Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1)

Precursor mRNA (pre-mRNA) splicing is catalyzed by a large ribonucleoprotein complex known as the spliceosome. Numerous studies have indicated that aberrant splicing patterns or mutations in spliceosome components, including the splicing factor 3b subunit 1 (SF3B1), are associated with hallmark cancer phenotypes. This has led to the identification and development of small molecules with spliceosome-modulating activity as potential anticancer agents. Jerantinine A (JA) is a novel indole alkaloid which displays potent anti-proliferative activities against human cancer cell lines by inhibiting tubulin polymerization and inducing G2/M cell cycle arrest. Using a combined pooled-genome wide shRNA library screen and global proteomic profiling, we showed that JA targets the spliceosome by up-regulating SF3B1 and SF3B3 protein in breast cancer cells. Notably, JA induced significant tumor-specific cell death and a significant increase in unspliced pre-mRNAs. In contrast, depletion of endogenous SF3B1 abrogated the apoptotic effects, but not the G2/M cell cycle arrest induced by JA. Further analyses showed that JA stabilizes endogenous SF3B1 protein in breast cancer cells and induced dissociation of the protein from the nucleosome complex. Together, these results demonstrate that JA exerts its antitumor activity by targeting SF3B1 and SF3B3 in addition to its reported targeting of tubulin polymerization

Functional variants regulating LGALS1 (Galectin 1) expression affect human susceptibility to influenza A(H7N9)

The fatality of avian influenza A(H7N9) infection in humans was over 30%. To identify human genetic susceptibility to A(H7N9) infection, we performed a genome-wide association study (GWAS) involving 102 A(H7N9) patients and 106 heavily-exposed healthy poultry workers, a sample size critically restricted by the small number of human A(H7N9) cases. To tackle the stringent significance cutoff of GWAS, we utilized an artificial imputation program SnipSnip to improve the association signals. In single-SNP analysis, one of the top SNPs was rs13057866 of LGALS1. The artificial imputation (AI) identified three non-genotyped causal variants, which can be represented by three anchor/partner SNP pairs rs13057866/rs9622682 (AI P = 1.81 × 10-7), rs4820294/rs2899292 (2.13 × 10-7) and rs62236673/rs2899292 (4.25 × 10-7) respectively. Haplotype analysis of rs4820294 and rs2899292 could simulate the signal of a causal variant. The rs4820294/rs2899292 haplotype GG, in association with protection from A(H7N9) infection (OR = 0.26, P = 5.92 × 10-7) correlated to significantly higher levels of LGALS1 mRNA (P = 0.050) and protein expression (P = 0.025) in lymphoblast cell lines. Additionally, rs4820294 was mapped as an eQTL in human primary monocytes and lung tissues. In conclusion, functional variants of LGALS1 causing the expression variations are contributable to the differential susceptibility to influenza A(H7N9).link_to_OA_fulltex

Endogenous Retinoic Acid Activity in Principal Cells and Intercalated Cells of Mouse Collecting Duct System

Background: Retinoic acid is the bioactive derivative of vitamin A, which plays an indispensible role in kidney development by activating retinoic acid receptors. Although the location, concentration and roles of endogenous retinoic acid in postnatal kidneys are poorly defined, there is accumulating evidence linking post-natal vitamin A deficiency to impaired renal concentrating and acidifying capacity associated with increased susceptibility to urolithiasis, renal inflammation and scarring. The aim of this study is to examine the presence and the detailed localization of endogenous retinoic acid activity in neonatal, young and adult mouse kidneys, to establish a fundamental ground for further research into potential target genes, as well as physiological and pathophysiological roles of endogenous retinoic acid in the post-natal kidneys.Methodology/Principal Findings: RARE-hsp68-lacZ transgenic mice were employed as a reporter for endogenous retinoic acid activity that was determined by X-gal assay and immunostaining of the reporter gene product, beta-galactosidase. Double immunostaining was performed for beta-galactosidase and markers of kidney tubules to localize retinoic acid activity. Distinct pattern of retinoic acid activity was observed in kidneys, which is higher in neonatal and 1- to 3-week-old mice than that in 5- and 8-week-old mice. The activity was present specifically in the principal cells and the intercalated cells of the collecting duct system in all age groups, but was absent from the glomeruli, proximal tubules, thin limbs of Henle's loop and distal tubules.Conclusions/Significance: Endogenous retinoic acid activity exists in principal cells and intercalated cells of the mouse collecting duct system after birth and persists into adulthood. This observation provides novel insights into potential roles for endogenous retinoic acid beyond nephrogenesis and warrants further studies to investigate target genes and functions of endogenous retinoic acid in the kidney after birth, particularly in the collecting duct system

