Three mutations in SASH1 cause the pathogenesis of dyschromatosis universalis hereditaria (DUH)

Dyschromatosis universalis hereditaria (DUH) is a rare genodermatosis characterized by hyper- and hypopigmented macules which form a reticulate or mottled pattern. The causal gene and the precise pathogenesis of DUH have been unclear since the disease was initially reported in 1933. However, we found three heterozygous mutations encoding amino acid substitutions in SASH1 in each of three nonconsanguineous DUH families. Immunohistochemistry and melanin staining showed distribution heterogenicity of melanocytes, predominantly melanized melanocytes in the epidermal tissues of a DUH patient. Specifically, we identified that mutations of SASH1 can up-regulate resident melanogenic proteins, transport proteins of melanosome, and induce increased mobility of melanocytes in vitro and in vivo. Furthermore, SASH1 was shown to interact with several proteins associated with melanogenesis in the MAPK signaling pathway and the endothelin signaling pathway, indicating an additional melanogenesis signaling pathway in the regulation of melanin biosynthesis. Collectively, these observations suggest that DUH is a heterogeneous disorder of increased production and transport of melanosomes caused by SASH1 mutation together with melanocyte maldistribution

The association between GAD1 gene polymorphisms and cerebral palsy in Chinese infants

Studies suggest that GAD1 gene was a functional candidate susceptibility gene for cerebral palsy (CP). In order to investigate the contribution of GAD1 gene to the etiology of CP in Chinese infants, we carried out a case-control association study between GAD1 gene and CP. In this study, 374 health controls and 392 infants with CP were recruited. Genomic DNA was extracted from venous blood and all three single nucleotide polymorphisms in GAD1 (rs3791874, rs3791862 and rs16858977) were genotyped by Sequenom’s MassARRAY system. There were no significant differences in allele or genotype frequencies between CP or mixed CP patients and controls at any of the three genetic polymorphisms. Through haplotype analysis we found that haplotype GG (rs3791862, rs16858977) frequency demonstrated significantly statistical difference between mixed CP patients and controls (p= 0.0371). Our positive findings of haplotype GG suggested that variation of GAD1 gene was an important risk factor for mixed CP.Предполагается, что ген GAD1 является функциональным кандидатом на роль гена подверженности церебральному параличу (ЦП). Для исследования вклада гена GAD1 в этиологию ЦП у китайских детей методом случай – контроль проведено исследование ассоциации между наличием гена GAD1 и ЦП. В исследовании были задействованы 374 здоровых ребенка (контроль) и 392 ребенка с ЦП. Геномную ДНК выделяли из венозной крови, и все три единичных нуклеотидных полиморфизма гена GAD1 (rs3791874, rs3791862 и rs16858977) были генотипированы в системе Sequenom MassARRAY. Ни для одного из трех генетических полиморфизмов не обнаружено существенных различий в частотах аллелей или генотипов между больными ЦП или смешанными больными ЦП и контролем. Анализ гаплотипов показал существенные статистические различия в частоте гаплотипа GG (rs3791862, rs16858977) у смешанных больных ЦП и контрольной группы (p = 0.0371). Позитивный результат по гаплотипу GG свидетельствует о том, что вариация гена GAD1 является важным фактором риска для смешанного ЦП

Targeting the metabolic profile of amino acids to identify the key metabolic characteristics in cerebral palsy

BackgroundCerebral palsy (CP) is a neurodevelopmental disorder characterized by motor impairment. In this study, we aimed to describe the characteristics of amino acids (AA) in the plasma of children with CP and identify AA that could play a potential role in the auxiliary diagnosis and treatment of CP.MethodsUsing high performance liquid chromatography, we performed metabolomics analysis of AA in plasma from 62 CP children and 60 healthy controls. Univariate and multivariate analyses were then applied to characterize different AA. AA markers associated with CP were then identified by machine learning based on the Lasso regression model for the validation of intra-sample interactions. Next, we calculated a discriminant formula and generated a receiver operating characteristic (ROC) curve based on the marker combination in the discriminant diagnostic model.ResultsA total of 33 AA were detected in the plasma of CP children and controls. Compared with controls, 5, 7, and 10 different AA were identified in total participants, premature infants, and full-term infants, respectively. Of these, β-amino-isobutyric acid [p = 2.9*10(−4), Fold change (FC) = 0.76, Variable importance of protection (VIP) = 1.75], tryptophan [p = 5.4*10(−4), FC = 0.87, VIP = 2.22], and asparagine [p = 3.6*10(−3), FC = 0.82, VIP = 1.64], were significantly lower in the three groups of CP patients than that in controls. The combination of β-amino-isobutyric acid, tryptophan, and taurine, provided high levels of diagnostic classification and risk prediction efficacy for preterm children with an area under the curve (AUC) value of 0.8741 [95% confidence interval (CI): 0.7322–1.000]. The discriminant diagnostic formula for preterm infant with CP based on the potential marker combination was defined by p = 1/(1 + e−(8.295–0.3848* BAIBA-0.1120*Trp + 0.0108*Tau)).ConclusionFull-spectrum analysis of amino acid metabolomics revealed a distinct profile in CP, including reductions in the levels of β-amino-isobutyric acid, tryptophan, and taurine. Our findings shed new light on the pathogenesis and diagnosis of premature infants with CP

