277 research outputs found

    The Eukaryotic Promoter Database (EPD): recent developments

    Get PDF
    The Eukaryotic Promoter Database (EPD) is an annotated non-redundant collection of eukaryotic POL II promoters, for which the transcription start site has been determined experimentally. Access to promoter sequences is provided by pointers to positions in nucleotide sequence entries. The annotation part of an entry includes description of the initiation site mapping data, cross-references to other databases, and bibliographic references. EPD is structured in a way that facilitates dynamic extraction of biologically meaningful promoter subsets for comparative sequence analysis. Recent efforts have focused on exhaustive cross-referencing to the EMBL nucleotide sequence database, and on the improvement of the WWW-based user interfaces and data retrieval mechanisms. EPD can be accessed at http://www.epd.isb-sib.c

    Association of change in cardiovascular risk factors with incident cardiovascular events

    Get PDF
    Importance: There is consistent evidence of the association between ideal cardiovascular health and lower incident cardiovascular disease (CVD); however, most studies used a single measure of cardiovascular health.Objective: To examine how cardiovascular health changes over time and whether these changes are associated with incident CVD.Design, Setting, and Participants: Prospective cohort study in a UK general community (Whitehall II), with examinations of cardiovascular health from 1985/1988 (baseline) and every 5 years thereafter until 2015/2016 and follow-up for incident CVD until March 2017.Exposures: Using the 7 metrics of the American Heart Association (nonsmoking; and ideal levels of body mass index, physical activity, diet, blood pressure, fasting blood glucose, and total cholesterol), participants with 0 to 2, 3 to 4, and 5 to 7 ideal metrics were categorized as having low, moderate, and high cardiovascular health. Change in cardiovascular health over 10 years between 1985/1988 and 1997/1999 was considered.Main Outcome and Measure: Incident CVD (coronary heart disease and stroke).Results: The study population included 9256 participants without prior CVD (mean [SD] age at baseline, 44.8 [6.0] years; 2941 [32%] women), of whom 6326 had data about cardiovascular health change. Over a median follow-up of 18.9 years after 1997/1999, 1114 incident CVD events occurred. In multivariable analysis and compared with individuals with persistently low cardiovascular health (consistently low group, 13.5% of participants; CVD incident rate per 1000 person-years, 9.6 [95% CI, 8.4-10.9]), there was no significant association with CVD risk in the low to moderate group (6.8% of participants; absolute rate difference per 1000 person-years, -1.9 [95% CI, -3.9 to 0.1]; HR, 0.84 [95% CI, 0.66-1.08]), the low to high group, (0.3% of participants; absolute rate difference per 1000 person-years, -7.7 [95% CI, -11.5 to -3.9]; HR, 0.19 [95% CI, 0.03-1.35]), and the moderate to low group (18.0% of participants; absolute rate difference per 1000 person-years, -1.3 [95% CI, -3.0 to 0.3]; HR, 0.96 [95% CI, 0.80-1.15]). A lower CVD risk was observed in the consistently moderate group (38.9% of participants; absolute rate difference per 1000 person-years, -4.2 [95% CI, -5.5 to -2.8]; HR, 0.62 [95% CI, 0.53-0.74]), the moderate to high group (5.8% of participants; absolute rate difference per 1000 person-years, -6.4 [95% CI, -8.0 to -4.7]; HR, 0.39 [95% CI, 0.27-0.56]), the high to low group (1.9% of participants; absolute rate difference per 1000 person-years, -5.3 [95% CI, -7.8 to -2.8]; HR, 0.49 [95% CI, 0.29-0.83]), the high to moderate group (9.3% of participants; absolute rate difference per 1000 person-years, -4.5 [95% CI, -6.2 to -2.9]; HR, 0.66 [95% CI, 0.51-0.85]), and the consistently high group (5.5% of participants; absolute rate difference per 1000 person-years, -5.6 [95% CI, -7.4 to -3.9]; HR, 0.57 [95% CI, 0.40-0.80]).Conclusions and Relevance: Among a group of participants without CVD who received follow-up over a median 18.9 years, there was no consistent relationship between direction of change in category of a composite metric of cardiovascular health and risk of CVD

    Implantable cardioverter defibrillator therapy for primary prevention of sudden cardiac death in the real world: Main findings from the French multicentre DAI-PP programme (pilot phase)

    Get PDF
    This review summarizes the main findings of the French multicentre DAI-PP pilot programme, and discusses the related clinical and research perspectives. This project included retrospectively (2002–2012 period) more than 5000 subjects with structural heart disease who received an implantable cardioverter defibrillator (ICD) for primary prevention of sudden cardiac death, and were followed for a mean period of 3 years. The pilot phase of the DAI-PP programme has provided valuable information on several practical and clinically relevant aspects of primary prevention ICD implantation in the real-world population, which are summarized in this review. This pilot has led to a prospective evaluation that started in May 2018, assessing ICD therapy in primary and secondary prevention in patients with structural and electrical heart diseases, with remote monitoring follow-up using a dedicated platform. This should further enhance our understanding of sudden cardiac death, to eventually optimize the field of preventative actions

    Polymer-Based Reconstruction of the Inferior Vena Cava in Rat: Stem Cells or RGD Peptide?

