized G2-like transcription factors are key regulatory factors controlling transport and signaling functions. Our meta-analysis highlights the role of biological processes not studied before in the context of the nitrate response such as root hair development and provides testable hypothesis to advance our understanding of nitrate responses in plants. PMID:24570678

Plant evolution at the interface of paleontology and developmental biology: An organism-centered paradigm.

PubMed

Rothwell, Gar W; Wyatt, Sarah E; Tomescu, Alexandru M F

2014-06-01

Paleontology yields essential evidence for inferring not only the pattern of evolution, but also the genetic basis of evolution within an ontogenetic framework. Plant fossils provide evidence for the pattern of plant evolution in the form of transformational series of structure through time. Developmentally diagnostic structural features that serve as "fingerprints" of regulatory genetic pathways also are preserved by plant fossils, and here we provide examples of how those fingerprints can be used to infer the mechanisms by which plant form and development have evolved. When coupled with an understanding of variations and systematic distributions of specific regulatory genetic pathways, this approach provides an avenue for testing evolutionary hypotheses at the organismal level that is analogous to employing bioinformatics to explore genetics at the genomic level. The positions where specific genes, gene families, and developmental regulatory mechanisms first appear in phylogenies are correlated with the positions where fossils with the corresponding structures occur on the tree, thereby yielding testable hypotheses that extend our understanding of the role of developmental changes in the evolution of the body plans of vascular plant sporophytes. As a result, we now have new and powerful methodologies for characterizing major evolutionary changes in morphology, anatomy, and physiology that have resulted from combinations of genetic regulatory changes and that have produced the synapomorphies by which we recognize major clades of plants. © 2014 Botanical Society of America, Inc.

Modelling the molecular mechanisms of aging

PubMed Central

Mc Auley, Mark T.; Guimera, Alvaro Martinez; Hodgson, David; Mcdonald, Neil; Mooney, Kathleen M.; Morgan, Amy E.

2017-01-01

The aging process is driven at the cellular level by random molecular damage that slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the aging process. The complexity of the aging process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards and discusses many specific examples of models that have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field. PMID:28096317

Quantitative Measurements of Autobiographical Memory Content

PubMed Central

Mainetti, Matteo; Ascoli, Giorgio A.

2012-01-01

Autobiographical memory (AM), subjective recollection of past experiences, is fundamental in everyday life. Nevertheless, characterization of the spontaneous occurrence of AM, as well as of the number and types of recollected details, remains limited. The CRAM (Cue-Recalled Autobiographical Memory) test (http://cramtest.info) adapts and combines the cue-word method with an assessment that collects counts of details recalled from different life periods. The SPAM (Spontaneous Probability of Autobiographical Memories) protocol samples introspection during everyday activity, recording memory duration and frequency. These measures provide detailed, naturalistic accounts of AM content and frequency, quantifying essential dimensions of recollection. AM content (∼20 details/recollection) decreased with the age of the episode, but less drastically than the probability of reporting remote compared to recent memories. AM retrieval was frequent (∼20/hour), each memory lasting ∼30 seconds. Testable hypotheses of the specific content retrieved in a fixed time from given life periods are presented. PMID:23028629

Cultural prototypes and dimensions of honor.

PubMed

Cross, Susan E; Uskul, Ayse K; Gerçek-Swing, Berna; Sunbay, Zeynep; Alözkan, Cansu; Günsoy, Ceren; Ataca, Bilge; Karakitapoglu-Aygün, Zahide

2014-02-01

Research evidence and theoretical accounts of honor point to differing definitions of the construct in differing cultural contexts. The current studies address the question "What is honor?" using a prototype approach in Turkey and the Northern United States. Studies 1a/1b revealed substantial differences in the specific features generated by members of the two groups, but Studies 2 and 3 revealed cultural similarities in the underlying dimensions of self-respect, moral behavior, and social status/respect. Ratings of the centrality and personal importance of these factors were similar across the two groups, but their association with other relevant constructs differed. The tripartite nature of honor uncovered in these studies helps observers and researchers alike understand how diverse responses to situations can be attributed to honor. Inclusion of a prototype analysis into the literature on honor cultures can provide enhanced coverage of the concept that may lead to testable hypotheses and new theoretical developments.

Genes, Environments, and Sex Differences in Alcohol Research.

PubMed

Salvatore, Jessica E; Cho, Seung Bin; Dick, Danielle M

2017-07-01

The study of sex differences has been identified as one way to enhance scientific reproducibility, and the National Institutes of Health (NIH) have implemented a new policy to encourage the explicit examination of sex differences. Our goal here is to address sex differences in behavioral genetic research on alcohol outcomes. We review sex differences for alcohol outcomes and whether the source and magnitude of genetic influences on alcohol consumption and alcohol use disorder (AUD) are the same across sexes; describe common research designs for studying sex-specific gene-by-environment interaction (G × E) effects; and discuss the role of statistical power and theory when testing sex-specific genetic effects. There are robust sex differences for many alcohol outcomes. The weight of evidence suggests that the source and magnitude of genetic influences on alcohol consumption and AUD are the same across sexes. Whether there are sex-specific G × E effects has received less attention to date. The new NIH policy necessitates a systematic approach for studying sex-specific genetic effects in alcohol research. Researchers are encouraged to report power for tests of these effects and to use theory to develop testable hypotheses, especially for studies of G × E.

Mining Twitter as a First Step toward Assessing the Adequacy of Gender Identification Terms on Intake Forms

PubMed Central

Hicks, Amanda; Hogan, William R.; Rutherford, Michael; Malin, Bradley; Xie, Mengjun; Fellbaum, Christiane; Yin, Zhijun; Fabbri, Daniel; Hanna, Josh; Bian, Jiang

2015-01-01

The Institute of Medicine (IOM) recommends that health care providers collect data on gender identity. If these data are to be useful, they should utilize terms that characterize gender identity in a manner that is 1) sensitive to transgender and gender non-binary individuals (trans* people) and 2) semantically structured to render associated data meaningful to the health care professionals. We developed a set of tools and approaches for analyzing Twitter data as a basis for generating hypotheses on language used to identify gender and discuss gender-related issues across regions and population groups. We offer sample hypotheses regarding regional variations in the usage of certain terms such as ‘genderqueer’, ‘genderfluid’, and ‘neutrois’ and their usefulness as terms on intake forms. While these hypotheses cannot be directly validated with Twitter data alone, our data and tools help to formulate testable hypotheses and design future studies regarding the adequacy of gender identification terms on intake forms. PMID:26958196

Perspective: researching the transition from non-living to the first microorganisms: methods and experiments are major challenges.

PubMed

Trevors, J T

2010-06-01

Methods to research the origin of microbial life are limited. However, microorganisms were the first organisms on the Earth capable of cell growth and division, and interactions with their environment, other microbial cells, and eventually with diverse eukaryotic organisms. The origin of microbial life and the supporting scientific evidence are both an enigma and a scientific priority. Numerous hypotheses have been proposed, scenarios imagined, speculations presented in papers, insights shared, and assumptions made without supporting experimentation, which have led to limited progress in understanding the origin of microbial life. The use of the human imagination to envision the origin of life events, without supporting experimentation, observation and independently replicated experiments required for science, is a significant constraint. The challenge remains how to better understand the origin of microbial life using observations and experimental methods as opposed to speculation, assumptions, scenarios, envisioning events and un-testable hypotheses. This is not an easy challenge as experimental design and plausible hypothesis testing are difficult. Since past approaches have been inconclusive in providing evidence for the origin of microbial life mechanisms and the manner in which genetic instructions was encoded into DNA/RNA, it is reasonable and logical to propose that progress will be made when testable, plausible hypotheses and methods are used in the origin of microbial life research, and the experimental observations are, or are not reproduced in independent laboratories. These perspectives will be discussed in this article as well as the possibility that a pre-biotic film preceded a microbial biofilm as a possible micro-location for the origin of microbial cells capable of growth and division. 2010 Elsevier B.V. All rights reserved.

Phylogenetic perspectives on noise-induced fear and annoyance

NASA Astrophysics Data System (ADS)

Bowles, Ann

2003-04-01

Negative human responses to noise are typically interpreted in terms of human psychological, cognitive, or social processes. However, it may be useful to frame hypotheses about human responses in terms of evolutionary history, during which negative responses have been part of a suite of adaptions to a variable sound environment. By comparing the responses of a range of nonhuman animals to various types of noise, it is possible to develop hypotheses about the ecology of human responses. Examples of noise-related phenomena that could be explained usefully from this perspective include the Schulz curve, noise-induced physical stress, acute fear responses induced by transient noise, and the relationship between temperament and noise-induced annoyance. Responses of animals from a range of taxa will be described and their behavior interpreted in terms of their life-history strategies. With this perspective, some testable hypotheses about noise-induced fear and annoyance will be suggested.

Causal Reasoning on Biological Networks: Interpreting Transcriptional Changes

NASA Astrophysics Data System (ADS)

Chindelevitch, Leonid; Ziemek, Daniel; Enayetallah, Ahmed; Randhawa, Ranjit; Sidders, Ben; Brockel, Christoph; Huang, Enoch

Over the past decade gene expression data sets have been generated at an increasing pace. In addition to ever increasing data generation, the biomedical literature is growing exponentially. The PubMed database (Sayers et al., 2010) comprises more than 20 million citations as of October 2010. The goal of our method is the prediction of putative upstream regulators of observed expression changes based on a set of over 400,000 causal relationships. The resulting putative regulators constitute directly testable hypotheses for follow-up.

White-nose syndrome initiates a cascade of physiologic disturbances in the hibernating bat host

USGS Publications Warehouse

Verant, Michelle L.; Meteyer, Carol U.; Speakman, John R.; Cryan, Paul M.; Lorch, Jeffrey M.; Blehert, David S.

2014-01-01

Integrating these novel findings on the physiological changes that occur in early-stage WNS with those previously documented in late-stage infections, we propose a multi-stage disease progression model that mechanistically describes the pathologic and physiologic effects underlying mortality of WNS in hibernating bats. This model identifies testable hypotheses for better understanding this disease, knowledge that will be critical for defining effective disease mitigation strategies aimed at reducing morbidity and mortality that results from WNS.

Designing for competence: spaces that enhance collaboration readiness in healthcare.

PubMed

Lamb, Gerri; Shraiky, James

2013-09-01

Many universities in the United States are investing in classrooms and campuses designed to increase collaboration and teamwork among the health professions. To date, we know little about whether these learning spaces are having the intended impact on student performance. Recent advances in the identification of interprofessional teamwork competencies provide a much-needed step toward a defined outcome metric. Rigorous study of the relationship between design and student competence in collaboration also requires clear specification of design concepts and development of testable frameworks. Such theory-based evaluation is crucial for design to become an integral part of interprofessional education strategies and initiatives. Current classroom and campus designs were analyzed for common themes and features in collaborative spaces as a starting place for specification of design concepts and model development. Four major themes were identified: flexibility, visual transparency/proximity, technology and environmental infrastructure. Potential models linking this preliminary set of design concepts to student competencies are proposed and used to generate hypotheses for future study of the impact of collaborative design spaces on student outcomes.

Evaluation of phylogenetic footprint discovery for predicting bacterial cis-regulatory elements and revealing their evolution.

PubMed

Janky, Rekin's; van Helden, Jacques

2008-01-23

The detection of conserved motifs in promoters of orthologous genes (phylogenetic footprints) has become a common strategy to predict cis-acting regulatory elements. Several software tools are routinely used to raise hypotheses about regulation. However, these tools are generally used as black boxes, with default parameters. A systematic evaluation of optimal parameters for a footprint discovery strategy can bring a sizeable improvement to the predictions. We evaluate the performances of a footprint discovery approach based on the detection of over-represented spaced motifs. This method is particularly suitable for (but not restricted to) Bacteria, since such motifs are typically bound by factors containing a Helix-Turn-Helix domain. We evaluated footprint discovery in 368 Escherichia coli K12 genes with annotated sites, under 40 different combinations of parameters (taxonomical level, background model, organism-specific filtering, operon inference). Motifs are assessed both at the levels of correctness and significance. We further report a detailed analysis of 181 bacterial orthologs of the LexA repressor. Distinct motifs are detected at various taxonomical levels, including the 7 previously characterized taxon-specific motifs. In addition, we highlight a significantly stronger conservation of half-motifs in Actinobacteria, relative to Firmicutes, suggesting an intermediate state in specificity switching between the two Gram-positive phyla, and thereby revealing the on-going evolution of LexA auto-regulation. The footprint discovery method proposed here shows excellent results with E. coli and can readily be extended to predict cis-acting regulatory signals and propose testable hypotheses in bacterial genomes for which nothing is known about regulation.

Scientific realism and wishful thinking in soil hydrology

NASA Astrophysics Data System (ADS)

Flühler, H.

2009-04-01

In our field we often learn - or could have learned - more from failures than from successes provided we had postulated testable hypotheses to be accepted or rejected. In soil hydrology, hypotheses are testable if independent information quantifying the pertinent system features is at hand. This view on how to operate is an idealized concept of how we could or should have worked. In reality, the path to success is more tortuous and we usually progress differently obeying to other professional musts. Although we missed some shortcuts over the past few decades, we definitely made significant progress in understanding vadose zone progresses, but we could have advanced our system understanding faster by more rigorously questioning the fundamental assumptions. I will try to illustrate the tortuous path of learning and identify some causes of the slowed-down learning curve. In the pioneering phase of vadose zone research many models have been mapped in our minds and implemented on our computers. Many of them are now well established, powerful and represent the state-of-the-art even when they do not work. Some of them are based on erroneous or misleading concepts. Even when based on adequate concepts they might have been applied in the wrong context or inadequate models may have lead to apparent success. I address this process of collective learning with the intention that we spend more time and efforts to find the right question instead of improving tools, which are questionably suitable for solving the main problems.

BETA: Behavioral testability analyzer and its application to high-level test generation and synthesis for testability. Ph.D. Thesis

NASA Technical Reports Server (NTRS)

Chen, Chung-Hsing

1992-01-01

In this thesis, a behavioral-level testability analysis approach is presented. This approach is based on analyzing the circuit behavioral description (similar to a C program) to estimate its testability by identifying controllable and observable circuit nodes. This information can be used by a test generator to gain better access to internal circuit nodes and to reduce its search space. The results of the testability analyzer can also be used to select test points or partial scan flip-flops in the early design phase. Based on selection criteria, a novel Synthesis for Testability approach call Test Statement Insertion (TSI) is proposed, which modifies the circuit behavioral description directly. Test Statement Insertion can also be used to modify circuit structural description to improve its testability. As a result, Synthesis for Testability methodology can be combined with an existing behavioral synthesis tool to produce more testable circuits.

Writing testable software requirements

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knirk, D.

1997-11-01

This tutorial identifies common problems in analyzing requirements in the problem and constructing a written specification of what the software is to do. It deals with two main problem areas: identifying and describing problem requirements, and analyzing and describing behavior specifications.

Curiosity at Vera Rubin Ridge: Testable Hypotheses, First Results, and Implications for Habitability

NASA Astrophysics Data System (ADS)

Fraeman, A.; Bedford, C.; Bridges, J.; Edgar, L. A.; Hardgrove, C.; Horgan, B. H. N.; Gabriel, T. S. J.; Grotzinger, J. P.; Gupta, S.; Johnson, J. R.; Rampe, E. B.; Morris, R. V.; Salvatore, M. R.; Schwenzer, S. P.; Stack, K.; Pinet, P. C.; Rubin, D. M.; Weitz, C. M.; Wellington, D. F.; Wiens, R. C.; Williams, A. J.; Vasavada, A. R.

2017-12-01

As of sol 1756, Curiosity was 250 meters from ascending Vera Rubin Ridge, a unique geomorphic feature preserved in the lower foothills of Aeolis Mons (informally known as Mt. Sharp) that is distinguishable from orbit. Vera Rubin Ridge (previously termed the Hematite Ridge) is characterized by a higher thermal inertia than the surrounding terrain, is comparatively resistant to erosion, and is capped with a hematite-bearing layer that is visible in 18 m/pixel CRISM data. A key hypothesis associated with this unit is that it represents a redox interface where ferrous iron oxidized and precipitated either as hematite or another ferric precursor. The Curiosity integrated payload is being used to determine the depositional environment(s), stratigraphic context and geochemical conditions associated with this interface, all of which will provide key insights into its past habitability potential and the relative timing of processes. Specifically, analysis of Curiosity data will address four major questions related to the history and evolution of ridge-forming strata: (1) What is the stratigraphic relationship between the units in the ridge and the Mt. Sharp group (see Grotzinger et al., 2015)? (2) What primary and secondary geologic processes deposited and modified the ridge units over time? (3) What is the nature and timing of the hematite precipitation environment, and how does it relate to similar oxidized phases in the Murray formation? (4) What are the implications for habitability and the preservation of organic molecules? Initial results of a systematic imaging campaign along the contact between the lower portion or the ridge and the Murray formation has revealed dm-scale cross bedding within the ridge stratigraphy, which provide clues about the depositional environments; these can be compared to suites of sedimentary structures within the adjacent Murray formation. Long distance ChemCam passive and Mastcam multispectral data show that hematite and likely other ferric phases are present in the upper ridge, consistent with orbital data. Curiosity will continue to take systematic observations that draw upon testable hypotheses about the ridge environments as the rover ascends Vera Rubin Ridge.

“Feature Detection” vs. “Predictive Coding” Models of Plant Behavior

PubMed Central

Calvo, Paco; Baluška, František; Sims, Andrew

2016-01-01

In this article we consider the possibility that plants exhibit anticipatory behavior, a mark of intelligence. If plants are able to anticipate and respond accordingly to varying states of their surroundings, as opposed to merely responding online to environmental contingencies, then such capacity may be in principle testable, and subject to empirical scrutiny. Our main thesis is that adaptive behavior can only take place by way of a mechanism that predicts the environmental sources of sensory stimulation. We propose to test for anticipation in plants experimentally by contrasting two empirical hypotheses: “feature detection” and “predictive coding.” We spell out what these contrasting hypotheses consist of by way of illustration from the animal literature, and consider how to transfer the rationale involved to the plant literature. PMID:27757094

Geophysical Evolution of Ch Asteroids and Testable Hypotheses for Future Missions

NASA Astrophysics Data System (ADS)

Castillo, J. C.

2017-12-01

The main population of asteroids related to meteorites in the collections remains to be explored in situ. Ch asteroids are the only midsized asteroids that display a signature of hydration (besides Pallas) and the spectral connection between Ch asteroids and CM chondrites suggests that the former represent potential parent bodies for the latter. This class of asteroids is particularly interesting because it hosts many objects 100-200 km in size, which are believed to belong to a primordial population of planetesimals. This presentation will explore multiple evolution pathways for Ch-asteroids leading to possible hypotheses on the geological, petrological, and geophysical properties that a disrupted parent body would present to a future mission. This work is being carried out at the Jet Propulsion Laboratory, California Institute of Technology, under contract to NASA.

Slot-like capacity and resource-like coding in a neural model of multiple-item working memory.

PubMed

Standage, Dominic; Pare, Martin

2018-06-27

For the past decade, research on the storage limitations of working memory has been dominated by two fundamentally different hypotheses. On the one hand, the contents of working memory may be stored in a limited number of `slots', each with a fixed resolution. On the other hand, any number of items may be stored, but with decreasing resolution. These two hypotheses have been invaluable in characterizing the computational structure of working memory, but neither provides a complete account of the available experimental data, nor speaks to the neural basis of the limitations it characterizes. To address these shortcomings, we simulated a multiple-item working memory task with a cortical network model, the cellular resolution of which allowed us to quantify the coding fidelity of memoranda as a function of memory load, as measured by the discriminability, regularity and reliability of simulated neural spiking. Our simulations account for a wealth of neural and behavioural data from human and non-human primate studies, and they demonstrate that feedback inhibition lowers both capacity and coding fidelity. Because the strength of inhibition scales with the number of items stored by the network, increasing this number progressively lowers fidelity until capacity is reached. Crucially, the model makes specific, testable predictions for neural activity on multiple-item working memory tasks.

What are health-related users tweeting? A qualitative content analysis of health-related users and their messages on twitter.

PubMed

Lee, Joy L; DeCamp, Matthew; Dredze, Mark; Chisolm, Margaret S; Berger, Zackary D

2014-10-15

Twitter is home to many health professionals who send messages about a variety of health-related topics. Amid concerns about physicians posting inappropriate content online, more in-depth knowledge about these messages is needed to understand health professionals' behavior on Twitter. Our goal was to characterize the content of Twitter messages, specifically focusing on health professionals and their tweets relating to health. We performed an in-depth content analysis of 700 tweets. Qualitative content analysis was conducted on tweets by health users on Twitter. The primary objective was to describe the general type of content (ie, health-related versus non-health related) on Twitter authored by health professionals and further to describe health-related tweets on the basis of the type of statement made. Specific attention was given to whether a tweet was personal (as opposed to professional) or made a claim that users would expect to be supported by some level of medical evidence (ie, a "testable" claim). A secondary objective was to compare content types among different users, including patients, physicians, nurses, health care organizations, and others. Health-related users are posting a wide range of content on Twitter. Among health-related tweets, 53.2% (184/346) contained a testable claim. Of health-related tweets by providers, 17.6% (61/346) were personal in nature; 61% (59/96) made testable statements. While organizations and businesses use Twitter to promote their services and products, patient advocates are using this tool to share their personal experiences with health. Twitter users in health-related fields tweet about both testable claims and personal experiences. Future work should assess the relationship between testable tweets and the actual level of evidence supporting them, including how Twitter users-especially patients-interpret the content of tweets posted by health providers.

What can we learn from a two-brain approach to verbal interaction?

PubMed

Schoot, Lotte; Hagoort, Peter; Segaert, Katrien

2016-09-01

Verbal interaction is one of the most frequent social interactions humans encounter on a daily basis. In the current paper, we zoom in on what the multi-brain approach has contributed, and can contribute in the future, to our understanding of the neural mechanisms supporting verbal interaction. Indeed, since verbal interaction can only exist between individuals, it seems intuitive to focus analyses on inter-individual neural markers, i.e. between-brain neural coupling. To date, however, there is a severe lack of theoretically-driven, testable hypotheses about what between-brain neural coupling actually reflects. In this paper, we develop a testable hypothesis in which between-pair variation in between-brain neural coupling is of key importance. Based on theoretical frameworks and empirical data, we argue that the level of between-brain neural coupling reflects speaker-listener alignment at different levels of linguistic and extra-linguistic representation. We discuss the possibility that between-brain neural coupling could inform us about the highest level of inter-speaker alignment: mutual understanding. Copyright © 2016 Elsevier Ltd. All rights reserved.

Simulating Cancer Growth with Multiscale Agent-Based Modeling

PubMed Central

Wang, Zhihui; Butner, Joseph D.; Kerketta, Romica; Cristini, Vittorio; Deisboeck, Thomas S.

2014-01-01

There have been many techniques developed in recent years to in silico model a variety of cancer behaviors. Agent-based modeling is a specific discrete-based hybrid modeling approach that allows simulating the role of diversity in cell populations as well as within each individual cell; it has therefore become a powerful modeling method widely used by computational cancer researchers. Many aspects of tumor morphology including phenotype-changing mutations, the adaptation to microenvironment, the process of angiogenesis, the influence of extracellular matrix, reactions to chemotherapy or surgical intervention, the effects of oxygen and nutrient availability, and metastasis and invasion of healthy tissues have been incorporated and investigated in agent-based models. In this review, we introduce some of the most recent agent-based models that have provided insight into the understanding of cancer growth and invasion, spanning multiple biological scales in time and space, and we further describe several experimentally testable hypotheses generated by those models. We also discuss some of the current challenges of multiscale agent-based cancer models. PMID:24793698

Single-Cell RNA-Seq of Mouse Dopaminergic Neurons Informs Candidate Gene Selection for Sporadic Parkinson Disease.

PubMed

Hook, Paul W; McClymont, Sarah A; Cannon, Gabrielle H; Law, William D; Morton, A Jennifer; Goff, Loyal A; McCallion, Andrew S

2018-03-01

Genetic variation modulating risk of sporadic Parkinson disease (PD) has been primarily explored through genome-wide association studies (GWASs). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal time points. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a postnatal neuroblast population and substantia nigra (SN) DA neurons. We use these population-specific data to develop a scoring system to prioritize candidate genes in all 49 GWAS intervals implicated in PD risk, including genes with known PD associations and many with extensive supporting literature. As proof of principle, we confirm that the nigrostriatal pathway is compromised in Cplx1-null mice. Ultimately, this systematic approach establishes biologically pertinent candidates and testable hypotheses for sporadic PD, informing a new era of PD genetic research. Copyright © 2018 American Society of Human Genetics. All rights reserved.

Dissecting the polysaccharide-rich grape cell wall matrix using recombinant pectinases during winemaking.

PubMed

Gao, Yu; Fangel, Jonatan U; Willats, William G T; Vivier, Melané A; Moore, John P

2016-11-05

The effectiveness of enzyme-mediated-maceration in red winemaking relies on the use of an optimum combination of specific enzymes. A lack of information on the relevant enzyme activities and the corresponding polysaccharide-rich berry cell wall structure is a major limitation. This study used different combinations of purified recombinant pectinases with cell wall profiling tools to follow the deconstruction process during winemaking. Multivariate data analysis of the glycan microarray (CoMPP) and gas chromatography (GC) results revealed that pectin lyase performed almost as effectively in de-pectination as certain commercial enzyme mixtures. Surprisingly the combination of endo-polygalacturonase and pectin-methyl-esterase only unraveled the cell walls without de-pectination. Datasets from the various combinations used confirmed pectin-rich and xyloglucan-rich layers within the grape pomace. These data support a proposed grape cell wall model which can serve as a foundation to evaluate testable hypotheses in future studies aimed at developing tailor-made enzymes for winemaking scenarios. Copyright © 2016 Elsevier Ltd. All rights reserved.

Differentiation without distancing. explaining bi-polarization of opinions without negative influence.

PubMed

Mäs, Michael; Flache, Andreas

2013-01-01

Explanations of opinion bi-polarization hinge on the assumption of negative influence, individuals' striving to amplify differences to disliked others. However, empirical evidence for negative influence is inconclusive, which motivated us to search for an alternative explanation. Here, we demonstrate that bi-polarization can be explained without negative influence, drawing on theories that emphasize the communication of arguments as central mechanism of influence. Due to homophily, actors interact mainly with others whose arguments will intensify existing tendencies for or against the issue at stake. We develop an agent-based model of this theory and compare its implications to those of existing social-influence models, deriving testable hypotheses about the conditions of bi-polarization. Hypotheses were tested with a group-discussion experiment (N = 96). Results demonstrate that argument exchange can entail bi-polarization even when there is no negative influence.

Evolutionary Perspectives on Genetic and Environmental Risk Factors for Psychiatric Disorders.

PubMed

Keller, Matthew C

2018-05-07

Evolutionary medicine uses evolutionary theory to help elucidate why humans are vulnerable to disease and disorders. I discuss two different types of evolutionary explanations that have been used to help understand human psychiatric disorders. First, a consistent finding is that psychiatric disorders are moderately to highly heritable, and many, such as schizophrenia, are also highly disabling and appear to decrease Darwinian fitness. Models used in evolutionary genetics to understand why genetic variation exists in fitness-related traits can be used to understand why risk alleles for psychiatric disorders persist in the population. The usual explanation for species-typical adaptations-natural selection-is less useful for understanding individual differences in genetic risk to disorders. Rather, two other types of models, mutation-selection-drift and balancing selection, offer frameworks for understanding why genetic variation in risk to psychiatric (and other) disorders exists, and each makes predictions that are now testable using whole-genome data. Second, species-typical capacities to mount reactions to negative events are likely to have been crafted by natural selection to minimize fitness loss. The pain reaction to tissue damage is almost certainly such an example, but it has been argued that the capacity to experience depressive symptoms such as sadness, anhedonia, crying, and fatigue in the face of adverse life situations may have been crafted by natural selection as well. I review the rationale and strength of evidence for this hypothesis. Evolutionary hypotheses of psychiatric disorders are important not only for offering explanations for why psychiatric disorders exist, but also for generating new, testable hypotheses and understanding how best to design studies and analyze data.

Vaping as a Catalyst for Smoking? An Initial Model on the Initiation of Electronic Cigarette Use and the Transition to Tobacco Smoking Among Adolescents.

PubMed

Schneider, Sven; Diehl, Katharina

2016-05-01

The popularity of electronic cigarettes (e-cigarettes) among adolescents is growing worldwide. A more accurate model than the much discussed but inadequate Gateway Hypothesis is needed to explain some adolescents' initial preference for e-cigarettes over tobacco cigarettes, as well as any transition from e-cigarettes to tobacco smoking. Our aim was to summarize the diffuse fear that adolescents will be indirectly encouraged to begin smoking tobacco via the use of e-cigarettes and to systematize the disparate causal hypotheses used thus far in relevant literature. We summarized the vague and fragmented hypotheses formulated thus far in literature on both trajectories from abstinence to e-cigarette use and from there to tobacco smoking into a set of empirically testable hypotheses and organized them into a comprehensive model. Our results indicate that the perceived health risks, specific product characteristics (such as taste, price and inconspicuous use), and higher levels of acceptance among peers and others potentially make e-cigarettes initially more attractive to adolescents than tobacco cigarettes. Later, increasing familiarity with nicotine could lead to the reevaluation of both electronic and tobacco cigarettes and subsequently to a potential transition to tobacco smoking. The suggested "catalyst model" takes variations in the nicotine content of e-cigarettes as well as the dual use of different substances into account. Our model provides causal hypotheses for the initiation of e-cigarette use and for the potential transition to tobacco smoking which, after being tested in empirical studies, could lead to the formulation of concrete recommendations for healthcare intervention and prevention measures. We developed a model that provides causal hypotheses for the initiation of e-cigarette use and for the potential transition to tobacco smoking. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Testing two principles of the Health Action Process Approach in individuals with type 2 diabetes.

PubMed

Lippke, Sonia; Plotnikoff, Ronald C

2014-01-01

The Health Action Process Approach (HAPA) proposes principles that can be translated into testable hypotheses. This is one of the first studies to have explicitly tested HAPA's first 2 principles, which are (1) health behavior change process can be subdivided into motivation and volition, and (2) volition can be grouped into intentional and action stages. The 3 stage groups are labeled preintenders, intenders, and actors. The hypotheses of the HAPA model were investigated in a sample of 1,193 individuals with Type 2 diabetes. Study participants completed a questionnaire assessing the HAPA variables. The hypotheses were evaluated by examining mean differences of test variables and by the use of multigroup structural equation modeling (MSEM). Findings support the HAPA's 2 principles and 3 distinct stages. The 3 HAPA stages were significantly different in several stage-specific variables, and discontinuity patterns were found in terms of nonlinear trends across means. In terms of predicting goals, action planning, and behavior, differences transpired between the 2 motivational stages (preintenders and intenders), and between the 2 volitional stages (intenders and actors). Results indicate implications for supporting behavior change processes, depending on in which stage a person is at: All individuals should be helped to increase self-efficacy. Preintenders and intenders require interventions targeting outcome expectancies. Actors benefit from an improvement in action planning to maintain and increase their previous behavior. Overall, the first 2 principles of the HAPA were supported and some evidence for the other principles was found. Future research should experimentally test these conclusions. 2014 APA, all rights reserved

Bovid mortality profiles in paleoecological context falsify hypotheses of endurance running-hunting and passive scavenging by early Pleistocene hominins

NASA Astrophysics Data System (ADS)

Bunn, Henry T.; Pickering, Travis Rayne

2010-11-01

The world's first archaeological traces from 2.6 million years ago (Ma) at Gona, in Ethiopia, include sharp-edged cutting tools and cut-marked animal bones, which indicate consumption of skeletal muscle by early hominin butchers. From that point, evidence of hominin meat-eating becomes increasingly more common throughout the Pleistocene archaeological record. Thus, the substantive debate about hominin meat-eating now centers on mode(s) of carcass resource acquisition. Two prominent hypotheses suggest, alternatively, (1) that early Homo hunted ungulate prey by running them to physiological failure and then dispatching them, or (2) that early Homo was relegated to passively scavenging carcass residues abandoned by carnivore predators. Various paleontologically testable predictions can be formulated for both hypotheses. Here we test four predictions concerning age-frequency distributions for bovids that contributed carcass remains to the 1.8 Ma. old FLK 22 Zinjanthropus (FLK Zinj, Olduvai Gorge, Tanzania) fauna, which zooarchaeological and taphonomic data indicate was formed predominantly by early Homo. In all but one case, the bovid mortality data from FLK Zinj violate test predictions of the endurance running-hunting and passive scavenging hypotheses. When combined with other taphonomic data, these results falsify both hypotheses, and lead to the hypothesis that early Homo operated successfully as an ambush predator.

Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia.

PubMed

Bossong, Matthijs G; Niesink, Raymond J M

2010-11-01

Cannabis use during adolescence increases the risk of developing psychotic disorders later in life. However, the neurobiological processes underlying this relationship are unknown. This review reports the results of a literature search comprising various neurobiological disciplines, ultimately converging into a model that might explain the neurobiology of cannabis-induced schizophrenia. The article briefly reviews current insights into brain development during adolescence. In particular, the role of the excitatory neurotransmitter glutamate in experience-dependent maturation of specific cortical circuitries is examined. The review also covers recent hypotheses regarding disturbances in strengthening and pruning of synaptic connections in the prefrontal cortex, and the link with latent psychotic disorders. In the present model, cannabis-induced schizophrenia is considered to be a distortion of normal late postnatal brain maturation. Distortion of glutamatergic transmission during critical periods may disturb prefrontal neurocircuitry in specific brain areas. Our model postulates that adolescent exposure to Δ9-tetrahydrocannabinol (THC), the primary psychoactive substance in cannabis, transiently disturbs physiological control of the endogenous cannabinoid system over glutamate and GABA release. As a result, THC may adversely affect adolescent experience-dependent maturation of neural circuitries within prefrontal cortical areas. Depending on dose, exact time window and duration of exposure, this may ultimately lead to the development of psychosis or schizophrenia. The proposed model provides testable hypotheses which can be addressed in future studies, including animal experiments, reanalysis of existing epidemiological data, and prospective epidemiological studies in which the role of the dose-time-effect relationship should be central. Copyright © 2010 Elsevier Ltd. All rights reserved.

PhyloDet: a scalable visualization tool for mapping multiple traits to large evolutionary trees

PubMed Central

Lee, Bongshin; Nachmanson, Lev; Robertson, George; Carlson, Jonathan M.; Heckerman, David

2009-01-01

Summary: Evolutionary biologists are often interested in finding correlations among biological traits across a number of species, as such correlations may lead to testable hypotheses about the underlying function. Because some species are more closely related than others, computing and visualizing these correlations must be done in the context of the evolutionary tree that relates species. In this note, we introduce PhyloDet (short for PhyloDetective), an evolutionary tree visualization tool that enables biologists to visualize multiple traits mapped to the tree. Availability: http://research.microsoft.com/cue/phylodet/ Contact: bongshin@microsoft.com. PMID:19633096

Quantitative imaging biomarker ontology (QIBO) for knowledge representation of biomedical imaging biomarkers.

PubMed

Buckler, Andrew J; Liu, Tiffany Ting; Savig, Erica; Suzek, Baris E; Ouellette, M; Danagoulian, J; Wernsing, G; Rubin, Daniel L; Paik, David

2013-08-01

A widening array of novel imaging biomarkers is being developed using ever more powerful clinical and preclinical imaging modalities. These biomarkers have demonstrated effectiveness in quantifying biological processes as they occur in vivo and in the early prediction of therapeutic outcomes. However, quantitative imaging biomarker data and knowledge are not standardized, representing a critical barrier to accumulating medical knowledge based on quantitative imaging data. We use an ontology to represent, integrate, and harmonize heterogeneous knowledge across the domain of imaging biomarkers. This advances the goal of developing applications to (1) improve precision and recall of storage and retrieval of quantitative imaging-related data using standardized terminology; (2) streamline the discovery and development of novel imaging biomarkers by normalizing knowledge across heterogeneous resources; (3) effectively annotate imaging experiments thus aiding comprehension, re-use, and reproducibility; and (4) provide validation frameworks through rigorous specification as a basis for testable hypotheses and compliance tests. We have developed the Quantitative Imaging Biomarker Ontology (QIBO), which currently consists of 488 terms spanning the following upper classes: experimental subject, biological intervention, imaging agent, imaging instrument, image post-processing algorithm, biological target, indicated biology, and biomarker application. We have demonstrated that QIBO can be used to annotate imaging experiments with standardized terms in the ontology and to generate hypotheses for novel imaging biomarker-disease associations. Our results established the utility of QIBO in enabling integrated analysis of quantitative imaging data.

Characterization of the expression patterns of LEAFY/FLORICAULA and NEEDLY orthologs in female and male cones of the conifer genera Picea, Podocarpus, and Taxus: implications for current evo-devo hypotheses for gymnosperms.

PubMed

Vázquez-Lobo, Alejandra; Carlsbecker, Annelie; Vergara-Silva, Francisco; Alvarez-Buylla, Elena R; Piñero, Daniel; Engström, Peter

2007-01-01

The identity of genes causally implicated in the development and evolutionary origin of reproductive characters in gymnosperms is largely unknown. Working within the framework of plant evolutionary developmental biology, here we have cloned, sequenced, performed phylogenetic analyses upon and tested the expression patterns of LEAFY/FLORICAULA and NEEDLY orthologs in reproductive structures from selected species of the conifer genera Picea, Podocarpus, and Taxus. Contrary to expectations based on previous assessments, expression of LFY/FLO and NLY in cones of these taxa was found to occur simultaneously in a single reproductive axis, initially overlapping but later in mutually exclusive primordia and/or groups of developing cells in both female and male structures. These observations directly affect the status of the "mostly male theory" for the origin of the angiosperm flower. On the other hand, comparative spatiotemporal patterns of the expression of these genes suggest a complex genetic regulatory network of cone development, as well as a scheme of functional divergence for LFY/FLO with respect to NLY homologs in gymnosperms, both with clear heterochronic aspects. Results presented in this study contribute to the understanding of the molecular-genetic basis of morphological evolution in conifer cones, and may aid in establishing a foundation for gymnosperm-specific, testable evo-devo hypotheses.

Traditional fire-use, landscape transition, and the legacies of social theory past.

PubMed

Coughlan, Michael R

2015-12-01

Fire-use and the scale and character of its effects on landscapes remain hotly debated in the paleo- and historical-fire literature. Since the second half of the nineteenth century, anthropology and geography have played important roles in providing theoretical propositions and testable hypotheses for advancing understandings of the ecological role of human-fire-use in landscape histories. This article reviews some of the most salient and persistent theoretical propositions and hypotheses concerning the role of humans in historical fire ecology. The review discusses this history in light of current research agendas, such as those offered by pyrogeography. The review suggests that a more theoretically cognizant historical fire ecology should strive to operationalize transdisciplinary theory capable of addressing the role of human variability in the evolutionary history of landscapes. To facilitate this process, researchers should focus attention on integrating more current human ecology theory into transdisciplinary research agendas.

Differentiation without Distancing. Explaining Bi-Polarization of Opinions without Negative Influence

PubMed Central

Mäs, Michael; Flache, Andreas

2013-01-01

Explanations of opinion bi-polarization hinge on the assumption of negative influence, individuals’ striving to amplify differences to disliked others. However, empirical evidence for negative influence is inconclusive, which motivated us to search for an alternative explanation. Here, we demonstrate that bi-polarization can be explained without negative influence, drawing on theories that emphasize the communication of arguments as central mechanism of influence. Due to homophily, actors interact mainly with others whose arguments will intensify existing tendencies for or against the issue at stake. We develop an agent-based model of this theory and compare its implications to those of existing social-influence models, deriving testable hypotheses about the conditions of bi-polarization. Hypotheses were tested with a group-discussion experiment (N = 96). Results demonstrate that argument exchange can entail bi-polarization even when there is no negative influence. PMID:24312164

Postmarketing surveillance: perspectives of a journal editor.

PubMed

Gelenberg, A J

1993-01-01

In the absence of a systematic monitoring program for drugs newly approved by the Food and Drug Administration (FDA), reports in clinical journals provide a legitimate forum for disseminating information about unexpected pharmacologic events. A journal editor bears the responsibility for publishing educated clinical observations that meet standards of scientific rigor while not giving premature credibility to chance and dubious reports of side effects of new drugs. Often this responsibility involves overcoming the fear of bad publicity and withstanding pressures from pharmaceutical companies to print only positive information about new products. Published preliminary observations may contribute to the problem of product liability, but they also generate testable hypotheses and healthy debate. If hypotheses later prove to be incorrect, they can be refuted by systematic studies and clarified in reviews and editorials. Our goal of effective education will be reached not by self-censorship but by scientific openness.

Avoidant/Restrictive Food Intake Disorder: a Three-Dimensional Model of Neurobiology with Implications for Etiology and Treatment.

PubMed

Thomas, Jennifer J; Lawson, Elizabeth A; Micali, Nadia; Misra, Madhusmita; Deckersbach, Thilo; Eddy, Kamryn T

2017-08-01

DSM-5 defined avoidant/restrictive food intake disorder (ARFID) as a failure to meet nutritional needs leading to low weight, nutritional deficiency, dependence on supplemental feedings, and/or psychosocial impairment. We summarize what is known about ARFID and introduce a three-dimensional model to inform research. Because ARFID prevalence, risk factors, and maintaining mechanisms are not known, prevailing treatment approaches are based on clinical experience rather than data. Furthermore, most ARFID research has focused on children, rather than adolescents or adults. We hypothesize a three-dimensional model wherein neurobiological abnormalities in sensory perception, homeostatic appetite, and negative valence systems underlie the three primary ARFID presentations of sensory sensitivity, lack of interest in eating, and fear of aversive consequences, respectively. Now that ARFID has been defined, studies investigating risk factors, prevalence, and pathophysiology are needed. Our model suggests testable hypotheses about etiology and highlights cognitive-behavioral therapy as one possible treatment.

Sexual and Emotional Infidelity: Evolved Gender Differences in Jealousy Prove Robust and Replicable.

PubMed

Buss, David M

2018-03-01

Infidelity poses threats to high-investment mating relationships. Because of gender differences in some aspects of reproductive biology, such as internal female fertilization, the nature of these threats differs for men and women. Men, but not women, for example, have recurrently faced the problem of uncertainty in their genetic parenthood. Jealousy is an emotion hypothesized to have evolved to combat these threats. The 1992 article Sex Differences in Jealousy: Evolution, Physiology, and Psychology reported three empirical studies using two different methods, forced-choice and physiological experiments. Results supported the evolution-based hypotheses. The article became highly cited for several reasons. It elevated the status of jealousy as an important emotion to be explained by any comprehensive theory of human emotions. Subsequent meta-analyses robustly supported the evolutionary hypotheses. Moreover, the work supported the evolutionary meta-theory of gender differences, which posits differences only in domains in which the sexes have recurrently faced distinct adaptive problems. It also heralded the newly emerging field of evolutionary psychology as a useful perspective that possesses the scientific virtues of testability, falsifiability, and heuristic value in discovering previously unknown psychological phenomena.

STOP using just GO: a multi-ontology hypothesis generation tool for high throughput experimentation

PubMed Central

2013-01-01

Background Gene Ontology (GO) enrichment analysis remains one of the most common methods for hypothesis generation from high throughput datasets. However, we believe that researchers strive to test other hypotheses that fall outside of GO. Here, we developed and evaluated a tool for hypothesis generation from gene or protein lists using ontological concepts present in manually curated text that describes those genes and proteins. Results As a consequence we have developed the method Statistical Tracking of Ontological Phrases (STOP) that expands the realm of testable hypotheses in gene set enrichment analyses by integrating automated annotations of genes to terms from over 200 biomedical ontologies. While not as precise as manually curated terms, we find that the additional enriched concepts have value when coupled with traditional enrichment analyses using curated terms. Conclusion Multiple ontologies have been developed for gene and protein annotation, by using a dataset of both manually curated GO terms and automatically recognized concepts from curated text we can expand the realm of hypotheses that can be discovered. The web application STOP is available at http://mooneygroup.org/stop/. PMID:23409969

Simulating cancer growth with multiscale agent-based modeling.

PubMed

Wang, Zhihui; Butner, Joseph D; Kerketta, Romica; Cristini, Vittorio; Deisboeck, Thomas S

2015-02-01

There have been many techniques developed in recent years to in silico model a variety of cancer behaviors. Agent-based modeling is a specific discrete-based hybrid modeling approach that allows simulating the role of diversity in cell populations as well as within each individual cell; it has therefore become a powerful modeling method widely used by computational cancer researchers. Many aspects of tumor morphology including phenotype-changing mutations, the adaptation to microenvironment, the process of angiogenesis, the influence of extracellular matrix, reactions to chemotherapy or surgical intervention, the effects of oxygen and nutrient availability, and metastasis and invasion of healthy tissues have been incorporated and investigated in agent-based models. In this review, we introduce some of the most recent agent-based models that have provided insight into the understanding of cancer growth and invasion, spanning multiple biological scales in time and space, and we further describe several experimentally testable hypotheses generated by those models. We also discuss some of the current challenges of multiscale agent-based cancer models. Copyright © 2014 Elsevier Ltd. All rights reserved.

Combined neurostimulation and neuroimaging in cognitive neuroscience: past, present, and future.

PubMed

Bestmann, Sven; Feredoes, Eva

2013-08-01

Modern neurostimulation approaches in humans provide controlled inputs into the operations of cortical regions, with highly specific behavioral consequences. This enables causal structure-function inferences, and in combination with neuroimaging, has provided novel insights into the basic mechanisms of action of neurostimulation on distributed networks. For example, more recent work has established the capacity of transcranial magnetic stimulation (TMS) to probe causal interregional influences, and their interaction with cognitive state changes. Combinations of neurostimulation and neuroimaging now face the challenge of integrating the known physiological effects of neurostimulation with theoretical and biological models of cognition, for example, when theoretical stalemates between opposing cognitive theories need to be resolved. This will be driven by novel developments, including biologically informed computational network analyses for predicting the impact of neurostimulation on brain networks, as well as novel neuroimaging and neurostimulation techniques. Such future developments may offer an expanded set of tools with which to investigate structure-function relationships, and to formulate and reconceptualize testable hypotheses about complex neural network interactions and their causal roles in cognition. © 2013 New York Academy of Sciences.

Rethinking intractable conflict: the perspective of dynamical systems.

PubMed

Vallacher, Robin R; Coleman, Peter T; Nowak, Andrzej; Bui-Wrzosinska, Lan

2010-01-01

Intractable conflicts are demoralizing. Beyond destabilizing the families, communities, or international regions in which they occur, they tend to perpetuate the very conditions of misery and hate that contributed to them in the first place. Although the common factors and processes associated with intractable conflicts have been identified through research, they represent an embarrassment of riches for theory construction. Thus, the current task in this area is integrating these diverse factors into an account that provides a coherent perspective yet allows for prediction and a basis for conflict resolution in specific conflict settings. We suggest that the perspective of dynamical systems provides such an account. This article outlines the key concepts and hypotheses associated with this approach. It is organized around a set of basic questions concerning intractable conflict for which the dynamical perspective offers fresh insight and testable propositions. The questions and answers are intended to provide readers with basic concepts and principles of complexity and dynamical systems that are useful for rethinking the nature of intractable conflict and the means by which such conflict can be transformed. Copyright 2010 APA, all rights reserved.

Phase 1 Space Fission Propulsion Energy Source Design

NASA Technical Reports Server (NTRS)

Houts, Mike; VanDyke, Melissa; Godfroy, Tom; Pedersen, Kevin; Martin, James; Dickens, Ricky; Salvail, Pat; Hrbud, Ivana; Carter, Robert; Rodgers, Stephen L. (Technical Monitor)

2002-01-01

Fission technology can enable rapid, affordable access to any point in the solar system. If fission propulsion systems are to be developed to their full potential; however, near-term customers must be identified and initial fission systems successfully developed, launched, and operated. Studies conducted in fiscal year 2001 (IISTP, 2001) show that fission electric propulsion (FEP) systems with a specific mass at or below 50 kg/kWjet could enhance or enable numerous robotic outer solar system missions of interest. At the required specific mass, it is possible to develop safe, affordable systems that meet mission requirements. To help select the system design to pursue, eight evaluation criteria were identified: system integration, safety, reliability, testability, specific mass, cost, schedule, and programmatic risk. A top-level comparison of four potential concepts was performed: a Testable, Passive, Redundant Reactor (TPRR), a Testable Multi-Cell In-Core Thermionic Reactor (TMCT), a Direct Gas Cooled Reactor (DGCR), and a Pumped Liquid Metal Reactor.(PLMR). Development of any of the four systems appears feasible. However, for power levels up to at least 500 kWt (enabling electric power levels of 125-175 kWe, given 25-35% power conversion efficiency) the TPRR has advantages related to several criteria and is competitive with respect to all. Hardware-based research and development has further increased confidence in the TPRR approach. Successful development and utilization of a "Phase I" fission electric propulsion system will enable advanced Phase 2 and Phase 3 systems capable of providing rapid, affordable access to any point in the solar system.

NDR proteins: lessons learned from Arabidopsis and animal cells prompt a testable hypothesis.

PubMed

Mudgil, Yashwanti; Jones, Alan M

2010-08-01

N-myc Down Regulated (NDR) genes were discovered more than fifteen years ago. Indirect evidence support a role in tumor progression and cellular differentiation, but their biochemical function is still unknown. Our detailed analyses on Arabidopsis NDL proteins show their involvement in altering auxin transport, local auxin gradients and expression level of auxin transport proteins. Animal NDL proteins may be involved in membrane recycling of E-cadherin and effector for the small GTPase. In light of these findings, we hypothesize that NDL proteins regulate vesicular trafficking of auxin transport facilitator PIN proteins by biochemically alterating the local lipid environment of PIN proteins.

A systems analysis of the erythropoietic responses to weightlessness. Volume 1: Mathematical model simulations of the erythropoietic responses to weightlessness

NASA Technical Reports Server (NTRS)

Leonard, J. I.

1985-01-01

Theoretical responses to weightlessness are summarized. The studies include development and validation of a model of erythropoiesis regulation, analysis of the behavior of erythropoiesis under a variety of conditions, simulations of bed rest and space flight, and an evaluation of ground-based animal studies which were conducted as analogs of zero-g. A review of all relevant space flight findings and a set of testable hypotheses which attempt to explain how red cell mass decreases in space flight are presented. An additional document describes details of the mathematical model used in these studies.

Common and specific liability to addiction: approaches to association studies of opioid addiction.

PubMed

Nielsen, David A; Kreek, Mary Jeanne

2012-06-01

Opioid addiction, whether to opiates such as heroin and morphine, and/or to non-medical use of opioids, is a major problem worldwide. Although drug-induced and environmental factors are essential for the liability to develop opioid addiction, the genetic background of an individual is now known also to play a substantial role. The overall goal of this article is to address the common and specific liabilities to addiction in the context of approaches to studies of one addiction, opioid addiction. Literature on identifying genetic variants that may play a role in the development of opioid addiction was reviewed. A substantial number of genetic variants have been reported to be associated with opioid addiction. No single variant has been found in any of the reported GWAS studies with a substantial effect size on the liability to develop heroin addiction. It appears that there is a complex interaction of a large number of variants, some rare, some common, which interact with the environment and in response to specific drugs of abuse to increase the liability of developing opioid addiction. In spite of the inherent difficulties in obtaining large well-phenotyped cohorts for genetic studies, new findings have been reported that are being used to develop testable hypotheses into the biological basis of opioid addiction. Copyright © 2012. Published by Elsevier Ireland Ltd.

Comparison of Three Ionic Liquid-Tolerant Cellulases by Molecular Dynamics

PubMed Central

Jaeger, Vance; Burney, Patrick; Pfaendtner, Jim

2015-01-01

We have employed molecular dynamics to investigate the differences in ionic liquid tolerance among three distinct family 5 cellulases from Trichoderma viride, Thermogata maritima, and Pyrococcus horikoshii. Simulations of the three cellulases were conducted at a range of temperatures in various binary mixtures of the ionic liquid 1-ethyl-3-methyl-imidazolium acetate with water. Our analysis demonstrates that the effects of ionic liquids on the enzymes vary in each individual case from local structural disturbances to loss of much of one of the enzyme’s secondary structure. Enzymes with more negatively charged surfaces tend to resist destabilization by ionic liquids. Specific and unique structural changes in the enzymes are induced by the presence of ionic liquids. Disruption of the secondary structure, changes in dynamical motion, and local changes in the binding pocket are observed in less tolerant enzymes. Ionic-liquid-induced denaturation of one of the enzymes is indicated over the 500 ns timescale. In contrast, the most tolerant cellulase behaves similarly in water and in ionic-liquid-containing mixtures. Unlike the heuristic approaches that attempt to predict enzyme stability using macroscopic properties, molecular dynamics allows us to predict specific atomic-level structural and dynamical changes in an enzyme’s behavior induced by ionic liquids and other mixed solvents. Using these insights, we propose specific experimentally testable hypotheses regarding the origin of activity loss for each of the systems investigated in this study. PMID:25692593

What Are Health-Related Users Tweeting? A Qualitative Content Analysis of Health-Related Users and Their Messages on Twitter

PubMed Central

DeCamp, Matthew; Dredze, Mark; Chisolm, Margaret S; Berger, Zackary D

2014-01-01

Background Twitter is home to many health professionals who send messages about a variety of health-related topics. Amid concerns about physicians posting inappropriate content online, more in-depth knowledge about these messages is needed to understand health professionals’ behavior on Twitter. Objective Our goal was to characterize the content of Twitter messages, specifically focusing on health professionals and their tweets relating to health. Methods We performed an in-depth content analysis of 700 tweets. Qualitative content analysis was conducted on tweets by health users on Twitter. The primary objective was to describe the general type of content (ie, health-related versus non-health related) on Twitter authored by health professionals and further to describe health-related tweets on the basis of the type of statement made. Specific attention was given to whether a tweet was personal (as opposed to professional) or made a claim that users would expect to be supported by some level of medical evidence (ie, a “testable” claim). A secondary objective was to compare content types among different users, including patients, physicians, nurses, health care organizations, and others. Results Health-related users are posting a wide range of content on Twitter. Among health-related tweets, 53.2% (184/346) contained a testable claim. Of health-related tweets by providers, 17.6% (61/346) were personal in nature; 61% (59/96) made testable statements. While organizations and businesses use Twitter to promote their services and products, patient advocates are using this tool to share their personal experiences with health. Conclusions Twitter users in health-related fields tweet about both testable claims and personal experiences. Future work should assess the relationship between testable tweets and the actual level of evidence supporting them, including how Twitter users—especially patients—interpret the content of tweets posted by health providers. PMID:25591063

Expert knowledge as a foundation for the management of secretive species and their habitat

USGS Publications Warehouse

Drew, C. Ashton; Collazo, Jaime

2012-01-01

In this chapter, we share lessons learned during the elicitation and application of expert knowledge in the form of a belief network model for the habitat of a waterbird, the King Rail (Rallus elegans). A belief network is a statistical framework used to graphically represent and evaluate hypothesized cause and effect relationships among variables. Our model was a pilot project to explore the value of such a model as a tool to help the US Fish and Wildlife Service (USFWS) conserve species that lack sufficient empirical data to guide management decisions. Many factors limit the availability of empirical data that can support landscape-scale conservation planning. Globally, most species simply have not yet been subject to empirical study (Wilson 2000). Even for well-studied species, data are often restricted to specific geographic extents, to particular seasons, or to specific segments of a species’ life history. The USFWS mandates that the agency’s conservation actions (1) be coordinated across regional landscapes, (2) be founded on the best available science (with testable assumptions), and (3) support adaptive management through monitoring and assessment of action outcomes. Given limits on the available data, the concept of “best available science” in the context of conservation planning generally includes a mix of empirical data and expert knowledge (Sullivan et al. 2006).

Application of Adverse Outcome Pathways (AOPs) in Human ...

EPA Pesticide Factsheets

The adverse outcome pathway (AOP) framework was developed to help organize and disseminate existing knowledge concerning the means through which specific perturbations of biological pathways can lead to adverse outcomes considered relevant to risk-based regulatory decision-making. Because many fundamental molecular and cellular pathways are conserved across taxa, data from assays that screen chemicals for their ability to interact with specific biomolecular targets can often be credibly applied to a broad range of species, even if the apical outcomes of those perturbations may differ. Information concerning the different trajectories of adversity that molecular initiating events may take in different taxa, life stages, and sexes of organisms can be captured in the form of an AOP network. As an example, AOPs documenting divergent consequences of thyroid peroxidase (TPO) and deiodinase (DIO) inhibition in mammals, amphibians, and fish have been developed. These AOPs provide the foundation for using data from common in vitro assays for TPO or DIO activity to inform both human health and ecological risk assessments. They also provide the foundation for an integrated approach to testing and assessment, where available information and biological understanding can be integrated in order to formulate plausible and testable hypotheses which can be used to target in vivo testing on the endpoints of greatest concern. Application of this AOP knowledge in several different r

Application of adverse outcome pathways (AOPs) in human ...

EPA Pesticide Factsheets

The adverse outcome pathway (AOP) framework was developed to help organize and disseminate existing knowledge concerning the means through which specific perturbations of biological pathways can lead to adverse outcomes considered relevant to risk-based regulatory decision-making. Because many fundamental molecular and cellular pathways are conserved across taxa, data from assays that screen chemicals for their ability to interact with specific biomolecular targets can often be credibly applied to a broad range of species, even if the apical outcomes of those perturbations may differ. Information concerning the different trajectories of adversity that molecular initiating events may take in different taxa, life stages, and sexes of organisms can be captured in the form of an AOP network. As an example, AOPs documenting divergent consequences of thyroid peroxidase (TPO) and deiodinase (DIO) inhibition in mammals, amphibians, and fish have been developed. These AOPs provide the foundation for using data from common in vitro assays for TPO or DIO activity to inform both human health and ecological risk assessments. They also provide the foundation for an integrated approach to testing and assessment, where available information and biological understanding can be integrated in order to formulate plausible and testable hypotheses which can be used to target in vivo testing on the endpoints of greatest concern. Application of this AOP knowledge in several different r

Actinobacteria phylogenomics, selective isolation from an iron oligotrophic environment and siderophore functional characterization, unveil new desferrioxamine traits.

PubMed

Cruz-Morales, Pablo; Ramos-Aboites, Hilda E; Licona-Cassani, Cuauhtémoc; Selem-Mójica, Nelly; Mejía-Ponce, Paulina M; Souza-Saldívar, Valeria; Barona-Gómez, Francisco

2017-09-01

Desferrioxamines are hydroxamate siderophores widely conserved in both aquatic and soil-dwelling Actinobacteria. While the genetic and enzymatic bases of siderophore biosynthesis and their transport in model families of this phylum are well understood, evolutionary studies are lacking. Here, we perform a comprehensive desferrioxamine-centric (des genes) phylogenomic analysis, which includes the genomes of six novel strains isolated from an iron and phosphorous depleted oasis in the Chihuahuan desert of Mexico. Our analyses reveal previously unnoticed desferrioxamine evolutionary patterns, involving both biosynthetic and transport genes, likely to be related to desferrioxamines chemical diversity. The identified patterns were used to postulate experimentally testable hypotheses after phenotypic characterization, including profiling of siderophores production and growth stimulation of co-cultures under iron deficiency. Based in our results, we propose a novel des gene, which we term desG, as responsible for incorporation of phenylacetyl moieties during biosynthesis of previously reported arylated desferrioxamines. Moreover, a genomic-based classification of the siderophore-binding proteins responsible for specific and generalist siderophore assimilation is postulated. This report provides a much-needed evolutionary framework, with specific insights supported by experimental data, to direct the future ecological and functional analysis of desferrioxamines in the environment. © FEMS 2017.

What to expect from an evolutionary hypothesis for a human disease: The case of type 2 diabetes.

PubMed

Watve, Milind; Diwekar-Joshi, Manawa

2016-10-01

Evolutionary medicine has a promise to bring in a conceptual revolution in medicine. However, as yet the field does not have the same theoretical rigour as that of many other fields in evolutionary studies. We discuss here with reference to type 2 diabetes mellitus (T2DM) what role an evolutionary hypothesis should play in the development of thinking in medicine. Starting with the thrifty gene hypothesis, evolutionary thinking in T2DM has undergone several transitions, modifications and refinements of the thrift family of hypotheses. In addition alternative hypotheses independent of thrift are also suggested. However, most hypotheses look at partial pictures; make selective use of supportive data ignoring inconvenient truths. Most hypotheses look at a superficial picture and avoid getting into the intricacies of underlying molecular, neuronal and physiological processes. Very few hypotheses have suggested clinical implications and none of them have been tested with randomized clinical trials. In the meanwhile the concepts in the pathophysiology of T2DM are undergoing radical changes and evolutionary hypotheses need to take them into account. We suggest an approach and a set of criteria to evaluate the relative merits of the alternative hypotheses. A number of hypotheses are likely to fail when critically evaluated against these criteria. It is possible that more than one selective process are at work in the evolution of propensity to T2DM, but the intercompatibility of the alternative selective forces and their relative contribution needs to be examined. The approach we describe could potentially lead to a sound evolutionary theory that is clinically useful and testable by randomized controlled clinical trials. Copyright © 2016 Elsevier GmbH. All rights reserved.

How and why does the immunological synapse form? Physical chemistry meets cell biology.

PubMed

Chakraborty, Arup K

2002-03-05

During T lymphocyte (T cell) recognition of an antigen, a highly organized and specific pattern of membrane proteins forms in the junction between the T cell and the antigen-presenting cell (APC). This specialized cell-cell junction is called the immunological synapse. It is several micrometers large and forms over many minutes. A plethora of experiments are being performed to study the mechanisms that underlie synapse formation and the way in which information transfer occurs across the synapse. The wealth of experimental data that is beginning to emerge must be understood within a mechanistic framework if it is to prove useful in developing modalities to control the immune response. Quantitative models can complement experiments in the quest for such a mechanistic understanding by suggesting experimentally testable hypotheses. Here, a quantitative synapse assembly model is described. The model uses concepts developed in physical chemistry and cell biology and is able to predict the spatiotemporal evolution of cell shape and receptor protein patterns observed during synapse formation. Attention is directed to how the juxtaposition of model predictions and experimental data has led to intriguing hypotheses regarding the role of null and self peptides during synapse assembly, as well as correlations between T cell effector functions and the robustness of synapse assembly. We remark on some ways in which synergistic experiments and modeling studies can improve current models, and we take steps toward a better understanding of information transfer across the T cell-APC junction.

Left-right asymmetry specification in amphioxus: review and prospects.

PubMed

Soukup, Vladimir

2017-01-01

Extant bilaterally symmetrical animals usually show asymmetry in the arrangement of their inner organs. However, the exaggerated left-right (LR) asymmetry in amphioxus represents a true peculiarity among them. The amphioxus larva shows completely disparate fates of left and right body sides, so that organs associated with pharynx are either positioned exclusively on the left or on the right side. Moreover, segmented paraxial structures such as muscle blocks and their neuronal innervation show offset arrangement between the sides making it difficult to propose any explanation or adaptivity to larval and adult life. First LR asymmetries can be traced back to an early embryonic period when morphological asymmetries are preceded by molecular asymmetries driven by the action of the Nodal signaling pathway. This review sums up recent advances in understanding LR asymmetry specification in amphioxus and proposes upstream events that may regulate asymmetric Nodal signaling. These events include the presence of the vertebrate-like LR organizer and a cilia-driven fluid flow that may be involved in the breaking of bilateral symmetry. The upstream pathways comprising the ion flux, Delta/Notch, Wnt/β-catenin and Wnt/PCP are hypothesized to regulate both formation of the LR organizer and expression of the downstream Nodal signaling pathway genes. These suggestions are in line with what we know from vertebrate and ambulacrarian LR axis specification and are directly testable by experimental manipulations. Thanks to the phylogenetic position of amphioxus, the proposed mechanisms may be helpful in understanding the evolution of LR axis specification across deuterostomes.

Social calls provide novel insights into the evolution of vocal learning

PubMed Central

Sewall, Kendra B.; Young, Anna M.; Wright, Timothy F.

2016-01-01

Learned song is among the best-studied models of animal communication. In oscine songbirds, where learned song is most prevalent, it is used primarily for intrasexual selection and mate attraction. Learning of a different class of vocal signals, known as contact calls, is found in a diverse array of species, where they are used to mediate social interactions among individuals. We argue that call learning provides a taxonomically rich system for studying testable hypotheses for the evolutionary origins of vocal learning. We describe and critically evaluate four nonmutually exclusive hypotheses for the origin and current function of vocal learning of calls, which propose that call learning (1) improves auditory detection and recognition, (2) signals local knowledge, (3) signals group membership, or (4) allows for the encoding of more complex social information. We propose approaches to testing these four hypotheses but emphasize that all of them share the idea that social living, not sexual selection, is a central driver of vocal learning. Finally, we identify future areas for research on call learning that could provide new perspectives on the origins and mechanisms of vocal learning in both animals and humans. PMID:28163325

Neurophysiological and neurocognitive mechanisms underlying the effects of yoga-based practices: towards a comprehensive theoretical framework

PubMed Central

Schmalzl, Laura; Powers, Chivon; Henje Blom, Eva

2015-01-01

During recent decades numerous yoga-based practices (YBP) have emerged in the West, with their aims ranging from fitness gains to therapeutic benefits and spiritual development. Yoga is also beginning to spark growing interest within the scientific community, and yoga-based interventions have been associated with measureable changes in physiological parameters, perceived emotional states, and cognitive functioning. YBP typically involve a combination of postures or movement sequences, conscious regulation of the breath, and various techniques to improve attentional focus. However, so far little if any research has attempted to deconstruct the role of these different component parts in order to better understand their respective contribution to the effects of YBP. A clear operational definition of yoga-based therapeutic interventions for scientific purposes, as well as a comprehensive theoretical framework from which testable hypotheses can be formulated, is therefore needed. Here we propose such a framework, and outline the bottom-up neurophysiological and top-down neurocognitive mechanisms hypothesized to be at play in YBP. PMID:26005409

The origin and early evolution of vascular plant shoots and leaves.

PubMed

Harrison, C Jill; Morris, Jennifer L

2018-02-05

The morphology of plant fossils from the Rhynie chert has generated longstanding questions about vascular plant shoot and leaf evolution, for instance, which morphologies were ancestral within land plants, when did vascular plants first arise and did leaves have multiple evolutionary origins? Recent advances combining insights from molecular phylogeny, palaeobotany and evo-devo research address these questions and suggest the sequence of morphological innovation during vascular plant shoot and leaf evolution. The evidence pinpoints testable developmental and genetic hypotheses relating to the origin of branching and indeterminate shoot architectures prior to the evolution of leaves, and demonstrates underestimation of polyphyly in the evolution of leaves from branching forms in 'telome theory' hypotheses of leaf evolution. This review discusses fossil, developmental and genetic evidence relating to the evolution of vascular plant shoots and leaves in a phylogenetic framework.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. © 2017 The Authors.

Neurophysiological and neurocognitive mechanisms underlying the effects of yoga-based practices: towards a comprehensive theoretical framework.

PubMed

Schmalzl, Laura; Powers, Chivon; Henje Blom, Eva

2015-01-01

During recent decades numerous yoga-based practices (YBP) have emerged in the West, with their aims ranging from fitness gains to therapeutic benefits and spiritual development. Yoga is also beginning to spark growing interest within the scientific community, and yoga-based interventions have been associated with measureable changes in physiological parameters, perceived emotional states, and cognitive functioning. YBP typically involve a combination of postures or movement sequences, conscious regulation of the breath, and various techniques to improve attentional focus. However, so far little if any research has attempted to deconstruct the role of these different component parts in order to better understand their respective contribution to the effects of YBP. A clear operational definition of yoga-based therapeutic interventions for scientific purposes, as well as a comprehensive theoretical framework from which testable hypotheses can be formulated, is therefore needed. Here we propose such a framework, and outline the bottom-up neurophysiological and top-down neurocognitive mechanisms hypothesized to be at play in YBP.

Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses.

PubMed

Bogenschutz, Michael P; Pommy, Jessica M

2012-01-01

Alcohol and drug addiction are major public health problems, and existing treatments are only moderately effective. Although there has been interest for over half a century in the therapeutic use of classic hallucinogens to treat addictions, clinical research with these drugs was halted at an early stage in the early 1970s, leaving many fundamental questions unanswered. In the past two decades, clinical research on classic hallucinogens has resumed, although addiction treatment trials are only now beginning. The purpose of this paper is to provide a targeted review of the research most relevant to the therapeutic potential of hallucinogens, and to integrate this information with current thinking about addiction and recovery. On the basis of this information, we present a heuristic model which organizes a number of hypotheses that may be tested in future research. We conclude that existing evidence provides a convincing rationale for further research on the effects of classic hallucinogens in the treatment of addiction. Copyright © 2012 John Wiley & Sons, Ltd.

The origin and early evolution of vascular plant shoots and leaves

PubMed Central

2018-01-01

The morphology of plant fossils from the Rhynie chert has generated longstanding questions about vascular plant shoot and leaf evolution, for instance, which morphologies were ancestral within land plants, when did vascular plants first arise and did leaves have multiple evolutionary origins? Recent advances combining insights from molecular phylogeny, palaeobotany and evo–devo research address these questions and suggest the sequence of morphological innovation during vascular plant shoot and leaf evolution. The evidence pinpoints testable developmental and genetic hypotheses relating to the origin of branching and indeterminate shoot architectures prior to the evolution of leaves, and demonstrates underestimation of polyphyly in the evolution of leaves from branching forms in ‘telome theory’ hypotheses of leaf evolution. This review discusses fossil, developmental and genetic evidence relating to the evolution of vascular plant shoots and leaves in a phylogenetic framework. This article is part of a discussion meeting issue ‘The Rhynie cherts: our earliest terrestrial ecosystem revisited’. PMID:29254961

Narrative meaning making and integration: Toward a better understanding of the way falling ill influences quality of life.

