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PubMed2006

Expression genetics and the phenotype revolution.

Genetic analysis of variation demands large numbers of individuals and even larger numbers of genotypes. The identification of alleles associated with Mendelian disorders has involved sample sizes of a thousand or more. Pervasive and common diseases that afflict human populations--cancer, heart disease, diabetes, neurodegeneration, addiction--are all polygenic and are even more demanding of large numbers. DeCode Genetics (http://www.decode.com) has harnessed the human resources of Iceland to unravel genetic and molecular causes of complex disease. The UK BioBank project (http://www.ukbiobank.ac.uk/) will incorporate 500,000 adult volunteers. The murine Collaborative Cross is the experimental equivalent of these human populations and will consist of a panel of approximately 1000 recombinant strains, expandable by intercrossing to much larger numbers of isogenic but heterozygous F(1)s. Massive projects of these types require efficient technologies. We have made enormous progress on the genotyping front, and it is now important to focus energy on devising ultrahigh-throughput methods to phenotype. Molecular phenotyping of the transcriptome has matured, and it is now possible to acquire hundreds of thousands of mRNA phenotypes at a cost matching those of SNPs. Proteomic and cell-based assays are also maturing rapidly. The acquisition of a personal genome along with a personal molecular phenome will provide an effective foundation for personalized medicine. Rodent models will be essential to test our ability to predict susceptibility and disease outcome using SNP data, molecular phenomes, and environmental exposures. These models will also be essential to test new treatments in a robust systems context that accounts for genetic variation.

Animals↗
PubMed2005

Dissecting innate immune responses with the tools of systems biology.

Systems biology strives to derive accurate predictive descriptions of complex systems such as innate immunity. The innate immune system is essential for host defense, yet the resulting inflammatory response must be tightly regulated. Current understanding indicates that this system is controlled by complex regulatory networks, which maintain homoeostasis while accurately distinguishing pathogenic infections from harmless exposures. Recent studies have used high throughput technologies and computational techniques that presage predictive models and will be the foundation of a systems level understanding of innate immunity.

Animals↗
PubMed2026

A systematic review of human avoidance learning: Cognition, computation, and methods.

Avoidance behaviour is fundamental for survival but can become maladaptive in clinical conditions. A large body of literature has accumulated on the dynamics of human avoidance learning. However, current theories and overviews do not provide an exhaustive account of this evidence. In this systematic review, we identify N = 116 studies on human avoidance learning. We analyse these studies with the goal of distilling robust empirical phenomena as a basis for theory-building, and examine their diagnostic value in differentiating between competing theories. We find that the evidence is difficult to reconcile with foundational two-factor and classical safety-signal accounts, and most strongly supports expectancy- and inference-based views, in which avoidance responses are selected with respect to represented consequences. At the same time, no current framework provides a complete account of the evidence: several findings point to an additional role for operant valuation, Pavlovian influences, and contextual or latent-state control over the expression of avoidance. Methodologically, we observe that the problem setting in the most common experimental paradigms is radically simpler than real-world avoidance and therefore unlikely to expose the limits of inferential or reflective mechanisms. Consequently, we argue that paradigms with greater computational demands and more realistic action affordances are required to identify the mechanisms underlying avoidance learning. Collectively, these insights provide a foundation for theoretical refinement, computational modelling, and methodological innovation, with implications for advancing interventions targeting maladaptive avoidance.

Humans↗
PubMed2002

An empirical quantitative framework for the seasonal population dynamics of the tick Ixodes ricinus.

The wide geographic and climatic range of the tick Ixodes ricinus, and the consequent marked variation in its seasonal population dynamics, have a direct impact on the transmission dynamics of the many pathogens vectored by this tick species. We use long-term observations on the seasonal abundance and fat contents (a marker of physiological ageing) of ticks, and contemporaneous microclimate at three field sites in the UK, to establish a simple quantitative framework for the phenology (i.e. seasonal cycle of development) of I. ricinus as a foundation for a generic population model. An hour-degree tick inter-stadial development model, driven by soil temperature and including diapause, predicts the recruitment (i.e. emergence from the previous stage) of a single cohort of each stage of ticks each year in the autumn. The timing of predicted emergence coincides exactly with the new appearance of high-fat nymphs and adults in the autumn. Thereafter, fat contents declined steadily until unfed ticks with very low energy reserves disappeared from the questing population within about 1 year from their recruitment. Very few newly emerged ticks were counted on the vegetation in the autumn, but they appeared in increasing numbers through the following spring. Larger ticks became active and subsequently left the questing population before smaller ones. Questing tick population dynamics are determined by seasonal patterns of tick behaviour, host-contact rates and mortality rates, superimposed on a basal phenology that is much less complex than has hitherto been portrayed.

