Science China Life Sciences最新文献

The emergence of drug resistance to virus (i.e., acyclovir (ACV) to herpesviruses) has been termed one of the common clinical issues, emphasizing the discovery of new antiviral agents. To address it, a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening was performed in mouse haploid embryonic stem cells infected with pseudorabies virus (PRV), an α-herpesvirus causing human and pig diseases. The results demonstrated that type 2 voltage-gated chloride channels (CLC-2) encoded by one of the identified genes, CLCN2, is a potential drug target for anti-herpesvirus therapy. CLC-2 inhibitors, omeprazole (OME) and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), can efficiently inhibit infection of multiple herpesviruses in cellulo (i.e., PRV, HSV and EBV), and effectively treat murine herpes simplex encephalitis (HSE). Additionally, DIDS was found to inhibit HSV-1 replication by blocking the PI3K/Akt pathway. Most importantly, both DIDS and OME were able to inhibit ACV-resistant HSV-1 strain infection. The study's findings suggest that targeting host-cell factors such as CLC-2 may be a promising approach to tackling herpesvirus drug resistance. The discovery of CLC-2 as a potential drug target for anti-herpesvirus therapy provides a new direction for the development of novel antiviral agents.

Autosomal recessive spinocerebellar ataxias (SCARs) are one of the most common neurodegenerative diseases characterized by progressive ataxia. Although SCARs are known to be caused by mutations in multiple genes, there are still many cases that go undiagnosed or are misdiagnosed. In this study, we presented a SCAR patient, and identified a probable novel pathogenic mutation (c.1A>G, p.M1V) in the AFG3L2 start codon. The proband's genotype included heterozygous mutations of the compound AFG3L2 (p.[M1V]; [R632X] (c.[1A>G]; [1894.C>T])), which were inherited from the father (c.1A>G, p.M1V) and mother (c.1894C>T, p.R632X). Functional studies performed on hiPSCs (human induced pluripotent stem cells) generated from the patients and HEK293T cells showed that the mutations impair mitochondrial function and the unbalanced expression of AFG3L2 mRNA and protein levels. Furthermore, this novel mutation resulted in the degradation of the protein and the reduction of the stability of the AFG3L2 protein, and MCU (mitochondrial calcium uniporter) complex mediated Ca²⁺ overload.

Ependymal cells line the wall of cerebral ventricles and ensure the unidirectional cerebrospinal fluid (CSF) flow by beating their motile cilia coordinately. The ependymal denudation or ciliary dysfunction causes hydrocephalus. Here, we report that the deficiency of regulator of G-protein signaling 22 (RGS22) results in severe congenital hydrocephalus in both mice and rats. Interestingly, RGS22 is specifically expressed in ependymal cells within the brain. Using conditional knock-out mice, we further demonstrate that the deletion of Rgs22 exclusively in nervous system is sufficient to induce hydrocephalus. Mechanistically, we show that Rgs22 deficiency leads to the ependymal denudation and impaired ciliogenesis. This phenomenon can be attributed to the excessive activation of lysophosphatidic acid receptor (LPAR) signaling under Rgs22^-/- condition, as the LPAR blockade effectively alleviates hydrocephalus in Rgs22^-/- rats. Therefore, our findings unveil a previously unrecognized role of RGS22 in the central nervous system, and present RGS22 as a potential diagnostic and therapeutic target for hydrocephalus.

Cohort evidence linking long-term survival of older adults with exposure to fine particulate matter (PM_2.5) constituents remains scarce in China. By constructing a dynamic cohort based on the Chinese Longitudinal Healthy Longevity Study, we aimed to assess the individual and joint associations of major PM_2.5 constituents with all-cause death in Chinese oldest-old (.80 years) adults. Time-dependent Cox proportional hazards models were adopted to estimate death risks of long-term exposure to PM_2.5 constituents. Among 14,884 participants, totaling 56,342 person-years of follow-up, 12,346 deaths were identified. The highest mortality risk associated with an interquartile range (IQR) increase in exposure was 1.081 (95% confidence interval [CI]: 1.055-1.108) for sulfate (IQR=4.1 μg m^-3), followed by 1.078 (95% CI: 1.056-1.101) for black carbon (IQR=1.6 μg m^-3), 1.056 (95% CI: 1.028-1.084) for ammonium (IQR=3.2 μg m^-3), 1.050 (95% CI: 1.021-1.080) for nitrate (IQR=5.8 μg m^-3), and 1.049 (95% CI: 1.024-1.074) for organic matter (IQR=10.3 μg m^-3). In joint exposure, each IQRequivalent rise of all five PM_2.5 constituents was associated with an 8.2% (95% CI: 4.0%-12.6%) increase in mortality risk. The weight analysis indicated the predominant role of sulfate and black carbon in driving PM_2.5-related mortality. Octogenarians (aged 80-89 years) and rural dwellers were at significantly greater risk of mortality from individual and joint exposures to PM_2.5 constituents. This study suggests that later-life exposure to PM_2.5 constituents, particularly sulfate and black carbon, may curtail long-term survival of the oldest-old in China.

