Evidence for a Functional Interaction between Integrins and G Protein-activated Inward Rectifier K+ Channels

Heteromultimeric G protein-activated inward rectifier K+ (GIRK) channels, abundant in heart and brain, help to determine the cellular membrane potential as well as the frequency and duration of electrical impulses. The sequence arginine-glycine-aspartate (RGD), located extracellularly between the first membrane-spanning region and the pore, is conserved among all identified GIRK subunits but is not found in the extracellular domain of any other cloned K+ channels. Many integrins, which, like channels, are integral membrane proteins, recognize this RGD sequence on other proteins, usually in the extracellular matrix. We therefore asked whether GIRK activity might be regulated by direct interaction with integrin. Here, we present evidence that mutation of the RGD site to RGE, particularly on the GIRK4 subunit, decreases or abolishes GIRK current. Furthermore, wild-type channels can be co-immunoprecipitated with integrin. The total cellular amount of expressed mutant GIRK channel protein is the same as the wild-type protein; however, the amount of mutant channel protein that localizes to the plasma membrane is decreased relative to wild-type, most likely accounting for the diminished GIRK current detected. GIRK channels appear to bind directly to integrin and to require this interaction for proper GIRK channel membrane localization and function

Gain-of-Function Mutation W493R in the Epithelial Sodium Channel Allosterically Reconfigures Intersubunit Coupling

Sodium absorption in epithelial cells is rate-limited by the epithelial sodium channel (ENaC) activity in lung, kidney, and the distal colon. Pathophysiological conditions, such as cystic fibrosis and Liddle syndrome, result from water-electrolyte imbalance partly due to malfunction of ENaC regulation. Because the quaternary structure of ENaC is yet undetermined, the bases of pathologically linked mutations in ENaC subunits α, β, and γ are largely unknown. Here, we present a structural model of heterotetrameric ENaC α1βα2γ that is consistent with previous cross-linking results and site-directed mutagenesis experiments. By using this model, we show that the disease-causing mutation αW493R rewires structural dynamics of the intersubunit interfaces α1β and α2γ. Changes in dynamics can allosterically propagate to the channel gate. We demonstrate that cleavage of the γ-subunit, which is critical for full channel activation, does not mediate activation of ENaC by αW493R. Our molecular dynamics simulations led us to identify a channel-activating electrostatic interaction between α2Arg-493 and γGlu-348 at the α2γ interface. By neutralizing a sodium-binding acidic patch at the α1β interface, we reduced ENaC activation of αW493R by more than 2-fold. By combining homology modeling, molecular dynamics, cysteine cross-linking, and voltage clamp experiments, we propose a dynamics-driven model for the gain-of-function in ENaC by αW493R. Our integrated computational and experimental approach advances our understanding of structure, dynamics, and function of ENaC in its disease-causing state

Interference Mitigation for the GPS Receiver Utilizing the Cyclic Spectral Analysis and RR-MSWF Algorithm

A method utilizing the cyclic spectral analysis (CSA) and reduced-rank multistage Wiener filtering (RR-MSWF) algorithm to mitigate the interference for the GPS receiver is proposed. In many cases, interference from adjacent channel or from cochannel overlaps on the weak global positioning system (GPS) signal in both time and frequency domains, and it is hard to mitigate this kind of strong interference with the conventional filtering techniques. While with the proposed method given in the paper, we can mitigate the interference effectively. The general process of the proposed method is that first we get the cyclic frequencies (CFs) of the strong interference by CSA of the received GPS signal. And then with the obtained CFs of the interference, we use the blind adaptive frequency shift (BA-FRESH) filter to get the principal process of mitigating the strong interference and separating the weak GPS signal. Finally by utilizing the efficient RR-MSWF algorithm to implement the BA-FRESH filtering, we can mitigate the strong interference effectively and hence improve the performance of the GPS receiver

New Family of Robust 2D Topological Insulators in van der Waals Heterostructures

We predict a new family of robust two-dimensional (2D) topological insulators in van der Waals heterostructures comprising graphene and chalcogenides BiTeX (X=Cl, Br and I). The layered structures of both constituent materials produce a naturally smooth interface that is conducive to proximity induced new topological states. First principles calculations reveal intrinsic topologically nontrivial bulk energy gaps as large as 70-80 meV, which can be further enhanced up to 120 meV by compression. The strong spin-orbit coupling in BiTeX has a significant influence on the graphene Dirac states, resulting in the topologically nontrivial band structure, which is confirmed by calculated nontrivial Z2 index and an explicit demonstration of metallic edge states. Such heterostructures offer an unique Dirac transport system that combines the 2D Dirac states from graphene and 1D Dirac edge states from the topological insulator, and it offers new ideas for innovative device designs

Multistage Random Growing Small-World Networks with Power-law degree Distribution

In this paper, a simply rule that generates scale-free networks with very large clustering coefficient and very small average distance is presented. These networks are called {\bf Multistage Random Growing Networks}(MRGN) as the adding process of a new node to the network is composed of two stages. The analytic results of power-law exponent $\gamma=3$ and clustering coefficient $C=0.81$ are obtained, which agree with the simulation results approximately. In addition, the average distance of the networks increases logarithmical with the number of the network vertices is proved analytically. Since many real-life networks are both scale-free and small-world networks, MRGN may perform well in mimicking reality.Comment: 3 figures, 4 page

Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH Mutations in Glioblastoma

Isocitrate dehydrogenases (IDHs) catalyse oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). IDH1 functions in the cytosol and peroxisomes, whereas IDH2 and IDH3 are both localized in the mitochondria. Heterozygous somatic mutations in IDH1 occur at codon 132 in 70% of grade II–III gliomas and secondary glioblastomas (GBMs), and in 5% of primary GBMs. Mutations in IDH2 at codon 172 are present in grade II–III gliomas at a low frequency. IDH1 and IDH2 mutations cause both loss of normal enzyme function and gain-of-function, causing reduction of α-KG to D-2-hydroxyglutarate (D-2HG) which accumulates. Excess hydroxyglutarate (2HG) can also be caused by germline mutations in D- and L-2-hydroxyglutarate dehydrogenases (D2HGDH and L2HGDH). If loss of IDH function is critical for tumourigenesis, we might expect some tumours to acquire somatic IDH3 mutations. Alternatively, if 2HG accumulation is critical, some tumours might acquire somatic D2HGDH or L2HGDH mutations. We therefore screened 47 glioblastoma samples looking for changes in these genes. Although IDH1 R132H was identified in 12% of samples, no mutations were identified in any of the other genes. This suggests that mutations in IDH3, D2HGDH and L2HGDH do not occur at an appreciable frequency in GBM. One explanation is simply that mono-allelic IDH1 and IDH2 mutations occur more frequently by chance than the bi-allelic mutations expected at IDH3, D2HGDH and L2HGDH. Alternatively, both loss of IDH function and 2HG accumulation might be required for tumourigenesis, and only IDH1 and IDH2 mutations have these dual effects

2-Hydroxyglutarate Production, but Not Dominant Negative Function, Is Conferred by Glioma-Derived NADP+-Dependent Isocitrate Dehydrogenase Mutations

Gliomas frequently contain mutations in the cytoplasmic NADP(+)-dependent isocitrate dehydrogenase (IDH1) or the mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2). Several different amino acid substitutions recur at either IDH1 R132 or IDH2 R172 in glioma patients. Genetic evidence indicates that these mutations share a common gain of function, but it is unclear whether the shared function is dominant negative activity, neomorphic production of (R)-2-hydroxyglutarate (2HG), or both.We show by coprecipitation that five cancer-derived IDH1 R132 mutants bind IDH1-WT but that three cancer-derived IDH2 R172 mutants exert minimal binding to IDH2-WT. None of the mutants dominant-negatively lower isocitrate dehydrogenase activity at physiological (40 µM) isocitrate concentrations in mammalian cell lysates. In contrast to this, all of these mutants confer 10- to 100-fold higher 2HG production to cells, and glioma tissues containing IDH1 R132 or IDH2 R172 mutations contain high levels of 2HG compared to glioma tissues without IDH mutations (54.4 vs. 0.1 mg 2HG/g protein).Binding to, or dominant inhibition of, WT IDH1 or IDH2 is not a shared feature of the IDH1 and IDH2 mutations, and thus is not likely to be important in cancer. The fact that the gain of the enzymatic activity to produce 2HG is a shared feature of the IDH1 and IDH2 mutations suggests that this is an important function for these mutants in driving cancer pathogenesis

Nutrient intakes of rural Tibetan mothers: a cross-sectional survey

<p>Abstract</p> <p>Background</p> <p>Tibetan food intake is influenced by the region's high altitude and unique culture. Few published studies of nutrient intakes among Tibetan women are available. The present study of Tibetan mothers with young children explores dietary patterns, nutrient intakes, and differences between socio-demographic groups.</p> <p>Methods</p> <p>A cross-sectional survey of 386 women with a child aged less than 24 months was conducted in rural areas surrounding Lhasa, Tibet. All participants were recruited using simple random sampling and were interviewed face-to-face by trained investigators. Dietary information was collected via a food frequency questionnaire. Nutrient intakes were calculated using food composition tables. Non-parametric tests were used to compare nutrient intakes according to socio-demographic variables, and to compare results with the <it>2002 Chinese National Nutrition and Health Survey </it>(2002 NNHS) and dietary reference intakes (DRIs).</p> <p>Results</p> <p>Median intakes of energy (<it>p </it>< 0.001), protein (<it>p </it>< 0.001), fat (<it>p </it>< 0.001), vitamin A (<it>p </it>< 0.001), vitamin B1 (<it>p </it>< 0.001), vitamin B2 (<it>p </it>< 0.001), vitamin C (<it>p </it>< 0.001), and vitamin E (<it>p </it>< 0.001) were lower than the average levels reported in 2002 NNHS. The median intakes of calcium (517 mg/d, <it>p </it>< 0.001), iron (35 mg/d, <it>p </it>< 0.001), and zinc (17.3 mg/d, <it>p </it>< 0.001) were higher than the average levels in 2002 NNHS. The highest education subgroup had significantly higher intakes of vitamins A and C than the lowest education subgroup.</p> <p>Conclusion</p> <p>Although the diet of Tibetan mothers with young children has been partially influenced by other factors, their dietary patterns are still mostly composed of Tibetan traditional foods. Compared with the 2002 NNHS, Tibetan women with young children appear to have insufficient intakes of many nutrients, which will affect their nutritional status.</p