The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice

Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member–encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-β–activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1–MKK3/6–p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38β agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging

Protocol for the phase 2 EDELIFE trial investigating the efficacy and safety of intra-amniotic ER004 administration to male subjects with X-linked hypohidrotic ectodermal dysplasia

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare genetic disorder characte-rised by abnormal development of the skin and its appendages, such as hair and sweat glands, the teeth, and mucous glands of the airways, resulting in serious, sometimes life-threatening complications like hyperthermia or recurrent respiratory infections. It is caused by pathogenic variants of the ectodysplasin A gene

Study of Beauty Hadron Decays into Pairs of Charm Hadrons

First observations of the decays A(b)(0) -> A(c)(+)D((s))(-) are reported using data corresponding to an integrated luminosity of 3 fb(-1) collected at 7 and 8 TeV center-of- ass energies in proton-proton collisions with the LHCb detector. In addition, the most precise measurement of the branching fraction B(B-s(0) -> D+Ds-) is made and a search is performed for the decays B-0((s)) -> A(c)(+)A(c)(-). The results obtained are B(A(b)(0) -> A(c)(+)D(-))/B(A(b)(0) -> A(c)(+)D(s)(-)) = 0.042 +/- 0.003 (stat) +/- 0.003 (syst), [B(A(b)(0) -> A(c)(+)D(s)(-))/B((B) over bar (0) -> D+Ds-)]/[B(A(b)(0) -> A(c)(+)pi(-))/B((B) over bar (0) -> D+pi(-))] = 0.96 +/- 0.02 (stat) +/- 0.06 (syst), B(B-s(0) -> D+Ds-)/B((B) over bar (0) -> D+Ds-) = 0.038 +/- 0.004 (stat) +/- (syst), B((B) over bar (0) -> A(c)(+)A(c)(-))/B((B) over bar (0) -> D+Ds-) A(c)(+)A(c)(-)) /B(B-s(0) -> D+Ds-) < 0.30[95% C.L.]. Measurement of the mass of the A(b)(0) baryon relative to the (B) over bar (0) meson gives M(A(b)(0)) ¿ M((B) over bar (0)) = 339.72 +/- 0.24 (stat) +/- 0.18 (syst) MeV/c(2). This result provides the most precise measurement of the mass of the A(b)(0) baryon to date

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Study of beauty hadron decays into pairs of harm hadrons

First observations of the decays Λ0b→Λ+cD−(s) are reported using data corresponding to an integrated luminosity of 3  fb−1 collected at 7 and 8 TeV center-of-mass energies in proton-proton collisions with the LHCb detector. In addition, the most precise measurement of the branching fraction B(B0s→D+D−s) is made and a search is performed for the decays B0(s)→Λ+cΛ−c. The results obtained are B(Λ0b→Λ+cD−)/B(Λ0b→Λ+cD−s)=0.042±0.003(stat)±0.003(syst),[B(Λ0b→Λ+cD−s)B(B¯0→D+D−s)]/[B(Λ0b→Λ+cπ−)B(B¯0→D+π−)]=0.96±0.02(stat)±0.06(syst),B(B0s→D+D−s)/B(B¯0→D+D−s)=0.038±0.004(stat)±0.003(syst),B(B¯0→Λ+cΛ−c)/B(B¯0→D+D−s)&#60;0.0022[95%  C.L.],B(B0s→Λ+cΛ−c)/B(B0s→D+D−s)&#60;0.30[95%  C.L.]. Measurement of the mass of the Λ0b baryon relative to the B¯0 meson gives M(Λ0b)−M(B¯0)=339.72±0.24(stat)±0.18(syst)  MeV/c2. This result provides the most precise measurement of the mass of the Λ0b baryon to date

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats

In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Development’s (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security