PubMed

Hartog, Iris; Scherer-Rath, Michael; Kruizinga, Renske; Netjes, Justine; Henriques, José; Nieuwkerk, Pythia; Sprangers, Mirjam; van Laarhoven, Hanneke

2017-09-01

Falling seriously ill is often experienced as a life event that causes conflict with people's personal goals and expectations in life and evokes existential questions. This article presents a new humanities approach to the way people make meaning of such events and how this influences their quality of life. Incorporating theories on contingency, narrative identity, and quality of life, we developed a theoretical model entailing the concepts life event, worldview, ultimate life goals, experience of contingency, narrative meaning making, narrative integration, and quality of life. We formulate testable hypotheses and describe the self-report questionnaire that was developed based on the model.

Planning and Studying Improvement in Patient Care: The Use of Theoretical Perspectives

PubMed Central

Grol, Richard PTM; Bosch, Marije C; Hulscher, Marlies EJL; Eccles, Martin P; Wensing, Michel

2007-01-01

A consistent finding in articles on quality improvement in health care is that change is difficult to achieve. According to the research literature, the majority of interventions are targeted at health care professionals. But success in achieving change may be influenced by factors other than those relating to individual professionals, and theories may help explain whether change is possible. This article argues for a more systematic use of theories in planning and evaluating quality-improvement interventions in clinical practice. It demonstrates how different theories can be used to generate testable hypotheses regarding factors that influence the implementation of change, and it shows how different theoretical assumptions lead to different quality-improvement strategies. PMID:17319808

Creativity, information, and consciousness: The information dynamics of thinking.

PubMed

Wiggins, Geraint A

2018-05-07

This paper presents a theory of the basic operation of mind, Information Dynamics of Thinking, which is intended for computational implementation and thence empirical testing. It is based on the information theory of Shannon, and treats the mind/brain as an information processing organ that aims to be information-efficient, in that it predicts its world, so as to use information efficiently, and regularly re-represents it, so as to store information efficiently. The theory is presented in context of a background review of various research areas that impinge upon its development. Consequences of the theory and testable hypotheses arising from it are discussed. Copyright © 2018. Published by Elsevier B.V.

Panarchy: theory and application

USGS Publications Warehouse

Allen, Craig R.; Angeler, David G.; Garmestani, Ahjond S.; Gunderson, Lance H.; Holling, Crawford S.

2014-01-01

The concept of panarchy provides a framework that characterizes complex systems of people and nature as dynamically organized and structured within and across scales of space and time. It has been more than a decade since the introduction of panarchy. Over this period, its invocation in peer-reviewed literature has been steadily increasing, but its use remains primarily descriptive and abstract. Here, we discuss the use of the concept in the literature to date, highlight where the concept may be useful, and discuss limitations to the broader applicability of panarchy theory for research in the ecological and social sciences. Finally, we forward a set of testable hypotheses to evaluate key propositions that follow from panarchy theory.

Semantic modeling for theory clarification: The realist vs liberal international relations perspective

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bray, O.H.

This paper describes a natural language based, semantic information modeling methodology and explores its use and value in clarifying and comparing political science theories and frameworks. As an example, the paper uses this methodology to clarify and compare some of the basic concepts and relationships in the realist (e.g. Waltz) and the liberal (e.g. Rosenau) paradigms for international relations. The methodology can provide three types of benefits: (1) it can clarify and make explicit exactly what is meant by a concept; (2) it can often identify unanticipated implications and consequence of concepts and relationships; and (3) it can help inmore » identifying and operationalizing testable hypotheses.« less

Architectural Analysis of Dynamically Reconfigurable Systems

NASA Technical Reports Server (NTRS)

Lindvall, Mikael; Godfrey, Sally; Ackermann, Chris; Ray, Arnab; Yonkwa, Lyly

2010-01-01

oTpics include: the problem (increased flexibility of architectural styles decrease analyzability, behavior emerges and varies depending on the configuration, does the resulting system run according to the intended design, and architectural decisions can impede or facilitate testing); top down approach to architecture analysis, detection of defects and deviations, and architecture and its testability; currently targeted projects GMSEC and CFS; analyzing software architectures; analyzing runtime events; actual architecture recognition; GMPUB in Dynamic SAVE; sample output from new approach; taking message timing delays into account; CFS examples of architecture and testability; some recommendations for improved testablity; and CFS examples of abstract interfaces and testability; CFS example of opening some internal details.

A Systems Biology Approach Reveals Converging Molecular Mechanisms that Link Different POPs to Common Metabolic Diseases.

PubMed

Ruiz, Patricia; Perlina, Ally; Mumtaz, Moiz; Fowler, Bruce A

2016-07-01

A number of epidemiological studies have identified statistical associations between persistent organic pollutants (POPs) and metabolic diseases, but testable hypotheses regarding underlying molecular mechanisms to explain these linkages have not been published. We assessed the underlying mechanisms of POPs that have been associated with metabolic diseases; three well-known POPs [2,3,7,8-tetrachlorodibenzodioxin (TCDD), 2,2´,4,4´,5,5´-hexachlorobiphenyl (PCB 153), and 4,4´-dichlorodiphenyldichloroethylene (p,p´-DDE)] were studied. We used advanced database search tools to delineate testable hypotheses and to guide laboratory-based research studies into underlying mechanisms by which this POP mixture could produce or exacerbate metabolic diseases. For our searches, we used proprietary systems biology software (MetaCore™/MetaDrug™) to conduct advanced search queries for the underlying interactions database, followed by directional network construction to identify common mechanisms for these POPs within two or fewer interaction steps downstream of their primary targets. These common downstream pathways belong to various cytokine and chemokine families with experimentally well-documented causal associations with type 2 diabetes. Our systems biology approach allowed identification of converging pathways leading to activation of common downstream targets. To our knowledge, this is the first study to propose an integrated global set of step-by-step molecular mechanisms for a combination of three common POPs using a systems biology approach, which may link POP exposure to diseases. Experimental evaluation of the proposed pathways may lead to development of predictive biomarkers of the effects of POPs, which could translate into disease prevention and effective clinical treatment strategies. Ruiz P, Perlina A, Mumtaz M, Fowler BA. 2016. A systems biology approach reveals converging molecular mechanisms that link different POPs to common metabolic diseases. Environ Health Perspect 124:1034-1041; http://dx.doi.org/10.1289/ehp.1510308.

Sexual imprinting: what strategies should we expect to see in nature?

PubMed

Chaffee, Dalton W; Griffin, Hayes; Gilman, R Tucker

2013-12-01

Sexual imprinting occurs when juveniles learn mate preferences by observing the phenotypes of other members of their populations, and it is ubiquitous in nature. Imprinting strategies, that is which individuals and phenotypes are observed and how strong preferences become, vary among species. Imprinting can affect trait evolution and the probability of speciation, and different imprinting strategies are expected to have different effects. However, little is known about how and why different imprinting strategies evolve, or which strategies we should expect to see in nature. We used a mathematical model to study how the evolution of sexual imprinting depends on (1) imprinting costs and (2) the sex-specific fitness effects of the phenotype on which individuals imprint. We found that even small fixed costs prevent the evolution of sexual imprinting, but small relative costs do not. When imprinting does evolve, we identified the conditions under which females should evolve to imprint on their fathers, their mothers, or on other members of their populations. Our results provide testable hypotheses for empirical work and help to explain the conditions under which sexual imprinting might evolve to promote speciation. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

Trajectories of women's abortion-related care: A conceptual framework.

PubMed

Coast, Ernestina; Norris, Alison H; Moore, Ann M; Freeman, Emily

2018-03-01

We present a new conceptual framework for studying trajectories to obtaining abortion-related care. It assembles for the first time all of the known factors influencing a trajectory and encourages readers to consider the ways these macro- and micro-level factors operate in multiple and sometimes conflicting ways. Based on presentation to and feedback from abortion experts (researchers, providers, funders, policymakers and advisors, advocates) (n = 325) between 03/06/2014 and 22/08/2015, and a systematic mapping of peer-reviewed literature (n = 424) published between 01/01/2011 and 30/10/2017, our framework synthesises the factors shaping abortion trajectories, grouped into three domains: abortion-specific experiences, individual contexts, and (inter)national and sub-national contexts. Our framework includes time-dependent processes involved in an individual trajectory, starting with timing of pregnancy awareness. This framework can be used to guide testable hypotheses about enabling and inhibiting influences on care-seeking behaviour and consideration about how abortion trajectories might be influenced by policy or practice. Research based on understanding of trajectories has the potential to improve women's experiences and outcomes of abortion-related care. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Toward a neighborhood resource-based theory of social capital for health: can Bourdieu and sociology help?

PubMed

Carpiano, Richard M

2006-01-01

Within the past several years, a considerable body of research on social capital has emerged in public health. Although offering the potential for new insights into how community factors impact health and well being, this research has received criticism for being undertheorized and methodologically flawed. In an effort to address some of these limitations, this paper applies Pierre Bourdieu's (1986) [Bourdieu, P. (1986). Handbook of theory and research for the sociology of education (pp. 241-258). New York: Greenwood] social capital theory to create a conceptual model of neighborhood socioeconomic processes, social capital (resources inhered within social networks), and health. After briefly reviewing the social capital conceptualizations of Bourdieu and Putnam, I attempt to integrate these authors' theories to better understand how social capital might operate within neighborhoods or local areas. Next, I describe a conceptual model that incorporates this theoretical integration of social capital into a framework of neighborhood social processes as health determinants. Discussion focuses on the utility of this Bourdieu-based neighborhood social capital theory and model for examining several under-addressed issues of social capital in the neighborhood effects literature and generating specific, empirically testable hypotheses for future research.

Synaptic augmentation in a cortical circuit model reproduces serial dependence in visual working memory

PubMed Central

D’Esposito, Mark

2017-01-01

Recent work has established that visual working memory is subject to serial dependence: current information in memory blends with that from the recent past as a function of their similarity. This tuned temporal smoothing likely promotes the stability of memory in the face of noise and occlusion. Serial dependence accumulates over several seconds in memory and deteriorates with increased separation between trials. While this phenomenon has been extensively characterized in behavior, its neural mechanism is unknown. In the present study, we investigate the circuit-level origins of serial dependence in a biophysical model of cortex. We explore two distinct kinds of mechanisms: stable persistent activity during the memory delay period and dynamic “activity-silent” synaptic plasticity. We find that networks endowed with both strong reverberation to support persistent activity and dynamic synapses can closely reproduce behavioral serial dependence. Specifically, elevated activity drives synaptic augmentation, which biases activity on the subsequent trial, giving rise to a spatiotemporally tuned shift in the population response. Our hybrid neural model is a theoretical advance beyond abstract mathematical characterizations, offers testable hypotheses for physiological research, and demonstrates the power of biological insights to provide a quantitative explanation of human behavior. PMID:29244810

Boolean Minimization and Algebraic Factorization Procedures for Fully Testable Sequential Machines

DTIC Science & Technology

1989-09-01

Boolean Minimization and Algebraic Factorization Procedures for Fully Testable Sequential Machines Srinivas Devadas and Kurt Keutzer F ( Abstract In this...Projects Agency under contract number N00014-87-K-0825. Author Information Devadas : Department of Electrical Engineering and Computer Science, Room 36...MA 02139; (617) 253-0292. 0 * Boolean Minimization and Algebraic Factorization Procedures for Fully Testable Sequential Machines Siivas Devadas

Advanced Diagnostic and Prognostic Testbed (ADAPT) Testability Analysis Report

NASA Technical Reports Server (NTRS)

Ossenfort, John

2008-01-01

As system designs become more complex, determining the best locations to add sensors and test points for the purpose of testing and monitoring these designs becomes more difficult. Not only must the designer take into consideration all real and potential faults of the system, he or she must also find efficient ways of detecting and isolating those faults. Because sensors and cabling take up valuable space and weight on a system, and given constraints on bandwidth and power, it is even more difficult to add sensors into these complex designs after the design has been completed. As a result, a number of software tools have been developed to assist the system designer in proper placement of these sensors during the system design phase of a project. One of the key functions provided by many of these software programs is a testability analysis of the system essentially an evaluation of how observable the system behavior is using available tests. During the design phase, testability metrics can help guide the designer in improving the inherent testability of the design. This may include adding, removing, or modifying tests; breaking up feedback loops, or changing the system to reduce fault propagation. Given a set of test requirements, the analysis can also help to verify that the system will meet those requirements. Of course, a testability analysis requires that a software model of the physical system is available. For the analysis to be most effective in guiding system design, this model should ideally be constructed in parallel with these efforts. The purpose of this paper is to present the final testability results of the Advanced Diagnostic and Prognostic Testbed (ADAPT) after the system model was completed. The tool chosen to build the model and to perform the testability analysis with is the Testability Engineering and Maintenance System Designer (TEAMS-Designer). The TEAMS toolset is intended to be a solution to span all phases of the system, from design and development through health management and maintenance. TEAMS-Designer is the model-building and testability analysis software in that suite.

Saccadic vector optokinetic perimetry in children with neurodisability or isolated visual pathway lesions: observational cohort study.

PubMed

Tailor, Vijay; Glaze, Selina; Unwin, Hilary; Bowman, Richard; Thompson, Graham; Dahlmann-Noor, Annegret

2016-10-01

Children and adults with neurological impairments are often not able to access conventional perimetry; however, information about the visual field is valuable. A new technology, saccadic vector optokinetic perimetry (SVOP), may have improved accessibility, but its accuracy has not been evaluated. We aimed to explore accessibility, testability and accuracy of SVOP in children with neurodisability or isolated visual pathway deficits. Cohort study; recruitment October 2013-May 2014, at children's eye clinics at a tertiary referral centre and a regional Child Development Centre; full orthoptic assessment, SVOP (central 30° of the visual field) and confrontation visual fields (CVF). Group 1: age 1-16 years, neurodisability (n=16), group 2: age 10-16 years, confirmed or suspected visual field defect (n=21); group 2 also completed Goldmann visual field testing (GVFT). Group 1: testability with a full 40-point test protocol is 12.5%; with reduced test protocols, testability is 100%, but plots may be clinically meaningless. Children (44%) and parents/carers (62.5%) find the test easy. SVOP and CVF agree in 50%. Group 2: testability is 62% for the 40-point protocol, and 90.5% for reduced protocols. Corneal changes in childhood glaucoma interfere with SVOP testing. All children and parents/carers find SVOP easy. Overall agreement with GVFT is 64.7%. While SVOP is highly accessible to children, many cannot complete a full 40-point test. Agreement with current standard tests is moderate to poor. Abnormal saccades cause an apparent non-specific visual field defect. In children with glaucoma or nystagmus SVOP calibration often fails. 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/

The relation between prior knowledge and students' collaborative discovery learning processes

NASA Astrophysics Data System (ADS)

Gijlers, Hannie; de Jong, Ton

2005-03-01

In this study we investigate how prior knowledge influences knowledge development during collaborative discovery learning. Fifteen dyads of students (pre-university education, 15-16 years old) worked on a discovery learning task in the physics field of kinematics. The (face-to-face) communication between students was recorded and the interaction with the environment was logged. Based on students' individual judgments of the truth-value and testability of a series of domain-specific propositions, a detailed description of the knowledge configuration for each dyad was created before they entered the learning environment. Qualitative analyses of two dialogues illustrated that prior knowledge influences the discovery learning processes, and knowledge development in a pair of students. Assessments of student and dyad definitional (domain-specific) knowledge, generic (mathematical and graph) knowledge, and generic (discovery) skills were related to the students' dialogue in different discovery learning processes. Results show that a high level of definitional prior knowledge is positively related to the proportion of communication regarding the interpretation of results. Heterogeneity with respect to generic prior knowledge was positively related to the number of utterances made in the discovery process categories hypotheses generation and experimentation. Results of the qualitative analyses indicated that collaboration between extremely heterogeneous dyads is difficult when the high achiever is not willing to scaffold information and work in the low achiever's zone of proximal development.

Improving accuracy and power with transfer learning using a meta-analytic database.

PubMed

Schwartz, Yannick; Varoquaux, Gaël; Pallier, Christophe; Pinel, Philippe; Poline, Jean-Baptiste; Thirion, Bertrand

2012-01-01

Typical cohorts in brain imaging studies are not large enough for systematic testing of all the information contained in the images. To build testable working hypotheses, investigators thus rely on analysis of previous work, sometimes formalized in a so-called meta-analysis. In brain imaging, this approach underlies the specification of regions of interest (ROIs) that are usually selected on the basis of the coordinates of previously detected effects. In this paper, we propose to use a database of images, rather than coordinates, and frame the problem as transfer learning: learning a discriminant model on a reference task to apply it to a different but related new task. To facilitate statistical analysis of small cohorts, we use a sparse discriminant model that selects predictive voxels on the reference task and thus provides a principled procedure to define ROIs. The benefits of our approach are twofold. First it uses the reference database for prediction, i.e., to provide potential biomarkers in a clinical setting. Second it increases statistical power on the new task. We demonstrate on a set of 18 pairs of functional MRI experimental conditions that our approach gives good prediction. In addition, on a specific transfer situation involving different scanners at different locations, we show that voxel selection based on transfer learning leads to higher detection power on small cohorts.

Addressing governance challenges in the provision of animal health services: A review of the literature and empirical application transaction cost theory.

PubMed

Ilukor, John; Birner, Regina; Nielsen, Thea

2015-11-01

Providing adequate animal health services to smallholder farmers in developing countries has remained a challenge, in spite of various reform efforts during the past decades. The focuses of the past reforms were on market failures to decide what the public sector, the private sector, and the "third sector" (the community-based sector) should do with regard to providing animal health services. However, such frameworks have paid limited attention to the governance challenges inherent in the provision of animal health services. This paper presents a framework for analyzing institutional arrangements for providing animal health services that focus not only on market failures, but also on governance challenges, such as elite capture, and absenteeism of staff. As an analytical basis, Williamson's discriminating alignment hypothesis is applied to assess the cost-effectiveness of different institutional arrangements for animal health services in view of both market failures and governance challenges. This framework is used to generate testable hypotheses on the appropriateness of different institutional arrangements for providing animal health services, depending on context-specific circumstances. Data from Uganda and Kenya on clinical veterinary services is used to provide an empirical test of these hypotheses and to demonstrate application of Williamson's transaction cost theory to veterinary service delivery. The paper concludes that strong public sector involvement, especially in building and strengthening a synergistic relation-based referral arrangement between paraprofessionals and veterinarians is imperative in improving animal health service delivery in developing countries. Copyright © 2015 Elsevier B.V. All rights reserved.

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

PubMed

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

2015-02-01

The multifactorial nature of traumatic brain injury (TBI), especially the complex secondary tissue injury involving intertwined networks of molecular pathways that mediate cellular behavior, has confounded attempts to elucidate the pathology underlying the progression of TBI. Here, systems biology strategies are exploited to identify novel molecular mechanisms and protein indicators of brain injury. To this end, we performed a meta-analysis of four distinct high-throughput gene expression studies involving different animal models of TBI. By using canonical pathways and a large human protein-interaction network as a scaffold, we separately overlaid the gene expression data from each study to identify molecular signatures that were conserved across the different studies. At 24 hr after injury, the significantly activated molecular signatures were nonspecific to TBI, whereas the significantly suppressed molecular signatures were specific to the nervous system. In particular, we identified a suppressed subnetwork consisting of 58 highly interacting, coregulated proteins associated with synaptic function. We selected three proteins from this subnetwork, postsynaptic density protein 95, nitric oxide synthase 1, and disrupted in schizophrenia 1, and hypothesized that their abundance would be significantly reduced after TBI. In a penetrating ballistic-like brain injury rat model of severe TBI, Western blot analysis confirmed our hypothesis. In addition, our analysis recovered 12 previously identified protein biomarkers of TBI. The results suggest that systems biology may provide an efficient, high-yield approach to generate testable hypotheses that can be experimentally validated to identify novel mechanisms of action and molecular indicators of TBI. © 2014 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

A Unified Approach to the Synthesis of Fully Testable Sequential Machines

DTIC Science & Technology

1989-10-01

N A Unified Approach to the Synthesis of Fully Testable Sequential Machines Srinivas Devadas and Kurt Keutzer Abstract • In this paper we attempt to...research was supported in part by the Defense Advanced Research Projects Agency under contract N00014-87-K-0825. Author Information Devadas : Department...Fully Testable Sequential Maine(S P Sritiivas Devadas Departinent of Electrical Engineerinig anid Comivi Sciec Massachusetts Institute of Technology

Factors That Affect Software Testability

NASA Technical Reports Server (NTRS)

Voas, Jeffrey M.

1991-01-01

Software faults that infrequently affect software's output are dangerous. When a software fault causes frequent software failures, testing is likely to reveal the fault before the software is releases; when the fault remains undetected during testing, it can cause disaster after the software is installed. A technique for predicting whether a particular piece of software is likely to reveal faults within itself during testing is found in [Voas91b]. A piece of software that is likely to reveal faults within itself during testing is said to have high testability. A piece of software that is not likely to reveal faults within itself during testing is said to have low testability. It is preferable to design software with higher testabilities from the outset, i.e., create software with as high of a degree of testability as possible to avoid the problems of having undetected faults that are associated with low testability. Information loss is a phenomenon that occurs during program execution that increases the likelihood that a fault will remain undetected. In this paper, I identify two brad classes of information loss, define them, and suggest ways of predicting the potential for information loss to occur. We do this in order to decrease the likelihood that faults will remain undetected during testing.

Opposing effects of oxidative challenge and carotenoids on antioxidant status and condition-dependent sexual signalling

PubMed Central

Tomášek, Oldřich; Gabrielová, Barbora; Kačer, Petr; Maršík, Petr; Svobodová, Jana; Syslová, Kamila; Vinkler, Michal; Albrecht, Tomáš

2016-01-01

Several recent hypotheses consider oxidative stress to be a primary constraint ensuring honesty of condition-dependent carotenoid-based signalling. The key testable difference between these hypotheses is the assumed importance of carotenoids for redox homeostasis, with carotenoids being either antioxidant, pro-oxidant or unimportant. We tested the role of carotenoids in redox balance and sexual signalling by exposing adult male zebra finches (Taeniopygia guttata) to oxidative challenge (diquat dibromide) and manipulating carotenoid intake. As the current controversy over the importance of carotenoids as antioxidants could stem from the hydrophilic basis of commonly-used antioxidant assays, we used the novel measure of in vivo lipophilic antioxidant capacity. Oxidative challenge reduced beak pigmentation but elicited an increase in antioxidant capacity suggesting resource reallocation from signalling to redox homeostasis. Carotenoids counteracted the effect of oxidative challenge on lipophilic (but not hydrophilic) antioxidant capacity, thereby supporting carotenoid antioxidant function in vivo. This is inconsistent with hypotheses proposing that signalling honesty is maintained through either ROS-induced carotenoid degradation or the pro-oxidant effect of high levels of carotenoid-cleavage products acting as a physiological handicap. Our data further suggest that assessment of lipophilic antioxidant capacity is necessary to fully understand the role of redox processes in ecology and evolution. PMID:27000655

Exploring Gusev Crater with Spirit: Review of science objectives and testable hypotheses

USGS Publications Warehouse

Cabrol, N.A.; Grin, E.A.; Carr, M.H.; Sutter, B.; Moore, Johnnie N.; Farmer, J.D.; Greeley, R.; Kuzmin, R.O.; DesMarais, D.J.; Kramer, M.G.; Newsom, H.; Barber, C.; Thorsos, I.; Tanaka, K.L.; Barlow, N.G.; Fike, D.A.; Urquhart, M.L.; Grigsby, B.; Grant, F.D.; de Goursac, O.

2003-01-01

Gusev Crater was selected as the landing site for the Mars Exploration Rover (MER) Spirit mission. Located at the outlet of Ma'adim Vallis and 250 km south of the volcano Apollinaris Patera, Gusev is an outstanding site to achieve the goals of the MER mission. The crater could have collected sediments from a variety of sources during its 3.9 Ga history, including fluvial, lacustrine, volcanic, glacial, impact, regional and local aeolian, and global air falls. It is a unique site to investigate the past history of water on Mars, climate and geological changes, and the potential habitability of the planet, which are central science objectives of the MER mission. Because of its complex history and potential diversity, Gusev will allow the testing of a large spectrum of hypotheses with the complete suite of MER instruments. Evidence consistent with long-lived lake episodes exist in the landing ellipse area. They might offer a unique opportunity to study, for the first time, Martian aqueous sediments and minerals formed in situ in their geological context. We review the geological history and diversity of the landing site, the science hypotheses that can be tested during the MER mission, and the relevance of Gusev to the MER mission objectives and payload. Copyright 2003 by the American Geophysical Union.

The importance of metagenomic surveys to microbial ecology: or why Darwin would have been a metagenomic scientist.

PubMed

Gilbert, Jack A; O'Dor, Ronald; King, Nicholas; Vogel, Timothy M

2011-06-14

Scientific discovery is incremental. The Merriam-Webster definition of 'Scientific Method' is "principles and procedures for the systematic pursuit of knowledge involving the recognition and formulation of a problem, the collection of data through observation and experiment, and the formulation and testing of hypotheses". Scientists are taught to be excellent observers, as observations create questions, which in turn generate hypotheses. After centuries of science we tend to assume that we have enough observations to drive science, and enable the small steps and giant leaps which lead to theories and subsequent testable hypotheses. One excellent example of this is Charles Darwin's Voyage of the Beagle, which was essentially an opportunistic survey of biodiversity. Today, obtaining funding for even small-scale surveys of life on Earth is difficult; but few argue the importance of the theory that was generated by Darwin from his observations made during this epic journey. However, these observations, even combined with the parallel work of Alfred Russell Wallace at around the same time have still not generated an indisputable 'law of biology'. The fact that evolution remains a 'theory', at least to the general public, suggests that surveys for new data need to be taken to a new level.

Capitalizing on Citizen Science Data for Validating Models and Generating Hypotheses Describing Meteorological Drivers of Mosquito-Borne Disease Risk

NASA Astrophysics Data System (ADS)

Boger, R. A.; Low, R.; Paull, S.; Anyamba, A.; Soebiyanto, R. P.

2017-12-01

Temperature and precipitation are important drivers of mosquito population dynamics, and a growing set of models have been proposed to characterize these relationships. Validation of these models, and development of broader theories across mosquito species and regions could nonetheless be improved by comparing observations from a global dataset of mosquito larvae with satellite-based measurements of meteorological variables. Citizen science data can be particularly useful for two such aspects of research into the meteorological drivers of mosquito populations: i) Broad-scale validation of mosquito distribution models and ii) Generation of quantitative hypotheses regarding changes to mosquito abundance and phenology across scales. The recently released GLOBE Observer Mosquito Habitat Mapper (GO-MHM) app engages citizen scientists in identifying vector taxa, mapping breeding sites and decommissioning non-natural habitats, and provides a potentially useful new tool for validating mosquito ubiquity projections based on the analysis of remotely sensed environmental data. Our early work with GO-MHM data focuses on two objectives: validating citizen science reports of Aedes aegypti distribution through comparison with accepted scientific data sources, and exploring the relationship between extreme temperature and precipitation events and subsequent observations of mosquito larvae. Ultimately the goal is to develop testable hypotheses regarding the shape and character of this relationship between mosquito species and regions.

Gas Replacements for GFP to Track Microbial Dynamics in Soils and Sediments

NASA Astrophysics Data System (ADS)

Cheng, Hsiao-Ying; Silberg, Jonathan; Masiello, Caroline

2016-04-01

Metagenomic analyses offer unprecedented views of soil microbial communities, and additionally provide a host of testable hypotheses about the biological mechanisms driving global biogeochemical fluxes. Outside the biogeosciences, hypotheses generated by metagenomics are often tested using biosensors, microbes programmed to respond in a detectable way to either changes in their metabolism or changes in the environment. A very large number of microbial behaviors can be monitored using biosensors, but these sensors typically report in ways that are undetectable in soils, e.g. by releasing green fluorescent protein (GFP). We are building a new class of biosensors that report by releasing easily-detected gases. We will provide an overview of the potential uses of gas-reporting biosensors in geobiology, and will report the current development these sensors. One goal in the development of these sensors is to make tractable the testing of gene expression hypotheses derived from metagenomics data. Examples of processes that could be tracked non-invasively with gas sensors include coordination of biofilm formation, nitrification, rhizobial infection of plant roots, and at least some forms of methanogenesis, all of which are managed by the easily-engineered acyl homoserine lactone cell-cell communication system. Another relatively simple process to track with gas sensors is horizontal gene transfer. We will report on the progress of these proof-of-concept examples.

Research by retrieving experiments.

PubMed

Blagosklonny, Mikhail V

2007-06-01

Newton did not discover that apples fall: the information was available prior to his gravitational hypothesis. Hypotheses can be tested not only by performing experiments but also by retrieving experiments from the literature (via PubMed, for example). Here I show how disconnected facts from known data, if properly connected, can generate novel predictions testable in turn by other published data. With examples from cell cycle, aging, cancer and other fields of biology and medicine, I discuss how new knowledge was and will be derived from old information. Millions of experiments have been already performed to test unrelated hypotheses and the results of those experiments are available to 'test' your hypotheses too. But most data (99% by some estimates) remain unpublished, because they were negative, seemed of low priority, or did not fit the story. Yet for other investigators those data may be valuable. The well-known story of Franklin and Watson is a case in point. By making preliminary data widely available, 'data-owners' will benefit most, receiving the credit for otherwise unused results. If posted (pre-published) on searchable databases, these data may fuel thousands of projects without the need for repetitive experiments. Enormous 'pre-published' databases coupled with Google-like search engines can change the structure of scientific research, and shrinking funding will make this inevitable.

Are evolutionary hypotheses for motion sickness "just-so" stories?

PubMed

Oman, Charles M

2012-01-01

Vertebrates have evolved rapidly conditionable nausea and vomiting reflexes mediated by gut and brainstem receptors, clearly as a defense against neurotoxin ingestion. In 1977 Treisman proposed that sensory orientation linkages to emetic centers evolved for the same reason, and that motion sickness was an accidental byproduct. It was an "adaptationist" explanation for motion sickness, since it assumed that evolution has shaped all phenotypic traits for survival advantage. Treisman's "poison" theory is plausible, and frequently cited as the accepted scientific explanation for motion sickness. However, alternative explanations have been proposed. The creation of hypotheses is an essential part of science - provided they are testable. This paper reviews the evidence for the Poison theory and several other adaptationist explanations. These hypotheses are certainly not "just-so stories", but supporting evidence is equivocal, and contradictory evidence exists Parsimony suggests an alternative "pluralistic" view: The vertebrate reticular formation maintains oxygenated blood flow to the brain, discriminates unexpected sensory stimuli- including postural disturbances, and detects and expels ingested neurotoxins. The three systems share neuroarchitectural elements but normally function independently. Brainstem sensory conflict neurons normally discriminate brief postural disturbances, but can be abnormally stimulated during prolonged passive transport (e.g. by boat, beginning about 150-200 generations ago). Sensory conflict signals cross couple into the neurotoxin expulsion and avoidance system, producing an arguably maladaptive emetic phenotype.

Opposing effects of oxidative challenge and carotenoids on antioxidant status and condition-dependent sexual signalling.

PubMed

Tomášek, Oldřich; Gabrielová, Barbora; Kačer, Petr; Maršík, Petr; Svobodová, Jana; Syslová, Kamila; Vinkler, Michal; Albrecht, Tomáš

2016-03-22

Several recent hypotheses consider oxidative stress to be a primary constraint ensuring honesty of condition-dependent carotenoid-based signalling. The key testable difference between these hypotheses is the assumed importance of carotenoids for redox homeostasis, with carotenoids being either antioxidant, pro-oxidant or unimportant. We tested the role of carotenoids in redox balance and sexual signalling by exposing adult male zebra finches (Taeniopygia guttata) to oxidative challenge (diquat dibromide) and manipulating carotenoid intake. As the current controversy over the importance of carotenoids as antioxidants could stem from the hydrophilic basis of commonly-used antioxidant assays, we used the novel measure of in vivo lipophilic antioxidant capacity. Oxidative challenge reduced beak pigmentation but elicited an increase in antioxidant capacity suggesting resource reallocation from signalling to redox homeostasis. Carotenoids counteracted the effect of oxidative challenge on lipophilic (but not hydrophilic) antioxidant capacity, thereby supporting carotenoid antioxidant function in vivo. This is inconsistent with hypotheses proposing that signalling honesty is maintained through either ROS-induced carotenoid degradation or the pro-oxidant effect of high levels of carotenoid-cleavage products acting as a physiological handicap. Our data further suggest that assessment of lipophilic antioxidant capacity is necessary to fully understand the role of redox processes in ecology and evolution.

Permo-Triassic vertebrate extinctions: A program

NASA Technical Reports Server (NTRS)

Olson, E. C.

1988-01-01

Since the time of the Authors' study on this subject, a great deal of new information has become available. Concepts of the nature of extinctions have changed materially. The Authors' conclusion that a catastrophic event was not responsible for the extinction of vertebrates has modified to the extent that hypotheses involving either the impact of a massive extra-terrestrial body or volcanism provide plausible but not currently fully testable hypotheses. Stated changes resulted in a rapid decrease in organic diversity, as the ratio of origins of taxa to extinctions shifted from strongly positive to negative, with momentary equilibrium being reached at about the Permo-Triassic boundary. The proximate causes of the changes in the terrestrial biota appear to lie in two primary factors: (1) strong climatic changes (global mean temperatures, temperature ranges, humidity) and (2) susceptibility of the dominant vertebrates (large dicynodonts) and the glossopteris flora to disruption of the equlibrium of the world ecosystem. The following proximate causes have been proposed: (1) rhythmic fluctuations in solar radiation, (2) tectonic events as Pangea assembled, altering land-ocean relationships, patterns of wind and water circulation and continental physiography, (3) volcanism, and (4) changes subsequent to impacts of one or more massive extra terrestrial objects, bodies or comets. These hypotheses are discussed.

Linking Microbiota to Human Diseases: A Systems Biology Perspective.

PubMed

Wu, Hao; Tremaroli, Valentina; Bäckhed, Fredrik

2015-12-01

The human gut microbiota encompasses a densely populated ecosystem that provides essential functions for host development, immune maturation, and metabolism. Alterations to the gut microbiota have been observed in numerous diseases, including human metabolic diseases such as obesity, type 2 diabetes (T2D), and irritable bowel syndrome, and some animal experiments have suggested causality. However, few studies have validated causality in humans and the underlying mechanisms remain largely to be elucidated. We discuss how systems biology approaches combined with new experimental technologies may disentangle some of the mechanistic details in the complex interactions of diet, microbiota, and host metabolism and may provide testable hypotheses for advancing our current understanding of human-microbiota interaction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Social response to technological disaster: the accident at Three Mile Island

DOE Office of Scientific and Technical Information (OSTI.GOV)

Richardson, B.B.

1984-01-01

Until recently the sociological study of man environment relations under extreme circumstances has been restricted to natural hazards (e.g., floods, hurricanes, tornadoes). Technological disasters are becoming more commonplace (e.g., Times Beach, MO, Love Canal, TMI-2) and are growing as potential sources of impact upon human populations. However, theory regarding the social impact of such disasters has not been developed. While research on natural disasters is in part applicable to technological disasters, theory adapted from environmental sociology and psychology are also utilized to develop a theory of social response to extreme environmental events produced by technology. Hypotheses are developed in themore » form of an empirically testable model based on the literature reviewed.« less

Reframing landscape fragmentation's effects on ecosystem services.

PubMed

Mitchell, Matthew G E; Suarez-Castro, Andrés F; Martinez-Harms, Maria; Maron, Martine; McAlpine, Clive; Gaston, Kevin J; Johansen, Kasper; Rhodes, Jonathan R

2015-04-01

Landscape structure and fragmentation have important effects on ecosystem services, with a common assumption being that fragmentation reduces service provision. This is based on fragmentation's expected effects on ecosystem service supply, but ignores how fragmentation influences the flow of services to people. Here we develop a new conceptual framework that explicitly considers the links between landscape fragmentation, the supply of services, and the flow of services to people. We argue that fragmentation's effects on ecosystem service flow can be positive or negative, and use our framework to construct testable hypotheses about the effects of fragmentation on final ecosystem service provision. Empirical efforts to apply and test this framework are critical to improving landscape management for multiple ecosystem services. Copyright © 2015 Elsevier Ltd. All rights reserved.

Modelling toehold-mediated RNA strand displacement.

PubMed

Šulc, Petr; Ouldridge, Thomas E; Romano, Flavio; Doye, Jonathan P K; Louis, Ard A

2015-03-10

We study the thermodynamics and kinetics of an RNA toehold-mediated strand displacement reaction with a recently developed coarse-grained model of RNA. Strand displacement, during which a single strand displaces a different strand previously bound to a complementary substrate strand, is an essential mechanism in active nucleic acid nanotechnology and has also been hypothesized to occur in vivo. We study the rate of displacement reactions as a function of the length of the toehold and temperature and make two experimentally testable predictions: that the displacement is faster if the toehold is placed at the 5' end of the substrate; and that the displacement slows down with increasing temperature for longer toeholds. Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Dietary n-3 PUFAs augment caspase 8 activation in Staphylococcal aureus enterotoxin B stimulated T-cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gill, R.

Epidemiological studies have linked consumption of n-3 PUFAs with a variety of beneficial health benefits, particularly with respect to putative anti-inflammatory effects. Unfortunately, many of these results remain somewhat controversial because in most instances there has not been a linkage to specific molecular mechanisms. For instance, dietary exposure to low levels of mercury has been shown to be damaging to neural development, but concomitant ingestion of n-3 PUFAs as occurs during consumption of fish, has been shown to counteract the detrimental effects. As the mechanisms mediating the neurotoxicity of environmental mercury are not fully delineated, it is difficult to conceptualizemore » a testable molecular mechanism explaining how n-3 PUFAs negate its neurotoxic effects. However, environmental exposure to mercury also has been linked to increased autoimmunity. By way of a molecular understanding of this immuno-toxic association, disruption of CD95 signaling is well established as a triggering factor for autoimmunity, and we have previously shown that environmentally relevant in vitro and dietary exposures to mercury interfere with CD95 signaling. In particular we have shown that activation of caspase 8, as well as downstream activation of caspase 3, in response to CD95 agonist stimulation is depressed by mercury. More recently we have shown in vitro that the n-3 PUFA docosahexaenoic acid counteracts the negative effect of mercury on CD95 signaling by restoring caspase activity. We hypothesized that concomitant ingestion of n-3 PUFAs with mercury might be protective from the immuno-toxic effects of mercury, as it is with mercury's neuro-toxic effects, and in the case of immuno-toxicity this would be related to restoration of CD95 signal strength. We now show that dietary ingestion of n-3 PUFAs generally promotes CD95 signaling by upregulating caspase 8 activation. Apart from accounting for the ability of n-3 PUFAs to specifically counteract autoimmune sequelae of mercury exposure, this novel finding for the first time suggests a testable molecular mechanism explaining the overall anti-inflammatory properties of n-3 PUFAs. - Highlights: • Dietary n-3 PUFAs counter Hg{sup 2+} immunotoxicity • Hg{sup 2+} interference with SEB-mediated signal transduction is ameliorated by n-3 PUFA rich diets. • Dietary n-3 PUFAs augment SEB-mediated activation of caspase 8 in vivo.« less

A quantitative systems physiology model of renal function and blood pressure regulation: Model description.

PubMed

Hallow, K M; Gebremichael, Y

2017-06-01

Renal function plays a central role in cardiovascular, kidney, and multiple other diseases, and many existing and novel therapies act through renal mechanisms. Even with decades of accumulated knowledge of renal physiology, pathophysiology, and pharmacology, the dynamics of renal function remain difficult to understand and predict, often resulting in unexpected or counterintuitive therapy responses. Quantitative systems pharmacology modeling of renal function integrates this accumulated knowledge into a quantitative framework, allowing evaluation of competing hypotheses, identification of knowledge gaps, and generation of new experimentally testable hypotheses. Here we present a model of renal physiology and control mechanisms involved in maintaining sodium and water homeostasis. This model represents the core renal physiological processes involved in many research questions in drug development. The model runs in R and the code is made available. In a companion article, we present a case study using the model to explore mechanisms and pharmacology of salt-sensitive hypertension. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Recent Advances in Tourette Syndrome

PubMed Central

Bloch, Michael; State, Matthew; Pittenger, Christopher

2014-01-01

Purpose of review The purpose of this review is to consider the recent literature pertaining to the neurobiology, genetics and treatment of Tourette syndrome (TS). Recent findings Over the last several years, both neuropathological and genetic findings have further focused attention on long-standing hypotheses regarding the role of the basal ganglia in the etiology of tics and TS. Moreover, while the field awaits the results the first large-scale genetic studies, recent findings have already mirrored developments in the neuropsychiatric genetics literature more broadly, highlighting the value of the study of rare variation and the overlap of risks among seemingly disparate diagnostic categories. Finally, treatment studies have underscored the importance of cognitive-behavioral as well as pharmacological interventions for the treatment of tic disorders. Summary Recent findings have led to novel, testable hypotheses regarding the molecular and cellular mechanisms underlying TS. These, in turn, have begun to provide new avenues to conceptualizing treatment strategies. While the development of additional medication options is a pressing need, recent data has demonstrated both the safety and efficacy of non-pharmacological approaches. PMID:21386676

Multidisciplinary approaches to understanding collective cell migration in developmental biology.

PubMed

Schumacher, Linus J; Kulesa, Paul M; McLennan, Rebecca; Baker, Ruth E; Maini, Philip K

2016-06-01

Mathematical models are becoming increasingly integrated with experimental efforts in the study of biological systems. Collective cell migration in developmental biology is a particularly fruitful application area for the development of theoretical models to predict the behaviour of complex multicellular systems with many interacting parts. In this context, mathematical models provide a tool to assess the consistency of experimental observations with testable mechanistic hypotheses. In this review, we showcase examples from recent years of multidisciplinary investigations of neural crest cell migration. The neural crest model system has been used to study how collective migration of cell populations is shaped by cell-cell interactions, cell-environmental interactions and heterogeneity between cells. The wide range of emergent behaviours exhibited by neural crest cells in different embryonal locations and in different organisms helps us chart out the spectrum of collective cell migration. At the same time, this diversity in migratory characteristics highlights the need to reconcile or unify the array of currently hypothesized mechanisms through the next generation of experimental data and generalized theoretical descriptions. © 2016 The Authors.

The development, evolution, and status of Holland's theory of vocational personalities: Reflections and future directions for counseling psychology.

PubMed

Nauta, Margaret M

2010-01-01

This article celebrates the 50th anniversary of the introduction of John L. Holland's (1959) theory of vocational personalities and work environments by describing the theory's development and evolution, its instrumentation, and its current status. Hallmarks of Holland's theory are its empirical testability and its user-friendliness. By constructing measures for operationalizing the theory's constructs, Holland and his colleagues helped ensure that the theory could be implemented in practice on a widespread basis. Empirical data offer considerable support for the existence of Holland's RIASEC types and their ordering among persons and environments. Although Holland's congruence hypotheses have received empirical support, congruence appears to have modest predictive power. Mixed support exists for Holland's hypotheses involving the secondary constructs of differentiation, consistency, and vocational identity. Evidence of the continued impact of Holland's theory on the field of counseling psychology, particularly in the area of interest assessment, can be seen from its frequent implementation in practice and its use by scholars. Ideas for future research and practice using Holland's theory are suggested.

Extended Testability Analysis Tool

NASA Technical Reports Server (NTRS)

Melcher, Kevin; Maul, William A.; Fulton, Christopher

2012-01-01

The Extended Testability Analysis (ETA) Tool is a software application that supports fault management (FM) by performing testability analyses on the fault propagation model of a given system. Fault management includes the prevention of faults through robust design margins and quality assurance methods, or the mitigation of system failures. Fault management requires an understanding of the system design and operation, potential failure mechanisms within the system, and the propagation of those potential failures through the system. The purpose of the ETA Tool software is to process the testability analysis results from a commercial software program called TEAMS Designer in order to provide a detailed set of diagnostic assessment reports. The ETA Tool is a command-line process with several user-selectable report output options. The ETA Tool also extends the COTS testability analysis and enables variation studies with sensor sensitivity impacts on system diagnostics and component isolation using a single testability output. The ETA Tool can also provide extended analyses from a single set of testability output files. The following analysis reports are available to the user: (1) the Detectability Report provides a breakdown of how each tested failure mode was detected, (2) the Test Utilization Report identifies all the failure modes that each test detects, (3) the Failure Mode Isolation Report demonstrates the system s ability to discriminate between failure modes, (4) the Component Isolation Report demonstrates the system s ability to discriminate between failure modes relative to the components containing the failure modes, (5) the Sensor Sensor Sensitivity Analysis Report shows the diagnostic impact due to loss of sensor information, and (6) the Effect Mapping Report identifies failure modes that result in specified system-level effects.

Software Users Manual (SUM): Extended Testability Analysis (ETA) Tool

NASA Technical Reports Server (NTRS)

Maul, William A.; Fulton, Christopher E.

2011-01-01

This software user manual describes the implementation and use the Extended Testability Analysis (ETA) Tool. The ETA Tool is a software program that augments the analysis and reporting capabilities of a commercial-off-the-shelf (COTS) testability analysis software package called the Testability Engineering And Maintenance System (TEAMS) Designer. An initial diagnostic assessment is performed by the TEAMS Designer software using a qualitative, directed-graph model of the system being analyzed. The ETA Tool utilizes system design information captured within the diagnostic model and testability analysis output from the TEAMS Designer software to create a series of six reports for various system engineering needs. The ETA Tool allows the user to perform additional studies on the testability analysis results by determining the detection sensitivity to the loss of certain sensors or tests. The ETA Tool was developed to support design and development of the NASA Ares I Crew Launch Vehicle. The diagnostic analysis provided by the ETA Tool was proven to be valuable system engineering output that provided consistency in the verification of system engineering requirements. This software user manual provides a description of each output report generated by the ETA Tool. The manual also describes the example diagnostic model and supporting documentation - also provided with the ETA Tool software release package - that were used to generate the reports presented in the manual

Network Simulation Models

DTIC Science & Technology

2008-12-01

1979; Wasserman and Faust, 1994). SNA thus relies heavily on graph theory to make predictions about network structure and thus social behavior...becomes a tool for increasing the specificity of theory , thinking through the theoretical implications, and generating testable predictions. In...to summarize Construct and its roots in constructural sociological theory . We discover that the (LPM) provides a mathematical bridge between

Training Signaling Pathway Maps to Biochemical Data with Constrained Fuzzy Logic: Quantitative Analysis of Liver Cell Responses to Inflammatory Stimuli

PubMed Central

Morris, Melody K.; Saez-Rodriguez, Julio; Clarke, David C.; Sorger, Peter K.; Lauffenburger, Douglas A.

2011-01-01

Predictive understanding of cell signaling network operation based on general prior knowledge but consistent with empirical data in a specific environmental context is a current challenge in computational biology. Recent work has demonstrated that Boolean logic can be used to create context-specific network models by training proteomic pathway maps to dedicated biochemical data; however, the Boolean formalism is restricted to characterizing protein species as either fully active or inactive. To advance beyond this limitation, we propose a novel form of fuzzy logic sufficiently flexible to model quantitative data but also sufficiently simple to efficiently construct models by training pathway maps on dedicated experimental measurements. Our new approach, termed constrained fuzzy logic (cFL), converts a prior knowledge network (obtained from literature or interactome databases) into a computable model that describes graded values of protein activation across multiple pathways. We train a cFL-converted network to experimental data describing hepatocytic protein activation by inflammatory cytokines and demonstrate the application of the resultant trained models for three important purposes: (a) generating experimentally testable biological hypotheses concerning pathway crosstalk, (b) establishing capability for quantitative prediction of protein activity, and (c) prediction and understanding of the cytokine release phenotypic response. Our methodology systematically and quantitatively trains a protein pathway map summarizing curated literature to context-specific biochemical data. This process generates a computable model yielding successful prediction of new test data and offering biological insight into complex datasets that are difficult to fully analyze by intuition alone. PMID:21408212

Modulation of hippocampal rhythms by subthreshold electric fields and network topology

PubMed Central

Berzhanskaya, Julia; Chernyy, Nick; Gluckman, Bruce J.; Schiff, Steven J.; Ascoli, Giorgio A.

2012-01-01

Theta (4–12 Hz) and gamma (30–80 Hz) rhythms are considered important for cortical and hippocampal function. Although several neuron types are implicated in rhythmogenesis, the exact cellular mechanisms remain unknown. Subthreshold electric fields provide a flexible, area-specific tool to modulate neural activity and directly test functional hypotheses. Here we present experimental and computational evidence of the interplay among hippocampal synaptic circuitry, neuronal morphology, external electric fields, and network activity. Electrophysiological data are used to constrain and validate an anatomically and biophysically realistic model of area CA1 containing pyramidal cells and two interneuron types: dendritic- and perisomatic-targeting. We report two lines of results: addressing the network structure capable of generating theta-modulated gamma rhythms, and demonstrating electric field effects on those rhythms. First, theta-modulated gamma rhythms require specific inhibitory connectivity. In one configuration, GABAergic axo-dendritic feedback on pyramidal cells is only effective in proximal but not distal layers. An alternative configuration requires two distinct perisomatic interneuron classes, one exclusively receiving excitatory contacts, the other additionally targeted by inhibition. These observations suggest novel roles for particular classes of oriens and basket cells. The second major finding is that subthreshold electric fields robustly alter the balance between different rhythms. Independent of network configuration, positive electric fields decrease, while negative fields increase the theta/gamma ratio. Moreover, electric fields differentially affect average theta frequency depending on specific synaptic connectivity. These results support the testable prediction that subthreshold electric fields can alter hippocampal rhythms, suggesting new approaches to explore their cognitive functions and underlying circuitry. PMID:23053863

A two-hypothesis approach to establishing a life detection/biohazard protocol for planetary samples

NASA Astrophysics Data System (ADS)

Conley, Catharine; Steele, Andrew

2016-07-01

The COSPAR policy on performing a biohazard assessment on samples brought from Mars to Earth is framed in the context of a concern for false-positive results. However, as noted during the 2012 Workshop for Life Detection in Samples from Mars (ref. Kminek et al., 2014), a more significant concern for planetary samples brought to Earth is false-negative results, because an undetected biohazard could increase risk to the Earth. This is the reason that stringent contamination control must be a high priority for all Category V Restricted Earth Return missions. A useful conceptual framework for addressing these concerns involves two complementary 'null' hypotheses: testing both of them, together, would allow statistical and community confidence to be developed regarding one or the other conclusion. As noted above, false negatives are of primary concern for safety of the Earth, so the 'Earth Safety null hypothesis' -- that must be disproved to assure low risk to the Earth from samples introduced by Category V Restricted Earth Return missions -- is 'There is native life in these samples.' False positives are of primary concern for Astrobiology, so the 'Astrobiology null hypothesis' -- that must be disproved in order to demonstrate the existence of extraterrestrial life is 'There is no life in these samples.' The presence of Earth contamination would render both of these hypotheses more difficult to disprove. Both these hypotheses can be tested following a strict science protocol; analyse, interprete, test the hypotheses and repeat. The science measurements undertaken are then done in an iterative fashion that responds to discovery with both hypotheses testable from interpretation of the scientific data. This is a robust, community involved activity that ensures maximum science return with minimal sample use.

Predicting Predator Recognition in a Changing World.

PubMed

Carthey, Alexandra J R; Blumstein, Daniel T

2018-02-01

Through natural as well as anthropogenic processes, prey can lose historically important predators and gain novel ones. Both predator gain and loss frequently have deleterious consequences. While numerous hypotheses explain the response of individuals to novel and familiar predators, we lack a unifying conceptual model that predicts the fate of prey following the introduction of a novel or a familiar (reintroduced) predator. Using the concept of eco-evolutionary experience, we create a new framework that allows us to predict whether prey will recognize and be able to discriminate predator cues from non-predator cues and, moreover, the likely persistence outcomes for 11 different predator-prey interaction scenarios. This framework generates useful and testable predictions for ecologists, conservation scientists, and decision-makers. Copyright © 2017 Elsevier Ltd. All rights reserved.

Graduate students' teaching experiences improve their methodological research skills.

PubMed

Feldon, David F; Peugh, James; Timmerman, Briana E; Maher, Michelle A; Hurst, Melissa; Strickland, Denise; Gilmore, Joanna A; Stiegelmeyer, Cindy

2011-08-19

Science, technology, engineering, and mathematics (STEM) graduate students are often encouraged to maximize their engagement with supervised research and minimize teaching obligations. However, the process of teaching students engaged in inquiry provides practice in the application of important research skills. Using a performance rubric, we compared the quality of methodological skills demonstrated in written research proposals for two groups of early career graduate students (those with both teaching and research responsibilities and those with only research responsibilities) at the beginning and end of an academic year. After statistically controlling for preexisting differences between groups, students who both taught and conducted research demonstrate significantly greater improvement in their abilities to generate testable hypotheses and design valid experiments. These results indicate that teaching experience can contribute substantially to the improvement of essential research skills.

A unifying model of the role of the infralimbic cortex in extinction and habits

PubMed Central

Taylor, Jane R.; Chandler, L. Judson

2014-01-01

The infralimbic prefrontal cortex (IL) has been shown to be critical for the regulation of flexible behavior, but its precise function remains unclear. This region has been shown to be critical for the acquisition, consolidation, and expression of extinction learning, leading many to hypothesize that IL suppresses behavior as part of a “stop” network. However, this framework is at odds with IL function in habitual behavior in which the IL has been shown to be required for the expression and acquisition of ongoing habitual behavior. Here, we will review the current state of knowledge of IL anatomy and function in behavioral flexibility and provide a testable framework for a single IL mechanism underlying its function in both extinction and habit learning. PMID:25128534

Seasonally-Dynamic Presence-Only Species Distribution Models for a Cryptic Migratory Bat Impacted by Wind Energy Development

PubMed Central

Hayes, Mark A.; Cryan, Paul M.; Wunder, Michael B.

2015-01-01

Understanding seasonal distribution and movement patterns of animals that migrate long distances is an essential part of monitoring and conserving their populations. Compared to migratory birds and other more conspicuous migrants, we know very little about the movement patterns of many migratory bats. Hoary bats (Lasiurus cinereus), a cryptic, wide-ranging, long-distance migrant, comprise a substantial proportion of the tens to hundreds of thousands of bat fatalities estimated to occur each year at wind turbines in North America. We created seasonally-dynamic species distribution models (SDMs) from 2,753 museum occurrence records collected over five decades in North America to better understand the seasonal geographic distributions of hoary bats. We used 5 SDM approaches: logistic regression, multivariate adaptive regression splines, boosted regression trees, random forest, and maximum entropy and consolidated outputs to generate ensemble maps. These maps represent the first formal hypotheses for sex- and season-specific hoary bat distributions. Our results suggest that North American hoary bats winter in regions with relatively long growing seasons where temperatures are moderated by proximity to oceans, and then move to the continental interior for the summer. SDMs suggested that hoary bats are most broadly distributed in autumn—the season when they are most susceptible to mortality from wind turbines; this season contains the greatest overlap between potentially suitable habitat and wind energy facilities. Comparing wind-turbine fatality data to model outputs could test many predictions, such as ‘risk from turbines is highest in habitats between hoary bat summering and wintering grounds’. Although future field studies are needed to validate the SDMs, this study generated well-justified and testable hypotheses of hoary bat migration patterns and seasonal distribution. PMID:26208098

Early developmental gene enhancers affect subcortical volumes in the adult human brain.

PubMed

Becker, Martin; Guadalupe, Tulio; Franke, Barbara; Hibar, Derrek P; Renteria, Miguel E; Stein, Jason L; Thompson, Paul M; Francks, Clyde; Vernes, Sonja C; Fisher, Simon E

2016-05-01

Genome-wide association screens aim to identify common genetic variants contributing to the phenotypic variability of complex traits, such as human height or brain morphology. The identified genetic variants are mostly within noncoding genomic regions and the biology of the genotype-phenotype association typically remains unclear. In this article, we propose a complementary targeted strategy to reveal the genetic underpinnings of variability in subcortical brain volumes, by specifically selecting genomic loci that are experimentally validated forebrain enhancers, active in early embryonic development. We hypothesized that genetic variation within these enhancers may affect the development and ultimately the structure of subcortical brain regions in adults. We tested whether variants in forebrain enhancer regions showed an overall enrichment of association with volumetric variation in subcortical structures of >13,000 healthy adults. We observed significant enrichment of genomic loci that affect the volume of the hippocampus within forebrain enhancers (empirical P = 0.0015), a finding which robustly passed the adjusted threshold for testing of multiple brain phenotypes (cutoff of P < 0.0083 at an alpha of 0.05). In analyses of individual single nucleotide polymorphisms (SNPs), we identified an association upstream of the ID2 gene with rs7588305 and variation in hippocampal volume. This SNP-based association survived multiple-testing correction for the number of SNPs analyzed but not for the number of subcortical structures. Targeting known regulatory regions offers a way to understand the underlying biology that connects genotypes to phenotypes, particularly in the context of neuroimaging genetics. This biology-driven approach generates testable hypotheses regarding the functional biology of identified associations. Hum Brain Mapp 37:1788-1800, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Seasonally-dynamic presence-only species distribution models for a cryptic migratory bat impacted by wind energy development

USGS Publications Warehouse

Hayes, Mark A.; Cryan, Paul M.; Wunder, Michael B.

2015-01-01

Understanding seasonal distribution and movement patterns of animals that migrate long distances is an essential part of monitoring and conserving their populations. Compared to migratory birds and other more conspicuous migrants, we know very little about the movement patterns of many migratory bats. Hoary bats (Lasiurus cinereus), a cryptic, wide-ranging, long-distance migrant, comprise a substantial proportion of the tens to hundreds of thousands of bat fatalities estimated to occur each year at wind turbines in North America. We created seasonally-dynamic species distribution models (SDMs) from 2,753 museum occurrence records collected over five decades in North America to better understand the seasonal geographic distributions of hoary bats. We used 5 SDM approaches: logistic regression, multivariate adaptive regression splines, boosted regression trees, random forest, and maximum entropy and consolidated outputs to generate ensemble maps. These maps represent the first formal hypotheses for sex- and season-specific hoary bat distributions. Our results suggest that North American hoary bats winter in regions with relatively long growing seasons where temperatures are moderated by proximity to oceans, and then move to the continental interior for the summer. SDMs suggested that hoary bats are most broadly distributed in autumn—the season when they are most susceptible to mortality from wind turbines; this season contains the greatest overlap between potentially suitable habitat and wind energy facilities. Comparing wind-turbine fatality data to model outputs could test many predictions, such as ‘risk from turbines is highest in habitats between hoary bat summering and wintering grounds’. Although future field studies are needed to validate the SDMs, this study generated well-justified and testable hypotheses of hoary bat migration patterns and seasonal distribution.

Modeling integrated cellular machinery using hybrid Petri-Boolean networks.

PubMed

Berestovsky, Natalie; Zhou, Wanding; Nagrath, Deepak; Nakhleh, Luay

2013-01-01

The behavior and phenotypic changes of cells are governed by a cellular circuitry that represents a set of biochemical reactions. Based on biological functions, this circuitry is divided into three types of networks, each encoding for a major biological process: signal transduction, transcription regulation, and metabolism. This division has generally enabled taming computational complexity dealing with the entire system, allowed for using modeling techniques that are specific to each of the components, and achieved separation of the different time scales at which reactions in each of the three networks occur. Nonetheless, with this division comes loss of information and power needed to elucidate certain cellular phenomena. Within the cell, these three types of networks work in tandem, and each produces signals and/or substances that are used by the others to process information and operate normally. Therefore, computational techniques for modeling integrated cellular machinery are needed. In this work, we propose an integrated hybrid model (IHM) that combines Petri nets and Boolean networks to model integrated cellular networks. Coupled with a stochastic simulation mechanism, the model simulates the dynamics of the integrated network, and can be perturbed to generate testable hypotheses. Our model is qualitative and is mostly built upon knowledge from the literature and requires fine-tuning of very few parameters. We validated our model on two systems: the transcriptional regulation of glucose metabolism in human cells, and cellular osmoregulation in S. cerevisiae. The model produced results that are in very good agreement with experimental data, and produces valid hypotheses. The abstract nature of our model and the ease of its construction makes it a very good candidate for modeling integrated networks from qualitative data. The results it produces can guide the practitioner to zoom into components and interconnections and investigate them using such more detailed mathematical models.

Modeling Integrated Cellular Machinery Using Hybrid Petri-Boolean Networks

PubMed Central

Berestovsky, Natalie; Zhou, Wanding; Nagrath, Deepak; Nakhleh, Luay

2013-01-01

The behavior and phenotypic changes of cells are governed by a cellular circuitry that represents a set of biochemical reactions. Based on biological functions, this circuitry is divided into three types of networks, each encoding for a major biological process: signal transduction, transcription regulation, and metabolism. This division has generally enabled taming computational complexity dealing with the entire system, allowed for using modeling techniques that are specific to each of the components, and achieved separation of the different time scales at which reactions in each of the three networks occur. Nonetheless, with this division comes loss of information and power needed to elucidate certain cellular phenomena. Within the cell, these three types of networks work in tandem, and each produces signals and/or substances that are used by the others to process information and operate normally. Therefore, computational techniques for modeling integrated cellular machinery are needed. In this work, we propose an integrated hybrid model (IHM) that combines Petri nets and Boolean networks to model integrated cellular networks. Coupled with a stochastic simulation mechanism, the model simulates the dynamics of the integrated network, and can be perturbed to generate testable hypotheses. Our model is qualitative and is mostly built upon knowledge from the literature and requires fine-tuning of very few parameters. We validated our model on two systems: the transcriptional regulation of glucose metabolism in human cells, and cellular osmoregulation in S. cerevisiae. The model produced results that are in very good agreement with experimental data, and produces valid hypotheses. The abstract nature of our model and the ease of its construction makes it a very good candidate for modeling integrated networks from qualitative data. The results it produces can guide the practitioner to zoom into components and interconnections and investigate them using such more detailed mathematical models. PMID:24244124

MetNet: Software to Build and Model the Biogenetic Lattice of Arabidopsis

DOE PAGES

Wurtele, Eve Syrkin; Li, Jie; Diao, Lixia; ...

2003-01-01

MetNet (http://www.botany.iastate.edu/∼mash/metnetex/metabolicnetex.html) is publicly available software in development for analysis of genome-wide RNA, protein and metabolite profiling data. The software is designed to enable the biologist to visualize, statistically analyse and model a metabolic and regulatory network map of Arabidopsis , combined with gene expression profiling data. It contains a JAVA interface to an interactions database (MetNetDB) containing information on regulatory and metabolic interactions derived from a combination of web databases (TAIR, KEGG, BRENDA) and input from biologists in their area of expertise. FCModeler captures input from MetNetDB in a graphical form. Sub-networks can be identified and interpreted using simplemore » fuzzy cognitive maps. FCModeler is intended to develop and evaluate hypotheses, and provide a modelling framework for assessing the large amounts of data captured by high-throughput gene expression experiments. FCModeler and MetNetDB are currently being extended to three-dimensional virtual reality display. The MetNet map, together with gene expression data, can be viewed using multivariate graphics tools in GGobi linked with the data analytic tools in R. Users can highlight different parts of the metabolic network and see the relevant expression data highlighted in other data plots. Multi-dimensional expression data can be rotated through different dimensions. Statistical analysis can be computed alongside the visual. MetNet is designed to provide a framework for the formulation of testable hypotheses regarding the function of specific genes, and in the long term provide the basis for identification of metabolic and regulatory networks that control plant composition and development.« less

Seasonally-Dynamic Presence-Only Species Distribution Models for a Cryptic Migratory Bat Impacted by Wind Energy Development.

PubMed

Hayes, Mark A; Cryan, Paul M; Wunder, Michael B

2015-01-01

Understanding seasonal distribution and movement patterns of animals that migrate long distances is an essential part of monitoring and conserving their populations. Compared to migratory birds and other more conspicuous migrants, we know very little about the movement patterns of many migratory bats. Hoary bats (Lasiurus cinereus), a cryptic, wide-ranging, long-distance migrant, comprise a substantial proportion of the tens to hundreds of thousands of bat fatalities estimated to occur each year at wind turbines in North America. We created seasonally-dynamic species distribution models (SDMs) from 2,753 museum occurrence records collected over five decades in North America to better understand the seasonal geographic distributions of hoary bats. We used 5 SDM approaches: logistic regression, multivariate adaptive regression splines, boosted regression trees, random forest, and maximum entropy and consolidated outputs to generate ensemble maps. These maps represent the first formal hypotheses for sex- and season-specific hoary bat distributions. Our results suggest that North American hoary bats winter in regions with relatively long growing seasons where temperatures are moderated by proximity to oceans, and then move to the continental interior for the summer. SDMs suggested that hoary bats are most broadly distributed in autumn-the season when they are most susceptible to mortality from wind turbines; this season contains the greatest overlap between potentially suitable habitat and wind energy facilities. Comparing wind-turbine fatality data to model outputs could test many predictions, such as 'risk from turbines is highest in habitats between hoary bat summering and wintering grounds'. Although future field studies are needed to validate the SDMs, this study generated well-justified and testable hypotheses of hoary bat migration patterns and seasonal distribution.

A transcriptional serenAID: the role of noncoding RNAs in class switch recombination

PubMed Central

Yewdell, William T.; Chaudhuri, Jayanta

2017-01-01

Abstract During an immune response, activated B cells may undergo class switch recombination (CSR), a molecular rearrangement that allows B cells to switch from expressing IgM and IgD to a secondary antibody heavy chain isotype such as IgG, IgA or IgE. Secondary antibody isotypes provide the adaptive immune system with distinct effector functions to optimally combat various pathogens. CSR occurs between repetitive DNA elements within the immunoglobulin heavy chain (Igh) locus, termed switch (S) regions and requires the DNA-modifying enzyme activation-induced cytidine deaminase (AID). AID-mediated DNA deamination within S regions initiates the formation of DNA double-strand breaks, which serve as biochemical beacons for downstream DNA repair pathways that coordinate the ligation of DNA breaks. Myriad factors contribute to optimal AID targeting; however, many of these factors also localize to genomic regions outside of the Igh locus. Thus, a current challenge is to explain the specific targeting of AID to the Igh locus. Recent studies have implicated noncoding RNAs in CSR, suggesting a provocative mechanism that incorporates Igh-specific factors to enable precise AID targeting. Here, we chronologically recount the rich history of noncoding RNAs functioning in CSR to provide a comprehensive context for recent and future discoveries. We present a model for the RNA-guided targeting of AID that attempts to integrate historical and recent findings, and highlight potential caveats. Lastly, we discuss testable hypotheses ripe for current experimentation, and explore promising ideas for future investigations. PMID:28535205

Co-Conserved MAPK Features Couple D-Domain Docking Groove to Distal Allosteric Sites via the C-Terminal Flanking Tail

PubMed Central

Nguyen, Tuan; Ruan, Zheng; Oruganty, Krishnadev; Kannan, Natarajan

2015-01-01

Mitogen activated protein kinases (MAPKs) form a closely related family of kinases that control critical pathways associated with cell growth and survival. Although MAPKs have been extensively characterized at the biochemical, cellular, and structural level, an integrated evolutionary understanding of how MAPKs differ from other closely related protein kinases is currently lacking. Here, we perform statistical sequence comparisons of MAPKs and related protein kinases to identify sequence and structural features associated with MAPK functional divergence. We show, for the first time, that virtually all MAPK-distinguishing sequence features, including an unappreciated short insert segment in the β4-β5 loop, physically couple distal functional sites in the kinase domain to the D-domain peptide docking groove via the C-terminal flanking tail (C-tail). The coupling mediated by MAPK-specific residues confers an allosteric regulatory mechanism unique to MAPKs. In particular, the regulatory αC-helix conformation is controlled by a MAPK-conserved salt bridge interaction between an arginine in the αC-helix and an acidic residue in the C-tail. The salt-bridge interaction is modulated in unique ways in individual sub-families to achieve regulatory specificity. Our study is consistent with a model in which the C-tail co-evolved with the D-domain docking site to allosterically control MAPK activity. Our study provides testable mechanistic hypotheses for biochemical characterization of MAPK-conserved residues and new avenues for the design of allosteric MAPK inhibitors. PMID:25799139

The linguistics of schizophrenia: thought disturbance as language pathology across positive symptoms.

PubMed

Hinzen, Wolfram; Rosselló, Joana

2015-01-01

We hypothesize that linguistic (dis-)organization in the schizophrenic brain plays a more central role in the pathogenesis of this disease than commonly supposed. Against the standard view, that schizophrenia is a disturbance of thought or selfhood, we argue that the origins of the relevant forms of thought and selfhood at least partially depend on language. The view that they do not is premised by a theoretical conception of language that we here identify as 'Cartesian' and contrast with a recent 'un-Cartesian' model. This linguistic model empirically argues for both (i) a one-to-one correlation between human-specific thought or meaning and forms of grammatical organization, and (ii) an integrative and co-dependent view of linguistic cognition and its sensory-motor dimensions. Core dimensions of meaning mediated by grammar on this model specifically concern forms of referential and propositional meaning. A breakdown of these is virtually definitional of core symptoms. Within this model the three main positive symptoms of schizophrenia fall into place as failures in language-mediated forms of meaning, manifest either as a disorder of speech perception (Auditory Verbal Hallucinations), abnormal speech production running without feedback control (Formal Thought Disorder), or production of abnormal linguistic content (Delusions). Our hypothesis makes testable predictions for the language profile of schizophrenia across symptoms; it simplifies the cognitive neuropsychology of schizophrenia while not being inconsistent with a pattern of neurocognitive deficits and their correlations with symptoms; and it predicts persistent findings on disturbances of language-related circuitry in the schizophrenic brain.

