253 research outputs found

    Using Heterogeneous Stocks for Fine-Mapping Genetically Complex Traits.

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    In this chapter we will review both the rationale and experimental design for using Heterogeneous Stock (HS) populations for fine-mapping of complex traits in mice and rats. We define an HS as an outbred population derived from an intercross between two or more inbred strains. HS have been used to perform genome-wide association studies (GWAS) for multiple behavioral, physiological, and gene expression traits. GWAS using HS require four key steps, which we review: selection of an appropriate HS population, phenotyping, genotyping, and statistical analysis. We provide advice on the selection of an HS, comment on key issues related to phenotyping, discuss genotyping methods relevant to these populations, and describe statistical genetic analyses that are applicable to genetic analyses that use HS

    Anti-influenza Hyperimmune Immunoglobulin Enhances Fc-functional Antibody Immunity during Human Influenza Infection

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    BACKGROUND: New treatments for severe influenza are needed. Passive transfer of influenza-specific hyperimmune pooled immunoglobulin (Flu-IVIG) boosts neutralising antibody responses to past strains in influenza-infected subjects. The effect of Flu-IVIG on antibodies with Fc-mediated functions, which may target diverse influenza strains, is unclear. METHODS: We studied the capacity of Flu-IVIG, relative to standard IVIG, to bind to Fc receptors and mediate antibody-dependent cellular cytotoxicity in vitro. The effect of Flu-IVIG infusion, compared to placebo infusion, was examined in serial plasma samples from 24 subjects with confirmed influenza infection in the INSIGHT FLU005 pilot study. RESULTS: Flu-IVIG contains higher concentrations of Fc-functional antibodies than IVIG against a diverse range of influenza hemagglutinins. Following infusion of Flu-IVIG into influenza-infected subjects, a transient increase in Fc-functional antibodies was present for 1-3 days against infecting and non-infecting strains of influenza. CONCLUSIONS: Flu-IVIG contains antibodies with Fc-mediated functions against influenza virus and passive transfer of Flu-IVIG increases anti-influenza Fc-functional antibodies in the plasma of influenza-infected subjects. Enhancement of Fc-functional antibodies to a diverse range of influenza strains suggests that Flu-IVIG infusion could prove useful in the context of novel influenza virus infections, when there may be minimal or no neutralising antibodies in the Flu-IVIG preparation

    Experimental modelling of cardiacpressure overload hypertrophy: Modified technique for precise,reproducible, safe and easy aorticarch banding-debanding in mice

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    Pressure overload left ventricular hypertrophy is a known precursor of heart failure with ominous prognosis. The development of experimental models that reproduce this phenomenon is instrumental for the advancement in our understanding of its pathophysiology. The gold standard of these models is the controlled constriction of the mid aortic arch in mice according to Rockman's technique (RT). We developed a modified technique that allows individualized and fully controlled constriction of the aorta, improves efficiency and generates a reproducible stenosis that is technically easy to perform and release. An algorithm calculates, based on the echocardiographic arch diameter, the intended perimeter at the constriction, and a suture is prepared with two knots separated accordingly. The aorta is encircled twice with the suture and the loop is closed with a microclip under both knots. We performed controlled aortic constriction with Rockman's and the double loop-clip (DLC) techniques in mice. DLC proved superiority in efficiency (mortality and invalid experiments) and more homogeneity of the results (transcoarctational gradients, LV mass, cardiomyocyte hypertrophy, gene expression) than RT. DLC technique optimizes animal use and generates a consistent and customized aortic constriction with homogeneous LV pressure overload morphofunctional, structural, and molecular features.This work was supported by grants from the Ministerio de Economía y Competitividad [Fondo de Investigaciones Sanitarias (PI15/01224), Red de Investigación Cardiovascular (RD12/0042/0018)]. Co-funded by the Fondo Europeo de Desarrollo Regional (FEDER). Fundació La Marató de TV3 (101/C/2015). JFN is afliated to the research network of the Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Spain

