A systematic review of environmental covariates and methods for spatial or temporal scrub typhus distribution prediction.

BACKGROUND: Scrub typhus is underdiagnosed and underreported but emerging as a global public health problem. To inform future burden and prediction studies we examined through a systematic review the potential effect of environmental covariates on scrub typhus occurrence and the methods which have been used for its prediction. METHODS: In this systematic review, we searched PubMed, Scopus, Web of Science, China National Knowledge Infrastructure and other databases, with no language and publication time restrictions, for studies that investigated environmental covariates or utilized methods to predict the spatial or temporal human. Data were manually extracted following a set of queries and systematic analysis was conducted. RESULTS: We included 68 articles published in 1978-2024 with relevant data from 7 countries/regions. Significant environmental risk factors for scrub typhus include temperature (showing positive or inverted-U relationships), precipitation (with positive or inverted-U patterns), humidity (exhibiting complex positive, inverted-U, or W-shaped associations), sunshine duration (with positive, inverted-U associations), elevation, the normalized difference vegetation index (NDVI), and the proportion of cropland. Socioeconomic and biological factors were rarely explored. Autoregressive Integrated Moving Average (ARIMA) (n = 8) and ecological niche modelling (ENM) approach (n = 11) were the most popular methods for predicting temporal trends and spatial distribution of scrub typhus, respectively. CONCLUSIONS: Our findings summarized the evidence on environmental covariates affecting scrub typhus occurrence and the methodologies used for predictive modelling. We review the existing knowledge gaps and outline recommendations for future studies modelling disease prediction and burden. TRIAL REGISTRATION: PROSPERO CRD42022315209.

A novel nonsense mutation c.747C>G in the NEUROD1 gene detected within a Chinese family affected by maturity-onset diabetes of the young type 6.

Highlights Maturity-onset diabetes of the young type 6 (MODY6) is a rare form of monogenic diabetes mellitus due to NEUROD1 gene mutation on chromosome 2q32. A 21-year-old woman exhibiting weight loss, polyuria, and hyperglycemia was initially misdiagnosed with type 1 diabetes mellitus. Considering the early-onset age, a three-generation family history of diabetes, and negative autoimmune antibodies, a MODY diagnosis was suspected. Genetic analysis revealed that she inherited a novel heterozygous nonsense NEUROD1 mutation c.747C>G (p.Tyr249*) from her father. Correct MODY6 diagnosis facilitates appropriate interventions.

Vascular endothelial growth factor receptor 2 as a potential host target for the inhibition of enterovirus replication.

Because host kinases are key regulators of multiple signaling pathways in response to viral infections, we previously screened a kinase inhibitor library using rhabdomyosarcoma cells and human intestinal organoids in parallel to identify potent inhibitors against EV-A71 infection. We found that Rho-associated coiled-coil-containing protein kinase (Rock) inhibitor efficiently suppressed the EV-A71 replication and further revealed Rock1 as a novel EV-A71 host factor. In this study, subsequent analysis found that a variety of vascular endothelial growth factor receptor (VEGFR) inhibitors also had potent antiviral effects. Among the hits, Pazopanib, with a selectivity index as high as 254, which was even higher than that of Pirodavir, a potent broad-spectrum picornavirus inhibitor targeting viral capsid protein VP1, was selected for further analysis. We demonstrated that Pazopanib not only efficiently suppressed the replication of EV-A71 in a dose-dependent manner, but also exhibited broad-spectrum anti-enterovirus activity. Mechanistically, Pazopanib probably induces alterations in host cells, thereby impeding viral genome replication and transcription. Notably, VEGFR2 knockdown and overexpression suppressed and facilitated EV-A71 replication, respectively, indicating that VEGFR2 is a novel host dependency factor for EV-A71 replication. Transcriptome analysis further proved that VEGFR2 potentially plays a crucial role in combating EV-A71 infection through the TSAd-Src-PI3K-Akt pathway. These findings expand the range of potential antiviral candidates of anti-enterovirus therapeutics and suggest that VEGFR2 may be a key host factor involved in EV-A71 replication, making it a potential target for the development of anti-enterovirus therapeutics. IMPORTANCE: As the first clinical case was identified in the United States, EV-A71, a significant neurotropic enterovirus, has been a common cause of hand, foot, and mouth disease (HFMD) in infants and young children. Developing an effective antiviral agent for EV-A71 and other human enteroviruses is crucial, as these viral pathogens consistently cause outbreaks in humans. In this study, we demonstrated that multiple inhibitors against VEGFRs effectively reduced EV-A71 replication, with Pazopanib emerging as the top candidate. Furthermore, Pazopanib also attenuated the replication of other enteroviruses, including CVA10, CVB1, EV-D70, and HRV-A, displaying broad-spectrum anti-enterovirus activity. Given that Pazopanib targets various VEGFRs, we narrowed the focus to VEGFR2 using knockdown and overexpression experiments. Transcriptomic analysis suggests that Pazopanib's potential downstream targets involve the TSAd-Src-PI3K-Akt pathway. Our work may contribute to identifying targets for antiviral inhibitors and advancing treatments for human enterovirus infections.

