Genetic predisposition to clinical tuberculosis: bridging the gap between simple and complex inheritance.
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ABSTRACT:
SUBMITTER: Abel L
PROVIDER: S-EPMC1287174 | biostudies-literature | 2000 Aug
REPOSITORIES: biostudies-literature
Publications
Genetic predisposition to clinical tuberculosis: bridging the gap between simple and complex inheritance.
American journal of human genetics 20000705 2
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Project description: Not available
| S-EPMC1287884 | biostudies-literature
Project description:In Tuberculosis (TB), given the complexity of its transmission dynamics, observations of reduced epidemiological risk associated with preventive interventions can be difficult to translate into mechanistic interpretations. Specifically, in clinical trials of vaccine efficacy, a readout of protection against TB disease can be mapped to multiple dynamical mechanisms, an issue that has been overlooked so far. Here, we describe this limitation and its effect on model-based evaluations of vaccine impact. Furthermore, we propose a methodology to analyze efficacy trials that circumvents it, leveraging a combination of compartmental models and stochastic simulations. Using our approach, we can disentangle the different possible mechanisms of action underlying vaccine protection effects against TB, conditioned to trial design, size, and duration. Our results unlock a deeper interpretation of the data emanating from efficacy trials of TB vaccines, which renders them more interpretable in terms of transmission models and translates into explicit recommendations for vaccine developers.
| S-EPMC6884451 | biostudies-literature
Project description:While substance abuse disorders only occur in humans, mice and other model organisms can make valuable contributions to genetic studies of these disorders. In this review, we consider a few specific examples of how model organisms have been used in conjunction with studies in humans to study the role of genetic factors in substance use disorders. In some examples genes that were first discovered in mice were subsequently studied in humans. In other examples genes or specific polymorphisms in genes were first studied in humans and then modeled in mice. Using anatomically and temporally specific genetic, pharmacological and other environmental manipulations in conjunction with histological analyses, mechanistic insights that would be difficult to obtain in humans have been obtained in mice. We hope these examples illustrate how novel biological insights about the effect of genes on substance use disorders can be obtained when mouse and human genetic studies are successfully integrated.
| S-EPMC3352994 | biostudies-literature
Project description:The transition from MIRU-VNTR-based epidemiology studies in tuberculosis (TB) to genomic epidemiology has transformed how we track transmission. However, short-read sequencing is poor at analyzing repetitive regions such as the MIRU-VNTR loci. This causes a gap between the new genomic data and the large amount of information stored in historical databases. Long-read sequencing could bridge this knowledge gap by allowing analysis of repetitive regions. However, the feasibility of extracting MIRU-VNTRs from long reads and linking them to historical data has not been evaluated. In our study, an in silico arm, consisting of inference of MIRU patterns from long-read sequences (using MIRUReader program), was compared with an experimental arm, involving standard amplification and fragment sizing. We analyzed overall performance on 39 isolates from South Africa and confirmed reproducibility in a sample enriched with 62 clustered cases from Spain. Finally, we ran 25 consecutive incident cases, demonstrating the feasibility of correctly assigning new clustered/orphan cases by linking data inferred from genomic analysis to MIRU-VNTR databases. Of the 3,024 loci analyzed, only 11 discrepancies (0.36%) were found between the two arms: three attributed to experimental error and eight to misassigned alleles from long-read sequencing. A second round of analysis of these discrepancies resulted in agreement between the experimental and in silico arms in all but one locus. Adjusting the MIRUReader program code allowed us to flag potential in silico misassignments due to suboptimal coverage or unfixed double alleles. Our study indicates that long-read sequencing could help address potential chronological and geographical gaps arising from the transition from molecular to genomic epidemiology of tuberculosis.ImportanceThe transition from molecular epidemiology in tuberculosis (TB), based on the analysis of repetitive regions (VNTR-based genotyping), to genomic epidemiology transforms in the precision with which we track transmission. However, short-read sequencing, the most common method for performing genomic analysis, is poor at analyzing repetitive regions. This means that we face a gap between the new genomic data and the large amount of information stored in historical databases, which is also an obstacle to cross-national surveillance involving settings where only molecular data are available. Long-read sequencing could help bridge this knowledge gap by allowing analysis of repetitive regions. Our study demonstrates that MIRU-VNTR patterns can be successfully inferred from long-read sequences, allowing the correct assignment of new cases as clustered/orphan by linking new data extracted from genomic analysis to historical MIRU-VNTR databases. Our data may provide a starting point for bridging the knowledge gap between the molecular and genomic eras in tuberculosis epidemiology.
