Local modulation of the Wnt/β‐catenin and bone morphogenic protein (BMP) pathways recapitulates rib defects analogous to cerebro‐costo‐mandibular syndrome

Ribs are seldom affected by developmental disorders, however, multiple defects in rib structure are observed in the spliceosomal disease cerebro‐costo‐mandibular syndrome (CCMS). These defects include rib gaps, found in the posterior part of the costal shaft in multiple ribs, as well as missing ribs, shortened ribs and abnormal costotransverse articulations, which result in inadequate ventilation at birth and high perinatal mortality. The genetic mechanism of CCMS is a loss‐of‐function mutation in SNRPB, a component of the major spliceosome, and knockdown of this gene in vitro affects the activity of the Wnt/β‐catenin and bone morphogenic protein (BMP) pathways. The aim of the present study was to investigate whether altering these pathways in vivo can recapitulate rib gaps and other rib abnormalities in the model animal. Chick embryos were implanted with beads soaked in Wnt/β‐catenin and BMP pathway modulators during somitogenesis, and incubated until the ribs were formed. Some embryos were harvested in the preceding days for analysis of the chondrogenic marker Sox9, to determine whether pathway modulation affected somite patterning or chondrogenesis. Wnt/β‐catenin inhibition manifested characteristic rib phenotypes seen in CCMS, including rib gaps (P < 0.05) and missing ribs (P < 0.05). BMP pathway activation did not cause rib gaps but yielded missing rib (P < 0.01) and shortened rib phenotypes (P < 0.05). A strong association with vertebral phenotypes was also noted with BMP4 (P < 0.001), including scoliosis (P < 0.05), a feature associated with CCMS. Reduced expression of Sox9 was detected with Wnt/β‐catenin inhibition, indicating that inhibition of chondrogenesis precipitated the rib defects in the presence of Wnt/β‐catenin inhibitors. BMP pathway activators also reduced Sox9 expression, indicating an interruption of somite patterning in the manifestation of rib defects with BMP4. The present study demonstrates that local inhibition of the Wnt/β‐catenin and activation of the BMP pathway can recapitulate rib defects, such as those observed in CCMS. The balance of Wnt/β‐catenin and BMP in the somite is vital for correct rib morphogenesis, and alteration of the activity of these two pathways in CCMS may perturb this balance during somite patterning, leading to the observed rib defects

Superconductivity in the Ferroquadrupolar State in the Quadrupolar Kondo Lattice PrTi2_2Al20_{20}

The cubic compound PrTi$_2$Al$_{20}$ is a quadrupolar Kondo lattice system that exhibits quadrupolar ordering due to the non-Kramers $\Gamma_3$ ground doublet and has strong hybridization between $4f$ and conduction electrons. Our study using high-purity single crystal reveals that PrTi$_2$Al$_{20}$ exhibits type-II superconductivity at $T_{\rm c} = 200$ mK in the nonmagnetic ferroquadrupolar state. The superconducting critical temperature and field phase diagram suggests moderately enhanced effective mass of $m^*/m_0 \sim 16$

Exclusion of integrins from CNS axons is regulated by Arf6 activation and the AIS.

Integrins are adhesion and survival molecules involved in axon growth during CNS development, as well as axon regeneration after injury in the peripheral nervous system (PNS). Adult CNS axons do not regenerate after injury, partly due to a low intrinsic growth capacity. We have previously studied the role of integrins in axon growth in PNS axons; in the present study, we investigate whether integrin mechanisms involved in PNS regeneration may be altered or lacking from mature CNS axons by studying maturing CNS neurons in vitro. In rat cortical neurons, we find that integrins are present in axons during initial growth but later become restricted to the somato-dendritic domain. We investigated how this occurs and whether it can be altered to enhance axonal growth potential. We find a developmental change in integrin trafficking; transport becomes predominantly retrograde throughout axons, but not dendrites, as neurons mature. The directionality of transport is controlled through the activation state of ARF6, with developmental upregulation of the ARF6 GEF ARNO enhancing retrograde transport. Lowering ARF6 activity in mature neurons restores anterograde integrin flow, allows transport into axons, and increases axon growth. In addition, we found that the axon initial segment is partly responsible for exclusion of integrins and removal of this structure allows integrins into axons. Changing posttranslational modifications of tubulin with taxol also allows integrins into the proximal axon. The experiments suggest that the developmental loss of regenerative ability in CNS axons is due to exclusion of growth-related molecules due to changes in trafficking.The authors thank Dr. Matthew N. Rasband for kindly providing the adenoviruses for ankG silencing experiment and Dr. Juan Bonifacino for AP-1 constructs. We also thank Menghon Cheah for his assistance. We acknowledge funding from the Medical Research Council, the Christopher and Dana Reeve Foundation, EU Framework 7 Project Plasticise, the European Research Council, the John and Lucille van Geest Foundation, and the NIHR Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from the Society for Neuroscience via http://dx.doi.org/10.1523/JNEUROSCI.2850-14.201