    Chatting Second Messengers: PIP3 and cAMP

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    3’-5’-cyclic adenosine monophosphate (cAMP) and phosphatidylinositol 3,4,5 trisphosphate (PIP3) are pleiotropic second messengers generated in response to activation of G protein-coupled receptors (GPCRs) by a wide array of hormones and neurotransmitters. Although these small molecules engage distinct and seem-ingly unrelated downstream signal transducers, a growing body of evidence points to a strict cooperation of cAMP and PIP3 cascades in the control of cardiomyocyte functions. Dynamic macromolecular complexes of cAMP and PIP3 molecular switches assemble into spatially and temporally restricted microdomains. Deci-phering how this compartmentalization complexes form and affect the interactions between the two signaling systems is of crucial importance, since both pathways are severely deregulated in major cardiac diseases, such as heart failure. This chapter summarizes recently described mechanisms governing the bidirectional crosstalk between cAMP and PIP3 signaling pathways in the pathophysiological control of cardiovascular function. In particular, we will describe how membrane-located PIP3 affects both initiation and termination of cAMP signaling as well as the negative feedback loop whereby the small and diffusible intracellular messen-ger, cAMP, influences PIP3 productio

    T cell costimulation blockade blunts pressure overload-induced heart failure

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    18nonenoneKallikourdis, Marinos; Martini, Elisa; Carullo, Pierluigi; Sardi, Claudia; Roselli, Giuliana; Greco, Carolina M.; Vignali, Debora; Riva, Federica; Ormbostad Berre, Anne Marie; St√łlen, Tomas O.; Fumero, Andrea; Faggian, Giuseppe; Di Pasquale, Elisa; Elia, Leonardo; Rumio, Cristiano; Catalucci, Daniele; Papait, Roberto; Condorelli, GianluigiKallikourdis, Marinos; Martini, Elisa; Carullo, Pierluigi; Sardi, Claudia; Roselli, Giuliana; Greco, Carolina M.; Vignali, Debora; Riva, Federica; Ormbostad Berre, Anne Marie; St√łlen, Tomas O.; Fumero, Andrea; Faggian, Giuseppe; Di Pasquale, Elisa; Elia, Leonardo; Rumio, Cristiano; Catalucci, Daniele; Papait, Roberto; Condorelli, Gianluig

    MiRNA Deregulation in Cardiac Aging and Associated Disorders

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    The prevalence of age-related diseases is increasing dramatically, among which cardiac disease represents the leading cause of death. Aging of the heart is characterized by various molecular and cellular hallmarks impairing both cardiomyocytes and noncardiomyocytes, and resulting in functional deteriorations of the cardiac system. The aging process includes desensitization of beta-adrenergic receptor (beta AR)-signaling and decreased calcium handling, altered growth signaling and cardiac hypertrophy, mitochondrial dysfunction and impaired autophagy, increased programmed cell death, lowgrade inflammation of noncanonical inflammatory cells, and increased ECM deposition.MiRNAs play a fundamental role in regulating the processes underlying these detrimental changes in the cardiac system, indicating that MiRNAs are crucially involved in aging. Among others, MiR-34, MiR-146a, and members of the MiR-17-92 cluster, are deregulated during senescence and drive cardiac aging processes. It is therefore suggested that MiRNAs form possible therapeutic targets to stabilize the aged failing myocardium.</p

    Tipping points in the dynamics of speciation.

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    Speciation can be gradual or sudden and involve few or many genetic changes. Inferring the processes generating such patterns is difficult, and may require consideration of emergent and non-linear properties of speciation, such as when small changes at tipping points have large effects on differentiation. Tipping points involve positive feedback and indirect selection stemming from associations between genomic regions, bi-stability due to effects of initial conditions and evolutionary history, and dependence on modularity of system components. These features are associated with sudden 'regime shifts' in other cellular, ecological, and societal systems. Thus, tools used to understand other complex systems could be fruitfully applied in speciation research

    Meta-analysis of individual-patient data from EVAR-1, DREAM, OVER and ACE trials comparing outcomes of endovascular or open repair for abdominal aortic aneurysm over 5 years.