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Project description:All decisions, whether they are personal, public, or business-related, are based on the decision maker's beliefs and values. Science can and should help decision makers by shaping their beliefs. Unfortunately, science is not easily accessible to decision makers, and scientists often do not understand decision makers' information needs. This article presents a framework for bridging the gap between science and decision making and illustrates it with two examples. The first example is a personal health decision. It shows how a formal representation of the beliefs and values can reflect scientific inputs by a physician to combine with the values held by the decision maker to inform a medical choice. The second example is a public policy decision about managing a potential environmental hazard. It illustrates how controversial beliefs can be reflected as uncertainties and informed by science to make better decisions. Both examples use decision analysis to bridge science and decisions. The conclusions suggest that this can be a helpful process that requires skills in both science and decision making.
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Project description:BackgroundTranslating the extraordinary scientific and technological advances occurring in medical research laboratories into care for patients in communities throughout the country has been a major challenge. One contributing factor has been the relative absence of community practitioners from the US biomedical research enterprise. Identifying and addressing the barriers that prevent their participation in research should help bridge the gap between basic research and practice to improve quality of care for all Americans.MethodsWe interviewed over 200 clinicians and other healthcare stakeholders from 2004 through 2005 to develop a conceptual framework and set of strategies for engaging a stable cadre of community clinicians in a clinical research program.ResultsLack of engagement of community practitioners, lack of necessary infrastructure, and the current misalignment of financial incentives and research participation emerged as the three primary barriers to community clinician research participation. Although every effort was made to learn key motivators for engagement in clinical research from interviewees, we did not observe their behavior and self-report by clinicians does not always track with their behavior.ConclusionsA paradigm shift involving acknowledgement of the value of clinicians in the context of community research, establishment of a stable infrastructure to support a cohort of clinicians across time and research studies, and realignment of incentives to encourage participation in clinical research is required.
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Project description:The recent advances in DNA sequencing technology are enabling a rapid increase in the number of genomes being sequenced. However, many fundamental questions in genome biology remain unanswered, because sequence data alone is unable to provide insight into how the genome is organised into chromosomes, the position and interaction of those chromosomes in the cell, and how chromosomes and their interactions with each other change in response to environmental stimuli or over time. The intimate relationship between DNA sequence and chromosome structure and function highlights the need to integrate genomic and cytogenetic data to more comprehensively understand the role genome architecture plays in genome plasticity. We propose adoption of the term 'chromosomics' as an approach encompassing genome sequencing, cytogenetics and cell biology, and present examples of where chromosomics has already led to novel discoveries, such as the sex-determining gene in eutherian mammals. More importantly, we look to the future and the questions that could be answered as we enter into the chromosomics revolution, such as the role of chromosome rearrangements in speciation and the role more rapidly evolving regions of the genome, like centromeres, play in genome plasticity. However, for chromosomics to reach its full potential, we need to address several challenges, particularly the training of a new generation of cytogeneticists, and the commitment to a closer union among the research areas of genomics, cytogenetics, cell biology and bioinformatics. Overcoming these challenges will lead to ground-breaking discoveries in understanding genome evolution and function.
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Project description:Translational neuroscience is intended as a holistic approach in the field of brain disorders, starting from the basic research of cerebral morphology and with the function of implementing it into clinical practice. This concept can be applied to the rehabilitation field to promote promising results that positively influence the patient's quality of life. The last decades have seen great scientific and technological improvements in the field of neurorehabilitation. In this paper, we discuss the main issues related to translational neurorehabilitation, from basic research to current clinical practice, and we also suggest possible future scenarios.
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Project description:Tourette syndrome is a childhood neuropsychiatric disorder, which presents with disruptive motor and vocal tics. The disease also has a high comorbidity with obsessive-compulsive disorder and attention deficit hyperactivity disorder, which may further increase the distress experienced by patients. Current treatments act with varying efficacies in alleviating symptoms, as the underlying biology of the disease is not fully understood to provide precise therapeutic targets. Moreover, the genetic complexity of the disorder presents a substantial challenge to the identification of genetic alterations that contribute to the Tourette's phenotype. Nevertheless, genetic studies have suggested involvement of dopaminergic, serotonergic, glutamatergic, and histaminergic pathways in the pathophysiology of at least some cases. In addition, genetic overlaps with other neuropsychiatric disorders may point toward a shared biology. The findings that are emerging from genetic studies will allow researchers to piece together the underlying components of the disease, in the hopes that a deeper understanding of Tourette's can lead to improved treatments for those affected by it.
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