Frequent mutation of hypoxia-related genes in persistent pulmonary hypertension of the newborn

AIMS: Persistent pulmonary hypertension of the newborn (PPHN) is characterized by sustained high levels of pulmonary vascular resistance after birth with etiology unclear; Arterial blood oxygen saturation of Tibetan newborns at high latitudes is higher than that of Han newborns at low latitudes, suggesting that genetic adaptation may allow sufficient oxygen to confer Tibetan populations with resistance to pulmonary hypertension; We have previously identified genetic factors related to PPHN through candidate gene sequencing; In this study, we first performed whole exome sequencing in PPHN patients to screen for genetic-related factors. METHODS AND RESULTS: In this two-phase genetic study, we first sequenced the whole exome of 20 Tibetan PPHN patients and compared it with the published genome sequences of 50 healthy high-altitude Tibetanshypoxia-related genes, a total of 166 PPHN-related variants were found, of which 49% were from 43 hypoxia-related genes; considering many studies have shown that the differences in the genetic background between Tibet and Han are characterized by hypoxia-related genetic polymorphisms, so it is necessary to further verify whether the association between hypoxia-related variants and PPHN is independent of high-altitude life. During the validation phase, 237 hypoxia-related genes were sequenced in another 80 Han PPHN patients living in low altitude areas, including genes at the discovery stage and known hypoxia tolerance, of which 413 variants from 127 of these genes were shown to be significantly associated with PPHN.hypoxia-related genes. CONCLUSIONS: Our results indicates that the association of hypoxia-related genes with PPHN does not depend on high-altitude life, at the same time, 21 rare mutations associated with PPHN were also found, including three rare variants of the tubulin tyrosine ligase-like family member 3 gene (TTLL3:p.E317K, TTLL3:p.P777S) and the integrin subunit alpha M gene (ITGAM:p.E1071D). These novel findings provide important information on the genetic basis of PPHN

ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function mechanism.

It is unclear whether mutations in fused in sarcoma (FUS) cause familial amyotrophic lateral sclerosis via a loss-of-function effect due to titrating FUS from the nucleus or a gain-of-function effect from cytoplasmic overabundance. To investigate this question, we generated a series of independent Caenorhabditis elegans lines expressing mutant or wild-type (WT) human FUS. We show that mutant FUS, but not WT-FUS, causes cytoplasmic mislocalization associated with progressive motor dysfunction and reduced lifespan. The severity of the mutant phenotype in C. elegans was directly correlated with the severity of the illness caused by the same mutation in humans, arguing that this model closely replicates key features of the human illness. Importantly, the mutant phenotype could not be rescued by overexpression of WT-FUS, even though WT-FUS had physiological intracellular localization, and was not recruited to the cytoplasmic mutant FUS aggregates. Our data suggest that FUS mutants cause neuronal dysfunction by a dominant gain-of-function effect related either to neurotoxic aggregates of mutant FUS in the cytoplasm or to dysfunction in its RNA-binding functions

Identification of Putative Genes Involved in Limonoids Biosynthesis in Citrus by Comparative Transcriptomic Analysis

Limonoids produced by citrus are a group of highly bioactive secondary metabolites which provide health benefits for humans. Currently there is a lack of information derived from research on the genetic mechanisms controlling the biosynthesis of limonoids, which has limited the improvement of citrus for high production of limonoids. In this study, the transcriptome sequences of leaves, phloems and seeds of pummelo (Citrus grandis (L.) Osbeck) at different development stages with variances in limonoids contents were used for digital gene expression profiling analysis in order to identify the genes corresponding to the biosynthesis of limonoids. Pair-wise comparison of transcriptional profiles between different tissues identified 924 differentially expressed genes commonly shared between them. Expression pattern analysis suggested that 382 genes from three conjunctive groups of K-means clustering could be possibly related to the biosynthesis of limonoids. Correlation analysis with the samples from different genotypes, and different developing tissues of the citrus revealed that the expression of 15 candidate genes were highly correlated with the contents of limonoids. Among them, the cytochrome P450s (CYP450s) and transcriptional factor MYB demonstrated significantly high correlation coefficients, which indicated the importance of those genes on the biosynthesis of limonoids. CiOSC gene encoding the critical enzyme oxidosqualene cyclase (OSC) for biosynthesis of the precursor of triterpene scaffolds was found positively corresponding to the accumulation of limonoids during the development of seeds. Suppressing the expression of CiOSC with VIGS (Virus-induced gene silencing) demonstrated that the level of gene silencing was significantly correlated to the reduction of limonoids contents. The results indicated that the CiOSC gene plays a pivotal role in biosynthesis of limonoids

