TNF-induced necroptosis in L929 cells is tightly regulated by multiple TNFR1 complex I and II members

TNF receptor 1 signaling induces NF-κB activation and necroptosis in L929 cells. We previously reported that cellular inhibitor of apoptosis protein-mediated receptor-interacting protein 1 (RIP1) ubiquitination acts as a cytoprotective mechanism, whereas knockdown of cylindromatosis, a RIP1-deubiquitinating enzyme, protects against tumor necrosis factor (TNF)-induced necroptosis. We report here that RIP1 is a crucial mediator of canonical NF-κB activation in L929 cells, therefore questioning the relative cytoprotective contribution of RIP1 ubiquitination versus canonical NF-κB activation. We found that attenuated NF-κB activation has no impact on TNF-induced necroptosis. However, we identified A20 and linear ubiquitin chain assembly complex as negative regulators of necroptosis. Unexpectedly, and in contrast to RIP3, we also found that knockdown of RIP1 did not block TNF cytotoxicity. Cell death typing revealed that RIP1-depleted cells switch from necroptotic to apoptotic death, indicating that RIP1 can also suppress apoptosis in L929 cells. Inversely, we observed that Fas-associated protein via a death domain, cellular FLICE inhibitory protein and caspase-8, which are all involved in the initiation of apoptosis, counteract necroptosis induction. Finally, we also report RIP1-independent but RIP3-mediated necroptosis in the context of TNF signaling in particular conditions

Clinical practice: Noninvasive respiratory support in newborns

The most important goal of introducing noninvasive ventilation (NIV) has been to decrease the need for intubation and, therefore, mechanical ventilation in newborns. As a result, this technique may reduce the incidence of bronchopulmonary dysplasia (BPD). In addition to nasal CPAP, improvements in sensors and flow delivery systems have resulted in the introduction of a variety of other types of NIV. For the optimal application of these novelties, a thorough physiological knowledge of mechanics of the respiratory system is necessary. In this overview, the modern insights of noninvasive respiratory therapy in newborns are discussed. These aspects include respiratory support in the delivery room; conventional and modern nCPAP; humidified, heated, and high-flow nasal cannula ventilation; and nasal intermittent positive pressure ventilation. Finally, an algorithm is presented describing common practice in taking care of respiratory distress in prematurely born infants

Sympatric woodland Myotis bats form tight-knit social groups with exclusive roost home ranges

Background: The structuring of wild animal populations can influence population dynamics, disease spread, and information transfer. Social network analysis potentially offers insights into these processes but is rarely, if ever, used to investigate more than one species in a community. We therefore compared the social, temporal and spatial networks of sympatric Myotis bats (M. nattereri (Natterer's bats) and M. daubentonii (Daubenton's bats)), and asked: (1) are there long-lasting social associations within species? (2) do the ranges occupied by roosting social groups overlap within or between species? (3) are M. daubentonii bachelor colonies excluded from roosting in areas used by maternity groups? Results: Using data on 490 ringed M. nattereri and 978 M. daubentonii from 379 colonies, we found that both species formed stable social groups encompassing multiple colonies. M. nattereri formed 11 mixed-sex social groups with few (4.3%) inter-group associations. Approximately half of all M. nattereri were associated with the same individuals when recaptured, with many associations being long-term (>100 days). In contrast, M. daubentonii were sexually segregated; only a quarter of pairs were associated at recapture after a few days, and inter-sex associations were not long-lasting. Social groups of M. nattereri and female M. daubentonii had small roost home ranges (mean 0.2 km2 in each case). Intra-specific overlap was low, but inter-specific overlap was high, suggesting territoriality within but not between species. M. daubentonii bachelor colonies did not appear to be excluded from roosting areas used by females. Conclusions: Our data suggest marked species- and sex-specific patterns of disease and information transmission are likely between bats of the same genus despite sharing a common habitat. The clear partitioning of the woodland amongst social groups, and their apparent reliance on small patches of habitat for roosting, means that localised woodland management may be more important to bat conservation than previously recognised

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Dissecting the Roles of MicroRNAs in Coronary Heart Disease via Integrative Genomic Analyses

© 2015 American Heart Association, Inc. OBJECTIVE—: The roles of microRNAs (miRNAs) in coronary heart disease (CHD) have not been well characterized. This study souWght to systematically characterize the complex genomic architecture of CHD by integrating whole blood miRNA and mRNA expression with genetic variation in 186 CHD cases and 186 controls. APPROACH AND RESULTS—: At false discovery rate <0.2, 15 miRNAs were differentially expressed between CHD cases and controls. To explore regulatory mechanisms, we integrated miRNA and mRNA expression with genome-wide genotype data to investigate miRNA and mRNA associations and relationships of genetic variation with miRNAs. We identified a large number of correlated miRNA–mRNA pairs and genetic loci that seem to regulate miRNA levels. Subsequently, we explored the relationships of these complex molecular associations with CHD status. We identified a large difference in miRNA–mRNA associations between CHD cases and controls, as demonstrated by a significantly higher proportion of inversely correlated miRNA–mRNA pairs in cases versus controls (80% versus 30%; P<1×10), suggesting a genome-wide shift in the regulatory structure of the transcriptome in CHD. The differentially coexpressed miRNA–mRNA pairs showed enrichment for CHD risk genetic variants affecting both miRNA and mRNA expression levels, implicating a putatively causal role in CHD. Furthermore, 3 miRNAs (miR-1275, miR-365a-3p, and miR-150-5p) were associated with an mRNA coexpression module that was causally linked to CHD and reflected the dysregulation of B-cell centered immune function. CONCLUSIONS—: Our results provide novel evidence that miRNAs are important regulators of biological processes involved in CHD via genetic control and via their tight coexpression with mRNAs