Acoustical analysis of trained and untrained singers onsite before and after prolonged voice use

NASA Astrophysics Data System (ADS)

Jackson, Christophe E.

Controlled acoustic environments are important in voice research. Recording environment affects the quality of voice recordings. While sound booths and anechoic chambers are examples of controlled acoustic environments widely used in research, they are both costly and not portable. The long-term goal of this project is to compare the voice usage and efficiency of trained and untrained singers onsite immediately before and after vocal performance. The specific goal of this project is the further of development a Portable Sound Booth (PSB) and standardization of onsite voice recording procedures under controlled conditions. We hypothesized that the simple and controlled acoustic environment provided by the PSB would enable consistent reliable onsite voice recordings and the immediate differences as a consequence of voice usage were measurable. Research has suggested that it would be possible to conduct onsite voice recordings. Proof of concept research titled "Construction and Characterization of a Portable Sound Booth for Onsite Measurement" was conducted before initiating the full research effort. Preliminary findings revealed that: (1) it was possible to make high-quality voice recordings onsite, (2) the use of a Portable Sound Booth (PSB) required further acoustic characterization of its inherent acoustic properties, and (3) testable differences before and after performance were evident. The specific aims were to (1) develop and refine onsite objective voice measurements in the PSB and (2) evaluate use of the PSB to measure voice quality changes before and after voice usage.

Symbiotic specificity, association patterns, and function determine community responses to global changes: defining critical research areas for coral-Symbiodinium symbioses.

PubMed

Fabina, Nicholas S; Putnam, Hollie M; Franklin, Erik C; Stat, Michael; Gates, Ruth D

2013-11-01

Climate change-driven stressors threaten the persistence of coral reefs worldwide. Symbiotic relationships between scleractinian corals and photosynthetic endosymbionts (genus Symbiodinium) are the foundation of reef ecosystems, and these associations are differentially impacted by stress. Here, we couple empirical data from the coral reefs of Moorea, French Polynesia, and a network theoretic modeling approach to evaluate how patterns in coral-Symbiodinium associations influence community stability under climate change. To introduce the effect of climate perturbations, we simulate local 'extinctions' that represent either the loss of coral species or the ability to engage in symbiotic interactions. Community stability is measured by determining the duration and number of species that persist through the simulated extinctions. Our results suggest that four factors greatly increase coral-Symbiodinium community stability in response to global changes: (i) the survival of generalist hosts and symbionts maximizes potential symbiotic unions; (ii) elevated symbiont diversity provides redundant or complementary symbiotic functions; (iii) compatible symbiotic assemblages create the potential for local recolonization; and (iv) the persistence of certain traits associate with symbiotic diversity and redundancy. Symbiodinium may facilitate coral persistence through novel environmental regimes, but this capacity is mediated by symbiotic specificity, association patterns, and the functional performance of the symbionts. Our model-based approach identifies general trends and testable hypotheses in coral-Symbiodinium community responses. Future studies should consider similar methods when community size and/or environmental complexity preclude experimental approaches. © 2013 John Wiley & Sons Ltd.

Multivariate ordination identifies vegetation types associated with spider conservation in brassica crops

PubMed Central

Saqib, Hafiz Sohaib Ahmed; You, Minsheng

2017-01-01

Conservation biological control emphasizes natural and other non-crop vegetation as a source of natural enemies to focal crops. There is an unmet need for better methods to identify the types of vegetation that are optimal to support specific natural enemies that may colonize the crops. Here we explore the commonality of the spider assemblage—considering abundance and diversity (H)—in brassica crops with that of adjacent non-crop and non-brassica crop vegetation. We employ spatial-based multivariate ordination approaches, hierarchical clustering and spatial eigenvector analysis. The small-scale mixed cropping and high disturbance frequency of southern Chinese vegetation farming offered a setting to test the role of alternate vegetation for spider conservation. Our findings indicate that spider families differ markedly in occurrence with respect to vegetation type. Grassy field margins, non-crop vegetation, taro and sweetpotato harbour spider morphospecies and functional groups that are also present in brassica crops. In contrast, pumpkin and litchi contain spiders not found in brassicas, and so may have little benefit for conservation biological control services for brassicas. Our findings also illustrate the utility of advanced statistical approaches for identifying spatial relationships between natural enemies and the land uses most likely to offer alternative habitats for conservation biological control efforts that generates testable hypotheses for future studies. PMID:29085741

Step-by-Step Construction of Gene Co-expression Networks from High-Throughput Arabidopsis RNA Sequencing Data.

PubMed

Contreras-López, Orlando; Moyano, Tomás C; Soto, Daniela C; Gutiérrez, Rodrigo A

2018-01-01

The rapid increase in the availability of transcriptomics data generated by RNA sequencing represents both a challenge and an opportunity for biologists without bioinformatics training. The challenge is handling, integrating, and interpreting these data sets. The opportunity is to use this information to generate testable hypothesis to understand molecular mechanisms controlling gene expression and biological processes (Fig. 1). A successful strategy to generate tractable hypotheses from transcriptomics data has been to build undirected network graphs based on patterns of gene co-expression. Many examples of new hypothesis derived from network analyses can be found in the literature, spanning different organisms including plants and specific fields such as root developmental biology.In order to make the process of constructing a gene co-expression network more accessible to biologists, here we provide step-by-step instructions using published RNA-seq experimental data obtained from a public database. Similar strategies have been used in previous studies to advance root developmental biology. This guide includes basic instructions for the operation of widely used open source platforms such as Bio-Linux, R, and Cytoscape. Even though the data we used in this example was obtained from Arabidopsis thaliana, the workflow developed in this guide can be easily adapted to work with RNA-seq data from any organism.

Defining the Construct of Synthetic Androgen Intoxication: An Application of General Brain Arousal.

PubMed

Hildebrandt, Tom; Heywood, Ashley; Wesley, Daniel; Schulz, Kurt

2018-01-01

Synthetic androgens (i. e., anabolic-androgenic steroids) are the primary component to the majority of problematic appearance and performance enhancing drug (APED) use. Despite evidence that these substances are associated with increased risk for aggression, violence, body image disturbances, and polypharmacy and can develop a pattern of chronic use consistent with drug dependence, there are no formal definitions of androgen intoxication. Consequently, the purpose of this paper is to establish a testable theory of androgen intoxication. We present evidence and theorize that synthetic androgen intoxication can be defined by a pattern of poor self-regulation characterized by increased propensity for a range of behaviors (e.g., aggression, sex, drug seeking, exercise, etc.) via androgen mediated effects on general brain arousal. This theory posits that androgens reduce threshold for emotional reactivity, motor response, and alertness to sensory stimuli and disrupt inhibitory control over the behaviors associated with synthetic androgen use. These changes result from alteration to basic neurocircuitry that amplifies limbic activation and reduces top-down cortical control. The implications for this definition are to inform APED specific hypotheses about the behavioral and psychological effects of APED use and provide a basis for establishing clinical, legal, and public health guidelines to address the use and misuse of these substances.

Defining the Construct of Synthetic Androgen Intoxication: An Application of General Brain Arousal

PubMed Central

Hildebrandt, Tom; Heywood, Ashley; Wesley, Daniel; Schulz, Kurt

2018-01-01

Synthetic androgens (i. e., anabolic-androgenic steroids) are the primary component to the majority of problematic appearance and performance enhancing drug (APED) use. Despite evidence that these substances are associated with increased risk for aggression, violence, body image disturbances, and polypharmacy and can develop a pattern of chronic use consistent with drug dependence, there are no formal definitions of androgen intoxication. Consequently, the purpose of this paper is to establish a testable theory of androgen intoxication. We present evidence and theorize that synthetic androgen intoxication can be defined by a pattern of poor self-regulation characterized by increased propensity for a range of behaviors (e.g., aggression, sex, drug seeking, exercise, etc.) via androgen mediated effects on general brain arousal. This theory posits that androgens reduce threshold for emotional reactivity, motor response, and alertness to sensory stimuli and disrupt inhibitory control over the behaviors associated with synthetic androgen use. These changes result from alteration to basic neurocircuitry that amplifies limbic activation and reduces top-down cortical control. The implications for this definition are to inform APED specific hypotheses about the behavioral and psychological effects of APED use and provide a basis for establishing clinical, legal, and public health guidelines to address the use and misuse of these substances. PMID:29651261

Qualitative exporation of relationships with important non-parental adults in the lives of youth in foster care

PubMed Central

Ahrens, Kym R.; DuBois, David Lane; Garrison, Michelle; Spencer, Renee; Richardson, Laura P.; Lozano, Paula

2012-01-01

Foster youth are at risk of poor adult outcomes. Research on the role of mentoring relationships for this population suggests the value of strategies that increase their access to adult sources of support, both while in foster care and as they reach adulthood. We conducted semi-structured, individual qualitative interviews with 23 former foster youth ages 18-25 regarding their relationships with supportive non-parental adults. We sought to identify factors that influence the formation, quality, and duration of these relationships and to develop testable hypotheses for intervention strategies. Findings suggest several themes related to relationship formation with non-parental adults, including barriers (e.g., youth's fears of being hurt) and facilitators (e.g., patience from the adult). Distinct themes were also identified relating to the ongoing development and longevity of these relationships. Youth also described multiple types of support and positive contributions to their development. Proposed intervention strategies include systematic incorporation of important non-parental adults into transition planning, enhanced training and matching procedures within formal mentoring programs, assistance for youth to strengthen their interpersonal awareness and skills, and the targeting of specific periods of need when linking youth to sources of adult support. Recommended research includes the development, pilot-testing, and evaluation of proposed strategies. PMID:22661797

The missing biology in land carbon models (Invited)

NASA Astrophysics Data System (ADS)

Prentice, I. C.; Cornwell, W.; Dong, N.; Maire, V.; Wang, H.; Wright, I.

2013-12-01

Models of terrestrial carbon cycling give divergent results, and recent developments - notably the inclusion of nitrogen-carbon cycle coupling - have apparently made matters worse. More extensive benchmarking of models would be highly desirable, but is not a panacea. Problems with current models include overparameterization (assigning separate sets of parameter values for each plant functional type can easily obscure more fundamental model limitations), and the widespread persistence of incorrect paradigms to describe plant responses to environment. Next-generation models require a more sound basis in observations and theory. A possible way forward will be outlined. It will be shown how the principle of optimization by natural selection can yield testable, general hypotheses about plant function. A specific optimality hypothesis about the control of CO2 drawdown versus water loss by leaves will be shown to yield global and quantitatively verifable predictions of plant behaviour as demonstrated in field gas-exchange measurements across species from different environments, and in the global pattern of stable carbon isotope discrimination by plants. Combined with the co-limitation hypothesis for the control of photosynthetic capacity and an economic approach to the costs of nutrient acquisition, this hypothesis provides a potential foundation for a comprehensive predictive understanding of the controls of primary production on land.

Multi-omics approach identifies molecular mechanisms of plant-fungus mycorrhizal interaction

DOE PAGES

Larsen, Peter E.; Sreedasyam, Avinash; Trivedi, Geetika; ...

2016-01-19

In mycorrhizal symbiosis, plant roots form close, mutually beneficial interactions with soil fungi. Before this mycorrhizal interaction can be established however, plant roots must be capable of detecting potential beneficial fungal partners and initiating the gene expression patterns necessary to begin symbiosis. To predict a plant root – mycorrhizal fungi sensor systems, we analyzed in vitro experiments of Populus tremuloides (aspen tree) and Laccaria bicolor (mycorrhizal fungi) interaction and leveraged over 200 previously published transcriptomic experimental data sets, 159 experimentally validated plant transcription factor binding motifs, and more than 120-thousand experimentally validated protein-protein interactions to generate models of pre-mycorrhizal sensormore » systems in aspen root. These sensor mechanisms link extracellular signaling molecules with gene regulation through a network comprised of membrane receptors, signal cascade proteins, transcription factors, and transcription factor biding DNA motifs. Modeling predicted four pre-mycorrhizal sensor complexes in aspen that interact with fifteen transcription factors to regulate the expression of 1184 genes in response to extracellular signals synthesized by Laccaria. Predicted extracellular signaling molecules include common signaling molecules such as phenylpropanoids, salicylate, and, jasmonic acid. Lastly, this multi-omic computational modeling approach for predicting the complex sensory networks yielded specific, testable biological hypotheses for mycorrhizal interaction signaling compounds, sensor complexes, and mechanisms of gene regulation.« less

Multi-omics approach identifies molecular mechanisms of plant-fungus mycorrhizal interaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Larsen, Peter E.; Sreedasyam, Avinash; Trivedi, Geetika

In mycorrhizal symbiosis, plant roots form close, mutually beneficial interactions with soil fungi. Before this mycorrhizal interaction can be established however, plant roots must be capable of detecting potential beneficial fungal partners and initiating the gene expression patterns necessary to begin symbiosis. To predict a plant root – mycorrhizal fungi sensor systems, we analyzed in vitro experiments of Populus tremuloides (aspen tree) and Laccaria bicolor (mycorrhizal fungi) interaction and leveraged over 200 previously published transcriptomic experimental data sets, 159 experimentally validated plant transcription factor binding motifs, and more than 120-thousand experimentally validated protein-protein interactions to generate models of pre-mycorrhizal sensormore » systems in aspen root. These sensor mechanisms link extracellular signaling molecules with gene regulation through a network comprised of membrane receptors, signal cascade proteins, transcription factors, and transcription factor biding DNA motifs. Modeling predicted four pre-mycorrhizal sensor complexes in aspen that interact with fifteen transcription factors to regulate the expression of 1184 genes in response to extracellular signals synthesized by Laccaria. Predicted extracellular signaling molecules include common signaling molecules such as phenylpropanoids, salicylate, and, jasmonic acid. Lastly, this multi-omic computational modeling approach for predicting the complex sensory networks yielded specific, testable biological hypotheses for mycorrhizal interaction signaling compounds, sensor complexes, and mechanisms of gene regulation.« less

Ecological resistance in urban streams: the role of natural and legacy attributes

USGS Publications Warehouse

Utz, Ryan M.; Hopkins, Kristina G.; Beesley, Leah; Booth, Derek B.; Hawley, Robert J.; Baker, Matthew E.; Freeman, Mary C.; Jones, Krista L.

2016-01-01

Urbanization substantially changes the physicochemical and biological characteristics of streams. The trajectory of negative effect is broadly similar around the world, but the nature and magnitude of ecological responses to urban growth differ among locations. Some heterogeneity in response arises from differences in the level of urban development and attributes of urban water management. However, the heterogeneity also may arise from variation in hydrologic, biological, and physicochemical templates that shaped stream ecosystems before urban development. We present a framework to develop hypotheses that predict how natural watershed and channel attributes in the pre-urban-development state may confer ecological resistance to urbanization. We present 6 testable hypotheses that explore the expression of such attributes under our framework: 1) greater water storage capacity mitigates hydrologic regime shifts, 2) coarse substrates and a balance between erosive forces and sediment supply buffer morphological changes, 3) naturally high ionic concentrations and pH pre-adapt biota to water-quality stress, 4) metapopulation connectivity results in retention of species richness, 5) high functional redundancy buffers trophic function from species loss, and 6) landuse history mutes or reverses the expected trajectory of eutrophication. Data from past comparative analyses support these hypotheses, but rigorous testing will require targeted investigations that account for confounding or interacting factors, such as diversity in urban infrastructure attributes. Improved understanding of the susceptibility or resistance of stream ecosystems could substantially strengthen conservation, management, and monitoring efforts in urban streams. We hope that these preliminary, conceptual hypotheses will encourage others to explore these ideas further and generate additional explanations for the heterogeneity observed in urban streams.

Module generation for self-testing integrated systems

NASA Astrophysics Data System (ADS)

Vanriessen, Ronald Pieter

Hardware used for self test in VLSI (Very Large Scale Integrated) systems is reviewed, and an architecture to control the test hardware in an integrated system is presented. Because of the increase of test times, the use of self test techniques has become practically and economically viable for VLSI systems. Beside the reduction in test times and costs, self test also provides testing at operational speeds. Therefore, a suitable combination of scan path and macrospecific (self) tests is required to reduce test times and costs. An expert system that can be used in a silicon compilation environment is presented. The approach requires a minimum of testability knowledge from a system designer. A user friendly interface was described for specifying and modifying testability requirements by a testability expert. A reason directed backtracking mechanism is used to solve selection failures. Both the hierarchical testable architecture and the design for testability expert system are used in a self test compiler. The definition of a self test compiler was given. A self test compiler is a software tool that selects an appropriate test method for every macro in a design. The hardware to control a macro test will be included in the design automatically. As an example, the integration of the self-test compiler in a silicon compilation system PIRAMID was described. The design of a demonstrator circuit by self test compiler is described. This circuit consists of two self testable macros. Control of the self test hardware is carried out via the test access port of the boundary scan standard.

The evolution of social and semantic networks in epistemic communities

NASA Astrophysics Data System (ADS)

Margolin, Drew Berkley

This study describes and tests a model of scientific inquiry as an evolving, organizational phenomenon. Arguments are derived from organizational ecology and evolutionary theory. The empirical subject of study is an epistemic community of scientists publishing on a research topic in physics: the string theoretic concept of "D-branes." The study uses evolutionary theory as a means of predicting change in the way members of the community choose concepts to communicate acceptable knowledge claims. It is argued that the pursuit of new knowledge is risky, because the reliability of a novel knowledge claim cannot be verified until after substantial resources have been invested. Using arguments from both philosophy of science and organizational ecology, it is suggested that scientists can mitigate and sensibly share the risks of knowledge discovery within the community by articulating their claims in legitimate forms, i.e., forms that are testable within and relevant to the community. Evidence from empirical studies of semantic usage suggests that the legitimacy of a knowledge claim is influenced by the characteristics of the concepts in which it is articulated. A model of conceptual retention, variation, and selection is then proposed for predicting the usage of concepts and conceptual co-occurrences in the future publications of the community, based on its past. Results substantially supported hypothesized retention and selection mechanisms. Future concept usage was predictable from previous concept usage, but was limited by conceptual carrying capacity as predicted by density dependence theory. Also as predicted, retention was stronger when the community showed a more cohesive social structure. Similarly, concepts that showed structural signatures of high testability and relevance were more likely to be selected after previous usage frequency was controlled for. By contrast, hypotheses for variation mechanisms were not supported. Surprisingly, concepts whose structural position suggested they would be easiest to discover through search processes were used less frequently, once previous usage frequency was controlled for. The study also makes a theoretical contribution by suggesting ways that evolutionary theory can be used to integrate findings from the study of science with insights from organizational communication. A variety of concrete directions for future studies of social and semantic network evolution are also proposed.

Refinement of Representation Theorems for Context-Free Languages

NASA Astrophysics Data System (ADS)

Fujioka, Kaoru

In this paper, we obtain some refinement of representation theorems for context-free languages by using Dyck languages, insertion systems, strictly locally testable languages, and morphisms. For instance, we improved the Chomsky-Schützenberger representation theorem and show that each context-free language L can be represented in the form L = h (D ∩ R), where D is a Dyck language, R is a strictly 3-testable language, and h is a morphism. A similar representation for context-free languages can be obtained, using insertion systems of weight (3, 0) and strictly 4-testable languages.

An empirical comparison of a dynamic software testability metric to static cyclomatic complexity

NASA Technical Reports Server (NTRS)

Voas, Jeffrey M.; Miller, Keith W.; Payne, Jeffrey E.

1993-01-01

This paper compares the dynamic testability prediction technique termed 'sensitivity analysis' to the static testability technique termed cyclomatic complexity. The application that we chose in this empirical study is a CASE generated version of a B-737 autoland system. For the B-737 system we analyzed, we isolated those functions that we predict are more prone to hide errors during system/reliability testing. We also analyzed the code with several other well-known static metrics. This paper compares and contrasts the results of sensitivity analysis to the results of the static metrics.

Mode and tempo in the evolution of socio-political organization: reconciling 'Darwinian' and 'Spencerian' evolutionary approaches in anthropology.

PubMed

Currie, Thomas E; Mace, Ruth

2011-04-12

Traditional investigations of the evolution of human social and political institutions trace their ancestry back to nineteenth century social scientists such as Herbert Spencer, and have concentrated on the increase in socio-political complexity over time. More recent studies of cultural evolution have been explicitly informed by Darwinian evolutionary theory and focus on the transmission of cultural traits between individuals. These two approaches to investigating cultural change are often seen as incompatible. However, we argue that many of the defining features and assumptions of 'Spencerian' cultural evolutionary theory represent testable hypotheses that can and should be tackled within a broader 'Darwinian' framework. In this paper we apply phylogenetic comparative techniques to data from Austronesian-speaking societies of Island South-East Asia and the Pacific to test hypotheses about the mode and tempo of human socio-political evolution. We find support for three ideas often associated with Spencerian cultural evolutionary theory: (i) political organization has evolved through a regular sequence of forms, (ii) increases in hierarchical political complexity have been more common than decreases, and (iii) political organization has co-evolved with the wider presence of hereditary social stratification.

Mathematical modeling of the female reproductive system: from oocyte to delivery.

PubMed

Clark, Alys R; Kruger, Jennifer A

2017-01-01

From ovulation to delivery, and through the menstrual cycle, the female reproductive system undergoes many dynamic changes to provide an optimal environment for the embryo to implant, and to develop successfully. It is difficult ethically and practically to observe the system over the timescales involved in growth and development (often hours to days). Even in carefully monitored conditions clinicians and biologists can only see snapshots of the development process. Mathematical models are emerging as a key means to supplement our knowledge of the reproductive process, and to tease apart complexity in the reproductive system. These models have been used successfully to test existing hypotheses regarding the mechanisms of female infertility and pathological fetal development, and also to provide new experimentally testable hypotheses regarding the process of development. This new knowledge has allowed for improvements in assisted reproductive technologies and is moving toward translation to clinical practice via multiscale assessments of the dynamics of ovulation, development in pregnancy, and the timing and mechanics of delivery. WIREs Syst Biol Med 2017, 9:e1353. doi: 10.1002/wsbm.1353 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.

Mode and tempo in the evolution of socio-political organization: reconciling ‘Darwinian’ and ‘Spencerian’ evolutionary approaches in anthropology

PubMed Central

Currie, Thomas E.; Mace, Ruth

2011-01-01

Traditional investigations of the evolution of human social and political institutions trace their ancestry back to nineteenth century social scientists such as Herbert Spencer, and have concentrated on the increase in socio-political complexity over time. More recent studies of cultural evolution have been explicitly informed by Darwinian evolutionary theory and focus on the transmission of cultural traits between individuals. These two approaches to investigating cultural change are often seen as incompatible. However, we argue that many of the defining features and assumptions of ‘Spencerian’ cultural evolutionary theory represent testable hypotheses that can and should be tackled within a broader ‘Darwinian’ framework. In this paper we apply phylogenetic comparative techniques to data from Austronesian-speaking societies of Island South-East Asia and the Pacific to test hypotheses about the mode and tempo of human socio-political evolution. We find support for three ideas often associated with Spencerian cultural evolutionary theory: (i) political organization has evolved through a regular sequence of forms, (ii) increases in hierarchical political complexity have been more common than decreases, and (iii) political organization has co-evolved with the wider presence of hereditary social stratification. PMID:21357233

The arsenic exposure hypothesis for Alzheimer disease.

PubMed

Gong, Gordon; OʼBryant, Sid E

2010-01-01

Prior research has shown that arsenic exposure induces changes that coincide with most of the developmental, biochemical, pathologic, and clinical features of Alzheimer disease (AD) and associated disorders. On the basis of this literature, we propose the Arsenic Exposure Hypothesis for AD that is inclusive of and cooperative with the existing hypotheses. Arsenic toxicity induces hyperphosphorylation of protein tau and overtranscription of the amyloid precursor protein, which are involved in the formation of neurofibrillary tangles and brain amyloid plaques, consistent with the amyloid hypothesis of AD. Arsenic exposure has been associated with cardiovascular diseases and associated risk factors, which is in agreement with the vascular hypothesis of AD. Arsenic exposure invokes brain inflammatory responses, which resonates with the inflammatory hypotheses of AD. Arsenic exposure has been linked to reduced memory and intellectual abilities in children and adolescents, which provides a biologic basis for the developmental origin of health and disease hypothesis for AD. Arsenic and its metabolites generate free radicals causing oxidative stress and neuronal death, which fits the existing oxidative stress hypothesis. Taken together, the arsenic exposure hypothesis for AD provides a parsimonious testable hypothesis for the development and progression of this devastating disease at least for some subsets of individuals.

Muscle MRI findings in facioscapulohumeral muscular dystrophy.

PubMed

Gerevini, Simonetta; Scarlato, Marina; Maggi, Lorenzo; Cava, Mariangela; Caliendo, Giandomenico; Pasanisi, Barbara; Falini, Andrea; Previtali, Stefano Carlo; Morandi, Lucia

2016-03-01

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by extremely variable degrees of facial, scapular and lower limb muscle involvement. Clinical and genetic determination can be difficult, as molecular analysis is not always definitive, and other similar muscle disorders may have overlapping clinical manifestations. Whole-body muscle MRI examination for fat infiltration, atrophy and oedema was performed to identify specific patterns of muscle involvement in FSHD patients (30 subjects), and compared to a group of control patients (23) affected by other myopathies (NFSHD). In FSHD patients, we detected a specific pattern of muscle fatty replacement and atrophy, particularly in upper girdle muscles. The most frequently affected muscles, including paucisymptomatic and severely affected FSHD patients, were trapezius, teres major and serratus anterior. Moreover, asymmetric muscle involvement was significantly higher in FSHD as compared to NFSHD patients. In conclusion, muscle MRI is very sensitive for identifying a specific pattern of involvement in FSHD patients and in detecting selective muscle involvement of non-clinically testable muscles. Muscle MRI constitutes a reliable tool for differentiating FSHD from other muscular dystrophies to direct diagnostic molecular analysis, as well as to investigate FSHD natural history and follow-up of the disease. Muscle MRI identifies a specific pattern of muscle involvement in FSHD patients. Muscle MRI may predict FSHD in asymptomatic and severely affected patients. Muscle MRI of upper girdle better predicts FSHD. Muscle MRI may differentiate FSHD from other forms of muscular dystrophy. Muscle MRI may show the involvement of non-clinical testable muscles.

Econometrics of exhaustible resource supply: a theory and an application

DOE Office of Scientific and Technical Information (OSTI.GOV)

Epple, D.

1983-01-01

This report takes a major step toward developing a fruitful approach to empirical analysis of resource supply. It is the first empirical application of resource theory that has successfully integrated the effects of depletion of nonrenewable resources with the effects of uncertainty about future costs and prices on supply behavior. Thus, the model is a major improvement over traditional engineering-optimization models that assume complete certainty, and over traditional econometrics models that are only implicitly related to the theory of resource supply. The model is used to test hypotheses about interdependence of oil and natural gas discoveries, depletion, ultimate recovery, andmore » the role of price expectations. This paper demonstrates the feasibility of using exhaustible resource theory in the development of empirically testable models. 19 refs., 1 fig., 5 tabs.« less

Brain Evolution and Human Neuropsychology: The Inferential Brain Hypothesis

PubMed Central

Koscik, Timothy R.; Tranel, Daniel

2013-01-01

Collaboration between human neuropsychology and comparative neuroscience has generated invaluable contributions to our understanding of human brain evolution and function. Further cross-talk between these disciplines has the potential to continue to revolutionize these fields. Modern neuroimaging methods could be applied in a comparative context, yielding exciting new data with the potential of providing insight into brain evolution. Conversely, incorporating an evolutionary base into the theoretical perspectives from which we approach human neuropsychology could lead to novel hypotheses and testable predictions. In the spirit of these objectives, we present here a new theoretical proposal, the Inferential Brain Hypothesis, whereby the human brain is thought to be characterized by a shift from perceptual processing to inferential computation, particularly within the social realm. This shift is believed to be a driving force for the evolution of the large human cortex. PMID:22459075

Injured Brains and Adaptive Networks: The Benefits and Costs of Hyperconnectivity.

PubMed

Hillary, Frank G; Grafman, Jordan H

2017-05-01

A common finding in human functional brain-imaging studies is that damage to neural systems paradoxically results in enhanced functional connectivity between network regions, a phenomenon commonly referred to as 'hyperconnectivity'. Here, we describe the various ways that hyperconnectivity operates to benefit a neural network following injury while simultaneously negotiating the trade-off between metabolic cost and communication efficiency. Hyperconnectivity may be optimally expressed by increasing connections through the most central and metabolically efficient regions (i.e., hubs). While adaptive in the short term, we propose that chronic hyperconnectivity may leave network hubs vulnerable to secondary pathological processes over the life span due to chronically elevated metabolic stress. We conclude by offering novel, testable hypotheses for advancing our understanding of the role of hyperconnectivity in systems-level brain plasticity in neurological disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Origin and Proliferation of Multiple-Drug Resistance in Bacterial Pathogens

PubMed Central

Chang, Hsiao-Han; Cohen, Ted; Grad, Yonatan H.; Hanage, William P.; O'Brien, Thomas F.

2015-01-01

SUMMARY Many studies report the high prevalence of multiply drug-resistant (MDR) strains. Because MDR infections are often significantly harder and more expensive to treat, they represent a growing public health threat. However, for different pathogens, different underlying mechanisms are traditionally used to explain these observations, and it is unclear whether each bacterial taxon has its own mechanism(s) for multidrug resistance or whether there are common mechanisms between distantly related pathogens. In this review, we provide a systematic overview of the causes of the excess of MDR infections and define testable predictions made by each hypothetical mechanism, including experimental, epidemiological, population genomic, and other tests of these hypotheses. Better understanding the cause(s) of the excess of MDR is the first step to rational design of more effective interventions to prevent the origin and/or proliferation of MDR. PMID:25652543

Exploring Culturally Based Intrafamilial Stressors Among Latino Adolescents

PubMed Central

Cordova, David; Ciofu, Amanda; Cervantes, Richard

2014-01-01

Despite the profound impact that intrafamilial stressors, including parent – adolescent acculturation discrepancies, may have on Latino adolescent behavioral and mental health, this line of research remains underdeveloped. The purpose of this study is to obtain rich descriptions from Latino adolescents of the most salient intrafamilial stressors. The authors employ focus group methodology with a grounded theory approach. A total of 25 focus groups were conducted with 170 Latino adolescents in the Northeast and Southwest United States. Findings indicate that Latino adolescents experience significant stressors related to parent – adolescent acculturation discrepancies. From this qualitative study the authors derive a series of testable hypotheses aimed at fully understanding the role of parent – adolescent acculturation discrepancies on Latino adolescent behavioral and mental health and informing the development of culturally responsive preventive interventions for this population. PMID:25530653

The biology and polymer physics underlying large‐scale chromosome organization

PubMed Central

2017-01-01

Chromosome large‐scale organization is a beautiful example of the interplay between physics and biology. DNA molecules are polymers and thus belong to the class of molecules for which physicists have developed models and formulated testable hypotheses to understand their arrangement and dynamic properties in solution, based on the principles of polymer physics. Biologists documented and discovered the biochemical basis for the structure, function and dynamic spatial organization of chromosomes in cells. The underlying principles of chromosome organization have recently been revealed in unprecedented detail using high‐resolution chromosome capture technology that can simultaneously detect chromosome contact sites throughout the genome. These independent lines of investigation have now converged on a model in which DNA loops, generated by the loop extrusion mechanism, are the basic organizational and functional units of the chromosome. PMID:29105235

Testability analysis on a hydraulic system in a certain equipment based on simulation model

NASA Astrophysics Data System (ADS)

Zhang, Rui; Cong, Hua; Liu, Yuanhong; Feng, Fuzhou

2018-03-01

Aiming at the problem that the complicated structure and the shortage of fault statistics information in hydraulic systems, a multi value testability analysis method based on simulation model is proposed. Based on the simulation model of AMESim, this method injects the simulated faults and records variation of test parameters ,such as pressure, flow rate, at each test point compared with those under normal conditions .Thus a multi-value fault-test dependency matrix is established. Then the fault detection rate (FDR) and fault isolation rate (FIR) are calculated based on the dependency matrix. Finally the system of testability and fault diagnosis capability are analyzed and evaluated, which can only reach a lower 54%(FDR) and 23%(FIR). In order to improve testability performance of the system,. number and position of the test points are optimized on the system. Results show the proposed test placement scheme can be used to solve the problems that difficulty, inefficiency and high cost in the system maintenance.

Investigating Evolutionary Conservation of Dendritic Cell Subset Identity and Functions

PubMed Central

Vu Manh, Thien-Phong; Bertho, Nicolas; Hosmalin, Anne; Schwartz-Cornil, Isabelle; Dalod, Marc

2015-01-01

Dendritic cells (DCs) were initially defined as mononuclear phagocytes with a dendritic morphology and an exquisite efficiency for naïve T-cell activation. DC encompass several subsets initially identified by their expression of specific cell surface molecules and later shown to excel in distinct functions and to develop under the instruction of different transcription factors or cytokines. Very few cell surface molecules are expressed in a specific manner on any immune cell type. Hence, to identify cell types, the sole use of a small number of cell surface markers in classical flow cytometry can be deceiving. Moreover, the markers currently used to define mononuclear phagocyte subsets vary depending on the tissue and animal species studied and even between laboratories. This has led to confusion in the definition of DC subset identity and in their attribution of specific functions. There is a strong need to identify a rigorous and consensus way to define mononuclear phagocyte subsets, with precise guidelines potentially applicable throughout tissues and species. We will discuss the advantages, drawbacks, and complementarities of different methodologies: cell surface phenotyping, ontogeny, functional characterization, and molecular profiling. We will advocate that gene expression profiling is a very rigorous, largely unbiased and accessible method to define the identity of mononuclear phagocyte subsets, which strengthens and refines surface phenotyping. It is uniquely powerful to yield new, experimentally testable, hypotheses on the ontogeny or functions of mononuclear phagocyte subsets, their molecular regulation, and their evolutionary conservation. We propose defining cell populations based on a combination of cell surface phenotyping, expression analysis of hallmark genes, and robust functional assays, in order to reach a consensus and integrate faster the huge but scattered knowledge accumulated by different laboratories on different cell types, organs, and species. PMID:26082777

Larval transport modeling of deep-sea invertebrates can aid the search for undiscovered populations.

PubMed

Yearsley, Jon M; Sigwart, Julia D

2011-01-01

Many deep-sea benthic animals occur in patchy distributions separated by thousands of kilometres, yet because deep-sea habitats are remote, little is known about their larval dispersal. Our novel method simulates dispersal by combining data from the Argo array of autonomous oceanographic probes, deep-sea ecological surveys, and comparative invertebrate physiology. The predicted particle tracks allow quantitative, testable predictions about the dispersal of benthic invertebrate larvae in the south-west Pacific. In a test case presented here, using non-feeding, non-swimming (lecithotrophic trochophore) larvae of polyplacophoran molluscs (chitons), we show that the likely dispersal pathways in a single generation are significantly shorter than the distances between the three known population centres in our study region. The large-scale density of chiton populations throughout our study region is potentially much greater than present survey data suggest, with intermediate 'stepping stone' populations yet to be discovered. We present a new method that is broadly applicable to studies of the dispersal of deep-sea organisms. This test case demonstrates the power and potential applications of our new method, in generating quantitative, testable hypotheses at multiple levels to solve the mismatch between observed and expected distributions: probabilistic predictions of locations of intermediate populations, potential alternative dispersal mechanisms, and expected population genetic structure. The global Argo data have never previously been used to address benthic biology, and our method can be applied to any non-swimming larvae of the deep-sea, giving information upon dispersal corridors and population densities in habitats that remain intrinsically difficult to assess.

Larval Transport Modeling of Deep-Sea Invertebrates Can Aid the Search for Undiscovered Populations

PubMed Central

Yearsley, Jon M.; Sigwart, Julia D.

2011-01-01

Background Many deep-sea benthic animals occur in patchy distributions separated by thousands of kilometres, yet because deep-sea habitats are remote, little is known about their larval dispersal. Our novel method simulates dispersal by combining data from the Argo array of autonomous oceanographic probes, deep-sea ecological surveys, and comparative invertebrate physiology. The predicted particle tracks allow quantitative, testable predictions about the dispersal of benthic invertebrate larvae in the south-west Pacific. Principal Findings In a test case presented here, using non-feeding, non-swimming (lecithotrophic trochophore) larvae of polyplacophoran molluscs (chitons), we show that the likely dispersal pathways in a single generation are significantly shorter than the distances between the three known population centres in our study region. The large-scale density of chiton populations throughout our study region is potentially much greater than present survey data suggest, with intermediate ‘stepping stone’ populations yet to be discovered. Conclusions/Significance We present a new method that is broadly applicable to studies of the dispersal of deep-sea organisms. This test case demonstrates the power and potential applications of our new method, in generating quantitative, testable hypotheses at multiple levels to solve the mismatch between observed and expected distributions: probabilistic predictions of locations of intermediate populations, potential alternative dispersal mechanisms, and expected population genetic structure. The global Argo data have never previously been used to address benthic biology, and our method can be applied to any non-swimming larvae of the deep-sea, giving information upon dispersal corridors and population densities in habitats that remain intrinsically difficult to assess. PMID:21857992

Report on phase 1 of the Microprocessor Seminar. [and associated large scale integration

NASA Technical Reports Server (NTRS)

1977-01-01

Proceedings of a seminar on microprocessors and associated large scale integrated (LSI) circuits are presented. The potential for commonality of device requirements, candidate processes and mechanisms for qualifying candidate LSI technologies for high reliability applications, and specifications for testing and testability were among the topics discussed. Various programs and tentative plans of the participating organizations in the development of high reliability LSI circuits are given.

The linguistics of schizophrenia: thought disturbance as language pathology across positive symptoms

PubMed Central

Hinzen, Wolfram; Rosselló, Joana

2015-01-01

We hypothesize that linguistic (dis-)organization in the schizophrenic brain plays a more central role in the pathogenesis of this disease than commonly supposed. Against the standard view, that schizophrenia is a disturbance of thought or selfhood, we argue that the origins of the relevant forms of thought and selfhood at least partially depend on language. The view that they do not is premised by a theoretical conception of language that we here identify as ‘Cartesian’ and contrast with a recent ‘un-Cartesian’ model. This linguistic model empirically argues for both (i) a one-to-one correlation between human-specific thought or meaning and forms of grammatical organization, and (ii) an integrative and co-dependent view of linguistic cognition and its sensory-motor dimensions. Core dimensions of meaning mediated by grammar on this model specifically concern forms of referential and propositional meaning. A breakdown of these is virtually definitional of core symptoms. Within this model the three main positive symptoms of schizophrenia fall into place as failures in language-mediated forms of meaning, manifest either as a disorder of speech perception (Auditory Verbal Hallucinations), abnormal speech production running without feedback control (Formal Thought Disorder), or production of abnormal linguistic content (Delusions). Our hypothesis makes testable predictions for the language profile of schizophrenia across symptoms; it simplifies the cognitive neuropsychology of schizophrenia while not being inconsistent with a pattern of neurocognitive deficits and their correlations with symptoms; and it predicts persistent findings on disturbances of language-related circuitry in the schizophrenic brain. PMID:26236257

Using next generation transcriptome sequencing to predict an ectomycorrhizal metablome.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Larsen, P. E.; Sreedasyam, A.; Trivedi, G

Mycorrhizae, symbiotic interactions between soil fungi and tree roots, are ubiquitous in terrestrial ecosystems. The fungi contribute phosphorous, nitrogen and mobilized nutrients from organic matter in the soil and in return the fungus receives photosynthetically-derived carbohydrates. This union of plant and fungal metabolisms is the mycorrhizal metabolome. Understanding this symbiotic relationship at a molecular level provides important contributions to the understanding of forest ecosystems and global carbon cycling. We generated next generation short-read transcriptomic sequencing data from fully-formed ectomycorrhizae between Laccaria bicolor and aspen (Populus tremuloides) roots. The transcriptomic data was used to identify statistically significantly expressed gene models usingmore » a bootstrap-style approach, and these expressed genes were mapped to specific metabolic pathways. Integration of expressed genes that code for metabolic enzymes and the set of expressed membrane transporters generates a predictive model of the ectomycorrhizal metabolome. The generated model of mycorrhizal metabolome predicts that the specific compounds glycine, glutamate, and allantoin are synthesized by L. bicolor and that these compounds or their metabolites may be used for the benefit of aspen in exchange for the photosynthetically-derived sugars fructose and glucose. The analysis illustrates an approach to generate testable biological hypotheses to investigate the complex molecular interactions that drive ectomycorrhizal symbiosis. These models are consistent with experimental environmental data and provide insight into the molecular exchange processes for organisms in this complex ecosystem. The method used here for predicting metabolomic models of mycorrhizal systems from deep RNA sequencing data can be generalized and is broadly applicable to transcriptomic data derived from complex systems.« less

Modeling trophic dependencies and exchanges among insects' bacterial symbionts in a host-simulated environment.

PubMed

Opatovsky, Itai; Santos-Garcia, Diego; Ruan, Zhepu; Lahav, Tamar; Ofaim, Shany; Mouton, Laurence; Barbe, Valérie; Jiang, Jiandong; Zchori-Fein, Einat; Freilich, Shiri

2018-05-25

Individual organisms are linked to their communities and ecosystems via metabolic activities. Metabolic exchanges and co-dependencies have long been suggested to have a pivotal role in determining community structure. In phloem-feeding insects such metabolic interactions with bacteria enable complementation of their deprived nutrition. The phloem-feeding whitefly Bemisia tabaci (Hemiptera: Aleyrodidae) harbors an obligatory symbiotic bacterium, as well as varying combinations of facultative symbionts. This well-defined bacterial community in B. tabaci serves here as a case study for a comprehensive and systematic survey of metabolic interactions within the bacterial community and their associations with documented occurrences of bacterial combinations. We first reconstructed the metabolic networks of five common B. tabaci symbionts genera (Portiera, Rickettsia, Hamiltonella, Cardinium and Wolbachia), and then used network analysis approaches to predict: (1) species-specific metabolic capacities in a simulated bacteriocyte-like environment; (2) metabolic capacities of the corresponding species' combinations, and (3) dependencies of each species on different media components. The predictions for metabolic capacities of the symbionts in the host environment were in general agreement with previously reported genome analyses, each focused on the single-species level. The analysis suggests several previously un-reported routes for complementary interactions and estimated the dependency of each symbiont in specific host metabolites. No clear association was detected between metabolic co-dependencies and co-occurrence patterns. The analysis generated predictions for testable hypotheses of metabolic exchanges and co-dependencies in bacterial communities and by crossing them with co-occurrence profiles, contextualized interaction patterns into a wider ecological perspective.

Genome-wide expression profiling in the peripheral blood of patients with fibromyalgia

PubMed Central

Jones, Kim D.; Gelbart, Terri; Whisenant, Thomas C.; Waalen, Jill; Mondala, Tony S.; Iklé, David N.; Salomon, Daniel R.; Bennett, Robert M.; Kurian, Sunil M.

2016-01-01

Objective Fibromyalgia (FM) is a common pain disorder characterised by nociceptive dysregulation. The basic biology of FM is poorly understood. Herein we have used agnostic gene expression as a potential probe for informing its underlying biology and the development of a proof-of-concept diagnostic gene expression signature. Methods We analysed RNA expression in 70 FM patients and 70 healthy controls. The isolated RNA was amplified and hybridised to Affymetrix® Human Gene 1.1 ST Peg arrays. The data was analysed using Partek Genomics Suite v. 6.6. Results Fibromyalgia patients exhibited a differential expression of 421 genes (p<0.001), several relevant to pathways for pain processing, such as glutamine/glutamate signaling and axonal development. There was also an upregulation of several inflammatory pathways and downregulation of pathways related to hypersensitivity and allergy. Using rigorous diagnostic modeling strategies, we show “locked” gene signatures discovered on Training and Test cohorts, that have a mean Area Under the Curve (AUC) of 0.81 on randomised, independent external data cohorts. Lastly, we identified a subset of 10 probesets that provided a diagnostic sensitivity for FM of 95% and a specificity of 96%. We also show that the signatures for FM were very specific to FM rather than common FM comorbidities. Conclusion These findings provide new insights relevant to the pathogenesis of FM, and provide several testable hypotheses that warrant further exploration and also establish the foundation for a first blood-based molecular signature in FM that needs to be validated in larger cohorts of patients. PMID:27157394

Pediatric Amblyopia Risk Investigation Study (PARIS).

PubMed

Savage, Howard I; Lee, Hester H; Zaetta, Deneen; Olszowy, Ronald; Hamburger, Ellie; Weissman, Mark; Frick, Kevin

2005-12-01

To assess the learning curve, testability, and reliability of vision screening modalities administered by pediatric health extenders. Prospective masked clinical trial. Two hundred subjects aged 3 to 6 underwent timed screening for amblyopia by physician extenders, including LEA visual acuity (LEA), stereopsis (RDE), and noncycloplegic autorefraction (NCAR). Patients returned for a comprehensive diagnostic eye examination performed by an ophthalmologist or optometrist. Average screening time was 5.4 +/- 1.6 minutes (LEA), 1.9 +/- 0.9 minutes (RDE), and 1.7 +/- 1.0 minutes (NCAR). Test time for NCAR and RDE fell by 40% during the study period. Overall testability was 92% (LEA), 96% (RDE), and 94% (NCAR). Testability among 3-year-olds was 73% (LEA), 96% (RDE), and 89% (NCAR). Reliability of LEA was moderate (r = .59). Reliability of NCAR was high for astigmatism (Cyl) (r = .89), moderate for spherical equivalent (SE) (r = .66), and low for anisometropia (ANISO) (r = .38). Correlation of cycloplegic autorefraction (CAR) with gold standard cycloplegic retinoscopic refraction (CRR) was very high for SE (.85), CYL (.77), and moderate for ANISO (.48). With NCAR, physician extenders can quickly and reliably detect astigmatism and spherical refractive error in one-third the time it takes to obtain visual acuity. LEA has a lower initial cost, but is time consuming, moderately reliable, and more difficult for 3-year-olds. Shorter examination time and higher reliability may make NCAR a more efficient screening tool for refractive amblyopia in younger children. Future study is needed to determine the sensitivity and specificity of NCAR and other screening methods in detecting amblyopia and amblyopia risk factors.

Generating Testable Questions in the Science Classroom: The BDC Model

ERIC Educational Resources Information Center

Tseng, ChingMei; Chen, Shu-Bi Shu-Bi; Chang, Wen-Hua

2015-01-01

Guiding students to generate testable scientific questions is essential in the inquiry classroom, but it is not easy. The purpose of the BDC ("Big Idea, Divergent Thinking, and Convergent Thinking") instructional model is to to scaffold students' inquiry learning. We illustrate the use of this model with an example lesson, designed…

Easily Testable PLA-Based Finite State Machines

DTIC Science & Technology

1989-03-01

PLATYPUS (20]. Then, justifi- type 1, 4 and 5 can be guaranteed to be testable via cation paths are obtained from the STG using simple logic...next state lines is found, if such a vector par that is gnrt d y the trupt eexists, using PLATYPUS [20]. pair that is generated by the first corrupted

LSI (Large Scale Integrated) Design for Testability. Final Report of Design, Demonstration, and Testability Analysis.

DTIC Science & Technology

1983-11-01

compound operations, with status. (h) Pre-programmed CRC and double-precision multiply/divide algo- rithms. (i) Double length accumulator with full...IH1.25 _ - MICROCOP ’ RESOLUTION TEST CHART NATIONAL BUREAU OF STANDARDS-1963-A .4 ’* • • . - . .. •. . . . . . . . . . . . . . • - -. .• ,. o. . . .- "o

Personality, foraging behavior and specialization: integrating behavioral and food web ecology at the individual level.

PubMed

Toscano, Benjamin J; Gownaris, Natasha J; Heerhartz, Sarah M; Monaco, Cristián J

2016-09-01

Behavioral traits and diet were traditionally thought to be highly plastic within individuals. This view was espoused in the widespread use of optimality models, which broadly predict that individuals can modify behavioral traits and diet across ecological contexts to maximize fitness. Yet, research conducted over the past 15 years supports an alternative view; fundamental behavioral traits (e.g., activity level, exploration, sociability, boldness and aggressiveness) and diet often vary among individuals and this variation persists over time and across contexts. This phenomenon has been termed animal personality with regard to behavioral traits and individual specialization with regard to diet. While these aspects of individual-level phenotypic variation have been thus far studied in isolation, emerging evidence suggests that personality and individual specialization may covary, or even be causally related. Building on this work, we present the overarching hypothesis that animal personality can drive specialization through individual differences in various aspects of consumer foraging behavior. Specifically, we suggest pathways by which consumer personality traits influence foraging activity, risk-dependent foraging, roles in social foraging groups, spatial aspects of foraging and physiological drivers of foraging, which in turn can lead to consistent individual differences in food resource use. These pathways provide a basis for generating testable hypotheses directly linking animal personality to ecological dynamics, a major goal in contemporary behavioral ecology.

Understanding individual resilience in the workplace: the international collaboration of workforce resilience model

PubMed Central

Rees, Clare S.; Breen, Lauren J.; Cusack, Lynette; Hegney, Desley

2015-01-01

When not managed effectively, high levels of workplace stress can lead to several negative personal and performance outcomes. Some professional groups work in highly stressful settings and are therefore particularly at risk of conditions such as anxiety, depression, secondary traumatic stress, and burnout. However, some individuals are less affected by workplace stress and the associated negative outcomes. Such individuals have been described as “resilient.” A number of studies have found relationships between levels of individual resilience and specific negative outcomes such as burnout and compassion fatigue. However, because psychological resilience is a multi-dimensional construct it is necessary to more clearly delineate it from other related and overlapping constructs. The creation of a testable theoretical model of individual workforce resilience, which includes both stable traits (e.g., neuroticism) as well as more malleable intrapersonal factors (e.g., coping style), enables information to be derived that can eventually inform interventions aimed at enhancing individual resilience in the workplace. The purpose of this paper is to introduce a new theoretical model of individual workforce resilience that includes several intrapersonal constructs known to be central in the appraisal of and response to stressors and that also overlap with the construct of psychological resilience. We propose a model in which psychological resilience is hypothesized to mediate the relationship between neuroticism, mindfulness, self-efficacy, coping, and psychological adjustment. PMID:25698999

Evolution of high duty cycle echolocation in bats.

PubMed

Fenton, M Brock; Faure, Paul A; Ratcliffe, John M

2012-09-01

Duty cycle describes the relative 'on time' of a periodic signal. In bats, we argue that high duty cycle (HDC) echolocation was selected for and evolved from low duty cycle (LDC) echolocation because increasing call duty cycle enhanced the ability of echolocating bats to detect, lock onto and track fluttering insects. Most echolocators (most bats and all birds and odontocete cetaceans) use LDC echolocation, separating pulse and echo in time to avoid forward masking. They emit short duration, broadband, downward frequency modulated (FM) signals separated by relatively long periods of silence. In contrast, bats using HDC echolocation emit long duration, narrowband calls dominated by a single constant frequency (CF) separated by relatively short periods of silence. HDC bats separate pulse and echo in frequency by exploiting information contained in Doppler-shifted echoes arising from their movements relative to background objects and their prey. HDC echolocators are particularly sensitive to amplitude and frequency glints generated by the wings of fluttering insects. We hypothesize that narrowband/CF calls produced at high duty cycle, and combined with neurobiological specializations for processing Doppler-shifted echoes, were essential to the evolution of HDC echolocation because they allowed bats to detect, lock onto and track fluttering targets. This advantage was especially important in habitats with dense vegetation that produce overlapping, time-smeared echoes (i.e. background acoustic clutter). We make four specific, testable predictions arising from this hypothesis.

NOXclass: prediction of protein-protein interaction types.

PubMed

Zhu, Hongbo; Domingues, Francisco S; Sommer, Ingolf; Lengauer, Thomas

2006-01-19

Structural models determined by X-ray crystallography play a central role in understanding protein-protein interactions at the molecular level. Interpretation of these models requires the distinction between non-specific crystal packing contacts and biologically relevant interactions. This has been investigated previously and classification approaches have been proposed. However, less attention has been devoted to distinguishing different types of biological interactions. These interactions are classified as obligate and non-obligate according to the effect of the complex formation on the stability of the protomers. So far no automatic classification methods for distinguishing obligate, non-obligate and crystal packing interactions have been made available. Six interface properties have been investigated on a dataset of 243 protein interactions. The six properties have been combined using a support vector machine algorithm, resulting in NOXclass, a classifier for distinguishing obligate, non-obligate and crystal packing interactions. We achieve an accuracy of 91.8% for the classification of these three types of interactions using a leave-one-out cross-validation procedure. NOXclass allows the interpretation and analysis of protein quaternary structures. In particular, it generates testable hypotheses regarding the nature of protein-protein interactions, when experimental results are not available. We expect this server will benefit the users of protein structural models, as well as protein crystallographers and NMR spectroscopists. A web server based on the method and the datasets used in this study are available at http://noxclass.bioinf.mpi-inf.mpg.de/.

Does salt have a permissive role in the induction of puberty?

PubMed

Pitynski, Dori; Flynn, Francis W; Skinner, Donal C

2015-10-01

Puberty is starting earlier than ever before and there are serious physiological and sociological implications as a result of this development. Current research has focused on the potential role of high caloric, and commensurate high adiposity, contributions to early puberty. However, girls with normal BMI also appear to be initiating puberty earlier. Westernized diets, in addition to being high in fat and sugar, are also high in salt. To date, no research has investigated a link between elevated salt and the reproductive axis. We hypothesize that a high salt diet can result in an earlier onset of puberty through three mechanisms that are not mutually exclusive. (1) High salt activates neurokinin B, a hormone that is involved in both the reproductive axis and salt regulation, and this induces kisspeptin release and ultimate activation of the reproductive axis. (2) Vasopressin released in response to high salt acts on vasopressin receptors expressed on kisspeptin neurons in the anteroventral periventricular nucleus, thereby stimulating gonadotropin releasing hormone and subsequently luteinizing hormone secretion. (3) Salt induces metabolic changes that affect the reproductive axis. Specifically, salt acts indirectly to modulate adiposity, ties in with the obesity epidemic, and further compounds the pathologic effects of obesity. Our overall hypothesis offers an additional cause behind the induction of puberty and provides testable postulates to determine the mechanism of potential salt-mediated affects on puberty. Copyright © 2015. Published by Elsevier Ltd.

Does salt have a permissive role in the induction of puberty?

PubMed Central

Pitynski, Dori; Flynn, Francis W.; Skinner, Donal C.

2017-01-01

Puberty is starting earlier than ever before and there are serious physiological and sociological implications as a result of this development. Current research has focused on the potential role of high caloric, and commensurate high adiposity, contributions to early puberty. However, girls with normal BMI also appear to be initiating puberty earlier. Westernized diets, in addition to being high in fat and sugar, are also high in salt. To date, no research has investigated a link between elevated salt and the reproductive axis. We hypothesize that a high salt diet can result in an earlier onset of puberty through three mechanisms that are not mutually exclusive. (1) High salt activates neurokinin B, a hormone that is involved in both the reproductive axis and salt regulation, and this induces kisspeptin release and ultimate activation of the reproductive axis. (2) Vasopressin released in response to high salt acts on vasopressin receptors expressed on kisspeptin neurons in the anteroventral periventricular nucleus, thereby stimulating gonadotropin releasing hormone and subsequently luteinizing hormone secretion. (3) Salt induces metabolic changes that affect the reproductive axis. Specifically, salt acts indirectly to modulate adiposity, ties in with the obesity epidemic, and further compounds the pathologic effects of obesity. Our overall hypothesis offers an additional cause behind the induction of puberty and provides testable postulates to determine the mechanism of potential salt-mediated affects on puberty. PMID:26190310

The interplay between the effectiveness of the grass-endophyte mutualism and the genetic variability of the host plant

PubMed Central

Gundel, Pedro E; Omacini, Marina; Sadras, Victor O; Ghersa, Claudio M

2010-01-01

Neotyphodium endophytic fungi, the asexual state of Epichloë species, protect cool-season grasses against stresses. The outcomes of Neotyphodium-grass symbioses are agronomically relevant as they may affect the productivity of pastures. It has been suggested that the mutualism is characteristic of agronomic grasses and that differential rates of gene flow between both partners’ populations are expected to disrupt the specificity of the association and, thus, the mutualism in wild grasses. We propose that compatibility is necessary but not sufficient to explain the outcomes of Neotyphodium-grass symbiosis, and advance a model that links genetic compatibility, mutualism effectiveness, and endophyte transmission efficiency. For endophytes that reproduce clonally and depend on allogamous hosts for reproduction and dissemination, we propose that this symbiosis works as an integrated entity where gene flow promotes its fitness and evolution. Compatibility between the host plant and the fungal endophyte would be high in genetically close parents; however, mutualism effectiveness and transmission efficiency would be low in fitness depressed host plants. Increasing the genetic distance of mating parents would increase mutualism effectiveness and transmission efficiency. This tendency would be broken when the genetic distance between parents is high (out-breeding depression). Our model allows for testable hypotheses that would contribute to understand the coevolutionary origin and future of the endophyte-grass mutualism. PMID:25567945

The power of projectomes: genetic mosaic labeling in the larval zebrafish brain reveals organizing principles of sensory circuits.

PubMed

Robles, Estuardo

2017-09-01

In no vertebrate species do we possess an accurate, comprehensive tally of neuron types in the brain. This is in no small part due to the vast diversity of neuronal types that comprise complex vertebrate nervous systems. A fundamental goal of neuroscience is to construct comprehensive catalogs of cell types defined by structure, connectivity, and physiological response properties. This type of information will be invaluable for generating models of how assemblies of neurons encode and distribute sensory information and correspondingly alter behavior. This review summarizes recent efforts in the larval zebrafish to construct sensory projectomes, comprehensive analyses of axonal morphologies in sensory axon tracts. Focusing on the olfactory and optic tract, these studies revealed principles of sensory information processing in the olfactory and visual systems that could not have been directly quantified by other methods. In essence, these studies reconstructed the optic and olfactory tract in a virtual manner, providing insights into patterns of neuronal growth that underlie the formation of sensory axon tracts. Quantitative analysis of neuronal diversity revealed organizing principles that determine information flow through sensory systems in the zebrafish that are likely to be conserved across vertebrate species. The generation of comprehensive cell type classifications based on structural, physiological, and molecular features will lead to testable hypotheses on the functional role of individual sensory neuron subtypes in controlling specific sensory-evoked behaviors.

The effective application of a discrete transition model to explore cell-cycle regulation in yeast

PubMed Central

2013-01-01

Background Bench biologists often do not take part in the development of computational models for their systems, and therefore, they frequently employ them as “black-boxes”. Our aim was to construct and test a model that does not depend on the availability of quantitative data, and can be directly used without a need for intensive computational background. Results We present a discrete transition model. We used cell-cycle in budding yeast as a paradigm for a complex network, demonstrating phenomena such as sequential protein expression and activity, and cell-cycle oscillation. The structure of the network was validated by its response to computational perturbations such as mutations, and its response to mating-pheromone or nitrogen depletion. The model has a strong predicative capability, demonstrating how the activity of a specific transcription factor, Hcm1, is regulated, and what determines commitment of cells to enter and complete the cell-cycle. Conclusion The model presented herein is intuitive, yet is expressive enough to elucidate the intrinsic structure and qualitative behavior of large and complex regulatory networks. Moreover our model allowed us to examine multiple hypotheses in a simple and intuitive manner, giving rise to testable predictions. This methodology can be easily integrated as a useful approach for the study of networks, enriching experimental biology with computational insights. PMID:23915717

Understanding individual resilience in the workplace: the international collaboration of workforce resilience model.

PubMed

Rees, Clare S; Breen, Lauren J; Cusack, Lynette; Hegney, Desley

2015-01-01

When not managed effectively, high levels of workplace stress can lead to several negative personal and performance outcomes. Some professional groups work in highly stressful settings and are therefore particularly at risk of conditions such as anxiety, depression, secondary traumatic stress, and burnout. However, some individuals are less affected by workplace stress and the associated negative outcomes. Such individuals have been described as "resilient." A number of studies have found relationships between levels of individual resilience and specific negative outcomes such as burnout and compassion fatigue. However, because psychological resilience is a multi-dimensional construct it is necessary to more clearly delineate it from other related and overlapping constructs. The creation of a testable theoretical model of individual workforce resilience, which includes both stable traits (e.g., neuroticism) as well as more malleable intrapersonal factors (e.g., coping style), enables information to be derived that can eventually inform interventions aimed at enhancing individual resilience in the workplace. The purpose of this paper is to introduce a new theoretical model of individual workforce resilience that includes several intrapersonal constructs known to be central in the appraisal of and response to stressors and that also overlap with the construct of psychological resilience. We propose a model in which psychological resilience is hypothesized to mediate the relationship between neuroticism, mindfulness, self-efficacy, coping, and psychological adjustment.

How Oliceridine (TRV-130) Binds and Stabilizes a μ-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways.

PubMed

Schneider, Sebastian; Provasi, Davide; Filizola, Marta

2016-11-22

Substantial attention has recently been devoted to G protein-biased agonism of the μ-opioid receptor (MOR) as an ideal new mechanism for the design of analgesics devoid of serious side effects. However, designing opioids with appropriate efficacy and bias is challenging because it requires an understanding of the ligand binding process and of the allosteric modulation of the receptor. Here, we investigated these phenomena for TRV-130, a G protein-biased MOR small-molecule agonist that has been shown to exert analgesia with less respiratory depression and constipation than morphine and that is currently being evaluated in human clinical trials for acute pain management. Specifically, we carried out multimicrosecond, all-atom molecular dynamics (MD) simulations of the binding of this ligand to the activated MOR crystal structure. Analysis of >50 μs of these MD simulations provides insights into the energetically preferred binding pathway of TRV-130 and its stable pose at the orthosteric binding site of MOR. Information transfer from the TRV-130 binding pocket to the intracellular region of the receptor was also analyzed, and was compared to a similar analysis carried out on the receptor bound to the classical unbiased agonist morphine. Taken together, these studies lead to a series of testable hypotheses of ligand-receptor interactions that are expected to inform the structure-based design of improved opioid analgesics.

Reviewing molecular adaptations of Lyme borreliosis spirochetes in the context of reproductive fitness in natural transmission cycles.

PubMed

Tsao, Jean I

2009-01-01

Lyme borreliosis (LB) is caused by a group of pathogenic spirochetes - most often Borrelia burgdorferi, B. afzelii, and B. garinii - that are vectored by hard ticks in the Ixodes ricinus-persulcatus complex, which feed on a variety of mammals, birds, and lizards. Although LB is one of the best-studied vector-borne zoonoses, the annual incidence in North America and Europe leads other vector-borne diseases and continues to increase. What factors make the LB system so successful, and how can researchers hope to reduce disease risk - either through vaccinating humans or reducing the risk of contacting infected ticks in nature? Discoveries of molecular interactions involved in the transmission of LB spirochetes have accelerated recently, revealing complex interactions among the spirochete-tick-vertebrate triad. These interactions involve multiple, and often redundant, pathways that reflect the evolution of general and specific mechanisms by which the spirochetes survive and reproduce. Previous reviews have focused on the molecular interactions or population biology of the system. Here molecular interactions among the LB spirochete, its vector, and vertebrate hosts are reviewed in the context of natural maintenance cycles, which represent the ecological and evolutionary contexts that shape these interactions. This holistic system approach may help researchers develop additional testable hypotheses about transmission processes, interpret laboratory results, and guide development of future LB control measures and management.

A dynamic bioenergetic model for coral-Symbiodinium symbioses and coral bleaching as an alternate stable state.

PubMed

Cunning, Ross; Muller, Erik B; Gates, Ruth D; Nisbet, Roger M

2017-10-27

Coral reef ecosystems owe their ecological success - and vulnerability to climate change - to the symbiotic metabolism of corals and Symbiodinium spp. The urgency to understand and predict the stability and breakdown of these symbioses (i.e., coral 'bleaching') demands the development and application of theoretical tools. Here, we develop a dynamic bioenergetic model of coral-Symbiodinium symbioses that demonstrates realistic steady-state patterns in coral growth and symbiont abundance across gradients of light, nutrients, and feeding. Furthermore, by including a mechanistic treatment of photo-oxidative stress, the model displays dynamics of bleaching and recovery that can be explained as transitions between alternate stable states. These dynamics reveal that "healthy" and "bleached" states correspond broadly to nitrogen- and carbon-limitation in the system, with transitions between them occurring as integrated responses to multiple environmental factors. Indeed, a suite of complex emergent behaviors reproduced by the model (e.g., bleaching is exacerbated by nutrients and attenuated by feeding) suggests it captures many important attributes of the system; meanwhile, its modular framework and open source R code are designed to facilitate further problem-specific development. We see significant potential for this modeling framework to generate testable hypotheses and predict integrated, mechanistic responses of corals to environmental change, with important implications for understanding the performance and maintenance of symbiotic systems. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

An Improved, Bias-Reduced Probabilistic Functional Gene Network of Baker's Yeast, Saccharomyces cerevisiae

PubMed Central

Lee, Insuk; Li, Zhihua; Marcotte, Edward M.

2007-01-01

Background Probabilistic functional gene networks are powerful theoretical frameworks for integrating heterogeneous functional genomics and proteomics data into objective models of cellular systems. Such networks provide syntheses of millions of discrete experimental observations, spanning DNA microarray experiments, physical protein interactions, genetic interactions, and comparative genomics; the resulting networks can then be easily applied to generate testable hypotheses regarding specific gene functions and associations. Methodology/Principal Findings We report a significantly improved version (v. 2) of a probabilistic functional gene network [1] of the baker's yeast, Saccharomyces cerevisiae. We describe our optimization methods and illustrate their effects in three major areas: the reduction of functional bias in network training reference sets, the application of a probabilistic model for calculating confidences in pair-wise protein physical or genetic interactions, and the introduction of simple thresholds that eliminate many false positive mRNA co-expression relationships. Using the network, we predict and experimentally verify the function of the yeast RNA binding protein Puf6 in 60S ribosomal subunit biogenesis. Conclusions/Significance YeastNet v. 2, constructed using these optimizations together with additional data, shows significant reduction in bias and improvements in precision and recall, in total covering 102,803 linkages among 5,483 yeast proteins (95% of the validated proteome). YeastNet is available from http://www.yeastnet.org. PMID:17912365

Flexing dual-systems models: How variable cognitive control in children informs our understanding of risk-taking across development.

PubMed

Li, Rosa

2017-10-01

Prevailing models of the development of decision-making propose that peak risk-taking occurs in adolescence due to a neural imbalance between two processes: gradual, linearly developing cognitive control and rapid, non-linearly developing reward-processing. Though many studies have found neural evidence supporting this dual-systems imbalance model, its behavioral predictions have been surprisingly difficult to document. Most laboratory studies have not found adolescents to exhibit greater risk-taking than children, and public health data show everyday risk-taking to peak in late adolescence/early adulthood. Moreover, when adolescents are provided detailed information about decision options and consequences, they evince similar behavior to adults. Such findings point to a critical feature of the development of decision-making that is missed by imbalance models. Specifically, the engagement of cognitive control is context dependent, such that cognitive control and therefore advantageous decision-making increases when available information is high and decreases when available information is low. Furthermore, the context dependence of cognitive control varies across development, such that increased information availability benefits children more than adolescents, who benefit more than adults. This review advances a flexible dual-systems model that is only imbalanced under certain conditions; explains disparities between neural, behavioral, and public health findings; and provides testable hypotheses for future research. Copyright © 2017 The Author. Published by Elsevier Ltd.. All rights reserved.

Optimal group size in a highly social mammal

PubMed Central

Markham, A. Catherine; Gesquiere, Laurence R.; Alberts, Susan C.; Altmann, Jeanne

2015-01-01

Group size is an important trait of social animals, affecting how individuals allocate time and use space, and influencing both an individual’s fitness and the collective, cooperative behaviors of the group as a whole. Here we tested predictions motivated by the ecological constraints model of group size, examining the effects of group size on ranging patterns and adult female glucocorticoid (stress hormone) concentrations in five social groups of wild baboons (Papio cynocephalus) over an 11-y period. Strikingly, we found evidence that intermediate-sized groups have energetically optimal space-use strategies; both large and small groups experience ranging disadvantages, in contrast to the commonly reported positive linear relationship between group size and home range area and daily travel distance, which depict a disadvantage only in large groups. Specifically, we observed a U-shaped relationship between group size and home range area, average daily distance traveled, evenness of space use within the home range, and glucocorticoid concentrations. We propose that a likely explanation for these U-shaped patterns is that large, socially dominant groups are constrained by within-group competition, whereas small, socially subordinate groups are constrained by between-group competition and predation pressures. Overall, our results provide testable hypotheses for evaluating group-size constraints in other group-living species, in which the costs of intra- and intergroup competition vary as a function of group size. PMID:26504236

Insights into Mechanisms of Chronic Neurodegeneration

PubMed Central

Diack, Abigail B.; Alibhai, James D.; Barron, Rona; Bradford, Barry; Piccardo, Pedro; Manson, Jean C.