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Ablation of klotho and premature aging: is 1,25-dihydroxyvitamin D the key middleman?

The reversal of soft-tissue abnormalities and prolonged lifespan observed in klotho −/− mice following genetic inactivation of 1α-hydroxylase underscores the pathophysiological role of 1,25-dihydroxyvitamin D in mediating some of the premature aging-like features observed in klotho −/− mice

A contingency view of the effects of sustainable shipping exploitation and exploration on business performance

Anchored to the resource-based view, this study identifies the types of sustainable shipping capabilities that can be pursued and developed by shipping companies to enhance their business performance. The paper also examines internal and external contextual factors that moderate the relationship between the identified shipping capabilities and business performance. Survey data were collected from 225 shipping companies with business offices in Singapore and analysed using structural equation modelling and a multiple-sample approach. The results show that both sustainable shipping exploitation and exploration capabilities have positive effects on business performance. Organisational slack and environmental uncertainty negatively moderate the relationship between sustainable exploitation capability and business performance but positively moderate the relationship between sustainable exploration capability and business performance. The results imply that sustainable shipping should be viewed as a dynamic capability rather than a set of practices, which connote stasis. In addition, management policies to develop sustainable exploitation or exploration capabilities should depend on the internal and external environment of shipping companies. This paper introduces an alternative theoretical lens through which to manage and improve the allocation of organisational resources to enhance corporate sustainability and business performance of shipping companies.This study was partially supported by the National Social Science Foundation of China [18BGL258], the Humanities and Social Science Foundation of the Ministry of Education of China [17YJCZH125] and the Basic Research Foundation of Central Universities of China [300102239663]

The determinants of customers’ intention to use smart lockers for last-mile deliveries

Anchored on the resource matching, perceived value, and transaction cost economics theories, this study analyses the determinants of customers' intention to use smart lockers for last-mile deliveries. Based on stratified sampling, survey data were collected from 230 smart locker users in China and analysed using structural equation modelling. The results show that the effects of convenience, privacy security, and reliability on customers’ intention are fully mediated by perceived value and transaction costs. This study enriches theoretical research on self-service technologies in last-mile deliveries, offers insights into consumer behavioural research on computer–human interactions, and provides implications for transport policy.This study was supported by the National Social Science Foundation of China [18BGL258], the Humanities and Social Science Foundation of the Ministry of Education of China [17YJCZH125] and the Basic Research Foundation of Central Universities of China [300102239663]

A theoretical investigation of user acceptance of autonomous public transport

Achieving a critical mass in the acceptance of fully autonomous public transport (APT) is crucial for a society to effectively realise APT’s intended environmental, social and economic benefits. The current study analyses the determinants contributing to user acceptance of APT through three theoretical lenses, namely, Unified Theory of Acceptance and Use of Technology (UTAUT), Perceived Value Theory and Social Exchange Theory. Survey data were collected from 476 commuters in Beijing, China. The results reveal that the five dimensions of UTAUT (i.e. performance expectancy, effort expectancy, social influence, facilitating conditions and hedonic motivation) have positive influence on users’ value perception of APT. Consequently, users’ value perception of APT exerts both direct and indirect influences on users’ acceptance of APT via trust. A key contribution of this study is the combination and synthesis of several complementary behavioural theories to explain user acceptance of autonomous vehicles. In addition, the results offer important implications for transport policymakers and operators, in particular, pertaining to areas on resource allocation, marketing, communication and education to improve user acceptance of APT