    Get PDF
    As part of a program targeted at developing a resorbable valved tube for replacement of the right ventricular outflow tract, we compared three biopolymers (polyurethane [PU], polyhydroxyalkanoate (the poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-4-hydroxyvalerate) [PHBVV]), and polydioxanone [PDO]) and two biofunctionalization techniques (using adipose-derived stem cells [ADSCs] or the arginine-glycine-aspartate [RGD] peptide) in a rat model of partial inferior vena cava (IVC) replacement. Fifty-three Wistar rats first underwent partial replacement of the IVC with an acellular electrospun PDO, PU, or PHBVV patch, and 31 nude rats subsequently underwent the same procedure using a PDO patch biofunctionalized either by ADSC or RGD. Results were assessed both in vitro (proliferation and survival of ADSC seeded onto the different materials) and in vivo by magnetic resonance imaging (MRI), histology, immunohistochemistry [against markers of vascular cells (von Willebrand factor [vWF], smooth muscle actin [SMA]), and macrophages ([ED1 and ED2] immunostaining)], and enzyme-linked immunosorbent assay (ELISA; for the expression of various cytokines and inducible NO synthase). PDO showed the best in vitro properties. Six weeks after implantation, MRI did not detect significant luminal changes in any group. All biopolymers were evenly lined by vWF-positive cells, but only PDO and PHBVV showed a continuous layer of SMA-positive cells at 3 months. PU patches resulted in a marked granulomatous inflammatory reaction. The ADSC and RGD biofunctionalization yielded similar outcomes. These data confirm the good biocompatibility of PDO and support the concept that appropriately peptide-functionalized polymers may be successfully substituted for cell-loaded materials

    II Congrés Internacional sobre Traducció : abril 1994 : actes

    Get PDF
    Machine learning-based approach unravels distinct pathological signatures induced by patient-derived α-synuclein seeds in monkeys. Dopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)-rich protein aggregates [termed "Lewy bodies" (LBs)], is a well-established characteristic of Parkinson's disease (PD). Much evidence, accumulated from multiple experimental models, has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here, we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from patients with PD. Unexpectedly, our results show that, in nonhuman primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD, as multiple causes can induce a similar outcome regarding dopaminergic neurodegeneratio

    Heart Rate and Risk of Cancer Death in Healthy Men

    Get PDF
    BACKGROUND: Data from several previous studies examining heart-rate and cardiovascular risk have hinted at a possible relationship between heart-rate and non-cardiac mortality. We thus systematically examined the predictive value of heart-rate variables on the subsequent risk of death from cancer. METHODS: In the Paris Prospective Study I, 6101 asymptomatic French working men aged 42 to 53 years, free of clinically detectable cardiovascular disease and cancer, underwent a standardized graded exercise test between 1967 and 1972. Resting heart-rate, heart-rate increase during exercise, and decrease during recovery were measured. Change in resting heart-rate over 5 years was also available in 5139 men. Mortality including 758 cancer deaths was assessed over the 25 years of follow-up. FINDINGS: There were strong, graded and significant relationships between all heart-rate parameters and subsequent cancer deaths. After adjustment for age and tobacco consumption and, compared with the lowest quartile, those with the highest quartile for resting heart-rate had a relative risk of 2.4 for cancer deaths (95% confidence interval: 1.9-2.9, p<0.0001) This was similar after adjustment for traditional cardiovascular risk factors and was observed for the commonest malignancies (respiratory and gastrointestinal). Similarly, significant relationships with cancer death were observed between poor heart rate increase during exercise, poor decrease during recovery and greater heart-rate increase over time (p<0.0001 for all). INTERPRETATION: Resting and exercise heart rate had consistent, graded and highly significant associations with subsequent cancer mortality in men

    Readiness for smoking cessation in coronary heart disease patients across Europe: results from the EUROASPIRE III survey