Simultaneous optical and radar observations of poleward moving auroral forms under different IMF conditions

Using high temporal resolution optical data obtained from three-wavelength all-sky imagers at Chinese Yellow River Station in the Arctic, together with the EISCAT Svalbard radar (ESR) and SuperDARN radars, we investigated the dayside poleward moving auroral forms (PMAFs) and the associated plasma features in the polar ionosphere under different interplanetary magnetic field (IMF) conditions, between 0900 and 1010 UT on 22 December 2003. Simultaneous optical and ESR observations revealed that all PMAFs were clearly associated with pulsed particle precipitations. During northward IMF, particles can precipitate into lower altitudes and reach the ionospheric E-region, and there is a reverse convection cell associated with these PMAFs. This cell is one of the typical signatures of the dayside high-latitude (lobe) reconnection in the polar ionosphere. These results indicate that the PMAFs were associated with the high-latitude reconnection. During southward IMF, the PMAFs show larger latitudinal motion, indicating a longer mean lifetime, and the associated ionospheric features indicate that the PMAFs were generated by the dayside low-latitude reconnection

SePreSA: a server for the prediction of populations susceptible to serious adverse drug reactions implementing the methodology of a chemical–protein interactome

Serious adverse drug reactions (SADRs) are caused by unexpected drug–human protein interactions, and some polymorphisms within binding pockets make the population carrying these polymorphisms susceptible to SADR. Predicting which populations are likely to be susceptible to SADR will not only strengthen drug safety, but will also assist enterprises to adjust R&D and marketing strategies. Making such predictions has recently been facilitated by the introduction of a web server named SePreSA. The server has a comprehensive collection of the structural models of nearly all the well known SADR targets. Once a drug molecule is submitted, the scale of its potential interaction with multi-SADR targets is calculated using the DOCK program. The server utilizes a 2-directional Z-transformation scoring algorithm, which computes the relative drug–protein interaction strength based on the docking-score matrix of a chemical–protein interactome, thus achieve greater accuracy in prioritizing SADR targets than simply using dock scoring functions. The server also suggests the binding pattern of the lowest docking score through 3D visualization, by highlighting and visualizing amino acid residues involved in the binding on the customer's browser. Polymorphism information for different populations for each of the interactive residues will be displayed, helping users to deduce the population-specific susceptibility of their drug molecule. The server is freely available at http://SePreSA.Bio-X.cn/

Mutations in TUBB8 and Human Oocyte Meiotic Arrest

BACKGROUND Human reproduction depends on the fusion of a mature oocyte with a sperm cell to form a fertilized egg. The genetic events that lead to the arrest of human oocyte maturation are unknown. METHODS We sequenced the exomes of five members of a four-generation family, three of whom had infertility due to oocyte meiosis I arrest. We performed Sanger sequencing of a candidate gene, TUBB8, in DNA samples from these members, additional family members, and members of 23 other affected families. The expression of TUBB8 and all other β-tubulin isotypes was assessed in human oocytes, early embryos, sperm cells, and several somatic tissues by means of a quantitative reverse- transcriptase–polymerase-chain-reaction assay. We evaluated the effect of the TUBB8 mutations on the assembly of the heterodimer consisting of one α-tubulin polypeptide and one β-tubulin polypeptide (α/β-tubulin heterodimer) in vitro, on microtubule architecture in HeLa cells, on microtubule dynamics in yeast cells, and on spindle assembly in mouse and human oocytes. RESULTS We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families. TUBB8 expression is unique to oocytes and the early embryo, in which this gene accounts for almost all the expressed β-tubulin. The mutations affect chaperone-dependent folding and assembly of the α/β-tubulin heterodimer, disrupt microtubule behavior on expression in cultured cells, alter microtubule dynamics in vivo, and cause catastrophic spindle-assembly defects and maturation arrest on expression in mouse and human oocytes. CONCLUSIONS TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility. (Funded by the National Basic Research Program of China and others.

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

A Long Short-Term Memory Network for Plasma Diagnosis from Langmuir Probe Data

Electrostatic probe diagnosis is the main method of plasma diagnosis. However, the traditional diagnosis theory is affected by many factors, and it is difficult to obtain accurate diagnosis results. In this study, a long short-term memory (LSTM) approach is used for plasma probe diagnosis to derive electron density (Ne) and temperature (Te) more accurately and quickly. The LSTM network uses the data collected by Langmuir probes as input to eliminate the influence of the discharge device on the diagnosis that can be applied to a variety of discharge environments and even space ionospheric diagnosis. In the high-vacuum gas discharge environment, the Langmuir probe is used to obtain current–voltage (I–V) characteristic curves under different Ne and Te. A part of the data input network is selected for training, the other part of the data is used as the test set to test the network, and the parameters are adjusted to make the network obtain better prediction results. Two indexes, namely, mean squared error (MSE) and mean absolute percentage error (MAPE), are evaluated to calculate the prediction accuracy. The results show that using LSTM to diagnose plasma can reduce the impact of probe surface contamination on the traditional diagnosis methods and can accurately diagnose the underdense plasma. In addition, compared with Te, the Ne diagnosis result output by LSTM is more accurate