Animals↗
PubMed1990

Molecular genetics of Na,K-ATPase.

Researchers in the past few years have successfully used molecular-genetic approaches to determine the primary structures of several P-type ATPases. The amino-acid sequences of distinct members of this class of ion-transport ATPases (Na,K-, H,K-, and Ca-ATPases) have been deduced by cDNA cloning and sequencing. The Na,K-ATPase belongs to a multiple gene family, the principal diversity apparently resulting from distinct catalytic alpha isoforms. Computer analyses of the hydrophobicity and potential secondary structure of the alpha subunits and primary sequence comparisons with homologs from various species as well as other P-type ATPases have identified common structural features. This has provided the molecular foundation for the design of models and hypotheses aimed at understanding the relationship between structure and function. Development of a hypothetical transmembrane organization for the alpha subunit and application of site-specific mutagenesis techniques have allowed significant progress to be made toward identifying amino acids involved in cardiac glycoside resistance and possibly binding. However, the complex structural and functional features of this protein indicate that extensive research is necessary before a clear understanding of the molecular basis of active cation transport is achieved. This is complicated further by the paucity of information regarding the structural and functional contributions of the beta subunit. Until such information is obtained, the proposed model and functional hypotheses should be considered judiciously. Considerable progress also has been made in characterizing the regulatory complexity involved in expression of multiple alpha-isoform and beta-subunit genes in various tissues and cells during development and in response to hormones and cations. The regulatory mechanisms appear to function at several molecular levels, involving transcriptional, posttranscriptional, translational, and posttranslational processes in a tissue- or cell-specific manner. However, much research is needed to precisely define the contributions of each of these mechanisms. Recent isolation of the genes for these subunits provides the framework for future advances in this area. Continued application of biochemical, biophysical, and molecular genetic techniques is required to provide a detailed understanding of the mechanisms involved in cation transport of this biologically and pharmacologically important enzyme.

Amino Acid Sequence↗
PubMed1999

Involvement of hippocampal synaptic plasticity in age-related memory decline.

This article examines the functional significance of Ca(2+)-dependent synaptic plasticity in relation to compromised memory function during aging. Research characterizing an age-related decline in memory for tasks that require proper hippocampal function is summarized. It is concluded that aged animals possess the mechanisms necessary for memory formation, and memory deficits, including rapid forgetting, result from more subtle changes in memory processes for memory storage or maintenance. A review of experimental studies concerning changes in hippocampal neural plasticity over the course of aging indicates that, during aging, there is a shift in mechanisms that regulate the thresholds for synaptic modification, including Ca(2+) channel function and subsequent Ca(2+)-dependent processes. The results, combined with theoretical considerations concerning synaptic modification thresholds, provide the basis for a model of age-related changes in hippocampal synaptic function. The model is employed as a foundation for interpretation of studies examining therapeutic intervention in age-related memory decline. The possible role of altered synaptic plasticity thresholds in learning and memory deficits suggests that treatments that modify synaptic plasticity may prove fruitful for the development of early therapeutic interventions in age-related neurodegenerative diseases.

Aging↗
PubMed1980

Cost containment: is it unjustly cutting therapeutic mental health services? The plight of neighborhood organizations.

A national emphasis on cost containment has resulted in the reduction of a host of activities at settlement houses and community centers that were formerly funded by mental health agencies. It is contended that this is penny wise and pound foolish because the neighborhood organizations provide preventive and therapeutic services. A rationale is developed to support this contention with an eleven point chart showing settlement--mental health links, a discussion of the urban condition and population disturbances, a foundation of medical and social models that support the value of settlement house activities, a review of current community mental health concepts that echo the goals of neighborhood organizations and a discussion of the roles of settlements in mental health programs. It is concluded that strong evidence exists to support the continued funding of the preventive and therapeutic mental health activities of neighborhood organizations such as settlement houses and community centers.

Community Mental Health Services↗
PubMed1997

Input from the medial nucleus of trapezoid body to an interaural level detector.