Gut microbial metabolism in ferroptosis and colorectal cancer.

Ferroptosis is programmed cell death induced by iron-driven lipid peroxidation. Numerous studies have shown that ferroptosis is implicated in the progression of colorectal cancer (CRC) and has emerged as a promising strategy to combat therapy-resistant CRC. While the intrinsic antiferroptotic and proferroptotic pathways in CRC cells have been well characterized, extrinsic metabolism pathways regulating ferroptosis in CRC pathogenesis remain less understood. Emerging evidence shows that gut microbial metabolism is tightly correlated with the progression of CRC. This review provides an overview of gut microbial metabolism and discusses how these metabolites derived from intestinal microflora contribute to cancer plasticity through ferroptosis. Targeting gut microbe-mediated ferroptosis is a potential approach for CRC treatment.

Apoptotic vesicle-mediated senolytics requires mechanical loading.

Rationale: Mechanical force plays crucial roles in extracellular vesicle biogenesis, release, composition and activity. However, it is unknown whether mechanical force regulates apoptotic vesicle (apoV) production. Methods: The effects of mechanical unloading on extracellular vesicles of bone marrow were evaluated through morphology, size distribution, yield, and protein mass spectrometry analysis using hindlimb unloading (HU) mouse model. Apoptosis resistance and aging related phenotype were assessed using HU mouse model in vivo and cell microgravity model in vitro. The therapeutic effects of apoVs on HU mouse model were assessed by using microcomputed tomography, histochemical and immunohistochemical, as well as histomorphometry analyses. SiRNA and chemicals were used for gain and loss-of-function assay. Results: In this study, we show that loss of mechanical force led to cellular apoptotic resistance and aging related phenotype, thus reducing the number of apoVs in the circulation due to down-regulated expression of Piezo1 and reduced calcium influx. And systemic infusion of apoVs was able to rescue Piezo1 expression and calcium influx, thereby, rescuing mechanical unloading-induced cellular apoptotic resistance, senescent cell accumulation. Conclusions: This study identified a previously unknown role of mechanical force in maintaining apoptotic homeostasis and eliminating senescent cells. Systemic infusion of mesenchymal stem cell-derived apoVs can effectively rescue apoptotic resistance and eliminate senescent cells in mechanical unloading mice.

Loss-of-function variants in RNA binding motif protein X-linked induce neuronal defects contributing to amyotrophic lateral sclerosis pathogenesis.

Despite being one of the most prevalent RNA modifications, the role of N6-methyladenosine (m6A) in amyotrophic lateral sclerosis (ALS) remains ambiguous. In this investigation, we explore the contribution of genetic defects of m6A-related genes to ALS pathogenesis. We scrutinized the mutation landscape of m6A genes through a comprehensive analysis of whole-exome sequencing cohorts, encompassing 508 ALS patients and 1660 population-matched controls. Our findings reveal a noteworthy enrichment of RNA binding motif protein X-linked (RBMX) variants among ALS patients, with a significant correlation between pathogenic m6A variants and adverse clinical outcomes. Furthermore, Rbmx knockdown in NSC-34 cells overexpressing mutant TDP43Q331K results in cell death mediated by an augmented p53 response. Similarly, RBMX knockdown in ALS motor neurons derived from induced pluripotent stem cells (iPSCs) manifests morphological defects and activation of the p53 pathway. Transcriptional analysis using publicly available single-cell sequencing data from the primary motor cortex indicates that RBMX-regulated genes selectively influence excitatory neurons and exhibit enrichment in ALS-implicated pathways. Through integrated analyses, our study underscores the emerging roles played by RBMX in ALS, suggesting a potential nexus between the disease and dysregulated m6A-mediated mRNA metabolism.