2016-01-01

Chronic neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and prion diseases are characterised by the accumulation of abnormal conformers of a host encoded protein in the central nervous system. The process leading to neurodegeneration is still poorly defined and thus development of early intervention strategies is challenging. Unique amongst these diseases are Transmissible Spongiform Encephalopathies (TSEs) or prion diseases, which have the ability to transmit between individuals. The infectious nature of these diseases has permitted in vivo and in vitro modelling of the time course of the disease process in a highly reproducible manner, thus early events can be defined. Recent evidence has demonstrated that the cell-to-cell spread of protein aggregates by a “prion-like mechanism” is common among the protein misfolding diseases. Thus, the TSE models may provide insights into disease mechanisms and testable hypotheses for disease intervention, applicable to a number of these chronic neurodegenerative diseases. PMID:26771599

Ethnic Enclaves and the Earnings of Immigrants

PubMed Central

Xie, Yu; Gough, Margaret

2011-01-01

A large literature in sociology concerns the implications of immigrants’ participation in ethnic enclaves for their economic and social well-being. The “enclave thesis” speculates that immigrants benefit from working in ethnic enclaves. Previous research concerning the effects of enclave participation on immigrants’ economic outcomes has come to mixed conclusions as to whether enclave effects are positive or negative. In this article, we seek to extend and improve upon past work by formulating testable hypotheses based on the enclave thesis and testing them with data from the 2003 New Immigrant Survey (NIS), employing both residence-based and workplace-based measures of the ethnic enclave. We compare the economic outcomes of immigrants working in ethnic enclaves with those of immigrants working in the mainstream economy. Our research yields minimal support for the enclave thesis. Our results further indicate that for some immigrant groups, ethnic enclave participation actually has a negative effect on economic outcomes. PMID:21863367

Sea ice microorganisms: environmental constraints and extracellular responses.

PubMed

Ewert, Marcela; Deming, Jody W

2013-03-28

Inherent to sea ice, like other high latitude environments, is the strong seasonality driven by changes in insolation throughout the year. Sea-ice organisms are exposed to shifting, sometimes limiting, conditions of temperature and salinity. An array of adaptations to survive these and other challenges has been acquired by those organisms that inhabit the ice. One key adaptive response is the production of extracellular polymeric substances (EPS), which play multiple roles in the entrapment, retention and survival of microorganisms in sea ice. In this concept paper we consider two main areas of sea-ice microbiology: the physico-chemical properties that define sea ice as a microbial habitat, imparting particular advantages and limits; and extracellular responses elicited in microbial inhabitants as they exploit or survive these conditions. Emphasis is placed on protective strategies used in the face of fluctuating and extreme environmental conditions in sea ice. Gaps in knowledge and testable hypotheses are identified for future research.

Similarities and differences between the Wnt and reelin pathways in the forming brain.

PubMed

Reiner, Orly; Sapir, Tamar

2005-01-01

One of the key features in development is the reutilization of successful signaling pathways. Here, we emphasize the involvement of the Wnt pathway, one of the five kinds of signal transduction pathway predominating early embryonic development of all animals, in regulating the formation of brain structure. We discuss the interrelationships between the Wnt and reelin pathways in the regulation of cortical layering. We summarize data emphasizing key molecules, which, when mutated, result in abnormal brain development. This integrated view, which is based on conservation of pathways, reveals the relative position of participants in the pathway, points to control mechanisms, and allows raising testable working hypotheses. Nevertheless, although signaling pathways are highly conserved from flies to humans, the overall morphology is not. We propose that future studies directed at understanding of diversification will provide fruitful insights on mammalian brain formation.

The Puzzle of Male Chronophilias.

PubMed

Seto, Michael C

2017-01-01

In this article, I return to the idea that pedophilia, a sexual interest in prepubescent children, can be considered a sexual orientation for age, in conjunction with the much more widely acknowledged and discussed sexual orientation for gender. Here, I broaden the scope to consider other chronophilias, referring to paraphilias for age/maturity categories other than young sexually mature adults. The puzzle of chronophilias includes questions about etiology and course, how chronophilias are related to each other, and what they can tell us about how human (male) sexuality is organized. In this article, I briefly review research on nepiophilia (infant/toddlers), pedophilia (prepubescent children), hebephilia (pubescent children), ephebophilia (postpubescent, sexually maturing adolescents), teleiophilia (young sexually mature adults, typically 20s and 30s), mesophilia (middle-aged adults, typically 40s and 50s), and gerontophilia (elderly adults, typically 60s and older) in the context of a multidimensional sexual orientations framework. Relevant research, limitations, and testable hypotheses for future work are identified.

Strength and Vulnerability Integration (SAVI): A Model of Emotional Well-Being Across Adulthood

PubMed Central

Charles, Susan Turk

2010-01-01

The following paper presents the theoretical model of Strength and Vulnerability Integration (SAVI) to explain factors that influence emotion regulation and emotional well-being across adulthood. The model posits that trajectories of adult development are marked by age-related enhancement in the use of strategies that serve to avoid or limit exposure to negative stimuli, but age-related vulnerabilities in situations that elicit high levels of sustained emotional arousal. When older adults avoid or reduce exposure to emotional distress, they often respond better than younger adults; when they experience high levels of sustained emotional arousal, however, age-related advantages in emotional well-being are attenuated, and older adults are hypothesized to have greater difficulties returning to homeostasis. SAVI provides a testable model to understand the literature on emotion and aging and to predict trajectories of emotional experience across the adult life span. PMID:21038939

Strength and vulnerability integration: a model of emotional well-being across adulthood.

PubMed

Charles, Susan Turk

2010-11-01

The following article presents the theoretical model of strength and vulnerability integration (SAVI) to explain factors that influence emotion regulation and emotional well-being across adulthood. The model posits that trajectories of adult development are marked by age-related enhancement in the use of strategies that serve to avoid or limit exposure to negative stimuli but by age-related vulnerabilities in situations that elicit high levels of sustained emotional arousal. When older adults avoid or reduce exposure to emotional distress, they often respond better than younger adults; when they experience high levels of sustained emotional arousal, however, age-related advantages in emotional well-being are attenuated, and older adults are hypothesized to have greater difficulties returning to homeostasis. SAVI provides a testable model to understand the literature on emotion and aging and to predict trajectories of emotional experience across the adult life span.

An application of statistics to comparative metagenomics

PubMed Central

Rodriguez-Brito, Beltran; Rohwer, Forest; Edwards, Robert A

2006-01-01

Background Metagenomics, sequence analyses of genomic DNA isolated directly from the environments, can be used to identify organisms and model community dynamics of a particular ecosystem. Metagenomics also has the potential to identify significantly different metabolic potential in different environments. Results Here we use a statistical method to compare curated subsystems, to predict the physiology, metabolism, and ecology from metagenomes. This approach can be used to identify those subsystems that are significantly different between metagenome sequences. Subsystems that were overrepresented in the Sargasso Sea and Acid Mine Drainage metagenome when compared to non-redundant databases were identified. Conclusion The methodology described herein applies statistics to the comparisons of metabolic potential in metagenomes. This analysis reveals those subsystems that are more, or less, represented in the different environments that are compared. These differences in metabolic potential lead to several testable hypotheses about physiology and metabolism of microbes from these ecosystems. PMID:16549025

An application of statistics to comparative metagenomics.

PubMed

Rodriguez-Brito, Beltran; Rohwer, Forest; Edwards, Robert A

2006-03-20

Metagenomics, sequence analyses of genomic DNA isolated directly from the environments, can be used to identify organisms and model community dynamics of a particular ecosystem. Metagenomics also has the potential to identify significantly different metabolic potential in different environments. Here we use a statistical method to compare curated subsystems, to predict the physiology, metabolism, and ecology from metagenomes. This approach can be used to identify those subsystems that are significantly different between metagenome sequences. Subsystems that were overrepresented in the Sargasso Sea and Acid Mine Drainage metagenome when compared to non-redundant databases were identified. The methodology described herein applies statistics to the comparisons of metabolic potential in metagenomes. This analysis reveals those subsystems that are more, or less, represented in the different environments that are compared. These differences in metabolic potential lead to several testable hypotheses about physiology and metabolism of microbes from these ecosystems.

The biology and polymer physics underlying large-scale chromosome organization.

PubMed

Sazer, Shelley; Schiessel, Helmut

2018-02-01

Chromosome large-scale organization is a beautiful example of the interplay between physics and biology. DNA molecules are polymers and thus belong to the class of molecules for which physicists have developed models and formulated testable hypotheses to understand their arrangement and dynamic properties in solution, based on the principles of polymer physics. Biologists documented and discovered the biochemical basis for the structure, function and dynamic spatial organization of chromosomes in cells. The underlying principles of chromosome organization have recently been revealed in unprecedented detail using high-resolution chromosome capture technology that can simultaneously detect chromosome contact sites throughout the genome. These independent lines of investigation have now converged on a model in which DNA loops, generated by the loop extrusion mechanism, are the basic organizational and functional units of the chromosome. © 2017 The Authors. Traffic published by John Wiley & Sons Ltd.

A Review of Recent Advancement in Integrating Omics Data with Literature Mining towards Biomedical Discoveries

PubMed Central

Raja, Kalpana; Patrick, Matthew; Gao, Yilin; Madu, Desmond; Yang, Yuyang

2017-01-01

In the past decade, the volume of “omics” data generated by the different high-throughput technologies has expanded exponentially. The managing, storing, and analyzing of this big data have been a great challenge for the researchers, especially when moving towards the goal of generating testable data-driven hypotheses, which has been the promise of the high-throughput experimental techniques. Different bioinformatics approaches have been developed to streamline the downstream analyzes by providing independent information to interpret and provide biological inference. Text mining (also known as literature mining) is one of the commonly used approaches for automated generation of biological knowledge from the huge number of published articles. In this review paper, we discuss the recent advancement in approaches that integrate results from omics data and information generated from text mining approaches to uncover novel biomedical information. PMID:28331849

Positive versus negative perfectionism in psychopathology: a comment on Slade and Owens's dual process model.

PubMed

Flett, Gordon L; Hewitt, Paul L

2006-07-01

This article reviews the concepts of positive and negative perfectionism and the dual process model of perfectionism outlined by Slade and Owens (1998). The authors acknowledge that the dual process model represents a conceptual advance in the study of perfectionism and that Slade and Owens should be commended for identifying testable hypotheses and future research directions. However, the authors take issue with the notion that there are two types of perfectionism, with one type of perfectionism representing a "normal" or "healthy" form of perfectionism. They suggest that positive perfectionism is motivated, at least in part, by an avoidance orientation and fear of failure, and recent attempts to define and conceptualize positive perfectionism may have blurred the distinction between perfectionism and conscientiousness. Research findings that question the adaptiveness of positive forms of perfectionism are highlighted, and key issues for future research are identified.

Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action.

PubMed

Canal, Clinton E

2018-03-13

Recent, well-controlled - albeit small-scale - clinical trials show that serotonergic psychedelics, including psilocybin and lysergic acid diethylamide, possess great promise for treating psychiatric disorders, including treatment-resistant depression. Additionally, fresh results from a deluge of clinical neuroimaging studies are unveiling the dynamic effects of serotonergic psychedelics on functional activity within, and connectivity across, discrete neural systems. These observations have led to testable hypotheses regarding neural processing mechanisms that contribute to psychedelic effects and therapeutic benefits. Despite these advances and a plethora of preclinical and clinical observations supporting a central role for brain serotonin 5-HT 2A receptors in producing serotonergic psychedelic effects, lingering and new questions about mechanisms abound. These chiefly pertain to molecular neuropharmacology. This chapter is devoted to illuminating and discussing such questions in the context of preclinical experimental approaches for studying mechanisms of action of serotonergic psychedelics, classic and new.

Insights about Striatal Circuit Function and Schizophrenia from a Mouse Model of D2 Receptor Upregulation

PubMed Central

Simpson, Eleanor H.; Kellendonk, Christoph

2016-01-01

The dopamine hypothesis of schizophrenia is supported by a large number of imaging studies that have identified an increase in dopamine binding at the D2 receptor selectively in the striatum. Here we review a decade of work using a regionally restricted and temporally regulated transgenic mouse model to investigate the behavioral, molecular, electrophysiological, and anatomical consequences of selective D2 receptor upregulation in the striatum. These studies have identified new and potentially important biomarkers at the circuit and molecular level that can now be explored in patients with schizophrenia. They provide an example of how animal models and their detailed level of neurobiological analysis allow a deepening of our understanding of the relationship between neuronal circuit function and symptoms of schizophrenia, and as a consequence generate new hypotheses that are testable in patients. PMID:27720388

Rice-arsenate interactions in hydroponics: a three-gene model for tolerance.

PubMed

Norton, Gareth J; Nigar, Meher; Williams, Paul N; Dasgupta, Tapash; Meharg, Andrew A; Price, Adam H

2008-01-01

In this study, the genetic mapping of the tolerance of root growth to 13.3 muM arsenate [As(V)] using the BalaxAzucena population is improved, and candidate genes for further study are identified. A remarkable three-gene model of tolerance is advanced, which appears to involve epistatic interaction between three major genes, two on chromosome 6 and one on chromosome 10. Any combination of two of these genes inherited from the tolerant parent leads to the plant having tolerance. Lists of potential positional candidate genes are presented. These are then refined using whole genome transcriptomics data and bioinformatics. Physiological evidence is also provided that genes related to phosphate transport are unlikely to be behind the genetic loci conferring tolerance. These results offer testable hypotheses for genes related to As(V) tolerance that might offer strategies for mitigating arsenic (As) accumulation in consumed rice.

Rice–arsenate interactions in hydroponics: a three-gene model for tolerance

PubMed Central

Norton, Gareth J.; Nigar, Meher; Dasgupta, Tapash; Meharg, Andrew A.; Price, Adam H.

2008-01-01

In this study, the genetic mapping of the tolerance of root growth to 13.3 μM arsenate [As(V)] using the Bala×Azucena population is improved, and candidate genes for further study are identified. A remarkable three-gene model of tolerance is advanced, which appears to involve epistatic interaction between three major genes, two on chromosome 6 and one on chromosome 10. Any combination of two of these genes inherited from the tolerant parent leads to the plant having tolerance. Lists of potential positional candidate genes are presented. These are then refined using whole genome transcriptomics data and bioinformatics. Physiological evidence is also provided that genes related to phosphate transport are unlikely to be behind the genetic loci conferring tolerance. These results offer testable hypotheses for genes related to As(V) tolerance that might offer strategies for mitigating arsenic (As) accumulation in consumed rice. PMID:18453529

Leveraging ecological theory to guide natural product discovery.

PubMed

Smanski, Michael J; Schlatter, Daniel C; Kinkel, Linda L

2016-03-01

Technological improvements have accelerated natural product (NP) discovery and engineering to the point that systematic genome mining for new molecules is on the horizon. NP biosynthetic potential is not equally distributed across organisms, environments, or microbial life histories, but instead is enriched in a number of prolific clades. Also, NPs are not equally abundant in nature; some are quite common and others markedly rare. Armed with this knowledge, random 'fishing expeditions' for new NPs are increasingly harder to justify. Understanding the ecological and evolutionary pressures that drive the non-uniform distribution of NP biosynthesis provides a rational framework for the targeted isolation of strains enriched in new NP potential. Additionally, ecological theory leads to testable hypotheses regarding the roles of NPs in shaping ecosystems. Here we review several recent strain prioritization practices and discuss the ecological and evolutionary underpinnings for each. Finally, we offer perspectives on leveraging microbial ecology and evolutionary biology for future NP discovery.

Functional Interdependence Theory: An Evolutionary Account of Social Situations.

PubMed

Balliet, Daniel; Tybur, Joshua M; Van Lange, Paul A M

2017-11-01

Social interactions are characterized by distinct forms of interdependence, each of which has unique effects on how behavior unfolds within the interaction. Despite this, little is known about the psychological mechanisms that allow people to detect and respond to the nature of interdependence in any given interaction. We propose that interdependence theory provides clues regarding the structure of interdependence in the human ancestral past. In turn, evolutionary psychology offers a framework for understanding the types of information processing mechanisms that could have been shaped under these recurring conditions. We synthesize and extend these two perspectives to introduce a new theory: functional interdependence theory (FIT). FIT can generate testable hypotheses about the function and structure of the psychological mechanisms for inferring interdependence. This new perspective offers insight into how people initiate and maintain cooperative relationships, select social partners and allies, and identify opportunities to signal social motives.

The ancestral flower of angiosperms and its early diversification

PubMed Central

Sauquet, Hervé; von Balthazar, Maria; Magallón, Susana; Doyle, James A.; Endress, Peter K.; Bailes, Emily J.; Barroso de Morais, Erica; Bull-Hereñu, Kester; Carrive, Laetitia; Chartier, Marion; Chomicki, Guillaume; Coiro, Mario; Cornette, Raphaël; El Ottra, Juliana H. L.; Epicoco, Cyril; Foster, Charles S. P.; Jabbour, Florian; Haevermans, Agathe; Haevermans, Thomas; Hernández, Rebeca; Little, Stefan A.; Löfstrand, Stefan; Luna, Javier A.; Massoni, Julien; Nadot, Sophie; Pamperl, Susanne; Prieu, Charlotte; Reyes, Elisabeth; dos Santos, Patrícia; Schoonderwoerd, Kristel M.; Sontag, Susanne; Soulebeau, Anaëlle; Staedler, Yannick; Tschan, Georg F.; Wing-Sze Leung, Amy; Schönenberger, Jürg

2017-01-01

Recent advances in molecular phylogenetics and a series of important palaeobotanical discoveries have revolutionized our understanding of angiosperm diversification. Yet, the origin and early evolution of their most characteristic feature, the flower, remains poorly understood. In particular, the structure of the ancestral flower of all living angiosperms is still uncertain. Here we report model-based reconstructions for ancestral flowers at the deepest nodes in the phylogeny of angiosperms, using the largest data set of floral traits ever assembled. We reconstruct the ancestral angiosperm flower as bisexual and radially symmetric, with more than two whorls of three separate perianth organs each (undifferentiated tepals), more than two whorls of three separate stamens each, and more than five spirally arranged separate carpels. Although uncertainty remains for some of the characters, our reconstruction allows us to propose a new plausible scenario for the early diversification of flowers, leading to new testable hypotheses for future research on angiosperms. PMID:28763051

The Fate of the Method of 'Paradigms' in Paleobiology.

PubMed

Rudwick, Martin J S

2017-11-02

An earlier article described the mid-twentieth century origins of the method of "paradigms" in paleobiology, as a way of making testable hypotheses about the functional morphology of extinct organisms. The present article describes the use of "paradigms" through the 1970s and, briefly, to the end of the century. After I had proposed the paradigm method to help interpret the ecological history of brachiopods, my students developed it in relation to that and other invertebrate phyla, notably in Euan Clarkson's analysis of vision in trilobites. David Raup's computer-aided "theoretical morphology" was then combined with my functional or adaptive emphasis, in Adolf Seilacher's tripartite "constructional morphology." Stephen Jay Gould, who had strongly endorsed the method, later switched to criticizing the "adaptationist program" he claimed it embodied. Although the explicit use of paradigms in paleobiology had declined by the end of the century, the method was tacitly subsumed into functional morphology as "biomechanics."

Sea Ice Microorganisms: Environmental Constraints and Extracellular Responses

PubMed Central

Ewert, Marcela; Deming, Jody W.

2013-01-01

Inherent to sea ice, like other high latitude environments, is the strong seasonality driven by changes in insolation throughout the year. Sea-ice organisms are exposed to shifting, sometimes limiting, conditions of temperature and salinity. An array of adaptations to survive these and other challenges has been acquired by those organisms that inhabit the ice. One key adaptive response is the production of extracellular polymeric substances (EPS), which play multiple roles in the entrapment, retention and survival of microorganisms in sea ice. In this concept paper we consider two main areas of sea-ice microbiology: the physico-chemical properties that define sea ice as a microbial habitat, imparting particular advantages and limits; and extracellular responses elicited in microbial inhabitants as they exploit or survive these conditions. Emphasis is placed on protective strategies used in the face of fluctuating and extreme environmental conditions in sea ice. Gaps in knowledge and testable hypotheses are identified for future research. PMID:24832800

Advancing Biological Understanding and Therapeutics Discovery with Small Molecule Probes

PubMed Central

Schreiber, Stuart L.; Kotz, Joanne D.; Li, Min; Aubé, Jeffrey; Austin, Christopher P.; Reed, John C.; Rosen, Hugh; White, E. Lucile; Sklar, Larry A.; Lindsley, Craig W.; Alexander, Benjamin R.; Bittker, Joshua A.; Clemons, Paul A.; de Souza, Andrea; Foley, Michael A.; Palmer, Michelle; Shamji, Alykhan F.; Wawer, Mathias J.; McManus, Owen; Wu, Meng; Zou, Beiyan; Yu, Haibo; Golden, Jennifer E.; Schoenen, Frank J.; Simeonov, Anton; Jadhav, Ajit; Jackson, Michael R.; Pinkerton, Anthony B.; Chung, Thomas D.Y.; Griffin, Patrick R.; Cravatt, Benjamin F.; Hodder, Peter S.; Roush, William R.; Roberts, Edward; Chung, Dong-Hoon; Jonsson, Colleen B.; Noah, James W.; Severson, William E.; Ananthan, Subramaniam; Edwards, Bruce; Oprea, Tudor I.; Conn, P. Jeffrey; Hopkins, Corey R.; Wood, Michael R.; Stauffer, Shaun R.; Emmitte, Kyle A.

2015-01-01

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the U.S. National Institutes of Health launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines, but also highlight the need to innovate the science of therapeutic discovery. PMID:26046436

Ecological Suitability and Spatial Distribution of Five Anopheles Species in Amazonian Brazil

PubMed Central

McKeon, Sascha N.; Schlichting, Carl D.; Povoa, Marinete M.; Conn, Jan E.

2013-01-01

Seventy-six sites characterized in Amazonian Brazil revealed distinct habitat diversification by examining the environmental factors associated with the distribution and abundance of five anopheline species (Diptera: Culicidae) in the subgenus Nyssorhynchus. These included three members of the Albitarsis Complex, Anopheles oryzalimnetes, Anopheles marajoara, Anopheles janconnae; Anopheles triannulatus, and Anopheles goeldii. Anopheles janconnae abundance had a positive correlation to water flow and a negative relationship to sun exposure. Abundance of An. oryzalimentes was associated with water chemistry. Anopheles goeldii larvae were abundant in shaded, more saline waters. Anopheles marajoara and An. triannulatus were negatively associated with available resources, although An. marajoara also showed several local correlations. These analyses suggest An. triannulatus is a habitat generalist, An. oryzalimentes and An. janconnae are specialists, and An. marajoara and An. goeldii could not be easily classified either way. Correlations described herein provide testable hypotheses for future research and identifying habitats for vector control. PMID:23546804

Segmental folding of chromosomes: a basis for structural and regulatory chromosomal neighborhoods?

PubMed

Nora, Elphège P; Dekker, Job; Heard, Edith

2013-09-01

We discuss here a series of testable hypotheses concerning the role of chromosome folding into topologically associating domains (TADs). Several lines of evidence suggest that segmental packaging of chromosomal neighborhoods may underlie features of chromatin that span large domains, such as heterochromatin blocks, association with the nuclear lamina and replication timing. By defining which DNA elements preferentially contact each other, the segmentation of chromosomes into TADs may also underlie many properties of long-range transcriptional regulation. Several observations suggest that TADs can indeed provide a structural basis to regulatory landscapes, by controlling enhancer sharing and allocation. We also discuss how TADs may shape the evolution of chromosomes, by causing maintenance of synteny over large chromosomal segments. Finally we suggest a series of experiments to challenge these ideas and provide concrete examples illustrating how they could be practically applied. © 2013 The Authors. Bioessays published by WILEY Periodicals, Inc.

Segmental folding of chromosomes: A basis for structural and regulatory chromosomal neighborhoods?

PubMed Central

Nora, Elphège P; Dekker, Job; Heard, Edith

2013-01-01

We discuss here a series of testable hypotheses concerning the role of chromosome folding into topologically associating domains (TADs). Several lines of evidence suggest that segmental packaging of chromosomal neighborhoods may underlie features of chromatin that span large domains, such as heterochromatin blocks, association with the nuclear lamina and replication timing. By defining which DNA elements preferentially contact each other, the segmentation of chromosomes into TADs may also underlie many properties of long-range transcriptional regulation. Several observations suggest that TADs can indeed provide a structural basis to regulatory landscapes, by controlling enhancer sharing and allocation. We also discuss how TADs may shape the evolution of chromosomes, by causing maintenance of synteny over large chromosomal segments. Finally we suggest a series of experiments to challenge these ideas and provide concrete examples illustrating how they could be practically applied. PMID:23832846

New streams and springs after the 2014 Mw6.0 South Napa earthquake.

PubMed

Wang, Chi-Yuen; Manga, Michael

2015-07-09

Many streams and springs, which were dry or nearly dry before the 2014 Mw6.0 South Napa earthquake, started to flow after the earthquake. A United States Geological Survey stream gauge also registered a coseismic increase in discharge. Public interest was heightened by a state of extreme drought in California. Since the new flows were not contaminated by pre-existing surface water, their composition allowed unambiguous identification of their origin. Following the earthquake we repeatedly surveyed the new flows, collecting data to test hypotheses about their origin. We show that the new flows originated from groundwater in nearby mountains released by the earthquake. The estimated total amount of new water is ∼ 10(6) m(3), about 1/40 of the annual water use in the Napa-Sonoma area. Our model also makes a testable prediction of a post-seismic decrease of seismic velocity in the shallow crust of the affected region.

Making the Most of Omics for Symbiosis Research

PubMed Central

Chaston, J.; Douglas, A.E.

2012-01-01

Omics, including genomics, proteomics and metabolomics, enable us to explain symbioses in terms of the underlying molecules and their interactions. The central task is to transform molecular catalogs of genes, metabolites etc. into a dynamic understanding of symbiosis function. We review four exemplars of omics studies that achieve this goal, through defined biological questions relating to metabolic integration and regulation of animal-microbial symbioses, the genetic autonomy of bacterial symbionts, and symbiotic protection of animal hosts from pathogens. As omic datasets become increasingly complex, computationally-sophisticated downstream analyses are essential to reveal interactions not evident to visual inspection of the data. We discuss two approaches, phylogenomics and transcriptional clustering, that can divide the primary output of omics studies – long lists of factors – into manageable subsets, and we describe how they have been applied to analyze large datasets and generate testable hypotheses. PMID:22983030

The hazards of hazard identification in environmental epidemiology.

PubMed

Saracci, Rodolfo

2017-08-09

Hazard identification is a major scientific challenge, notably for environmental epidemiology, and is often surrounded, as the recent case of glyphosate shows, by debate arising in the first place by the inherently problematic nature of many components of the identification process. Particularly relevant in this respect are components less amenable to logical or mathematical formalization and essentially dependent on scientists' judgment. Four such potentially hazardous components that are capable of distorting the correct process of hazard identification are reviewed and discussed from an epidemiologist perspective: (1) lexical mix-up of hazard and risk (2) scientific questions as distinct from testable hypotheses, and implications for the hierarchy of strength of evidence obtainable from different types of study designs (3) assumptions in prior beliefs and model choices and (4) conflicts of interest. Four suggestions are put forward to strengthen a process that remains in several aspects judgmental, but not arbitrary, in nature.

Functional neurological symptom disorder (conversion disorder): A role for microglial-based plasticity mechanisms?

PubMed

Stephenson, Chris P; Baguley, Ian J

2018-02-01

Functional Neurological Symptom Disorder (FND) is a relatively common neurological condition, accounting for approximately 3-6% of neurologist referrals. FND is considered a transient disorder of neuronal function, sometimes linked to physical trauma and psychological stress. Despite this, chronic disability is common, for example, around 40% of adults with motor FND have permanent disability. Building on current theoretical models, this paper proposes that microglial dysfunction could perpetuate functional changes within acute motor FND, thus providing a pathophysiological mechanism underlying the chronic stage of the motor FND phenotypes seen clinically. Core to our argument is microglia's dual role in modulating neuroimmunity and their control of synaptic plasticity, which places them at a pathophysiological nexus wherein coincident physical trauma and psychological stress could cause long-term change in neuronal networks without producing macroscopic structural abnormality. This model proposes a range of hypotheses that are testable with current technologies. Copyright © 2017. Published by Elsevier Ltd.

Eye Examination Testability in Children with Autism and in Typical Peers

PubMed Central

Coulter, Rachel Anastasia; Bade, Annette; Tea, Yin; Fecho, Gregory; Amster, Deborah; Jenewein, Erin; Rodena, Jacqueline; Lyons, Kara Kelley; Mitchell, G. Lynn; Quint, Nicole; Dunbar, Sandra; Ricamato, Michele; Trocchio, Jennie; Kabat, Bonnie; Garcia, Chantel; Radik, Irina

2015-01-01

ABSTRACT Purpose To compare testability of vision and eye tests in an examination protocol of 9- to 17-year-old patients with autism spectrum disorder (ASD) to typically developing (TD) peers. Methods In a prospective pilot study, 61 children and adolescents (34 with ASD and 27 who were TD) aged 9 to 17 years completed an eye examination protocol including tests of visual acuity, refraction, convergence (eye teaming), stereoacuity (depth perception), ocular motility, and ocular health. Patients who required new refractive correction were retested after wearing their updated spectacle prescription for 1 month. The specialized protocol incorporated visual, sensory, and communication supports. A psychologist determined group status/eligibility using DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) criteria by review of previous evaluations and parent responses on the Social Communication Questionnaire. Before the examination, parents provided information regarding patients’ sex, race, ethnicity, and, for ASD patients, verbal communication level (nonverbal, uses short words, verbal). Parents indicated whether the patient wore a refractive correction, whether the patient had ever had an eye examination, and the age at the last examination. Chi-square tests compared testability results for TD and ASD groups. Results Typically developing and ASD groups did not differ by age (p = 0.54), sex (p = 0.53), or ethnicity (p = 0.22). Testability was high on most tests (TD, 100%; ASD, 88 to 100%), except for intraocular pressure (IOP), which was reduced for both the ASD (71%) and the TD (89%) patients. Among ASD patients, IOP testability varied greatly with verbal communication level (p < 0.001). Although IOP measurements were completed on all verbal patients, only 37.5% of nonverbal and 44.4% of ASD patients who used short words were successful. Conclusions Patients with ASD can complete most vision and eye tests within an examination protocol. Testability of IOPs is reduced, particularly for nonverbal patients and patients who use short words to communicate. PMID:25415280

Using Dynamic Time Warping and Data Forensics to Examine Tradeoffs among Land-Energy-Water Networks Across the Conterminous United States

NASA Astrophysics Data System (ADS)

McManamay, R.; Allen, M. R.; Piburn, J.; Sanyal, J.; Stewart, R.; Bhaduri, B. L.

2017-12-01

Characterizing interdependencies among land-energy-water sectors, their vulnerabilities, and tipping points, is challenging, especially if all sectors are simultaneously considered. Because such holistic system behavior is uncertain, largely unmodeled, and in need of testable hypotheses of system drivers, these dynamics are conducive to exploratory analytics of spatiotemporal patterns, powered by tools, such as Dynamic Time Warping (DTW). Here, we conduct a retrospective analysis (1950 - 2010) of temporal trends in land use, energy use, and water use within US counties to identify commonalities in resource consumption and adaptation strategies to resource limitations. We combine existing and derived data from statistical downscaling to synthesize a temporally comprehensive land-energy-water dataset at the US county level and apply DTW and subsequent hierarchical clustering to examine similar temporal trends in resource typologies for land, energy, and water sectors. As expected, we observed tradeoffs among water uses (e.g., public supply vs irrigation) and land uses (e.g., urban vs ag). Strong associations between clusters amongst sectors reveal tight system interdependencies, whereas weak associations suggest unique behaviors and potential for human adaptations towards disruptive technologies and less resource-dependent population growth. Our framework is useful for exploring complex human-environmental system dynamics and generating hypotheses to guide subsequent energy-water-nexus research.

Drivers and mechanisms of tree mortality in moist tropical forests.

PubMed

McDowell, Nate; Allen, Craig D; Anderson-Teixeira, Kristina; Brando, Paulo; Brienen, Roel; Chambers, Jeff; Christoffersen, Brad; Davies, Stuart; Doughty, Chris; Duque, Alvaro; Espirito-Santo, Fernando; Fisher, Rosie; Fontes, Clarissa G; Galbraith, David; Goodsman, Devin; Grossiord, Charlotte; Hartmann, Henrik; Holm, Jennifer; Johnson, Daniel J; Kassim, Abd Rahman; Keller, Michael; Koven, Charlie; Kueppers, Lara; Kumagai, Tomo'omi; Malhi, Yadvinder; McMahon, Sean M; Mencuccini, Maurizio; Meir, Patrick; Moorcroft, Paul; Muller-Landau, Helene C; Phillips, Oliver L; Powell, Thomas; Sierra, Carlos A; Sperry, John; Warren, Jeff; Xu, Chonggang; Xu, Xiangtao

2018-02-16

Tree mortality rates appear to be increasing in moist tropical forests (MTFs) with significant carbon cycle consequences. Here, we review the state of knowledge regarding MTF tree mortality, create a conceptual framework with testable hypotheses regarding the drivers, mechanisms and interactions that may underlie increasing MTF mortality rates, and identify the next steps for improved understanding and reduced prediction. Increasing mortality rates are associated with rising temperature and vapor pressure deficit, liana abundance, drought, wind events, fire and, possibly, CO 2 fertilization-induced increases in stand thinning or acceleration of trees reaching larger, more vulnerable heights. The majority of these mortality drivers may kill trees in part through carbon starvation and hydraulic failure. The relative importance of each driver is unknown. High species diversity may buffer MTFs against large-scale mortality events, but recent and expected trends in mortality drivers give reason for concern regarding increasing mortality within MTFs. Models of tropical tree mortality are advancing the representation of hydraulics, carbon and demography, but require more empirical knowledge regarding the most common drivers and their subsequent mechanisms. We outline critical datasets and model developments required to test hypotheses regarding the underlying causes of increasing MTF mortality rates, and improve prediction of future mortality under climate change. No claim to original US government works New Phytologist © 2018 New Phytologist Trust.

Is titin a 'winding filament'? A new twist on muscle contraction.

PubMed

Nishikawa, Kiisa C; Monroy, Jenna A; Uyeno, Theodore E; Yeo, Sang Hoon; Pai, Dinesh K; Lindstedt, Stan L

2012-03-07

Recent studies have demonstrated a role for the elastic protein titin in active muscle, but the mechanisms by which titin plays this role remain to be elucidated. In active muscle, Ca(2+)-binding has been shown to increase titin stiffness, but the observed increase is too small to explain the increased stiffness of parallel elastic elements upon muscle activation. We propose a 'winding filament' mechanism for titin's role in active muscle. First, we hypothesize that Ca(2+)-dependent binding of titin's N2A region to thin filaments increases titin stiffness by preventing low-force straightening of proximal immunoglobulin domains that occurs during passive stretch. This mechanism explains the difference in length dependence of force between skeletal myofibrils and cardiac myocytes. Second, we hypothesize that cross-bridges serve not only as motors that pull thin filaments towards the M-line, but also as rotors that wind titin on the thin filaments, storing elastic potential energy in PEVK during force development and active stretch. Energy stored during force development can be recovered during active shortening. The winding filament hypothesis accounts for force enhancement during stretch and force depression during shortening, and provides testable predictions that will encourage new directions for research on mechanisms of muscle contraction.

Is titin a ‘winding filament’? A new twist on muscle contraction

PubMed Central

Nishikawa, Kiisa C.; Monroy, Jenna A.; Uyeno, Theodore E.; Yeo, Sang Hoon; Pai, Dinesh K.; Lindstedt, Stan L.

2012-01-01

Recent studies have demonstrated a role for the elastic protein titin in active muscle, but the mechanisms by which titin plays this role remain to be elucidated. In active muscle, Ca2+-binding has been shown to increase titin stiffness, but the observed increase is too small to explain the increased stiffness of parallel elastic elements upon muscle activation. We propose a ‘winding filament’ mechanism for titin's role in active muscle. First, we hypothesize that Ca2+-dependent binding of titin's N2A region to thin filaments increases titin stiffness by preventing low-force straightening of proximal immunoglobulin domains that occurs during passive stretch. This mechanism explains the difference in length dependence of force between skeletal myofibrils and cardiac myocytes. Second, we hypothesize that cross-bridges serve not only as motors that pull thin filaments towards the M-line, but also as rotors that wind titin on the thin filaments, storing elastic potential energy in PEVK during force development and active stretch. Energy stored during force development can be recovered during active shortening. The winding filament hypothesis accounts for force enhancement during stretch and force depression during shortening, and provides testable predictions that will encourage new directions for research on mechanisms of muscle contraction. PMID:21900329

Authors’ response: mirror neurons: tests and testability.

PubMed

Catmur, Caroline; Press, Clare; Cook, Richard; Bird, Geoffrey; Heyes, Cecilia

2014-04-01

Commentators have tended to focus on the conceptual framework of our article, the contrast between genetic and associative accounts of mirror neurons, and to challenge it with additional possibilities rather than empirical data. This makes the empirically focused comments especially valuable. The mirror neuron debate is replete with ideas; what it needs now are system-level theories and careful experiments – tests and testability.

Discovery as a process

DOE Office of Scientific and Technical Information (OSTI.GOV)

Loehle, C.

1994-05-01

The three great myths, which form a sort of triumvirate of misunderstanding, are the Eureka! myth, the hypothesis myth, and the measurement myth. These myths are prevalent among scientists as well as among observers of science. The Eureka! myth asserts that discovery occurs as a flash of insight, and as such is not subject to investigation. This leads to the perception that discovery or deriving a hypothesis is a moment or event rather than a process. Events are singular and not subject to description. The hypothesis myth asserts that proper science is motivated by testing hypotheses, and that if somethingmore » is not experimentally testable then it is not scientific. This myth leads to absurd posturing by some workers conducting empirical descriptive studies, who dress up their study with a ``hypothesis`` to obtain funding or get it published. Methods papers are often rejected because they do not address a specific scientific problem. The fact is that many of the great breakthroughs in silence involve methods and not hypotheses or arise from largely descriptive studies. Those captured by this myth also try to block funding for those developing methods. The third myth is the measurement myth, which holds that determining what to measure is straightforward, so one doesn`t need a lot of introspection to do science. As one ecologist put it to me ``Don`t give me any of that philosophy junk, just let me out in the field. I know what to measure.`` These myths lead to difficulties for scientists who must face peer review to obtain funding and to get published. These myths also inhibit the study of science as a process. Finally, these myths inhibit creativity and suppress innovation. In this paper I first explore these myths in more detail and then propose a new model of discovery that opens the supposedly miraculous process of discovery to doser scrutiny.« less

Disentangling mechanisms that mediate the balance between stochastic and deterministic processes in microbial succession.

PubMed

Dini-Andreote, Francisco; Stegen, James C; van Elsas, Jan Dirk; Salles, Joana Falcão

2015-03-17

Ecological succession and the balance between stochastic and deterministic processes are two major themes within microbial ecology, but these conceptual domains have mostly developed independent of each other. Here we provide a framework that integrates shifts in community assembly processes with microbial primary succession to better understand mechanisms governing the stochastic/deterministic balance. Synthesizing previous work, we devised a conceptual model that links ecosystem development to alternative hypotheses related to shifts in ecological assembly processes. Conceptual model hypotheses were tested by coupling spatiotemporal data on soil bacterial communities with environmental conditions in a salt marsh chronosequence spanning 105 years of succession. Analyses within successional stages showed community composition to be initially governed by stochasticity, but as succession proceeded, there was a progressive increase in deterministic selection correlated with increasing sodium concentration. Analyses of community turnover among successional stages--which provide a larger spatiotemporal scale relative to within stage analyses--revealed that changes in the concentration of soil organic matter were the main predictor of the type and relative influence of determinism. Taken together, these results suggest scale-dependency in the mechanisms underlying selection. To better understand mechanisms governing these patterns, we developed an ecological simulation model that revealed how changes in selective environments cause shifts in the stochastic/deterministic balance. Finally, we propose an extended--and experimentally testable--conceptual model integrating ecological assembly processes with primary and secondary succession. This framework provides a priori hypotheses for future experiments, thereby facilitating a systematic approach to understand assembly and succession in microbial communities across ecosystems.

Hypotheses for Near-Surface Exchange of Methane on Mars.

PubMed

Hu, Renyu; Bloom, A Anthony; Gao, Peter; Miller, Charles E; Yung, Yuk L

2016-07-01

The Curiosity rover recently detected a background of 0.7 ppb and spikes of 7 ppb of methane on Mars. This in situ measurement reorients our understanding of the martian environment and its potential for life, as the current theories do not entail any geological source or sink of methane that varies sub-annually. In particular, the 10-fold elevation during the southern winter indicates episodic sources of methane that are yet to be discovered. Here we suggest a near-surface reservoir could explain this variability. Using the temperature and humidity measurements from the rover, we find that perchlorate salts in the regolith deliquesce to form liquid solutions, and deliquescence progresses to deeper subsurface in the season of the methane spikes. We therefore formulate the following three testable hypotheses. The first scenario is that the regolith in Gale Crater adsorbs methane when dry and releases this methane to the atmosphere upon deliquescence. The adsorption energy needs to be 36 kJ mol(-1) to explain the magnitude of the methane spikes, higher than existing laboratory measurements. The second scenario is that microorganisms convert organic matter in the soil to methane when they are in liquid solutions. This scenario does not require regolith adsorption but entails extant life on Mars. The third scenario is that deep subsurface aquifers produce the bursts of methane. Continued in situ measurements of methane and water, as well as laboratory studies of adsorption and deliquescence, will test these hypotheses and inform the existence of the near-surface reservoir and its exchange with the atmosphere. Mars-Methane-Astrobiology-Regolith. Astrobiology 16, 539-550.

Hypotheses for Near-Surface Exchange of Methane on Mars

NASA Astrophysics Data System (ADS)

Hu, Renyu; Bloom, A. Anthony; Gao, Peter; Miller, Charles E.; Yung, Yuk L.

2016-07-01

The Curiosity rover recently detected a background of 0.7 ppb and spikes of 7 ppb of methane on Mars. This in situ measurement reorients our understanding of the martian environment and its potential for life, as the current theories do not entail any geological source or sink of methane that varies sub-annually. In particular, the 10-fold elevation during the southern winter indicates episodic sources of methane that are yet to be discovered. Here we suggest a near-surface reservoir could explain this variability. Using the temperature and humidity measurements from the rover, we find that perchlorate salts in the regolith deliquesce to form liquid solutions, and deliquescence progresses to deeper subsurface in the season of the methane spikes. We therefore formulate the following three testable hypotheses. The first scenario is that the regolith in Gale Crater adsorbs methane when dry and releases this methane to the atmosphere upon deliquescence. The adsorption energy needs to be 36 kJ mol-1 to explain the magnitude of the methane spikes, higher than existing laboratory measurements. The second scenario is that microorganisms convert organic matter in the soil to methane when they are in liquid solutions. This scenario does not require regolith adsorption but entails extant life on Mars. The third scenario is that deep subsurface aquifers produce the bursts of methane. Continued in situ measurements of methane and water, as well as laboratory studies of adsorption and deliquescence, will test these hypotheses and inform the existence of the near-surface reservoir and its exchange with the atmosphere.

Artificial Intelligence Applications to Testability.

DTIC Science & Technology

1984-10-01

general software assistant; examining testability utilization of it should wait a few years until the software assistant is a well defined product ...ago. It provides a single host which satisfies the needs of developers, product developers, and end users . As shown in table 5.10-2, it also provides...follows a trend towards more user -oriented design approaches to interactive computer systems. The implicit goal in this trend is the

Racial disparity in pathophysiologic pathways of preterm birth based on genetic variants

PubMed Central

Menon, Ramkumar; Pearce, Brad; Velez, Digna R; Merialdi, Mario; Williams, Scott M; Fortunato, Stephen J; Thorsen, Poul

2009-01-01

Objective To study pathophysiologic pathways in spontaneous preterm birth and possibly the racial disparity associating with maternal and fetal genetic variations, using bioinformatics tools. Methods A large scale candidate gene association study was performed on 1442 SNPs in 130 genes in a case (preterm birth < 36 weeks) control study (term birth > 37 weeks). Both maternal and fetal DNA from Caucasians (172 cases and 198 controls) and 279 African-Americans (82 cases and 197 controls) were used. A single locus association (genotypic) analysis followed by hierarchical clustering was performed, where clustering was based on p values for significant associations within each race. Using Ingenuity Pathway Analysis (IPA) software, known pathophysiologic pathways in both races were determined. Results From all SNPs entered into the analysis, the IPA mapped genes to specific disease functions. Gene variants in Caucasians were implicated in disease functions shared with other known disorders; specifically, dermatopathy, inflammation, and hematological disorders. This may reflect abnormal cervical ripening and decidual hemorrhage. In African-Americans inflammatory pathways were the most prevalent. In Caucasians, maternal gene variants showed the most prominent role in disease functions, whereas in African Americans it was fetal variants. The IPA software was used to generate molecular interaction maps that differed between races and also between maternal and fetal genetic variants. Conclusion Differences at the genetic level revealed distinct disease functions and operational pathways in African Americans and Caucasians in spontaneous preterm birth. Differences in maternal and fetal contributions in pregnancy outcome are also different between African Americans and Caucasians. These results present a set of explicit testable hypotheses regarding genetic associations with preterm birth in African Americans and Caucasians PMID:19527514

A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4

PubMed Central

Brook, Bindi S.

2017-01-01

The chemokine receptor CCR7 drives leukocyte migration into and within lymph nodes (LNs). It is activated by chemokines CCL19 and CCL21, which are scavenged by the atypical chemokine receptor ACKR4. CCR7-dependent navigation is determined by the distribution of extracellular CCL19 and CCL21, which form concentration gradients at specific microanatomical locations. The mechanisms underpinning the establishment and regulation of these gradients are poorly understood. In this article, we have incorporated multiple biochemical processes describing the CCL19–CCL21–CCR7–ACKR4 network into our model of LN fluid flow to establish a computational model to investigate intranodal chemokine gradients. Importantly, the model recapitulates CCL21 gradients observed experimentally in B cell follicles and interfollicular regions, building confidence in its ability to accurately predict intranodal chemokine distribution. Parameter variation analysis indicates that the directionality of these gradients is robust, but their magnitude is sensitive to these key parameters: chemokine production, diffusivity, matrix binding site availability, and CCR7 abundance. The model indicates that lymph flow shapes intranodal CCL21 gradients, and that CCL19 is functionally important at the boundary between B cell follicles and the T cell area. It also predicts that ACKR4 in LNs prevents CCL19/CCL21 accumulation in efferent lymph, but does not control intranodal gradients. Instead, it attributes the disrupted interfollicular CCL21 gradients observed in Ackr4-deficient LNs to ACKR4 loss upstream. Our novel approach has therefore generated new testable hypotheses and alternative interpretations of experimental data. Moreover, it acts as a framework to investigate gradients at other locations, including those that cannot be visualized experimentally or involve other chemokines. PMID:28807994

Hospital electronic medical record enterprise application strategies: do they matter?

PubMed

Fareed, Naleef; Ozcan, Yasar A; DeShazo, Jonathan P

2012-01-01

Successful implementations and the ability to reap the benefits of electronic medical record (EMR) systems may be correlated with the type of enterprise application strategy that an administrator chooses when acquiring an EMR system. Moreover, identifying the most optimal enterprise application strategy is a task that may have important linkages with hospital performance. This study explored whether hospitals that have adopted differential EMR enterprise application strategies concomitantly differ in their overall efficiency. Specifically, the study examined whether hospitals with a single-vendor strategy had a higher likelihood of being efficient than those with a best-of-breed strategy and whether hospitals with a best-of-suite strategy had a higher probability of being efficient than those with best-of-breed or single-vendor strategies. A conceptual framework was used to formulate testable hypotheses. A retrospective cross-sectional approach using data envelopment analysis was used to obtain efficiency scores of hospitals by EMR enterprise application strategy. A Tobit regression analysis was then used to determine the probability of a hospital being inefficient as related to its EMR enterprise application strategy, while moderating for the hospital's EMR "implementation status" and controlling for hospital and market characteristics. The data envelopment analysis of hospitals suggested that only 32 hospitals were efficient in the study's sample of 2,171 hospitals. The results from the post hoc analysis showed partial support for the hypothesis that hospitals with a best-of-suite strategy were more likely to be efficient than those with a single-vendor strategy. This study underscores the importance of understanding the differences between the three strategies discussed in this article. On the basis of the findings, hospital administrators should consider the efficiency associations that a specific strategy may have compared with another prior to moving toward an enterprise application strategy.

The diffusion of evidence-based decision making among local health department practitioners in the United States.

PubMed

Harris, Jenine K; Erwin, Paul C; Smith, Carson; Brownson, Ross C

2015-01-01

Evidence-based decision making (EBDM) is the process, in local health departments (LHDs) and other settings, of translating the best available scientific evidence into practice. Local health departments are more likely to be successful if they use evidence-based strategies. However, EBDM and use of evidence-based strategies by LHDs are not widespread. Drawing on diffusion of innovations theory, we sought to understand how LHD directors and program managers perceive the relative advantage, compatibility, simplicity, and testability of EBDM. Directors and managers of programs in chronic disease, environmental health, and infectious disease from LHDs nationwide completed a survey including demographic information and questions about diffusion attributes (advantage, compatibility, simplicity, and testability) related to EBDM. Bivariate inferential tests were used to compare responses between directors and managers and to examine associations between participant characteristics and diffusion attributes. Relative advantage and compatibility scores were high for directors and managers, whereas simplicity and testability scores were lower. Although health department directors and managers of programs in chronic disease generally had higher scores than other groups, there were few significant or large differences between directors and managers across the diffusion attributes. Larger jurisdiction population size was associated with higher relative advantage and compatibility scores for both directors and managers. Overall, directors and managers were in strong agreement on the relative advantage of an LHD using EBDM, with directors in stronger agreement than managers. Perceived relative advantage has been demonstrated to be the most important factor in the rate of innovation adoption, suggesting an opportunity for directors to speed EBDM adoption. However, lower average scores across all groups for simplicity and testability may be hindering EBDM adoption. Recommended strategies for increasing perceived EBDM simplicity and testability are provided.

Minimization of extracellular space as a driving force in prokaryote association and the origin of eukaryotes.

PubMed

Hooper, Scott L; Burstein, Helaine J

2014-11-18

Internalization-based hypotheses of eukaryotic origin require close physical association of host and symbiont. Prior hypotheses of how these associations arose include chance, specific metabolic couplings between partners, and prey-predator/parasite interactions. Since these hypotheses were proposed, it has become apparent that mixed-species, close-association assemblages (biofilms) are widespread and predominant components of prokaryotic ecology. Which forces drove prokaryotes to evolve the ability to form these assemblages are uncertain. Bacteria and archaea have also been found to form membrane-lined interconnections (nanotubes) through which proteins and RNA pass. These observations, combined with the structure of the nuclear envelope and an energetic benefit of close association (see below), lead us to propose a novel hypothesis of the driving force underlying prokaryotic close association and the origin of eukaryotes. Respiratory proton transport does not alter external pH when external volume is effectively infinite. Close physical association decreases external volume. For small external volumes, proton transport decreases external pH, resulting in each transported proton increasing proton motor force to a greater extent. We calculate here that in biofilms this effect could substantially decrease how many protons need to be transported to achieve a given proton motor force. Based as it is solely on geometry, this energetic benefit would occur for all prokaryotes using proton-based respiration. This benefit may be a driving force in biofilm formation. Under this hypothesis a very wide range of prokaryotic species combinations could serve as eukaryotic progenitors. We use this observation and the discovery of prokaryotic nanotubes to propose that eukaryotes arose from physically distinct, functionally specialized (energy factory, protein factory, DNA repository/RNA factory), obligatorily symbiotic prokaryotes in which the protein factory and DNA repository/RNA factory cells were coupled by nanotubes and the protein factory ultimately internalized the other two. This hypothesis naturally explains many aspects of eukaryotic physiology, including the nuclear envelope being a folded single membrane repeatedly pierced by membrane-bound tubules (the nuclear pores), suggests that species analogous or homologous to eukaryotic progenitors are likely unculturable as monocultures, and makes a large number of testable predictions. This article was reviewed by Purificación López-García and Toni Gabaldón.

The Art of Grid Fields: Geometry of Neuronal Time

PubMed Central

Shilnikov, Andrey L.; Maurer, Andrew Porter

2016-01-01

The discovery of grid cells in the entorhinal cortex has both elucidated our understanding of spatial representations in the brain, and germinated a large number of theoretical models regarding the mechanisms of these cells’ striking spatial firing characteristics. These models cross multiple neurobiological levels that include intrinsic membrane resonance, dendritic integration, after hyperpolarization characteristics and attractor dynamics. Despite the breadth of the models, to our knowledge, parallels can be drawn between grid fields and other temporal dynamics observed in nature, much of which was described by Art Winfree and colleagues long before the initial description of grid fields. Using theoretical and mathematical investigations of oscillators, in a wide array of mediums far from the neurobiology of grid cells, Art Winfree has provided a substantial amount of research with significant and profound similarities. These theories provide specific inferences into the biological mechanisms and extraordinary resemblances across phenomenon. Therefore, this manuscript provides a novel interpretation on the phenomenon of grid fields, from the perspective of coupled oscillators, postulating that grid fields are the spatial representation of phase resetting curves in the brain. In contrast to prior models of gird cells, the current manuscript provides a sketch by which a small network of neurons, each with oscillatory components can operate to form grid cells, perhaps providing a unique hybrid between the competing attractor neural network and oscillatory interference models. The intention of this new interpretation of the data is to encourage novel testable hypotheses. PMID:27013981

Paleolithic nutrition: twenty-five years later.

PubMed

Konner, Melvin; Eaton, S Boyd

2010-12-01

A quarter century has passed since the first publication of the evolutionary discordance hypothesis, according to which departures from the nutrition and activity patterns of our hunter-gatherer ancestors have contributed greatly and in specifically definable ways to the endemic chronic diseases of modern civilization. Refinements of the model have changed it in some respects, but anthropological evidence continues to indicate that ancestral human diets prevalent during our evolution were characterized by much lower levels of refined carbohydrates and sodium, much higher levels of fiber and protein, and comparable levels of fat (primarily unsaturated fat) and cholesterol. Physical activity levels were also much higher than current levels, resulting in higher energy throughput. We said at the outset that such evidence could only suggest testable hypotheses and that recommendations must ultimately rest on more conventional epidemiological, clinical, and laboratory studies. Such studies have multiplied and have supported many aspects of our model, to the extent that in some respects, official recommendations today have targets closer to those prevalent among hunter-gatherers than did comparable recommendations 25 years ago. Furthermore, doubts have been raised about the necessity for very low levels of protein, fat, and cholesterol intake common in official recommendations. Most impressively, randomized controlled trials have begun to confirm the value of hunter-gatherer diets in some high-risk groups, even as compared with routinely recommended diets. Much more research needs to be done, but the past quarter century has proven the interest and heuristic value, if not yet the ultimate validity, of the model.

Rapid Analysis of Pharmacology for Infectious Diseases

PubMed Central

Hopkins, Andrew L; Bickerton, G. Richard; Carruthers, Ian M; Boyer, Stephen K; Rubin, Harvey; Overington, John P

2011-01-01

Pandemic, epidemic and endemic infectious diseases are united by a common problem: how do we rapidly and cost-effectively identify potential pharmacological interventions to treat infections? Given the large number of emerging and neglected infectious diseases and the fact that they disproportionately afflict the poorest members of the global society, new ways of thinking are required to develop high productivity discovery systems that can be applied to a large number of pathogens. The growing availability of parasite genome data provides the basis for developing methods to prioritize, a priori potential drug targets and analyze the pharmacological landscape of an infectious disease. Thus the overall objective of infectious disease informatics is to enable the rapid generation of plausible, novel medical hypotheses of test-able pharmacological experiments, by uncovering undiscovered relationships in the wealth of biomedical literature and databases that were collected for other purposes. In particular our goal is to identify potential drug targets present in a pathogen genome and prioritize which pharmacological experiments are most likely to discover drug-like lead compounds rapidly against a pathogen (i.e. which specific compounds and drug targets should be screened, in which assays and where they can be sourced). An integral part of the challenge is the development and integration of methods to predict druggability, essentiality, synthetic lethality and polypharmocology in pathogen genomes, while simultaneously integrating the inevitable issues of chemical tractability and the potential for acquired drug resistance from the start. PMID:21401504

Emulating the Visual Receptive Field Properties of MST Neurons with a Template Model of Heading Estimation

NASA Technical Reports Server (NTRS)

Perrone, John A.; Stone, Leland S.

1997-01-01

We have previously proposed a computational neural-network model by which the complex patterns of retinal image motion generated during locomotion (optic flow) can be processed by specialized detectors acting as templates for specific instances of self-motion. The detectors in this template model respond to global optic flow by sampling image motion over a large portion of the visual field through networks of local motion sensors with properties similar to neurons found in the middle temporal (MT) area of primate extrastriate visual cortex. The model detectors were designed to extract self-translation (heading), self-rotation, as well as the scene layout (relative distances) ahead of a moving observer, and are arranged in cortical-like heading maps to perform this function. Heading estimation from optic flow has been postulated by some to be implemented within the medial superior temporal (MST) area. Others have questioned whether MST neurons can fulfill this role because some of their receptive-field properties appear inconsistent with a role in heading estimation. To resolve this issue, we systematically compared MST single-unit responses with the outputs of model detectors under matched stimulus conditions. We found that the basic physiological properties of MST neurons can be explained by the template model. We conclude that MST neurons are well suited to support heading estimation and that the template model provides an explicit set of testable hypotheses which can guide future exploration of MST and adjacent areas within the primate superior temporal sulcus.

Testability Design Rating System: Testability Handbook. Volume 1

DTIC Science & Technology

1992-02-01

4-10 4.7.5 Summary of False BIT Alarms (FBA) ............................. 4-10 4.7.6 Smart BIT Technique...Circuit Board PGA Pin Grid Array PLA Programmable Logic Array PLD Programmable Logic Device PN Pseudo-Random Number PREDICT Probabilistic Estimation of...11 4.7.6 Smart BIT ( reference: RADC-TR-85-198). " Smart " BIT is a term given to BIT circuitry in a system LRU which includes dedicated processor/memory

Smart substrates: Making multi-chip modules smarter

NASA Astrophysics Data System (ADS)

Wunsch, T. F.; Treece, R. K.

1995-05-01

A novel multi-chip module (MCM) design and manufacturing methodology which utilizes active CMOS circuits in what is normally a passive substrate realizes the 'smart substrate' for use in highly testable, high reliability MCMS. The active devices are used to test the bare substrate, diagnose assembly errors or integrated circuit (IC) failures that require rework, and improve the testability of the final MCM assembly. A static random access memory (SRAM) MCM has been designed and fabricated in Sandia Microelectronics Development Laboratory in order to demonstrate the technical feasibility of this concept and to examine design and manufacturing issues which will ultimately determine the economic viability of this approach. The smart substrate memory MCM represents a first in MCM packaging. At the time the first modules were fabricated, no other company or MCM vendor had incorporated active devices in the substrate to improve manufacturability and testability, and thereby improve MCM reliability and reduce cost.

Querying quantitative logic models (Q2LM) to study intracellular signaling networks and cell-cytokine interactions.

PubMed

Morris, Melody K; Shriver, Zachary; Sasisekharan, Ram; Lauffenburger, Douglas A

2012-03-01

Mathematical models have substantially improved our ability to predict the response of a complex biological system to perturbation, but their use is typically limited by difficulties in specifying model topology and parameter values. Additionally, incorporating entities across different biological scales ranging from molecular to organismal in the same model is not trivial. Here, we present a framework called "querying quantitative logic models" (Q2LM) for building and asking questions of constrained fuzzy logic (cFL) models. cFL is a recently developed modeling formalism that uses logic gates to describe influences among entities, with transfer functions to describe quantitative dependencies. Q2LM does not rely on dedicated data to train the parameters of the transfer functions, and it permits straight-forward incorporation of entities at multiple biological scales. The Q2LM framework can be employed to ask questions such as: Which therapeutic perturbations accomplish a designated goal, and under what environmental conditions will these perturbations be effective? We demonstrate the utility of this framework for generating testable hypotheses in two examples: (i) a intracellular signaling network model; and (ii) a model for pharmacokinetics and pharmacodynamics of cell-cytokine interactions; in the latter, we validate hypotheses concerning molecular design of granulocyte colony stimulating factor. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Parvovirus B19 Infection in Children With Arterial Ischemic Stroke.

PubMed

Fullerton, Heather J; Luna, Jorge M; Wintermark, Max; Hills, Nancy K; Tokarz, Rafal; Li, Ying; Glaser, Carol; DeVeber, Gabrielle A; Lipkin, W Ian; Elkind, Mitchell S V

2017-10-01

Case-control studies suggest that acute infection transiently increases the risk of childhood arterial ischemic stroke. We hypothesized that an unbiased pathogen discovery approach utilizing MassTag-polymerase chain reaction would identify pathogens in the blood of childhood arterial ischemic stroke cases. The multicenter international VIPS study (Vascular Effects of Infection in Pediatric Stroke) enrolled arterial ischemic stroke cases, and stroke-free controls, aged 29 days through 18 years. Parental interview included questions on recent infections. In this pilot study, we used MassTag-polymerase chain reaction to test the plasma of the first 161 cases and 34 controls enrolled for a panel of 28 common bacterial and viral pathogens. Pathogen DNA was detected in no controls and 14 cases (8.7%): parvovirus B19 (n=10), herpesvirus 6 (n=2), adenovirus (n=1), and rhinovirus 6C (n=1). Parvovirus B19 infection was confirmed by serologies in all 10; infection was subclinical in 8. Four cases with parvovirus B19 had underlying congenital heart disease, whereas another 5 had a distinct arteriopathy involving a long-segment stenosis of the distal internal carotid and proximal middle cerebral arteries. Using MassTag-polymerase chain reaction, we detected parvovirus B19-a virus known to infect erythrocytes and endothelial cells-in some cases of childhood arterial ischemic stroke. This approach can generate new, testable hypotheses about childhood stroke pathogenesis. © 2017 American Heart Association, Inc.

Cyclin A2 promotes DNA repair in the brain during both development and aging.

PubMed

Gygli, Patrick E; Chang, Joshua C; Gokozan, Hamza N; Catacutan, Fay P; Schmidt, Theresa A; Kaya, Behiye; Goksel, Mustafa; Baig, Faisal S; Chen, Shannon; Griveau, Amelie; Michowski, Wojciech; Wong, Michael; Palanichamy, Kamalakannan; Sicinski, Piotr; Nelson, Randy J; Czeisler, Catherine; Otero, José J

2016-07-01

Various stem cell niches of the brain have differential requirements for Cyclin A2. Cyclin A2 loss results in marked cerebellar dysmorphia, whereas forebrain growth is retarded during early embryonic development yet achieves normal size at birth. To understand the differential requirements of distinct brain regions for Cyclin A2, we utilized neuroanatomical, transgenic mouse, and mathematical modeling techniques to generate testable hypotheses that provide insight into how Cyclin A2 loss results in compensatory forebrain growth during late embryonic development. Using unbiased measurements of the forebrain stem cell niche, we parameterized a mathematical model whereby logistic growth instructs progenitor cells as to the cell-types of their progeny. Our data was consistent with prior findings that progenitors proliferate along an auto-inhibitory growth curve. The growth retardation inCCNA2-null brains corresponded to cell cycle lengthening, imposing a developmental delay. We hypothesized that Cyclin A2 regulates DNA repair and that CCNA2-null progenitors thus experienced lengthened cell cycle. We demonstrate that CCNA2-null progenitors suffer abnormal DNA repair, and implicate Cyclin A2 in double-strand break repair. Cyclin A2's DNA repair functions are conserved among cell lines, neural progenitors, and hippocampal neurons. We further demonstrate that neuronal CCNA2 ablation results in learning and memory deficits in aged mice.

Sexual division of labor: energetic and evolutionary scenarios.

PubMed

Panter-Brick, Catherine

2002-01-01

This article examines comparative energetic data on hunter-gatherers in the context of evolutionary scenarios of the sexual division of labor, with respect to both specific task allocation and overall levels of daily physical activity. The division of labor between men and women, well marked in contemporary foraging societies, was once posited as the "true watershed" for the evolution of the genus Homo. Some research on brain-wiring even links sex differences in cognitive and spatial abilities to sex-specific foraging activities. Most recent evolutionary arguments posit that men focus on hunting and women on gathering activities to realize potentially conflicting mating and parenting goals. A range of cooperative strategies (male/female and female/female) for child provisioning is also under investigation. Attention to energetic and reproductive trade-offs has usefully challenged the proposition that women are excluded from big-game hunting due to constraints of foraging ecology and reproduction. Simplistic assumptions about gender roles are thus increasingly questioned in anthropology, as well as in archaeology. Current models in behavioral ecology explore ways in which foraging practices vary with ecological circumstances, aiming to derive testable hypotheses from fine-grained data on the behavior of contemporary hunter-gatherers. Data on overall physical activity levels (PAL) can also serve to evaluate relative male/female workloads in modern groups, reconstruct hominid energy requirements and activity profiles, and examine changes with subsistence intensification. Male/female PAL ratios show that a task-specific division of labor does not readily extrapolate to 24-hour energy expenditure and that male/female differences in workloads were not necessarily reduced with the transition to agriculture. With respect to gender roles and PAL, a shift away from facile stereotypes of human behavior is evident. The challenge is to incorporate a range of behavioral responses to ecological circumstances in reconstructions of our evolutionary past. Copyright 2002 Wiley-Liss, Inc.

Use of direct gradient analysis to uncover biological hypotheses in 16s survey data and beyond.

PubMed

Erb-Downward, John R; Sadighi Akha, Amir A; Wang, Juan; Shen, Ning; He, Bei; Martinez, Fernando J; Gyetko, Margaret R; Curtis, Jeffrey L; Huffnagle, Gary B

2012-01-01

This study investigated the use of direct gradient analysis of bacterial 16S pyrosequencing surveys to identify relevant bacterial community signals in the midst of a "noisy" background, and to facilitate hypothesis-testing both within and beyond the realm of ecological surveys. The results, utilizing 3 different real world data sets, demonstrate the utility of adding direct gradient analysis to any analysis that draws conclusions from indirect methods such as Principal Component Analysis (PCA) and Principal Coordinates Analysis (PCoA). Direct gradient analysis produces testable models, and can identify significant patterns in the midst of noisy data. Additionally, we demonstrate that direct gradient analysis can be used with other kinds of multivariate data sets, such as flow cytometric data, to identify differentially expressed populations. The results of this study demonstrate the utility of direct gradient analysis in microbial ecology and in other areas of research where large multivariate data sets are involved.

New streams and springs after the 2014 Mw6.0 South Napa earthquake

PubMed Central

Wang, Chi-Yuen; Manga, Michael

2015-01-01

Many streams and springs, which were dry or nearly dry before the 2014 Mw6.0 South Napa earthquake, started to flow after the earthquake. A United States Geological Survey stream gauge also registered a coseismic increase in discharge. Public interest was heightened by a state of extreme drought in California. Since the new flows were not contaminated by pre-existing surface water, their composition allowed unambiguous identification of their origin. Following the earthquake we repeatedly surveyed the new flows, collecting data to test hypotheses about their origin. We show that the new flows originated from groundwater in nearby mountains released by the earthquake. The estimated total amount of new water is ∼106 m3, about 1/40 of the annual water use in the Napa–Sonoma area. Our model also makes a testable prediction of a post-seismic decrease of seismic velocity in the shallow crust of the affected region. PMID:26158898

Deciphering Epithelial–Mesenchymal Transition Regulatory Networks in Cancer through Computational Approaches

PubMed Central

Burger, Gerhard A.; Danen, Erik H. J.; Beltman, Joost B.

2017-01-01

Epithelial–mesenchymal transition (EMT), the process by which epithelial cells can convert into motile mesenchymal cells, plays an important role in development and wound healing but is also involved in cancer progression. It is increasingly recognized that EMT is a dynamic process involving multiple intermediate or “hybrid” phenotypes rather than an “all-or-none” process. However, the role of EMT in various cancer hallmarks, including metastasis, is debated. Given the complexity of EMT regulation, computational modeling has proven to be an invaluable tool for cancer research, i.e., to resolve apparent conflicts in experimental data and to guide experiments by generating testable hypotheses. In this review, we provide an overview of computational modeling efforts that have been applied to regulation of EMT in the context of cancer progression and its associated tumor characteristics. Moreover, we identify possibilities to bridge different modeling approaches and point out outstanding questions in which computational modeling can contribute to advance our understanding of pathological EMT. PMID:28824874

Hypothesis for cognitive effects of transcranial direct current stimulation: Externally- and internally-directed cognition.

