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At least 775 records · Page 43Linked to original sources
PubMed2006

From genes to systems: new global strategies for the characterization of NCL biology.

Neuronal ceroid lipofuscinoses (NCL) are rare neurological disorders with a uniform phenotype, caused by mutations in seven known genes. NCL provide a unique model to characterize molecular pathways critical for normal neuronal development and pathological neuronal degeneration. Systems biology based approach utilizes the rapidly developing tools of genomics, proteomics, lipidomics and metabolomics and aims at thorough understanding of the functions of cells, tissues and whole organisms by molecular analysis and biocomputing-assisted modeling. The systems level understanding of NCL is now possible by utilizing different model organisms. Initial work has revealed disturbed metabolic pathways in several NCL disorders and most analyses have utilized the infantile (INCL/CLN1) and juvenile (JNCL/CLN3) disease modeling and utilized mainly human and mouse samples. To date, the data obtained from transcript and lipidomic profiling has pinpointed the role of lipid metabolism and synaptic function in the infantile NCL. Changes in glutamate utilization and amino acid metabolism have been a common theme emerging from the transcript and metabolite profiling of the juvenile NCL. Further experimental models are being developed and systematic sample collection as well as data integration projects are needed. The combined analyses of the global information should provide means to expose all the NCL-associated molecular pathways.

Animals↗
PubMed2006

Genetics of human obesity.

This chapter presents the current state of knowledge in the field of the genetics of human obesity. The molecular approach has proved to be powerful in defining new syndromes associated with obesity. The pivotal role of leptin and melanocortin pathways has been recognized, but only in rare cases of obesity. In the more common form of obesity a multitude of polymorphisms located in genes and candidate regions throughout the genome regulate an individual's susceptibility to weight gain in a permissive environment. The effects are often uncertain and the results not always confirmed. Combining these single nucleotide polymorphisms and defining the associated risks for obesity will be a real challenge in the future. It is now necessary to integrate data of various origins (environment, genotype, expression) to clarify this field.

Body Mass Index↗
PubMed2026

Can Psychiatric Genetics Advance Without Incorporating a Life Course Perspective?

Psychiatric disorders unfold over the life course; however, genomic studies of these conditions overwhelmingly rely on phenotypes collected at a single time point, often in adulthood. Therefore, genome-wide association studies (GWASs) of psychiatric conditions may miss genetic variants with time-varying relevance to etiology, prevention, and treatment, such as those that influence trajectories of symptoms and behaviors, age at onset, course of treatment response, and the co-evolution of comorbidities. With recent advances in longitudinal biobanks and analytic tools, we posit that incorporating a life course perspective in psychiatric genetics will enable critically relevant insights into each of these areas of investigation. We propose that the current inconsistent portability of polygenic scores across age groups can be reconciled through the design of carefully considered longitudinal GWASs in age-diverse samples. Pioneering longitudinal GWASs in psychiatry have revealed novel genomic signals associated with time-dependent phenotypes that are distinct from those influencing lifetime diagnosis, suggesting that the study of longitudinal phenotypes will complement cross-sectional approaches and empower biological and therapeutic discoveries. Advances in post-GWAS functional annotation resources and analytic approaches now enable us to contextualize the genetic contributions to psychiatric disorders as dynamic age- and exposure-dependent processes. Although longitudinal GWASs pose unique challenges with regard to data availability, selection bias, and missing data, integrating temporality into psychiatric genetics at scale is now attainable and promises to reveal novel biology and therapeutic opportunities for psychiatric conditions.

Cohort study↗
PubMed2004

Using the Unified Modelling Language (UML) to guide the systemic description of biological processes and systems.

One of the main issues in Systems Biology is to deal with semantic data integration. Previously, we examined the requirements for a reference conceptual model to guide semantic integration based on the systemic principles. In the present paper, we examine the usefulness of the Unified Modelling Language (UML) to describe and specify biological systems and processes. This makes unambiguous representations of biological systems, which would be suitable for translation into mathematical and computational formalisms, enabling analysis, simulation and prediction of these systems behaviours.

Epigenesis, Genetic↗
PubMed2005

MeCP2 expression and function during brain development: implications for Rett syndrome's pathogenesis and clinical evolution.

Most cases of Rett syndrome (RTT) are associated with mutations of the transcriptional regulator MeCP2. On the basis of molecular structure, ontogeny, and subcellular and regional distribution, MeCP2 appears to be a link between synaptic activity and neuronal transcription. Integrating data on MeCP2 neurobiology, RTT neurobiology, MeCP2 mutational patterns in RTT and other disorders, histone profiles of relevance to RTT, and genotype-phenotype correlations in RTT, we update here our synaptic hypothesis of RTT. We postulate that MeCP2 dysfunction leads to abnormal brain development through maladjustment of neuronal gene expression to synaptic and other extra-cellular signals, mainly during the critical period of synaptic maturation. RTT phenotype will develop, only if severe MeCP2 dysfunction is present during early neuronal differentiation. Two models are proposed for explaining general and regional neuronal abnormalities in RTT and the phenotypical outcome of MeCP2 dysfunction, respectively.

