Spatiotemporal dynamics, community assembly and functional potential of sedimentary archaea in reservoirs: coaction of stochasticity and nutrient load.

Archaea participate in biogeochemical cycles in aquatic ecosystems, and deciphering their community dynamics and assembly mechanisms is key to understanding their ecological functions. Here, sediments from 12 selected reservoirs from the Wujiang and Pearl River basins in southwest China were investigated using 16S rRNA Illumina sequencing and quantitative PCR for archaeal abundance and richness in all seasons. Generally, archaeal abundance and α-diversity were significantly correlated with temperature; however, ß-diversity analysis showed that community structures varied greatly among locations rather than seasons, indicating a distance-decay pattern with geographical variation. The null model revealed the major contribution of stochasticity to archaeal community assembly, which was further confirmed by the neutral community model that could explain 71.7% and 90.2% of the variance in archaeal assembly in the Wujiang and Pearl River basins, respectively. Moreover, sediment total nitrogen and organic carbon levels were significantly correlated with archaeal abundance and α-diversity. Interestingly, these nutrient levels were positively and negatively correlated, respectively, with the abundance of methanogenic and ammonia-oxidized archaea: the dominant sedimentary archaea in these reservoirs. Taken together, this work systematically characterized archaeal community profiles in reservoir sediments and demonstrated the combined action of stochastic processes and nutrient load in shaping archaeal communities in reservoir ecosystems.

The mutation spectrum of Parkinson-disease-related genes in early-onset Parkinson's disease in ethnic Chinese.

BACKGROUND AND PURPOSE: Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD-related genes and determine the mutational spectrum of early-onset PD in ethnic Chinese. METHODS: In this study, whole-exome sequencing and/or gene dosage analysis were performed in 704 early-onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty-six PD-related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed. RESULTS: Eighty-two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD-related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi-allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein-truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late-onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction. CONCLUSIONS: Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD.

Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.

Association Analysis of WNT3, HLA-DRB5 and IL1R2 Polymorphisms in Chinese Patients With Parkinson's Disease and Multiple System Atrophy.

Background: The association between inflammation and neurodegeneration has long been observed in parkinson's disease (PD) and multiple system atrophy (MSA). Previous genome-wide association studies (GWAS) and meta-analyses have identified several risk loci in inflammation-associated genes associated with PD. Objective: To investigate whether polymorphisms in some inflammation-associated genes could modulate the risk of developing PD and MSA in a Southwest Chinese population. Methods: A total of 2,706 Chinese subjects comprising 1340 PD, 483 MSA and 883 healthy controls were recruited in the study. Three polymorphisms (rs2074404 GG/GT/TT, rs17425622 CC/CT/TT, rs34043159 CC/CT/TT) in genes linked to inflammation in all the subjects were genotyped by using the Sequenom iPLEX Assay. Results: The allele G of WNT3 rs2074404 can increase risk on PD (OR: 1.048, 95% CI: 1.182-1.333, p = 0.006), exclusively in the LOPD subgroup (OR: 1.166, 95% CI:1.025-1.327, p = 0.019), but not in EOPD or MSA. And the recessive model analysis also demonstrated an increased PD risk in GG genotype of this locus (OR = 1.331, p = 0.007). However, no significant differences were observed in the genotype distributions and alleles of HLA-DRB5 rs17425622 and IL1R2 rs34043159 between the PD patients and controls, between the MSA patients and controls, or between subgroups of PD or MSA and controls. Conclusion: Our results suggested the allele G of WNT3 rs2074404 have an adverse effect on PD and particularly, on the LOPD subgroup among a Chinese population.

Design, Synthesis, and Evaluation of Small Molecule Gαq/11 Protein Inhibitors for the Treatment of Uveal Melanoma.

Uveal melanoma is the ocular malignancy and mainly driven by oncogenic mutations of Gαq/11 proteins. Previous targeted therapy for melanoma treatment was limited to specific downstream signaling pathway, and inhibiting the "molecular switches" G proteins for melanoma treatment therapy was rarely described. We herein report the discovery of imidazopiperazine derivatives as Gαq/11 protein inhibitors. The most promising compound GQ127 showed good efficacy and safety in inositol monophosphate (IP1) assay by directly inhibiting Gαq/11 proteins. GQ127 induced uveal melanoma cells apoptosis and displayed potent antitumor activities in uveal melanoma cells viability, migration, and invasion. The effects of GQ127 on Gαq/11 signaling pathway were confirmed by analyzing the downstream effectors yes-associated protein (YAP) and extracellular signal-regulated kinase (ERK). More importantly, GQ127 significantly suppressed UM xenograft growth in mouse model without severe toxicity at the testing dose. These findings provide a lead compound that directly targets the Gαq/11 proteins for uveal melanoma treatment.