The medial nucleus of the trapezoid body (MNTB) contains components of a neural network that functions as an interaural level difference (ILD) detector. In the cat, lateral superior olivary (LSO) neurons compare the contralateral inhibitory input from the MNTB with an excitatory input form the ipsilateral anteroventral cochlear nucleus to extract information about binaural stimuli. To better specify the inhibitory inputs to the LSO and gain a better understanding of the inhibitory component of the LSO network, the response characteristics of MNTB neurons were examined in cats under stimulus conditions similar to those used to study LSO inhibitory responses. The inhibitory tuning curves of LSO units were wider than the tuning curves of MNTB units. Hence, MNTB neurons with similar, but not identical, characteristic frequencies converge to provide inhibitory input to single LSO neurons. Variations in the number of converging MNTB inputs produced a range of LSO excitatory-inhibitory threshold differences, thus creating a coding mechanism for representing the ILD. Convergence of MNTB inputs also increased the dynamic range over which contralateral stimulus level effects LSO binaural responses beyond the dynamic ranges of individual MNTB units, thus expanding the ILD range encoded by the LSO network. The differences between the first-spike latencies of MNTB and LSO tone burst responses were small and the precision of the LSO first-spike discharges was significantly greater than that of MNTB units. As tone bursts delivered simultaneously to the two ears can consistently inhibit LSO first-spike discharges, the inhibitory input must match the LSO precision by converging a number of the more variably timed MNTB discharges. Because of their precision LSO first-spike discharges may be used to encode interaural time-of-arrival differences of mid- to high-frequency transients. These findings add to the foundation for a comprehensive network model that describes the inputs to the LSO as point processes, delimits the biophysical mechanisms underlying excitatory and inhibitory interactions at the single neuron level, and reveals how these inputs determine the response to different binaural stimulus conditions.

Acoustic Stimulation↗
PubMed2002

Three-dimensional representation and qualitative comparisons of the amount of tissue ablation to treat mixed and compound astigmatism.

PURPOSE: To compare the shape and volume of the lenticules of corneal tissue ablated for the correction of spherical, cylindrical, and spherocylindrical refractive errors using Boolean operations of theoretical 3-dimensional (3-D) surfaces. SETTING: Department of Ophthalmology, Rothschild Foundation, Paris, France. METHODS: Digital modeling software was used to perform graphic representations of ablated lenticules on 3-D virtual surfaces. Various Boolean operations were performed between different preoperative and postoperative surfaces, and the additional and subtractive properties of ablated theoretical lenticules were analyzed to determine profiles of ablated lenticules for mixed and compound myopic and hyperopic astigmatism. RESULTS: Negative-cylindrical treatment, used to treat simple myopic astigmatism, was equivalent to the combination of a positive-cylindrical and a negative-spherical treatment of the same magnitude. Combining a pure negative-cylindrical and a positive-spherical treatment in a sequential strategy when treating compound astigmatism resulted in redundant ablation (plano lenticule), leading to an unnecessary increase in the amount of tissue ablation. CONCLUSIONS: Negative-cylindrical treatments result in greater tissue ablation than corresponding positive-cylindrical treatments. For any given compound astigmatic error, the strategy using the greater magnitude of positive cylinder incurs the minimal amount of tissue ablation.

Astigmatism↗
PubMed2005

Doping highly ordered organic semiconductors: experimental results and fits to a self-consistent model of excitonic processes, doping, and transport.

An in-depth study of n-type doping in a crystalline perylene diimide organic semiconductor (PPEEB) reveals that electrostatic attractions between the dopant electron and its conjugate dopant cation cause the free carrier density to be much lower than the doping density. Measurements of the dark currents as a function of field, doping density, electrode spacing, and temperature are reported along with preliminary Hall-effect measurements. The activation energy of the current, E(aJ), decreases with increasing field and with increasing dopant density, n(d). It is the measured change in E(aJ) with n(d) that accounts primarily for the variations between PPEEB films; the two adjustable parameters employed to fit the current-voltage data proved to be almost constants, independent of n(d) and temperature. The free electron density and the electron mobility are nonlinearly coupled through their shared dependences on both field and temperature. The data are fit to a modified Poole-Frenkel-like model that is shown to be valid for three important electronic processes in organic (excitonic) semiconductors: excitonic effects, doping, and transport. At room temperature, the electron mobility in PPEEB films is estimated to be 0.3 cm(2)/Vs; the fitted value of the mobility for an ideal PPEEB crystal is 3.4 +/- 2.7 cm(2)/Vs. The modified Poole-Frenkel factor that describes the field dependence of the current is 2 +/- 1 x 10(-4) eV (cm/V)(1/2). The analytical model is surprisingly accurate for a system that would require a coupled set of nonlinear tensor equations to describe it precisely. Being based on general electrostatic considerations, our model can form the requisite foundation for treatments of more complex systems. Some analogies to adventitiously doped materials such as pi-conjugated polymers are proposed.

Journal Article↗
PubMed2002

Defining the cultural milieu for implementing faculty practice in Pakistan.

