A novel coronavirus disease, designated as COVID-19, has become a pandemic worldwide. This study aims to estimate the incubation period and serial interval of COVID-19. We collected contact tracing ...data in a municipality in Hubei province during a full outbreak period. The date of infection and infector–infectee pairs were inferred from the history of travel in Wuhan or exposed to confirmed cases. The incubation periods and serial intervals were estimated using parametric accelerated failure time models, accounting for interval censoring of the exposures. Our estimated median incubation period of COVID-19 is 5.4 days (bootstrapped 95% confidence interval (CI) 4.8–6.0), and the 2.5th and 97.5th percentiles are 1 and 15 days, respectively; while the estimated serial interval of COVID-19 falls within the range of −4 to 13 days with 95% confidence and has a median of 4.6 days (95% CI 3.7–5.5). Ninety-five per cent of symptomatic cases showed symptoms by 13.7 days (95% CI 12.5–14.9). The incubation periods and serial intervals were not significantly different between male and female, and among age groups. Our results suggest a considerable proportion of secondary transmission occurred prior to symptom onset. And the current practice of 14-day quarantine period in many regions is reasonable.
Ongoing studies have determined that the gut microbiota is a major factor influencing both health and disease. Host genetic factors and environmental factors contribute to differences in gut ...microbiota composition and function. Intestinal dysbiosis is a cause or a contributory cause for diseases in multiple body systems, ranging from the digestive system to the immune, cardiovascular, respiratory, and even nervous system. Investigation of pathogenesis has identified specific species or strains, bacterial genes, and metabolites that play roles in certain diseases and represent potential drug targets. As research progresses, gut microbiome–based diagnosis and therapy are proposed and applied, which might lead to considerable progress in precision medicine. We further discuss the limitations of current studies and potential solutions.
Chemokine levels in severe coronavirus disease 2019 (COVID-19) patients have been shown to be markedly elevated. But the role of chemokines in mild COVID-19 has not yet been established. According to ...the epidemiological statistics, most of the COVID-19 cases in Shiyan City, China, have been mild. The purpose of this study was to evaluate the level of chemokines in mild COVID-19 patients and explore the correlation between chemokines and host immune response.
In this study, we used an enzyme-linked immunosorbent assay to detect serum levels of chemokines in COVID-19 patients in Shiyan City. Expression of chemokine receptors and of other signaling molecules was measured by real-time polymerase chain reaction.
We first demonstrated that COVID-19 patients, both sever and mild cases, are characterized by higher level of chemokines. Specifically, monocyte chemotactic protein 1 (MCP-1) is expressed at higher levels both in severe and mild cases of COVID-19. The receptor of MCP-1, C-C chemokine receptor type 2, was expressed at higher levels in mild COVID-19 patients. Finally, we observed a significant negative correlation between expression levels of interferon (IFN) regulatory factor 3 (IRF3) and serum levels of MCP-1 in mild COVID-19 patients.
Higher expression of MCP-1 in mild COVID-19 patients might be correlated with inhibition of IFN signaling. The finding adds to our understanding of the immunopathological mechanisms of severe acute respiratory syndrome coronavirus 2 infection and provides potential therapeutic targets and strategies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Autism spectrum disorders and epilepsies are heterogeneous human disorders that have miscellaneous etiologies and pathophysiology. There is considerable risk of frequent epilepsy in autism that ...facilitates amplified morbidity and mortality. Several biological pathways appear to be involved in disease progression, including gene transcription regulation, cellular growth, synaptic channel function, and maintenance of synaptic structure. Here, abnormalities in excitatory/inhibitory (E/I) balance ratio are reviewed along with part of an epileptiform activity that may drive both overconnectivity and genetic disorders where autism spectrum disorders and epilepsy frequently co-occur. The most current ideas concerning common etiological and molecular mechanisms for co-occurrence of both autism spectrum disorders and epilepsy are discussed along with the powerful pharmacological therapies that protect the cognition and behavior of patients. Better understanding is necessary to identify a biological mechanism that might lead to possible treatments for these neurological disorders.
Acid–base homeostasis is critical for proper physiological function and pathology. The SLC4 family of HCO3− transmembrane cotransporters is one of the HCO3− transmembrane transport carriers ...responsible for cellular pH regulation and the uptake or secretion of HCO3− in epithelial cells. NBCn1 (SLC4A7), an electroneutral Na+/HCO3− cotransporter, is extensively expressed in several tissues and functions as a cotransporter for net acid extrusion after cellular acidification. However, the expression and activity level of NBCn1 remain elusive. In addition, NBCn1 has been involved in numerous other cellular processes such as cell volume, cell death/survival balance, transepithelial transport, as well as regulation of cell viability. This review aims to give an inclusive overview of the most recent advances in the research of NBCn1, emphasizing the basic features, regulation, and tissue-specific physiology as well as the development and application of potent inhibitors of NBCn1 transporter in cancer therapy. Research and development of targeted therapies should be carried out for NBCn1 and its associated pathways.
