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INTRODUCTION: Emergence of highly infectious SARS-CoV-2 variants are reducing protection provided by current vaccines, requiring constant updates in antiviral approaches. The virus encodes four structural and sixteen nonstructural proteins which play important roles in viral genome replication and transcription, virion assembly, release , entry into cells, and compromising host cellular defenses. As alien proteins to host cells, many viral proteins represent potential targets for combating the SARS-CoV-2. AREAS COVERED: Based on literature from PubMed and Web of Science databases, the authors summarize the typical characteristics of SARS-CoV-2 from the whole viral particle to the individual viral proteins and their corresponding functions in virus life cycle. The authors also discuss the potential and emerging targeted interventions to curb virus replication and spread in detail to provide unique insights into SARS-CoV-2 infection and countermeasures against it. EXPERT OPINION: Our comprehensive analysis highlights the rationale to focus on non-spike viral proteins that are less mutated but have important functions. Examples of this include: structural proteins (e.g. nucleocapsid protein, envelope protein) and extensively-concerned nonstructural proteins (e.g. NSP3, NSP5, NSP12) along with the ones with relatively less attention (e.g. NSP1, NSP10, NSP14 and NSP16), for developing novel drugs to overcome resistance of SARS-CoV-2 variants to preexisting vaccines and antibody-based treatments.
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COVID-19 , SARS-CoV-2 , Humanos , Antivirales/farmacología , Antivirales/química , SARS-CoV-2/genética , Proteínas no Estructurales Virales/metabolismo , Proteínas Virales/metabolismoRESUMEN
Three bi-quaternary ammonium methacrylates (biQAMA-12, biQAMA-14, and biQAMA-16) with different alkyl chain length were synthesized with the purpose of endowing dental resin composites (DRCs) with antibacterial activity without sacrificing physicochemical properties of DRCs. All of biQAMAs were confirmed by 1H-NMR spectra and incorporated into Bis-GMA/TEGDMA (60 wt/40 wt) resin matrix with a mass fraction of 5 wt% as antibacterial agent. The obtained resin matrixes were mixed with commercial silaned glass fillers at a mass ratio of 30 wt/70 wt to prepare antibacterial DRCs. The double bond conversion (DC), antibacterial activity against S. mutans., surface charge density, water contact angle, water sorption (WS) and solubility (SL), mechanical properties, and cytotoxicity of biQAMAs containing DRCs were investigated. The DRC without biQAMAs was used as control. The results showed that all biQAMAs containing DRCs had antibacterial rate higher than 90%, and DRC with biQAMA-12 had the highest antibacterial rate due to its highest surface charge density. Adding 5 wt% of biQAMAs would not bring out negative effect on physicochemical properties of DRCs, except for increasing WS, but the resultant WS still met the ISO requirement on WS of restorative materials. Both biQAMA-14 and biQAMA-16 containing DRCs showed higher cytotoxicity than control, thus biQAMA-12 was considered as the optimal antibacterial agent in this research.
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Compuestos de Amonio , Metacrilatos , Antibacterianos/química , Antibacterianos/farmacología , Anticestodos , Bisfenol A Glicidil Metacrilato/química , Resinas Compuestas/farmacología , Ensayo de Materiales , Metacrilatos/química , Metacrilatos/farmacología , Agua/químicaRESUMEN
The coding regions account for only a small part of the human genome, and the remaining vast majority of the regions generate large amounts of non-coding RNAs. Although non-coding RNAs do not code for any protein, they are suggested to work as either tumor suppressers or oncogenes through modulating the expression of genes and functions of proteins at transcriptional, posttranscriptional and post-translational levels. Acute Lymphoblastic Leukemia (ALL) originates from malignant transformed B/T-precursor-stage lymphoid progenitors in the bone marrow (BM). The pathogenesis of ALL is closely associated with aberrant genetic alterations that block lymphoid differentiation and drive abnormal cell proliferation as well as survival. While treatment of pediatric ALL represents a major success story in chemotherapy-based elimination of a malignancy, adult ALL remains a devastating disease with relatively poor prognosis. Thus, novel aspects in the pathogenesis and progression of ALL, especially in the adult population, need to be further explored. Accumulating evidence indicated that genetic changes alone are rarely sufficient for development of ALL. Recent advances in cytogenic and sequencing technologies revealed epigenetic alterations including that of non-coding RNAs as cooperating events in ALL etiology and progression. While the role of micro RNAs in ALL has been extensively reviewed, less attention, relatively, has been paid to other non-coding RNAs. Herein, we review the involvement of linear and circular long non-coding RNAs in the etiology, maintenance, and progression of ALL, highlighting the contribution of these non-coding RNAs in ALL classification and diagnosis, risk stratification as well as treatment.
