Novel thiobarbiturates as potent urease inhibitors with potential antibacterial activity: Design,synthesis, radiolabeling and biodistribution study

Urease enzyme is a virulence factor that helps in colonization and maintenance of highly pathogenic bacteria in human. Hence, the inhibition of urease enzymes is well-established to be a promising approach for preventing deleterious effects of ureolytic bacterial infections. In this work, novel thiobarbiturate derivatives were synthesized and evaluated for their urease inhibitory activity. All tested compounds effectively inhibited the activity of urease enzyme. Compounds 1, 2a, 2b, 4 and 9 displayed remarkable anti-urease activity (IC₅₀ = 8.21–16.95 μM) superior to that of thiourea reference standard (IC₅₀ = 20.04 μM). Moreover, compounds 3a, 3g, 5 and 8 were equipotent to thiourea. Among the tested compounds, morpholine derivative 4 (IC₅₀ = 8.21 µM) was the most potent one, showing 2.5 folds the activity of thiourea. In addition, the antibacterial activity of the synthesized compounds was estimated against both standard strains and clinical isolates of urease producing bacteria. Compound 4 explored the highest potency exceeding that of cephalexin reference drug. Moreover, biodistribution study using radiolabeling approach revealed a remarked uptake of ^99mTc-compound 4 into infection induced in mice. Furthermore, a molecular docking analysis revealed proper orientation of title compounds into the urease active site rationalizing their potent anti-urease activity.     

Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

Many neuropsychiatric disorders exhibit differences in prevalence, age of onset, symptoms or course of illness between males and females. For the most part, the origins of these differences are not well understood. In this article, we provide an overview of sex differences in psychiatric disorders including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), anxiety, depression, alcohol and substance abuse, schizophrenia, eating disorders and risk of suicide. We discuss both genetic and nongenetic mechanisms that have been hypothesized to underlie these differences, including ascertainment bias, environmental stressors, X‐ or Y‐linked risk loci, and differential liability thresholds in males and females. We then review the use of twin, family and genome‐wide association approaches to study potential genetic mechanisms of sex differences and the extent to which these designs have been employed in studies of psychiatric disorders. We describe the utility of genetic epidemiologic study designs, including classical twin and family studies, large‐scale studies of population registries, derived recurrence risks, and molecular genetic analyses of genome‐wide variation that may enhance our understanding sex differences in neuropsychiatric disorders.     

Association between METTL3 gene polymorphisms and neuroblastoma susceptibility: A nine‐centre case‐control study

Neuroblastoma ranks as the most commonly seen and deadly solid tumour in infancy. The aberrant activity of m⁶A‐RNA methyltransferase METTL3 is involved in human cancers. Therefore, functional genetic variants in the METTL3 gene may contribute to neuroblastoma risk. In the current nine‐centre case‐control study, we aimed to analyse the association between the METTL3 gene single nucleotide polymorphisms (SNPs) and neuroblastoma susceptibility. We genotyped four METTL3 gene SNPs (rs1061026 T>G, rs1061027 C>A, rs1139130 A>G, and rs1263801 G>C) in 968 neuroblastoma patients and 1814 controls in China. We found significant associations between these SNPs and neuroblastoma risk in neither single‐locus nor combined analyses. Interestingly, in the stratified analysis, we observed a significant risk association with rs1061027 AA in subgroups of children ≤ 18 months of age (adjusted OR = 1.87, 95% CI = 1.03‐3.41, P = .040) and females (adjusted OR = 1.86, 95% CI = 1.07‐3.24, P = .028). Overall, we identified a significant association between METTL3 gene rs1061027 C>A polymorphism and neuroblastoma risk in children ≤18 months of age and females. Our findings provide novel insights into the genetic determinants of neuroblastoma.     

Genomic atlases of introgression and differentiation reveal breeding footprints in Chinese cultivated rice

The long history of cultivation and breeding has left a variety of footprints in the genomes of Asian cultivated rice (Oryza sativa L.). In this study, we focus on two types of genomic footprints, introgression and differentiation, in a population of more than 1200 Chinese rice accessions. We found that a Xian/indica and a temperate Geng/japonica accession respectively contained an average of 19.3-Mb and 6.8-Mb alien introgressed chromosomal segments, of which many contained functional sequence variants, quantitative trait loci, or genes controlling flowering, grain, and resistance traits. Notably, we found most introgressions, including the known heterotic loci Hd3a and TAC1, were distributed differentially between the female and male parents of three-line indica hybrid rice, indicating their potential contribution to heterosis. We also found many differentiated regions between subgroups within a subpopulation contained agronomically important loci, such as DTH7, Hd1 for heading date, and qCT7 for cold tolerance, providing new candidates for studying local adaptation or heterosis. Tracing these footprints allows us to better understand the genetic exchange or differentiation underlying agronomic traits in modern Chinese rice cultivars. These findings also provide potential targets for rice genetic research and breeding.     

Molecular identification of selected bees from the Indian Himalaya: A preliminary effort

DNA barcoding has largely been tested for a wide range of taxa and evidenced as a reliable and rapid molecular tool for species-level identification. The present study lends to generate 156 DNA barcodes, of which 141 belonged to 30 morphologically identified bees from the Indian Himalayan Regions (IHRs). The generated barcode data along with 84 sequences of global database distinctly discriminated all the studied species with sufficient genetic distances and cohesive monophyletic clustering in Bayesian analysis (BA) phylogeny. The species delimitation methods, Automatic Barcode Gap Discovery (ABGD), Bayesian Poisson-Tree-Processes (bPTP), and General Mixed Yule-coalescent (GMYC) yielded 68, 70, and 71 molecular operational taxonomic units (MOTUs) respectively. The present DNA barcode-based examination detected the possible cryptic diversity in two Apis species (A. cerana and A. dorsata), Bombus hypnorum, Lepidotrigona arcifera, and Ceratina sutepensis. The present study also evidenced the species complexes within Bombus albopleuralis and Bombus trifasciatus in the IHRs. The species delimitation methods also detected an additional seven putative species from the IHRs, which were identified up to the genus level. In conclusion, this preliminary effort helps to develop a reliable barcode database of bees from the Indian IHRs to facilitate the future systematics study. These molecular data can be utilized to evaluate the population structures and assist to formulate the effective plans for bee conservation.     

A Bayes factor approach with informative prior for rare genetic variant analysis from next generation sequencing data

The discovery of rare genetic variants through next generation sequencing is a very challenging issue in the field of human genetics. We propose a novel region‐based statistical approach based on a Bayes Factor (BF) to assess evidence of association between a set of rare variants (RVs) located on the same genomic region and a disease outcome in the context of case‐control design. Marginal likelihoods are computed under the null and alternative hypotheses assuming a binomial distribution for the RV count in the region and a beta or mixture of Dirac and beta prior distribution for the probability of RV. We derive the theoretical null distribution of the BF under our prior setting and show that a Bayesian control of the false Discovery Rate can be obtained for genome‐wide inference. Informative priors are introduced using prior evidence of association from a Kolmogorov‐Smirnov test statistic. We use our simulation program, sim1000G, to generate RV data similar to the 1000 genomes sequencing project. Our simulation studies showed that the new BF statistic outperforms standard methods (SKAT, SKAT‐O, Burden test) in case‐control studies with moderate sample sizes and is equivalent to them under large sample size scenarios. Our real data application to a lung cancer case‐control study found enrichment for RVs in known and novel cancer genes. It also suggests that using the BF with informative prior improves the overall gene discovery compared to the BF with noninformative prior.