PubMed

Greenwood, Pamela M; Blumberg, Eric J; Scheldrup, Melissa R

2018-03-01

A comprehensive explanation is lacking for the broad array of cognitive effects modulated by transcranial direct current stimulation (tDCS). We advanced the testable hypothesis that tDCS to the default mode network (DMN) increases processing of goals and stored information at the expense of external events. We further hypothesized that tDCS to the dorsal attention network (DAN) increases processing of external events at the expense of goals and stored information. A literature search (PsychINFO) identified 42 empirical studies and 3 meta-analyses examining effects of prefrontal and/or parietal tDCS on tasks that selectively required external and/or internal processing. Most, though not all, of the studies that met our search criteria supported our hypothesis. Three meta-analyses supported our hypothesis. The hypothesis we advanced provides a framework for the design and interpretation of results in light of the role of large-scale intrinsic networks that govern attention. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genetics and epigenetics of rheumatoid arthritis

PubMed Central

Viatte, Sebastien; Plant, Darren; Raychaudhuri, Soumya

2013-01-01

Investigators have made key advances in rheumatoid arthritis (RA) genetics in the past 10 years. Although genetic studies have had limited influence on clinical practice and drug discovery, they are currently generating testable hypotheses to explain disease pathogenesis. Firstly, we review here the major advances in identifying RA genetic susceptibility markers both within and outside of the MHC. Understanding how genetic variants translate into pathogenic mechanisms and ultimately into phenotypes remains a mystery for most of the polymorphisms that confer susceptibility to RA, but functional data are emerging. Interplay between environmental and genetic factors is poorly understood and in need of further investigation. Secondly, we review current knowledge of the role of epigenetics in RA susceptibility. Differences in the epigenome could represent one of the ways in which environmental exposures translate into phenotypic outcomes. The best understood epigenetic phenomena include post-translational histone modifications and DNA methylation events, both of which have critical roles in gene regulation. Epigenetic studies in RA represent a new area of research with the potential to answer unsolved questions. PMID:23381558

The juggling paradigm: a novel social neuroscience approach to identify neuropsychophysiological markers of team mental models.

PubMed

Filho, Edson; Bertollo, Maurizio; Robazza, Claudio; Comani, Silvia

2015-01-01

Since the discovery of the mirror neuron system in the 1980s, little, if any, research has been devoted to the study of interactive motor tasks (Goldman, 2012). Scientists interested in the neuropsychophysiological markers of joint motor action have relied on observation paradigms and passive tasks rather than dynamic paradigms and interactive tasks (Konvalinka and Roepstorff, 2012). Within this research scenario, we introduce a novel research paradigm that uses cooperative juggling as a platform to capture peripheral (e.g., skin conductance, breathing and heart rates, electromyographic signals) and central neuropsychophysiological (e.g., functional connectivity within and between brains) markers underlying the notion of team mental models (TMM). We discuss the epistemological and theoretical grounds of a cooperative juggling paradigm, and propose testable hypotheses on neuropsychophysiological markers underlying TMM. Furthermore, we present key methodological concerns that may influence peripheral responses as well as single and hyperbrain network configurations during joint motor action. Preliminary findings of the paradigm are highlighted. We conclude by delineating avenues for future research.

The evolution of speech: a comparative review.

PubMed

Fitch

2000-07-01

The evolution of speech can be studied independently of the evolution of language, with the advantage that most aspects of speech acoustics, physiology and neural control are shared with animals, and thus open to empirical investigation. At least two changes were necessary prerequisites for modern human speech abilities: (1) modification of vocal tract morphology, and (2) development of vocal imitative ability. Despite an extensive literature, attempts to pinpoint the timing of these changes using fossil data have proven inconclusive. However, recent comparative data from nonhuman primates have shed light on the ancestral use of formants (a crucial cue in human speech) to identify individuals and gauge body size. Second, comparative analysis of the diverse vertebrates that have evolved vocal imitation (humans, cetaceans, seals and birds) provides several distinct, testable hypotheses about the adaptive function of vocal mimicry. These developments suggest that, for understanding the evolution of speech, comparative analysis of living species provides a viable alternative to fossil data. However, the neural basis for vocal mimicry and for mimesis in general remains unknown.

Fast gene ontology based clustering for microarray experiments.

PubMed

Ovaska, Kristian; Laakso, Marko; Hautaniemi, Sampsa

2008-11-21

Analysis of a microarray experiment often results in a list of hundreds of disease-associated genes. In order to suggest common biological processes and functions for these genes, Gene Ontology annotations with statistical testing are widely used. However, these analyses can produce a very large number of significantly altered biological processes. Thus, it is often challenging to interpret GO results and identify novel testable biological hypotheses. We present fast software for advanced gene annotation using semantic similarity for Gene Ontology terms combined with clustering and heat map visualisation. The methodology allows rapid identification of genes sharing the same Gene Ontology cluster. Our R based semantic similarity open-source package has a speed advantage of over 2000-fold compared to existing implementations. From the resulting hierarchical clustering dendrogram genes sharing a GO term can be identified, and their differences in the gene expression patterns can be seen from the heat map. These methods facilitate advanced annotation of genes resulting from data analysis.

Modeling T-cell activation using gene expression profiling and state-space models.

PubMed

Rangel, Claudia; Angus, John; Ghahramani, Zoubin; Lioumi, Maria; Sotheran, Elizabeth; Gaiba, Alessia; Wild, David L; Falciani, Francesco

2004-06-12

We have used state-space models to reverse engineer transcriptional networks from highly replicated gene expression profiling time series data obtained from a well-established model of T-cell activation. State space models are a class of dynamic Bayesian networks that assume that the observed measurements depend on some hidden state variables that evolve according to Markovian dynamics. These hidden variables can capture effects that cannot be measured in a gene expression profiling experiment, e.g. genes that have not been included in the microarray, levels of regulatory proteins, the effects of messenger RNA and protein degradation, etc. Bootstrap confidence intervals are developed for parameters representing 'gene-gene' interactions over time. Our models represent the dynamics of T-cell activation and provide a methodology for the development of rational and experimentally testable hypotheses. Supplementary data and Matlab computer source code will be made available on the web at the URL given below. http://public.kgi.edu/~wild/LDS/index.htm

[Mechanisms of action of voltage-gated sodium channel ligands].

PubMed

Tikhonov, D B

2007-05-01

The voltage-gated sodium channels play a key role in the generation of action potential in excitable cells. Sodium channels are targeted by a number of modulating ligands. Despite numerous studies, the mechanisms of action of many ligands are still unknown. The main cause of the problem is the absence of the channel structure. Sodium channels belong to the superfamily of P-loop channels that also the data abowt includes potassium and calcium channels and the channels of ionotropic glutamate receptors. Crystallization of several potassium channels has opened a possibility to analyze the structure of other members of the superfamily using the homology modeling approach. The present study summarizes the results of several recent modelling studies of such sodium channel ligands as tetrodotoxin, batrachotoxin and local anesthetics. Comparison of available experimental data with X-ray structures of potassium channels has provided a new level of understanding of the mechanisms of action of sodium channel ligands and has allowed proposing several testable hypotheses.

The ORF1 Protein Encoded by LINE-1: Structure and Function During L1 Retrotransposition

PubMed Central

Martin, Sandra L.

2006-01-01

LINE-1, or L1 is an autonomous non-LTR retrotransposon in mammals. Retrotransposition requires the function of the two, L1-encoded polypeptides, ORF1p and ORF2p. Early recognition of regions of homology between the predicted amino acid sequence of ORF2 and known endonuclease and reverse transcriptase enzymes led to testable hypotheses regarding the function of ORF2p in retrotransposition. As predicted, ORF2p has been demonstrated to have both endonuclease and reverse transcriptase activities. In contrast, no homologs of known function have contributed to our understanding of the function of ORF1p during retrotransposition. Nevertheless, significant advances have been made such that we now know that ORF1p is a high affinity RNA binding protein that forms a ribonucleoprotein particle together with L1 RNA. Furthermore, ORF1p is a nucleic acid chaperone and this nucleic acid chaperone activity is required for L1 retrotransposition. PMID:16877816

Gender and Physics: a Theoretical Analysis

NASA Astrophysics Data System (ADS)

Rolin, Kristina

This article argues that the objections raised by Koertge (1998), Gross and Levitt (1994), and Weinberg (1996) against feminist scholarship on gender and physics are unwarranted. The objections are that feminist science studies perpetuate gender stereotypes, are irrelevant to the content of physics, or promote epistemic relativism. In the first part of this article I argue that the concept of gender, as it has been developed in feminist theory, is a key to understanding why the first objection is misguided. Instead of reinforcing gender stereotypes, feminist science studies scholars can formulate empirically testable hypotheses regarding local and contested beliefs about gender. In the second part of this article I argue that a social analysis of scientific knowledge is a key to understanding why the second and the third objections are misguided. The concept of gender is relevant for understanding the social practice of physics, and the social practice of physics can be of epistemic importance. Instead of advancing epistemic relativism, feminist science studies scholars can make important contributions to a subfield of philosophy called social epistemology.

Five potential consequences of climate change for invasive species.

PubMed

Hellmann, Jessica J; Byers, James E; Bierwagen, Britta G; Dukes, Jeffrey S

2008-06-01

Scientific and societal unknowns make it difficult to predict how global environmental changes such as climate change and biological invasions will affect ecological systems. In the long term, these changes may have interacting effects and compound the uncertainty associated with each individual driver. Nonetheless, invasive species are likely to respond in ways that should be qualitatively predictable, and some of these responses will be distinct from those of native counterparts. We used the stages of invasion known as the "invasion pathway" to identify 5 nonexclusive consequences of climate change for invasive species: (1) altered transport and introduction mechanisms, (2) establishment of new invasive species, (3) altered impact of existing invasive species, (4) altered distribution of existing invasive species, and (5) altered effectiveness of control strategies. We then used these consequences to identify testable hypotheses about the responses of invasive species to climate change and provide suggestions for invasive-species management plans. The 5 consequences also emphasize the need for enhanced environmental monitoring and expanded coordination among entities involved in invasive-species management.

Color Vision Deficiency in Preschool Children

PubMed Central

Xie, John Z.; Tarczy-Hornoch, Kristina; Lin, Jesse; Cotter, Susan A.; Torres, Mina; Varma, Rohit

2016-01-01

Purpose To determine the sex- and ethnicity-specific prevalence of color vision deficiency (CVD) in black, Asian, Hispanic, and non-Hispanic white preschool children. Design Population-based, cross-sectional study. Participants The Multi-Ethnic Pediatric Eye Disease Study is a population-based evaluation of the prevalence of vision disorders in children in Southern California. A total of 5960 subjects 30 to 72 months of age were recruited for the study, of whom 4177 were able to complete color vision testing (1265 black, 812 Asian, 1280 Hispanic, and 820 non-Hispanic white). Methods Color vision testing was performed using Color Vision Testing Made Easy color plates (Home Vision Care, Gulf Breeze, FL), and diagnostic confirmatory testing was performed using the Waggoner HRR Diagnostic Test color plates (Home Vision Care). Main Outcome Measures Testability of color vision in preschool children between 30 and 72 months of age and prevalence of CVD stratified by age, sex, and ethnicity. Results Testability was 17% in children younger than 37 months of age, increasing to 57% in children 37 to 48 months of age, 89% in children 49 to 60 months of age, and 98% in children 61 to 72 months of age. The prevalence of CVD among boys was 1.4% for black, 3.1% for Asian, 2.6% for Hispanic, and 5.6% for non-Hispanic white children; the prevalence in girls was 0.0% to 0.5% for all ethnicities. The ethnic difference in CVD was statistically significant between black and non-Hispanic white children (P = 0.0003) and between Hispanic and non-Hispanic white children (P = 0.02). In boys, most CVD cases were either deutan (51%) or protan (34%); 32% were classified as mild, 15% as moderate, and 41% as severe. Conclusions Testability for CVD in preschool children is high by 4 years of age. The prevalence of CVD in preschool boys varies by ethnicity, with the highest prevalence in non-Hispanic white and lowest in black children. PMID:24702753

Flight control system design factors for applying automated testing techniques

NASA Technical Reports Server (NTRS)

Sitz, Joel R.; Vernon, Todd H.

1990-01-01

The principal design features and operational experiences of the X-29 forward-swept-wing aircraft and F-18 high alpha research vehicle (HARV) automated test systems are discussed. It is noted that operational experiences in developing and using these automated testing techniques have highlighted the need for incorporating target system features to improve testability. Improved target system testability can be accomplished with the addition of nonreal-time and real-time features. Online access to target system implementation details, unobtrusive real-time access to internal user-selectable variables, and proper software instrumentation are all desirable features of the target system. Also, test system and target system design issues must be addressed during the early stages of the target system development. Processing speeds of up to 20 million instructions/s and the development of high-bandwidth reflective memory systems have improved the ability to integrate the target system and test system for the application of automated testing techniques. It is concluded that new methods of designing testability into the target systems are required.

Comparison on testability of visual acuity, stereo acuity and colour vision tests between children with learning disabilities and children without learning disabilities in government primary schools.

PubMed

Abu Bakar, Nurul Farhana; Chen, Ai-Hong

2014-02-01

Children with learning disabilities might have difficulties to communicate effectively and give reliable responses as required in various visual function testing procedures. The purpose of this study was to compare the testability of visual acuity using the modified Early Treatment Diabetic Retinopathy Study (ETDRS) and Cambridge Crowding Cards, stereo acuity using Lang Stereo test II and Butterfly stereo tests and colour perception using Colour Vision Test Made Easy (CVTME) and Ishihara's Test for Colour Deficiency (Ishihara Test) between children in mainstream classes and children with learning disabilities in special education classes in government primary schools. A total of 100 primary school children (50 children from mainstream classes and 50 children from special education classes) matched in age were recruited in this cross-sectional comparative study. The testability was determined by the percentage of children who were able to give reliable respond as required by the respective tests. 'Unable to test' was defined as inappropriate response or uncooperative despite best efforts of the screener. The testability of the modified ETDRS, Butterfly stereo test and Ishihara test for respective visual function tests were found lower among children in special education classes ( P < 0.001) but not in Cambridge Crowding Cards, Lang Stereo test II and CVTME. Non verbal or "matching" approaches were found to be more superior in testing visual functions in children with learning disabilities. Modifications of vision testing procedures are essential for children with learning disabilities.

Opportunities and obstacles for deep learning in biology and medicine.

PubMed

Ching, Travers; Himmelstein, Daniel S; Beaulieu-Jones, Brett K; Kalinin, Alexandr A; Do, Brian T; Way, Gregory P; Ferrero, Enrico; Agapow, Paul-Michael; Zietz, Michael; Hoffman, Michael M; Xie, Wei; Rosen, Gail L; Lengerich, Benjamin J; Israeli, Johnny; Lanchantin, Jack; Woloszynek, Stephen; Carpenter, Anne E; Shrikumar, Avanti; Xu, Jinbo; Cofer, Evan M; Lavender, Christopher A; Turaga, Srinivas C; Alexandari, Amr M; Lu, Zhiyong; Harris, David J; DeCaprio, Dave; Qi, Yanjun; Kundaje, Anshul; Peng, Yifan; Wiley, Laura K; Segler, Marwin H S; Boca, Simina M; Swamidass, S Joshua; Huang, Austin; Gitter, Anthony; Greene, Casey S

2018-04-01

Deep learning describes a class of machine learning algorithms that are capable of combining raw inputs into layers of intermediate features. These algorithms have recently shown impressive results across a variety of domains. Biology and medicine are data-rich disciplines, but the data are complex and often ill-understood. Hence, deep learning techniques may be particularly well suited to solve problems of these fields. We examine applications of deep learning to a variety of biomedical problems-patient classification, fundamental biological processes and treatment of patients-and discuss whether deep learning will be able to transform these tasks or if the biomedical sphere poses unique challenges. Following from an extensive literature review, we find that deep learning has yet to revolutionize biomedicine or definitively resolve any of the most pressing challenges in the field, but promising advances have been made on the prior state of the art. Even though improvements over previous baselines have been modest in general, the recent progress indicates that deep learning methods will provide valuable means for speeding up or aiding human investigation. Though progress has been made linking a specific neural network's prediction to input features, understanding how users should interpret these models to make testable hypotheses about the system under study remains an open challenge. Furthermore, the limited amount of labelled data for training presents problems in some domains, as do legal and privacy constraints on work with sensitive health records. Nonetheless, we foresee deep learning enabling changes at both bench and bedside with the potential to transform several areas of biology and medicine. © 2018 The Authors.

Speaking the right language: the scientific method as a framework for a continuous quality improvement program within academic medical research compliance units.

PubMed

Nolte, Kurt B; Stewart, Douglas M; O'Hair, Kevin C; Gannon, William L; Briggs, Michael S; Barron, A Marie; Pointer, Judy; Larson, Richard S

2008-10-01

The authors developed a novel continuous quality improvement (CQI) process for academic biomedical research compliance administration. A challenge in developing a quality improvement program in a nonbusiness environment is that the terminology and processes are often foreign. Rather than training staff in an existing quality improvement process, the authors opted to develop a novel process based on the scientific method--a paradigm familiar to all team members. The CQI process included our research compliance units. Unit leaders identified problems in compliance administration where a resolution would have a positive impact and which could be resolved or improved with current resources. They then generated testable hypotheses about a change to standard practice expected to improve the problem, and they developed methods and metrics to assess the impact of the change. The CQI process was managed in a "peer review" environment. The program included processes to reduce the incidence of infections in animal colonies, decrease research protocol-approval times, improve compliance and protection of animal and human research subjects, and improve research protocol quality. This novel CQI approach is well suited to the needs and the unique processes of research compliance administration. Using the scientific method as the improvement paradigm fostered acceptance of the project by unit leaders and facilitated the development of specific improvement projects. These quality initiatives will allow us to improve support for investigators while ensuring that compliance standards continue to be met. We believe that our CQI process can readily be used in other academically based offices of research.

Bioinformatics Knowledge Map for Analysis of Beta-Catenin Function in Cancer

PubMed Central

Arighi, Cecilia N.; Wu, Cathy H.

2015-01-01

Given the wealth of bioinformatics resources and the growing complexity of biological information, it is valuable to integrate data from disparate sources to gain insight into the role of genes/proteins in health and disease. We have developed a bioinformatics framework that combines literature mining with information from biomedical ontologies and curated databases to create knowledge “maps” of genes/proteins of interest. We applied this approach to the study of beta-catenin, a cell adhesion molecule and transcriptional regulator implicated in cancer. The knowledge map includes post-translational modifications (PTMs), protein-protein interactions, disease-associated mutations, and transcription factors co-activated by beta-catenin and their targets and captures the major processes in which beta-catenin is known to participate. Using the map, we generated testable hypotheses about beta-catenin biology in normal and cancer cells. By focusing on proteins participating in multiple relation types, we identified proteins that may participate in feedback loops regulating beta-catenin transcriptional activity. By combining multiple network relations with PTM proteoform-specific functional information, we proposed a mechanism to explain the observation that the cyclin dependent kinase CDK5 positively regulates beta-catenin co-activator activity. Finally, by overlaying cancer-associated mutation data with sequence features, we observed mutation patterns in several beta-catenin PTM sites and PTM enzyme binding sites that varied by tissue type, suggesting multiple mechanisms by which beta-catenin mutations can contribute to cancer. The approach described, which captures rich information for molecular species from genes and proteins to PTM proteoforms, is extensible to other proteins and their involvement in disease. PMID:26509276

Opportunities and obstacles for deep learning in biology and medicine

PubMed Central

2018-01-01

Deep learning describes a class of machine learning algorithms that are capable of combining raw inputs into layers of intermediate features. These algorithms have recently shown impressive results across a variety of domains. Biology and medicine are data-rich disciplines, but the data are complex and often ill-understood. Hence, deep learning techniques may be particularly well suited to solve problems of these fields. We examine applications of deep learning to a variety of biomedical problems—patient classification, fundamental biological processes and treatment of patients—and discuss whether deep learning will be able to transform these tasks or if the biomedical sphere poses unique challenges. Following from an extensive literature review, we find that deep learning has yet to revolutionize biomedicine or definitively resolve any of the most pressing challenges in the field, but promising advances have been made on the prior state of the art. Even though improvements over previous baselines have been modest in general, the recent progress indicates that deep learning methods will provide valuable means for speeding up or aiding human investigation. Though progress has been made linking a specific neural network's prediction to input features, understanding how users should interpret these models to make testable hypotheses about the system under study remains an open challenge. Furthermore, the limited amount of labelled data for training presents problems in some domains, as do legal and privacy constraints on work with sensitive health records. Nonetheless, we foresee deep learning enabling changes at both bench and bedside with the potential to transform several areas of biology and medicine. PMID:29618526

An evolutionary approach to major histocompatibility diversity based on allele supertypes.

PubMed

Naugler, Christopher; Liwski, Robert

2008-01-01

Human leukocyte antigens are traditionally classified by serologic or molecular techniques into a bewildering variety of alleles. It is generally believed that this allelic diversity is maintained by selection pressures for inbreeding avoidance and/or maximal immune system diversity. While the usual antigen-based classification of individual alleles may be most appropriate in the artificial situation of tissue transplantation, we hypothesize that a functional classification based on allele supertypes may represent a more biologically relevant way to view MHC diversity in the contexts of mate choice and disease pathogenesis. Furthermore, immune system diversity could be quantitatively estimated by calculating a Supertype Diversity Index (SDI) which is the number of different MHC supertypes possessed by an individual. This hypothesis generates a number of testable predictions. First, it predicts that a reduced inherited diversity of MHC allele supertypes may predispose to the development of malignancies because of a decreased native ability to present different tumor-associated antigens. Furthermore, specific autoimmune diseases may be associated with the presence or absence of a particular MHC supertype rather than a particular MHC haplotype. In transplant medicine, it is possible that unmatched alleles may trigger a weaker foreign antigen response if they are matched by allele supertype. Finally, there have been several studies documenting dissortative mating in humans for dissimilar MHC alleles. We predict that natural selection should favor maximization of the heterozygosity of allele supertypes instead of the heterozygosity of individual alleles and that the previously observed dissortative mating may actually be an adaptive strategy to maximize allele supertype diversity.

General and specialized brain correlates for analogical reasoning: A meta-analysis of functional imaging studies.

PubMed

Hobeika, Lucie; Diard-Detoeuf, Capucine; Garcin, Béatrice; Levy, Richard; Volle, Emmanuelle

2016-05-01

Reasoning by analogy allows us to link distinct domains of knowledge and to transfer solutions from one domain to another. Analogical reasoning has been studied using various tasks that have generally required the consideration of the relationships between objects and their integration to infer an analogy schema. However, these tasks varied in terms of the level and the nature of the relationships to consider (e.g., semantic, visuospatial). The aim of this study was to identify the cerebral network involved in analogical reasoning and its specialization based on the domains of information and task specificity. We conducted a coordinate-based meta-analysis of 27 experiments that used analogical reasoning tasks. The left rostrolateral prefrontal cortex was one of the regions most consistently activated across the studies. A comparison between semantic and visuospatial analogy tasks showed both domain-oriented regions in the inferior and middle frontal gyri and a domain-general region, the left rostrolateral prefrontal cortex, which was specialized for analogy tasks. A comparison of visuospatial analogy to matrix problem tasks revealed that these two relational reasoning tasks engage, at least in part, distinct right and left cerebral networks, particularly separate areas within the left rostrolateral prefrontal cortex. These findings highlight several cognitive and cerebral differences between relational reasoning tasks that can allow us to make predictions about the respective roles of distinct brain regions or networks. These results also provide new, testable anatomical hypotheses about reasoning disorders that are induced by brain damage. Hum Brain Mapp 37:1953-1969, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Extensive Differences in Gene Expression Between Symbiotic and Aposymbiotic Cnidarians

PubMed Central

Lehnert, Erik M.; Mouchka, Morgan E.; Burriesci, Matthew S.; Gallo, Natalya D.; Schwarz, Jodi A.; Pringle, John R.

2013-01-01

Coral reefs provide habitats for a disproportionate number of marine species relative to the small area of the oceans that they occupy. The mutualism between the cnidarian animal hosts and their intracellular dinoflagellate symbionts provides the nutritional foundation for coral growth and formation of reef structures, because algal photosynthesis can provide >90% of the total energy of the host. Disruption of this symbiosis (“coral bleaching”) is occurring on a large scale due primarily to anthropogenic factors and poses a major threat to the future of coral reefs. Despite the importance of this symbiosis, the cellular mechanisms involved in its establishment, maintenance, and breakdown remain largely unknown. We report our continued development of genomic tools to study these mechanisms in Aiptasia, a small sea anemone with great promise as a model system for studies of cnidarian–dinoflagellate symbiosis. Specifically, we have generated de novo assemblies of the transcriptomes of both a clonal line of symbiotic anemones and their endogenous dinoflagellate symbionts. We then compared transcript abundances in animals with and without dinoflagellates. This analysis identified >900 differentially expressed genes and allowed us to generate testable hypotheses about the cellular functions affected by symbiosis establishment. The differentially regulated transcripts include >60 encoding proteins that may play roles in transporting various nutrients between the symbiotic partners; many more encoding proteins functioning in several metabolic pathways, providing clues regarding how the transported nutrients may be used by the partners; and several encoding proteins that may be involved in host recognition and tolerance of the dinoflagellate. PMID:24368779

Emulating the visual receptive-field properties of MST neurons with a template model of heading estimation

NASA Technical Reports Server (NTRS)

Perrone, J. A.; Stone, L. S.

1998-01-01

We have proposed previously a computational neural-network model by which the complex patterns of retinal image motion generated during locomotion (optic flow) can be processed by specialized detectors acting as templates for specific instances of self-motion. The detectors in this template model respond to global optic flow by sampling image motion over a large portion of the visual field through networks of local motion sensors with properties similar to those of neurons found in the middle temporal (MT) area of primate extrastriate visual cortex. These detectors, arranged within cortical-like maps, were designed to extract self-translation (heading) and self-rotation, as well as the scene layout (relative distances) ahead of a moving observer. We then postulated that heading from optic flow is directly encoded by individual neurons acting as heading detectors within the medial superior temporal (MST) area. Others have questioned whether individual MST neurons can perform this function because some of their receptive-field properties seem inconsistent with this role. To resolve this issue, we systematically compared MST responses with those of detectors from two different configurations of the model under matched stimulus conditions. We found that the characteristic physiological properties of MST neurons can be explained by the template model. We conclude that MST neurons are well suited to support self-motion estimation via a direct encoding of heading and that the template model provides an explicit set of testable hypotheses that can guide future exploration of MST and adjacent areas within the superior temporal sulcus.

Romantic love modulates women's identification of men's body odors.

PubMed

Lundström, Johan N; Jones-Gotman, Marilyn

2009-02-01

Romantic love is one of our most potent and powerful emotions, but very little is known with respect to the hormonal and psychological mechanisms in play. Romantic love is thought to help intimate partners stay committed to each other and two mechanisms have been proposed to mediate this commitment: increased attention towards one's partner or deflected attention away from other potential partners. Both mechanisms find support in the literature. We explored the potential influence of each of these mechanisms by assessing women's ability to identify (ID) body odors originating from their boyfriend, a same-sex friend, and an opposite-sex friend and the relationship between this ability and the degree of romantic love expressed towards their boyfriend. We hypothesized that an increase in attention towards one's partner would render a positive correlation between ID of a boyfriend's body odor and degree of romantic love; conversely, we hypothesized that attention deflected away from other potential partners would render a negative correlation between ID of an opposite-sex friend's body odor and degree of romantic love for the boyfriend. Our results supported the deflection theory as we found a negative correlation between the degree of romantic love for the subjects' boyfriends and their ability to ID the body odor of an opposite-sex friend but not of their boyfriend or same-sex friend. Our results indicate that romantic love deflects attention away from potential new partners rather than towards the present partner. These changes are likely mediated by circulating neuropeptides and a testable model is suggested.

Testability, Test Automation and Test Driven Development for the Trick Simulation Toolkit

NASA Technical Reports Server (NTRS)

Penn, John

2014-01-01

This paper describes the adoption of a Test Driven Development approach and a Continuous Integration System in the development of the Trick Simulation Toolkit, a generic simulation development environment for creating high fidelity training and engineering simulations at the NASA Johnson Space Center and many other NASA facilities. It describes the approach, and the significant benefits seen, such as fast, thorough and clear test feedback every time code is checked into the code repository. It also describes an approach that encourages development of code that is testable and adaptable.

What makes Darwinian hydrology "Darwinian"? Asking a different kind of question about landscapes

NASA Astrophysics Data System (ADS)

Harman, C.; Troch, P. A.

2014-02-01

There have been repeated calls for a Darwinian approach to hydrologic science, or for a synthesis of Darwinian and Newtonian approaches, to deepen understanding of the hydrologic system in the larger landscape context, and so develop a better basis for predictions now and in an uncertain future. But what exactly makes a Darwinian approach to hydrology "Darwinian"? While there have now been a number of discussions of Darwinian approaches, many referencing Harte (2002), the term is potentially a source of confusion because its connections to Darwin remain allusive rather than explicit. Here we suggest that the Darwinian approach to hydrology follows the example of Charles Darwin by focusing attention on the patterns of variation in populations and seeking hypotheses that explain these patterns in terms of the mechanisms and conditions that determine their historical development. These hypotheses do not simply catalog patterns or predict them statistically - they connect the present structure with processes operating in the past. Nor are they explanations presented without independent evidence or critical analysis - Darwin's hypotheses about the mechanisms underlying present-day variation could be independently tested and validated. With a Darwinian framework in mind, it is easy to see that a great deal of hydrologic research has already been done that contributes to a Darwinian hydrology - whether deliberately or not. We discuss some practical and philosophical issues with this approach to hydrologic science: how are explanatory hypotheses generated? What constitutes a good hypothesis? How are hypotheses tested? "Historical" sciences - including paleohydrology - have long grappled with these questions, as must a Darwinian hydrologic science. We can draw on Darwin's own example for some answers, though there are ongoing debates about the philosophical nature of his methods and reasoning. Darwin used a range of methods of historical reasoning to develop explanatory hypotheses: extrapolating mechanisms, space for time substitution, and looking for signatures of history. Some of these are already in use, while others are not and could be used to develop new insights. He sought explanatory hypotheses that intelligibly unified disparate facts, were testable against evidence, and had fertile implications for further research. He provided evidence to support his hypotheses by deducing corollary conditions ("if explanation A is true, then B will also be true") and comparing these to observations. While a synthesis of the Darwinian and Newtonian approaches remains a goal, the Darwinian approach to hydrologic science has significant value of its own. The Darwinian hydrology that has been conducted already has not been coordinated or linked into a general body of theory and knowledge, but the time is coming when this will be possible.

Initial eccentricity fluctuations and their relation to higher-order flow harmonics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lacey, R.; Wei,R.; Jia,J.

2011-06-01

Monte Carlo simulations are used to compute the centrality dependence of the participant eccentricities ({var_epsilon}{sub n}) in Au+Au collisions for the two primary models currently employed for eccentricity estimates - the Glauber and the factorized Kharzeev-Levin-Nardi (fKLN) models. They suggest specific testable predictions for the magnitude and centrality dependence of the flow coefficients v{sub n}, respectively measured relative to the event planes {Psi}{sub n}. They also indicate that the ratios of several of these coefficients may provide an additional constraint for distinguishing between the models. Such a constraint could be important for a more precise determination of the specific viscositymore » of the matter produced in heavy ion collisions.« less

Comparison on testability of visual acuity, stereo acuity and colour vision tests between children with learning disabilities and children without learning disabilities in government primary schools

PubMed Central

Abu Bakar, Nurul Farhana; Chen, Ai-Hong

2014-01-01

Context: Children with learning disabilities might have difficulties to communicate effectively and give reliable responses as required in various visual function testing procedures. Aims: The purpose of this study was to compare the testability of visual acuity using the modified Early Treatment Diabetic Retinopathy Study (ETDRS) and Cambridge Crowding Cards, stereo acuity using Lang Stereo test II and Butterfly stereo tests and colour perception using Colour Vision Test Made Easy (CVTME) and Ishihara's Test for Colour Deficiency (Ishihara Test) between children in mainstream classes and children with learning disabilities in special education classes in government primary schools. Materials and Methods: A total of 100 primary school children (50 children from mainstream classes and 50 children from special education classes) matched in age were recruited in this cross-sectional comparative study. The testability was determined by the percentage of children who were able to give reliable respond as required by the respective tests. ‘Unable to test’ was defined as inappropriate response or uncooperative despite best efforts of the screener. Results: The testability of the modified ETDRS, Butterfly stereo test and Ishihara test for respective visual function tests were found lower among children in special education classes (P < 0.001) but not in Cambridge Crowding Cards, Lang Stereo test II and CVTME. Conclusion: Non verbal or “matching” approaches were found to be more superior in testing visual functions in children with learning disabilities. Modifications of vision testing procedures are essential for children with learning disabilities. PMID:24008790

The parental antagonism theory of language evolution: preliminary evidence for the proposal.

PubMed

Brown, William M

2011-04-01

Language--as with most communication systems--likely evolved by means of natural selection. Accounts for the genetical selection of language can usually be divided into two scenarios, either of which used in isolation of the other appear insufficient to explain the phenomena: (1) there are group benefits from communicating, and (2) there are individual benefits from being a better communicator. In contrast, it is hypothesized that language phenotypes emerged during a coevolutionary struggle between parental genomes via genomic imprinting, which is differential gene expression depending on parental origin of the genetic element. It is hypothesized that relatedness asymmetries differentially selected for patrigene-caused language phenotypes to extract resources from mother (early in development) and matrigene-caused language phenotypes to influence degree of cooperativeness among asymmetric kin (later in development). This paper reports that imprinted genes have a high frequency of involvement in language phenotypes (~36%), considering their presumed rarity in the human genome (~2%). For example, two well-studied genes associated with language impairments (FOXP2 and UBE3A) exhibit parent-of- origin effects. Specifically, FOXP2 is putatively paternally expressed, whereas UBE3A is a maternally expressed imprinted gene. It is also hypothesized that the more unique and cooperative aspects of human language emerged to the benefit of matrilineal inclusive fitness. Consistent with this perspective, it is reported here that the X-chromosome has higher involvement in loci that have associations with language than would be expected by chance. It is also reported, for the first time, that human and chimpanzee maternally expressed overlapping imprinted genes exhibit greater evolutionary divergence (in terms of the degree of overlapping transcripts) than paternally expressed overlapping imprinted genes. Finally, an analysis of global language patterns reveals that paternally but not maternally silenced Alu elements are positively correlated with language diversity. Furthermore, there is a much higher than expected frequency of Alu elements inserted into the protein-coding machinery of imprinted and X-chromosomal language loci compared with nonimprinted language loci. Taken together these findings provide some support for parental antagonism theory. Unlike previous theories for language evolution, parental antagonism theory generates testable predictions at the proximate (e.g., neurocognitive areas important for social transmission and language capacities), ontogenetic (e.g., the function of language at different points of development), ultimate (e.g., inclusive fitness), and phylogenetic levels (e.g., the spread of maternally derived brain components in mammals, particularly in the hominin lineage), thus making human capacities for culture more tractable than previously thought.

Bayesian Network Webserver: a comprehensive tool for biological network modeling.

PubMed

Ziebarth, Jesse D; Bhattacharya, Anindya; Cui, Yan

2013-11-01

The Bayesian Network Webserver (BNW) is a platform for comprehensive network modeling of systems genetics and other biological datasets. It allows users to quickly and seamlessly upload a dataset, learn the structure of the network model that best explains the data and use the model to understand relationships between network variables. Many datasets, including those used to create genetic network models, contain both discrete (e.g. genotype) and continuous (e.g. gene expression traits) variables, and BNW allows for modeling hybrid datasets. Users of BNW can incorporate prior knowledge during structure learning through an easy-to-use structural constraint interface. After structure learning, users are immediately presented with an interactive network model, which can be used to make testable hypotheses about network relationships. BNW, including a downloadable structure learning package, is available at http://compbio.uthsc.edu/BNW. (The BNW interface for adding structural constraints uses HTML5 features that are not supported by current version of Internet Explorer. We suggest using other browsers (e.g. Google Chrome or Mozilla Firefox) when accessing BNW). ycui2@uthsc.edu. Supplementary data are available at Bioinformatics online.

A Biosocial Developmental Model of Borderline Personality: Elaborating and Extending Linehan’s Theory

PubMed Central

Crowell, Sheila E.; Beauchaine, Theodore P.; Linehan, Marsha M.

2009-01-01

Over the past several decades, research has focused increasingly on developmental precursors to psychological disorders that were previously assumed to emerge only in adulthood. This change in focus follows from the recognition that complex transactions between biological vulnerabilities and psychosocial risk factors shape emotional and behavioral development beginning at conception. To date, however, empirical research on the development of borderline personality is extremely limited. Indeed, in the decade since M. M. Linehan initially proposed a biosocial model of the development of borderline personality disorder, there have been few attempts to test the model among at-risk youth. In this review, diverse literatures are reviewed that can inform understanding of the ontogenesis of borderline pathology, and testable hypotheses are proposed to guide future research with at-risk children and adolescents. One probable pathway is identified that leads to borderline personality disorder; it begins with early vulnerability, expressed initially as impulsivity and followed by heightened emotional sensitivity. These vulnerabilities are potentiated across development by environmental risk factors that give rise to more extreme emotional, behavioral, and cognitive dysregulation. PMID:19379027

The Comparative Toxicogenomics Database: update 2017.

PubMed

Davis, Allan Peter; Grondin, Cynthia J; Johnson, Robin J; Sciaky, Daniela; King, Benjamin L; McMorran, Roy; Wiegers, Jolene; Wiegers, Thomas C; Mattingly, Carolyn J

2017-01-04

The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) provides information about interactions between chemicals and gene products, and their relationships to diseases. Core CTD content (chemical-gene, chemical-disease and gene-disease interactions manually curated from the literature) are integrated with each other as well as with select external datasets to generate expanded networks and predict novel associations. Today, core CTD includes more than 30.5 million toxicogenomic connections relating chemicals/drugs, genes/proteins, diseases, taxa, Gene Ontology (GO) annotations, pathways, and gene interaction modules. In this update, we report a 33% increase in our core data content since 2015, describe our new exposure module (that harmonizes exposure science information with core toxicogenomic data) and introduce a novel dataset of GO-disease inferences (that identify common molecular underpinnings for seemingly unrelated pathologies). These advancements centralize and contextualize real-world chemical exposures with molecular pathways to help scientists generate testable hypotheses in an effort to understand the etiology and mechanisms underlying environmentally influenced diseases. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Paleolithic vs. modern diets--selected pathophysiological implications.

PubMed

Eaton, S B; Eaton, S B

2000-04-01

The nutritional patterns of Paleolithic humans influenced genetic evolution during the time segment within which defining characteristics of contemporary humans were selected. Our genome can have changed little since the beginnings of agriculture, so, genetically, humans remain Stone Agers--adapted for a Paleolithic dietary regimen. Such diets were based chiefly on wild game, fish and uncultivated plant foods. They provided abundant protein; a fat profile much different from that of affluent Western nations; high fibre; carbohydrate from fruits and vegetables (and some honey) but not from cereals, refined sugars and dairy products; high levels of micronutrients and probably of phytochemicals as well. Differences between contemporary and ancestral diets have many pathophysiological implications. This review addresses phytochemicals and cancer; calcium, physical exertion, bone mineral density and bone structural geometry; dietary protein, potassium, renal acid secretion and urinary calcium loss; and finally sarcopenia, adiposity, insulin receptors and insulin resistance. While not, yet, a basis for formal recommendations, awareness of Paleolithic nutritional patterns should generate novel, testable hypotheses grounded in evolutionary theory and it should dispel complacency regarding currently accepted nutritional tenets.

A biosocial developmental model of borderline personality: Elaborating and extending Linehan's theory.

PubMed

Crowell, Sheila E; Beauchaine, Theodore P; Linehan, Marsha M

2009-05-01

Over the past several decades, research has focused increasingly on developmental precursors to psychological disorders that were previously assumed to emerge only in adulthood. This change in focus follows from the recognition that complex transactions between biological vulnerabilities and psychosocial risk factors shape emotional and behavioral development beginning at conception. To date, however, empirical research on the development of borderline personality is extremely limited. Indeed, in the decade since M. M. Linehan initially proposed a biosocial model of the development of borderline personality disorder, there have been few attempts to test the model among at-risk youth. In this review, diverse literatures are reviewed that can inform understanding of the ontogenesis of borderline pathology, and testable hypotheses are proposed to guide future research with at-risk children and adolescents. One probable pathway is identified that leads to borderline personality disorder; it begins with early vulnerability, expressed initially as impulsivity and followed by heightened emotional sensitivity. These vulnerabilities are potentiated across development by environmental risk factors that give rise to more extreme emotional, behavioral, and cognitive dysregulation. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

Where do mirror neurons come from?

PubMed

Heyes, Cecilia

2010-03-01

Debates about the evolution of the 'mirror neuron system' imply that it is an adaptation for action understanding. Alternatively, mirror neurons may be a byproduct of associative learning. Here I argue that the adaptation and associative hypotheses both offer plausible accounts of the origin of mirror neurons, but the associative hypothesis has three advantages. First, it provides a straightforward, testable explanation for the differences between monkeys and humans that have led some researchers to question the existence of a mirror neuron system. Second, it is consistent with emerging evidence that mirror neurons contribute to a range of social cognitive functions, but do not play a dominant, specialised role in action understanding. Finally, the associative hypothesis is supported by recent data showing that, even in adulthood, the mirror neuron system can be transformed by sensorimotor learning. The associative account implies that mirror neurons come from sensorimotor experience, and that much of this experience is obtained through interaction with others. Therefore, if the associative account is correct, the mirror neuron system is a product, as well as a process, of social interaction. (c) 2009 Elsevier Ltd. All rights reserved.

Conservation in the face of climate change: The roles of alternative models, monitoring, and adaptation in confronting and reducing uncertainty

USGS Publications Warehouse

Conroy, M.J.; Runge, M.C.; Nichols, J.D.; Stodola, K.W.; Cooper, R.J.

2011-01-01

The broad physical and biological principles behind climate change and its potential large scale ecological impacts on biota are fairly well understood, although likely responses of biotic communities at fine spatio-temporal scales are not, limiting the ability of conservation programs to respond effectively to climate change outside the range of human experience. Much of the climate debate has focused on attempts to resolve key uncertainties in a hypothesis-testing framework. However, conservation decisions cannot await resolution of these scientific issues and instead must proceed in the face of uncertainty. We suggest that conservation should precede in an adaptive management framework, in which decisions are guided by predictions under multiple, plausible hypotheses about climate impacts. Under this plan, monitoring is used to evaluate the response of the system to climate drivers, and management actions (perhaps experimental) are used to confront testable predictions with data, in turn providing feedback for future decision making. We illustrate these principles with the problem of mitigating the effects of climate change on terrestrial bird communities in the southern Appalachian Mountains, USA. ?? 2010 Elsevier Ltd.

Preference Reversals in Decision Making Under Risk are Accompanied by Changes in Attention to Different Attributes.

PubMed

Kim, Betty E; Seligman, Darryl; Kable, Joseph W

2012-01-01

Recent work has shown that visual fixations reflect and influence trial-to-trial variability in people's preferences between goods. Here we extend this principle to attribute weights during decision making under risk. We measured eye movements while people chose between two risky gambles or bid on a single gamble. Consistent with previous work, we found that people exhibited systematic preference reversals between choices and bids. For two gambles matched in expected value, people systematically chose the higher probability option but provided a higher bid for the option that offered the greater amount to win. This effect was accompanied by a shift in fixations of the two attributes, with people fixating on probabilities more during choices and on amounts more during bids. Our results suggest that the construction of value during decision making under risk depends on task context partly because the task differentially directs attention at probabilities vs. amounts. Since recent work demonstrates that neural correlates of value vary with visual fixations, our results also suggest testable hypotheses regarding how task context modulates the neural computation of value to generate preference reversals.

A Global Classification System for Catchment Hydrology

NASA Astrophysics Data System (ADS)

Woods, R. A.

2004-05-01

It is a shocking state of affairs - there is no underpinning scientific taxonomy of catchments. There are widely used global classification systems for climate, river morphology, lakes and wetlands, but for river catchments there exists only a plethora of inconsistent, incomplete regional schemes. By proceeding without a common taxonomy for catchments, freshwater science has missed one of its key developmental stages, and has leapt from definition of phenomena to experiments, theories and models, without the theoretical framework of a classification. I propose the development of a global hierarchical classification system for physical aspects of river catchments, to help underpin physical science in the freshwater environment and provide a solid foundation for classification of river ecosystems. Such a classification scheme can open completely new vistas in hydrology: for example it will be possible to (i) rationally transfer experimental knowledge of hydrological processes between basins anywhere in the world, provided they belong to the same class; (ii) perform meaningful meta-analyses in order to reconcile studies that show inconsistent results (iii) generate new testable hypotheses which involve locations worldwide.

Human Facial Expressions as Adaptations:Evolutionary Questions in Facial Expression Research

PubMed Central

SCHMIDT, KAREN L.; COHN, JEFFREY F.

2007-01-01

The importance of the face in social interaction and social intelligence is widely recognized in anthropology. Yet the adaptive functions of human facial expression remain largely unknown. An evolutionary model of human facial expression as behavioral adaptation can be constructed, given the current knowledge of the phenotypic variation, ecological contexts, and fitness consequences of facial behavior. Studies of facial expression are available, but results are not typically framed in an evolutionary perspective. This review identifies the relevant physical phenomena of facial expression and integrates the study of this behavior with the anthropological study of communication and sociality in general. Anthropological issues with relevance to the evolutionary study of facial expression include: facial expressions as coordinated, stereotyped behavioral phenotypes, the unique contexts and functions of different facial expressions, the relationship of facial expression to speech, the value of facial expressions as signals, and the relationship of facial expression to social intelligence in humans and in nonhuman primates. Human smiling is used as an example of adaptation, and testable hypotheses concerning the human smile, as well as other expressions, are proposed. PMID:11786989

Characterizing behavioural ‘characters’: an evolutionary framework

PubMed Central

Araya-Ajoy, Yimen G.; Dingemanse, Niels J.

2014-01-01

Biologists often study phenotypic evolution assuming that phenotypes consist of a set of quasi-independent units that have been shaped by selection to accomplish a particular function. In the evolutionary literature, such quasi-independent functional units are called ‘evolutionary characters’, and a framework based on evolutionary principles has been developed to characterize them. This framework mainly focuses on ‘fixed’ characters, i.e. those that vary exclusively between individuals. In this paper, we introduce multi-level variation and thereby expand the framework to labile characters, focusing on behaviour as a worked example. We first propose a concept of ‘behavioural characters’ based on the original evolutionary character concept. We then detail how integration of variation between individuals (cf. ‘personality’) and within individuals (cf. ‘individual plasticity’) into the framework gives rise to a whole suite of novel testable predictions about the evolutionary character concept. We further propose a corresponding statistical methodology to test whether observed behaviours should be considered expressions of a hypothesized evolutionary character. We illustrate the application of our framework by characterizing the behavioural character ‘aggressiveness’ in wild great tits, Parus major. PMID:24335984

Developmental Perspectives on Oxytocin and Vasopressin

PubMed Central

Hammock, Elizabeth A D

2015-01-01

The related neuropeptides oxytocin and vasopressin are involved in species-typical behavior, including social recognition behavior, maternal behavior, social bonding, communication, and aggression. A wealth of evidence from animal models demonstrates significant modulation of adult social behavior by both of these neuropeptides and their receptors. Over the last decade, there has been a flood of studies in humans also implicating a role for these neuropeptides in human social behavior. Despite popular assumptions that oxytocin is a molecule of social bonding in the infant brain, less mechanistic research emphasis has been placed on the potential role of these neuropeptides in the developmental emergence of the neural substrates of behavior. This review summarizes what is known and assumed about the developmental influence of these neuropeptides and outlines the important unanswered questions and testable hypotheses. There is tremendous translational need to understand the functions of these neuropeptides in mammalian experience-dependent development of the social brain. The activity of oxytocin and vasopressin during development should inform our understanding of individual, sex, and species differences in social behavior later in life. PMID:24863032

Walking backwards into the future: the need for a holistic evolutionary approach in Pacific health research.

PubMed

Matisoo-Smith, Elizabeth; Gosling, Anna L

2018-05-01

The Pacific region has had a complex human history. It has been subject to multiple major human dispersal and colonisation events, including some of the earliest Out-of-Africa migrations, the so-called Austronesian expansion of people out of Island Southeast Asia, and the more recent arrival of Europeans. Despite models of island isolation, evidence suggests significant levels of interconnectedness that vary in direction and frequency over time. The Pacific Ocean covers a vast area and its islands provide an array of different physical environments with variable pathogen loads and subsistence opportunities. These diverse environments likely caused Pacific peoples to adapt (both genetically and culturally) in unique ways. Differences in genetic background, in combination with adaptation, likely affect their susceptibility to non-communicable diseases. Here we provide an overview of some of the key issues in the natural and human history of the Pacific region which are likely to impact human health. We argue that understanding the evolutionary and cultural history of Pacific peoples is essential for the generation of testable hypotheses surrounding potential causes of elevated disease susceptibility among Pacific peoples.

There is more than one way to model an elephant. Experiment-driven modeling of the actin cytoskeleton.

PubMed

Ditlev, Jonathon A; Mayer, Bruce J; Loew, Leslie M

2013-02-05

Mathematical modeling has established its value for investigating the interplay of biochemical and mechanical mechanisms underlying actin-based motility. Because of the complex nature of actin dynamics and its regulation, many of these models are phenomenological or conceptual, providing a general understanding of the physics at play. But the wealth of carefully measured kinetic data on the interactions of many of the players in actin biochemistry cries out for the creation of more detailed and accurate models that could permit investigators to dissect interdependent roles of individual molecular components. Moreover, no human mind can assimilate all of the mechanisms underlying complex protein networks; so an additional benefit of a detailed kinetic model is that the numerous binding proteins, signaling mechanisms, and biochemical reactions can be computationally organized in a fully explicit, accessible, visualizable, and reusable structure. In this review, we will focus on how comprehensive and adaptable modeling allows investigators to explain experimental observations and develop testable hypotheses on the intracellular dynamics of the actin cytoskeleton. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

There is More Than One Way to Model an Elephant. Experiment-Driven Modeling of the Actin Cytoskeleton

PubMed Central

Ditlev, Jonathon A.; Mayer, Bruce J.; Loew, Leslie M.

2013-01-01

Mathematical modeling has established its value for investigating the interplay of biochemical and mechanical mechanisms underlying actin-based motility. Because of the complex nature of actin dynamics and its regulation, many of these models are phenomenological or conceptual, providing a general understanding of the physics at play. But the wealth of carefully measured kinetic data on the interactions of many of the players in actin biochemistry cries out for the creation of more detailed and accurate models that could permit investigators to dissect interdependent roles of individual molecular components. Moreover, no human mind can assimilate all of the mechanisms underlying complex protein networks; so an additional benefit of a detailed kinetic model is that the numerous binding proteins, signaling mechanisms, and biochemical reactions can be computationally organized in a fully explicit, accessible, visualizable, and reusable structure. In this review, we will focus on how comprehensive and adaptable modeling allows investigators to explain experimental observations and develop testable hypotheses on the intracellular dynamics of the actin cytoskeleton. PMID:23442903

Computational investigation of feedback loop as a potential source of neuromechanical wave speed discrepancy in swimming animals

NASA Astrophysics Data System (ADS)

Patel, Namu; Patankar, Neelesh A.

2017-11-01

Aquatic locomotion relies on feedback loops to generate the flexural muscle moment needed to attain the reference shape. Experimentalists have consistently reported a difference between the electromyogram (EMG) and curvature wave speeds. The EMG wave speed has been found to correlate with the cross-sectional moment wave. The correlation, however, remains unexplained. Using feedback dependent controller models, we demonstrate two scenarios - one at higher passive elastic stiffness and another at lower passive elastic stiffness of the body. The former case becomes equivalent to the penalty type mathematical model for swimming used in prior literature and it does not reproduce neuromechanical wave speed discrepancy. The latter case at lower elastic stiffness does reproduce the wave speed discrepancy and appears to be biologically most relevant. These findings are applied to develop testable hypotheses about control mechanisms that animals might be using at during low and high Reynolds number swimming. This work is supported by NSF Grants DMS-1547394, CBET-1066575, ACI-1460334, and IOS-1456830. Travel for NP is supported by Institute for Defense Analyses.

Condition-dependent functional connectivity: syntax networks in bilinguals

PubMed Central

Dodel, Silke; Golestani, Narly; Pallier, Christophe; ElKouby, Vincent; Le Bihan, Denis; Poline, Jean-Baptiste

2005-01-01

This paper introduces a method to study the variation of brain functional connectivity networks with respect to experimental conditions in fMRI data. It is related to the psychophysiological interaction technique introduced by Friston et al. and extends to networks of correlation modulation (CM networks). Extended networks containing several dozens of nodes are determined in which the links correspond to consistent correlation modulation across subjects. In addition, we assess inter-subject variability and determine networks in which the condition-dependent functional interactions can be explained by a subject-dependent variable. We applied the technique to data from a study on syntactical production in bilinguals and analysed functional interactions differentially across tasks (word reading or sentence production) and across languages. We find an extended network of consistent functional interaction modulation across tasks, whereas the network comparing languages shows fewer links. Interestingly, there is evidence for a specific network in which the differences in functional interaction across subjects can be explained by differences in the subjects' syntactical proficiency. Specifically, we find that regions, including ones that have previously been shown to be involved in syntax and in language production, such as the left inferior frontal gyrus, putamen, insula, precentral gyrus, as well as the supplementary motor area, are more functionally linked during sentence production in the second, compared with the first, language in syntactically more proficient bilinguals than in syntactically less proficient ones. Our approach extends conventional activation analyses to the notion of networks, emphasizing functional interactions between regions independently of whether or not they are activated. On the one hand, it gives rise to testable hypotheses and allows an interpretation of the results in terms of the previous literature, and on the other hand, it provides a basis for studying the structure of functional interactions as a whole, and hence represents a further step towards the notion of large-scale networks in functional imaging. PMID:16087437

Dissecting Leishmania infantum Energy Metabolism - A Systems Perspective

PubMed Central

Subramanian, Abhishek; Jhawar, Jitesh; Sarkar, Ram Rup

2015-01-01

Leishmania infantum, causative agent of visceral leishmaniasis in humans, illustrates a complex lifecycle pertaining to two extreme environments, namely, the gut of the sandfly vector and human macrophages. Leishmania is capable of dynamically adapting and tactically switching between these critically hostile situations. The possible metabolic routes ventured by the parasite to achieve this exceptional adaptation to its varying environments are still poorly understood. In this study, we present an extensively reconstructed energy metabolism network of Leishmania infantum as an attempt to identify certain strategic metabolic routes preferred by the parasite to optimize its survival in such dynamic environments. The reconstructed network consists of 142 genes encoding for enzymes performing 237 reactions distributed across five distinct model compartments. We annotated the subcellular locations of different enzymes and their reactions on the basis of strong literature evidence and sequence-based detection of cellular localization signal within a protein sequence. To explore the diverse features of parasite metabolism the metabolic network was implemented and analyzed as a constraint-based model. Using a systems-based approach, we also put forth an extensive set of lethal reaction knockouts; some of which were validated using published data on Leishmania species. Performing a robustness analysis, the model was rigorously validated and tested for the secretion of overflow metabolites specific to Leishmania under varying extracellular oxygen uptake rate. Further, the fate of important non-essential amino acids in L. infantum metabolism was investigated. Stage-specific scenarios of L. infantum energy metabolism were incorporated in the model and key metabolic differences were outlined. Analysis of the model revealed the essentiality of glucose uptake, succinate fermentation, glutamate biosynthesis and an active TCA cycle as driving forces for parasite energy metabolism and its optimal growth. Finally, through our in silico knockout analysis, we could identify possible therapeutic targets that provide experimentally testable hypotheses. PMID:26367006

Binding proteins enhance specific uptake rate by increasing the substrate-transporter encounter rate.

PubMed

Bosdriesz, Evert; Magnúsdóttir, Stefanía; Bruggeman, Frank J; Teusink, Bas; Molenaar, Douwe

2015-06-01

Microorganisms rely on binding-protein assisted, active transport systems to scavenge for scarce nutrients. Several advantages of using binding proteins in such uptake systems have been proposed. However, a systematic, rigorous and quantitative analysis of the function of binding proteins is lacking. By combining knowledge of selection pressure and physiochemical constraints, we derive kinetic, thermodynamic, and stoichiometric properties of binding-protein dependent transport systems that enable a maximal import activity per amount of transporter. Under the hypothesis that this maximal specific activity of the transport complex is the selection objective, binding protein concentrations should exceed the concentration of both the scarce nutrient and the transporter. This increases the encounter rate of transporter with loaded binding protein at low substrate concentrations, thereby enhancing the affinity and specific uptake rate. These predictions are experimentally testable, and a number of observations confirm them. © 2015 FEBS.

Toward a Graded Psycholexical Space Mapping Model: Sublexical and Lexical Representations in Chinese Character Reading Development.

PubMed

Tong, Xiuli; McBride, Catherine

2017-07-01

Following a review of contemporary models of word-level processing for reading and their limitations, we propose a new hypothetical model of Chinese character reading, namely, the graded lexical space mapping model that characterizes how sublexical radicals and lexical information are involved in Chinese character reading development. The underlying assumption of this model is that Chinese character recognition is a process of competitive mappings of phonology, semantics, and orthography in both lexical and sublexical systems, operating as functions of statistical properties of print input based on the individual's specific level of reading. This model leads to several testable predictions concerning how the quasiregularity and continuity of Chinese-specific radicals are organized in memory for both child and adult readers at different developmental stages of reading.

New Insights into Non-Avian Dinosaur Reproduction and Their Evolutionary and Ecological Implications: Linking Fossil Evidence to Allometries of Extant Close Relatives

PubMed Central

Werner, Jan; Griebeler, Eva Maria

2013-01-01

It has been hypothesized that a high reproductive output contributes to the unique gigantism in large dinosaur taxa. In order to infer more information on dinosaur reproduction, we established allometries between body mass and different reproductive traits (egg mass, clutch mass, annual clutch mass) for extant phylogenetic brackets (birds, crocodiles and tortoises) of extinct non-avian dinosaurs. Allometries were applied to nine non-avian dinosaur taxa (theropods, hadrosaurs, and sauropodomorphs) for which fossil estimates on relevant traits are currently available. We found that the reproductive traits of most dinosaurs conformed to similar-sized or scaled-up extant reptiles or birds. The reproductive traits of theropods, which are considered more bird-like, were indeed consistent with birds, while the traits of sauropodomorphs conformed better to reptiles. Reproductive traits of hadrosaurs corresponded to both reptiles and birds. Excluding Massospondylus carinatus , all dinosaurs studied had an intermediary egg to body mass relationship to reptiles and birds. In contrast, dinosaur clutch masses fitted with either the masses predicted from allometries of birds (theropods) or to the masses of reptiles (all other taxa). Theropods studied had probably one clutch per year. For sauropodomorphs and hadrosaurs, more than one clutch per year was predicted. Contrary to current hypotheses, large dinosaurs did not have exceptionally high annual egg numbers (AEN). Independent of the extant model, the estimated dinosaur AEN did not exceed 850 eggs (75,000 kg sauropod) for any of the taxa studied. This estimated maximum is probably an overestimation due to unrealistic assumptions. According to most AEN estimations, the dinosaurs studied laid less than 200 eggs per year. Only some AEN estimates obtained for medium to large sized sauropods were higher (200-400 eggs). Our results provide new (testable) hypotheses, especially for reproductive traits that are insufficiently documented or lacking from the fossil record. This contributes to the understanding of their evolution. PMID:23991160

New insights into non-avian dinosaur reproduction and their evolutionary and ecological implications: linking fossil evidence to allometries of extant close relatives.

PubMed

Werner, Jan; Griebeler, Eva Maria

2013-01-01

It has been hypothesized that a high reproductive output contributes to the unique gigantism in large dinosaur taxa. In order to infer more information on dinosaur reproduction, we established allometries between body mass and different reproductive traits (egg mass, clutch mass, annual clutch mass) for extant phylogenetic brackets (birds, crocodiles and tortoises) of extinct non-avian dinosaurs. Allometries were applied to nine non-avian dinosaur taxa (theropods, hadrosaurs, and sauropodomorphs) for which fossil estimates on relevant traits are currently available. We found that the reproductive traits of most dinosaurs conformed to similar-sized or scaled-up extant reptiles or birds. The reproductive traits of theropods, which are considered more bird-like, were indeed consistent with birds, while the traits of sauropodomorphs conformed better to reptiles. Reproductive traits of hadrosaurs corresponded to both reptiles and birds. Excluding Massospondyluscarinatus, all dinosaurs studied had an intermediary egg to body mass relationship to reptiles and birds. In contrast, dinosaur clutch masses fitted with either the masses predicted from allometries of birds (theropods) or to the masses of reptiles (all other taxa). Theropods studied had probably one clutch per year. For sauropodomorphs and hadrosaurs, more than one clutch per year was predicted. Contrary to current hypotheses, large dinosaurs did not have exceptionally high annual egg numbers (AEN). Independent of the extant model, the estimated dinosaur AEN did not exceed 850 eggs (75,000 kg sauropod) for any of the taxa studied. This estimated maximum is probably an overestimation due to unrealistic assumptions. According to most AEN estimations, the dinosaurs studied laid less than 200 eggs per year. Only some AEN estimates obtained for medium to large sized sauropods were higher (200-400 eggs). Our results provide new (testable) hypotheses, especially for reproductive traits that are insufficiently documented or lacking from the fossil record. This contributes to the understanding of their evolution.

Biodiversity and agriculture in dynamic landscapes: Integrating ground and remotely-sensed baseline surveys.

PubMed

Gillison, Andrew N; Asner, Gregory P; Fernandes, Erick C M; Mafalacusser, Jacinto; Banze, Aurélio; Izidine, Samira; da Fonseca, Ambrósio R; Pacate, Hermenegildo

2016-07-15

Sustainable biodiversity and land management require a cost-effective means of forecasting landscape response to environmental change. Conventional species-based, regional biodiversity assessments are rarely adequate for policy planning and decision making. We show how new ground and remotely-sensed survey methods can be coordinated to help elucidate and predict relationships between biodiversity, land use and soil properties along complex biophysical gradients that typify many similar landscapes worldwide. In the lower Zambezi valley, Mozambique we used environmental, gradient-directed transects (gradsects) to sample vascular plant species, plant functional types, vegetation structure, soil properties and land-use characteristics. Soil fertility indices were derived using novel multidimensional scaling of soil properties. To facilitate spatial analysis, we applied a probabilistic remote sensing approach, analyzing Landsat 7 satellite imagery to map photosynthetically active and inactive vegetation and bare soil along each gradsect. Despite the relatively low sample number, we found highly significant correlations between single and combined sets of specific plant, soil and remotely sensed variables that permitted testable spatial projections of biodiversity and soil fertility across the regional land-use mosaic. This integrative and rapid approach provides a low-cost, high-return and readily transferable methodology that permits the ready identification of testable biodiversity indicators for adaptive management of biodiversity and potential agricultural productivity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Color vision deficiency in preschool children: the multi-ethnic pediatric eye disease study.

PubMed

Xie, John Z; Tarczy-Hornoch, Kristina; Lin, Jesse; Cotter, Susan A; Torres, Mina; Varma, Rohit

2014-07-01

To determine the sex- and ethnicity-specific prevalence of color vision deficiency (CVD) in black, Asian, Hispanic, and non-Hispanic white preschool children. Population-based, cross-sectional study. The Multi-Ethnic Pediatric Eye Disease Study is a population-based evaluation of the prevalence of vision disorders in children in Southern California. A total of 5960 subjects 30 to 72 months of age were recruited for the study, of whom 4177 were able to complete color vision testing (1265 black, 812 Asian, 1280 Hispanic, and 820 non-Hispanic white). Color vision testing was performed using Color Vision Testing Made Easy color plates (Home Vision Care, Gulf Breeze, FL), and diagnostic confirmatory testing was performed using the Waggoner HRR Diagnostic Test color plates (Home Vision Care). Testability of color vision in preschool children between 30 and 72 months of age and prevalence of CVD stratified by age, sex, and ethnicity. Testability was 17% in children younger than 37 months of age, increasing to 57% in children 37 to 48 months of age, 89% in children 49 to 60 months of age, and 98% in children 61 to 72 months of age. The prevalence of CVD among boys was 1.4% for black, 3.1% for Asian, 2.6% for Hispanic, and 5.6% for non-Hispanic white children; the prevalence in girls was 0.0% to 0.5% for all ethnicities. The ethnic difference in CVD was statistically significant between black and non-Hispanic white children (P = 0.0003) and between Hispanic and non-Hispanic white children (P = 0.02). In boys, most CVD cases were either deutan (51%) or protan (34%); 32% were classified as mild, 15% as moderate, and 41% as severe. Testability for CVD in preschool children is high by 4 years of age. The prevalence of CVD in preschool boys varies by ethnicity, with the highest prevalence in non-Hispanic white and lowest in black children. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Ecosystem function in complex mountain terrain: Combining models and long-term observations to advance process-based understanding

NASA Astrophysics Data System (ADS)

Wieder, William R.; Knowles, John F.; Blanken, Peter D.; Swenson, Sean C.; Suding, Katharine N.

2017-04-01

Abiotic factors structure plant community composition and ecosystem function across many different spatial scales. Often, such variation is considered at regional or global scales, but here we ask whether ecosystem-scale simulations can be used to better understand landscape-level variation that might be particularly important in complex terrain, such as high-elevation mountains. We performed ecosystem-scale simulations by using the Community Land Model (CLM) version 4.5 to better understand how the increased length of growing seasons may impact carbon, water, and energy fluxes in an alpine tundra landscape. The model was forced with meteorological data and validated with observations from the Niwot Ridge Long Term Ecological Research Program site. Our results demonstrate that CLM is capable of reproducing the observed carbon, water, and energy fluxes for discrete vegetation patches across this heterogeneous ecosystem. We subsequently accelerated snowmelt and increased spring and summer air temperatures in order to simulate potential effects of climate change in this region. We found that vegetation communities that were characterized by different snow accumulation dynamics showed divergent biogeochemical responses to a longer growing season. Contrary to expectations, wet meadow ecosystems showed the strongest decreases in plant productivity under extended summer scenarios because of disruptions in hydrologic connectivity. These findings illustrate how Earth system models such as CLM can be used to generate testable hypotheses about the shifting nature of energy, water, and nutrient limitations across space and through time in heterogeneous landscapes; these hypotheses may ultimately guide further experimental work and model development.

Metabolomics as a Hypothesis-Generating Functional Genomics Tool for the Annotation of Arabidopsis thaliana Genes of “Unknown Function”

PubMed Central

Quanbeck, Stephanie M.; Brachova, Libuse; Campbell, Alexis A.; Guan, Xin; Perera, Ann; He, Kun; Rhee, Seung Y.; Bais, Preeti; Dickerson, Julie A.; Dixon, Philip; Wohlgemuth, Gert; Fiehn, Oliver; Barkan, Lenore; Lange, Iris; Lange, B. Markus; Lee, Insuk; Cortes, Diego; Salazar, Carolina; Shuman, Joel; Shulaev, Vladimir; Huhman, David V.; Sumner, Lloyd W.; Roth, Mary R.; Welti, Ruth; Ilarslan, Hilal; Wurtele, Eve S.; Nikolau, Basil J.

2012-01-01

Metabolomics is the methodology that identifies and measures global pools of small molecules (of less than about 1,000 Da) of a biological sample, which are collectively called the metabolome. Metabolomics can therefore reveal the metabolic outcome of a genetic or environmental perturbation of a metabolic regulatory network, and thus provide insights into the structure and regulation of that network. Because of the chemical complexity of the metabolome and limitations associated with individual analytical platforms for determining the metabolome, it is currently difficult to capture the complete metabolome of an organism or tissue, which is in contrast to genomics and transcriptomics. This paper describes the analysis of Arabidopsis metabolomics data sets acquired by a consortium that includes five analytical laboratories, bioinformaticists, and biostatisticians, which aims to develop and validate metabolomics as a hypothesis-generating functional genomics tool. The consortium is determining the metabolomes of Arabidopsis T-DNA mutant stocks, grown in standardized controlled environment optimized to minimize environmental impacts on the metabolomes. Metabolomics data were generated with seven analytical platforms, and the combined data is being provided to the research community to formulate initial hypotheses about genes of unknown function (GUFs). A public database (www.PlantMetabolomics.org) has been developed to provide the scientific community with access to the data along with tools to allow for its interactive analysis. Exemplary datasets are discussed to validate the approach, which illustrate how initial hypotheses can be generated from the consortium-produced metabolomics data, integrated with prior knowledge to provide a testable hypothesis concerning the functionality of GUFs. PMID:22645570

Rethinking energy in parkinsonian motor symptoms: a potential role for neural metabolic deficits

PubMed Central

Amano, Shinichi; Kegelmeyer, Deborah; Hong, S. Lee

2015-01-01

Parkinson’s disease (PD) is characterized as a chronic and progressive neurodegenerative disorder that results in a variety of debilitating symptoms, including bradykinesia, resting tremor, rigidity, and postural instability. Research spanning several decades has emphasized basal ganglia dysfunction, predominantly resulting from dopaminergic (DA) cell loss, as the primarily cause of the aforementioned parkinsonian features. But, why those particular features manifest themselves remains an enigma. The goal of this paper is to develop a theoretical framework that parkinsonian motor features are behavioral consequence of a long-term adaptation to their inability (inflexibility or lack of capacity) to meet energetic demands, due to neural metabolic deficits arising from mitochondrial dysfunction associated with PD. Here, we discuss neurophysiological changes that are generally associated with PD, such as selective degeneration of DA neurons in the substantia nigra pars compacta (SNc), in conjunction with metabolic and mitochondrial dysfunction. We then characterize the cardinal motor symptoms of PD, bradykinesia, resting tremor, rigidity and gait disturbance, reviewing literature to demonstrate how these motor patterns are actually energy efficient from a metabolic perspective. We will also develop three testable hypotheses: (1) neural metabolic deficits precede the increased rate of neurodegeneration and onset of behavioral symptoms in PD; (2) motor behavior of persons with PD are more sensitive to changes in metabolic/bioenergetic state; and (3) improvement of metabolic function could lead to better motor performance in persons with PD. These hypotheses are designed to introduce a novel viewpoint that can elucidate the connections between metabolic, neural and motor function in PD. PMID:25610377

Non-degradative Ubiquitination of Protein Kinases

PubMed Central

Ball, K. Aurelia; Johnson, Jeffrey R.; Lewinski, Mary K.; Guatelli, John; Verschueren, Erik; Krogan, Nevan J.; Jacobson, Matthew P.