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    BACKGROUND: The erosion of the early mortality advantage of elective endovascular aneurysm repair (EVAR) compared with open repair of abdominal aortic aneurysm remains without a satisfactory explanation. METHODS: An individual-patient data meta-analysis of four multicentre randomized trials of EVAR versus open repair was conducted to a prespecified analysis plan, reporting on mortality, aneurysm-related mortality and reintervention. RESULTS: The analysis included 2783 patients, with 14‚ÄČ245 person-years of follow-up (median 5¬∑5‚ÄČyears). Early (0-6 months after randomization) mortality was lower in the EVAR groups (46 of 1393 versus 73 of 1390 deaths; pooled hazard ratio 0¬∑61, 95 per cent c.i. 0¬∑42 to 0¬∑89; P = 0¬∑010), primarily because 30-day operative mortality was lower in the EVAR groups (16 deaths versus 40 for open repair; pooled odds ratio 0¬∑40, 95 per cent c.i. 0¬∑22 to 0¬∑74). Later (within 3 years) the survival curves converged, remaining converged to 8 years. Beyond 3 years, aneurysm-related mortality was significantly higher in the EVAR groups (19 deaths versus 3 for open repair; pooled hazard ratio 5¬∑16, 1¬∑49 to 17¬∑89; P = 0¬∑010). Patients with moderate renal dysfunction or previous coronary artery disease had no early survival advantage under EVAR. Those with peripheral artery disease had lower mortality under open repair (39 deaths versus 62 for EVAR; P‚ÄČ=‚ÄČ0¬∑022) in the period from 6 months to 4 years after randomization. CONCLUSION: The early survival advantage in the EVAR group, and its subsequent erosion, were confirmed. Over 5‚ÄČyears, patients of marginal fitness had no early survival advantage from EVAR compared with open repair. Aneurysm-related mortality and patients with low ankle‚ÄČ:‚ÄČbrachial pressure index contributed to the erosion of the early survival advantage for the EVAR group. Trial registration numbers: EVAR-1, ISRCTN55703451; DREAM‚ÄČ(Dutch Randomized Endovascular Aneurysm Management), NCT00421330; ACE (An√©vrysme de l'aorte abdominale, Chirurgie versus Endoproth√®se), NCT00224718; OVER (Open Versus Endovascular Repair Trial for Abdominal Aortic Aneurysms), NCT00094575

    Notch-independent RBPJ controls angiogenesis in the adult heart

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    Increasing angiogenesis has long been considered a therapeutic target for improving heart function after injury such as acute myocardial infarction. However, gene, protein and cell therapies to increase microvascularization have not been successful, most likely because the studies failed to achieve regulated and concerted expression of pro-angiogenic and angiostatic factors needed to produce functional microvasculature. Here, we report that the transcription factor RBPJ is a homoeostatic repressor of multiple pro-angiogenic and angiostatic factor genes in cardiomyocytes. RBPJ controls angiogenic factor gene expression independently of Notch by antagonizing the activity of hypoxia-inducible factors (HIFs). In contrast to previous strategies, the cardiomyocyte-specific deletion of Rbpj increased microvascularization of the heart without adversely affecting cardiac structure or function even into old age. Furthermore, the loss of RBPJ in cardiomyocytes increased hypoxia tolerance, improved heart function and decreased pathological remodelling after myocardial infarction, suggesting that inhibiting RBPJ might be therapeutic for ischaemic injury

    How consistent are the transcriptome changes associated with cold acclimation in two species of the Drosophila virilis group?

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    This work was financially support by a Marie Curie Initial Training Network grant, ‚ÄúUnderstanding the evolutionary origin of biological diversity‚ÄĚ (ITN-2008‚Äď213780 SPECIATION), grants from the Academy of Finland to A.H. (project 132619) and M.K. (projects 268214 and 272927), a grant from NERC, UK to M.G.R. (grant NE/J020818/1), and NERC, UK PhD studentship to D.J.P. (NE/I528634/1).For many organisms the ability to cold acclimate with the onset of seasonal cold has major implications for their fitness. In insects, where this ability is widespread, the physiological changes associated with increased cold tolerance have been well studied. Despite this, little work has been done to trace changes in gene expression during cold acclimation that lead to an increase in cold tolerance. We used an RNA-Seq approach to investigate this in two species of the Drosophila virilis group. We found that the majority of genes that are differentially expressed during cold acclimation differ between the two species. Despite this, the biological processes associated with the differentially expressed genes were broadly similar in the two species. These included: metabolism, cell membrane composition, and circadian rhythms, which are largely consistent with previous work on cold acclimation/cold tolerance. In addition, we also found evidence of the involvement of the rhodopsin pathway in cold acclimation, a pathway that has been recently linked to thermotaxis. Interestingly, we found no evidence of differential expression of stress genes implying that long-term cold acclimation and short-term stress response may have a different physiological basis.PostprintPeer reviewe
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