Animals↗
PubMed2003

Interplay of transcriptomics and proteomics.

Despite the obvious attractions of parallel profiling of transcripts and proteins on a global 'omic' scale, there are practical and biological differences involved in their application. Transcriptomics is now a robust, high-throughput, cost-effective technology capable of simultaneously quantifying tens of thousands of defined mRNA species in a miniaturized, automated format. Conversely, proteomic analysis is currently much more limited in breadth and depth of coverage owing to variations in protein abundance, hydrophobicity, stability, size and charge. Nevertheless, transcriptomic and proteomic data can be compared and contrasted provided the studies are carefully designed and interpreted. Differential splicing, post-translational modifications and data integration are among some of the future challenges to tackle.

Biotechnology↗
PubMed2006

Genetics of human obesity.

We present the knowledge acquired in the field of the genetics of human obesity. The molecular approach proved to be powerful to define new syndromes associated to obesity. The pivotal role of leptin and melanocortin pathways were recognized but in rare obesity cases. In the commoner form of obesities, a multitude of polymorphisms located in genes and candidate regions participate in an individual susceptibility to weight gain in a permissive environment. The effects are often uncertain and the results not always confirmed. It is now necessary to integrate data of various origins (environment, genotype, expression) to clarify the domain.

Animals↗
PubMed2006

Quantitative models of developmental pattern formation.

Pattern formation in developing organisms can be regulated at a variety of levels, from gene sequence to anatomy. At this level of complexity, mechanistic models of development become essential for integrating data, guiding future experiments, and predicting the effects of genetic and physical perturbations. However, the formulation and analysis of quantitative models of development are limited by high levels of uncertainty in experimental measurements, a large number of both known and unknown system components, and the multiscale nature of development. At the same time, an expanding arsenal of experimental tools can constrain models and directly test their predictions, making the modeling efforts not only necessary, but feasible. Using a number of problems in fruit fly development, we discuss how models can be used to test the feasibility of proposed patterning mechanisms and characterize their systems-level properties.

Animals↗
PubMed2005

Objectives and structure of the DRAIN project: an extensive study of the delivery from the drainage basin of the Venice Lagoon (Italy).

The Venice Lagoon and its drainage basin form a vast system, where historical and recent cities, large and medium-small industrial districts and intensive agricultural activities coexist within a peculiar environment. The drainage basin constituted of an ensemble of tributary sub-basins with contrasting characteristics and freshwater fluxes; the hydraulic pathways are generally complex and not univocally established. With the main objectives to measure the annual freshwater discharge into the Venice Lagoon and to estimate the related load of pollutants, an intense field activity was carried out in the ambit of the DRAIN project. The 12 main tributaries of the drainage basin were monitored for more than 2 years (1998-2000), obtaining a relevant data set of hydrodynamic, physico-chemical and chemical data. Integrative investigations were also developed in a multidisciplinary approach, covering the existing knowledge gaps on the hydrology and behaviour of such a complex system. The paper describes the characteristics of the system, the selected approach to investigate it, and the main project outcomes.

Cities↗
PubMed2005

Time-space modeling of journey-time exposure to traffic-related air pollution using GIS.

Journey-time exposures represent an important, though as yet little-studied, component of human exposure to traffic-related air pollution, potentially with important health effects. Methods for assessing journey-time exposures, either as part of epidemiological studies or for policy assessment, are, however, poorly developed. This paper describes the development and testing of a GIS-based system for modeling human journey-time exposures to traffic-related air pollution: STEMS (Space-Time Exposure Modeling System). The model integrates data on source activity, pollutant dispersion, and travel behavior to derive individual- or group-level exposure measures to atmospheric pollution. The model, which is designed to simulate exposures of people as they move through a changing air pollution field, was developed, validated, and trialed in Northampton, UK. The system currently uses ArcInfo to couple four separate submodels: a source activity/emission model (SATURN), a proprietary atmospheric dispersion model (ADMS-Urban), an empirically derived background air pollution model, and a purposely designed time-activity-based exposure model (TOTEM). This paper describes the structure of the modeling system; presents results of field calibration, validation, and sensitivity analysis; and illustrates the use of the model to analyze journey-time exposures of schoolchildren.

Air Pollution↗
PubMed2006

Role of quality of life in men with metastatic hormone-refractory prostate cancer: how does atrasentan influence quality of life?