2016-01-01

Growing evidence supports other regulatory roles for protein ubiquitination in addition to serving as a tag for proteasomal degradation. In contrast to other common post-translational modifications, such as phosphorylation, little is known about how non-degradative ubiquitination modulates protein structure, dynamics, and function. Due to the wealth of knowledge concerning protein kinase structure and regulation, we examined kinase ubiquitination using ubiquitin remnant immunoaffinity enrichment and quantitative mass spectrometry to identify ubiquitinated kinases and the sites of ubiquitination in Jurkat and HEK293 cells. We find that, unlike phosphorylation, ubiquitination most commonly occurs in structured domains, and on the kinase domain, ubiquitination is concentrated in regions known to be important for regulating activity. We hypothesized that ubiquitination, like other post-translational modifications, may alter the conformational equilibrium of the modified protein. We chose one human kinase, ZAP-70, to simulate using molecular dynamics with and without a monoubiquitin modification. In Jurkat cells, ZAP-70 is ubiquitinated at several sites that are not sensitive to proteasome inhibition and thus may have other regulatory roles. Our simulations show that ubiquitination influences the conformational ensemble of ZAP-70 in a site-dependent manner. When monoubiquitinated at K377, near the C-helix, the active conformation of the ZAP-70 C-helix is disrupted. In contrast, when monoubiquitinated at K476, near the kinase hinge region, an active-like ZAP-70 C-helix conformation is stabilized. These results lead to testable hypotheses that ubiquitination directly modulates kinase activity, and that ubiquitination is likely to alter structure, dynamics, and function in other protein classes as well. PMID:27253329

The iron source in phreatomagmatic pipes in the Tunguska Basin (eastern Siberia): insights into hydrothermal-metasomatic leaching processes from Fe isotopes, microstructures, and mass balances.

NASA Astrophysics Data System (ADS)

John, Timm; Svensen, Henrik; Weyer, Stefan; Polozov, Alexander; Planke, Sverre

2010-05-01

The Siberian iron-bearing phreatomagmatic pipes represent world class Fe-ore deposit, and 5-6 are currently mined in eastern Siberia. The pipes formed within the vast Tunguska Basin, cutting thick accumulations of carbonates (dolostones) and evaporites (anhydrite, halite, dolostone). These sediments were intruded by the sub-volcanic part of the Siberian Traps at 252 Ma, and sills and dykes are abundant throughout the basin. The pipes formed during sediment-magma interactions in the deep parts of the basin, and the degassing is believed to have triggered the end-Permian environmental crisis. A major problem with understanding the pipe formation is related to the source of iron. Available hypotheses state that the iron was leached from a Fe-enriched magmatic melt that incorporated dolostones. It is currently unclear how the magmatic, hydrothermal, and sedimentary processes interacted to form the deposits, as there are no actual constraints to pin down the iron source. We hypothesize two end-member scenarios to account for the magnetite enrichment and deposition, which is testable by analyzing Fe-isotopes of magnetite: 1) Iron sourced from dolerite magma through leaching and metasomatism by chloride brines. 2) Leaching of iron from sedimentary rocks (shale, dolostone) during magma-sediment interactions. We focus on understanding the Fe-isotopic architecture of the pipes in order constrain the source of the Fe and the mechanism that caused this significant Fe redistribution. We further evaluate possible fractionation during fast metasomatic ore-forming process that took place soon after pipe formation.

Parent-offspring conflict over family size in current China.

PubMed

Liu, Jianghua; Duan, Chongli; Lummaa, Virpi

2017-05-06

In China, the recent replacement of the one-child policy with a two-child policy could potentially change family ecology-parents may switch investment from exclusively one child to two. The parent-offspring conflict theory provides testable hypotheses concerning possible firstborn opposition toward further reproduction of their mother, and who wins the conflict. We tested the hypotheses that if there is any opposition, it will differ between sexes, weaken with offspring age and family resource availability, and affect maternal reproductive decision-making. Using survey data of 531 non-pregnant mothers of only one child from Xi'an (China), logistic regression was used to examine effects of age, family income, and sex on the attitudes of firstborn children toward having a sibling; ordinal regression was used to investigate how such attitudes affect maternal intention to reproduce again. Firstborns' unsupportive attitude toward their mothers' further reproduction weakened with age and was overall more frequent in low-income families. Sons' unsupportive tendency displayed a somewhat U-shaped relationship, whereas daughters' weakened with family income; consequently, sons were more likely than daughters to be unsupportive in high-income families, suggesting a tendency to be more demanding. Forty-nine percent of mothers supported by their firstborns intended to reproduce again, whilst only 9% of mothers not supported by firstborns had such an intention. Our study contributes to evolutionary literature on parent-offspring conflict and its influence on female reproductive strategy in modern human societies, and has also important implications for understanding fertility patterns and conducting interventions in family conflict in China. © 2016 Wiley Periodicals, Inc.

Twelve testable hypotheses on the geobiology of weathering.

PubMed

Brantley, S L; Megonigal, J P; Scatena, F N; Balogh-Brunstad, Z; Barnes, R T; Bruns, M A; Van Cappellen, P; Dontsova, K; Hartnett, H E; Hartshorn, A S; Heimsath, A; Herndon, E; Jin, L; Keller, C K; Leake, J R; McDowell, W H; Meinzer, F C; Mozdzer, T J; Petsch, S; Pett-Ridge, J; Pregitzer, K S; Raymond, P A; Riebe, C S; Shumaker, K; Sutton-Grier, A; Walter, R; Yoo, K

2011-03-01

Critical Zone (CZ) research investigates the chemical, physical, and biological processes that modulate the Earth's surface. Here, we advance 12 hypotheses that must be tested to improve our understanding of the CZ: (1) Solar-to-chemical conversion of energy by plants regulates flows of carbon, water, and nutrients through plant-microbe soil networks, thereby controlling the location and extent of biological weathering. (2) Biological stoichiometry drives changes in mineral stoichiometry and distribution through weathering. (3) On landscapes experiencing little erosion, biology drives weathering during initial succession, whereas weathering drives biology over the long term. (4) In eroding landscapes, weathering-front advance at depth is coupled to surface denudation via biotic processes. (5) Biology shapes the topography of the Critical Zone. (6) The impact of climate forcing on denudation rates in natural systems can be predicted from models incorporating biogeochemical reaction rates and geomorphological transport laws. (7) Rising global temperatures will increase carbon losses from the Critical Zone. (8) Rising atmospheric P(CO2) will increase rates and extents of mineral weathering in soils. (9) Riverine solute fluxes will respond to changes in climate primarily due to changes in water fluxes and secondarily through changes in biologically mediated weathering. (10) Land use change will impact Critical Zone processes and exports more than climate change. (11) In many severely altered settings, restoration of hydrological processes is possible in decades or less, whereas restoration of biodiversity and biogeochemical processes requires longer timescales. (12) Biogeochemical properties impart thresholds or tipping points beyond which rapid and irreversible losses of ecosystem health, function, and services can occur. © 2011 Blackwell Publishing Ltd.

Towards a theory of PACS deployment: an integrative PACS maturity framework.

PubMed

van de Wetering, Rogier; Batenburg, Ronald

2014-06-01

Owing to large financial investments that go along with the picture archiving and communication system (PACS) deployments and inconsistent PACS performance evaluations, there is a pressing need for a better understanding of the implications of PACS deployment in hospitals. We claim that there is a gap in the research field, both theoretically and empirically, to explain the success of the PACS deployment and maturity in hospitals. Theoretical principles are relevant to the PACS performance; maturity and alignment are reviewed from a system and complexity perspective. A conceptual model to explain the PACS performance and a set of testable hypotheses are then developed. Then, structural equation modeling (SEM), i.e. causal modeling, is applied to validate the model and hypotheses based on a research sample of 64 hospitals that use PACS, i.e. 70 % of all hospitals in the Netherlands. Outcomes of the SEM analyses substantiate that the measurements of all constructs are reliable and valid. The PACS alignment-modeled as a higher-order construct of five complementary organizational dimensions and maturity levels-has a significant positive impact on the PACS performance. This result is robust and stable for various sub-samples and segments. This paper presents a conceptual model that explains how alignment in deploying PACS in hospitals is positively related to the perceived performance of PACS. The conceptual model is extended with tools as checklists to systematically identify the improvement areas for hospitals in the PACS domain. The holistic approach towards PACS alignment and maturity provides a framework for clinical practice.

Hypotheses for a Near-Surface Reservoir of Methane and Its Release on Mars

NASA Astrophysics Data System (ADS)

Hu, R.; Bloom, A. A.; Gao, P.; Miller, C. E.; Yung, Y. L.

2015-12-01

The Curiosity rover recently detected a background of 0.7 ppb and spikes of 7 ppb of methane on Mars. This in situ measurement reorients our understanding of the Martian environment and its potential for life, as the current theories do not entail any active source or sink of methane. In particular, the 10-fold elevation during the southern winter indicates episodic sources of methane that are yet to be discovered. Using the temperature and humidity measurements from the rover, we find that perchlorate salts in the regolith deliquesce to form liquid solutions, and deliquescence progresses to deeper subsurface in the season of the methane spikes. We therefore formulate the following three testable hypotheses as an attempt to explain the apparent variability of the atmospheric methane abundance. The first scenario is that the regolith in Gale Crater adsorbs methane when dry and releases this methane to the atmosphere upon deliquescence. The adsorption energy needs to be 36 kJ mol-1 to explain the magnitude of the methane spikes, higher than laboratory measurements. The second scenario is that microorganisms exist and convert organic matter in the soil to methane when they are in liquid solutions. This scenario does not require regolith adsorption. The third scenario is that deep subsurface aquifers sealed by ice or clathrate produce bursts of methane as a result of freezing and thawing of the permafrost, as the terrestrial arctic tundra. Continued monitoring of methane by Curiosity will test the existence of the near-surface reservoir and its exchange with the atmosphere.

Multidisciplinary analysis and design of printed wiring boards

NASA Astrophysics Data System (ADS)

Fulton, Robert E.; Hughes, Joseph L.; Scott, Waymond R., Jr.; Umeagukwu, Charles; Yeh, Chao-Pin

1991-04-01

Modern printed wiring board design depends on electronic prototyping using computer-based simulation and design tools. Existing electrical computer-aided design (ECAD) tools emphasize circuit connectivity with only rudimentary analysis capabilities. This paper describes a prototype integrated PWB design environment denoted Thermal Structural Electromagnetic Testability (TSET) being developed at Georgia Tech in collaboration with companies in the electronics industry. TSET provides design guidance based on enhanced electrical and mechanical CAD capabilities including electromagnetic modeling testability analysis thermal management and solid mechanics analysis. TSET development is based on a strong analytical and theoretical science base and incorporates an integrated information framework and a common database design based on a systematic structured methodology.

Bayesian naturalness, simplicity, and testability applied to the B ‑ L MSSM GUT

NASA Astrophysics Data System (ADS)

Fundira, Panashe; Purves, Austin

2018-04-01

Recent years have seen increased use of Bayesian model comparison to quantify notions such as naturalness, simplicity, and testability, especially in the area of supersymmetric model building. After demonstrating that Bayesian model comparison can resolve a paradox that has been raised in the literature concerning the naturalness of the proton mass, we apply Bayesian model comparison to GUTs, an area to which it has not been applied before. We find that the GUTs are substantially favored over the nonunifying puzzle model. Of the GUTs we consider, the B ‑ L MSSM GUT is the most favored, but the MSSM GUT is almost equally favored.

Two fundamental questions about protein evolution.

PubMed

Penny, David; Zhong, Bojian

2015-12-01

Two basic questions are considered that approach protein evolution from different directions; the problems arising from using Markov models for the deeper divergences, and then the origin of proteins themselves. The real problem for the first question (going backwards in time) is that at deeper phylogenies the Markov models of sequence evolution must lose information exponentially at deeper divergences, and several testable methods are suggested that should help resolve these deeper divergences. For the second question (coming forwards in time) a problem is that most models for the origin of protein synthesis do not give a role for the very earliest stages of the process. From our knowledge of the importance of replication accuracy in limiting the length of a coding molecule, a testable hypothesis is proposed. The length of the code, the code itself, and tRNAs would all have prior roles in increasing the accuracy of RNA replication; thus proteins would have been formed only after the tRNAs and the length of the triplet code are already formed. Both questions lead to testable predictions. Copyright © 2014 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Should tumbling E go out of date in amblyopia screening? Evidence from a population-based sample normative in children aged 3-4 years.

PubMed

Guimaraes, Sandra; Fernandes, Tiago; Costa, Patrício; Silva, Eduardo

2018-06-01

To determine a normative of tumbling E optotype and its feasibility for visual acuity (VA) assessment in children aged 3-4 years. A cross-sectional study of 1756 children who were invited to participate in a comprehensive non-invasive eye exam. Uncorrected monocular VA with crowded tumbling E with a comprehensive ophthalmological examination were assessed. Testability rates of the whole population and VA of the healthy children for different age subgroups, gender, school type and the order of testing in which the ophthalmological examination was performed were evaluated. The overall testability rate was 95% (92% and 98% for children aged 3 and 4 years, respectively). The mean VA of the first-day assessment (first-VA) and best-VA over 2 days' assessments was 0.14 logMAR (95% CI 0.14 to 0.15) (decimal=0.72, 95% CI 0.71 to 0.73) and 0.13 logMAR (95% CI 0.13 to 0.14) (decimal=0.74, 95% CI 0.73 to 0.74). Analysis with age showed differences between groups in first-VA (F(3,1146)=10.0; p<0.001; η2=0.026) and best-VA (F(3,1155)=8.8; p<0.001; η2=0.022). Our normative was very highly correlated with previous reported HOTV-Amblyopia-Treatment-Study (HOTV-ATS) (first-VA, r=0.97; best-VA, r=0.99), with 0.8 to 0.7 lines consistent overestimation for HOTV-ATS as described in literature. Overall false-positive referral was 1.3%, being specially low regarding anisometropias of ≥2 logMAR lines (0.17%). Interocular difference ≥1 line VA logMAR was not associated with age (p=0.195). This is the first normative for European Caucasian children with single crowded tumbling E in healthy eyes and the largest study comparing 3 and 4 years old testability. Testability rates are higher than found in literature with other optotypes, especially in children aged 3 years, where we found 5%-11% better testability rates. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Psychological stress and fibromyalgia: a review of the evidence suggesting a neuroendocrine link

PubMed Central

Gupta, Anindya; Silman, Alan J

2004-01-01

The present review attempts to reconcile the dichotomy that exists in the literature in relation to fibromyalgia, in that it is considered either a somatic response to psychological stress or a distinct organically based syndrome. Specifically, the hypothesis explored is that the link between chronic stress and the subsequent development of fibromyalgia can be explained by one or more abnormalities in neuroendocrine function. There are several such abnormalities recognised that both occur as a result of chronic stress and are observed in fibromyalgia. Whether such abnormalities have an aetiologic role remains uncertain but should be testable by well-designed prospective studies. PMID:15142258

A Gradualist Scenario for Language Evolution: Precise Linguistic Reconstruction of Early Human (and Neandertal) Grammars

PubMed Central

Progovac, Ljiljana

2016-01-01

In making an argument for the antiquity of language, based on comparative evidence, Dediu and Levinson (2013) express hope that some combinations of structural features will prove so conservative that they will allow deep linguistic reconstruction. I propose that the earliest stages of syntax/grammar as reconstructed in Progovac (2015a), based on a theoretical and data-driven linguistic analysis, provide just such a conservative platform, which would have been commanded also by Neandertals and the common ancestor. I provide a fragment of this proto-grammar, which includes flat verb-noun compounds used for naming and insult (e.g., rattle-snake, cry-baby, scatter-brain), and paratactic (loose) combinations of such flat structures (e.g., Come one, come all; You seek, you find). This flat, binary, paratactic platform is found in all languages, and can be shown to serve as foundation for any further structure building. However, given the degree and nature of variation across languages in elaborating syntax beyond this proto-stage, I propose that hierarchical syntax did not emerge once and uniformly in all its complexity, but rather multiple times, either within Africa, or after dispersion from Africa. If so, then, under the uniregional hypothesis, our common ancestor with Neandertals, H. heidelbergensis, could not have commanded hierarchical syntax, but “only” the proto-grammar. Linguistic reconstructions of this kind are necessary for formulating precise and testable hypotheses regarding language evolution. In addition to the hominin timeline, this reconstruction can also engage, and negotiate between, the fields of neuroscience and genetics, as I illustrate with one specific scenario involving FOXP2 gene. PMID:27877146

Self-disturbance and schizophrenia: structure, specificity, pathogenesis (Current issues, New directions).

PubMed

Sass, Louis A

2014-01-01

This paper offers an overview and clarification of the ipseity-disturbance or self-disorder hypothesis regarding schizophrenia, with focus on some recent and recommended research and theoretical refinements. There is need to expand research and theorizing in several directions-in order to: 1, specify more precisely what is truly distinctive in the schizophrenia spectrum, 2, explore internal structure and explanatory potential of this purported disturbance of minimal- or core-self experience, 3, generate testable hypotheses concerning pathogenetic pathways and psychotherapeutic interventions. Comparative studies can make a crucial scientific contribution. Some recent, exploratory studies are described: published reports were examined for alterations of self-experience in conditions outside the schizophrenia spectrum-mania, psychotic depression, and depersonalization disorder-and in one unusual attitudinal stance: intense introspection (as refined in early 20th century psychological research). Remarkable similarities (e.g., alienation/reification of thoughts and bodily experiences, fading of self and world) as well as some important differences (e.g., absence, outside schizophrenia, of severe erosion of minimal self-experience or real confusion of self and other) in types of self-anomalies were found. These support but also refine the ipseity-disturbance model. Future research should treat self-experience as an independent variable, manipulating and measuring this dimension (in both schizophrenic and non-schizophrenic populations) to study its associations with anomalies of cognition, affect, expression, and neural functioning already identified in schizophrenia. The self-disorder model offers an integrative and dynamic view of schizophrenia congruent with recent trends in cognitive neuroscience and consistent with the heterogeneous, varying, and holistic nature of this enigmatic illness. Copyright © 2013. Published by Elsevier B.V.

Neuroimaging in human MDMA (Ecstasy) users: A cortical model

PubMed Central

Cowan, Ronald L; Roberts, Deanne M; Joers, James M

2009-01-01

MDMA (3,4 methylenedioxymethamphetamine) has been used by millions of people worldwide as a recreational drug. MDMA and Ecstasy are often used synonymously but it is important to note that the purity of Ecstasy sold as MDMA is not certain. MDMA use is of public health concern, not so much because MDMA produces a common or severe dependence syndrome, but rather because rodent and non-human primate studies have indicated that MDMA (when administered at certain dosages and intervals) can cause long-lasting reductions in markers of brain serotonin (5-HT) that appear specific to fine diameter axons arising largely from the dorsal raphe nucleus (DR). Given the popularity of MDMA, the potential for the drug to produce long-lasting or permanent 5-HT axon damage or loss, and the widespread role of 5-HT function in the brain, there is a great need for a better understanding of brain function in human users of this drug. To this end, neuropsychological, neuroendocrine, and neuroimaging studies have all suggested that human MDMA users may have long-lasting changes in brain function consistent with 5-HT toxicity. Data from animal models leads to testable hypotheses regarding MDMA effects on the human brain. Because neuropsychological and neuroimaging findings have focused on the neocortex, a cortical model is developed to provide context for designing and interpreting neuroimaging studies in MDMA users. Aspects of the model are supported by the available neuroimaging data but there are controversial findings in some areas and most findings have not been replicated across different laboratories and using different modalities. This paper reviews existing findings in the context of a cortical model and suggests directions for future research. PMID:18991874

The complex genetics of human insulin-like growth factor 2 are not reflected in public databases.

PubMed

Rotwein, Peter

2018-03-23

Recent advances in genetics present unique opportunities for enhancing knowledge about human physiology and disease susceptibility. Understanding this information at the individual gene level is challenging and requires extracting, collating, and interpreting data from a variety of public gene repositories. Here, I illustrate this challenge by analyzing the gene for human insulin-like growth factor 2 ( IGF2 ) through the lens of several databases. IGF2, a 67-amino acid secreted peptide, is essential for normal prenatal growth and is involved in other physiological and pathophysiological processes in humans. Surprisingly, none of the genetic databases accurately described or completely delineated human IGF2 gene structure or transcript expression, even though all relevant information could be found in the published literature. Although IGF2 shares multiple features with the mouse Igf2 gene, it has several unique properties, including transcription from five promoters. Both genes undergo parental imprinting, with IGF2 / Igf2 being expressed primarily from the paternal chromosome and the adjacent H19 gene from the maternal chromosome. Unlike mouse Igf2 , whose expression declines after birth, human IGF2 remains active throughout life. This characteristic has been attributed to a unique human gene promoter that escapes imprinting, but as shown here, it involves several different promoters with distinct tissue-specific expression patterns. Because new testable hypotheses could lead to critical insights into IGF2 actions in human physiology and disease, it is incumbent that our fundamental understanding is accurate. Similar challenges affecting knowledge of other human genes should promote attempts to critically evaluate, interpret, and correct human genetic data in publicly available databases. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Review: Assessment of completeness of reporting in intervention studies using livestock: an example from pain mitigation interventions in neonatal piglets.

PubMed

O'Connor, A; Anthony, R; Bergamasco, L; Coetzee, J F; Dzikamunhenga, R S; Johnson, A K; Karriker, L A; Marchant-Forde, J N; Martineau, G P; Millman, S T; Pajor, E A; Rutherford, K; Sprague, M; Sutherland, M A; von Borell, E; Webb, S R

2016-04-01

Accurate and complete reporting of study methods, results and interpretation are essential components for any scientific process, allowing end-users to evaluate the internal and external validity of a study. When animals are used in research, excellence in reporting is expected as a matter of continued ethical acceptability of animal use in the sciences. Our primary objective was to assess completeness of reporting for a series of studies relevant to mitigation of pain in neonatal piglets undergoing routine management procedures. Our second objective was to illustrate how authors can report the items in the Reporting guidElines For randomized controLled trials for livEstoCk and food safety (REFLECT) statement using examples from the animal welfare science literature. A total of 52 studies from 40 articles were evaluated using a modified REFLECT statement. No single study reported all REFLECT checklist items. Seven studies reported specific objectives with testable hypotheses. Six studies identified primary or secondary outcomes. Randomization and blinding were considered to be partially reported in 21 and 18 studies, respectively. No studies reported the rationale for sample sizes. Several studies failed to report key design features such as units for measurement, means, standard deviations, standard errors for continuous outcomes or comparative characteristics for categorical outcomes expressed as either rates or proportions. In the discipline of animal welfare science, authors, reviewers and editors are encouraged to use available reporting guidelines to ensure that scientific methods and results are adequately described and free of misrepresentations and inaccuracies. Complete and accurate reporting increases the ability to apply the results of studies to the decision-making process and prevent wastage of financial and animal resources.

Neuroimaging in human MDMA (Ecstasy) users.

PubMed

Cowan, Ronald L; Roberts, Deanne M; Joers, James M

2008-10-01

MDMA (3,4 methylenedioxymethamphetamine) has been used by millions of people worldwide as a recreational drug. The terms "MDMA" and "Ecstasy" are often used synonymously, but it is important to note that the purity of Ecstasy sold as MDMA is not certain. MDMA use is of public health concern, not so much because MDMA produces a common or severe dependence syndrome, but rather because rodent and nonhuman primate studies have indicated that MDMA (when administered at certain dosages and intervals) can cause long-lasting reductions in markers of brain serotonin (5-HT) that appear specific to fine-diameter axons arising largely from the dorsal raphe nucleus (DR). Given the popularity of MDMA, the potential for the drug to produce long-lasting or permanent 5-HT axon damage or loss, and the widespread role of 5-HT function in the brain, there is a great need for a better understanding of brain function in human users of this drug. To this end, neuropsychological, neuroendocrine, and neuroimaging studies have all suggested that human MDMA users may have long-lasting changes in brain function consistent with 5-HT toxicity. Data from animal models leads to testable hypotheses regarding MDMA's effects on the human brain. Because neuropsychological and neuroimaging findings have focused on the neocortex, a cortical model is developed to provide a context for designing and interpreting neuroimaging studies in MDMA users. Aspects of the model are supported by the available neuroimaging data, but there are controversial findings in some areas and most findings have not been replicated across different laboratories and using different modalities. This paper reviews existing findings in the context of a cortical model and suggests directions for future research.

Asthma and risk of lethal prostate cancer in the Health Professionals Follow-Up Study.

PubMed

Platz, Elizabeth A; Drake, Charles G; Wilson, Kathryn M; Sutcliffe, Siobhan; Kenfield, Stacey A; Mucci, Lorelei A; Stampfer, Meir J; Willett, Walter C; Camargo, Carlos A; Giovannucci, Edward

2015-08-15

Inflammation, and more generally, the immune response are thought to influence the development of prostate cancer. To determine the components of the immune response that are potentially contributory, we prospectively evaluated the association of immune-mediated conditions, asthma and hayfever, with lethal prostate cancer risk in the Health Professionals Follow-up Study. We included 47,880 men aged 40-75 years with no prior cancer diagnosis. On the baseline questionnaire in 1986, the men reported diagnoses of asthma and hayfever and year of onset. On the follow-up questionnaires, they reported new asthma and prostate cancer diagnoses. We used Cox proportional hazards regression to estimate relative risks (RRs). In total, 9.2% reported ever having been diagnosed with asthma. In all, 25.3% reported a hayfever diagnosis at baseline. During 995,176 person-years of follow-up by 2012, we confirmed 798 lethal prostate cancer cases (diagnosed with distant metastases, progressed to distant metastasis or died of prostate cancer [N = 625]). Ever having a diagnosis of asthma was inversely associated with risk of lethal (RR = 0.71, 95% confidence interval [CI] = 0.51-1.00) and fatal (RR = 0.64, 95% CI = 0.42-0.96) disease. Hayfever with onset in the distant past was possibly weakly positively associated with risk of lethal (RR = 1.10, 95% CI = 0.92-1.33) and fatal (RR = 1.12, 95% CI = 0.91-1.37) disease. Men who were ever diagnosed with asthma were less likely to develop lethal and fatal prostate cancer. Our findings may lead to testable hypotheses about specific immune profiles in the etiology of lethal prostate cancer. © 2015 UICC.

The UK National Registry of ABO and HLA Antibody Incompatible Renal Transplantation: Pretransplant Factors Associated With Outcome in 879 Transplants

PubMed Central

Pankhurst, Laura; Hudson, Alex; Mumford, Lisa; Willicombe, Michelle; Galliford, Jack; Shaw, Olivia; Thuraisingham, Raj; Puliatti, Carmelo; Talbot, David; Griffin, Sian; Torpey, Nicholas; Ball, Simon; Clark, Brendan; Briggs, David; Fuggle, Susan V.; Higgins, Robert M.

2017-01-01

Background ABO and HLA antibody incompatible (HLAi) renal transplants (AIT) now comprise around 10% of living donor kidney transplants. However, the relationship between pretransplant factors and medium-term outcomes are not fully understood, especially in relation to factors that may vary between centers. Methods The comprehensive national registry of AIT in the United Kingdom was investigated to describe the donor, recipient and transplant characteristics of AIT. Kaplan-Meier analysis was used to compare survival of AIT to all other compatible kidney transplants performed in the United Kingdom. Cox proportional hazards regression modeling was used to determine which pretransplant factors were associated with transplant survival in HLAi and ABOi separately. The primary outcome was transplant survival, taking account of death and graft failure. Results For 522 HLAi and 357 ABO incompatible (ABOi) transplants, 5-year transplant survival rates were 71% (95% confidence interval [CI], 66-75%) for HLAi and 83% (95% CI, 78-87%) for ABOi, compared with 88% (95% CI, 87-89%) for 7290 standard living donor transplants, and 78% (95% CI, 77-79%) for 15 322 standard deceased donor transplants (P < 0.0001). Increased chance of transplant loss in HLAi was associated with increasing number of donor specific HLA antibodies, center performing the transplant, antibody level at the time of transplant, and an interaction between donor age and dialysis status. In ABOi, transplant loss was associated with no use of IVIg, cytomegalovirus seronegative recipient, 000 HLA donor-recipient mismatch; and increasing recipient age. Conclusions Results of AIT were acceptable, certainly in the context of a choice between living donor AIT and an antibody compatible deceased donor transplant. Several factors were associated with increased chance of transplant loss, and these can lead to testable hypotheses for further improving therapy. PMID:28706984

Distinguishing Biologically Controlled Calcareous Biomineralization in Fossil Organisms Using Electron Backscatter Diffraction (EBSD)

NASA Astrophysics Data System (ADS)

Päßler, Jan-Filip; Jarochowska, Emilia; Bestmann, Michel; Munnecke, Axel

2018-02-01

Although carbonate-precipitating cyanobacteria are ubiquitous in aquatic ecosystems today, the criteria used to identify them in the geological record are subjective and rarely testable. Differences in the mode of biomineralization between cyanobacteria and eukaryotes, i.e. biologically induced calcification (BIM) vs. biologically controlled calcification (BCM), result in different crystallographic structures which might be used as a criterion to test cyanobacterial affinities. Cyanobacteria are often used as a ‘wastebasket taxon’, to which various microfossils are assigned. The lack of a testable criterion for the identification of cyanobacteria may bias their fossil record severely. We employed electron backscatter diffraction (EBSD) to investigate the structure of calcareous skeletons in two microproblematica widespread in Palaeozoic marine ecosystems: Rothpletzella, hypothesized to be a cyanobacterium, and an incertae sedis microorganism Allonema. We used a calcareous trilobite shell as a BCM reference. The mineralized structure of Allonema has a simple single-layered structure of acicular crystals perpendicular to the surface of the organism. The c-axes of these crystals are parallel to the elongation and thereby normal to the surface of the organism. EBSD pole figures and misorientation axes distribution reveal a fibre texture around the c-axis with a small degree of variation (up to 30°), indicating a highly ordered structure. A comparable pattern was found in the trilobite shell. This structure allows excluding biologically induced mineralization as the mechanism of shell formation in Allonema. In Rothpletzella, the c-axes of the microcrystalline sheath show a broader clustering compared to Allonema, but still reveal crystals tending to be perpendicular to the surface of the organism. The misorientation axes of adjacent crystals show an approximately random distribution. Rothpletzella also shares morphological similarities with extant cyanobacteria. We propose that the occurrence of a strong misorientation relationship between adjacent crystals with misorientation axes clustering around the c-axis can be used as a proxy for the degree of control exerted by an organism on its mineralized structures. Therefore, precisely constrained distributions of misorientations (misorientation angle and misorientation axis) may be used to identify BCM in otherwise problematic fossils and can be used to ground-truth the cyanobacterial affinities commonly proposed for problematic extinct organisms.

Is Ecosystem-Atmosphere Observation in Long-Term Networks actually Science?

NASA Astrophysics Data System (ADS)

Schmid, H. P. E.

2015-12-01

Science uses observations to build knowledge by testable explanations and predictions. The "scientific method" requires controlled systematic observation to examine questions, hypotheses and predictions. Thus, enquiry along the scientific method responds to questions of the type "what if …?" In contrast, long-term observation programs follow a different strategy: we commonly take great care to minimize our influence on the environment of our measurements, with the aim to maximize their external validity. We observe what we think are key variables for ecosystem-atmosphere exchange and ask questions such as "what happens next?" or "how did this happen?" This apparent deviation from the scientific method begs the question whether any explanations we come up with for the phenomena we observe are actually contributing to testable knowledge, or whether their value remains purely anecdotal. Here, we present examples to argue that, under certain conditions, data from long-term observations and observation networks can have equivalent or even higher scientific validity than controlled experiments. Internal validity is particularly enhanced if observations are combined with modeling. Long-term observations of ecosystem-atmosphere fluxes identify trends and temporal scales of variability. Observation networks reveal spatial patterns and variations, and long-term observation networks combine both aspects. A necessary condition for such observations to gain validity beyond the anecdotal is the requirement that the data are comparable: a comparison of two measured values, separated in time or space, must inform us objectively whether (e.g.) one value is larger than the other. In turn, a necessary condition for the comparability of data is the compatibility of the sensors and procedures used to generate them. Compatibility ensures that we compare "apples to apples": that measurements conducted in identical conditions give the same values (within suitable uncertainty intervals). In principle, a useful tool to achieve comparability and compatibility is the standardization of sensors and methods. However, due to the diversity of ecosystems and settings, standardization in ecosystem-atmosphere exchange is difficult. We discuss some of the challenges and pitfalls of standardization across networks.

The psychological advantage of unfalsifiability: the appeal of untestable religious and political ideologies.

PubMed

Friesen, Justin P; Campbell, Troy H; Kay, Aaron C

2015-03-01

We propose that people may gain certain "offensive" and "defensive" advantages for their cherished belief systems (e.g., religious and political views) by including aspects of unfalsifiability in those belief systems, such that some aspects of the beliefs cannot be tested empirically and conclusively refuted. This may seem peculiar, irrational, or at least undesirable to many people because it is assumed that the primary purpose of a belief is to know objective truth. However, past research suggests that accuracy is only one psychological motivation among many, and falsifiability or testability may be less important when the purpose of a belief serves other psychological motives (e.g., to maintain one's worldviews, serve an identity). In Experiments 1 and 2 we demonstrate the "offensive" function of unfalsifiability: that it allows religious adherents to hold their beliefs with more conviction and political partisans to polarize and criticize their opponents more extremely. Next we demonstrate unfalsifiability's "defensive" function: When facts threaten their worldviews, religious participants frame specific reasons for their beliefs in more unfalsifiable terms (Experiment 3) and political partisans construe political issues as more unfalsifiable ("moral opinion") instead of falsifiable ("a matter of facts"; Experiment 4). We conclude by discussing how in a world where beliefs and ideas are becoming more easily testable by data, unfalsifiability might be an attractive aspect to include in one's belief systems, and how unfalsifiability may contribute to polarization, intractability, and the marginalization of science in public discourse. PsycINFO Database Record (c) 2015 APA, all rights reserved.

Reliability/maintainability/testability design for dormancy

NASA Astrophysics Data System (ADS)

Seman, Robert M.; Etzl, Julius M.; Purnell, Arthur W.

1988-05-01

This document has been prepared as a tool for designers of dormant military equipment and systems. The purpose of this handbook is to provide design engineers with Reliability/Maintainability/Testability design guidelines for systems which spend significant portions of their life cycle in a dormant state. The dormant state is defined as a nonoperating mode where a system experiences very little or no electrical stress. The guidelines in this report present design criteria in the following categories: (1) Part Selection and Control; (2) Derating Practices; (3) Equipment/System Packaging; (4) Transportation and Handling; (5) Maintainability Design; (6) Testability Design; (7) Evaluation Methods for In-Plant and Field Evaluation; and (8) Product Performance Agreements. Whereever applicable, design guidelines for operating systems were included with the dormant design guidelines. This was done in an effort to produce design guidelines for a more complete life cycle. Although dormant systems spend significant portions of their life cycle in a nonoperating mode, the designer must design the system for the complete life cycle, including nonoperating as well as operating modes. The guidelines are primarily intended for use in the design of equipment composed of electronic parts and components. However, they can also be used for the design of systems which encompass both electronic and nonelectronic parts, as well as for the modification of existing systems.

Delay test generation for synchronous sequential circuits

NASA Astrophysics Data System (ADS)

Devadas, Srinivas

1989-05-01

We address the problem of generating tests for delay faults in non-scan synchronous sequential circuits. Delay test generation for sequential circuits is a considerably more difficult problem than delay testing of combinational circuits and has received much less attention. In this paper, we present a method for generating test sequences to detect delay faults in sequential circuits using the stuck-at fault sequential test generator STALLION. The method is complete in that it will generate a delay test sequence for a targeted fault given sufficient CPU time, if such a sequence exists. We term faults for which no delay test sequence exists, under out test methodology, sequentially delay redundant. We describe means of eliminating sequential delay redundancies in logic circuits. We present a partial-scan methodology for enhancing the testability of difficult-to-test of untestable sequential circuits, wherein a small number of flip-flops are selected and made controllable/observable. The selection process guarantees the elimination of all sequential delay redundancies. We show that an intimate relationship exists between state assignment and delay testability of a sequential machine. We describe a state assignment algorithm for the synthesis of sequential machines with maximal delay fault testability. Preliminary experimental results using the test generation, partial-scan and synthesis algorithm are presented.

Ocular biometric parameters among 3-year-old Chinese children: testability, distribution and association with anthropometric parameters

PubMed Central

Huang, Dan; Chen, Xuejuan; Gong, Qi; Yuan, Chaoqun; Ding, Hui; Bai, Jing; Zhu, Hui; Fu, Zhujun; Yu, Rongbin; Liu, Hu

2016-01-01

This survey was conducted to determine the testability, distribution and associations of ocular biometric parameters in Chinese preschool children. Ocular biometric examinations, including the axial length (AL) and corneal radius of curvature (CR), were conducted on 1,688 3-year-old subjects by using an IOLMaster in August 2015. Anthropometric parameters, including height and weight, were measured according to a standardized protocol, and body mass index (BMI) was calculated. The testability was 93.7% for the AL and 78.6% for the CR overall, and both measures improved with age. Girls performed slightly better in AL measurements (P = 0.08), and the difference in CR was statistically significant (P < 0.05). The AL distribution was normal in girls (P = 0.12), whereas it was not in boys (P < 0.05). For CR1, all subgroups presented normal distributions (P = 0.16 for boys; P = 0.20 for girls), but the distribution varied when the subgroups were combined (P < 0.05). CR2 presented a normal distribution (P = 0.11), whereas the AL/CR ratio was abnormal (P < 0.001). Boys exhibited a significantly longer AL, a greater CR and a greater AL/CR ratio than girls (all P < 0.001). PMID:27384307

Bacterial Overgrowth and Irritable Bowel Syndrome: Unifying Hypothesis or a Spurious Consequence of Proton Pump Inhibitors?

PubMed Central

Spiegel, Brennan M.R.; Chey, William D.; Chang, Lin

2010-01-01

Some studies indicate that small intestinal bacterial overgrowth (SIBO), as measured by hydrogen breath tests (HBT), is more prevalent in patients with irritable bowel syndrome (IBS) vs. matched controls without IBS. Although the data are conflicting, this observation has led to the hypothesis that SIBO may be a primary cause of IBS. Yet, it remains unclear whether SIBO is truly fundamental to the pathophysiology of IBS, or is instead a mere epiphenomenon or bystander of something else altogether. We hypothesize that SIBO might be a byproduct of the disproportionate use of proton pump inhibitors (PPIs) in IBS, as follows: (1) IBS patients are more likely than controls to receive PPI therapy; (2) PPI therapy may promote varying forms of SIBO by eliminating gastric acid; and (3) existing studies linking SIBO to IBS have not adjusted for or excluded the use of PPI therapy. When linked together, these premises form the basis for a simple and testable hypothesis: the relationship between SIBO and IBS may be confounded by PPIs. Our article explores these premises, lays out the argument supporting this “PPI hypothesis,” discusses potential implications, and outlines next steps to further investigate this possibility. PMID:19086951

Pathways to cognitive design.

PubMed

Wertz, Annie E; Moya, Cristina

2018-05-30

Despite a shared recognition that the design of the human mind and the design of human culture are tightly linked, researchers in the evolutionary social sciences tend to specialize in understanding one at the expense of the other. The disciplinary boundaries roughly correspond to research traditions that focus more on natural selection and those that focus more on cultural evolution. In this paper, we articulate how two research traditions within the evolutionary social sciences-evolutionary psychology and cultural evolution-approach the study of design. We focus our analysis on the design of cognitive mechanisms that are the result of the interplay of genetic and cultural evolution. We aim to show how the approaches of these two research traditions can complement each other, and provide a framework for developing a wider range of testable hypotheses about cognitive design. To do so, we provide concrete illustrations of how this integrated approach can be used to interrogate cognitive design using examples from our own work on plant and symbolic group boundary cognition. We hope this recognition of different pathways to design will broaden the hypothesis space in the evolutionary social sciences and encourage methodological pluralism in the investigation of the mind. Copyright © 2018 Elsevier B.V. All rights reserved.

Microbiome Networks: A Systems Framework for Identifying Candidate Microbial Assemblages for Disease Management.

PubMed

Poudel, R; Jumpponen, A; Schlatter, D C; Paulitz, T C; Gardener, B B McSpadden; Kinkel, L L; Garrett, K A

2016-10-01

Network models of soil and plant microbiomes provide new opportunities for enhancing disease management, but also challenges for interpretation. We present a framework for interpreting microbiome networks, illustrating how observed network structures can be used to generate testable hypotheses about candidate microbes affecting plant health. The framework includes four types of network analyses. "General network analysis" identifies candidate taxa for maintaining an existing microbial community. "Host-focused analysis" includes a node representing a plant response such as yield, identifying taxa with direct or indirect associations with that node. "Pathogen-focused analysis" identifies taxa with direct or indirect associations with taxa known a priori as pathogens. "Disease-focused analysis" identifies taxa associated with disease. Positive direct or indirect associations with desirable outcomes, or negative associations with undesirable outcomes, indicate candidate taxa. Network analysis provides characterization not only of taxa with direct associations with important outcomes such as disease suppression, biofertilization, or expression of plant host resistance, but also taxa with indirect associations via their association with other key taxa. We illustrate the interpretation of network structure with analyses of microbiomes in the oak phyllosphere, and in wheat rhizosphere and bulk soil associated with the presence or absence of infection by Rhizoctonia solani.

Global Change And Water Availability And Quality: Challenges Ahead

NASA Astrophysics Data System (ADS)

Larsen, M. C.; Ryker, S. J.

2012-12-01

The United States is in the midst of a continental-scale, multi-year water-resources experiment, in which society has not defined testable hypotheses or set the duration and scope of the experiment. What are we doing? We are expanding population at two to three times the national growth rate in our most water-scarce states, in the southwest, where water stress is already great and modeling predicts decreased streamflow by the middle of this century. We are expanding irrigated agriculture from the west into the east, particularly to the southeastern states, where increased competition for ground and surface water has urban, agricultural, and environmental interests at odds, and increasingly, in court. We are expanding our consumption of pharmaceutical and personal care products to historic high levels and disposing of them in surface and groundwater, through sewage treatment plants and individual septic systems that were not designed to treat them. These and other examples of our national-scale experiment are likely to continue well into the 21st century. This experiment and related challenges will continue and likely intensify as non-climatic and climatic factors, such as predicted rising temperature and changes in the distribution of precipitation in time and space, continue to develop.

Computational Approaches to Drug Repurposing and Pharmacology

PubMed Central

Hodos, Rachel A; Kidd, Brian A; Khader, Shameer; Readhead, Ben P; Dudley, Joel T

2016-01-01

Data in the biological, chemical, and clinical domains are accumulating at ever-increasing rates and have the potential to accelerate and inform drug development in new ways. Challenges and opportunities now lie in developing analytic tools to transform these often complex and heterogeneous data into testable hypotheses and actionable insights. This is the aim of computational pharmacology, which uses in silico techniques to better understand and predict how drugs affect biological systems, which can in turn improve clinical use, avoid unwanted side effects, and guide selection and development of better treatments. One exciting application of computational pharmacology is drug repurposing- finding new uses for existing drugs. Already yielding many promising candidates, this strategy has the potential to improve the efficiency of the drug development process and reach patient populations with previously unmet needs such as those with rare diseases. While current techniques in computational pharmacology and drug repurposing often focus on just a single data modality such as gene expression or drug-target interactions, we rationalize that methods such as matrix factorization that can integrate data within and across diverse data types have the potential to improve predictive performance and provide a fuller picture of a drug's pharmacological action. PMID:27080087

Evolutionary medicine: update on the relevance to family practice.

PubMed

Naugler, Christopher T

2008-09-01

To review the relevance of evolutionary medicine to family practice and family physician training. Articles were located through a MEDLINE search, using the key words evolution, Darwin, and adaptation. Most references presented level III evidence (expert opinion), while a minority provided level II evidence (epidemiologic studies). Evolutionary medicine deals with the interplay of biology and the environment in the understanding of human disease. Yet medical schools have virtually ignored the need for family physicians to have more than a cursory knowledge of this topic. A review of the main trends in this field most relevant to family practice revealed that a basic knowledge of evolutionary medicine might help in explaining the causation of diseases to patients. Evolutionary medicine has also proven key to explaining the reasons for the development of antibiotic resistance and has the potential to explain cancer pathogenesis. As an organizing principle, this field also has potential in the teaching of family medicine. Evolutionary medicine should be studied further and incorporated into medical training and practice. Its practical utility will be proven through the generation of testable hypotheses and their application in relation to disease causation and possible prevention.

Characterizing Mystery Cell Lines: Student-driven Research Projects in an Undergraduate Neuroscience Laboratory Course.

PubMed

Lemons, Michele L

2012-01-01

Inquiry-based projects promote discovery and retention of key concepts, increase student engagement, and stimulate interest in research. Described here are a series of lab exercises within an undergraduate upper level neuroscience course that train students to design, execute and analyze their own hypothesis-driven research project. Prior to developing their own projects, students learn several research techniques including aseptic cell culture, cell line maintenance, immunocytochemistry and fluorescent microscopy. Working in groups, students choose how to use these techniques to characterize and identify a "mystery" cell line. Each lab group is given a unique cell line with either a neural, astrocyte, or Schwann cell origin. Working together, students plan and execute experiments to determine the cellular origin and other unique characteristics of their mystery cell line. Students generate testable hypotheses, design interpretable experiments, generate and analyze data, and report their findings in both oral and written formats. Students receive instructor and peer feedback throughout the entire project. In summary, these labs train students the process of scientific research. This series of lab exercises received very strong positive feedback from the students. Reflections on student feedback and plans for future improvements are discussed.

The genomic response of skeletal muscle to methylprednisolone using microarrays: tailoring data mining to the structure of the pharmacogenomic time series

PubMed Central

DuBois, Debra C; Piel, William H; Jusko, William J

2008-01-01

High-throughput data collection using gene microarrays has great potential as a method for addressing the pharmacogenomics of complex biological systems. Similarly, mechanism-based pharmacokinetic/pharmacodynamic modeling provides a tool for formulating quantitative testable hypotheses concerning the responses of complex biological systems. As the response of such systems to drugs generally entails cascades of molecular events in time, a time series design provides the best approach to capturing the full scope of drug effects. A major problem in using microarrays for high-throughput data collection is sorting through the massive amount of data in order to identify probe sets and genes of interest. Due to its inherent redundancy, a rich time series containing many time points and multiple samples per time point allows for the use of less stringent criteria of expression, expression change and data quality for initial filtering of unwanted probe sets. The remaining probe sets can then become the focus of more intense scrutiny by other methods, including temporal clustering, functional clustering and pharmacokinetic/pharmacodynamic modeling, which provide additional ways of identifying the probes and genes of pharmacological interest. PMID:15212590

Characterizing Mystery Cell Lines: Student-driven Research Projects in an Undergraduate Neuroscience Laboratory Course

PubMed Central

Lemons, Michele L.

2012-01-01

Inquiry-based projects promote discovery and retention of key concepts, increase student engagement, and stimulate interest in research. Described here are a series of lab exercises within an undergraduate upper level neuroscience course that train students to design, execute and analyze their own hypothesis-driven research project. Prior to developing their own projects, students learn several research techniques including aseptic cell culture, cell line maintenance, immunocytochemistry and fluorescent microscopy. Working in groups, students choose how to use these techniques to characterize and identify a “mystery” cell line. Each lab group is given a unique cell line with either a neural, astrocyte, or Schwann cell origin. Working together, students plan and execute experiments to determine the cellular origin and other unique characteristics of their mystery cell line. Students generate testable hypotheses, design interpretable experiments, generate and analyze data, and report their findings in both oral and written formats. Students receive instructor and peer feedback throughout the entire project. In summary, these labs train students the process of scientific research. This series of lab exercises received very strong positive feedback from the students. Reflections on student feedback and plans for future improvements are discussed. PMID:23504583

A Scientific Cognitive-Behavioral Model of Tinnitus: Novel Conceptualizations of Tinnitus Distress

PubMed Central

McKenna, Laurence; Handscomb, Lucy; Hoare, Derek J.; Hall, Deborah A.

2014-01-01

The importance of psychological factors in tinnitus distress has been formally recognized for almost three decades. The psychological understanding of why tinnitus can be a distressing condition posits that it becomes problematic when it acquires an emotive significance through cognitive processes. Principle therapeutic efforts are directed at reducing or removing the cognitive (and behavioral) obstacles to habituation. Here, the evidence relevant to a new psychological model of tinnitus is critically reviewed. The model posits that patients’ interpretations of tinnitus and the changes in behavior that result are given a central role in creating and maintaining distress. The importance of selective attention and the possibility that this leads to distorted perception of tinnitus is highlighted. From this body of evidence, we propose a coherent cognitive-behavioral model of tinnitus distress that is more in keeping with contemporary psychological theories of clinical problems (particularly that of insomnia) and which postulates a number of behavioral processes that are seen as cognitively mediated. This new model provides testable hypotheses to guide future research to unravel the complex mechanisms underpinning tinnitus distress. It is also well suited to define individual symptomatology and to provide a framework for the delivery of cognitive-behavioral therapy. PMID:25339938

A parallel implementation of an off-lattice individual-based model of multicellular populations

NASA Astrophysics Data System (ADS)

Harvey, Daniel G.; Fletcher, Alexander G.; Osborne, James M.; Pitt-Francis, Joe

2015-07-01

As computational models of multicellular populations include ever more detailed descriptions of biophysical and biochemical processes, the computational cost of simulating such models limits their ability to generate novel scientific hypotheses and testable predictions. While developments in microchip technology continue to increase the power of individual processors, parallel computing offers an immediate increase in available processing power. To make full use of parallel computing technology, it is necessary to develop specialised algorithms. To this end, we present a parallel algorithm for a class of off-lattice individual-based models of multicellular populations. The algorithm divides the spatial domain between computing processes and comprises communication routines that ensure the model is correctly simulated on multiple processors. The parallel algorithm is shown to accurately reproduce the results of a deterministic simulation performed using a pre-existing serial implementation. We test the scaling of computation time, memory use and load balancing as more processes are used to simulate a cell population of fixed size. We find approximate linear scaling of both speed-up and memory consumption on up to 32 processor cores. Dynamic load balancing is shown to provide speed-up for non-regular spatial distributions of cells in the case of a growing population.

Covariations in ecological scaling laws fostered by community dynamics.

PubMed

Zaoli, Silvia; Giometto, Andrea; Maritan, Amos; Rinaldo, Andrea

2017-10-03

Scaling laws in ecology, intended both as functional relationships among ecologically relevant quantities and the probability distributions that characterize their occurrence, have long attracted the interest of empiricists and theoreticians. Empirical evidence exists of power laws associated with the number of species inhabiting an ecosystem, their abundances, and traits. Although their functional form appears to be ubiquitous, empirical scaling exponents vary with ecosystem type and resource supply rate. The idea that ecological scaling laws are linked has been entertained before, but the full extent of macroecological pattern covariations, the role of the constraints imposed by finite resource supply, and a comprehensive empirical verification are still unexplored. Here, we propose a theoretical scaling framework that predicts the linkages of several macroecological patterns related to species' abundances and body sizes. We show that such a framework is consistent with the stationary-state statistics of a broad class of resource-limited community dynamics models, regardless of parameterization and model assumptions. We verify predicted theoretical covariations by contrasting empirical data and provide testable hypotheses for yet unexplored patterns. We thus place the observed variability of ecological scaling exponents into a coherent statistical framework where patterns in ecology embed constrained fluctuations.

Temporal Structure in Cooperative Interactions: What Does the Timing of Exploitation Tell Us about Its Cost?

PubMed Central

Barker, Jessica L.; Bronstein, Judith L.

2016-01-01

Exploitation in cooperative interactions both within and between species is widespread. Although it is assumed to be costly to be exploited, mechanisms to control exploitation are surprisingly rare, making the persistence of cooperation a fundamental paradox in evolutionary biology and ecology. Focusing on between-species cooperation (mutualism), we hypothesize that the temporal sequence in which exploitation occurs relative to cooperation affects its net costs and argue that this can help explain when and where control mechanisms are observed in nature. Our principal prediction is that when exploitation occurs late relative to cooperation, there should be little selection to limit its effects (analogous to “tolerated theft” in human cooperative groups). Although we focus on cases in which mutualists and exploiters are different individuals (of the same or different species), our inferences can readily be extended to cases in which individuals exhibit mixed cooperative-exploitative strategies. We demonstrate that temporal structure should be considered alongside spatial structure as an important process affecting the evolution of cooperation. We also provide testable predictions to guide future empirical research on interspecific as well as intraspecific cooperation. PMID:26841169

Taking Bioinformatics to Systems Medicine.

PubMed

van Kampen, Antoine H C; Moerland, Perry D

2016-01-01

Systems medicine promotes a range of approaches and strategies to study human health and disease at a systems level with the aim of improving the overall well-being of (healthy) individuals, and preventing, diagnosing, or curing disease. In this chapter we discuss how bioinformatics critically contributes to systems medicine. First, we explain the role of bioinformatics in the management and analysis of data. In particular we show the importance of publicly available biological and clinical repositories to support systems medicine studies. Second, we discuss how the integration and analysis of multiple types of omics data through integrative bioinformatics may facilitate the determination of more predictive and robust disease signatures, lead to a better understanding of (patho)physiological molecular mechanisms, and facilitate personalized medicine. Third, we focus on network analysis and discuss how gene networks can be constructed from omics data and how these networks can be decomposed into smaller modules. We discuss how the resulting modules can be used to generate experimentally testable hypotheses, provide insight into disease mechanisms, and lead to predictive models. Throughout, we provide several examples demonstrating how bioinformatics contributes to systems medicine and discuss future challenges in bioinformatics that need to be addressed to enable the advancement of systems medicine.

BioAssay Research Database (BARD): chemical biology and probe-development enabled by structured metadata and result types

PubMed Central

Howe, E.A.; de Souza, A.; Lahr, D.L.; Chatwin, S.; Montgomery, P.; Alexander, B.R.; Nguyen, D.-T.; Cruz, Y.; Stonich, D.A.; Walzer, G.; Rose, J.T.; Picard, S.C.; Liu, Z.; Rose, J.N.; Xiang, X.; Asiedu, J.; Durkin, D.; Levine, J.; Yang, J.J.; Schürer, S.C.; Braisted, J.C.; Southall, N.; Southern, M.R.; Chung, T.D.Y.; Brudz, S.; Tanega, C.; Schreiber, S.L.; Bittker, J.A.; Guha, R.; Clemons, P.A.

2015-01-01

BARD, the BioAssay Research Database (https://bard.nih.gov/) is a public database and suite of tools developed to provide access to bioassay data produced by the NIH Molecular Libraries Program (MLP). Data from 631 MLP projects were migrated to a new structured vocabulary designed to capture bioassay data in a formalized manner, with particular emphasis placed on the description of assay protocols. New data can be submitted to BARD with a user-friendly set of tools that assist in the creation of appropriately formatted datasets and assay definitions. Data published through the BARD application program interface (API) can be accessed by researchers using web-based query tools or a desktop client. Third-party developers wishing to create new tools can use the API to produce stand-alone tools or new plug-ins that can be integrated into BARD. The entire BARD suite of tools therefore supports three classes of researcher: those who wish to publish data, those who wish to mine data for testable hypotheses, and those in the developer community who wish to build tools that leverage this carefully curated chemical biology resource. PMID:25477388

A General, Synthetic Model for Predicting Biodiversity Gradients from Environmental Geometry.

PubMed

Gross, Kevin; Snyder-Beattie, Andrew

2016-10-01

Latitudinal and elevational biodiversity gradients fascinate ecologists, and have inspired dozens of explanations. The geometry of the abiotic environment is sometimes thought to contribute to these gradients, yet evaluations of geometric explanations are limited by a fragmented understanding of the diversity patterns they predict. This article presents a mathematical model that synthesizes multiple pathways by which environmental geometry can drive diversity gradients. The model characterizes species ranges by their environmental niches and limits on range sizes and places those ranges onto the simplified geometries of a sphere or cone. The model predicts nuanced and realistic species-richness gradients, including latitudinal diversity gradients with tropical plateaus and mid-latitude inflection points and elevational diversity gradients with low-elevation diversity maxima. The model also illustrates the importance of a mid-environment effect that augments species richness at locations with intermediate environments. Model predictions match multiple empirical biodiversity gradients, depend on ecological traits in a testable fashion, and formally synthesize elements of several geometric models. Together, these results suggest that previous assessments of geometric hypotheses should be reconsidered and that environmental geometry may play a deeper role in driving biodiversity gradients than is currently appreciated.

How do arbuscular mycorrhizal fungi handle phosphate? New insight into fine-tuning of phosphate metabolism.

PubMed

Ezawa, Tatsuhiro; Saito, Katsuharu

2018-04-27

Contents Summary I. Introduction II. Foraging for phosphate III. Fine-tuning of phosphate homeostasis IV. The frontiers: phosphate translocation and export V. Conclusions and outlook Acknowledgements References SUMMARY: Arbuscular mycorrhizal fungi form symbiotic associations with most land plants and deliver mineral nutrients, in particular phosphate, to the host. Therefore, understanding the mechanisms of phosphate acquisition and delivery in the fungi is critical for full appreciation of the mutualism in this association. Here, we provide updates on physical, chemical, and biological strategies of the fungi for phosphate acquisition, including interactions with phosphate-solubilizing bacteria, and those on the regulatory mechanisms of phosphate homeostasis based on resurveys of published genome sequences and a transcriptome with reference to the latest findings in a model fungus. For the mechanisms underlying phosphate translocation and export to the host, which are major research frontiers in this field, not only recent advances but also testable hypotheses are proposed. Lastly, we briefly discuss applicability of the latest tools to gene silencing in the fungi, which will be breakthrough techniques for comprehensive understanding of the molecular basis of fungal phosphate metabolism. © 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.

Motor control may support mirror neuron research with new hypotheses and methods. Reply to comments on "Grasping synergies: A motor-control approach to the mirror neuron mechanism"

NASA Astrophysics Data System (ADS)

D'Ausilio, Alessandro; Bartoli, Eleonora; Maffongelli, Laura

2015-03-01

We are grateful to all commentators for their insightful commentaries and observations that enrich our proposal. One of our aims was indeed to bridge the gap between fields of research that, progressing independently, are facing similar issues regarding the neural representation of motor knowledge. In this respect, we were pleased to receive feedback from eminent researchers on both the mirror neuron as well as the motor control fields. Their expertise covers animal and human neurophysiology, as well as the computational modeling of neural and behavioral processes. Given their heterogeneous cultural perspectives and research approaches, a number of important open questions were raised. For simplicity we separated these issues into four sections. In the first section we present methodological aspects regarding how synergies can be measured in paradigms investigating the human mirror system. The second section regards the fundamental definition of what exactly synergies might be. The third concerns how synergies can generate testable predictions in mirror neuron research. Finally, the fourth section deals with the ultimate question regarding the function of the mirror neuron system.

Formalizing an integrative, multidisciplinary cancer therapy discovery workflow

PubMed Central

McGuire, Mary F.; Enderling, Heiko; Wallace, Dorothy I.; Batra, Jaspreet; Jordan, Marie; Kumar, Sushil; Panetta, John C.; Pasquier, Eddy

2014-01-01

Although many clinicians and researchers work to understand cancer, there has been limited success to effectively combine forces and collaborate over time, distance, data and budget constraints. Here we present a workflow template for multidisciplinary cancer therapy that was developed during the 2nd Annual Workshop on Cancer Systems Biology sponsored by Tufts University, Boston, MA in July 2012. The template was applied to the development of a metronomic therapy backbone for neuroblastoma. Three primary groups were identified: clinicians, biologists, and scientists (mathematicians, computer scientists, physicists and engineers). The workflow described their integrative interactions; parallel or sequential processes; data sources and computational tools at different stages as well as the iterative nature of therapeutic development from clinical observations to in vitro, in vivo, and clinical trials. We found that theoreticians in dialog with experimentalists could develop calibrated and parameterized predictive models that inform and formalize sets of testable hypotheses, thus speeding up discovery and validation while reducing laboratory resources and costs. The developed template outlines an interdisciplinary collaboration workflow designed to systematically investigate the mechanistic underpinnings of a new therapy and validate that therapy to advance development and clinical acceptance. PMID:23955390

Stereoacuity of preschool children with and without vision disorders.

PubMed

Ciner, Elise B; Ying, Gui-Shuang; Kulp, Marjean Taylor; Maguire, Maureen G; Quinn, Graham E; Orel-Bixler, Deborah; Cyert, Lynn A; Moore, Bruce; Huang, Jiayan

2014-03-01

To evaluate associations between stereoacuity and presence, type, and severity of vision disorders in Head Start preschool children and determine testability and levels of stereoacuity by age in children without vision disorders. Stereoacuity of children aged 3 to 5 years (n = 2898) participating in the Vision in Preschoolers (VIP) Study was evaluated using the Stereo Smile II test during a comprehensive vision examination. This test uses a two-alternative forced-choice paradigm with four stereoacuity levels (480 to 60 seconds of arc). Children were classified by the presence (n = 871) or absence (n = 2027) of VIP Study-targeted vision disorders (amblyopia, strabismus, significant refractive error, or unexplained reduced visual acuity), including type and severity. Median stereoacuity between groups and among severity levels of vision disorders was compared using Wilcoxon rank sum and Kruskal-Wallis tests. Testability and stereoacuity levels were determined for children without VIP Study-targeted disorders overall and by age. Children with VIP Study-targeted vision disorders had significantly worse median stereoacuity than that of children without vision disorders (120 vs. 60 seconds of arc, p < 0.001). Children with the most severe vision disorders had worse stereoacuity than that of children with milder disorders (median 480 vs. 120 seconds of arc, p < 0.001). Among children without vision disorders, testability was 99.6% overall, increasing with age to 100% for 5-year-olds (p = 0.002). Most of the children without vision disorders (88%) had stereoacuity at the two best disparities (60 or 120 seconds of arc); the percentage increasing with age (82% for 3-, 89% for 4-, and 92% for 5-year-olds; p < 0.001). The presence of any VIP Study-targeted vision disorder was associated with significantly worse stereoacuity in preschool children. Severe vision disorders were more likely associated with poorer stereopsis than milder or no vision disorders. Testability was excellent at all ages. These results support the validity of the Stereo Smile II for assessing random-dot stereoacuity in preschool children.

Darwinian hydrology: can the methodology Charles Darwin pioneered help hydrologic science?

NASA Astrophysics Data System (ADS)

Harman, C.; Troch, P. A.

2013-05-01

There have been repeated calls for a Darwinian approach to hydrologic science or for a synthesis of Darwinian and Newtonian approaches, to deepen understanding the hydrologic system in the larger landscape context, and so develop a better basis for predictions now and in an uncertain future. But what exactly makes a Darwinian approach to hydrology "Darwinian"? While there have now been a number of discussions of Darwinian approaches, many referencing Harte (2002), the term is potentially a source of confusion while its connections to Darwin remain allusive rather than explicit. Here we discuss the methods that Charles Darwin pioneered to understand a variety of complex systems in terms of their historical processes of change. We suggest that the Darwinian approach to hydrology follows his lead by focusing attention on the patterns of variation in populations, seeking hypotheses that explain these patterns in terms of the mechanisms and conditions that determine their historical development, using deduction and modeling to derive consequent hypotheses that follow from a proposed explanation, and critically testing these hypotheses against new observations. It is not sufficient to catalogue the patterns or predict them statistically. Nor is it sufficient for the explanations to amount to a "just-so" story not subject to critical analysis. Darwin's theories linked present-day variation to mechanisms that operated over history, and could be independently test and falsified by comparing new observations to the predictions of corollary hypotheses they generated. With a Darwinian framework in mind it is easy to see that a great deal of hydrologic research has already been done that contributes to a Darwinian hydrology - whether deliberately or not. The various heuristic methods that Darwin used to develop explanatory theories - extrapolating mechanisms, space for time substitution, and looking for signatures of history - have direct application in hydrologic science. Some are already in use, while others are not and could be used to develop new insights. Darwin sought explanatory theories that intelligibly connected disparate facts, that were testable and falsifiable, and that had fertile implications for further research. While a synthesis of the Darwinian and Newtonian approaches remains a goal, the Darwinian approach to hydrologic science has significant value of its own The Darwinian hydrology that has been conducted already has not been coordinated or linked into a general body of theory and knowledge, but the time is ccoming when this will be possible.

Language, music, syntax and the brain.

PubMed

Patel, Aniruddh D

2003-07-01

The comparative study of music and language is drawing an increasing amount of research interest. Like language, music is a human universal involving perceptually discrete elements organized into hierarchically structured sequences. Music and language can thus serve as foils for each other in the study of brain mechanisms underlying complex sound processing, and comparative research can provide novel insights into the functional and neural architecture of both domains. This review focuses on syntax, using recent neuroimaging data and cognitive theory to propose a specific point of convergence between syntactic processing in language and music. This leads to testable predictions, including the prediction that that syntactic comprehension problems in Broca's aphasia are not selective to language but influence music perception as well.

Family nonuniversal Z' models with protected flavor-changing interactions

NASA Astrophysics Data System (ADS)

Celis, Alejandro; Fuentes-Martín, Javier; Jung, Martin; Serôdio, Hugo

2015-07-01

We define a new class of Z' models with neutral flavor-changing interactions at tree level in the down-quark sector. They are related in an exact way to elements of the quark mixing matrix due to an underlying flavored U(1)' gauge symmetry, rendering these models particularly predictive. The same symmetry implies lepton-flavor nonuniversal couplings, fully determined by the gauge structure of the model. Our models allow us to address presently observed deviations from the standard model and specific correlations among the new physics contributions to the Wilson coefficients C9,10' ℓ can be tested in b →s ℓ+ℓ- transitions. We furthermore predict lepton-universality violations in Z' decays, testable at the LHC.

Using biological markets principles to examine patterns of grooming exchange in Macaca thibetana.

PubMed

Balasubramaniam, K N; Berman, C M; Ogawa, H; Li, J

2011-12-01

Biological markets principles offer testable hypotheses to explain variation in grooming exchange patterns among nonhuman primates. They predict that when within-group contest competition (WGC) is high and dominance hierarchies steep, grooming interchange with other "commodity" behaviors (such as agonistic support) should prevail. In contrast, when WGC is low and gradients shallow, market theory predicts that grooming reciprocity should prevail. We tested these predictions in a wild, provisioned Tibetan macaque (Macaca thibetana) group across six time periods during which the group had been subjected to varying degrees of range restriction. Data on female-female aggression, grooming, and support were collected using all-occurrences and focal animal sampling techniques, and analyzed using ANCOVA methods and correlation analyses. We found that hierarchical steepness varied significantly across periods, but did not correlate with two indirect indicators of WGC (group size and range restriction) in predicted directions. Contrary to expectations, we found a negative correlation between steepness and group size, perhaps because the responses of group members to external risks (i.e. prolonged and unavoidable exposure to humans) may have overshadowed the effects of WGC. As predicted, grooming reciprocity was significant in each period and negatively correlated with steepness, even after we controlled group size, kinship, rank differences, and proximity. In contrast, there was no evidence for grooming interchange with agonistic support or for a positive relationship between interchange and steepness. We hypothesize that stressful conditions and/or the presence of stable hierarchies during each period may have led to a greater market demand for grooming than support. We suggest that future studies testing these predictions consider more direct measures of WGC and commodities in addition to support, such as feeding tolerance and access to infants. © 2011 Wiley Periodicals, Inc.

A Motor-Gradient and Clustering Model of the Centripetal Motility of MTOCs in Meiosis I of Mouse Oocytes

PubMed Central

2016-01-01

Asters nucleated by Microtubule (MT) organizing centers (MTOCs) converge on chromosomes during spindle assembly in mouse oocytes undergoing meiosis I. Time-lapse imaging suggests that this centripetal motion is driven by a biased ‘search-and-capture’ mechanism. Here, we develop a model of a random walk in a drift field to test the nature of the bias and the spatio-temporal dynamics of the search process. The model is used to optimize the spatial field of drift in simulations, by comparison to experimental motility statistics. In a second step, this optimized gradient is used to determine the location of immobilized dynein motors and MT polymerization parameters, since these are hypothesized to generate the gradient of forces needed to move MTOCs. We compare these scenarios to self-organized mechanisms by which asters have been hypothesized to find the cell-center- MT pushing at the cell-boundary and clustering motor complexes. By minimizing the error between simulation outputs and experiments, we find a model of “pulling” by a gradient of dynein motors alone can drive the centripetal motility. Interestingly, models of passive MT based “pushing” at the cortex, clustering by cross-linking motors and MT-dynamic instability gradients alone, by themselves do not result in the observed motility. The model predicts the sensitivity of the results to motor density and stall force, but not MTs per aster. A hybrid model combining a chromatin-centered immobilized dynein gradient, diffusible minus-end directed clustering motors and pushing at the cell cortex, is required to comprehensively explain the available data. The model makes experimentally testable predictions of a spatial bias and self-organized mechanisms by which MT asters can find the center of a large cell. PMID:27706163

Rooster feathering, androgenic alopecia, and hormone dependent tumor growth: What is in common?