Faculty practice can promote a collaborative partnership mutually beneficial to both nursing education and service. However, little is known about its implementation in developing countries. The purpose of this study was to explore the potential for introducing faculty practice within the cultural milieu of Karachi, Pakistan. Focus groups of nursing faculty, staff and students were conducted in various settings: government, semigovernment and private institutions to elicit the data. Data analysis revealed that a more comprehensive definition of faculty practice is needed that will provide the foundation for a culturally acceptable model of faculty practice in Pakistan. Hierarchy dominates the current cultural milieu and must be addressed before faculty practice can be implemented.

Attitude of Health Personnel↗
PubMed2003

Dialogue and decision in a moral context.

One of the most widely accepted tenets in postmetaphysical normative ethics is the principle of dialogue as a foundational authority. Conceptually, the dialogical model is valuable, in that it allows a binding yet mutable underpinning of moral discourse. However, dialogue has its limits. The main drawback lies in the fact that deliberations can be very lengthy, perhaps even infinite. In other words, deliberation does not always lend itself to action. From the vantage point of applied ethics, in this case, bioethics and forensic ethics, this is not a minor shortcoming since these disciplines are concerned with situations involving some sort of urgency. Aporia is not an option in most cases. It is thus pressing to consider the moment of decision inherent to moral judgement and action that puts an end to dialogue. From the realm of abstract norm justification, one must move on to the contextualist discourse of application. To be rational, however, decision must avoid authoritativeness or any type of arbitrariness. What, then, could serve as a reasonable criteria for the rational application of norms? What aspects should be envisaged for a sound reflective decision? This paper will attempt to sketch some answers that could contribute to the question of the necessary contextual application of accepted norms by paying heed to, systemizing and sometimes finding fault in the arguments given by judges who had to settle cases touching sensitive moral issues.

Decision Making↗
PubMed2006

Immunosuppression in pediatric solid organ transplantation.

This report reviews the immunosuppressive regimens that are used in pediatric transplantation. There are predominant themes developing in the field involving the minimization of the total exposure of immunosuppression through limiting the number of agents and newer pharmacokinetic modeling. Calcineurin inhibitors are the foundation of most immunosuppressive regimens. However, there are new pharmacologic monitoring techniques to reduce the potential for long-term side effects of this class of agents. Although tacrolimus remains one of the mainstays of current protocols, there are strides being made to reduce the patient's long-term exposure to it with transitioning to sirolimus. Corticosteroids are still used predominantly, but there is growing evidence of successful steroid-sparing protocols that are as effective and avoid the chronic morbidity of steroids. Antibody induction therapy remains a standard with clearer evidence of the efficacy of IL-2 receptor antagonists. There is preliminary clinical evidence that polyclonal antibody therapy is efficacious in pediatric transplantation. Future studies will determine the best way to assess the functional immune status of a pediatric transplant recipient to maintain the fine balance and avoid the complications of either excessive or inadequate immunosuppression.

Adrenal Cortex Hormones↗
PubMed1982

Rural health care: opportunities for established group practices.

Many rural areas of the United States are considered medically underserved. At the core of this underservice is a lack of physicians. Physicians are not attracted to rural areas for a variety of personal and professional reasons. We explore the role of established group practices (EGPs) in dealing with these barriers, by using a model of small associated group practices (AGPs) created in rural communities in association with a larger EGP located elsewhere. We also describe the use of this model by the Lovelace Medical Foundation in New Mexico in creating three rural group practices and planning a fourth.

Attitude↗
PubMed2004

Gnotobiotic zebrafish reveal evolutionarily conserved responses to the gut microbiota.

Animals have developed the means for supporting complex and dynamic consortia of microorganisms during their life cycle. A transcendent view of vertebrate biology therefore requires an understanding of the contributions of these indigenous microbial communities to host development and adult physiology. These contributions are most obvious in the gut, where studies of gnotobiotic mice have disclosed that the microbiota affects a wide range of biological processes, including nutrient processing and absorption, development of the mucosal immune system, angiogenesis, and epithelial renewal. The zebrafish (Danio rerio) provides an opportunity to investigate the molecular mechanisms underlying these interactions through genetic and chemical screens that take advantage of its transparency during larval and juvenile stages. Therefore, we developed methods for producing and rearing germ-free zebrafish through late juvenile stages. DNA microarray comparisons of gene expression in the digestive tracts of 6 days post fertilization germ-free, conventionalized, and conventionally raised zebrafish revealed 212 genes regulated by the microbiota, and 59 responses that are conserved in the mouse intestine, including those involved in stimulation of epithelial proliferation, promotion of nutrient metabolism, and innate immune responses. The microbial ecology of the digestive tracts of conventionally raised and conventionalized zebrafish was characterized by sequencing libraries of bacterial 16S rDNA amplicons. Colonization of germ-free zebrafish with individual members of its microbiota revealed the bacterial species specificity of selected host responses. Together, these studies establish gnotobiotic zebrafish as a useful model for dissecting the molecular foundations of host-microbial interactions in the vertebrate digestive tract.

