Mutation in NSUN2, which Encodes an RNA Methyltransferase, Causes Autosomal-Recessive Intellectual Disability

Causes of autosomal-recessive intellectual disability (ID) have, until very recently, been under researched because of the high degree of genetic heterogeneity. However, now that genome-wide approaches can be applied to single multiplex consanguineous families, the identification of genes harboring disease-causing mutations by autozygosity mapping is expanding rapidly. Here, we have mapped a disease locus in a consanguineous Pakistani family affected by ID and distal myopathy. We genotyped family members on genome-wide SNP microarrays and used the data to determine a single 2.5 Mb homozygosity-by-descent (HBD) locus in region 5p15.32–p15.31; we identified the missense change c.2035G>A (p.Gly679Arg) at a conserved residue within NSUN2. This gene encodes a methyltransferase that catalyzes formation of 5-methylcytosine at C34 of tRNA-leu(CAA) and plays a role in spindle assembly during mitosis as well as chromosome segregation. In mouse brains, we show that NSUN2 localizes to the nucleolus of Purkinje cells in the cerebellum. The effects of the mutation were confirmed by the transfection of wild-type and mutant constructs into cells and subsequent immunohistochemistry. We show that mutation to arginine at this residue causes NSUN2 to fail to localize within the nucleolus. The ID combined with a unique profile of comorbid features presented here makes this an important genetic discovery, and the involvement of NSUN2 highlights the role of RNA methyltransferase in human neurocognitive development

Effects of a Synbiotic on Plasma Immune Activity Markers and Short-Chain Fatty Acids in Children and Adults with ADHD—A Randomized Controlled Trial

Synbiotic 2000, a pre + probiotic, reduced comorbid autistic traits and emotion dysregulation in attention deficit hyperactivity disorder (ADHD) patients. Immune activity and bacteria-derived short-chain fatty acids (SCFAs) are microbiota–gut–brain axis mediators. The aim was to investigate Synbiotic 2000 effects on plasma levels of immune activity markers and SCFAs in children and adults with ADHD. ADHD patients (n = 182) completed the 9-week intervention with Synbiotic 2000 or placebo and 156 provided blood samples. Healthy adult controls (n = 57) provided baseline samples. At baseline, adults with ADHD had higher pro-inflammatory sICAM-1 and sVCAM-1 and lower SCFA levels than controls. Children with ADHD had higher baseline sICAM-1, sVCAM-1, IL-12/IL-23p40, IL-2Rα, and lower formic, acetic, and propionic acid levels than adults with ADHD. sICAM-1, sVCAM-1, and propionic acid levels were more abnormal in children on medication. Synbiotic 2000, compared to placebo, reduced IL-12/IL-23p40 and sICAM-1 and increased propionic acid levels in children on medication. SCFAs correlated negatively with sICAM-1 and sVCAM-1. Preliminary human aortic smooth-muscle-cell experiments indicated that SCFAs protected against IL-1β-induced ICAM-1 expression. These findings suggest that treatment with Synbiotic 2000 reduces IL12/IL-23p40 and sICAM-1 and increases propionic acid levels in children with ADHD. Propionic acid, together with formic and acetic acid, may contribute to the lowering of the higher-than-normal sICAM-1 levels

Dynamic scaling and aging phenomena in short-range Ising spin glass: Cu0.5_{0.5}Co0.5_{0.5}Cl2_{2}-FeCl3_{3} graphite bi-intercalation compound