PubMed Central

Mayer, Julie Ann; Chuong, Cheng-Ming; Widelitz, Randall

2015-01-01

Different epithelial organs form as a result of epithelial - mesenchymal interactions and share a common theme modulated by variations (Chuong edit. In Molecular Basis of Epithelial Appendage Morphogenesis, 1998). One of the major modulators is the sex hormone pathway that acts on the prototype signaling pathway to alter organ phenotypes. Here we focus on how the sex hormone pathway interfaces with epithelia morphogenesis related signaling pathways. We first survey these sex hormone regulated morphogenetic processes in various epithelial organs. Sexual dimorphism of hairs and feathers has implications in sexual selection. Diseases of these pathways result in androgenic alopecia, hirsutism, henny feathering, etc. The growth and development of mammary glands, prostate glands and external genitalia essential for reproductive function are also dependent on sex hormones. Diseases affecting these organs include congenital anomalies and hormone dependent type of breast and prostate cancers. To study the role of sex hormones in new growth in the context of system biology / pathology, an in vivo model in which organ formation starts from stem cells is essential. With recent developments (Yu et al., The morphogenesis of feathers. Nature 420:308–312, 2002), the growth of tail feathers in roosters and hens has become a testable model in which experimental manipulations are possible. We show exemplary data of differences in their growth rate, proliferative cell population and signaling molecule expression. Working hypotheses are proposed on how the sex hormone pathways may interact with growth pathways. It is now possible to test these hypotheses using the chicken model to learn fundamental mechanisms on how sex hormones affect organogenesis, epithelial organ cycling, and growth related tumorigenesis. PMID:15617560

A genetics-based approach confirms immune associations with life history across multiple populations of an aquatic vertebrate (Gasterosteus aculeatus).

PubMed

Whiting, James R; Magalhaes, Isabel S; Singkam, Abdul R; Robertson, Shaun; D'Agostino, Daniele; Bradley, Janette E; MacColl, Andrew D C

2018-06-20

Understanding how wild immune variation covaries with other traits can reveal how costs and trade-offs shape immune evolution in the wild. Divergent life history strategies may increase or alleviate immune costs, helping shape immune variation in a consistent, testable way. Contrasting hypotheses suggest that shorter life histories may alleviate costs by offsetting them against increased mortality; or increase the effect of costs if immune responses are traded off against development or reproduction. We investigated the evolutionary relationship between life history and immune responses within an island radiation of three-spined stickleback, with discrete populations of varying life histories and parasitism. We sampled two short-lived, two long-lived and an anadromous population using qPCR to quantify current immune profile and RAD-seq data to study the distribution of immune variants within our assay genes and across the genome. Short-lived populations exhibited significantly increased expression of all assay genes, which was accompanied by a strong association with population-level variation in local alleles and divergence in a gene that may be involved in complement pathways. In addition, divergence around the eda gene in anadromous fish is likely associated with increased inflammation. A wider analysis of 15 populations across the island revealed that immune genes across the genome show evidence of having diverged alongside life history strategies. Parasitism and reproductive investment were also important sources of variation for expression, highlighting the caution required when assaying immune responses in the wild. These results provide strong, gene-based support for current hypotheses linking life history and immune variation across multiple populations of a vertebrate model. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Boundary Condition Effects on Hillslope Form and Soil Development Along a Climatic Gradient From Semiarid to Hyperarid in Northern Chile

NASA Astrophysics Data System (ADS)

Owen, J. J.; Dietrich, W. E.; Nishiizumi, K.; Bellugi, D.; Amundson, R.

2008-12-01

Modeling the development of hillslopes using mass balance equations has generated many testable hypotheses related to morphology, process rates, and soil properties, however it is only relatively recently that techniques for constraining these models (such as cosmogenic radionuclides) have become commonplace. As such, many hypotheses related to the effects of boundary conditions or climate on process rates and soil properties have been left untested. We selected pairs of hillslopes along a precipitation gradient in northern Chile (24°-30° S) which were either bounded by actively eroding (bedrock-bedded) channels or by stable or aggradational landforms (pediments, colluvial aprons, valley bottoms). For each hillslope we measured soil properties, atmospheric deposition rates, and bedrock denudation rates. We observe significant changes in soil properties with climate: there is a shift from thick, weathered soils in the semiarid south, to the near absence of soil in the arid middle, to salt-rich soils in the hyperarid north. Coincident with these are dramatic changes in the types and rates of processes acting on the soils. We found relatively quick, biotically-driven soil formation and transport in the south, and very slow, salt-driven processes in the north. Additionally, we observe systematic differences between hillslopes of different boundary condition within the same climate zone, such as thicker soils, gentler slopes, and slower erosion rates on hillslopes with a non-eroding boundary versus an eroding boundary. These support general predictions based on hillslope soil mass balance equations and geomorphic transport laws. Using parameters derived from our field data, we attempt to use a mass balance model of hillslope development to explore the effect of changing boundary conditions and/or shifting climate.

A four-component model of the action potential in mouse detrusor smooth muscle cell

PubMed Central

Brain, Keith L.; Young, John S.; Manchanda, Rohit

2018-01-01

Background and hypothesis Detrusor smooth muscle cells (DSMCs) of the urinary bladder are electrically connected to one another via gap junctions and form a three dimensional syncytium. DSMCs exhibit spontaneous electrical activity, including passive depolarizations and action potentials. The shapes of spontaneous action potentials (sAPs) observed from a single DSM cell can vary widely. The biophysical origins of this variability, and the precise components which contribute to the complex shapes observed are not known. To address these questions, the basic components which constitute the sAPs were investigated. We hypothesized that linear combinations of scaled versions of these basic components can produce sAP shapes observed in the syncytium. Methods and results The basic components were identified as spontaneous evoked junction potentials (sEJP), native AP (nAP), slow after hyperpolarization (sAHP) and very slow after hyperpolarization (vsAHP). The experimental recordings were grouped into two sets: a training data set and a testing data set. A training set was used to estimate the components, and a test set to evaluate the efficiency of the estimated components. We found that a linear combination of the identified components when appropriately amplified and time shifted replicated various AP shapes to a high degree of similarity, as quantified by the root mean square error (RMSE) measure. Conclusions We conclude that the four basic components—sEJP, nAP, sAHP, and vsAHP—identified and isolated in this work are necessary and sufficient to replicate all varieties of the sAPs recorded experimentally in DSMCs. This model has the potential to generate testable hypotheses that can help identify the physiological processes underlying various features of the sAPs. Further, this model also provides a means to classify the sAPs into various shape classes. PMID:29351282

A four-component model of the action potential in mouse detrusor smooth muscle cell.

PubMed

Padmakumar, Mithun; Brain, Keith L; Young, John S; Manchanda, Rohit

2018-01-01

Detrusor smooth muscle cells (DSMCs) of the urinary bladder are electrically connected to one another via gap junctions and form a three dimensional syncytium. DSMCs exhibit spontaneous electrical activity, including passive depolarizations and action potentials. The shapes of spontaneous action potentials (sAPs) observed from a single DSM cell can vary widely. The biophysical origins of this variability, and the precise components which contribute to the complex shapes observed are not known. To address these questions, the basic components which constitute the sAPs were investigated. We hypothesized that linear combinations of scaled versions of these basic components can produce sAP shapes observed in the syncytium. The basic components were identified as spontaneous evoked junction potentials (sEJP), native AP (nAP), slow after hyperpolarization (sAHP) and very slow after hyperpolarization (vsAHP). The experimental recordings were grouped into two sets: a training data set and a testing data set. A training set was used to estimate the components, and a test set to evaluate the efficiency of the estimated components. We found that a linear combination of the identified components when appropriately amplified and time shifted replicated various AP shapes to a high degree of similarity, as quantified by the root mean square error (RMSE) measure. We conclude that the four basic components-sEJP, nAP, sAHP, and vsAHP-identified and isolated in this work are necessary and sufficient to replicate all varieties of the sAPs recorded experimentally in DSMCs. This model has the potential to generate testable hypotheses that can help identify the physiological processes underlying various features of the sAPs. Further, this model also provides a means to classify the sAPs into various shape classes.

A model study on the circuit mechanism underlying decision-making in Drosophila.

PubMed

Wu, Zhihua; Guo, Aike

2011-05-01

Previous elegant experiments in a flight simulator showed that conditioned Drosophila is able to make a clear-cut decision to avoid potential danger. When confronted with conflicting visual cues, the relative saliency of two competing cues is found to be a sensory ruler for flies to judge which cue should be used for decision-making. Further genetic manipulations and immunohistological analysis revealed that the dopamine system and mushroom bodies are indispensable for such a clear-cut or nonlinear decision. The neural circuit mechanism, however, is far from being clear. In this paper, we adopt a computational modeling approach to investigate how different brain areas and the dopamine system work together to drive a fly to make a decision. By developing a systems-level neural network, a two-pathway circuit is proposed. Besides a direct pathway from a feature binding area to the motor center, another connects two areas via the mushroom body, a target of dopamine release. A raised dopamine level is hypothesized to be induced by complex choice tasks and to enhance lateral inhibition and steepen the units' response gain in the mushroom body. Simulations show that training helps to assign values to formerly neutral features. For a circuit model with a blocked mushroom body, the direct pathway passes all alternatives to the motor center without changing original values, giving rise to a simple choice characterized by a linear choice curve. With respect to an intact circuit, enhanced lateral inhibition dependent on dopamine critically promotes competition between alternatives, turning the linear- into nonlinear choice behavior. Results account well for experimental data, supporting the reasonableness of model working hypotheses. Several testable predictions are made for future studies. Copyright © 2011 Elsevier Ltd. All rights reserved.

A review of the evolution of viviparity in squamate reptiles: the past, present and future role of molecular biology and genomics.

PubMed

Murphy, Bridget F; Thompson, Michael B

2011-07-01

Squamate reptiles (lizards and snakes) offer a unique model system for testing hypotheses about the evolutionary transition from oviparity (egg-laying) to viviparity (live-bearing) in amniote vertebrates. The evolution of squamate viviparity has occurred remarkably frequently (>108 times) and has resulted in major changes in reproductive physiology. Such frequent changes in reproductive strategy pose two questions: (1) what are the molecular mechanisms responsible for the evolution of squamate viviparity? (2) Are these molecular mechanisms the same for separate origins of viviparity? Molecular approaches, such as RT-PCR, in situ hybridisation, Western blotting and immunofluorescence, have been invaluable for identifying genes and proteins that are involved in squamate placental development, materno-foetal immunotolerance, placental transport, placental angiogenesis, hormone synthesis and hormone receptor expression. However, the candidate-gene or -protein approach that has been used until now does not allow for de novo gene/protein discovery; results to date suggest that the reproductive physiologies of mammals and squamate reptiles are very similar, but this conclusion may simply be due to a limited capacity to study the subset of genes and proteins that are unique to reptiles. Progress has also been slowed by the lack of appropriate molecular and genomic resources for squamate reptiles. The advent of next-generation sequencing provides a relatively inexpensive way to conduct rapid high-throughput sequencing of genomes and transcriptomes. We discuss the potential use of next-generation sequencing technologies to analyse differences in gene expression between oviparous and viviparous squamates, provide important sequence information for reptiles, and generate testable hypotheses for the evolution of viviparity.

A Motor-Gradient and Clustering Model of the Centripetal Motility of MTOCs in Meiosis I of Mouse Oocytes.

PubMed

Khetan, Neha; Athale, Chaitanya A

2016-10-01

Asters nucleated by Microtubule (MT) organizing centers (MTOCs) converge on chromosomes during spindle assembly in mouse oocytes undergoing meiosis I. Time-lapse imaging suggests that this centripetal motion is driven by a biased 'search-and-capture' mechanism. Here, we develop a model of a random walk in a drift field to test the nature of the bias and the spatio-temporal dynamics of the search process. The model is used to optimize the spatial field of drift in simulations, by comparison to experimental motility statistics. In a second step, this optimized gradient is used to determine the location of immobilized dynein motors and MT polymerization parameters, since these are hypothesized to generate the gradient of forces needed to move MTOCs. We compare these scenarios to self-organized mechanisms by which asters have been hypothesized to find the cell-center- MT pushing at the cell-boundary and clustering motor complexes. By minimizing the error between simulation outputs and experiments, we find a model of "pulling" by a gradient of dynein motors alone can drive the centripetal motility. Interestingly, models of passive MT based "pushing" at the cortex, clustering by cross-linking motors and MT-dynamic instability gradients alone, by themselves do not result in the observed motility. The model predicts the sensitivity of the results to motor density and stall force, but not MTs per aster. A hybrid model combining a chromatin-centered immobilized dynein gradient, diffusible minus-end directed clustering motors and pushing at the cell cortex, is required to comprehensively explain the available data. The model makes experimentally testable predictions of a spatial bias and self-organized mechanisms by which MT asters can find the center of a large cell.

Forensic interpretation of molecular variation on networks of disease transmission and genetic inheritance.

PubMed

Velsko, Stephan P; Osburn, Joanne; Allen, Jonathan

2014-11-01

This paper describes the inference-on-networks (ION) framework for forensic interpretat ION of molecular typing data in cases involving allegations of infectious microbial transmission, association of disease outbreaks with alleged sources, and identifying familial relationships using mitochondrial or Y chromosomal DNA. The framework is applicable to molecular typing data obtained using any technique, including those based on electrophoretic separations. A key insight is that the networks associated with disease transmission or DNA inheritance can be used to define specific testable relationships and avoid the ambiguity and subjectivity associated with the criteria used for inferring genetic relatedness now in use. We discuss specific applications of the framework to the 2003 severe acute respiratory syndrome (SARS) outbreak in Singapore and the 2001 foot-and-mouth disease virus (FMDV) outbreak in Great Britain. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

A discrete control model of PLANT

NASA Technical Reports Server (NTRS)

Mitchell, C. M.

1985-01-01

A model of the PLANT system using the discrete control modeling techniques developed by Miller is described. Discrete control models attempt to represent in a mathematical form how a human operator might decompose a complex system into simpler parts and how the control actions and system configuration are coordinated so that acceptable overall system performance is achieved. Basic questions include knowledge representation, information flow, and decision making in complex systems. The structure of the model is a general hierarchical/heterarchical scheme which structurally accounts for coordination and dynamic focus of attention. Mathematically, the discrete control model is defined in terms of a network of finite state systems. Specifically, the discrete control model accounts for how specific control actions are selected from information about the controlled system, the environment, and the context of the situation. The objective is to provide a plausible and empirically testable accounting and, if possible, explanation of control behavior.

Black/White Differences in Adolescent Drug Use: A Test of Six Hypotheses

ERIC Educational Resources Information Center

Rote, Sunshine M.; Taylor, John

2014-01-01

Six specific hypotheses have been developed to account for why Caucasians have higher rates of drug use compared to African-Americans. This article utilizes data from a South Florida-based community study of 893 young adults (1998-2002) to test these hypotheses. Specifically, Caucasians (1) initiate drug use at younger ages than African-Americans…

A simple theoretical framework for understanding heterogeneous differentiation of CD4+ T cells

PubMed Central

2012-01-01

Background CD4+ T cells have several subsets of functional phenotypes, which play critical yet diverse roles in the immune system. Pathogen-driven differentiation of these subsets of cells is often heterogeneous in terms of the induced phenotypic diversity. In vitro recapitulation of heterogeneous differentiation under homogeneous experimental conditions indicates some highly regulated mechanisms by which multiple phenotypes of CD4+ T cells can be generated from a single population of naïve CD4+ T cells. Therefore, conceptual understanding of induced heterogeneous differentiation will shed light on the mechanisms controlling the response of populations of CD4+ T cells under physiological conditions. Results We present a simple theoretical framework to show how heterogeneous differentiation in a two-master-regulator paradigm can be governed by a signaling network motif common to all subsets of CD4+ T cells. With this motif, a population of naïve CD4+ T cells can integrate the signals from their environment to generate a functionally diverse population with robust commitment of individual cells. Notably, two positive feedback loops in this network motif govern three bistable switches, which in turn, give rise to three types of heterogeneous differentiated states, depending upon particular combinations of input signals. We provide three prototype models illustrating how to use this framework to explain experimental observations and make specific testable predictions. Conclusions The process in which several types of T helper cells are generated simultaneously to mount complex immune responses upon pathogenic challenges can be highly regulated, and a simple signaling network motif can be responsible for generating all possible types of heterogeneous populations with respect to a pair of master regulators controlling CD4+ T cell differentiation. The framework provides a mathematical basis for understanding the decision-making mechanisms of CD4+ T cells, and it can be helpful for interpreting experimental results. Mathematical models based on the framework make specific testable predictions that may improve our understanding of this differentiation system. PMID:22697466

Knowledge-based compact disease models identify new molecular players contributing to early-stage Alzheimer’s disease

PubMed Central

2013-01-01

Background High-throughput profiling of human tissues typically yield as results the gene lists comprised of a mix of relevant molecular entities with multiple false positives that obstruct the translation of such results into mechanistic hypotheses. From general probabilistic considerations, gene lists distilled for the mechanistically relevant components can be far more useful for subsequent experimental design or data interpretation. Results The input candidate gene lists were processed into different tiers of evidence consistency established by enrichment analysis across subsets of the same experiments and across different experiments and platforms. The cut-offs were established empirically through ontological and semantic enrichment; resultant shortened gene list was re-expanded by Ingenuity Pathway Assistant tool. The resulting sub-networks provided the basis for generating mechanistic hypotheses that were partially validated by literature search. This approach differs from previous consistency-based studies in that the cut-off on the Receiver Operating Characteristic of the true-false separation process is optimized by flexible selection of the consistency building procedure. The gene list distilled by this analytic technique and its network representation were termed Compact Disease Model (CDM). Here we present the CDM signature for the study of early-stage Alzheimer’s disease. The integrated analysis of this gene signature allowed us to identify the protein traffic vesicles as prominent players in the pathogenesis of Alzheimer’s. Considering the distances and complexity of protein trafficking in neurons, it is plausible that spontaneous protein misfolding along with a shortage of growth stimulation result in neurodegeneration. Several potentially overlapping scenarios of early-stage Alzheimer pathogenesis have been discussed, with an emphasis on the protective effects of AT-1 mediated antihypertensive response on cytoskeleton remodeling, along with neuronal activation of oncogenes, luteinizing hormone signaling and insulin-related growth regulation, forming a pleiotropic model of its early stages. Alignment with emerging literature confirmed many predictions derived from early-stage Alzheimer’s disease’ CDM. Conclusions A flexible approach for high-throughput data analysis, the Compact Disease Model generation, allows extraction of meaningful, mechanism-centered gene sets compatible with instant translation of the results into testable hypotheses. PMID:24196233

A clinical treatment intervention for dysphoria: externalizing metaphors therapy.

PubMed

McGuinty, Everett; Armstrong, David; Carrière, Anne-Marie

2014-01-01

The purpose of this article is to explore a novel, short-term treatment intervention for internalizing behaviours. This intervention is primarily based upon an externalizing process, transforming of metaphoric imagery, and shifting of underlying maladaptive emotional schemas. This article addresses the clinical population of children and youth, specifically through outlining the protocol, externalizing metaphors therapy. A selective review of significant works regarding the efficacy of short-term therapy was conducted, including the process of change within narrative therapy. It is proposed that two specific processes account for the mental health change experienced by clients who receive this new treatment intervention: (1) externalization of problems and (2) purposeful client-generated metaphor manipulation, impacting upon underlying schemas. From these theoretical constructs, the present article outlines a three-session treatment protocol that manualizes these key clinical processes. A case study is presented to illustrate this intervention for anxiety and depression. Further clinical research is underway to address the testable hypotheses resulting from the current theoretical model. Clinical trials in brief psychotherapy are suggested to empirically evaluate the efficacy of this new treatment intervention for dysphoria. This article outlines a short-term treatment intervention for anxiety and depression (dysphoira) through a novel 3-session model, where the clinician-practitioner can obtain competency through a one-day workshop.Its relevance for the clinical researcher and the mental health community is in its versatility in addressing internalizing behavior for four clinical populations: (1) children and adolescents; (2) children and adolescents on the autism spectrum; (3) adults in general; and, (4) adults with a dual-diagnosis. The treatment protocol described within is based upon the externalizing and deconstructive properties of Narrative Therapy, and the transformation of metaphoric imagery of Metaphor Therapy; both of which have little empirical support with narrative practices gaining international attention and widespread usage - through brief therapy, long-term therapy, and walk-in clinics in North America. For the first time, the theoretical constructs of the 3-session model are described and a case example illustrates the interlinking concepts. Copyright © 2013 John Wiley & Sons, Ltd.

The role of beta-endorphin in the pathophysiology of major depression.

PubMed

Hegadoren, K M; O'Donnell, T; Lanius, R; Coupland, N J; Lacaze-Masmonteil, N

2009-10-01

A role for beta-endorphin (beta-END) in the pathophysiology of major depressive disorder (MDD) is suggested by both animal research and studies examining clinical populations. The major etiological theories of depression include brain regions and neural systems that interact with opioid systems and beta-END. Recent preclinical data have demonstrated multiple roles for beta-END in the regulation of complex homeostatic and behavioural processes that are affected during a depressive episode. Additionally, beta-END inputs to regulatory pathways involving feeding behaviours, motivation, and specific types of motor activity have important implications in defining the biological foundations for specific depressive symptoms. Early research linking beta-END to MDD did so in the context of the hypothalamic-pituitary-adrenal (HPA) axis activity, where it was suggested that HPA axis dysregulation may account for depressive symptoms in some individuals. The primary aims of this paper are to use both preclinical and clinical research (a) to critically review data that explores potential roles for beta-END in the pathophysiology of MDD and (b) to highlight gaps in the literature that limit further development of etiological theories of depression and testable hypotheses. In addition to examining methodological and theoretical challenges of past clinical studies, we summarize studies that have investigated basal beta-END levels in MDD and that have used challenge tests to examine beta-END responses to a variety of experimental paradigms. A brief description of the synthesis, location in the CNS and behavioural pharmacology of this neuropeptide is also provided to frame this discussion. Given the lack of clinical improvement observed with currently available antidepressants in a significant proportion of depressed individuals, it is imperative that novel mechanisms be investigated for antidepressant potential. We conclude that the renewed interest in elucidating the role of beta-END in the pathophysiology of MDD must be paralleled by consensus building within the research community around the heterogeneity inherent in mood disorders, standardization of experimental protocols, improved discrimination of POMC products in analytical techniques and consistent attention paid to important confounds like age and gender.

A Predictive Model of the Oxygen and Heme Regulatory Network in Yeast

PubMed Central

Kundaje, Anshul; Xin, Xiantong; Lan, Changgui; Lianoglou, Steve; Zhou, Mei; Zhang, Li; Leslie, Christina

2008-01-01

Deciphering gene regulatory mechanisms through the analysis of high-throughput expression data is a challenging computational problem. Previous computational studies have used large expression datasets in order to resolve fine patterns of coexpression, producing clusters or modules of potentially coregulated genes. These methods typically examine promoter sequence information, such as DNA motifs or transcription factor occupancy data, in a separate step after clustering. We needed an alternative and more integrative approach to study the oxygen regulatory network in Saccharomyces cerevisiae using a small dataset of perturbation experiments. Mechanisms of oxygen sensing and regulation underlie many physiological and pathological processes, and only a handful of oxygen regulators have been identified in previous studies. We used a new machine learning algorithm called MEDUSA to uncover detailed information about the oxygen regulatory network using genome-wide expression changes in response to perturbations in the levels of oxygen, heme, Hap1, and Co2+. MEDUSA integrates mRNA expression, promoter sequence, and ChIP-chip occupancy data to learn a model that accurately predicts the differential expression of target genes in held-out data. We used a novel margin-based score to extract significant condition-specific regulators and assemble a global map of the oxygen sensing and regulatory network. This network includes both known oxygen and heme regulators, such as Hap1, Mga2, Hap4, and Upc2, as well as many new candidate regulators. MEDUSA also identified many DNA motifs that are consistent with previous experimentally identified transcription factor binding sites. Because MEDUSA's regulatory program associates regulators to target genes through their promoter sequences, we directly tested the predicted regulators for OLE1, a gene specifically induced under hypoxia, by experimental analysis of the activity of its promoter. In each case, deletion of the candidate regulator resulted in the predicted effect on promoter activity, confirming that several novel regulators identified by MEDUSA are indeed involved in oxygen regulation. MEDUSA can reveal important information from a small dataset and generate testable hypotheses for further experimental analysis. Supplemental data are included. PMID:19008939

Evolution of a global regulator: Lrp in four orders of γ-Proteobacteria.

PubMed

Unoarumhi, Yvette; Blumenthal, Robert M; Matson, Jyl S

2016-05-20

Bacterial global regulators each regulate the expression of several hundred genes. In Escherichia coli, the top seven global regulators together control over half of all genes. Leucine-responsive regulatory protein (Lrp) is one of these top seven global regulators. Lrp orthologs are very widely distributed, among both Bacteria and Archaea. Surprisingly, even within the phylum γ-Proteobacteria (which includes E. coli), Lrp is a global regulator in some orders and a local regulator in others. This raises questions about the evolution of Lrp and, more broadly, of global regulators. We examined Lrp sequences from four bacterial orders of the γ-Proteobacteria using phylogenetic and Logo analyses. The orders studied were Enterobacteriales and Vibrionales, in which Lrp plays a global role in tested species; Pasteurellales, in which Lrp is a local regulator in the tested species; and Alteromonadales, an order closely related to the other three but in which Lrp has not yet been studied. For comparison, we analyzed the Lrp paralog AsnC, which in all tested cases is a local regulator. The Lrp and AsnC phylogenetic clusters each divided, as expected, into subclusters representing the Enterobacteriales, Vibrionales, and Pasteuralles. However the Alteromonadales did not yield coherent clusters for either Lrp or AsnC. Logo analysis revealed signatures associated with globally- vs. locally- acting Lrp orthologs, providing testable hypotheses for which portions of Lrp are responsible for a global vs. local role. These candidate regions include both ends of the Lrp polypeptide but not, interestingly, the highly-conserved helix-turn-helix motif responsible for DNA sequence specificity. Lrp and AsnC have conserved sequence signatures that allow their unambiguous annotation, at least in γ-Proteobacteria. Among Lrp orthologs, specific residues correlated with global vs. local regulatory roles, and can now be tested to determine which are functionally relevant and which simply reflect divergence. In the Alteromonadales, it appears that there are different subgroups of Lrp orthologs, one of which may act globally while the other may act locally. These results suggest experiments to improve our understanding of the evolution of bacterial global regulators.

On testing VLSI chips for the big Viterbi decoder

NASA Technical Reports Server (NTRS)

Hsu, I. S.

1989-01-01

A general technique that can be used in testing very large scale integrated (VLSI) chips for the Big Viterbi Decoder (BVD) system is described. The test technique is divided into functional testing and fault-coverage testing. The purpose of functional testing is to verify that the design works functionally. Functional test vectors are converted from outputs of software simulations which simulate the BVD functionally. Fault-coverage testing is used to detect and, in some cases, to locate faulty components caused by bad fabrication. This type of testing is useful in screening out bad chips. Finally, design for testability, which is included in the BVD VLSI chip design, is described in considerable detail. Both the observability and controllability of a VLSI chip are greatly enhanced by including the design for the testability feature.

Model-Based Testability Assessment and Directed Troubleshooting of Shuttle Wiring Systems

NASA Technical Reports Server (NTRS)

Deb, Somnath; Domagala, Chuck; Shrestha, Roshan; Malepati, Venkatesh; Cavanaugh, Kevin; Patterson-Hine, Ann; Sanderfer, Dwight; Cockrell, Jim; Norvig, Peter (Technical Monitor)

2000-01-01

We have recently completed a pilot study on the Space shuttle wiring system commissioned by the Wiring Integrity Research (WIRe) team at NASA Ames Research Center, As the space shuttle ages, it is experiencing wiring degradation problems including arcing, chaffing insulation breakdown and broken conductors. A systematic and comprehensive test process is required to thoroughly test and quality assure (QA) the wiring systems. The NASA WIRe team recognized the value of a formal model based analysis for risk-assessment and fault coverage analysis. However. wiring systems are complex and involve over 50,000 wire segments. Therefore, NASA commissioned this pilot study with Qualtech Systems. Inc. (QSI) to explore means of automatically extracting high fidelity multi-signal models from wiring information database for use with QSI's Testability Engineering and Maintenance System (TEAMS) tool.

QUANTITATIVE TESTS OF ELMS AS INTERMEDIATE N PEELING-BALOONING MODES

DOE Office of Scientific and Technical Information (OSTI.GOV)

LAO,LL; SNYDER,PB; LEONARD,AW

2003-03-01

A271 QUANTITATIVE TESTS OF ELMS AS INTERMEDIATE N PEELING-BALOONING MODES. Several testable features of the working model of edge localized modes (ELMs) as intermediate toroidal mode number peeling-ballooning modes are evaluated quantitatively using DIII-D and JT-60U experimental data and the ELITE MHD stability code. These include the hypothesis that ELM sizes are related to the radial widths of the unstable MHD modes, the unstable modes have a strong ballooning character localized in the outboard bad curvature region, and ELM size generally becomes smaller at high edge collisionality. ELMs are triggered when the growth rates of the unstable MHD modes becomemore » significantly large. These testable features are consistent with many ELM observations in DIII-D and JT-60U discharges.« less

Gene Duplication and Transference of Function in the paleoAP3 Lineage of Floral Organ Identity Genes

PubMed Central

Galimba, Kelsey D.; Martínez-Gómez, Jesús; Di Stilio, Verónica S.

2018-01-01

The floral organ identity gene APETALA3 (AP3) is a MADS-box transcription factor involved in stamen and petal identity that belongs to the B-class of the ABC model of flower development. Thalictrum (Ranunculaceae), an emerging model in the non-core eudicots, has AP3 homologs derived from both ancient and recent gene duplications. Prior work has shown that petals have been lost repeatedly and independently in Ranunculaceae in correlation with the loss of a specific AP3 paralog, and Thalictrum represents one of these instances. The main goal of this study was to conduct a functional analysis of the three AP3 orthologs present in Thalictrum thalictroides, representing the paleoAP3 gene lineage, to determine the degree of redundancy versus divergence after gene duplication. Because Thalictrum lacks petals, and has lost the petal-specific AP3, we also asked whether heterotopic expression of the remaining AP3 genes contributes to the partial transference of petal function to the first whorl found in insect-pollinated species. To address these questions, we undertook functional characterization by virus-induced gene silencing (VIGS), protein–protein interaction and binding site analyses. Our results illustrate partial redundancy among Thalictrum AP3s, with deep conservation of B-class function in stamen identity and a novel role in ectopic petaloidy of sepals. Certain aspects of petal function of the lost AP3 locus have apparently been transferred to the other paralogs. A novel result is that the protein products interact not only with each other, but also as homodimers. Evidence presented here also suggests that expression of the different ThtAP3 paralogs is tightly integrated, with an apparent disruption of B function homeostasis upon silencing of one of the paralogs that codes for a truncated protein. To explain this result, we propose two testable alternative scenarios: that the truncated protein is a dominant negative mutant or that there is a compensational response as part of a back-up circuit. The evidence for promiscuous protein–protein interactions via yeast two-hybrid combined with the detection of AP3 specific binding motifs in all B-class gene promoters provide partial support for these hypotheses. PMID:29628932

The Assurance Challenges of Advanced Packaging Technologies for Electronics

NASA Technical Reports Server (NTRS)

Sampson, Michael J.

2010-01-01

Advances in microelectronic parts performance are driving towards finer feature sizes, three-dimensional geometries and ever-increasing number of transistor equivalents that are resulting in increased die sizes and interconnection (I/O) counts. The resultant packaging necessary to provide assemble-ability, environmental protection, testability and interconnection to the circuit board for the active die creates major challenges, particularly for space applications, Traditionally, NASA has used hermetically packaged microcircuits whenever available but the new demands make hermetic packaging less and less practical at the same time as more and more expensive, Some part types of great interest to NASA designers are currently only available in non-hermetic packaging. It is a far more complex quality and reliability assurance challenge to gain confidence in the long-term survivability and effectiveness of nonhermetic packages than for hermetic ones. Although they may provide more rugged environmental protection than the familiar Plastic Encapsulated Microcircuits (PEMs), the non-hermetic Ceramic Column Grid Array (CCGA) packages that are the focus of this presentation present a unique combination of challenges to assessing their suitability for spaceflight use. The presentation will discuss the bases for these challenges, some examples of the techniques proposed to mitigate them and a proposed approach to a US MIL specification Class for non-hermetic microcircuits suitable for space application, Class Y, to be incorporated into M. IL-PRF-38535. It has recently emerged that some major packaging suppliers are offering hermetic area array packages that may offer alternatives to the nonhermetic CCGA styles but have also got their own inspectability and testability issues which will be briefly discussed in the presentation,

JACOB: an enterprise framework for computational chemistry.

PubMed

Waller, Mark P; Dresselhaus, Thomas; Yang, Jack

2013-06-15

Here, we present just a collection of beans (JACOB): an integrated batch-based framework designed for the rapid development of computational chemistry applications. The framework expedites developer productivity by handling the generic infrastructure tier, and can be easily extended by user-specific scientific code. Paradigms from enterprise software engineering were rigorously applied to create a scalable, testable, secure, and robust framework. A centralized web application is used to configure and control the operation of the framework. The application-programming interface provides a set of generic tools for processing large-scale noninteractive jobs (e.g., systematic studies), or for coordinating systems integration (e.g., complex workflows). The code for the JACOB framework is open sourced and is available at: www.wallerlab.org/jacob. Copyright © 2013 Wiley Periodicals, Inc.

A diagnostic expert system for aircraft generator control unit (GCU)

NASA Astrophysics Data System (ADS)

Ho, Ting-Long; Bayles, Robert A.; Havlicsek, Bruce L.

The modular VSCF (variable-speed constant-frequency) generator families are described as using standard modules to reduce the maintenance cost and to improve the product's testability. A general diagnostic expert system shell that guides troubleshooting of modules or line replaceable units (LRUs) is introduced. An application of the diagnostic system to a particular LRU, the generator control unit (GCU) is reported. The approach to building the diagnostic expert system is first to capture general diagnostic strategy in an expert system shell. This shell can be easily applied to different devices or LRUs by writing rules to capture only additional device-specific diagnostic information from expert repair personnel. The diagnostic system has the necessary knowledge embedded in its programs and exhibits expertise to troubleshoot the GCU.

Higher-order Fourier analysis over finite fields and applications

NASA Astrophysics Data System (ADS)

Hatami, Pooya

Higher-order Fourier analysis is a powerful tool in the study of problems in additive and extremal combinatorics, for instance the study of arithmetic progressions in primes, where the traditional Fourier analysis comes short. In recent years, higher-order Fourier analysis has found multiple applications in computer science in fields such as property testing and coding theory. In this thesis, we develop new tools within this theory with several new applications such as a characterization theorem in algebraic property testing. One of our main contributions is a strong near-equidistribution result for regular collections of polynomials. The densities of small linear structures in subsets of Abelian groups can be expressed as certain analytic averages involving linear forms. Higher-order Fourier analysis examines such averages by approximating the indicator function of a subset by a function of bounded number of polynomials. Then, to approximate the average, it suffices to know the joint distribution of the polynomials applied to the linear forms. We prove a near-equidistribution theorem that describes these distributions for the group F(n/p) when p is a fixed prime. This fundamental fact was previously known only under various extra assumptions about the linear forms or the field size. We use this near-equidistribution theorem to settle a conjecture of Gowers and Wolf on the true complexity of systems of linear forms. Our next application is towards a characterization of testable algebraic properties. We prove that every locally characterized affine-invariant property of functions f : F(n/p) → R with n∈ N, is testable. In fact, we prove that any such property P is proximity-obliviously testable. More generally, we show that any affine-invariant property that is closed under subspace restrictions and has "bounded complexity" is testable. We also prove that any property that can be described as the property of decomposing into a known structure of low-degree polynomials is locally characterized and is, hence, testable. We discuss several notions of regularity which allow us to deduce algorithmic versions of various regularity lemmas for polynomials by Green and Tao and by Kaufman and Lovett. We show that our algorithmic regularity lemmas for polynomials imply algorithmic versions of several results relying on regularity, such as decoding Reed-Muller codes beyond the list decoding radius (for certain structured errors), and prescribed polynomial decompositions. Finally, motivated by the definition of Gowers norms, we investigate norms defined by different systems of linear forms. We give necessary conditions on the structure of systems of linear forms that define norms. We prove that such norms can be one of only two types, and assuming that |F p| is sufficiently large, they essentially are equivalent to either a Gowers norm or Lp norms.

Linking short-term responses to ecologically-relevant outcomes

EPA Pesticide Factsheets

Opportunity to participate in the conduct of collaborative integrative lab, field and modelling efforts to characterize molecular-to-organismal level responses and make quantitative testable predictions of population level outcomes

CrossCheck: an open-source web tool for high-throughput screen data analysis.

PubMed

Najafov, Jamil; Najafov, Ayaz

2017-07-19

Modern high-throughput screening methods allow researchers to generate large datasets that potentially contain important biological information. However, oftentimes, picking relevant hits from such screens and generating testable hypotheses requires training in bioinformatics and the skills to efficiently perform database mining. There are currently no tools available to general public that allow users to cross-reference their screen datasets with published screen datasets. To this end, we developed CrossCheck, an online platform for high-throughput screen data analysis. CrossCheck is a centralized database that allows effortless comparison of the user-entered list of gene symbols with 16,231 published datasets. These datasets include published data from genome-wide RNAi and CRISPR screens, interactome proteomics and phosphoproteomics screens, cancer mutation databases, low-throughput studies of major cell signaling mediators, such as kinases, E3 ubiquitin ligases and phosphatases, and gene ontological information. Moreover, CrossCheck includes a novel database of predicted protein kinase substrates, which was developed using proteome-wide consensus motif searches. CrossCheck dramatically simplifies high-throughput screen data analysis and enables researchers to dig deep into the published literature and streamline data-driven hypothesis generation. CrossCheck is freely accessible as a web-based application at http://proteinguru.com/crosscheck.

Ventral–striatal responsiveness during reward anticipation in ADHD and its relation to trait impulsivity in the healthy population: A meta-analytic review of the fMRI literature

PubMed Central

Plichta, Michael M.; Scheres, Anouk

2013-01-01

A review of the existing functional magnetic resonance imaging (fMRI) studies on reward anticipation in patients with attention-deficit/hyperactivity disorder (ADHD) is provided. Meta-analysis showed a significant medium effect size (Cohen’s d = 0.48–0.58) in terms of ventral–striatal (VS)-hyporesponsiveness in ADHD. Studies on VS-responsiveness and trait impulsivity in the healthy population demonstrate the opposite relationship, i.e. impulsivity-scores positively correlated with VS activation during reward processing. Against the background that ADHD may represent an extreme on a continuum of normal variability, the question arises as to how these contrasting findings can be integrated. We discuss three theoretical approaches, each of which integrates the opposing findings: (1) an inverted-u-shape model; (2) a (genetic) moderator model; and (3) the “unrelated model”. We conclude that at the present stage the number of existing studies in the healthy population as well as in ADHD groups is too small for a final answer. Therefore, our presented integrative approaches should be understood as an attempt to frame future research directions by generating testable hypotheses and giving practical suggestions for future studies. PMID:23928090

How cognitive heuristics can explain social interactions in spatial movement.

PubMed

Seitz, Michael J; Bode, Nikolai W F; Köster, Gerta

2016-08-01

The movement of pedestrian crowds is a paradigmatic example of collective motion. The precise nature of individual-level behaviours underlying crowd movements has been subject to a lively debate. Here, we propose that pedestrians follow simple heuristics rooted in cognitive psychology, such as 'stop if another step would lead to a collision' or 'follow the person in front'. In other words, our paradigm explicitly models individual-level behaviour as a series of discrete decisions. We show that our cognitive heuristics produce realistic emergent crowd phenomena, such as lane formation and queuing behaviour. Based on our results, we suggest that pedestrians follow different cognitive heuristics that are selected depending on the context. This differs from the widely used approach of capturing changes in behaviour via model parameters and leads to testable hypotheses on changes in crowd behaviour for different motivation levels. For example, we expect that rushed individuals more often evade to the side and thus display distinct emergent queue formations in front of a bottleneck. Our heuristics can be ranked according to the cognitive effort that is required to follow them. Therefore, our model establishes a direct link between behavioural responses and cognitive effort and thus facilitates a novel perspective on collective behaviour. © 2016 The Author(s).

When cooperation begets cooperation: the role of key individuals in galvanizing support.

PubMed

McAuliffe, Katherine; Wrangham, Richard; Glowacki, Luke; Russell, Andrew F

2015-12-05

Life abounds with examples of conspecifics actively cooperating to a common end, despite conflicts of interest being expected concerning how much each individual should contribute. Mathematical models typically find that such conflict can be resolved by partial-response strategies, leading investors to contribute relatively equitably. Using a case study approach, we show that such model expectations can be contradicted in at least four disparate contexts: (i) bi-parental care; (ii) cooperative breeding; (iii) cooperative hunting; and (iv) human cooperation. We highlight that: (a) marked variation in contributions is commonplace; and (b) individuals can often respond positively rather than negatively to the contributions of others. Existing models have surprisingly limited power in explaining these phenomena. Here, we propose that, although among-individual variation in cooperative contributions will be influenced by differential costs and benefits, there is likely to be a strong genetic or epigenetic component. We then suggest that selection can maintain high investors (key individuals) when their contributions promote support by increasing the benefits and/or reducing the costs for others. Our intentions are to raise awareness in--and provide testable hypotheses of--two of the most poorly understood, yet integral, questions regarding cooperative ventures: why do individuals vary in their contributions and when does cooperation beget cooperation? © 2015 The Author(s).

How cognitive heuristics can explain social interactions in spatial movement

PubMed Central

Köster, Gerta

2016-01-01

The movement of pedestrian crowds is a paradigmatic example of collective motion. The precise nature of individual-level behaviours underlying crowd movements has been subject to a lively debate. Here, we propose that pedestrians follow simple heuristics rooted in cognitive psychology, such as ‘stop if another step would lead to a collision’ or ‘follow the person in front’. In other words, our paradigm explicitly models individual-level behaviour as a series of discrete decisions. We show that our cognitive heuristics produce realistic emergent crowd phenomena, such as lane formation and queuing behaviour. Based on our results, we suggest that pedestrians follow different cognitive heuristics that are selected depending on the context. This differs from the widely used approach of capturing changes in behaviour via model parameters and leads to testable hypotheses on changes in crowd behaviour for different motivation levels. For example, we expect that rushed individuals more often evade to the side and thus display distinct emergent queue formations in front of a bottleneck. Our heuristics can be ranked according to the cognitive effort that is required to follow them. Therefore, our model establishes a direct link between behavioural responses and cognitive effort and thus facilitates a novel perspective on collective behaviour. PMID:27581483

The cancer Warburg effect may be a testable example of the minimum entropy production rate principle

NASA Astrophysics Data System (ADS)

Marín, Dolores; Sabater, Bartolomé

2017-04-01

Cancer cells consume more glucose by glycolytic fermentation to lactate than by respiration, a characteristic known as the Warburg effect. In contrast with the 36 moles of ATP produced by respiration, fermentation produces two moles of ATP per mole of glucose consumed, which poses a puzzle with regard to the function of the Warburg effect. The production of free energy (ΔG), enthalpy (ΔH), and entropy (ΔS) per mole linearly varies with the fraction (x) of glucose consumed by fermentation that is frequently estimated around 0.9. Hence, calculation shows that, in respect to pure respiration, the predominant fermentative metabolism decreases around 10% the production of entropy per mole of glucose consumed in cancer cells. We hypothesize that increased fermentation could allow cancer cells to accomplish the Prigogine theorem of the trend to minimize the rate of production of entropy. According to the theorem, open cellular systems near the steady state could evolve to minimize the rates of entropy production that may be reached by modified replicating cells producing entropy at a low rate. Remarkably, at CO2 concentrations above 930 ppm, glucose respiration produces less entropy than fermentation, which suggests experimental tests to validate the hypothesis of minimization of the rate of entropy production through the Warburg effect.

TEPAPA: a novel in silico feature learning pipeline for mining prognostic and associative factors from text-based electronic medical records.

PubMed

Lin, Frank Po-Yen; Pokorny, Adrian; Teng, Christina; Epstein, Richard J

2017-07-31

Vast amounts of clinically relevant text-based variables lie undiscovered and unexploited in electronic medical records (EMR). To exploit this untapped resource, and thus facilitate the discovery of informative covariates from unstructured clinical narratives, we have built a novel computational pipeline termed Text-based Exploratory Pattern Analyser for Prognosticator and Associator discovery (TEPAPA). This pipeline combines semantic-free natural language processing (NLP), regular expression induction, and statistical association testing to identify conserved text patterns associated with outcome variables of clinical interest. When we applied TEPAPA to a cohort of head and neck squamous cell carcinoma patients, plausible concepts known to be correlated with human papilloma virus (HPV) status were identified from the EMR text, including site of primary disease, tumour stage, pathologic characteristics, and treatment modalities. Similarly, correlates of other variables (including gender, nodal status, recurrent disease, smoking and alcohol status) were also reliably recovered. Using highly-associated patterns as covariates, a patient's HPV status was classifiable using a bootstrap analysis with a mean area under the ROC curve of 0.861, suggesting its predictive utility in supporting EMR-based phenotyping tasks. These data support using this integrative approach to efficiently identify disease-associated factors from unstructured EMR narratives, and thus to efficiently generate testable hypotheses.

The challenges to inferring the regulators of biodiversity in deep time.

PubMed

Ezard, Thomas H G; Quental, Tiago B; Benton, Michael J

2016-04-05

Attempts to infer the ecological drivers of macroevolution in deep time have long drawn inspiration from work on extant systems, but long-term evolutionary and geological changes complicate the simple extrapolation of such theory. Recent efforts to incorporate a more informed ecology into macroevolution have moved beyond the descriptive, seeking to isolate generating mechanisms and produce testable hypotheses of how groups of organisms usurp each other or coexist over vast timespans. This theme issue aims to exemplify this progress, providing a series of case studies of how novel modelling approaches are helping infer the regulators of biodiversity in deep time. In this Introduction, we explore the challenges of these new approaches. First, we discuss how our choices of taxonomic units have implications for the conclusions drawn. Second, we emphasize the need to embrace the interdependence of biotic and abiotic changes, because no living organism ignores its environment. Third, in the light of parts 1 and 2, we discuss the set of dynamic signatures that we might expect to observe in the fossil record. Finally, we ask whether these dynamics represent the most ecologically informative foci for research efforts aimed at inferring the regulators of biodiversity in deep time. The papers in this theme issue contribute in each of these areas. © 2016 The Author(s).

Collective thermoregulation in bee clusters

PubMed Central

Ocko, Samuel A.; Mahadevan, L.

2014-01-01

Swarming is an essential part of honeybee behaviour, wherein thousands of bees cling onto each other to form a dense cluster that may be exposed to the environment for several days. This cluster has the ability to maintain its core temperature actively without a central controller. We suggest that the swarm cluster is akin to an active porous structure whose functional requirement is to adjust to outside conditions by varying its porosity to control its core temperature. Using a continuum model that takes the form of a set of advection–diffusion equations for heat transfer in a mobile porous medium, we show that the equalization of an effective ‘behavioural pressure’, which propagates information about the ambient temperature through variations in density, leads to effective thermoregulation. Our model extends and generalizes previous models by focusing the question of mechanism on the form and role of the behavioural pressure, and allows us to explain the vertical asymmetry of the cluster (as a consequence of buoyancy-driven flows), the ability of the cluster to overpack at low ambient temperatures without breaking up at high ambient temperatures, and the relative insensitivity to large variations in the ambient temperature. Our theory also makes testable hypotheses for the response of the cluster to external temperature inhomogeneities and suggests strategies for biomimetic thermoregulation. PMID:24335563

Model averaging, optimal inference, and habit formation

PubMed Central

FitzGerald, Thomas H. B.; Dolan, Raymond J.; Friston, Karl J.

2014-01-01

Postulating that the brain performs approximate Bayesian inference generates principled and empirically testable models of neuronal function—the subject of much current interest in neuroscience and related disciplines. Current formulations address inference and learning under some assumed and particular model. In reality, organisms are often faced with an additional challenge—that of determining which model or models of their environment are the best for guiding behavior. Bayesian model averaging—which says that an agent should weight the predictions of different models according to their evidence—provides a principled way to solve this problem. Importantly, because model evidence is determined by both the accuracy and complexity of the model, optimal inference requires that these be traded off against one another. This means an agent's behavior should show an equivalent balance. We hypothesize that Bayesian model averaging plays an important role in cognition, given that it is both optimal and realizable within a plausible neuronal architecture. We outline model averaging and how it might be implemented, and then explore a number of implications for brain and behavior. In particular, we propose that model averaging can explain a number of apparently suboptimal phenomena within the framework of approximate (bounded) Bayesian inference, focusing particularly upon the relationship between goal-directed and habitual behavior. PMID:25018724

Inoculation Stress Hypothesis of Environmental Enrichment

PubMed Central

Crofton, Elizabeth J.; Zhang, Yafang; Green, Thomas A.

2014-01-01

One hallmark of psychiatric conditions is the vast continuum of individual differences in susceptibility vs. resilience resulting from the interaction of genetic and environmental factors. The environmental enrichment paradigm is an animal model that is useful for studying a range of psychiatric conditions, including protective phenotypes in addiction and depression models. The major question is how environmental enrichment, a non-drug and non-surgical manipulation, can produce such robust individual differences in such a wide range of behaviors. This paper draws from a variety of published sources to outline a coherent hypothesis of inoculation stress as a factor producing the protective enrichment phenotypes. The basic tenet suggests that chronic mild stress from living in a complex environment and interacting non-aggressively with conspecifics can inoculate enriched rats against subsequent stressors and/or drugs of abuse. This paper reviews the enrichment phenotypes, mulls the fundamental nature of environmental enrichment vs. isolation, discusses the most appropriate control for environmental enrichment, and challenges the idea that cortisol/corticosterone equals stress. The intent of the inoculation stress hypothesis of environmental enrichment is to provide a scaffold with which to build testable hypotheses for the elucidation of the molecular mechanisms underlying these protective phenotypes and thus provide new therapeutic targets to treat psychiatric/neurological conditions. PMID:25449533

Inoculation stress hypothesis of environmental enrichment.

PubMed

Crofton, Elizabeth J; Zhang, Yafang; Green, Thomas A

2015-02-01

One hallmark of psychiatric conditions is the vast continuum of individual differences in susceptibility vs. resilience resulting from the interaction of genetic and environmental factors. The environmental enrichment paradigm is an animal model that is useful for studying a range of psychiatric conditions, including protective phenotypes in addiction and depression models. The major question is how environmental enrichment, a non-drug and non-surgical manipulation, can produce such robust individual differences in such a wide range of behaviors. This paper draws from a variety of published sources to outline a coherent hypothesis of inoculation stress as a factor producing the protective enrichment phenotypes. The basic tenet suggests that chronic mild stress from living in a complex environment and interacting non-aggressively with conspecifics can inoculate enriched rats against subsequent stressors and/or drugs of abuse. This paper reviews the enrichment phenotypes, mulls the fundamental nature of environmental enrichment vs. isolation, discusses the most appropriate control for environmental enrichment, and challenges the idea that cortisol/corticosterone equals stress. The intent of the inoculation stress hypothesis of environmental enrichment is to provide a scaffold with which to build testable hypotheses for the elucidation of the molecular mechanisms underlying these protective phenotypes and thus provide new therapeutic targets to treat psychiatric/neurological conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Emphasizing the process of science using demonstrations in conceptual chemistry

NASA Astrophysics Data System (ADS)

Lutz, Courtney A.

The purpose of this project was to teach students a method for employing the process of science in a conceptual chemistry classroom when observing a demonstration of a discrepant event. Students observed six demonstrations throughout a trimester study of chemistry and responded to each demonstration by asking as many questions as they could think of, choosing one testable question to answer by making as many hypotheses as possible, and choosing one hypothesis to make predictions about observed results of this hypothesis when tested. Students were evaluated on their curiosity, confidence, knowledge of the process of science, and knowledge of the nature of science before and after the six demonstrations. Many students showed improvement in using or mastery of the process of science within the context of conceptual chemistry after six intensive experiences with it. Results of the study also showed students gained confidence in their scientific abilities after completing one trimester of conceptual chemistry. Curiosity and knowledge of the nature of science did not show statistically significant improvement according to the assessment tool. This may have been due to the scope of the demonstration and response activities, which focused on the process of science methodology instead of knowledge of the nature of science or the constraints of the assessment tool.

Slowly switching between environments facilitates reverse evolution in small populations.

PubMed

Tan, Longzhi; Gore, Jeff

2012-10-01

Natural populations must constantly adapt to ever-changing environmental conditions. A particularly interesting question is whether such adaptations can be reversed by returning the population to an ancestral environment. Such evolutionary reversals have been observed in both natural and laboratory populations. However, the factors that determine the reversibility of evolution are still under debate. The time scales of environmental change vary over a wide range, but little is known about how the rate of environmental change influences the reversibility of evolution. Here, we demonstrate computationally that slowly switching between environments increases the reversibility of evolution for small populations that are subject to only modest clonal interference. For small populations, slow switching reduces the mean number of mutations acquired in a new environment and also increases the probability of reverse evolution at each of these "genetic distances." As the population size increases, slow switching no longer reduces the genetic distance, thus decreasing the evolutionary reversibility. We confirm this effect using both a phenomenological model of clonal interference and also a Wright-Fisher stochastic simulation that incorporates genetic diversity. Our results suggest that the rate of environmental change is a key determinant of the reversibility of evolution, and provides testable hypotheses for experimental evolution. © 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.

The cancer Warburg effect may be a testable example of the minimum entropy production rate principle.

PubMed

Marín, Dolores; Sabater, Bartolomé

2017-04-28

Cancer cells consume more glucose by glycolytic fermentation to lactate than by respiration, a characteristic known as the Warburg effect. In contrast with the 36 moles of ATP produced by respiration, fermentation produces two moles of ATP per mole of glucose consumed, which poses a puzzle with regard to the function of the Warburg effect. The production of free energy (ΔG), enthalpy (ΔH), and entropy (ΔS) per mole linearly varies with the fraction (x) of glucose consumed by fermentation that is frequently estimated around 0.9. Hence, calculation shows that, in respect to pure respiration, the predominant fermentative metabolism decreases around 10% the production of entropy per mole of glucose consumed in cancer cells. We hypothesize that increased fermentation could allow cancer cells to accomplish the Prigogine theorem of the trend to minimize the rate of production of entropy. According to the theorem, open cellular systems near the steady state could evolve to minimize the rates of entropy production that may be reached by modified replicating cells producing entropy at a low rate. Remarkably, at CO 2 concentrations above 930 ppm, glucose respiration produces less entropy than fermentation, which suggests experimental tests to validate the hypothesis of minimization of the rate of entropy production through the Warburg effect.

Constructive anthropomorphism: a functional evolutionary approach to the study of human-like cognitive mechanisms in animals.

PubMed

Arbilly, Michal; Lotem, Arnon

2017-10-25

Anthropomorphism, the attribution of human cognitive processes and emotional states to animals, is commonly viewed as non-scientific and potentially misleading. This is mainly because apparent similarity to humans can usually be explained by alternative, simpler mechanisms in animals, and because there is no explanatory power in analogies to human phenomena when these phenomena are not well understood. Yet, because it is also difficult to preclude real similarity and continuity in the evolution of humans' and animals' cognitive abilities, it may not be productive to completely ignore our understanding of human behaviour when thinking about animals. Here we propose that in applying a functional approach to the evolution of cognitive mechanisms, human cognition may be used to broaden our theoretical thinking and to generate testable hypotheses. Our goal is not to 'elevate' animals, but rather to find the minimal set of mechanistic principles that may explain 'advanced' cognitive abilities in humans, and consider under what conditions these mechanisms were likely to enhance fitness and to evolve in animals. We illustrate this approach, from relatively simple emotional states, to more advanced mechanisms, involved in planning and decision-making, episodic memory, metacognition, theory of mind, and consciousness. © 2017 The Author(s).

Is prenatal smoking associated with a developmental pattern of conduct problems in young boys?

PubMed

Wakschlag, Lauren S; Pickett, Kate E; Kasza, Kristen E; Loeber, Rolf

2006-04-01

Prenatal smoking is robustly associated with increased risk of conduct problems in offspring. Observational studies that provide detailed phenotypic description are critical for generating testable hypotheses about underlying processes through which the effects of prenatal smoking may operate. To this end, we use a developmental framework to examine the association of exposure with (1) oppositional defiant disorder and attention-deficit/hyperactivity disorder in young boys and (2) the pattern of delinquent behavior at adolescence. Using diagnostic measures and repeated measures of delinquency, we compare exposed and nonexposed boys from the youngest cohort of the Pittsburgh Youth Study (N = 448). Exposed boys were significantly more likely to (1) develop oppositional defiant disorder and comorbid oppositional defiant disorder-attention-deficit/hyperactivity disorder but not attention-deficit/hyperactivity disorder alone and (2) to have an earlier onset of significant delinquent behavior. The early emergence and developmental coherence of exposure-related conduct problems is striking and is consistent with a behavioral teratological model. Phenotypically, exposure-related conduct problems appear to be characterized by socially resistant and impulsively aggressive behavior. Whether prenatal smoking plays an etiological role in or is a risk marker for the development of conduct problems, exposed offspring are at increased risk of an early-starter pathway to conduct problems.

The Contribution of Psychosocial Stress to the Obesity Epidemic

PubMed Central

Siervo, M.; Wells, J. C. K.; Cizza, G.

2009-01-01

The Thrifty Gene hypothesis theorizes that during evolution a set of genes has been selected to ensure survival in environments with limited food supply and marked seasonality. Contemporary environments have predictable and unlimited food availability, an attenuated seasonality due to artificial lighting, indoor heating during the winter and air conditioning during the summer, and promote sedentariness and overeating. In this setting the thrifty genes are constantly activated to enhance energy storage. Psychosocial stress and sleep deprivation are other features of modern societies. Stress-induced hypercortisolemia in the setting of unlimited food supply promotes adiposity. Modern man is becoming obese because these ancient mechanisms are efficiently promoting a positive energy balance. We propose that in today’s plentifully provisioned societies, where sedentariness and mental stress have become typical traits, chronic activation of the neuroendocrine systems may contribute to the increased prevalence of obesity. We suggest that some of the yet unidentified thrifty genes may be linked to highly conserved energy sensing mechanisms (AMP kinase, mTOR kinase). These hypotheses are testable. Rural societies that are becoming rapidly industrialized and are witnessing a dramatic increase in obesity may provide a historical opportunity to conduct epidemiological studies of the thrifty genotype. In experimental settings, the effects of various forms of psychosocial stress in increasing metabolic efficiency and gene expression can be further tested. PMID:19156597

River and Wetland Food Webs in Australia's Wet-Dry Tropics: General Principles and Implications for Management.

NASA Astrophysics Data System (ADS)

Douglas, M. M.; Bunn, S. E.; Davies, P. M.

2005-05-01

The tropical rivers of northern Australia are internationally recognised for their high ecological and cultural values. They have largely unmodified flow regimes and are comparatively free of the impacts associated with intensive land use. However, there is growing demand for agricultural development and existing pressures, such as weeds and feral animals, threaten their ecological integrity. Using the international literature to provide a conceptual framework and drawing on limited published and unpublished data on rivers in northern Australia, we have derived five general principles about food webs and related ecosystem processes that both characterise tropical rivers of northern Australia and have important implications for their management. These are: (1) Seasonal hydrology is a strong driver of ecosystem processes and food web structure; (2) Hydrological connectivity is largely intact and underpins important terrestrial-aquatic food web subsidies; (3) River and wetland food webs are strongly dependent on algal production; (4) A few common macroconsumers species have a strong influence on benthic food webs; (5) Omnivory is widespread and food chains are short. These principles have implications for the management and protection of tropical rivers and wetlands of northern Australia and provide a framework for the formation of testable hypotheses in future research programs.

Cortical Transformation of Spatial Processing for Solving the Cocktail Party Problem: A Computational Model123

PubMed Central

Dong, Junzi; Colburn, H. Steven

2016-01-01

In multisource, “cocktail party” sound environments, human and animal auditory systems can use spatial cues to effectively separate and follow one source of sound over competing sources. While mechanisms to extract spatial cues such as interaural time differences (ITDs) are well understood in precortical areas, how such information is reused and transformed in higher cortical regions to represent segregated sound sources is not clear. We present a computational model describing a hypothesized neural network that spans spatial cue detection areas and the cortex. This network is based on recent physiological findings that cortical neurons selectively encode target stimuli in the presence of competing maskers based on source locations (Maddox et al., 2012). We demonstrate that key features of cortical responses can be generated by the model network, which exploits spatial interactions between inputs via lateral inhibition, enabling the spatial separation of target and interfering sources while allowing monitoring of a broader acoustic space when there is no competition. We present the model network along with testable experimental paradigms as a starting point for understanding the transformation and organization of spatial information from midbrain to cortex. This network is then extended to suggest engineering solutions that may be useful for hearing-assistive devices in solving the cocktail party problem. PMID:26866056

Barriers to Gene Flow in the Marine Environment: Insights from Two Common Intertidal Limpet Species of the Atlantic and Mediterranean

PubMed Central

Sá-Pinto, Alexandra; Branco, Madalena S.; Alexandrino, Paulo B.; Fontaine, Michaël C.; Baird, Stuart J. E.

2012-01-01

Knowledge of the scale of dispersal and the mechanisms governing gene flow in marine environments remains fragmentary despite being essential for understanding evolution of marine biota and to design management plans. We use the limpets Patella ulyssiponensis and Patella rustica as models for identifying factors affecting gene flow in marine organisms across the North-East Atlantic and the Mediterranean Sea. A set of allozyme loci and a fragment of the mitochondrial gene cytochrome C oxidase subunit I were screened for genetic variation through starch gel electrophoresis and DNA sequencing, respectively. An approach combining clustering algorithms with clinal analyses was used to test for the existence of barriers to gene flow and estimate their geographic location and abruptness. Sharp breaks in the genetic composition of individuals were observed in the transitions between the Atlantic and the Mediterranean and across southern Italian shores. An additional break within the Atlantic cluster separates samples from the Alboran Sea and Atlantic African shores from those of the Iberian Atlantic shores. The geographic congruence of the genetic breaks detected in these two limpet species strongly supports the existence of transpecific barriers to gene flow in the Mediterranean Sea and Northeastern Atlantic. This leads to testable hypotheses regarding factors restricting gene flow across the study area. PMID:23239977

Interrogating selectivity in catalysis using molecular vibrations

NASA Astrophysics Data System (ADS)

Milo, Anat; Bess, Elizabeth N.; Sigman, Matthew S.

2014-03-01

The delineation of molecular properties that underlie reactivity and selectivity is at the core of physical organic chemistry, and this knowledge can be used to inform the design of improved synthetic methods or identify new chemical transformations. For this reason, the mathematical representation of properties affecting reactivity and selectivity trends, that is, molecular parameters, is paramount. Correlations produced by equating these molecular parameters with experimental outcomes are often defined as free-energy relationships and can be used to evaluate the origin of selectivity and to generate new, experimentally testable hypotheses. The premise behind successful correlations of this type is that a systematically perturbed molecular property affects a transition-state interaction between the catalyst, substrate and any reaction components involved in the determination of selectivity. Classic physical organic molecular descriptors, such as Hammett, Taft or Charton parameters, seek to independently probe isolated electronic or steric effects. However, these parameters cannot address simultaneous, non-additive variations to more than one molecular property, which limits their utility. Here we report a parameter system based on the vibrational response of a molecule to infrared radiation that can be used to mathematically model and predict selectivity trends for reactions with interlinked steric and electronic effects at positions of interest. The disclosed parameter system is mechanistically derived and should find broad use in the study of chemical and biological systems.

Beyond the bucket: testing the effect of experimental design on rate and sequence of decay

NASA Astrophysics Data System (ADS)

Gabbott, Sarah; Murdock, Duncan; Purnell, Mark

2016-04-01

Experimental decay has revealed the potential for profound biases in our interpretations of exceptionally preserved fossils, with non-random sequences of character loss distorting the position of fossil taxa in phylogenetic trees. By characterising these sequences we can rewind this distortion and make better-informed interpretations of the affinity of enigmatic fossil taxa. Equally, rate of character loss is crucial for estimating the preservation potential of phylogentically informative characters, and revealing the mechanisms of preservation themselves. However, experimental decay has been criticised for poorly modeling 'real' conditions, and dismissed as unsophisticated 'bucket science'. Here we test the effect of a differing experimental parameters on the rate and sequence of decay. By doing so, we can test the assumption that the results of decay experiments are applicable to informing interpretations of exceptionally preserved fossils from diverse preservational settings. The results of our experiments demonstrate the validity of using the sequence of character loss as a phylogenetic tool, and sheds light on the extent to which environment must be considered before making decay-informed interpretations, or reconstructing taphonomic pathways. With careful consideration of experimental design, driven by testable hypotheses, decay experiments are robust and informative - experimental taphonomy needn't kick the bucket just yet.

Different gastric microbiota compositions in two human populations with high and low gastric cancer risk in Colombia

PubMed Central

Yang, Ines; Woltemate, Sabrina; Piazuelo, M. Blanca; Bravo, Luis E.; Yepez, Maria Clara; Romero-Gallo, Judith; Delgado, Alberto G.; Wilson, Keith T.; Peek, Richard M.; Correa, Pelayo; Josenhans, Christine; Fox, James G.; Suerbaum, Sebastian

2016-01-01

Inhabitants of Túquerres in the Colombian Andes have a 25-fold higher risk of gastric cancer than inhabitants of the coastal town Tumaco, despite similar H. pylori prevalences. The gastric microbiota was recently shown in animal models to accelerate the development of H. pylori-induced precancerous lesions. 20 individuals from each town, matched for age and sex, were selected, and gastric microbiota analyses were performed by deep sequencing of amplified 16S rDNA. In parallel, analyses of H. pylori status, carriage of the cag pathogenicity island and assignment of H. pylori to phylogeographic groups were performed to test for correlations between H. pylori strain properties and microbiota composition. The gastric microbiota composition was highly variable between individuals, but showed a significant correlation with the town of origin. Multiple OTUs were detected exclusively in either Tumaco or Túquerres. Two operational taxonomic units (OTUs), Leptotrichia wadei and a Veillonella sp., were significantly more abundant in Túquerres, and 16 OTUs, including a Staphylococcus sp. were significantly more abundant in Tumaco. There was no significant correlation of H. pylori phylogeographic population or carriage of the cagPAI with microbiota composition. From these data, testable hypotheses can be generated and examined in suitable animal models and prospective clinical trials. PMID:26729566

When cooperation begets cooperation: the role of key individuals in galvanizing support

PubMed Central

McAuliffe, Katherine; Wrangham, Richard; Glowacki, Luke; Russell, Andrew F.

2015-01-01

Life abounds with examples of conspecifics actively cooperating to a common end, despite conflicts of interest being expected concerning how much each individual should contribute. Mathematical models typically find that such conflict can be resolved by partial-response strategies, leading investors to contribute relatively equitably. Using a case study approach, we show that such model expectations can be contradicted in at least four disparate contexts: (i) bi-parental care; (ii) cooperative breeding; (iii) cooperative hunting; and (iv) human cooperation. We highlight that: (a) marked variation in contributions is commonplace; and (b) individuals can often respond positively rather than negatively to the contributions of others. Existing models have surprisingly limited power in explaining these phenomena. Here, we propose that, although among-individual variation in cooperative contributions will be influenced by differential costs and benefits, there is likely to be a strong genetic or epigenetic component. We then suggest that selection can maintain high investors (key individuals) when their contributions promote support by increasing the benefits and/or reducing the costs for others. Our intentions are to raise awareness in—and provide testable hypotheses of—two of the most poorly understood, yet integral, questions regarding cooperative ventures: why do individuals vary in their contributions and when does cooperation beget cooperation? PMID:26503685

Cortical Transformation of Spatial Processing for Solving the Cocktail Party Problem: A Computational Model(1,2,3).

PubMed

Dong, Junzi; Colburn, H Steven; Sen, Kamal

2016-01-01

In multisource, "cocktail party" sound environments, human and animal auditory systems can use spatial cues to effectively separate and follow one source of sound over competing sources. While mechanisms to extract spatial cues such as interaural time differences (ITDs) are well understood in precortical areas, how such information is reused and transformed in higher cortical regions to represent segregated sound sources is not clear. We present a computational model describing a hypothesized neural network that spans spatial cue detection areas and the cortex. This network is based on recent physiological findings that cortical neurons selectively encode target stimuli in the presence of competing maskers based on source locations (Maddox et al., 2012). We demonstrate that key features of cortical responses can be generated by the model network, which exploits spatial interactions between inputs via lateral inhibition, enabling the spatial separation of target and interfering sources while allowing monitoring of a broader acoustic space when there is no competition. We present the model network along with testable experimental paradigms as a starting point for understanding the transformation and organization of spatial information from midbrain to cortex. This network is then extended to suggest engineering solutions that may be useful for hearing-assistive devices in solving the cocktail party problem.

A parsimonious modular approach to building a mechanistic belowground carbon and nitrogen model

NASA Astrophysics Data System (ADS)

Abramoff, Rose Z.; Davidson, Eric A.; Finzi, Adrien C.

2017-09-01

Soil decomposition models range from simple empirical functions to those that represent physical, chemical, and biological processes. Here we develop a parsimonious, modular C and N cycle model, the Dual Arrhenius Michaelis-Menten-Microbial Carbon and Nitrogen Phyisology (DAMM-MCNiP), that generates testable hypotheses regarding the effect of temperature, moisture, and substrate supply on C and N cycling. We compared this model to DAMM alone and an empirical model of heterotrophic respiration based on Harvard Forest data. We show that while different model structures explain similar amounts of variation in respiration, they differ in their ability to infer processes that affect C flux. We applied DAMM-MCNiP to explain an observed seasonal hysteresis in the relationship between respiration and temperature and show using an exudation simulation that the strength of the priming effect depended on the stoichiometry of the inputs. Low C:N inputs stimulated priming of soil organic matter decomposition, but high C:N inputs were preferentially utilized by microbes as a C source with limited priming. The simplicity of DAMM-MCNiP's simultaneous representations of temperature, moisture, substrate supply, enzyme activity, and microbial growth processes is unique among microbial physiology models and is sufficiently parsimonious that it could be incorporated into larger-scale models of C and N cycling.

