Knockout of two uridine diphosphate-glycosyltransferase genes increases the susceptibility of Spodoptera litura to Bacillus thuringiensis toxins.

Uridine diphosphate-glycosyltransferases (UGTs) catalyze sugar conjugation of endogenous and exogenous molecules in insects. In this study, 45 putative UGT genes in 11 families were identified from the genome of S. litura. Exposure to Bt toxins in 5th-instar larvae of the WT strain led to a significant upregulation of midgut UGT40 expression, particularly of SlUGT40D20, SlUGT40D22, and SlUGT40F25. This upregulation was not observed following exposure to chemical pesticides. Knockout of the UGT genes SlUGT40D20 and SlUGT40D22 in S. litura (mutant strains SlUGT40D20-KO and SlUGT40D22-KO) via CRISPR/Cas9-mediated mutagenesis increased susceptibility of S. litura to Bacillus thuringiensis (Bt) insecticidal proteins. However, in comparison with the wild-type (WT) strain, the mutants did not change susceptibility to chemical pesticides. Observations of 5th-instar larval midgut by electron microscopy revealed severe damage to the midgut epithelium caused by Cry1Ac toxin at 10 µg/g in the SlUGT40D20-KO strain compared to the WT. SDS-PAGE and LC MS/MS analyses identified a specific protein band corresponding to putative proteoglycans in the peritrophic matrix of the WT strain, which was absent in the SlUGT40D20-KO strain. Our study suggests an inverse correlation between expression of some UGTs and the susceptibility of S. litura larvae to some Bt toxins.

Erythroid-intrinsic activation of TLR8 impairs erythropoiesis in inherited anemia.

Inherited non-hemolytic anemia is a group of rare bone marrow disorders characterized by erythroid defects. Although concerted efforts have been made to explore the underlying pathogenetic mechanisms of these diseases, the understanding of the causative mutations are still incomplete. Here we identify in a diseased pedigree that a gain-of-function mutation in toll-like receptor 8 (TLR8) is implicated in inherited non-hemolytic anemia. TLR8 is expressed in erythroid lineage and erythropoiesis is impaired by TLR8 activation whereas enhanced by TLR8 inhibition from erythroid progenitor stage. Mechanistically, TLR8 activation blocks annexin A2 (ANXA2)-mediated plasma membrane localization of STAT5 and disrupts EPO signaling in HuDEP2 cells. TLR8 inhibition improves erythropoiesis in RPS19+/- HuDEP2 cells and CD34+ cells from healthy donors and inherited non-hemolytic anemic patients. Collectively, we identify a gene implicated in inherited anemia and a previously undescribed role for TLR8 in erythropoiesis, which could potentially be explored for therapeutic benefit in inherited anemia.

Drug delivery systems for enhanced tumour treatment by eliminating intra-tumoral bacteria.

Cancer remains one of the serious threats to human health. The relationship between bacteria and various tumours has been widely reported in recent years, and studies on intra-tumoral bacteria have become important as intra-tumoral bacteria directly affect the tumorigenesis, progression, immunity and metastatic processes. Therefore, eliminating these commensal intra-tumoral bacteria while treating tumour is expected to be a potential strategy to further enhance the clinical outcome of tumour therapy. Drug delivery systems (DDSs) are widely used to deliver antibiotics and chemotherapeutic drugs for antibacterial and anticancer applications, respectively. Thus, this review firstly provides a comprehensive summary of the association between intra-tumoral bacteria and a host of tumours, followed by a description of advanced DDSs for improving the therapeutic efficacy of cancer treatment through the elimination of intra-tumoral bacteria. It is hoped that this review will provide guidelines for the therapeutic and "synergistic antimicrobial and antitumour" drug delivery strategy.

Decoding the pathogenesis of Diamond-Blackfan anemia using single-cell RNA-seq.

Ribosomal protein dysfunction causes diverse human diseases, including Diamond-Blackfan anemia (DBA). Despite the universal need for ribosomes in all cell types, the mechanisms underlying ribosomopathies, which are characterized by tissue-specific defects, are still poorly understood. In the present study, we analyzed the transcriptomes of single purified erythroid progenitors isolated from the bone marrow of DBA patients. These patients were categorized into untreated, glucocorticoid (GC)-responsive and GC-non-responsive groups. We found that erythroid progenitors from untreated DBA patients entered S-phase of the cell cycle under considerable duress, resulting in replication stress and the activation of P53 signaling. In contrast, cell cycle progression was inhibited through induction of the type 1 interferon pathway in treated, GC-responsive patients, but not in GC-non-responsive patients. Notably, a low dose of interferon alpha treatment stimulated the production of erythrocytes derived from DBA patients. By linking the innately shorter cell cycle of erythroid progenitors to DBA pathogenesis, we demonstrated that interferon-mediated cell cycle control underlies the clinical efficacy of glucocorticoids. Our study suggests that interferon administration may constitute a new alternative therapeutic strategy for the treatment of DBA. The trial was registered at www.chictr.org.cn as ChiCTR2000038510.

Prevalence and Factors Associated With Sarcopenia in Suburb-dwelling Older Chinese Using the Asian Working Group for Sarcopenia Definition.

BACKGROUND: Sarcopenia is a common condition in older people. The aim of the present study was to examine the prevalence and factors associated with sarcopenia in an elderly Chinese suburb-dwelling population. METHODS: This study was conducted on 1,069 Chinese suburb-dwelling participants aged ≥60 years to evaluate sarcopenia using the Asian Working Group for Sarcopenia criteria. Sociodemographic and behavioral characteristics, as well as medical conditions, were considered independent variables to determine factors associated with sarcopenia using a logistic regression model. RESULTS: The prevalence of sarcopenia was 6.4% in men and 11.5% in women. Age was a significant factor in both sexes. In addition, presence of sarcopenia was inversely associated with BMI for both sexes. The odds ration and 95% confidence interval for factors statistically significantly associated with sarcopenia were 5.04 (1.70-14.89) and 2.36 (1.06-5.25) for diabetes in males and females, respectively; 10.60 (1.75-64.24) for daily consumption of alcohol (daily drinkers), 5.58 (2.13-14.59) for peptic ulcer in female (not statistically significant in males). CONCLUSIONS: The Asian Working Group for Sarcopenia criterion is useful for defining sarcopenia, and our data suggest that the prevalence of sarcopenia in the general elderly suburb-dwelling Chinese population is high. Moreover, we find that high body mass index is inversely associated with the likelihood of being sarcopenic and that several others factors such as diabetes, peptic ulcer, and drinking habits increase the prevalence of sarcopenia.