Research status and hotspots of tight junctions and colorectal cancer: A bibliometric and visualization analysis.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death. Over the past two decades, numerous researchers have provided important evidence regarding the role of tight junction (TJ) proteins in the occurrence and progression of CRC. The causal relationship between the presence of specific TJ proteins and the development of CRC has also been confirmed. Despite the large number of publications in this field, a bibliometric study to review the current state of research and highlight the research trends and hotspots in this field has not yet been performed. AIM: To analyze research on TJs and CRC, summarize the field's history and current status, and predict future research directions. METHODS: We searched the Science Citation Index Expanded database for all literature on CRC and TJs from 2001-2023. We used bibliometrics to analyze the data of these papers, such as the authors, countries, institutions, and references. Co-authorship, co-citation, and co-occurrence analyses were the main methods of analysis. CiteSpace and VOSviewer were used to visualize the results. RESULTS: A total of 205 studies were ultimately identified. The number of publications on this topic has steadily increased since 2007. China and the United States have made the largest contributions to this field. Anticancer Research was the most prolific journal, publishing 8 articles, while the journal Oncogene had the highest average citation rate (68.33). Professor Dhawan P was the most prolific and cited author in this field. Co-occurrence analysis of keywords revealed that "tight junction protein expression", "colorectal cancer", "intestinal microbiota", and "inflammatory bowel disease" had the highest frequency of occurrence, revealing the research hotspots and trends in this field. CONCLUSION: This bibliometric analysis evaluated the scope and trends of TJ proteins in CRC, providing valuable research perspectives and future directions for studying the connection between the two. It is recommended to focus on emerging research hotspots, such as the correlations among intestinal microbiota, inflammatory bowel disease, TJ protein expression, and CRC.

Plant natural product-based pesticides in crop protection: semi-synthesis, mono-crystal structures and agrochemical activities of osthole ester derivatives, and study of their toxicology against Tetranychus cinnabarinus (Boisduval).

BACKGROUND: Owing to large amounts of synthetic pesticides being extensively and unreasonably used for crop protection, currently, resistance and negative impacts on human health and environment safety have appeared. Therefore, development of potential pesticide candidates is highly urgent. Herein, a series of ester derivatives of osthole were designed and synthesized as pesticidal agents. RESULTS: Six spatial configurations of 4'-(p-toluenoyloxy)osthole (4b), 4'-(m-fluorobenzoyloxy)osthole (4f), 4'-(p-fluorophenylacetyloxy)osthole (4m), 4'-(3'',4''-methylenedioxybenzoyloxy)osthole (4q), 4'-formyloxyosthole (4u) and 4'-acetyloxyosthole (4v) were determined by X-ray mono-crystal diffraction. Compounds 4b, 4'-(p-chlorobenzoyloxy)osthole (4g), 4'-(m-chlorobenzoyloxy)osthole (4h), 4'-(p-bromobenzoyloxy)osthole (4i) and 4'-(2''-chloropyridin-3''-ylcarbonyloxy)osthole (4p) showed higher insecticidal activity than toosendanin against Mythimna separata Walker; notably, compound 4b displayed 1.8 times insecticidal activity of the precursor osthole. Against Tetranychus cinnabarinus Boisduval, compounds 4g and 4h showed 3.3 and 2.6 times acaricidal activity of osthole, and good control effects in the glasshouse. Scanning electron microscopy assay demonstrated that compound 4g can damage the cuticle layer of T. cinnabarinus resulting in death. CONCLUSION: Compounds 4g and 4h can be further studied as lead pesticidal agents for the management of M. separata and T. cinnabarinus. These results will pave the way for application of osthole derivatives as agrochemicals. © 2024 Society of Chemical Industry.

[Research Progress in the Role of the Ventral Tegmental Area-Medial Prefrontal Cortex Neural Circuit in the Regulation of Arousal].