Critical Roles of the Direct GABAergic Pallido-cortical Pathway in Controlling Absence Seizures

PubMed Central

Li, Min; Ma, Tao; Wu, Shengdun; Ma, Jingling; Cui, Yan; Xia, Yang; Xu, Peng; Yao, Dezhong

2015-01-01

The basal ganglia (BG), serving as an intermediate bridge between the cerebral cortex and thalamus, are believed to play crucial roles in controlling absence seizure activities generated by the pathological corticothalamic system. Inspired by recent experiments, here we systematically investigate the contribution of a novel identified GABAergic pallido-cortical pathway, projecting from the globus pallidus externa (GPe) in the BG to the cerebral cortex, to the control of absence seizures. By computational modelling, we find that both increasing the activation of GPe neurons and enhancing the coupling strength of the inhibitory pallido-cortical pathway can suppress the bilaterally synchronous 2–4 Hz spike and wave discharges (SWDs) during absence seizures. Appropriate tuning of several GPe-related pathways may also trigger the SWD suppression, through modulating the activation level of GPe neurons. Furthermore, we show that the previously discovered bidirectional control of absence seizures due to the competition between other two BG output pathways also exists in our established model. Importantly, such bidirectional control is shaped by the coupling strength of this direct GABAergic pallido-cortical pathway. Our work suggests that the novel identified pallido-cortical pathway has a functional role in controlling absence seizures and the presented results might provide testable hypotheses for future experimental studies. PMID:26496656

A SEU-Hard Flip-Flop for Antifuse FPGAs

NASA Technical Reports Server (NTRS)

Katz, R.; Wang, J. J.; McCollum, J.; Cronquist, B.; Chan, R.; Yu, D.; Kleyner, I.; Day, John H. (Technical Monitor)

2001-01-01

A single event upset (SEU)-hardened flip-flop has been designed and developed for antifuse Field Programmable Gate Array (FPGA) application. Design and application issues, testability, test methods, simulation, and results are discussed.

The changing features of the body-mind problem.

PubMed

Agassi, Joseph

2007-01-01

The body-mind problem invites scientific study, since mental events are repeated and repeatable and invite testable explanations. They seemed troublesome because of the classical theory of substance that failed to solve its own central problems. These are soluble with the aid of the theory of the laws of nature, particularly in its emergentist version [Bunge, M., 1980. The Body-mind Problem, Pergamon, Oxford] that invites refutable explanations [Popper, K.R., 1959. The Logic of Scientific Discovery, Hutchinson, London]. The view of mental properties as emergent is a modification of the two chief classical views, materialism and dualism. As this view invites testable explanations of events of the inner world, it is better than the quasi-behaviorist view of self-awareness as computer-style self-monitoring [Minsky, M., Laske, O., 1992. A conversation with Marvin Minsky. AI Magazine 13 (3), 31-45].

Testability of evolutionary game dynamics based on experimental economics data

NASA Astrophysics Data System (ADS)

Wang, Yijia; Chen, Xiaojie; Wang, Zhijian

2017-11-01

Understanding the dynamic processes of a real game system requires an appropriate dynamics model, and rigorously testing a dynamics model is nontrivial. In our methodological research, we develop an approach to testing the validity of game dynamics models that considers the dynamic patterns of angular momentum and speed as measurement variables. Using Rock-Paper-Scissors (RPS) games as an example, we illustrate the geometric patterns in the experiment data. We then derive the related theoretical patterns from a series of typical dynamics models. By testing the goodness-of-fit between the experimental and theoretical patterns, we show that the validity of these models can be evaluated quantitatively. Our approach establishes a link between dynamics models and experimental systems, which is, to the best of our knowledge, the most effective and rigorous strategy for ascertaining the testability of evolutionary game dynamics models.

Design for testability and diagnosis at the system-level

NASA Technical Reports Server (NTRS)

Simpson, William R.; Sheppard, John W.

1993-01-01

The growing complexity of full-scale systems has surpassed the capabilities of most simulation software to provide detailed models or gate-level failure analyses. The process of system-level diagnosis approaches the fault-isolation problem in a manner that differs significantly from the traditional and exhaustive failure mode search. System-level diagnosis is based on a functional representation of the system. For example, one can exercise one portion of a radar algorithm (the Fast Fourier Transform (FFT) function) by injecting several standard input patterns and comparing the results to standardized output results. An anomalous output would point to one of several items (including the FFT circuit) without specifying the gate or failure mode. For system-level repair, identifying an anomalous chip is sufficient. We describe here an information theoretic and dependency modeling approach that discards much of the detailed physical knowledge about the system and analyzes its information flow and functional interrelationships. The approach relies on group and flow associations and, as such, is hierarchical. Its hierarchical nature allows the approach to be applicable to any level of complexity and to any repair level. This approach has been incorporated in a product called STAMP (System Testability and Maintenance Program) which was developed and refined through more than 10 years of field-level applications to complex system diagnosis. The results have been outstanding, even spectacular in some cases. In this paper we describe system-level testability, system-level diagnoses, and the STAMP analysis approach, as well as a few STAMP applications.

Transcriptional Analysis of Aggressiveness and Heterogeneity across Grades of Astrocytomas

PubMed Central

Wang, Chunjing; Funk, Cory C.; Eddy, James A.; Price, Nathan D.

2013-01-01

Astrocytoma is the most common glioma, accounting for half of all primary brain and spinal cord tumors. Late detection and the aggressive nature of high-grade astrocytomas contribute to high mortality rates. Though many studies identify candidate biomarkers using high-throughput transcriptomic profiling to stratify grades and subtypes, few have resulted in clinically actionable results. This shortcoming can be attributed, in part, to pronounced lab effects that reduce signature robustness and varied individual gene expression among patients with the same tumor. We addressed these issues by uniformly preprocessing publicly available transcriptomic data, comprising 306 tumor samples from three astrocytoma grades (Grade 2, 3, and 4) and 30 non-tumor samples (normal brain as control tissues). Utilizing Differential Rank Conservation (DIRAC), a network-based classification approach, we examined the global and individual patterns of network regulation across tumor grades. Additionally, we applied gene-based approaches to identify genes whose expression changed consistently with increasing tumor grade and evaluated their robustness across multiple studies using statistical sampling. Applying DIRAC, we observed a global trend of greater network dysregulation with increasing tumor aggressiveness. Individual networks displaying greater differences in regulation between adjacent grades play well-known roles in calcium/PKC, EGF, and transcription signaling. Interestingly, many of the 90 individual genes found to monotonically increase or decrease with astrocytoma grade are implicated in cancer-affected processes such as calcium signaling, mitochondrial metabolism, and apoptosis. The fact that specific genes monotonically increase or decrease with increasing astrocytoma grade may reflect shared oncogenic mechanisms among phenotypically similar tumors. This work presents statistically significant results that enable better characterization of different human astrocytoma grades and hopefully can contribute towards improvements in diagnosis and therapy choices. Our results also identify a number of testable hypotheses relating to astrocytoma etiology that may prove helpful in developing much-needed biomarkers for earlier disease detection. PMID:24146911

Transcriptional analysis of aggressiveness and heterogeneity across grades of astrocytomas.

PubMed

Wang, Chunjing; Funk, Cory C; Eddy, James A; Price, Nathan D

2013-01-01

Astrocytoma is the most common glioma, accounting for half of all primary brain and spinal cord tumors. Late detection and the aggressive nature of high-grade astrocytomas contribute to high mortality rates. Though many studies identify candidate biomarkers using high-throughput transcriptomic profiling to stratify grades and subtypes, few have resulted in clinically actionable results. This shortcoming can be attributed, in part, to pronounced lab effects that reduce signature robustness and varied individual gene expression among patients with the same tumor. We addressed these issues by uniformly preprocessing publicly available transcriptomic data, comprising 306 tumor samples from three astrocytoma grades (Grade 2, 3, and 4) and 30 non-tumor samples (normal brain as control tissues). Utilizing Differential Rank Conservation (DIRAC), a network-based classification approach, we examined the global and individual patterns of network regulation across tumor grades. Additionally, we applied gene-based approaches to identify genes whose expression changed consistently with increasing tumor grade and evaluated their robustness across multiple studies using statistical sampling. Applying DIRAC, we observed a global trend of greater network dysregulation with increasing tumor aggressiveness. Individual networks displaying greater differences in regulation between adjacent grades play well-known roles in calcium/PKC, EGF, and transcription signaling. Interestingly, many of the 90 individual genes found to monotonically increase or decrease with astrocytoma grade are implicated in cancer-affected processes such as calcium signaling, mitochondrial metabolism, and apoptosis. The fact that specific genes monotonically increase or decrease with increasing astrocytoma grade may reflect shared oncogenic mechanisms among phenotypically similar tumors. This work presents statistically significant results that enable better characterization of different human astrocytoma grades and hopefully can contribute towards improvements in diagnosis and therapy choices. Our results also identify a number of testable hypotheses relating to astrocytoma etiology that may prove helpful in developing much-needed biomarkers for earlier disease detection.

Molecular mechanisms of OLIG2 transcription factor in brain cancer

PubMed Central

Lian, Nathan; Kesari, Santosh

2016-01-01

Oligodendrocyte lineage transcription factor 2 (OLIG2) plays a pivotal role in glioma development. Here we conducted a comprehensive study of the critical gene regulatory networks involving OLIG2. These include the networks responsible for OLIG2 expression, its translocation to nucleus, cell cycle, epigenetic regulation, and Rho-pathway interactions. We described positive feedback loops including OLIG2: loops of epigenetic regulation and loops involving receptor tyrosine kinases. These loops may be responsible for the prolonged oncogenic activity of OLIG2. The proposed schemes for epigenetic regulation of the gene networks involving OLIG2 are confirmed by patient survival (Kaplan–Meier) curves based on the cancer genome atlas (TCGA) datasets. Finally, we elucidate the Coherent-Gene Modules (CGMs) networks—framework of OLIG2 involvement in cancer. We showed that genes interacting with OLIG2 formed eight CGMs having a set of intermodular connections. We showed also that among the genes involved in these modules the most connected hub is EGFR, then, on lower level, HSP90 and CALM1, followed by three lower levels including epigenetic genes KDM1A and NCOR1. The genes on the six upper levels of the hierarchy are involved in interconnections of all eight CGMs and organize functionally defined gene-signaling subnetworks having specific functions. For example, CGM1 is involved in epigenetic control. CGM2 is significantly related to cell proliferation and differentiation. CGM3 includes a number of interconnected helix–loop–helix transcription factors (bHLH) including OLIG2. Many of these TFs are partially controlled by OLIG2. The CGM4 is involved in PDGF-related: angiogenesis, tumor cell proliferation and differentiation. These analyses provide testable hypotheses and approaches to inhibit OLIG2 pathway and relevant feed-forward and feedback loops to be interrogated. This broad approach can be applied to other TFs. PMID:27447975

Associations between repetitive questioning, resistance to change, temper outbursts and anxiety in Prader-Willi and Fragile-X syndromes.

PubMed

Woodcock, K; Oliver, C; Humphreys, G

2009-03-01

The behavioural phenotypes of Prader-Willi (PWS) and Fragile-X (FraX) syndromes both comprise repetitive behaviours with differences between the profiles. In this study we investigated the context and antecedents to the repetitive behaviours and the association with other behavioural phenotypic characteristics in order to generate testable hypotheses regarding the cause of the behaviours. The parents or carers of 46 children with PWS (mean age 14.1 years; 20 girls), and 33 boys with FraX (mean age 13.11 years) were interviewed about their children's repetitive behaviour in a semi-structured format. Children showed negative emotional behaviour (PWS: 87.0%; FraX: 79.4%) and repetitive questions (PWS: 78.3%; FraX: 73.5%) following changes in routine or expectations. Significantly more temper outbursts were reported to follow changes in children with PWS (89.1%) compared with boys with FraX (41.2%) (chi(2) = 20.93; P < 0.001). Anxiety that was frequently associated with repetitive and self-injurious behaviours in boys with FraX, followed changes in significantly more boys with FraX (76.5%) compared with children with PWS (6.5%) (chi(2) = 43.19, P < 0.001). On the basis of these reports and existing literature, we hypothesise that decreases in predictability are aversive to children with PWS and FraX. We also hypothesise that these children have a propensity to show a syndrome-related pattern of behaviour (temper outbursts in PWS and displays of anxiety in FraX) when an event in the environment has this aversive property. We hypothesise that questions may be reinforcing to children in their own right by increasing the predictability of the environment. We outline how a specific cognitive deficit in the endophenotypes associated with both PWS and FraX could be investigated as a potential explanation for the hypothesised aversive properties of decreased predictability.

Sources, Sinks, and Model Accuracy

EPA Science Inventory

Spatial demographic models are a necessary tool for understanding how to manage landscapes sustainably for animal populations. These models, therefore, must offer precise and testable predications about animal population dynamics and how animal demographic parameters respond to ...

Mechanisms of mindfulness training: Monitor and Acceptance Theory (MAT).

PubMed

Lindsay, Emily K; Creswell, J David

2017-02-01

Despite evidence linking trait mindfulness and mindfulness training with a broad range of effects, still little is known about its underlying active mechanisms. Mindfulness is commonly defined as (1) the ongoing monitoring of present-moment experience (2) with an orientation of acceptance. Building on conceptual, clinical, and empirical work, we describe a testable theoretical account to help explain mindfulness effects on cognition, affect, stress, and health outcomes. Specifically, Monitor and Acceptance Theory (MAT) posits that (1), by enhancing awareness of one's experiences, the skill of attention monitoring explains how mindfulness improves cognitive functioning outcomes, yet this same skill can increase affective reactivity. Second (2), by modifying one's relation to monitored experience, acceptance is necessary for reducing affective reactivity, such that attention monitoring and acceptance skills together explain how mindfulness improves negative affectivity, stress, and stress-related health outcomes. We discuss how MAT contributes to mindfulness science, suggest plausible alternatives to the account, and offer specific predictions for future research. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mechanisms of Mindfulness Training: Monitor and Acceptance Theory (MAT)1

PubMed Central

Lindsay, Emily K.; Creswell, J. David

2016-01-01

Despite evidence linking trait mindfulness and mindfulness training with a broad range of effects, still little is known about its underlying active mechanisms. Mindfulness is commonly defined as (1) the ongoing monitoring of present-moment experience (2) with an orientation of acceptance. Building on conceptual, clinical, and empirical work, we describe a testable theoretical account to help explain mindfulness effects on cognition, affect, stress, and health outcomes. Specifically, Monitor and Acceptance Theory (MAT) posits that (1), by enhancing awareness of one’s experiences, the skill of attention monitoring explains how mindfulness improves cognitive functioning outcomes, yet this same skill can increase affective reactivity. Second (2), by modifying one’s relation to monitored experience, acceptance is necessary for reducing affective reactivity, such that attention monitoring and acceptance skills together explain how mindfulness improves negative affectivity, stress, and stress-related health outcomes. We discuss how MAT contributes to mindfulness science, suggest plausible alternatives to the account, and offer specific predictions for future research. PMID:27835764

Mathematical models of the fate of lymphoma B cells after antigen receptor ligation with specific antibodies.

PubMed

Alarcón, Tomás; Marches, Radu; Page, Karen M

2006-05-07

We formulate models of the mechanism(s) by which B cell lymphoma cells stimulated with an antibody specific to the B cell receptor (IgM) become quiescent or apoptotic. In particular, we aim to reproduce experimental results by Marches et al. according to which the fate of the targeted cells (Daudi) depends on the levels of expression of p21(Waf1) (p21) cell-cycle inhibitor. A simple model is formulated in which the basic ingredients are p21 and caspase activity, and their mutual inhibition. We show that this model does not reproduce the experimental results and that further refinement is needed. A second model successfully reproduces the experimental observations, for a given set of parameter values, indicating a critical role for Myc in the fate decision process. We use bifurcation analysis and objective sensitivity analysis to assess the robustness of our results. Importantly, this analysis yields experimentally testable predictions on the role of Myc, which could have therapeutic implications.

Anxiety psychopathology in African American adults: literature review and development of an empirically informed sociocultural model.

PubMed

Hunter, Lora Rose; Schmidt, Norman B

2010-03-01

In this review, the extant literature concerning anxiety psychopathology in African American adults is summarized to develop a testable, explanatory framework with implications for future research. The model was designed to account for purported lower rates of anxiety disorders in African Americans compared to European Americans, along with other ethnoracial differences reported in the literature. Three specific beliefs or attitudes related to the sociocultural experience of African Americans are identified: awareness of racism, stigma of mental illness, and salience of physical illnesses. In our model, we propose that these psychological processes influence interpretations and behaviors relevant to the expression of nonpathological anxiety as well as features of diagnosable anxiety conditions. Moreover, differences in these processes may explain the differential assessed rates of anxiety disorders in African Americans. The model is discussed in the context of existing models of anxiety etiology. Specific follow-up research is also suggested, along with implications for clinical assessment, diagnosis, and treatment.

Research review: dopamine transfer deficit: a neurobiological theory of altered reinforcement mechanisms in ADHD.

PubMed

Tripp, Gail; Wickens, Jeff R

2008-07-01

This review considers the hypothesis that changes in dopamine signalling might account for altered sensitivity to positive reinforcement in children with ADHD. The existing evidence regarding dopamine cell activity in relation to positive reinforcement is reviewed. We focus on the anticipatory firing of dopamine cells brought about by a transfer of dopamine cell responses to cues that precede reinforcers. It is proposed that in children with ADHD there is diminished anticipatory dopamine cell firing, which we call the dopamine transfer deficit (DTD). The DTD theory leads to specific and testable predictions for human and animal research. The extent to which DTD explains symptoms of ADHD and effects of pharmacological interventions is discussed. We conclude by considering the neural changes underlying the etiology of DTD.

Electrical test prediction using hybrid metrology and machine learning

NASA Astrophysics Data System (ADS)

Breton, Mary; Chao, Robin; Muthinti, Gangadhara Raja; de la Peña, Abraham A.; Simon, Jacques; Cepler, Aron J.; Sendelbach, Matthew; Gaudiello, John; Emans, Susan; Shifrin, Michael; Etzioni, Yoav; Urenski, Ronen; Lee, Wei Ti

2017-03-01

Electrical test measurement in the back-end of line (BEOL) is crucial for wafer and die sorting as well as comparing intended process splits. Any in-line, nondestructive technique in the process flow to accurately predict these measurements can significantly improve mean-time-to-detect (MTTD) of defects and improve cycle times for yield and process learning. Measuring after BEOL metallization is commonly done for process control and learning, particularly with scatterometry (also called OCD (Optical Critical Dimension)), which can solve for multiple profile parameters such as metal line height or sidewall angle and does so within patterned regions. This gives scatterometry an advantage over inline microscopy-based techniques, which provide top-down information, since such techniques can be insensitive to sidewall variations hidden under the metal fill of the trench. But when faced with correlation to electrical test measurements that are specific to the BEOL processing, both techniques face the additional challenge of sampling. Microscopy-based techniques are sampling-limited by their small probe size, while scatterometry is traditionally limited (for microprocessors) to scribe targets that mimic device ground rules but are not necessarily designed to be electrically testable. A solution to this sampling challenge lies in a fast reference-based machine learning capability that allows for OCD measurement directly of the electrically-testable structures, even when they are not OCD-compatible. By incorporating such direct OCD measurements, correlation to, and therefore prediction of, resistance of BEOL electrical test structures is significantly improved. Improvements in prediction capability for multiple types of in-die electrically-testable device structures is demonstrated. To further improve the quality of the prediction of the electrical resistance measurements, hybrid metrology using the OCD measurements as well as X-ray metrology (XRF) is used. Hybrid metrology is the practice of combining information from multiple sources in order to enable or improve the measurement of one or more critical parameters. Here, the XRF measurements are used to detect subtle changes in barrier layer composition and thickness that can have second-order effects on the electrical resistance of the test structures. By accounting for such effects with the aid of the X-ray-based measurements, further improvement in the OCD correlation to electrical test measurements is achieved. Using both types of solution incorporation of fast reference-based machine learning on nonOCD-compatible test structures, and hybrid metrology combining OCD with XRF technology improvement in BEOL cycle time learning could be accomplished through improved prediction capability.

Work-Centered Technology Development (WTD)

DTIC Science & Technology

2005-03-01

theoretical, testable, inductive, and repeatable foundations of science. o Theoretical foundations include notions such as statistical versus analytical...Human Factors and Ergonomics Society, 263-267. 179 Eggleston, R. G. (2005). Coursebook : Work-Centered Design (WCD). AFRL/HECS WCD course training

All pure bipartite entangled states can be self-tested

PubMed Central

Coladangelo, Andrea; Goh, Koon Tong; Scarani, Valerio

2017-01-01

Quantum technologies promise advantages over their classical counterparts in the fields of computation, security and sensing. It is thus desirable that classical users are able to obtain guarantees on quantum devices, even without any knowledge of their inner workings. That such classical certification is possible at all is remarkable: it is a consequence of the violation of Bell inequalities by entangled quantum systems. Device-independent self-testing refers to the most complete such certification: it enables a classical user to uniquely identify the quantum state shared by uncharacterized devices by simply inspecting the correlations of measurement outcomes. Self-testing was first demonstrated for the singlet state and a few other examples of self-testable states were reported in recent years. Here, we address the long-standing open question of whether every pure bipartite entangled state is self-testable. We answer it affirmatively by providing explicit self-testing correlations for all such states. PMID:28548093

All pure bipartite entangled states can be self-tested

NASA Astrophysics Data System (ADS)

Coladangelo, Andrea; Goh, Koon Tong; Scarani, Valerio

2017-05-01

Quantum technologies promise advantages over their classical counterparts in the fields of computation, security and sensing. It is thus desirable that classical users are able to obtain guarantees on quantum devices, even without any knowledge of their inner workings. That such classical certification is possible at all is remarkable: it is a consequence of the violation of Bell inequalities by entangled quantum systems. Device-independent self-testing refers to the most complete such certification: it enables a classical user to uniquely identify the quantum state shared by uncharacterized devices by simply inspecting the correlations of measurement outcomes. Self-testing was first demonstrated for the singlet state and a few other examples of self-testable states were reported in recent years. Here, we address the long-standing open question of whether every pure bipartite entangled state is self-testable. We answer it affirmatively by providing explicit self-testing correlations for all such states.

All pure bipartite entangled states can be self-tested.

PubMed

Coladangelo, Andrea; Goh, Koon Tong; Scarani, Valerio

2017-05-26

Quantum technologies promise advantages over their classical counterparts in the fields of computation, security and sensing. It is thus desirable that classical users are able to obtain guarantees on quantum devices, even without any knowledge of their inner workings. That such classical certification is possible at all is remarkable: it is a consequence of the violation of Bell inequalities by entangled quantum systems. Device-independent self-testing refers to the most complete such certification: it enables a classical user to uniquely identify the quantum state shared by uncharacterized devices by simply inspecting the correlations of measurement outcomes. Self-testing was first demonstrated for the singlet state and a few other examples of self-testable states were reported in recent years. Here, we address the long-standing open question of whether every pure bipartite entangled state is self-testable. We answer it affirmatively by providing explicit self-testing correlations for all such states.

Testing Specific Hypotheses Concerning Latent Group Differences in Multi-group Covariance Structure Analysis with Structured Means.

ERIC Educational Resources Information Center

Dolan, Conor V.; Molenaar, Peter C. M.

1994-01-01

In multigroup covariance structure analysis with structured means, the traditional latent selection model is formulated as a special case of phenotypic selection. Illustrations with real and simulated data demonstrate how one can test specific hypotheses concerning selection on latent variables. (SLD)

Encoding dependence in Bayesian causal networks

USDA-ARS?s Scientific Manuscript database

Bayesian networks (BNs) represent complex, uncertain spatio-temporal dynamics by propagation of conditional probabilities between identifiable states with a testable causal interaction model. Typically, they assume random variables are discrete in time and space with a static network structure that ...

Psyche: The Science of a Metal World

NASA Astrophysics Data System (ADS)

Elkins-Tanton, L. T.

2016-12-01

(16) Psyche is a large metallic asteroid orbiting in the outer main belt at 3 AU. Psyche's metal composition is indicated by high radar albedo, thermal inertia, and density. Models show that among the accretionary collisions early in the solar system, some destructive "hit and run" impacts could strip the silicate mantle from differentiated bodies. This is the leading hypothesis for Psyche's formation: it is a bare planetesimal core. It is the only one we can explore for substantial information about a metal core (other metallic asteroids are far smaller and not roughly spherical). If our observations indicate that it is not a core, Psyche may instead be highly reduced, primordial metal-rich materials that accreted closer to the Sun, and never melted. Psyche is also a Discovery-class mission, selected for a Step 2 concept study, to investigate this metal body. The Psyche investigation has three broad goals: Understand a previously unexplored building block of planet formation: iron cores. Look inside the terrestrial planets, including Earth, by directly examining the interior of a differentiated body, which otherwise could not be seen. Explore a new type of world. For the first time, examine a world made not of rock, ice, or gas, but of metal. We will meet our science objectives with three domestic high heritage instruments and radio science: Multispectral imagers with clear and seven color filters map surface morphology and reveal the distribution of residual mantle silicates. A gamma-ray and neutron spectrometer determines elemental composition, particularly the concentrations of iron, nickel, silicon, and potassium. Dual fluxgate magnetometers, in a gradiometer configuration, characterize the magnetic field. Radio science maps the gravity field sufficiently to differentiate among core-formation hypotheses. New models for magnetic dynamo generation and solidification of planetesimal cores make testable predictions for geophysical measurements, and lead as well to predictions about tectonics and surface compositions. In this presentation we will show how measurements from these flight instruments can confirm or disprove hypotheses for Psyche's formation and evolution.

Developing biosafety risk hypotheses for invertebrates exposed to GM plants using conceptual food webs: a case study with elevated triacylglyceride levels in ryegrass.

PubMed

Barratt, Barbara I P; Todd, Jacqui H; Burgess, Elisabeth P J; Malone, Louise A

2010-01-01

Regulators are acutely aware of the need for meaningful risk assessments to support decisions on the safety of GM crops to non-target invertebrates in determining their suitability for field release. We describe a process for developing appropriate, testable risk hypotheses for invertebrates in agroecosystems that might be exposed to plants developed by GM and future novel technologies. An existing model (PRONTI) generates a ranked list of invertebrate species for biosafety testing by accessing a database of biological, ecological and food web information about species which occur in cropping environments and their potential interactions with a particular stressor (Eco Invertebase). Our objective in this contribution is to explore and further utilise these resources to assist in the process of problem formulation by identifying potentially significant effects of the stressor on the invertebrate community and the ecosystem services they provide. We propose that for high ranking species, a conceptual food web using information in Eco Invertebase is constructed, and using an accepted regulatory risk analysis framework, the likelihood of risk, and magnitude of impact for each link in the food web is evaluated. Using as filters only those risks evaluated as likely to extremely likely, and the magnitude of an effect being considered as moderate to massive, the most significant potential effects can be identified. A stepwise approach is suggested to develop a sequence of appropriate tests. The GM ryegrass plant used as the "stressor" in this study has been modified to increase triacylglyceride levels in foliage by 100% to increase the metabolisable energy content of forage for grazing animals. The high-ranking "test" species chosen to illustrate the concept are New Zealand native species Wiseana cervinata (Walker) (Lepidoptera: Hepialidae), Persectania aversa (Walker) (Lepidoptera: Noctuidae), and the self-introduced grey field slug, Deroceras reticulatum (Müller). © ISBR, EDP Sciences, 2011.

An evolutionary link between capsular biogenesis and surface motility in bacteria.

PubMed

Agrebi, Rym; Wartel, Morgane; Brochier-Armanet, Céline; Mignot, Tâm

2015-05-01

Studying the evolution of macromolecular assemblies is important to improve our understanding of how complex cellular structures evolved, and to identify the functional building blocks that are involved. Recent studies suggest that the macromolecular complexes that are involved in two distinct processes in Myxococcus xanthus - surface motility and sporulation - are derived from an ancestral polysaccharide capsule assembly system. In this Opinion article, we argue that the available data suggest that the motility machinery evolved from this capsule assembly system following a gene duplication event, a change in carbohydrate polymer specificity and the acquisition of additional proteins by the motility complex, all of which are key features that distinguish the motility and sporulation systems. Furthermore, the presence of intermediates of these systems in bacterial genomes suggests a testable evolutionary model for their emergence and spread.

Genetic models of homosexuality: generating testable predictions

PubMed Central

Gavrilets, Sergey; Rice, William R

2006-01-01

Homosexuality is a common occurrence in humans and other species, yet its genetic and evolutionary basis is poorly understood. Here, we formulate and study a series of simple mathematical models for the purpose of predicting empirical patterns that can be used to determine the form of selection that leads to polymorphism of genes influencing homosexuality. Specifically, we develop theory to make contrasting predictions about the genetic characteristics of genes influencing homosexuality including: (i) chromosomal location, (ii) dominance among segregating alleles and (iii) effect sizes that distinguish between the two major models for their polymorphism: the overdominance and sexual antagonism models. We conclude that the measurement of the genetic characteristics of quantitative trait loci (QTLs) found in genomic screens for genes influencing homosexuality can be highly informative in resolving the form of natural selection maintaining their polymorphism. PMID:17015344

A narrative method for analyzing transitions in urban water management: The case of the Miami-Dade Water and Sewer Department

NASA Astrophysics Data System (ADS)

Treuer, Galen; Koebele, Elizabeth; Deslatte, Aaron; Ernst, Kathleen; Garcia, Margaret; Manago, Kim

2017-01-01

Although the water management sector is often characterized as resistant to risk and change, urban areas across the United States are increasingly interested in creating opportunities to transition toward more sustainable water management practices. These transitions are complex and difficult to predict - the product of water managers acting in response to numerous biophysical, regulatory, political, and financial factors within institutional constraints. Gaining a better understanding of how these transitions occur is crucial for continuing to improve water management. This paper presents a replicable methodology for analyzing how urban water utilities transition toward sustainability. The method combines standardized quantitative measures of variables that influence transitions with contextual qualitative information about a utility's unique decision making context to produce structured, data-driven narratives. Data-narratives document the broader context, the utility's pretransition history, key events during an accelerated period of change, and the consequences of transition. Eventually, these narratives should be compared across cases to develop empirically-testable hypotheses about the drivers of and barriers to utility-level urban water management transition. The methodology is illustrated through the case of the Miami-Dade Water and Sewer Department (WASD) in Miami-Dade County, Florida, and its transition toward more sustainable water management in the 2000s, during which per capita water use declined, conservation measures were enacted, water rates increased, and climate adaptive planning became the new norm.

Linguistic Diversity and Traffic Accidents: Lessons from Statistical Studies of Cultural Traits

PubMed Central

Roberts, Seán; Winters, James

2013-01-01

The recent proliferation of digital databases of cultural and linguistic data, together with new statistical techniques becoming available has lead to a rise in so-called nomothetic studies [1]–[8]. These seek relationships between demographic variables and cultural traits from large, cross-cultural datasets. The insights from these studies are important for understanding how cultural traits evolve. While these studies are fascinating and are good at generating testable hypotheses, they may underestimate the probability of finding spurious correlations between cultural traits. Here we show that this kind of approach can find links between such unlikely cultural traits as traffic accidents, levels of extra-martial sex, political collectivism and linguistic diversity. This suggests that spurious correlations, due to historical descent, geographic diffusion or increased noise-to-signal ratios in large datasets, are much more likely than some studies admit. We suggest some criteria for the evaluation of nomothetic studies and some practical solutions to the problems. Since some of these studies are receiving media attention without a widespread understanding of the complexities of the issue, there is a risk that poorly controlled studies could affect policy. We hope to contribute towards a general skepticism for correlational studies by demonstrating the ease of finding apparently rigorous correlations between cultural traits. Despite this, we see well-controlled nomothetic studies as useful tools for the development of theories. PMID:23967132

Gait control in a soft robot by sensing interactions with the environment using self-deformation.

PubMed

Umedachi, Takuya; Kano, Takeshi; Ishiguro, Akio; Trimmer, Barry A

2016-12-01

All animals use mechanosensors to help them move in complex and changing environments. With few exceptions, these sensors are embedded in soft tissues that deform in normal use such that sensory feedback results from the interaction of an animal with its environment. Useful information about the environment is expected to be embedded in the mechanical responses of the tissues during movements. To explore how such sensory information can be used to control movements, we have developed a soft-bodied crawling robot inspired by a highly tractable animal model, the tobacco hornworm Manduca sexta . This robot uses deformations of its body to detect changes in friction force on a substrate. This information is used to provide local sensory feedback for coupled oscillators that control the robot's locomotion. The validity of the control strategy is demonstrated with both simulation and a highly deformable three-dimensionally printed soft robot. The results show that very simple oscillators are able to generate propagating waves and crawling/inching locomotion through the interplay of deformation in different body parts in a fully decentralized manner. Additionally, we confirmed numerically and experimentally that the gait pattern can switch depending on the surface contact points. These results are expected to help in the design of adaptable, robust locomotion control systems for soft robots and also suggest testable hypotheses about how soft animals use sensory feedback.

Neuromechanical simulation of the locust jump

PubMed Central

Cofer, D.; Cymbalyuk, G.; Heitler, W. J.; Edwards, D. H.

2010-01-01

The neural circuitry and biomechanics of kicking in locusts have been studied to understand their roles in the control of both kicking and jumping. It has been hypothesized that the same neural circuit and biomechanics governed both behaviors but this hypothesis was not testable with current technology. We built a neuromechanical model to test this and to gain a better understanding of the role of the semi-lunar process (SLP) in jump dynamics. The jumping and kicking behaviors of the model were tested by comparing them with a variety of published data, and were found to reproduce the results from live animals. This confirmed that the kick neural circuitry can produce the jump behavior. The SLP is a set of highly sclerotized bands of cuticle that can be bent to store energy for use during kicking and jumping. It has not been possible to directly test the effects of the SLP on jump performance because it is an integral part of the joint, and attempts to remove its influence prevent the locust from being able to jump. Simulations demonstrated that the SLP can significantly increase jump distance, power, total energy and duration of the jump impulse. In addition, the geometry of the joint enables the SLP force to assist leg flexion when the leg is flexed, and to assist extension once the leg has begun to extend. PMID:20228342

Gait control in a soft robot by sensing interactions with the environment using self-deformation

PubMed Central

Ishiguro, Akio; Trimmer, Barry A.

2016-01-01

All animals use mechanosensors to help them move in complex and changing environments. With few exceptions, these sensors are embedded in soft tissues that deform in normal use such that sensory feedback results from the interaction of an animal with its environment. Useful information about the environment is expected to be embedded in the mechanical responses of the tissues during movements. To explore how such sensory information can be used to control movements, we have developed a soft-bodied crawling robot inspired by a highly tractable animal model, the tobacco hornworm Manduca sexta. This robot uses deformations of its body to detect changes in friction force on a substrate. This information is used to provide local sensory feedback for coupled oscillators that control the robot's locomotion. The validity of the control strategy is demonstrated with both simulation and a highly deformable three-dimensionally printed soft robot. The results show that very simple oscillators are able to generate propagating waves and crawling/inching locomotion through the interplay of deformation in different body parts in a fully decentralized manner. Additionally, we confirmed numerically and experimentally that the gait pattern can switch depending on the surface contact points. These results are expected to help in the design of adaptable, robust locomotion control systems for soft robots and also suggest testable hypotheses about how soft animals use sensory feedback. PMID:28083114

VirtualPlant: A Software Platform to Support Systems Biology Research1[W][OA

PubMed Central

Katari, Manpreet S.; Nowicki, Steve D.; Aceituno, Felipe F.; Nero, Damion; Kelfer, Jonathan; Thompson, Lee Parnell; Cabello, Juan M.; Davidson, Rebecca S.; Goldberg, Arthur P.; Shasha, Dennis E.; Coruzzi, Gloria M.; Gutiérrez, Rodrigo A.

2010-01-01

Data generation is no longer the limiting factor in advancing biological research. In addition, data integration, analysis, and interpretation have become key bottlenecks and challenges that biologists conducting genomic research face daily. To enable biologists to derive testable hypotheses from the increasing amount of genomic data, we have developed the VirtualPlant software platform. VirtualPlant enables scientists to visualize, integrate, and analyze genomic data from a systems biology perspective. VirtualPlant integrates genome-wide data concerning the known and predicted relationships among genes, proteins, and molecules, as well as genome-scale experimental measurements. VirtualPlant also provides visualization techniques that render multivariate information in visual formats that facilitate the extraction of biological concepts. Importantly, VirtualPlant helps biologists who are not trained in computer science to mine lists of genes, microarray experiments, and gene networks to address questions in plant biology, such as: What are the molecular mechanisms by which internal or external perturbations affect processes controlling growth and development? We illustrate the use of VirtualPlant with three case studies, ranging from querying a gene of interest to the identification of gene networks and regulatory hubs that control seed development. Whereas the VirtualPlant software was developed to mine Arabidopsis (Arabidopsis thaliana) genomic data, its data structures, algorithms, and visualization tools are designed in a species-independent way. VirtualPlant is freely available at www.virtualplant.org. PMID:20007449

Linguistic diversity and traffic accidents: lessons from statistical studies of cultural traits.

PubMed

Roberts, Seán; Winters, James

2013-01-01

The recent proliferation of digital databases of cultural and linguistic data, together with new statistical techniques becoming available has lead to a rise in so-called nomothetic studies [1]-[8]. These seek relationships between demographic variables and cultural traits from large, cross-cultural datasets. The insights from these studies are important for understanding how cultural traits evolve. While these studies are fascinating and are good at generating testable hypotheses, they may underestimate the probability of finding spurious correlations between cultural traits. Here we show that this kind of approach can find links between such unlikely cultural traits as traffic accidents, levels of extra-martial sex, political collectivism and linguistic diversity. This suggests that spurious correlations, due to historical descent, geographic diffusion or increased noise-to-signal ratios in large datasets, are much more likely than some studies admit. We suggest some criteria for the evaluation of nomothetic studies and some practical solutions to the problems. Since some of these studies are receiving media attention without a widespread understanding of the complexities of the issue, there is a risk that poorly controlled studies could affect policy. We hope to contribute towards a general skepticism for correlational studies by demonstrating the ease of finding apparently rigorous correlations between cultural traits. Despite this, we see well-controlled nomothetic studies as useful tools for the development of theories.

Construction of regulatory networks using expression time-series data of a genotyped population.

PubMed

Yeung, Ka Yee; Dombek, Kenneth M; Lo, Kenneth; Mittler, John E; Zhu, Jun; Schadt, Eric E; Bumgarner, Roger E; Raftery, Adrian E

2011-11-29

The inference of regulatory and biochemical networks from large-scale genomics data is a basic problem in molecular biology. The goal is to generate testable hypotheses of gene-to-gene influences and subsequently to design bench experiments to confirm these network predictions. Coexpression of genes in large-scale gene-expression data implies coregulation and potential gene-gene interactions, but provide little information about the direction of influences. Here, we use both time-series data and genetics data to infer directionality of edges in regulatory networks: time-series data contain information about the chronological order of regulatory events and genetics data allow us to map DNA variations to variations at the RNA level. We generate microarray data measuring time-dependent gene-expression levels in 95 genotyped yeast segregants subjected to a drug perturbation. We develop a Bayesian model averaging regression algorithm that incorporates external information from diverse data types to infer regulatory networks from the time-series and genetics data. Our algorithm is capable of generating feedback loops. We show that our inferred network recovers existing and novel regulatory relationships. Following network construction, we generate independent microarray data on selected deletion mutants to prospectively test network predictions. We demonstrate the potential of our network to discover de novo transcription-factor binding sites. Applying our construction method to previously published data demonstrates that our method is competitive with leading network construction algorithms in the literature.

An analytical model of non-photorespiratory CO₂release in the light and dark in leaves of C₃species based on stoichiometric flux balance.

PubMed

Buckley, Thomas N; Adams, Mark A

2011-01-01

Leaf respiration continues in the light but at a reduced rate. This inhibition is highly variable, and the mechanisms are poorly known, partly due to the lack of a formal model that can generate testable hypotheses. We derived an analytical model for non-photorespiratory CO₂ release by solving steady-state supply/demand equations for ATP, NADH and NADPH, coupled to a widely used photosynthesis model. We used this model to evaluate causes for suppression of respiration by light. The model agrees with many observations, including highly variable suppression at saturating light, greater suppression in mature leaves, reduced assimilatory quotient (ratio of net CO₂ and O₂ exchange) concurrent with nitrate reduction and a Kok effect (discrete change in quantum yield at low light). The model predicts engagement of non-phosphorylating pathways at moderate to high light, or concurrent with processes that yield ATP and NADH, such as fatty acid or terpenoid synthesis. Suppression of respiration is governed largely by photosynthetic adenylate balance, although photorespiratory NADH may contribute at sub-saturating light. Key questions include the precise diel variation of anabolism and the ATP : 2e⁻ ratio for photophosphorylation. Our model can focus experimental research and is a step towards a fully process-based model of CO₂ exchange. © 2010 Blackwell Publishing Ltd.

Emergent Spatial Patterns of Excitatory and Inhibitory Synaptic Strengths Drive Somatotopic Representational Discontinuities and their Plasticity in a Computational Model of Primary Sensory Cortical Area 3b

PubMed Central

Grajski, Kamil A.

2016-01-01

Mechanisms underlying the emergence and plasticity of representational discontinuities in the mammalian primary somatosensory cortical representation of the hand are investigated in a computational model. The model consists of an input lattice organized as a three-digit hand forward-connected to a lattice of cortical columns each of which contains a paired excitatory and inhibitory cell. Excitatory and inhibitory synaptic plasticity of feedforward and lateral connection weights is implemented as a simple covariance rule and competitive normalization. Receptive field properties are computed independently for excitatory and inhibitory cells and compared within and across columns. Within digit representational zones intracolumnar excitatory and inhibitory receptive field extents are concentric, single-digit, small, and unimodal. Exclusively in representational boundary-adjacent zones, intracolumnar excitatory and inhibitory receptive field properties diverge: excitatory cell receptive fields are single-digit, small, and unimodal; and the paired inhibitory cell receptive fields are bimodal, double-digit, and large. In simulated syndactyly (webbed fingers), boundary-adjacent intracolumnar receptive field properties reorganize to within-representation type; divergent properties are reacquired following syndactyly release. This study generates testable hypotheses for assessment of cortical laminar-dependent receptive field properties and plasticity within and between cortical representational zones. For computational studies, present results suggest that concurrent excitatory and inhibitory plasticity may underlie novel emergent properties. PMID:27504086

Extending systems thinking in planning and evaluation using group concept mapping and system dynamics to tackle complex problems.

PubMed

Hassmiller Lich, Kristen; Urban, Jennifer Brown; Frerichs, Leah; Dave, Gaurav

2017-02-01

Group concept mapping (GCM) has been successfully employed in program planning and evaluation for over 25 years. The broader set of systems thinking methodologies (of which GCM is one), have only recently found their way into the field. We present an overview of systems thinking emerging from a system dynamics (SD) perspective, and illustrate the potential synergy between GCM and SD. As with GCM, participatory processes are frequently employed when building SD models; however, it can be challenging to engage a large and diverse group of stakeholders in the iterative cycles of divergent thinking and consensus building required, while maintaining a broad perspective on the issue being studied. GCM provides a compelling resource for overcoming this challenge, by richly engaging a diverse set of stakeholders in broad exploration, structuring, and prioritization. SD provides an opportunity to extend GCM findings by embedding constructs in a testable hypothesis (SD model) describing how system structure and changes in constructs affect outcomes over time. SD can be used to simulate the hypothesized dynamics inherent in GCM concept maps. We illustrate the potential of the marriage of these methodologies in a case study of BECOMING, a federally-funded program aimed at strengthening the cross-sector system of care for youth with severe emotional disturbances. Copyright © 2016 Elsevier Ltd. All rights reserved.

The theory of music, mood and movement to improve health outcomes

PubMed Central

Murrock, Carolyn J.; Higgins, Patricia A.

2013-01-01

Aim This paper presents a discussion of the development of a middle-range nursing theory of the effects of music on physical activity and improved health outcomes. Background Due to the high rate of physical inactivity and the associated negative health outcomes worldwide, nurses need new evidence-based theories and interventions to increase physical activity. Data sources The theory of music, mood and movement (MMM) was developed from physical activity guidelines and music theory using the principles of statement and theory synthesis. The concepts of music, physical activity and health outcomes were searched using the CINAHL, MEDLINE, ProQuest Nursing and Allied Health Source, PsycINFO and Cochrane Library databases covering the years 1975–2008. Discussion The theory of MMM was synthesized by combining the psychological and physiological responses of music to increase physical activity and improve health outcomes. It proposes that music alters mood, is a cue for movement, and makes physical activity more enjoyable leading to improved health outcomes of weight, blood pressure, blood sugar and cardiovascular risk factor management, and improved quality of life. Conclusion As it was developed from the physical activity guidelines, the middle-range theory is prescriptive, produces testable hypotheses, and can guide nursing research and practice. The middle-range theory needs to be tested to determine its usefulness for nurses to develop physical activity programmes to improve health outcomes across various cultures. PMID:20568327

Sticky tunes: how do people react to involuntary musical imagery?

PubMed

Williamson, Victoria J; Liikkanen, Lassi A; Jakubowski, Kelly; Stewart, Lauren

2014-01-01

The vast majority of people experience involuntary musical imagery (INMI) or 'earworms'; perceptions of spontaneous, repetitive musical sound in the absence of an external source. The majority of INMI episodes are not bothersome, while some cause disruption ranging from distraction to anxiety and distress. To date, little is known about how the majority of people react to INMI, in particular whether evaluation of the experience impacts on chosen response behaviours or if attempts at controlling INMI are successful or not. The present study classified 1046 reports of how people react to INMI episodes. Two laboratories in Finland and the UK conducted an identical qualitative analysis protocol on reports of INMI reactions and derived visual descriptive models of the outcomes using grounded theory techniques. Combined analysis carried out across the two studies confirmed that many INMI episodes were considered neutral or pleasant, with passive acceptance and enjoyment being among the most popular response behaviours. A significant number of people, however, reported on attempts to cope with unwanted INMI. The most popular and effective behaviours in response to INMI were seeking out the tune in question, and musical or verbal distraction. The outcomes of this study contribute to our understanding of the aetiology of INMI, in particular within the framework of memory theory, and present testable hypotheses for future research on successful INMI coping strategies.

Sticky Tunes: How Do People React to Involuntary Musical Imagery?

PubMed Central

Williamson, Victoria J.; Liikkanen, Lassi A.; Jakubowski, Kelly; Stewart, Lauren

2014-01-01

The vast majority of people experience involuntary musical imagery (INMI) or ‘earworms’; perceptions of spontaneous, repetitive musical sound in the absence of an external source. The majority of INMI episodes are not bothersome, while some cause disruption ranging from distraction to anxiety and distress. To date, little is known about how the majority of people react to INMI, in particular whether evaluation of the experience impacts on chosen response behaviours or if attempts at controlling INMI are successful or not. The present study classified 1046 reports of how people react to INMI episodes. Two laboratories in Finland and the UK conducted an identical qualitative analysis protocol on reports of INMI reactions and derived visual descriptive models of the outcomes using grounded theory techniques. Combined analysis carried out across the two studies confirmed that many INMI episodes were considered neutral or pleasant, with passive acceptance and enjoyment being among the most popular response behaviours. A significant number of people, however, reported on attempts to cope with unwanted INMI. The most popular and effective behaviours in response to INMI were seeking out the tune in question, and musical or verbal distraction. The outcomes of this study contribute to our understanding of the aetiology of INMI, in particular within the framework of memory theory, and present testable hypotheses for future research on successful INMI coping strategies. PMID:24497938

Origin of the Eumetazoa: testing ecological predictions of molecular clocks against the Proterozoic fossil record

NASA Technical Reports Server (NTRS)

Peterson, Kevin J.; Butterfield, Nicholas J.

2005-01-01

Molecular clocks have the potential to shed light on the timing of early metazoan divergences, but differing algorithms and calibration points yield conspicuously discordant results. We argue here that competing molecular clock hypotheses should be testable in the fossil record, on the principle that fundamentally new grades of animal organization will have ecosystem-wide impacts. Using a set of seven nuclear-encoded protein sequences, we demonstrate the paraphyly of Porifera and calculate sponge/eumetazoan and cnidarian/bilaterian divergence times by using both distance [minimum evolution (ME)] and maximum likelihood (ML) molecular clocks; ME brackets the appearance of Eumetazoa between 634 and 604 Ma, whereas ML suggests it was between 867 and 748 Ma. Significantly, the ME, but not the ML, estimate is coincident with a major regime change in the Proterozoic acritarch record, including: (i) disappearance of low-diversity, evolutionarily static, pre-Ediacaran acanthomorphs; (ii) radiation of the high-diversity, short-lived Doushantuo-Pertatataka microbiota; and (iii) an order-of-magnitude increase in evolutionary turnover rate. We interpret this turnover as a consequence of the novel ecological challenges accompanying the evolution of the eumetazoan nervous system and gut. Thus, the more readily preserved microfossil record provides positive evidence for the absence of pre-Ediacaran eumetazoans and strongly supports the veracity, and therefore more general application, of the ME molecular clock.

What's hot, what's new in basic science: report from the American Transplant Congress 2015.

PubMed

Heeger, P S

2015-11-01

Research reports presented at the American Transplant Congress 2015 provided an array of basic science findings of relevance to the transplant community. Among key themes is the concept that ischemia-reperfusion injury and early posttransplantation inflammation is linked to adaptive alloimmunity and transplant injury. Molecular and cellular mechanisms contributing to these interactions were highlighted. The relevance of understanding how blocking costimulation, including CD40/CD154 interactions, affects various aspects of the alloimmune response was enhanced by the description of preclinical studies demonstrating efficacy of a unique, blocking anti-CD40 monoclonal antibody that could potentially be used in humans. The identification of mechanisms underlying interactions among T cell subsets and B cells, including follicular helper T cells, regulatory T cells, effector B cells, and regulatory B cells, provides multiple previously unrecognized targets for future therapeutic interventions. Additional reports of interest include novel insights into effects of the gut microbiome on graft survival and the ability to differentiate insulin-secreting, islet-like cells from induced pluripotent stem cells. Overall, the reported basic science findings from American Transplant Congress 2015 add to the fundamental understanding of innate and adaptive alloimmunity and provide novel and testable hypotheses that have the potential to be translated into improved clinical care of transplant patients. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

The theory of music, mood and movement to improve health outcomes.

PubMed

Murrock, Carolyn J; Higgins, Patricia A

2009-10-01

This paper presents a discussion of the development of a middle-range nursing theory of the effects of music on physical activity and improved health outcomes. Due to the high rate of physical inactivity and the associated negative health outcomes worldwide, nurses need new evidence-based theories and interventions to increase physical activity. The theory of music, mood and movement (MMM) was developed from physical activity guidelines and music theory using the principles of statement and theory synthesis. The concepts of music, physical activity and health outcomes were searched using the CINAHL, MEDLINE, ProQuest Nursing and Allied Health Source, PsycINFO and Cochrane Library databases covering the years 1975-2008. The theory of MMM was synthesized by combining the psychological and physiological responses of music to increase physical activity and improve health outcomes. It proposes that music alters mood, is a cue for movement, and makes physical activity more enjoyable leading to improved health outcomes of weight, blood pressure, blood sugar and cardiovascular risk factor management, and improved quality of life. As it was developed from the physical activity guidelines, the middle-range theory is prescriptive, produces testable hypotheses, and can guide nursing research and practice. The middle-range theory needs to be tested to determine its usefulness for nurses to develop physical activity programmes to improve health outcomes across various cultures.

Choice Experiments to Quantify Preferences for Health and Healthcare: State of the Practice.

PubMed

Mühlbacher, Axel; Johnson, F Reed

2016-06-01

Stated-preference methods increasingly are used to quantify preferences in health economics, health technology assessment, benefit-risk analysis and health services research. The objective of stated-preference studies is to acquire information about trade-off preferences among treatment outcomes, prioritization of clinical decision criteria, likely uptake or adherence to healthcare products and acceptability of healthcare services or policies. A widely accepted approach to eliciting preferences is discrete-choice experiments. Patient, physician, insurant or general-public respondents choose among constructed, experimentally controlled alternatives described by decision-relevant features or attributes. Attributes can represent complete health states, sets of treatment outcomes or characteristics of a healthcare system. The observed pattern of choice reveals how different respondents or groups of respondents implicitly weigh, value and assess different characteristics of treatments, products or services. An important advantage of choice experiments is their foundation in microeconomic utility theory. This conceptual framework provides tests of internal validity, guidance for statistical analysis of latent preference structures, and testable behavioural hypotheses. Choice experiments require expertise in survey-research methods, random-utility theory, experimental design and advanced statistical analysis. This paper should be understood as an introduction to setting up a basic experiment rather than an exhaustive critique of the latest findings and procedures. Where appropriate, we have identified topics of active research where a broad consensus has not yet been established.

Using statistical process control to make data-based clinical decisions.

PubMed

Pfadt, A; Wheeler, D J

1995-01-01

Applied behavior analysis is based on an investigation of variability due to interrelationships among antecedents, behavior, and consequences. This permits testable hypotheses about the causes of behavior as well as for the course of treatment to be evaluated empirically. Such information provides corrective feedback for making data-based clinical decisions. This paper considers how a different approach to the analysis of variability based on the writings of Walter Shewart and W. Edwards Deming in the area of industrial quality control helps to achieve similar objectives. Statistical process control (SPC) was developed to implement a process of continual product improvement while achieving compliance with production standards and other requirements for promoting customer satisfaction. SPC involves the use of simple statistical tools, such as histograms and control charts, as well as problem-solving techniques, such as flow charts, cause-and-effect diagrams, and Pareto charts, to implement Deming's management philosophy. These data-analytic procedures can be incorporated into a human service organization to help to achieve its stated objectives in a manner that leads to continuous improvement in the functioning of the clients who are its customers. Examples are provided to illustrate how SPC procedures can be used to analyze behavioral data. Issues related to the application of these tools for making data-based clinical decisions and for creating an organizational climate that promotes their routine use in applied settings are also considered.

Elevated carbon dioxide is predicted to promote coexistence among competing species in a trait-based model

DOE PAGES

Ali, Ashehad A.; Medlyn, Belinda E.; Aubier, Thomas G.; ...

2015-10-06

Differential species responses to atmospheric CO 2 concentration (C a) could lead to quantitative changes in competition among species and community composition, with flow-on effects for ecosystem function. However, there has been little theoretical analysis of how elevated C a (eC a) will affect plant competition, or how composition of plant communities might change. Such theoretical analysis is needed for developing testable hypotheses to frame experimental research. Here, we investigated theoretically how plant competition might change under eC a by implementing two alternative competition theories, resource use theory and resource capture theory, in a plant carbon and nitrogen cycling model.more » The model makes several novel predictions for the impact of eC a on plant community composition. Using resource use theory, the model predicts that eC a is unlikely to change species dominance in competition, but is likely to increase coexistence among species. Using resource capture theory, the model predicts that eC a may increase community evenness. Collectively, both theories suggest that eC a will favor coexistence and hence that species diversity should increase with eC a. Our theoretical analysis leads to a novel hypothesis for the impact of eC a on plant community composition. In this study, the hypothesis has potential to help guide the design and interpretation of eC a experiments.« less

Theory of cortical function

PubMed Central

Heeger, David J.

2017-01-01

Most models of sensory processing in the brain have a feedforward architecture in which each stage comprises simple linear filtering operations and nonlinearities. Models of this form have been used to explain a wide range of neurophysiological and psychophysical data, and many recent successes in artificial intelligence (with deep convolutional neural nets) are based on this architecture. However, neocortex is not a feedforward architecture. This paper proposes a first step toward an alternative computational framework in which neural activity in each brain area depends on a combination of feedforward drive (bottom-up from the previous processing stage), feedback drive (top-down context from the next stage), and prior drive (expectation). The relative contributions of feedforward drive, feedback drive, and prior drive are controlled by a handful of state parameters, which I hypothesize correspond to neuromodulators and oscillatory activity. In some states, neural responses are dominated by the feedforward drive and the theory is identical to a conventional feedforward model, thereby preserving all of the desirable features of those models. In other states, the theory is a generative model that constructs a sensory representation from an abstract representation, like memory recall. In still other states, the theory combines prior expectation with sensory input, explores different possible perceptual interpretations of ambiguous sensory inputs, and predicts forward in time. The theory, therefore, offers an empirically testable framework for understanding how the cortex accomplishes inference, exploration, and prediction. PMID:28167793

A LINE-1 Component to Human Aging: Do LINE elements exact a longevity cost for evolutionary advantage?

PubMed Central

Laurent, Georges St.; Hammell, Neil; McCaffrey, Timothy A.

2010-01-01

Advancing age remains the largest risk factor for devastating diseases, such as heart disease, stroke, and cancer. The mechanisms by which advancing age predisposes to disease are now beginning to unfold, due in part, to genetic and environmental manipulations of longevity in lower organisms. Converging lines of evidence suggest that DNA damage may be a final common pathway linking several proposed mechanisms of aging. The present review forwards a theory for an additional aging pathway that involves modes of inherent genetic instability. Long interspersed nuclear elements (LINEs) are endogenous non-LTR retrotransposons that compose about 20% of the human genome. The LINE-1 (L1) gene products, ORF1p and ORF2p, possess mRNA binding, endonuclease, and reverse transcriptase activity that enable retrotransposition. While principally active only during embryogenesis, L1 transcripts are detected in adult somatic cells under certain conditions. The present hypothesis proposes that L1s act as an ‘endogenous clock’, slowly eroding genomic integrity by competing with the organism’s double-strand break repair mechanism. Thus, while L1s are an accepted mechanism of genetic variation fueling evolution, it is proposed that longevity is negatively impacted by somatic L1 activity. The theory predicts testable hypotheses about the relationship between L1 activity, DNA repair, healthy aging, and longevity. PMID:20346965

Alcohol, drugs, caffeine, tobacco, and environmental contaminant exposure: reproductive health consequences and clinical implications.

PubMed

Sadeu, J C; Hughes, Claude L; Agarwal, Sanjay; Foster, Warren G

2010-08-01

Reproductive function and fertility are thought to be compromised by behaviors such as cigarette smoking, substance abuse, and alcohol consumption; however, the strength of these associations are uncertain. Furthermore, the reproductive system is thought to be under attack from exposure to environmental contaminants, particularly those chemicals shown to affect endocrine homeostasis. The relationship between exposure to environmental contaminants and adverse effects on human reproductive health are frequently debated in the scientific literature and these controversies have spread into the lay press drawing increased public and regulatory attention. Therefore, the objective of the present review was to critically evaluate the literature concerning the relationship between lifestyle exposures and adverse effects on fertility as well as examining the evidence for a role of environmental contaminants in the purported decline of semen quality and the pathophysiology of subfertility, polycystic ovarian syndrome, and endometriosis. The authors conclude that whereas cigarette smoking is strongly associated with adverse reproductive outcomes, high-level exposures to other lifestyle factors are only weakly linked with negative fertility impacts. Finally, there is no compelling evidence that environmental contaminants, at concentrations representative of the levels measured in contemporary biomonitoring studies, have any effect, positive or negative, on reproductive health in the general population. Further research using prospective study designs with robust sample sizes are needed to evaluate testable hypotheses that address the relationship between exposure and adverse reproductive health effects.

Description and Validation of a Dynamical Systems Model of Presynaptic Serotonin Function: Genetic Variation, Brain Activation and Impulsivity

PubMed Central

Stoltenberg, Scott F.; Nag, Parthasarathi

2010-01-01

Despite more than a decade of empirical work on the role of genetic polymorphisms in the serotonin system on behavior, the details across levels of analysis are not well understood. We describe a mathematical model of the genetic control of presynaptic serotonergic function that is based on control theory, implemented using systems of differential equations, and focused on better characterizing pathways from genes to behavior. We present the results of model validation tests that include the comparison of simulation outcomes with empirical data on genetic effects on brain response to affective stimuli and on impulsivity. Patterns of simulated neural firing were consistent with recent findings of additive effects of serotonin transporter and tryptophan hydroxylase-2 polymorphisms on brain activation. In addition, simulated levels of cerebral spinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) were negatively correlated with Barratt Impulsiveness Scale (Version 11) Total scores in college students (r = −.22, p = .002, N = 187), which is consistent with the well-established negative correlation between CSF 5-HIAA and impulsivity. The results of the validation tests suggest that the model captures important aspects of the genetic control of presynaptic serotonergic function and behavior via brain activation. The proposed model can be: (1) extended to include other system components, neurotransmitter systems, behaviors and environmental influences; (2) used to generate testable hypotheses. PMID:20111992

Automated Testability Decision Tool

DTIC Science & Technology

1991-09-01

Vol. 16,1968, pp. 538-558. Bertsekas, D. P., "Constraints Optimization and Lagrange Multiplier Methods," Academic Press, New York. McLeavey , D.W... McLeavey , J.A., "Parallel Optimization Methods in Standby Reliability, " University of Connecticut, School of Business Administration, Bureau of Business

Role of the Epistemic Subject in Piaget's Genetic Epistemology and Its Importance for Science Education.

ERIC Educational Resources Information Center

Niaz, Mansoor

1991-01-01

Discusses differences between the epistemic and the psychological subject, the relationship between the epistemic subject and the ideal gas law, the development of general cognitive operations, and the empirical testability of Piaget's epistemic subject. (PR)

Small Town in Mass Society Revisited.

ERIC Educational Resources Information Center

Young, Frank W.

1996-01-01

A 1958 New York community study dramatized the thesis that macro forces (urbanization, industrialization, bureaucratization) have undermined all small communities' autonomy. Such "oppositional case studies" succeed when they render the dominant view immediately obsolete, have plausible origins, are testable, and generate new research.…

Bayesian Meta-Analysis of Cronbach's Coefficient Alpha to Evaluate Informative Hypotheses

ERIC Educational Resources Information Center

Okada, Kensuke

2015-01-01

This paper proposes a new method to evaluate informative hypotheses for meta-analysis of Cronbach's coefficient alpha using a Bayesian approach. The coefficient alpha is one of the most widely used reliability indices. In meta-analyses of reliability, researchers typically form specific informative hypotheses beforehand, such as "alpha of…

Cognitive Scientists Prefer Theories and Testable Principles with Teeth

ERIC Educational Resources Information Center

Graesser, Arthur C.

2009-01-01

Alexander, Schallert, and Reynolds (2009/this issue) proposed a definition and landscape of learning that included 9 principles and 4 dimensions ("what," "who," "where," "when"). This commentary reflects on the utility of this definition and 4-dimensional landscape from the standpoint of educational…

Dynamical Model of Drug Accumulation in Bacteria: Sensitivity Analysis and Experimentally Testable Predictions

DOE PAGES

Vesselinova, Neda; Alexandrov, Boian; Wall, Michael E.

2016-11-08

We present a dynamical model of drug accumulation in bacteria. The model captures key features in experimental time courses on ofloxacin accumulation: initial uptake; two-phase response; and long-term acclimation. In combination with experimental data, the model provides estimates of import and export rates in each phase, the time of entry into the second phase, and the decrease of internal drug during acclimation. Global sensitivity analysis, local sensitivity analysis, and Bayesian sensitivity analysis of the model provide information about the robustness of these estimates, and about the relative importance of different parameters in determining the features of the accumulation time coursesmore » in three different bacterial species: Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The results lead to experimentally testable predictions of the effects of membrane permeability, drug efflux and trapping (e.g., by DNA binding) on drug accumulation. A key prediction is that a sudden increase in ofloxacin accumulation in both E. coli and S. aureus is accompanied by a decrease in membrane permeability.« less

Perceptual Decision-Making as Probabilistic Inference by Neural Sampling.

PubMed

Haefner, Ralf M; Berkes, Pietro; Fiser, József

2016-05-04

We address two main challenges facing systems neuroscience today: understanding the nature and function of cortical feedback between sensory areas and of correlated variability. Starting from the old idea of perception as probabilistic inference, we show how to use knowledge of the psychophysical task to make testable predictions for the influence of feedback signals on early sensory representations. Applying our framework to a two-alternative forced choice task paradigm, we can explain multiple empirical findings that have been hard to account for by the traditional feedforward model of sensory processing, including the task dependence of neural response correlations and the diverging time courses of choice probabilities and psychophysical kernels. Our model makes new predictions and characterizes a component of correlated variability that represents task-related information rather than performance-degrading noise. It demonstrates a normative way to integrate sensory and cognitive components into physiologically testable models of perceptual decision-making. Copyright © 2016 Elsevier Inc. All rights reserved.

Dynamical Model of Drug Accumulation in Bacteria: Sensitivity Analysis and Experimentally Testable Predictions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vesselinova, Neda; Alexandrov, Boian; Wall, Michael E.

We present a dynamical model of drug accumulation in bacteria. The model captures key features in experimental time courses on ofloxacin accumulation: initial uptake; two-phase response; and long-term acclimation. In combination with experimental data, the model provides estimates of import and export rates in each phase, the time of entry into the second phase, and the decrease of internal drug during acclimation. Global sensitivity analysis, local sensitivity analysis, and Bayesian sensitivity analysis of the model provide information about the robustness of these estimates, and about the relative importance of different parameters in determining the features of the accumulation time coursesmore » in three different bacterial species: Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. The results lead to experimentally testable predictions of the effects of membrane permeability, drug efflux and trapping (e.g., by DNA binding) on drug accumulation. A key prediction is that a sudden increase in ofloxacin accumulation in both E. coli and S. aureus is accompanied by a decrease in membrane permeability.« less

Experimental Test of Compatibility-Loophole-Free Contextuality with Spatially Separated Entangled Qutrits.

PubMed

Hu, Xiao-Min; Chen, Jiang-Shan; Liu, Bi-Heng; Guo, Yu; Huang, Yun-Feng; Zhou, Zong-Quan; Han, Yong-Jian; Li, Chuan-Feng; Guo, Guang-Can

2016-10-21

The physical impact and the testability of the Kochen-Specker (KS) theorem is debated because of the fact that perfect compatibility in a single quantum system cannot be achieved in practical experiments with finite precision. Here, we follow the proposal of A. Cabello and M. T. Cunha [Phys. Rev. Lett. 106, 190401 (2011)], and present a compatibility-loophole-free experimental violation of an inequality of noncontextual theories by two spatially separated entangled qutrits. A maximally entangled qutrit-qutrit state with a fidelity as high as 0.975±0.001 is prepared and distributed to separated spaces, and these two photons are then measured locally, providing the compatibility requirement. The results show that the inequality for noncontextual theory is violated by 31 standard deviations. Our experiments pave the way to close the debate about the testability of the KS theorem. In addition, the method to generate high-fidelity and high-dimension entangled states will provide significant advantages in high-dimension quantum encoding and quantum communication.

What is a delusion? Epistemological dimensions.

PubMed

Leeser, J; O'Donohue, W

1999-11-01

Although the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1994) clearly indicates delusions have an epistemic dimension, it fails to accurately identify the epistemic properties of delusions. The authors explicate the regulative causes of belief revision for rational agents and argue that delusions are unresponsive to these. They argue that delusions are (a) protected beliefs made unfalsifiable either in principle or because the agent refuses to admit anything as a potential falsifier; (b) the protected belief is not typically considered a "properly basic" belief; (c) the belief is not of the variety of protected scientific beliefs; (d) in response to an apparent falsification, the subject posits not a simple, testable explanation for the inconsistency but one that is more complicated, less testable, and provides no new corroborations; (e) the subject has a strong emotional attachment to the belief; and (f) the belief is typically supported by (or originates from) trivial occurrences that are interpreted by the subject as highly unusual, significant, having personal reference, or some combination of these.

Requirements for an Advanced Ocean Radiometer

NASA Technical Reports Server (NTRS)

Meister, Gerhard; McClain, Charles R.; Ahmad, Ziauddin; Bailey, Sean W.; Barnes, Robert A.; Brown, Steven; Eplee, Robert E.; Franz, Bryan; Holmes, Alan; Monosmith, W. Bryan;

Principles of protein folding--a perspective from simple exact models.

PubMed Central

Dill, K. A.; Bromberg, S.; Yue, K.; Fiebig, K. M.; Yee, D. P.; Thomas, P. D.; Chan, H. S.

1995-01-01

General principles of protein structure, stability, and folding kinetics have recently been explored in computer simulations of simple exact lattice models. These models represent protein chains at a rudimentary level, but they involve few parameters, approximations, or implicit biases, and they allow complete explorations of conformational and sequence spaces. Such simulations have resulted in testable predictions that are sometimes unanticipated: The folding code is mainly binary and delocalized throughout the amino acid sequence. The secondary and tertiary structures of a protein are specified mainly by the sequence of polar and nonpolar monomers. More specific interactions may refine the structure, rather than dominate the folding code. Simple exact models can account for the properties that characterize protein folding: two-state cooperativity, secondary and tertiary structures, and multistage folding kinetics--fast hydrophobic collapse followed by slower annealing. These studies suggest the possibility of creating "foldable" chain molecules other than proteins. The encoding of a unique compact chain conformation may not require amino acids; it may require only the ability to synthesize specific monomer sequences in which at least one monomer type is solvent-averse. PMID:7613459