First identification of PODXL nonsense mutations in autosomal dominant focal segmental glomerulosclerosis

Recently, a novel heterozygous missense mutation c.T1421G (p. L474R) in the PODXL gene encoding podocalyxin, was identified in an autosomal dominant focal segmental glomerulosclerosis (AD-FSGS) pedigree. However, this PODXL mutation appeared not to impair podocalyxin function and it is necessary to identify new PODXL mutations and determine their causative role for FSGS. In this study, we report the identification of a heterozygous nonsense PODXL mutations (Arg326X) in a Chinese pedigree featured by proteinuria and renal insufficiency with AD inheritance by whole exome sequencing (WES). Total mRNA and PODXL protein abundance were decreased in available peripheral blood cell samples of two affected patients undergoing hemodialysis, compared to those in healthy controls and hemodialysis controls without PODXL mutation. We identified another novel PODXL heterozygous nonsense mutation (c.C1133G; p.Ser378X) in a British-Indian pedigree of AD-FSGS by WES. In vitro study showed that, human embryonic kidney (HEK) 293T cells transfected with the pEGFP-PODXL-Arg326X or pEGFP-PODXL-Ser378X plasmid expressed significantly lower mRNA and PODXL protein compared to cells transfected with the wild-type plasmid. Blocking nonsense-mediated mRNA decay (NMD) significantly restored the amount of mutant mRNA and PODXL proteins, which indicated that the pathogenic effect of PODXL nonsense mutations is likely due to NMD, resulting in podocalyxin deficiency. Functional consequences caused by the PODXL nonsense mutations were inferred by siRNA knockdown in cultured podocytes and podocalyxin downregulation by siRNA resulted in decreased RhoA and ezrin activities, cell migration and stress fiber formation. Our results provided new data implicating heterozygous PODXL nonsense mutations in the development of FSGS

miR-9 and miR-124 synergistically affect regulation of dendritic branching via the AKT/GSK3β pathway by targeting Rap2a

A single microRNA (miRNA) can regulate expression of multiple proteins, and expression of an individual protein may be controlled by numerous miRNAs. This regulatory pattern strongly suggests that synergistic effects of miRNAs play critical roles in regulating biological processes. miR-9 and miR-124, two of the most abundant miRNAs in the mammalian nervous system, have important functions in neuronal development. In this study, we identified the small GTP-binding protein Rap2a as a common target of both miR-9 and miR-124. miR-9 and miR-124 together, but neither miRNA alone, strongly suppressed Rap2a, thereby promoting neuronal differentiation of neural stem cells (NSCs) and dendritic branching of differentiated neurons. Rap2a also diminished the dendritic complexity of mature neurons by decreasing the levels of pAKT and pGSK3β. Our results reveal a novel pathway in which miR-9 and miR-124 synergistically repress expression of Rap2a to sustain homeostatic dendritic complexity during neuronal development and maturation

FLASH: Heterogeneity-Aware Federated Learning at Scale

Federated learning (FL) becomes a promising machine learning paradigm. The impact of heterogeneous hardware specifications and dynamic states on the FL process has not yet been studied systematically. This paper presents the first large-scale study of this impact based on real-world data collected from 136k smartphones. We conducted extensive experiments on our proposed heterogeneity-aware FL platform namely FLASH , to systematically explore the performance of state-of-the-art FL algorithms and key FL configurations in heterogeneity-aware and -unaware settings, finding the following. (1) Heterogeneity causes accuracy to drop by up to 9.2% and convergence time to increase by 2.32×. (2) Heterogeneity negatively impacts popular aggregation algorithms, e.g., the accuracy variance reduction brought by q-FedAvg drops by 17.5%. (3) Heterogeneity does not worsen the accuracy loss caused by gradient-compression algorithms significantly, but it compromises the convergence time by up to 2.5×. (4) Heterogeneity hinders client-selection algorithms from selecting wanted clients, thus reducing effectiveness. e.g., the accuracy increase brought by the state-of-the-art client-selection algorithm drops by 73.9%. (5) Heterogeneity causes the optimal FL hyper-parameters to drift significantly. More specifically, the heterogeneity-unaware setting favors looser deadline and higher reporting fraction to achieve better training performance. (6) Heterogeneity results in non-trivial failed clients (more than 10%) and leads to participation bias (the top 30% of clients contribute 86% of computations). Our FLASH platform and data have been publicly open sourced