There are mutual neural projections between the ventral tegmental area (VTA) and the medial prefrontal cortex (mPFC),which form a circuit.Recent studies have shown that this circuit is vital in regulating arousal from sleep and general anesthesia.This paper introduces the anatomical structures of VTA and mPFC and the roles of various neurons and projection pathways in the regulation of arousal,aiming to provide new ideas for further research on the mechanism of arousal from sleep and general anesthesia.

Longitudinal on-treatment circulating tumor DNA as a biomarker for real-time dynamic risk monitoring in cancer patients: The EP-SEASON study.

Recurrence risks of cancer patient can change during treatment as a result of treatment-related tumor evolution. However, biomarkers that can monitor these changes are lacking. Here, we investigated whether tracking circulating tumor DNA (ctDNA) dynamics through liquid biopsy can inform real-time recurrence risk. Nasopharyngeal carcinoma (NPC) provides an ideal model where cell-free Epstein-Barr virus (EBV) DNA (cfEBV DNA), a ctDNA, can be sensitively detected. We conducted the EP-SEASON study (NCT03855020) and prospectively recruited 1,000 NPC patients undergoing per-protocol cfEBV DNA assessments at 11 time points and receiving sequential chemo-radiotherapy. Longitudinal cfEBV DNA displayed distinct patterns during neoadjuvant chemotherapy and radiotherapy. Despite the prognostic significance of cfEBV DNA at each time point, real-time recurrence risks changed in sync with cfEBV DNA dynamics. Furthermore, we identified phenotypes of whole-course ctDNA changing dynamics associated with different survival outcomes. In conclusion, tracking longitudinal on-treatment ctDNA can forecast real-time recurrence risk, facilitating risk-adapted, individualized patient management.

Heterogeneous associations of multiplexed environmental factors and multidimensional aging metrics.

Complicated associations between multiplexed environmental factors and aging are poorly understood. We manipulated aging using multidimensional metrics such as phenotypic age, brain age, and brain volumes in the UK Biobank. Weighted quantile sum regression was used to examine the relative individual contributions of multiplexed environmental factors to aging, and self-organizing maps (SOMs) were used to examine joint effects. Air pollution presented a relatively large contribution in most cases. We also found fair heterogeneities in which the same environmental factor contributed inconsistently to different aging metrics. Particulate matter contributed the most to variance in aging, while noise and green space showed considerable contribution to brain volumes. SOM identified five subpopulations with distinct environmental exposure patterns and the air pollution subpopulation had the worst aging status. This study reveals the heterogeneous associations of multiplexed environmental factors with multidimensional aging metrics and serves as a proof of concept when analyzing multifactors and multiple outcomes.

Modeling and biological evaluation of pegmolesatide, a novel and potent erythropoiesis-stimulating agent.

Pegmolesatide, a synthetic, polyethylene-glycolylated, peptide-based erythropoiesis-stimulating agent (ESA), has been recently approved in China. Pegmolesatide is derived from the structure of endogenous erythropoietin (EPO), a natural product in mammals. This study compared the in vitro effects and selectivity of pegmolesatide to those of recombinant EPO and carbamylated EPO (CEPO) through computer-aided analyses and biological tests. The findings indicate that pegmolesatide exhibited the same stimulating effect on erythropoiesis as EPO with fewer side effects than EPO and CEPO.

Natural selection shaped the protective effect of the mtDNA lineage against obesity in Han Chinese populations.

Mitochondria play a key role in lipid metabolism, and mitochondrial DNA (mtDNA) mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function. In this study, we investigated mtDNA variants that may affect obesity risk in 2877 Han Chinese individuals from three independent populations. The association analysis of 16 basal mtDNA haplogroups with body mass index, waist circumference, and waist-to-hip ratio revealed that only haplogroup M7 was significantly negatively correlated with all three adiposity-related anthropometric traits in the overall cohort, verified by the analysis of a single population, i.e., the Zhengzhou population. Furthermore, subhaplogroup analysis suggested that M7b1a1 was the most likely haplogroup associated with a decreased obesity risk, and the variation T12811C (causing Y159H in ND5) harbored in M7b1a1 may be the most likely candidate for altering the mitochondrial function. Specifically, we found that proportionally more nonsynonymous mutations accumulated in M7b1a1 carriers, indicating that M7b1a1 was either under positive selection or subject to a relaxation of selective constraints. We also found that nuclear variants, especially in DACT2 and PIEZO1, may functionally interact with M7b1a1.