Genetic Analysis of ZNF Protein Family Members for Early-Onset Parkinson's Disease in Chinese Population.

Functional and genetic studies have identified association between several Zinc finger (ZNF) proteins and Parkinson's disease (PD). However, most of them were still awaiting further replications, especially in the Asian population. Here, we systematically selected PD-relevant ZNF genes and analyzed the genetic associations between these ZNFs and PD in a large Chinese PD cohort. We identified rare variants (minor allele frequency < 0.01) in 743 unrelated patients with early-onset PD (EOPD, age at onset < 50 years) using whole exome sequencing and evaluated the association between rare variants and EOPD at both allele and gene levels. Totally 91 rare variants were identified in ZNF746, ZNF646, ZNF184, ZNF165, ZND219, and GLIS1. One variant p.R373H in ZNF219 and two variants p.G161D and p.R158H in ZNF746 were significantly associated with EOPD, and gene-based burden analysis showed enrichment of rare variants of ZNF746 in EOPD. Our findings build up the connection between ZNF746 and PD from a genetic perspective for the first time, supplement current understanding for the genetic role of ZNFs in EOPD, and broaden the mutation spectrum in PD.

Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies.

Src homology containing protein tyrosine phosphatase 2 (SHP2) represents a noteworthy target for various diseases, serving as a well-known oncogenic phosphatase in cancers. As a result of the low cell permeability and poor bioavailability, the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy. Recently, a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified. In particular, few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors. This review summarizes the development and structure-activity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies, with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity, higher oral bioavailability and better physicochemical properties.

Organocatalytic Asymmetric Synthesis of Benzothiazolopyrimidines via [4 + 2] Cyclization of 2-Benzothiazolimines and Aldehydes.

We report the direct asymmetric synthesis of pyrimido[2,1-b]benzothiazoles using a commercially available chiral amine catalyst. A variety of 2-benzothiazolimines and aldehydes were well tolerated under the reaction conditions and generated the corresponding products in 81-99% yields with excellent diastereoselectivities and enantioselectivities (up to >20:1 dr, 99% ee). Furthermore, the products could be easily converted to other useful chiral building blocks.

Creatine kinase in the diagnosis and prognostic prediction of amyotrophic lateral sclerosis: a retrospective case-control study.

Creatine kinase is a muscle enzyme that has been reported at various levels in different studies involving patients with amyotrophic lateral sclerosis. In the present retrospective case-control study, we included 582 patients with amyotrophic lateral sclerosis and 582 age- and sex-matched healthy controls. All amyotrophic lateral sclerosis participants received treatment in the Department of Neurology, West China Hospital, China, between May 2008 and December 2018. Serum creatine kinase levels in patients with amyotrophic lateral sclerosis were significantly higher than those in healthy controls. Subgroup analysis revealed that serum creatine kinase levels in men were higher than those in women in both amyotrophic lateral sclerosis patients and healthy controls. Compared with patients with bulbar-onset amyotrophic lateral sclerosis, patients with limb-onset amyotrophic lateral sclerosis had higher creatine kinase levels. Spearman's correlation analysis revealed that serum creatine kinase levels were not correlated with body mass index, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, or progression rate. After adjusting for prognostic covariates, higher log creatine kinase values were correlated with higher overall survival in the amyotrophic lateral sclerosis patients. We also investigated the longitudinal changes in serum creatine kinase levels in 81 amyotrophic lateral sclerosis patients; serum creatine kinase levels were decreased at the second blood test, which was sampled at least 6 months after the first blood test. Together, our results suggest that serum creatine kinase levels can be used as an independent factor for predicting the prognosis of amyotrophic lateral sclerosis patients. This study received ethical approval from the Ethics Committee of West China Hospital, China (approval No. 2015(236)) on December 23, 2015.

Asymmetric Synthesis of Oxindole-Derived Vicinal Tetrasubstituted Acyclic Amino Acid Derivatives by the Mannich-Type Reaction.

The catalytic asymmetric Mannich-type reaction of 3-hydroxy/3-aminooxindoles with 2-aminoacrylates to afford oxindole-derived acyclic amino acid derivatives bearing vicinal tetrasubstituted stereocenters is reported. (DHQ)2PHAL (4g) and quinine-derived squaramide (4d) were identified as efficient catalysts. Transformations of the Mannich-type reaction products highlight the utility of this synthetic strategy.