Static and dynamic behavior of short-range Ising-spin glass Cu$_{0.5}$Co$_{0.5}$Cl$_{2}$-FeCl$_{3}$ graphite bi-intercalation compounds (GBIC) has been studied with SQUID DC and AC magnetic susceptibility. The $T$ dependence of the zero-field relaxation time $\tau$ above a spin-freezing temperature $T_{g}$ (= 3.92 $\pm$ 0.11 K) is well described by critical slowing down. The absorption $\chi^{\prime\prime}$ below $T_{g}$ decreases with increasing angular frequency $\omega$, which is in contrast to the case of 3D Ising spin glass. The dynamic freezing temperature $T_{f}(H,\omega)$ at which d$M_{FC}(T,H)/$d$H=\chi^{\prime}(T,H=0,\omega)$, is determined as a function of frequency (0.01 Hz $\leq \omega/2\pi \leq$ 1 kHz) and magnetic field (0 $\leq H \leq$ 5 kOe). The dynamic scaling analysis of the relaxation time $\tau(T,H)$ defined as $\tau = 1/\omega$ at $T = T_{f}(H,\omega)$ suggests the absence of SG phase in the presence of $H$ (at least above 100 Oe). Dynamic scaling analysis of $\chi^{\prime \prime}(T, \omega)$ and $\tau(T,H)$ near $T_{g}$ leads to the critical exponents ($\beta$ = 0.36 $\pm$ 0.03, $\gamma$ = 3.5 $\pm$ 0.4, $\nu$ = 1.4 $\pm$ 0.2, $z$ = 6.6 $\pm$ 1.2, $\psi$ = 0.24 $\pm$ 0.02, and $\theta$ = 0.13 $\pm$ 0.02). The aging phenomenon is studied through the absorption $\chi^{\prime \prime}(\omega, t)$ below $T_{g}$. It obeys a $(\omega t)^{-b^{\prime \prime}}$ power-law decay with an exponent $b^{\prime \prime}\approx 0.15 - 0.2$. The rejuvenation effect is also observed under sufficiently large (temperature and magnetic-field) perturbations.Comment: 14 pages, 19 figures; to be published in Phys. Rev. B (September 1, 2003

Dynamic response of an Arctic epishelf lake to seasonal and long-term forcing: Implications for ice shelf thickness

Changes in the depth of the freshwater-seawater interface in epishelf lakes have been used to infer long-term changes in the minimum thickness of ice shelves; however, little is known about the dynamics of epishelf lakes and what other factors may influence their depth. Continuous observations collected between 2011 and 2014 in the Milne Fiord epishelf lake, in the Canadian Arctic, showed that the depth of the halocline varied seasonally by up to 3.3m, which was comparable to interannual variability. The seasonal depth variation was controlled by the magnitude of surface meltwater inflow and the hydraulics of the inferred outflow pathway, a narrow basal channel in the Milne Ice She

A gene expression signature distinguishes innate response and resistance to proteasome inhibitors in multiple myeloma

Extensive interindividual variation in response to chemotherapy is a major stumbling block in achieving desirable efficacy in the treatment of cancers, including multiple myeloma (MM). In this study, our goal was to develop a gene expression signature that predicts response specific to proteasome inhibitor (PI) treatment in MM. Using a well-characterized panel of human myeloma cell lines (HMCLs) representing the biological and genetic heterogeneity of MM, we created an in vitro chemosensitivity profile in response to treatment with the four PIs bortezomib, carfilzomib, ixazomib and oprozomib as single agents. Gene expression profiling was performed using next-generation high-throughput RNA-sequencing. Applying machine learning-based computational approaches including the supervised ensemble learning methods Random forest and Random survival forest, we identified a 42-gene expression signature that could not only distinguish good and poor PI response in the HMCL panel, but could also be successfully applied to four different clinical data sets on MM patients undergoing PI-based chemotherapy to distinguish between extraordinary (good and poor) outcomes. Our results demonstrate the use of in vitro modeling and machine learning-based approaches to establish predictive biomarkers of response and resistance to drugs that may serve to better direct myeloma patient treatment options

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter

Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS

We present the results of a search for new, heavy particles that decay at a significant distance from their production point into a final state containing charged hadrons in association with a high-momentum muon. The search is conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS detector operating at the Large Hadron Collider. Production of such particles is expected in various scenarios of physics beyond the standard model. We observe no signal and place limits on the production cross-section of supersymmetric particles in an R-parity-violating scenario as a function of the neutralino lifetime. Limits are presented for different squark and neutralino masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final version to appear in Physics Letters