Topological phase diagram and saddle point singularity in a tunable topological crystalline insulator

We report the evolution of the surface electronic structure and surface material properties of a topological crystalline insulator (TCI) Pb1-xSnxSe as a function of various material parameters including composition x, temperature T and crystal structure. Our spectroscopic data demonstrate the electronic groundstate condition for the saddle point singularity, the tunability of surface chemical potential, and the surface states' response to circularly polarized light. Our results show that each material parameter can tune the system between trivial and topological phase in a distinct way unlike as seen in Bi2Se3 and related compounds, leading to a rich and unique topological phase diagram. Our systematic studies of the TCI Pb1-xSnxSe are valuable materials guide to realize new topological phenomena.Comment: 10 pages, 7 figures. Expanded version of arXiv:1403.156

Visceral hyperalgesia induced by forebrain-specific suppression of native Kv7/KCNQ/M-current in mice

<p>Abstract</p> <p>Background</p> <p>Dysfunction of brain-gut interaction is thought to underlie visceral hypersensitivity which causes unexplained abdominal pain syndromes. However, the mechanism by which alteration of brain function in the brain-gut axis influences the perception of visceral pain remains largely elusive. In this study we investigated whether altered brain activity can generate visceral hyperalgesia.</p> <p>Results</p> <p>Using a forebrain specific αCaMKII promoter, we established a line of transgenic (Tg) mice expressing a dominant-negative pore mutant of the Kv7.2/KCNQ2 channel which suppresses native KCNQ/M-current and enhances forebrain neuronal excitability. Brain slice recording of hippocampal pyramidal neurons from these Tg mice confirmed the presence of hyperexcitable properties with increased firing. Behavioral evaluation of Tg mice exhibited increased sensitivity to visceral pain induced by intraperitoneal (i.p.) injection of either acetic acid or magnesium sulfate, and intracolon capsaicin stimulation, but not cutaneous sensation for thermal or inflammatory pain. Immunohistological staining showed increased c-Fos expression in the somatosensory SII cortex and insular cortex of Tg mice that were injected intraperitoneally with acetic acid. To mimic the effect of cortical hyperexcitability on visceral hyperalgesia, we injected KCNQ/M channel blocker XE991 into the lateral ventricle of wild type (WT) mice. Intracerebroventricular injection of XE991 resulted in increased writhes of WT mice induced by acetic acid, and this effect was reversed by co-injection of the channel opener retigabine.</p> <p>Conclusions</p> <p>Our findings provide evidence that forebrain hyperexcitability confers visceral hyperalgesia, and suppression of central hyperexcitability by activation of KCNQ/M-channel function may provide a therapeutic potential for treatment of abdominal pain syndromes.</p

Dynamic Evolution Model of Isothermal Voids and Shocks

We explore self-similar hydrodynamic evolution of central voids embedded in an isothermal gas of spherical symmetry under the self-gravity. More specifically, we study voids expanding at constant radial speeds in an isothermal gas and construct all types of possible void solutions without or with shocks in surrounding envelopes. We examine properties of void boundaries and outer envelopes. Voids without shocks are all bounded by overdense shells and either inflows or outflows in the outer envelope may occur. These solutions, referred to as type $\mathcal{X}$ void solutions, are further divided into subtypes $\mathcal{X}_{\rm I}$ and $\mathcal{X}_{\rm II}$ according to their characteristic behaviours across the sonic critical line (SCL). Void solutions with shocks in envelopes are referred to as type $\mathcal{Z}$ voids and can have both dense and quasi-smooth edges. Asymptotically, outflows, breezes, inflows, accretions and static outer envelopes may all surround such type $\mathcal{Z}$ voids. Both cases of constant and varying temperatures across isothermal shock fronts are analyzed; they are referred to as types $\mathcal{Z}_{\rm I}$ and $\mathcal{Z}_{\rm II}$ void shock solutions. We apply the `phase net matching procedure' to construct various self-similar void solutions. We also present analysis on void generation mechanisms and describe several astrophysical applications. By including self-gravity, gas pressure and shocks, our isothermal self-similar void (ISSV) model is adaptable to various astrophysical systems such as planetary nebulae, hot bubbles and superbubbles in the interstellar medium as well as supernova remnants.Comment: 24 pages, 13 figuers, accepted by ApS