Organocatalytic Asymmetric Three-Component Povarov Reactions of Anilines and Aldehydes.

We report the first highly enantio- and diastereoselective three-component Povarov reaction between anilines and aldehydes catalyzed by a chiral amine catalyst. A wide variety of substituted tetrahydroquinolines were obtained with moderate to good yields and excellent enantioselectivity and diastereoselectivity (up to 99% ee and >95:5 dr) under the reaction conditions. Furthermore, the reaction intermediates could be efficiently converted to other valuable building blocks.

Asymmetric Total Synthesis and Biological Evaluation of the Natural PDE4 Inhibitor Toddacoumalone.

We describe herein the first asymmetric total synthesis and biological evaluation of the natural PDE4 inhibitor toddacoumalone and its stereoisomers. The key step of the total synthesis is a formal asymmetric [4 + 2] cycloaddition reaction catalyzed by chiral secondary amine catalysts. A variety of pyranoquinolinones and 3-methylcrotonaldehyde are well tolerated under the optimized reaction conditions, which paved the way for further SAR studies. Further biological evaluation showed 1a' with the best PDE4 inhibitory activity (IC50 = 0.18 µM).

Water management impacts the soil microbial communities and total arsenic and methylated arsenicals in rice grains.

The bioavailability of the metalloid arsenic (As) in paddy soil is controlled by microbial cycling of As and other elements such as iron (Fe) and sulfur (S), which are strongly influenced by water management in paddy fields. In this study, we evaluated how water management affects As bioavailability by growing rice plants in a geogenic As-contaminated soil. We determined As speciation in soil porewater and the diversity of the associated microbial community. Continuous flooding enhanced the release of Fe and As and increased arsenite (As(III)) and methylated As species concentrations in the rice grain compared with aerobic treatment. Total inorganic and organic As in the grain was 84% and 81% lower, respectively, in the aerobic treatment compared with the continuous flooding treatment. The amounts of Fe(III)-reducing bacteria (FeRB) increased in the flooded rhizosphere soil. The abundance of FeRB in the soil correlated with the dissolution of Fe and As. Among the As-transformation genes quantified, the aioA gene for As(III) oxidation and arsM gene for As(III) methylation were most abundant. The arsM copy number correlated positively with the levels of dsrB (dissimilatory (bi) sulfite reductase ß-subunit), suggesting that dissimilatory sulfate-reducing bacteria (SRB) may play an important role in dimethylarsenate (DMAs(V)) production in soil. Our results show that decreased populations of rhizosphere FeRB and SRB contributed to a lower bioavailability of As, and decreased production of methylated arsenicals under oxic conditions.

Temporal and spatial impact of Spartina alterniflora invasion on methanogens community in Chongming Island, China.

Methane production by methanogens in wetland is recognized as a significant contributor to global warming. Spartina alterniflora (S. alterniflora), which is an invasion plant in China's wetland, was reported to have enormous effects on methane production. But studies on shifts in the methanogen community in response to S. alterniflora invasion at temporal and spatial scales in the initial invasion years are rare. Sediments derived from the invasive species S. alterniflora and the native species Phragmites australis (P. australis) in pairwise sites and an invasion chronosequence patch (4 years) were analyzed to investigate the abundance and community structure of methanogens using quantitative real-time PCR (qPCR) and Denaturing gradient gel electrophoresis (DGGE) cloning of the methyl-coenzyme M reductase A (mcrA) gene. For the pairwise sites, the abundance of methanogens in S. alterniflora soils was lower than that of P. australis soils. For the chronosequence patch, the abundance and diversity of methanogens was highest in the soil subjected to two years invasion, in which we detected some rare groups including Methanocellales and Methanococcales. These results indicated a priming effect at the initial invasion stages of S. alterniflora for microorganisms in the soil, which was also supported by the diverse root exudates. The shifts of methanogen communities after S. alterniflora invasion were due to changes in pH, salinity and sulfate. The results indicate that root exudates from S. alterniflora have a priming effect on methanogens in the initial years after invasion, and the predominate methylotrophic groups (Methanosarcinales) may adapt to the availability of diverse substrates and reflects the potential for high methane production after invasion by S. alterniflora.

Analysis of clinical risk factors in relapsed patients with class IV lupus nephritis.

