Despite rapid progresses in the genome-editing field, in vivo simultaneous overexpression of multiple genes remains challenging. We generated a transgenic mouse using an improved dCas9 system that enables simultaneous and precise in vivo transcriptional activation of multiple genes and long noncoding RNAs in the nervous system. As proof of concept, we were able to use targeted activation of endogenous neurogenic genes in these transgenic mice to directly and efficiently convert astrocytes into functional neurons in vivo. This system provides a flexible and rapid screening platform for studying complex gene networks and gain-of-function phenotypes in the mammalian brain.

Background: COVID-19 is currently a global pandemic, but the response of human immune system to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unclear. Noncoding RNAs serve as immune regulators and thus may play a critical role in disease progression. Methods: We performed multi-transcriptome sequencing of both noncoding RNAs and mRNAs isolated from the red blood cell depleted whole blood of moderate and severe COVID-19 patients. The functions of noncoding RNAs were validated by analyses of the expression of downstream mRNAs. We further utilized the single-cell RNA-seq data of COVID-19 patients from Wilk et al. and Chua et al. to characterize noncoding RNA functions in different cell types. Results: We defined four types of microRNAs with different expression tendencies that could serve as biomarkers for COVID-19 progress. We also identified miR-146a-5p, miR-21-5p, miR-142-3p, and miR-15b-5p as potential contributors to the disease pathogenesis, possibly serving as biomarkers of severe COVID-19 and as candidate therapeutic targets. In addition, the transcriptome profiles consistently suggested hyperactivation of the immune response, loss of T-cell function, and immune dysregulation in severe patients.

Mutant huntingtin (htt) carries an expanded polyglutamine (polyQ) repeat (>36 glutamines) in its N-terminal region, which leads htt to become misfolded and kill neuronal cells in Huntington disease (HD). The cytotoxicity of N-terminal mutant htt fragments is evident by severe neurological phenotypes of transgenic mice that express these htt fragments. Clearance of mutant htt is primarily mediated by the ubiquitin-proteasomal sysmtem (UPS) and autophagy. However, the relative efficiency of these two systems to remove toxic forms of mutant htt has not been rigorously compared. Using cellular and mouse models of HD, we found that inhibiting the UPS leads to a greater accumulation of mutant htt than inhibiting autophagy. Moreover, N-terminal mutant htt fragments, but not full-length mutant htt, accumulate in the HD mouse brains after inhibiting the UPS. These findings suggest that the UPS is more efficient than autophagy to remove N-terminal mutant htt.

SCAP has a protective effect on ethanol-induced liver injury in mice and cells, and the mechanism underlying may be via inhibiting the expression of CYP2E1 protein and then alleviating oxidative stress injury induced by ethanol.

Hearing loss is the most common sensory disorder in humans, and a significant number of cases is due to the ototoxicity of drugs such as cisplatin that cause hair cell (HC) damage. Thus, there is great interest in finding agents and mechanisms that protect HCs from ototoxic drug damage. It has been proposed that epigenetic modifications are related to inner ear development and play a significant role in HC protection and HC regeneration; however, whether the m6A modification and the ethyl ester form of meclofenamic acid (MA2), which is a highly selective inhibitor of FTO (fatmass and obesity-associated enzyme, one of the primary human demethylases), can affect the process of HC apoptosis induced by ototoxic drugs remains largely unexplored. In this study, we took advantage of the HEI-OC1 cell line, which is a cochlear HC-like cell line, to investigate the role of epigenetic modifications in cisplatin-induced cell death. We found that cisplatin injury caused reactive oxygen species accumulation and increased apoptosis in HEI-OC1 cells, and the cisplatin injury was reduced by co-treatment with MA2 compared to the cisplatin-only group. Further investigation showed that MA2 attenuated cisplatin-induced oxidative stress and apoptosis in HEI-OC1 cells. We next found that the cisplatin-induced upregulation of autophagy was significantly inhibited after MA2 treatment, indicating that MA2 inhibited the cisplatin-induced excessive autophagy. Our findings show that MA2 has a protective effect and improves the viability of HEI-OC1 cells after cisplatin treatment, and they provide new insights into potential therapeutic targets for the amelioration of cisplatin-induced ototoxicity.

Drawing on a qualitative case study and deploying Bourdieu's thinking tools, this article attempts to understand rural students' subjectivities and practices in a Chinese elite university, relating the types and volumes of capital they possessed to the process of position-takings. It contextualises their experiences against the backdrop of the rural-urban divide in China and the great educational inequality thus entailed. Rurality in the metropolitan space resulted in a strong feeling of being out of place. Lack of the legitimate cultural forms, together with pervasive financial constraints, constituted a major cause of frustration and alienation for these former academic stars. Exclusion and self-exclusion from the 'consecrated' culture, high-status societies and social activities further handicapped their acquisition of valued capitals. Under such conditions, rural participants produced diversified strategies and practices, through which we catch a glimpse of their evolving habitus.

To examine the anti-fatigue function of anwulignan from Schisandra and its underlying mechanism.

Effective recognition of viral infection and subsequent triggering of antiviral innate immune responses are essential for the host antiviral defense, which is tightly regulated by multiple regulators, including microRNAs. Previous reports have shown that some microRNAs are induced during virus infection and participate in the regulation of the innate antiviral response. However, whether the type I IFN response is regulated by miR-223 is still unknown. Here, we reported that vesicular stomatitis virus (VSV) infection induced significant up-regulation of miR-223 in murine macrophages. We observed that miR-223 overexpression up-regulated type I IFN expression levels in VSV-infected macrophages. We also demonstrated that miR-223 directly targets FOXO3 to regulate the type I IFN production. Furthermore, type I IFN, which is triggered by VSV infection, is responsible for the up-regulation of miR-223, thus forming a positive regulatory loop for type I IFN production. Our results uncovered a novel mechanism of miR-223-mediated regulation of type I IFN production in the antiviral innate immunity for the first time.Host innate immune response is the first line of defense following viral infection, which recognizes viral components and produces proinflammatory cytokines and interferons (1-8). The IFN family of antiviral cytokines, especially type I IFN, plays pivotal roles in the host antiviral innate immune response. They are known to inhibit viral replication and mediate protection against viral infection (1-4). Type I IFN production during virus infection should be tightly controlled by multiple intracellular regulators to initiate an appropriate immune response for eliminating the invading pathogens and preventing the development of immunopathological conditions; principal among these is the family of interferon regulatory factors (9 -12). Among the interferon regulatory factors, IRF3 and IRF7 are crucial in the host response to virus infection, inducing the transcription of the type I IFN genes, including the Ifn-␤ gene as well as a number of Ifn-␣ genes (13-16). It has been reported that IRF7 is regulated at three different levels, including the transcriptional, post-transcriptional, and post-translational levels. Transcription of the Irf7 gene is induced by viral infection or type I IFN stimulation (17), although the stability of IRF7 is regulated by FOXO3 (18).MicroRNAs (miRNAs) 4 are small, non-coding, regulatory RNAs that range from 18 to 22 nucleotides in length. They are mainly encoded by gene introns but are also sometimes encoded by dedicated genes. The miRNAs regulate the expression of specific target proteins by either inhibiting translation or degrading the corresponding mRNA (19,20). They regulate between one-and two-thirds of the human genome and participate in most of the cell's main functions (including growth, proliferation, differentiation, signal transduction, apoptosis, metabolism, and aging) (21). It has been reported that, with respect to virus infection, miRNAs constitute a critical additional c...