Dynamic Evolution of a Quasi-Spherical General Polytropic Magnetofluid with Self-Gravity

In various astrophysical contexts, we analyze self-similar behaviours of magnetohydrodynamic (MHD) evolution of a quasi-spherical polytropic magnetized gas under self-gravity with the specific entropy conserved along streamlines. In particular, this MHD model analysis frees the scaling parameter $n$ in the conventional polytropic self-similar transformation from the constraint of $n+\gamma=2$ with $\gamma$ being the polytropic index and therefore substantially generalizes earlier analysis results on polytropic gas dynamics that has a constant specific entropy everywhere in space at all time. On the basis of the self-similar nonlinear MHD ordinary differential equations, we examine behaviours of the magnetosonic critical curves, the MHD shock conditions, and various asymptotic solutions. We then construct global semi-complete self-similar MHD solutions using a combination of analytical and numerical means and indicate plausible astrophysical applications of these magnetized flow solutions with or without MHD shocks.Comment: 21 pages, 7 figures, accepted for publication in APS

A new allele of acid soil tolerance gene from a malting barley variety

Background: Acid soil is a serious limitation to crop production all over the world. Toxic aluminium (Al) cations in acid soil inhibit root growth and reduce yield. Although a gene tolerant to acid soil has been identified, it has not been used in malting barley breeding, which is partly due to the acid soil tolerance gene being linked to unfavorable malting quality traits. Results: A Brazilian malting barley variety Br2 was identified as tolerant to acid soil. A doubled haploid (DH) population was developed from a cross between Br2 and the Australian acid-sensitive cultivar Hamelin. The DH population was tested for acid soil tolerance in native acid soil and a hydroponic system with pH 4.2, pH 4.2 + Al or pH 6.5, and genotyped using SSR, DArT and gene-specific markers. A single QTL was detected for all parameters related to acid soil tolerance. The QTL was mapped to the known HvMATE location on chromosome 4H. Sequence alignment of the HvMATE gene identified 13 INDELs and 87 SNPs, where one SNP coded for a single amino acid difference between the two varieties. A gene-specific marker was developed to detect the single nucleotide polymorphism between Hamelin and Br2. This marker co-segregated with aluminium tolerance and accounted for 79 % of phenotypic variation for acid soil tolerance. Conclusion: The present study identified a novel source of acid soil/Al tolerance from a Brazilian malting barley cultivar Br2. This variety tolerated Al toxicity but was sensitive to low pH which is similar to most other Al-tolerant varieties. A gene-specific marker Cit7 was developed based on the HvMATE gene sequence. Cit7 will improve the efficiency of molecular-assisted selection of new barley varieties with tolerance to acid soil. Multiple alleles exist for the acid soil tolerance gene on chromosome 4H, so a malting barley variety that tolerates acid soil could be developed by selecting suitable tolerant alleles. Tolerance to low pH may play an important role for barley to adapt to acid soils

Source Attributions of Pollution to the Western Arctic During the NASA ARCTAS Field Campaign

We use the NASA GEOS-5 transport model with tagged tracers to investigate the contributions of different regional sources of CO and black carbon (BC) to their concentrations in the Western Arctic (i.e., 50-90 deg N and 190- 320 deg E) in spring and summer 2008. The model is evaluated by comparing the results with airborne measurements of CO and BC from the NASA Arctic Research of the Composition of the Troposphere from Aircraft and Satellites (ARCTAS) field campaigns to demonstrate the strengths and limitations of our simulations. We also examine the reliability of tagged CO tracers in characterizing air mass origins using the measured fossil fuel tracer of dichloromethane and the biomass burning tracer of acetonitrile. Our tagged CO simulations suggest that most of the enhanced CO concentrations (above background level from CH4 production) observed during April originate from Asian anthropogenic emissions. Boreal biomass burning emissions and Asian anthropogenic emissions are of similar importance in July domain wise, although the biomass burning CO fraction is much larger in the area of the ARCTAS field experiments. The fraction of CO from Asian anthropogenic emissions is larger in spring than in summer. European sources make up no more than 10% of CO levels in the campaign domain during either period. Comparisons of CO concentrations along the flight tracks with regional averages from GEOS-5 show that the alongtrack measurements are representative of the concentrations within the large domain of the Western Arctic in April but not in July