Cardiac rehabilitation, a comprehensive exercise-based lifestyle and medical management, is effective in decreasing morbidity and improving life quality in patients with coronary heart disease. Endothelial function, an irreplaceable indicator in coronary heart disease progression, is measured by various methods in traditional cardiac rehabilitation pathways, including medicinal treatment, aerobic training, and smoking cessation. Nevertheless, studies on the effect of some emerging cardiac rehabilitation programs on endothelial function are limited. This article briefly reviewed the endothelium-beneficial effects of different cardiac rehabilitation pathways, including exercise training, lifestyle modification and psychological intervention in patients with coronary heart disease, and related experimental models, and summarized both uncovered and potential cellular and molecular mechanisms of the beneficial roles of various cardiac rehabilitation pathways on endothelial function. In exercise training and some lifestyle interventions, the enhanced bioavailability of nitric oxide, increased circulating endothelial progenitor cells (EPCs), and decreased oxidative stress are major contributors to preventing endothelial dysfunction in coronary heart disease. Moreover, the preservation of endothelial-dependent hyperpolarizing factors and inflammatory suppression play roles. On the one hand, to develop more endothelium-protective rehabilitation methods in coronary heart disease, adequately designed and sized randomized multicenter clinical trials should be advanced using standardized cardiac rehabilitation programs and existing assessment methods. On the other hand, additional studies using suitable experimental models are warranted to elucidate the relationship between some new interventions and endothelial protection in both macro- and microvasculature.

Many long noncoding RNAs (lncRNAs) have been identified through siRNA-based screening as essential regulators of embryonic stem cell (ESC) pluripotency. However, the biological and molecular functions of most lncRNAs remain unclear. Here, we employed CRISPR/Cas9-mediated knockout technology to explore the functions of 8 lncRNAs previously reported to promote pluripotency in mouse ESCs. Unexpectedly, all of these lncRNAs were dispensable for pluripotency maintenance and proliferation in mouse ESCs when disrupted individually or in combination. Single-cell transcriptomic analysis also showed that the knockout of these lncRNAs has a minimal impact on pluripotency gene expression and cell identity. We further showed that several small hairpin RNAs (shRNAs) previously used to knock down lncRNAs caused the downregulation of pluripotency genes in the corresponding lncRNA-knockout ESCs, indicating that off-target effects likely responsible for the pluripotency defects caused by these shRNAs. Interestingly, linc1343-knockout and linc1343-knockdown ESCs failed to form cystic structures and exhibited high expression of pluripotency genes during embryoid body (EB) differentiation. By reintroducing RNA products generated from the linc1343 locus, we found that two snoRNAs, Snora73a and Snora73b, but not lncRNAs, could rescue pluripotency silencing defects during EB differentiation of linc1343 knockout ESCs. Our results suggest that the 8 previously annotated pluripotency-regulating lncRNAs have no overt functions in conventional ESC culture; however, we identified snoRNA products derived from an annotated lncRNA locus as essential regulators for silencing pluripotency genes.

Climate and land-use changes are predicted to impact biodiversity, threatening ecosystem services and functions. However, their combined effects on the functional diversity of mammals at the regional scale remain unclear, especially at the beta level. Here, we use projected climate and land-use changes in China to investigate their potential effects on the alpha and beta functional diversities of terrestrial mammals under low- and high-emission scenarios. In the current projection, we showed strong positive spatial correlations between functional richness and species richness. Functional evenness (FEve), functional specialization (FSpe), and functional originality (FOri) decreased with species richness, and functional divergence (FDiv) increased first and then plateaued. Functional beta diversity was dominated by its nestedness component, in contrast to the taxonomic facet. Potential changes in species richness are more strongly influenced by land-use change under the low-emission scenario, while under the high-emission scenario, they are more strongly influenced by climate change. Changes in functional richness (FRic) were inconsistent with those in species richness, with a magnitude of decreases greater than predicted from species richness. Moreover, mammal assemblages showed potential functional differentiation (FD) across the country, and the trends exceeded those towards taxonomic differentiation (TD). Our findings help us understand the processes underlying biodiversity responses to global changes on multiple facets and provide new insight for conservation plans.