OBJECTIVE: Progression of hormone-refractory prostate cancer (HRPC) is associated with skeletal complications and bone pain, which contribute to deterioration in quality of life (QOL). The effects of new HRPC therapies on patients' QOL need to be studied. Patient-based assessments that help quantify the risk-benefit profile of HRPC therapies are warranted. This review summarizes the known QOL literature and estimates the potential effect of atrasentan, a novel, selective endothelin A receptor antagonist (SERA), on the QOL of HRPC patients. METHODS: Published studies were identified through a structured, detailed literature review. Clinical studies that report QOL data were reviewed, along with recent QOL data from atrasentan studies. RESULTS: HRPC studies have begun to use QOL assessments as primary endpoints, but different assessments and therapies are not comparable. Very few data integrate QOL with clinical endpoints. Atrasentan clinical trials demonstrated a statistically significant difference in the prostate cancer-specific QOL in favor of atrasentan (p=.032) and an increased quality-adjusted time to progression in men with HRPC. CONCLUSIONS: Atrasentan provides QOL benefits relevant to HRPC. The quality-adjusted analyses applied in the atrasentan studies have begun to lay the foundation for interpreting clinical endpoints in conjunction with QOL. These analyses will facilitate better QOL comparisons within studies and across trials. Further evaluation of atrasentan in HRPC is warranted.

Atrasentan↗
PubMed2004

The direct effect of leptin on skeletal muscle thermogenesis is mediated by substrate cycling between de novo lipogenesis and lipid oxidation.

We report here studies that integrate data of respiration rate from mouse skeletal muscle in response to leptin and pharmacological interference with intermediary metabolism, together with assays for phosphatidylinositol 3-kinase (PI3K) and AMP-activated protein kinase (AMPK). Our results suggest that the direct effect of leptin in stimulating thermogenesis in skeletal muscle is mediated by substrate cycling between de novo lipogenesis and lipid oxidation, and that this cycle requires both PI3K and AMPK signaling. This substrate cycling linking glucose and lipid metabolism to thermogenesis provides a novel thermogenic mechanism by which leptin protects skeletal muscle from excessive fat storage and lipotoxicity.

Adenylate Kinase↗
PubMed2025

ELFN1 deficiency: The mechanistic basis and phenotypic spectrum of a neurodevelopmental disorder with epilepsy.

PURPOSE: Synaptic communication deficits are central to many neurodevelopmental disorders. However, for rare monogenic conditions, these disorders remain poorly defined, with limited understanding of their molecular etiology. A homozygous frameshift variant in the synaptic cell adhesion molecule ELFN1 was reported in a family with 3 affected siblings with epileptic encephalopathy, alongside a missense variant of uncertain significance in a cohort study involving a family with intellectual disability. Therefore, we sought to evaluate the role and mechanism of biallelic ELFN1 variants in disease pathogenesis. METHODS: We describe 8 newly identified individuals from 5 unrelated families, all carrying homozygous ELFN1 variants, including frameshift and in-frame deletions. By integrating data from these cases with clinical details from 6 previously reported individuals, we delineate the phenotypic spectrum associated with ELFN1 variants. RESULTS: Clinical features include varying degrees of developmental delay/intellectual disability, epilepsy, and movement disorders. Molecular investigations reveal that these variants disrupt ELFN1 protein trafficking to the cell surface, resulting in loss of function. Functional modeling in mice and zebrafish demonstrates the role of Elfn1 loss in motor activity abnormalities and seizures. CONCLUSION: Our findings establish ELFN1 deficiency as the cause of a distinct, rare neurodevelopmental disorder, providing a foundation for future investigations into its pathophysiology and therapeutic strategies.

Humans↗
PubMed2005

Anomalous "benign" coronary arteries detected by multidetector computed tomography.

Being usually asymptomatic, anomalous coronary arteries (ACAs) are discovered in adulthood using invasive coronary angiography (CA) performed for suspected coronary artery disease. However, if only based on CA, the correct diagnosis is not easily made. We report on the importance of integrated data obtained by using multidetector computed tomography, and perfusional myocardial scintigraphy as alternative non-invasive imaging techniques in evaluating the exact course and the functional importance of usually considered "benign" ACAs in three symptomatic subjects, and of the development of official recommendations for the practitioners in the management of such patients.

Aged↗
PubMed2005

Comparative analysis of Cystic Fibrosis Registry data from the UK with USA, France and Australasia.