Air Sacs↗
PubMed2001

Dissection of a nuclear localization signal.

The regulated process of protein import into the nucleus of a eukaryotic cell is mediated by specific nuclear localization signals (NLSs) that are recognized by protein import receptors. This study seeks to decipher the energetic details of NLS recognition by the receptor importin alpha through quantitative analysis of variant NLSs. The relative importance of each residue in two monopartite NLS sequences was determined using an alanine scanning approach. These measurements yield an energetic definition of a monopartite NLS sequence where a required lysine residue is followed by two other basic residues in the sequence K(K/R)X(K/R). In addition, the energetic contributions of the second basic cluster in a bipartite NLS ( approximately 3 kcal/mol) as well as the energy of inhibition of the importin alpha importin beta-binding domain ( approximately 3 kcal/mol) were also measured. These data allow the generation of an energetic scale of nuclear localization sequences based on a peptide's affinity for the importin alpha-importin beta complex. On this scale, a functional NLS has a binding constant of approximately 10 nm, whereas a nonfunctional NLS has a 100-fold weaker affinity of 1 microm. Further correlation between the current in vitro data and in vivo function will provide the foundation for a comprehensive quantitative model of protein import.

Amino Acid Sequence↗
PubMed2001

Relative survival: comparison of regressive models and advice for the user.

BACKGROUND: Relative survival is a method of analysis of failure-time data used to estimate the net survival. Cancer registries frequently use this method. The main regressive models are the Hakulinen and Tenkanen model, and the Esteve et al. model, which are easily used in practice thanks to their specific software (SURV and RELSURV, respectively). An assessment of the behaviour of the models is made, with the aim of giving advice for users of lifetime data in practice. METHODS: Simulations were done by respecting, then violating, the basic hypothesis supporting the theoretical foundation of these two proportional hazard models (independence of the death and censor process, proportionality of risks). For each simulation, 100 files of either 100, 1,000, or 10,000 individuals were generated to assess the behaviour of the model. RESULTS: Moderate censor rates, with or without proportionality assumption, lead to the use of the Hakulinen and Tenkanen model, especially for studies with little information. Non-proportionality of risks in the Hakulinen and Tenkanen model could be tested and analysed. If assumptions underlying the models are respected, the Esteve et al. model seems to be more precise. DISCUSSION: The choice of a model in practice depends on its performance, and on the user's knowledge of statistics and computer science. Non-proportionality of risks is common in cancer registries. In theory, non-proportionality of risks could be taken into account for both relative survival models but, for the moment, it is feasible in routine only for the Hakulinen and Tenkanen model. Characteristics of the software should also be taken into account for routine relative survival analyses.

Data Interpretation, Statistical↗
PubMed1993

[Determination of endogenous N-excretion and nitrogen balance in the range of low N-intake in rats].

The investigations were carried out in order to develop foundations for a complex growth model including the effect of N-efficiency mechanism first of all for the rat. Therefore N-balance trials with rats of different live weights were made using diets of equal protein quality. The curve of the regressively calculated N-efficiency function courses relatively linear in its lower part, i.e. for low N-intakes. The protein quality value "A.b" was proved to be constant for all investigated live weight ranges. In similar trials with different protein qualities was also found a linear course for low N-intakes. The regressively estimated N-maintenance requirement (for N-Intake = 0) related to metabolic live weight (NMR/LWkg0.67) amounts to 180 mg/d. In addition endogenous N-excretions were determined in 15N tracer experiments on animals of different live weight fed graduated amounts of a quality constant protein. The NMR-values (sum of endogenous excretions from faeces and urea) depend on the level of N-intake, i.e. they can not be considered as constant. The endogenous faecal N-loss related to metabolic live weight is relatively constant indeed, whereas the amount of endogenous urea N-loss is dependent on the level of N-intake. Therefore calculations based on the N-efficiency curve, e.g. amino acid requirement dependent on performance and prediction of N-deposition respectively, should not be carried out on the basis of "N-retention" (N-balance + NMR) but only on the basis of N-balance.

Animals↗