Increased reactive oxygen species levels in the mitochondrial matrix can induce Parkin-dependent mitophagy, which selectively degrades dysfunctional mitochondria via the autolysosome pathway. ...Phosphorylated mitofusin-2 (MFN2), a receptor of parkin RBR E3 ubiquitin-protein ligase (Parkin), interacts with Parkin to promote the ubiquitination of mitochondrial proteins; meanwhile, the mitophagy receptors Optineurin (OPTN) and nuclear dot protein 52 (NDP52) are recruited to damaged mitochondria to promote mitophagy. However, previous studies have not investigated changes in the levels of OPTN, MFN2, and NDP52 during Parkin-mediated mitophagy. Here, we show that mild and sustained hydrogen peroxide (H
O
) stimulation induces Parkin-dependent mitophagy accompanied by downregulation of the mitophagy-associated proteins OPTN, NDP52, and MFN2. We further demonstrate that H
O
promotes the expression of the miR-106b-93-25 cluster and that miR-106b and miR-93 synergistically inhibit the translation of OPTN, NDP52, and MFN2 by targeting their 3' untranslated regions. We further reveal that compromised phosphorylation of MYC proto-oncogene protein (c-Myc) at threonine 58 (T58) (producing an unstable form of c-Myc) caused by reduced nuclear glycogen synthase kinase-3 beta (GSK3β) levels contributes to the promotion of miR-106b-93-25 cluster expression upon H
O
induction. Furthermore, miR-106b-mediated and miR-93-mediated inhibition of mitophagy-associated proteins (OPTN, MFN2, and NDP52) restrains cell death by controlling excessive mitophagy. Our data suggest that microRNAs (miRNAs) targeting mitophagy-associated proteins maintain cell survival, which is a novel mechanism of mitophagy control. Thus, our findings provide mechanistic insight into how miRNA-mediated regulation alters the biological process of mitophagy.
Upon activation by the pathogen through T-cell receptors (TCRs), γδT cells suppress the pathogenic replication and thus play important roles against viral infections. Targeting SARS-CoV-2
via
γδT ...cells provides alternative therapeutic strategies. However, little is known about the recognition of SARS-CoV-2 antigens by γδT cells. We discovered a specific Vγ9/δ2 CDR3 by analyzing γδT cells derived from the patients infected by SARS-CoV-2. Using a cell model exogenously expressing γδ-TCR established, we further screened the structural motifs within the CDR3 responsible for binding to γδ-TCR. Importantly, these sequences were mapped to NSP8, a non-structural protein in SARS-CoV-2. Our results suggest that NSP8 mediates the recognition by γδT cells and thus could serve as a potential target for vaccines.
Parkinson's disease is a neurodegenerative disorder, and ferroptosis plays a significant role in the pathological mechanism underlying Parkinson's disease. Rapamycin, an autophagy inducer, has been ...shown to have neuroprotective effects in Parkinson's disease. However, the link between rapamycin and ferroptosis in Parkinson's disease is not entirely clear. In this study, rapamycin was administered to a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease mouse model and a 1-methyl-4-phenylpyridinium-induced Parkinson's disease PC12 cell model. The results showed that rapamycin improved the behavioral symptoms of Parkinson's disease model mice, reduced the loss of dopamine neurons in the substantia nigra pars compacta, and reduced the expression of ferroptosis-related indicators (glutathione peroxidase 4, recombinant solute carrier family 7, member 11, glutathione, malondialdehyde, and reactive oxygen species). In the Parkinson's disease cell model, rapamycin improved cell viability and reduced ferroptosis. The neuroprotective effect of rapamycin was attenuated by a ferroptosis inducer (methyl (1S,3R)-2-(2-chloroacetyl)-1-(4-methoxycarbonylphenyl)-1,3,4,9-tetrahyyridoindole-3-carboxylate) and an autophagy inhibitor (3-methyladenine). Inhibiting ferroptosis by activating autophagy may be an important mechanism by which rapamycin exerts its neuroprotective effects. Therefore, the regulation of ferroptosis and autophagy may provide a therapeutic target for drug treatments in Parkinson's disease.
Cardiac hypertrophy is defined as increased heart mass in response to increased hemodynamic requirements. Long-term cardiac hypertrophy, if not counteracted, will ultimately lead to heart failure. ...The incidence of heart failure is related to myocardial infarction, which could be salvaged by reperfusion and ultimately invites unfavorable myocardial ischemia-reperfusion injury. The Na+/H+ exchangers (NHEs) are membrane transporters that exchange one intracellular proton for one extracellular Na+. The first discovered NHE isoform, NHE1, is expressed almost ubiquitously in all tissues, especially in the myocardium. During myocardial ischemia-reperfusion, NHE1 catalyzes increased uptake of intracellular Na+, which in turn leads to Ca2+ overload and subsequently myocardial injury. Numerous preclinical research has shown that NHE1 is involved in cardiac hypertrophy and heart failure, but the exact molecular mechanisms remain elusive. The objective of this review is to demonstrate the potential role of NHE1 in cardiac hypertrophy and heart failure and investigate the underlying mechanisms.
Although potassium channelopathies have been linked to a wide range of neurological conditions, the underlying pathogenic mechanism is not always clear, and a systematic summary of clinical ...manifestation is absent. Several neurological disorders have been associated with alterations of calcium-activated potassium channels (KCa channels), such as loss- or gain-of-function mutations, post-transcriptional modification, etc. Here, we outlined the current understanding of the molecular and cellular properties of three subtypes of KCa channels, including big conductance KCa channels (BK), small conductance KCa channels (SK), and the intermediate conductance KCa channels (IK). Next, we comprehensively reviewed the loss- or gain-of-function mutations of each KCa channel and described the corresponding mutation sites in specific diseases to broaden the phenotypic-genotypic spectrum of KCa-related neurological disorders. Moreover, we reviewed the current pharmaceutical strategies targeting KCa channels in KCa-related neurological disorders to provide new directions for drug discovery in anti-seizure medication.
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