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MicroARNs , Leucemia-Linfoma Linfoblástico de Células Precursoras , ARN Largo no Codificante , Adulto , Médula Ósea/metabolismo , Niño , Humanos , MicroARNs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Schizophrenia is a complex polygenic disease that is affected by genetic, developmental, and environmental factors. Accumulating evidence indicates that environmental factors such as maternal infection and excessive prenatal neuroinflammation may contribute to the onset of schizophrenia by affecting epigenetic modification. We recently identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA) RP5-998N21.4 by transcriptomic analysis of monozygotic twins discordant for schizophrenia. Importantly, we found that genes coexpressed with RP5-998N21.4 were enriched in immune defense-related biological processes in twin subjects and in RP5-998N21.4-overexpressing (OE) SK-N-SH cell lines. We then identified two genes encoding an interferon-induced protein with tetratricopeptide repeat (IFIT) 2 and 3, which play an important role in immune defense, as potential targets of RP5-998N21.4 by integrative analysis of RP5-998N21.4OE-induced differentially expressed genes (DEGs) in SK-N-SH cells and RP5-998N21.4-coexpressed schizophrenia-associated DEGs from twin subjects. We further demonstrated that RP5-998N21.4 positively regulates the transcription of IFIT2 and IFIT3 by binding to their promoter regions and affecting their histone modifications. In addition, as a general nuclear coactivator, RMB14 (encoding RNA binding motif protein 14) was identified to facilitate the regulatory role of RP5-998N21.4 in IFIT2 and IFIT3 transcription. Finally, we observed that RP5-998N21.4OE can enhance IFIT2- and IFIT3-mediated immune defense responses through activation of signal transducer and activator of transcription 1 (STAT1) signaling pathway in U251 astrocytoma cells under treatment with the viral mimetic polyinosinic: polycytidylic acid (poly I:C). Taken together, our findings suggest that lncRNA RP5-998N21.4 is a critical regulator of immune defense, providing etiological and therapeutic implications for schizophrenia.
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The non-Mendelian features of phenotypic variations within monozygotic twins are likely complicated by environmental modifiers of genetic effects that have yet to be elucidated. Here, we performed methylome and genome analyses of blood DNA from psychiatric disorder-discordant monozygotic twins to study how allele-specific methylation (ASM) mediates phenotypic variations. We identified that thousands of genetic variants with ASM imbalances exhibit phenotypic variation-associated switching at regulatory loci. These ASMs have plausible causal associations with psychiatric disorders through effects on interactions between transcription factors, DNA methylations, and other epigenomic markers and then contribute to dysregulated gene expression, which eventually increases disease susceptibility. Moreover, we also experimentally validated the model that the rs4854158 alternative C allele at an ASM switching regulatory locus of EIPR1 encoding endosome-associated recycling protein-interacting protein 1, is associated with demethylation and higher RNA expression and shows lower TF binding affinities in unaffected controls. An epigenetic ASM switching induces C allele hypermethylation and then recruits repressive Polycomb repressive complex 2 (PRC2), reinforces trimethylation of lysine 27 on histone 3 and inhibits its transcriptional activity, thus leading to downregulation of EIPR1 in schizophrenia. Moreover, disruption of rs4854158 induces gain of EIPR1 function and promotes neural development and vesicle trafficking. Our study provides a powerful framework for identifying regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic variants in mediating psychiatric disorder susceptibility.
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Metilación de ADN , Proteínas Nucleares/genética , Esquizofrenia , Alelos , Metilación de ADN/genética , Epigénesis Genética/genética , Humanos , Regiones Promotoras Genéticas , Esquizofrenia/genética , Gemelos Monocigóticos/genéticaRESUMEN
Genome-wide association studies (GWAS) have accelerated the discovery of numerous genetic variants associated with schizophrenia. However, most risk variants show a small effect size (odds ratio (OR) <1.2), suggesting that more functional risk variants remain to be identified. Here, we employed region-based multi-marker analysis of genomic annotation (MAGMA) to identify additional risk loci containing variants with large OR value from Psychiatry Genomics Consortium (PGC2) schizophrenia GWAS data and then employed summary-data-based mendelian randomization (SMR) to prioritize schizophrenia susceptibility genes. The top-ranked susceptibility gene ATP5MD, encoding an ATP synthase membrane subunit, is observed to be downregulated in schizophrenia by the risk allele of CNNM2-rs1926032 in the schizophrenia-associated 10q24.32 locus. The Atp5md knockout (KO) in mice was associated with abnormal startle reflex and gait, and ATP5MD knockdown (KD) in human induced pluripotent stem cell-derived neurons disrupted the neural development and mitochondrial respiration and ATP production. Moreover, CNNM2-rs1926032 KO could induce downregulation of ATP5MD expression and disruptions of mitochondrial respiration and ATP production. This study constitutes an important mechanistic component that links schizophrenia-associated CNNM2 regions to disruption in energy adenosine system modulation and neuronal function by long-distance chromatin domain downregulation of ATP5MD. This pathogenic mechanism provides therapeutic implications for schizophrenia.
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BACKGROUND: To investigate the readiness for hospital discharge of patients discharged with tubes from the department of hepatobiliary surgery and to explore the influencing factors. METHODS: A cross-sectional survey was conducted for the 161 patients with tubes who were discharged from the department of hepatobiliary surgery of Shaoxing Second Hospital by using the modified Chinese version of Readiness for Hospital Discharge Scale (RHDS) and Quality of Discharge Teaching Scale (QDTS). General data of the patients, such as gender, age, BMI (body mass index), and educational level, were collected. RESULTS: According to the statistical results, the total score of the RHDS was 142.40 ± 23.98, and that of the QDTS was 148.14 ± 17.74. Multiple linear step-wise regression analysis revealed that the total score of the QDTS, residence and educational level were the independent influencing factors of the readiness for hospital discharge (p < 0.05). CONCLUSION: The level of the readiness for hospital discharge of the 161 discharged patients with tubes from the department of hepatobiliary surgery was in the middle and lower level. For the patients who are far away from the hospital and have a low education level, we should pay more attention to health education and discharge teaching, so as to improve the readiness for hospital discharge of relatively vulnerable patients, reduce the incidence of adverse events after discharge with tubes, and ensure the health and safety of patients.