Anthropogenic Effects on Hydrogeochemical Characterization of the Shallow Groundwater in an Arid Irrigated Plain in Northwestern China

Many irrigated plains in arid and semi-arid regions have groundwater quality issues due to both intensive human activity and natural processes. Comprehensive studies are urgently needed to explore hydrogeochemical evolutions, investigate possible pollution sources, and understand the controls on groundwater compositions in such regions. Here, we combine geostatistical techniques and hydrogeochemical assessments to characterize groundwater quality over time in the Yinchuan Plain (a typical irrigated plain in China), using 12 physicochemical variables derived from sampling in 600 and 602 wells in 2004 and 2014, respectively. Our results show that groundwater-rock interactions and evaporation are the key natural factors controlling groundwater compositions. Hydrogeochemical water types in both 2004 and 2014 were Ca-HCO3, Na-Cl, and mixed Ca·Mg-Cl. Along with the hydrogeochemical compositions, we used ionic ratios and the saturation index to delineate mineral solution reactions and weathering processes. Dissolution of gypsum, halite, fluorite, and mirabilite, along with silicate weathering and cation exchange, were identified in the study area. Our results indicated rising ion concentrations in groundwater, which could be the result of anthropogenic influences. Increasing total hardness and nitrates over the study period were most likely caused by agricultural activity and the discharge of waste water from human residential areas

Prevalence, demographics, and cognitive dysfunction among methamphetamine-dependent individuals with childhood maltreatment

Previous studies have shown that dependent individuals (DIs) have higher rates of childhood maltreatment and poorer cognitive performance compared with healthy controls. However, little attention has been paid to the cognitive dysfunction of DIs with childhood maltreatment. The purpose of this study was to explore the cognitive deficits of maltreated methamphetamine-dependent individuals (METH-DIs) using a cross-sectional and case -control design. In addition, we aimed to examine the prevalence of childhood maltreatment and the demographic and clinical characteristics of Chinese male METH-DIs. 330 METH-DIs and 143 healthy controls were recruited and completed a detailed questionnaire on demographic and drug-related variables. Childhood abuse data were collected from the Childhood Trauma Questionnaire-Short Form (CTQ-SF). Cognitive function was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The Beck Depression Inventory, Beck Anxiety Inventory, and Visual Analogue Scale (VAS) were used to assess the clinical state of the METH-DIs. 166 of 326 (50.9%) METH-DIs had experienced at least one type of childhood maltreatment. Maltreated METH-DIs were more likely to have a lower level of education (t(324) = 5.81, p < 0.001), a higher level of depression(t(324) =-2.68, p < 0.01), and a younger onset age of drug use (t(324) = 3.58, p < 0.01) than METH-DIs who had no experience of childhood maltreatment. Maltreated METH-DIs also performed worse on the RBANS attention score than METH-DIs who did not experience maltreatment (F-1,F-324 = 15.41, p < 0.001, partial eta(2) = 0.05). Our findings revealed that some demographic and clinical variables were associated with maltreatment among METH-DIs. Moreover, attention dysfunction was found in maltreated METH-DIs, which conforms to the theory of latent vulnerability

ALS mutations in FUS causes neuronal dysfunction and death in C. elegans by a dominant gainof-function mechanism. Hum Mol Genet

It is unclear whether mutations in fused in sarcoma (FUS) cause familial amyotrophic lateral sclerosis via a loss-of-function effect due to titrating FUS from the nucleus or a gain-of-function effect from cytoplasmic overabundance. To investigate this question, we generated a series of independent Caenorhabditis elegans lines expressing mutant or wild-type (WT) human FUS. We show that mutant FUS, but not WT-FUS, causes cytoplasmic mislocalization associated with progressive motor dysfunction and reduced lifespan. The severity of the mutant phenotype in C. elegans was directly correlated with the severity of the illness caused by the same mutation in humans, arguing that this model closely replicates key features of the human illness. Importantly, the mutant phenotype could not be rescued by overexpression of WT-FUS, even though WT-FUS had physiological intracellular localization, and was not recruited to the cytoplasmic mutant FUS aggregates. Our data suggest that FUS mutants cause neuronal dysfunction by a dominant gain-of-function effect related either to neurotoxic aggregates of mutant FUS in the cytoplasm or to dysfunction in its RNA-binding functions