The present study aimed to investigate risk factors for renal recurrence in patients with type IV lupus nephritis (LN). Univariate and multivariate analyses were conducted to using the Cox proportional hazard model and the Kaplan-Meier method. A total 244 patients were diagnosed with type IV LN; 100 (28.49%) relapsed and 144 (41.03%) recovered successfully. Kaplan-Meier method analysis indicated that patients with type IV LN affecting the digestive tract had high renal recurrence rates. Patients with hyperglobulinemia, positive anti-ribonucleoprotein and anti-Sjögren's syndrome type B (anti-SSB) antibodies, thrombus in the loop or non-inflammatory necrotizing vasculopathy also had a high recurrence rate. Furthermore, patients achieving partial remission had an increased recurrence rate compared with patients achieving complete remission. Patients undergoing maintenance treatment with glucocorticoids alone had a higher recurrence rate compared with patients who used alternative treatment schemes. Univariate and multivariate regression analyses by the Cox proportional hazard model determined that the effect of systemic lupus erythematosus in the gastrointestinal tract, increased serum globulin levels and positive anti-SSB antibody at onset were risk factors for the recurrence of LN type IV. The present study demonstrated that clinical risk factors of renal recurrence in patients with LN type IV include LN in the gastrointestinal tract, increased serum globulin levels, positive anti-SSB antibodies at onset and the use of glucocorticoid-only maintenance treatment.

The predominant phytoplankton of Pseudoanabaena holding specific biosynthesis gene-derived occurrence of 2-MIB in a drinking water reservoir.

With the increasing occurrence of water eutrophication and blooms, earthy-musty odor problems caused by cyanobacteria have been more and more apparent. These problems have a serious impact on aquatic ecosystems and drinking water safety and become one of the priorities of the water environment researches and managements. In the present study, genes associated with 2-MIB synthesis in cyanobacteria were studied by systematic investigation on molecular characterization and quantity of 2-MIB-producing cyanobacteria in China. Our results founded that Pseudoanabaena is an important 2-MIB-producing phytoplankton and predominant in summer in Qingcaosha reservoir, and the copy number of mic and 2-MIB concentration have strongly positive correlation. We also demonstrated that abundance of mic in water was significant correlation with that in sediment. These results will help us to understand the main taxa of the odoriferous cyanobacteria in the water bodies in China, understand the genetic basis of the odor substances in the cyanobacteria. Rapid, reliable monitoring and ecological research methods for the production of odor cyanobacteria in water bodies can be established based on these results.

The relationship between cell apoptosis dysfunction and FEN1 E160D mutation in lupus nephritis patients.

OBJECTIVE: This study aims to evaluate the role of FEN1 E160D mutation in lupus nephritis (LN) patients with cell apoptosis dysfunction. METHODS: (1) Cell apoptosis was detected from 50 paraffin samples obtained from renal biopsies of patients with Class IV LN by TUNEL method and the relationship of the systemic lupus erythematosus disease activity index 2000 (SLEDAI 2000) and renal tissue cell apoptotic index (AI) was discussed. (2) FEN1 gene 61563142-61563342 containing E160D were analysed by extracting genomic DNA from peripheral blood collected from the above 50 LN patients and 25 patients with nephrectomy caused by renal trauma. The difference between these two groups was statistically significant. RESULTS: Cell apoptosis was detected in all patients with LN, and correlation analysis results revealed a positive relationship between SLEDAI 2000 and AI (r = 0.39, p = .032). The FEN1 gene 61563142-61563342 fragment had site mutations at C/- (+61563189), A/T (+61563198), A/- (+61563204), G/T (+61563303), and T/C (+61563304). However, no statistical significance was found between LN patients detected with cell apoptosis and healthy individuals. CONCLUSIONS: This study revealed that cell apoptosis dysfunction plays a key role in the pathogenesis of LN, even though the difference in FEN1 gene 61563142-61563342 between LN patients and healthy individuals was not statistically significant. Larger sample size studies or genome-wide association studies are needed.

Generation and characterization of Brassica rapa ssp. pekinensis - B. oleracea var. capitata monosomic and disomic alien addition lines.

Five monosomic alien addition lines (MAALs) of Brassica rapa ssp. pekinensis - B. oleracea var. capitata were obtained by hybridization and backcrossing between B. rapa ssp. pekinensis (female parent) and B. oleracea var. capitata. The alien linkage groups were identified using 42 B. oleracea var. capitata linkage group-specific markers as B. oleracea linkage groups C2, C3, C6, C7 and C8. Based on the chromosomal karyotype of root tip cells, these five MAALs added individual chromosomes from B. oleracea var. capitata: chr 1 (the longest), chr 2 or 3, chr 5 (small locus of 25S rDNA), chr 7 (satellite-carrying) and chr 9 (the shortest). Five disomic alien addition lines were then generated by selfing their corresponding MAALs.