    No full text
    Background: Readiness for smoking cessation is an important predictor of quit attempts and cessation success. We aimed to investigate the prevalence and correlates of readiness for smoking cessation in coronary heart disease (CHD) patients. Design: The EUROpean Action on Secondary and Primary Prevention by Intervention to Reduce Events III (EUROASPIRE III) survey is a cross-sectional study conducted in 2006–2007 among CHD patients <80 years of age from 22 European regions. Methods: Patients were interviewed on average 15 months after hospital admission for an acute coronary event or procedure. Readiness for smoking cessation was assessed using the smoking stages of change (SSC) short form questionnaire. Breath carbon monoxide was measured to validate self-reported non-smoking. Results: Among 2585 patients who were smoking prior to hospital admission, 25.6%, 16.8%, 8.1%, 5.6% and 44.0% were in the precontemplation (no intention to quit), contemplation (thinking of quitting), preparation (planning to quit), action (having quit within six months) and maintenance (having quit more than six months ago) stages, respectively. Significant multivariable correlates of advancement in SSC showed positive associations of older age and attended cardiac rehabilitation and negative associations of severe depressive symptoms, longer smoking duration and environmental tobacco smoke (ETS) exposure. Conclusions: One-quarter of CHD patients across Europe who were smoking prior to hospitalisation have no intention to quit, and an additional quarter is thinking of quitting or planning to quit. Patients who are younger, do not attend cardiac rehabilitation, have severe depressive symptoms, have been smoking for longer periods of time and are exposed to ETS may need to be specifically targeted in cessation interventions

    Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models

    Get PDF
    Failure of remyelination of multiple sclerosis (MS) lesions contributes to neurodegeneration that correlates with chronic disability in patients. Currently, there are no available treatments to reduce neurodegeneration, but one therapeutic approach to fill this unmet need is to promote remyelination. As many demyelinated MS lesions contain plentiful oligodendrocyte precursor cells (OPCs), but no mature myelinating oligodendrocytes, research has previously concentrated on promoting OPC maturation. However, some MS lesions contain few OPCs, and therefore, remyelination failure may also be secondary to OPC recruitment failure. Here, in a series of MS samples, we determined how many lesions contained few OPCs, and correlated this to pathological subtype and expression of the chemotactic molecules Semaphorin (Sema) 3A and 3F. 37 % of MS lesions contained low numbers of OPCs, and these were mostly chronic active lesions, in which cells expressed Sema3A (chemorepellent). To test the hypothesis that differential Sema3 expression in demyelinated lesions alters OPC recruitment and the efficiency of subsequent remyelination, we used a focal myelinotoxic mouse model of demyelination. Adding recombinant (r)Sema3A (chemorepellent) to demyelinated lesions reduced OPC recruitment and remyelination, whereas the addition of rSema3F (chemoattractant), or use of transgenic mice with reduced Sema3A expression increased OPC recruitment and remyelination. We conclude that some MS lesions fail to remyelinate secondary to reduced OPC recruitment, and that chemotactic molecules are involved in the mechanism, providing a new group of drug targets to improve remyelination, with a specific target in the Sema3A receptor neuropilin-1. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-013-1112-y) contains supplementary material, which is available to authorized users

    PINK1 Is Necessary for Long Term Survival and Mitochondrial Function in Human Dopaminergic Neurons

    Get PDF
    Parkinson's disease (PD) is a common age-related neurodegenerative disease and it is critical to develop models which recapitulate the pathogenic process including the effect of the ageing process. Although the pathogenesis of sporadic PD is unknown, the identification of the mendelian genetic factor PINK1 has provided new mechanistic insights. In order to investigate the role of PINK1 in Parkinson's disease, we studied PINK1 loss of function in human and primary mouse neurons. Using RNAi, we created stable PINK1 knockdown in human dopaminergic neurons differentiated from foetal ventral mesencephalon stem cells, as well as in an immortalised human neuroblastoma cell line. We sought to validate our findings in primary neurons derived from a transgenic PINK1 knockout mouse. For the first time we demonstrate an age dependent neurodegenerative phenotype in human and mouse neurons. PINK1 deficiency leads to reduced long-term viability in human neurons, which die via the mitochondrial apoptosis pathway. Human neurons lacking PINK1 demonstrate features of marked oxidative stress with widespread mitochondrial dysfunction and abnormal mitochondrial morphology. We report that PINK1 plays a neuroprotective role in the mitochondria of mammalian neurons, especially against stress such as staurosporine. In addition we provide evidence that cellular compensatory mechanisms such as mitochondrial biogenesis and upregulation of lysosomal degradation pathways occur in PINK1 deficiency. The phenotypic effects of PINK1 loss-of-function described here in mammalian neurons provides mechanistic insight into the age-related degeneration of nigral dopaminergic neurons seen in PD
    • …
    corecore