BACKGROUND: Using the UK Cystic Fibrosis Database, we analysed the health of the UK CF paediatric population (UKPP) in terms of their biographical, clinical and infection status and compared outcomes with the US, French and Australasian CF Registries. METHODS: UKPP data were collected for 2,673 patients aged less than 18 years in 2001 and used as a reference base for comparison with the most recent equivalent CF Registry reports. RESULTS: Although differences exist between National CF Registries, all record similar demographic factors and key outcomes. Where plausible comparisons can be made, we report that the UKPP had the oldest median age (15.0 years), the Australasian population had the lowest median age at diagnosis (1.8 months). Approximately, double the expected number of UKPP patients (23% and 19%, respectively) fall below the 10th centile for height and weight with similar outcomes in Australasia. UKPP and French populations had similar proportions with FEV1 >80% predicted (53% and 54%, respectively). CONCLUSION: Each Registry's data systems have developed independently providing a first step towards international comparisons. Standardisation of data collection criteria and definition for national CF Registries is required and we propose a standardised minimum data set, which would facilitate data integration as part of a global Registry for CF.

Adolescent↗
PubMed2005

Simulation of vegetation dynamics and management strategies on south Texas, semi-arid rangeland.

In this paper, we describe a model designed to simulate seasonal dynamics of warm and cool season grasses and forbs, as well as the dynamics of woody plant succession through five seral stages, in each of nine different plant communities on the Rob and Bessie Welder Wildlife Refuge. The Welder Wildlife Refuge (WWR) is located in the Gulf Coastal Prairies and Marshes ecoregion of Texas. The model utilizes and integrates data from a wide array of research projects that have occurred in south Texas and WWR. It is designed to investigate the effects of alternative livestock grazing programs and brush control practices, with particular emphasis on prescribed burning, the preferred treatment for brush on the WWR. We evaluated the model by simulating changes in the plant communities under historical (1974-2000) temperature, rainfall, livestock grazing rotation, and brush control regimes, and comparing simulation results to field data on herbaceous biomass and brush canopy cover collected on the WWR over the same period. We then used the model to simulate the effects of 13 alternative management schemes, under each of four weather regimes, over the next 25 years. We found that over the simulation period, years 1974-2000, the model does well in simulating the magnitude and seasonality of herbaceous biomass production and changes in percent brush canopy cover on the WWR. It also does well in simulating the effects of variations in cattle stocking rates, grazing rotation programs, and brush control regimes on plant communities, thus providing insight into the combined effects of temperature, precipitation, cattle stocking rates, grazing rotation programs, and brush control on the overall productivity and state of woody plant succession on the WWR. Simulation of alternative management schemes suggests that brush canopy removal differs little between summer and winter prescribed burn treatments when precipitation remains near the long-term average, but during periods of low precipitation canopy removal is greater under winter prescribed burning. The model provides a useful tool to assist refuge personnel with developing long-term brush management and livestock grazing strategies.

Algorithms↗
PubMed2005

Ethical issues in the conduct of longitudinal studies of addiction treatment.

Many complex ethical issues arise in the day-to-day conduct of longitudinal studies of addiction treatment. These issues are rooted, in part, in the sustained and potentially ambiguous relationship between research staff and study participants, the frequently changing clinical and legal status of study participants, the assertive methods required to generate high follow-up rates, and the numerous systems of care and control in which participants are involved. To identify common ethical issues that arise in such studies, the authors conducted individual and group interviews with seasoned members (case trackers, field trackers, interviewers, and supervisors) of the research team. The ethical dilemmas identified through these interviews fell into seven broad arenas: (1) informed consent for research participation, (2) confidentiality and information disclosure, (3) relationship boundaries between study participants and research staff, (4) duty to warn/report responsibilities, (5) questions of autonomy and privacy, (6) issues related to compensation for research participation, and (7) data integrity. Case studies that illustrate common ethical dilemmas within each of these seven areas are presented and discussed. Ethical dilemmas in the study of addiction treatment can be effectively managed via ethically informed research protocols, staff training in ethical decision-making, monitoring and supervision, and collective debriefing of critical events.

Adult↗
PubMed2006

Age estimation from the degree of osteophyte formation of vertebral columns in Japanese.

To assess the age estimation from the degree of osteophyte formation of vertebral column, we set grading scores from 0 to 3 for the osteophyte formation based on the height of the process of vertebral column, and defined the average of the values at the cervical, thoracic and lumbar parts of the vertebra to be 'osteophyte formation index' for an individual. We evaluated osteophyte formation in autopsied 225 bodies (138 males, 87 females) during 5 years, and statistically analyzed the integrated data. The following were statistically obtained for each sex: correlation coefficient, regression equation, standard error of estimate (SE) between the score at each part of the vertebral column and age, and between 'osteophyte formation index' and age. In all the parts of the vertebra, there was a significant correlation between the score value and age. We recognized a significant correlation between 'osteophyte formation index' (X) and age (Y), and regression lines were Y = 37.90 + 12.07X (SE; 12.6 y.o.) in males and Y = 36.67+18.64X (SE; 11.9 y.o.) in females. It was apparent that to know the degree of the osteophyte formation was useful in age estimation.

Adult↗