Search for the Invisible Decay of Neutrons with KamLAND

The Kamioka Liquid scintillator Anti-Neutrino Detector (KamLAND) is used in a search for single neutron or two neutron intra-nuclear disappearance that would produce holes in the $\it{s}$-shell energy level of $^{12}$C nuclei. Such holes could be created as a result of nucleon decay into invisible modes ($inv$), e.g. $n \to 3\nu$ or $nn \to 2\nu$. The de-excitation of the corresponding daughter nucleus results in a sequence of space and time correlated events observable in the liquid scintillator detector. We report on new limits for one- and two-neutron disappearance: $\tau(n\to inv)> 5.8\times 10^{29}$ years and $\tau (nn \to inv)> 1.4 \times 10^{30}$ years at 90% CL. These results represent an improvement of factors of $\sim$3 and $>10^4$ over previous experiments.Comment: 5 pages, 3 figure

Carriers of Loss-of-Function Mutations in ABCA1 Display Pancreatic β-Cell Dysfunction

OBJECTIVE: Abnormal cellular cholesterol handling in islets may contribute to beta-cell dysfunction in type 2 diabetes. beta-Cell deficiency for the ATP binding cassette transporter A1 (ABCA1), which mediates the efflux of cellular cholesterol, leads to altered intracellular cholesterol homeostasis and impaired insulin secretion in mice. We aimed to assess the impact of ABCA1 dysfunction on glucose homeostasis in humans. RESEARCH DESIGN AND METHODS: In heterozygous carriers of disruptive mutations in ABCA1 and family-based noncarriers of similar age, sex, and BMI, we performed oral glucose tolerance tests (OGTTs) (n = 15 vs. 14) and hyperglycemic clamps (n = 8 vs. 8). RESULTS: HDL cholesterol levels in carriers were less than half those in noncarriers, but LDL cholesterol levels did not differ. Although fasting plasma glucose was similar between groups, glucose curves after an OGTT were mildly higher in carriers than in noncarriers. During hyperglycemic clamps, carriers demonstrated lower first-phase insulin secretion than noncarriers but no difference in insulin sensitivity. The disposition index (a measure of beta-cell function adjusted for insulin sensitivity) of the carriers was significantly reduced in ABCA1 heterozygotes. CONCLUSIONS: Carriers of loss-of-function mutations in ABCA1 show impaired insulin secretion without insulin resistance. Our data provide evidence that ABCA1 is important for normal beta-cell function in human

Measurement of Neutrino Oscillation with KamLAND: Evidence of Spectral Distortion

We present results of a study of neutrino oscillation based on a 766 ton-year exposure of KamLAND to reactor anti-neutrinos. We observe 258 \nuebar\ candidate events with energies above 3.4 MeV compared to 365.2 events expected in the absence of neutrino oscillation. Accounting for 17.8 expected background events, the statistical significance for reactor \nuebar disappearance is 99.998%. The observed energy spectrum disagrees with the expected spectral shape in the absence of neutrino oscillation at 99.6% significance and prefers the distortion expected from \nuebar oscillation effects. A two-neutrino oscillation analysis of the KamLAND data gives \DeltaMSq = 7.9$^{+0.6}_{-0.5}\times10^{-5}$ eV$^2$. A global analysis of data from KamLAND and solar neutrino experiments yields \DeltaMSq = 7.9$^{+0.6}_{-0.5}\times10^{-5}$ eV$^2$ and \ThetaParam = 0.40$^{+0.10}_{-0.07}$, the most precise determination to date.Comment: 5 pages, 4 figures; submitted to Phys.Rev.Letter

First Results from KamLAND: Evidence for Reactor Anti-Neutrino Disappearance

KamLAND has been used to measure the flux of $\bar{\nu}_e$'s from distant nuclear reactors. In an exposure of 162 ton$\cdot$yr (145.1 days) the ratio of the number of observed inverse $\beta$-decay events to the expected number of events without disappearance is $0.611\pm 0.085 {\rm (stat)} \pm 0.041 {\rm (syst)}$ for $\bar{\nu}_e$ energies $>$ 3.4 MeV. The deficit of events is inconsistent with the expected rate for standard $\bar{\nu}_e$ propagation at the 99.95% confidence level. In the context of two-flavor neutrino oscillations with CPT invariance, these results exclude all oscillation solutions but the `Large Mixing Angle' solution to the solar neutrino problem using reactor $\bar{\nu}_e$ sources.Comment: 6 pages, 6 figure

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in &gt;100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P &lt; 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD

Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells

Concomitant activation of the Wnt pathway and suppression of Mapk signalling by two small molecule inhibitors (2i) in the presence of leukaemia inhibitory factor (LIF) (hereafter termed 2i/L) induces a naive state in mouse embryonic stem (ES) cells that resembles the inner cell mass (ICM) of the pre-implantation embryo. Since the ICM exists only transiently in vivo, it remains unclear how sustained propagation of naive ES cells in vitro affects their stability and functionality. Here we show that prolonged culture of male mouse ES cells in 2i/L results in irreversible epigenetic and genomic changes that impair their developmental potential. Furthermore, we find that female ES cells cultured in conventional serum plus LIF medium phenocopy male ES cells cultured in 2i/L. Mechanistically, we demonstrate that the inhibition of Mek1/2 is predominantly responsible for these effects, in part through the downregulation of DNA methyltransferases and their cofactors. Finally, we show that replacement of the Mek1/2 inhibitor with a Src inhibitor preserves the epigenetic and genomic integrity as well as the developmental potential of ES cells. Taken together, our data suggest that, although short-term suppression of Mek1/2 in ES cells helps to maintain an ICM-like epigenetic state, prolonged suppression results in irreversible changes that compromise their developmental potential