Influence of EGCG oxidation on inhibitory activity against the SARS-CoV-2 main protease.

SARS-CoV-2 main protease (Mpro) is a well-recognized target for COVID-19 therapy. Green tea (-)-epigallocatechin-3-gallate (EGCG) possesses Mpro-inhibitory activity; however, the influence of EGCG oxidation on its inhibition activity remains obscure, given its high oxidation propensity. This study reveals that prolonged EGCG oxidation in the presence of Mpro dramatically increases its inhibitory activity with an IC50 of 0.26 µM. The inhibitory mechanism is that EGCG-quinone preferentially binds the active site Mpro-Cys145-SH, which forms a quinoprotein. Though Mpro is present in the cell lysate, EGCG preferentially depletes its thiols. Non-cytotoxic EGCG effectively generates a quinoprotein in living cells, thus EGCG might selectively inhibit Mpro in SARS-CoV-2 infected cells. Chlorogenic acid facilitates EGCG oxidation. Together, they synergistically deplete multiple Mpro thiols though this is not more beneficial than EGCG alone. By contrast, excessive EGCG oxidation prior to incubation with Mpro largely compromises its inhibitory activity. Overall, the low IC50 and the high selectivity imply that EGCG is a promising dietary Mpro inhibitor. While EGCG oxidation in the presence of Mpro has a pivotal role in inhibition, enhancing EGCG oxidation by chlorogenic acid no longer increases its inhibitory potential. EGCG oxidation in the absence of Mpro should be avoided to maximize its Mpro-inhibitory activity.

Loss of ADAR1 induces ferroptosis of breast cancer cells.

Adenosine deaminases acting on RNA 1(ADAR1), an RNA editing enzyme that converts adenosine to inosine by deamination in double-stranded RNAs, plays an important role in occurrence and progression of various types of cancer. Ferroptosis has emerged as a hot topic of cancer research in recent years. We have previously reported that ADAR1 promotes breast cancer progression by regulating miR-335-5p and METTL3. However, whether ADAR1 has effects on ferroptosis in breast cancer cells is largely unknown. In this study, we knocked down ADAR1 using CRISPR-Cas9 technology or over-expressed ADAR1 protein using plasmid expressing ADAR1 in MCF-7 and MDA-MB-231 breast cancer cell lines, then detected cell viability, and levels of ROS, MDA, GSH, Fe2+, GPX4 protein and miR-335-5p. We showed that the cell proliferation was inhibited, levels of ROS, MDA, Fe2+, and miR-335-5p were increased, while GSH and GPX4 levels were decreased after loss of ADAR1, compared to the control group. The opposite effects were observed after ADAR1 overexpression in the cells. Further, we demonstrated that ADAR1-controlled miR-335-5p targeted Sp1 transcription factor of GPX4, a known ferroptosis molecular marker, leading to inhibition of ferroptosis by ADAR1 in breast cancer cells. Moreover, RNA editing activity of ADAR1 is not essential for inducing ferroptosis. Collectively, loss of ADAR1 induces ferroptosis in breast cancer cells by regulating miR-335-5p/Sp1/GPX4 pathway. The findings may provide insights into the mechanism by which ADAR1 promotes breast cancer progression via inhibiting ferroptosis.

Ratio of Red Blood Cell Distribution Width to Albumin Level and Risk of Mortality.

Importance: The ratio of red blood cell distribution width (RDW) to albumin concentration (RAR) has emerged as a reliable prognostic marker for mortality in patients with various diseases. However, whether RAR is associated with mortality in the general population remains unknown. Objectives: To explore whether RAR is associated with all-cause and cause-specific mortality and to elucidate their dose-response association. Design, Setting, and Participants: This population-based prospective cohort study used data from participants in the 1998-2018 US National Health and Nutrition Examination Survey (NHANES) and from the UK Biobank with baseline information provided from 2006 to 2010. Included participants had complete data on serum albumin concentration, RDW, and cause of death. The NHANES data were linked to the National Death Index records through December 31, 2019. For the UK Biobank, dates and causes of death were obtained from the National Health Service Information Centre (England and Wales) and the National Health Service Central Register Scotland (Scotland) to November 30, 2022. Main Outcomes and Measures: Potential associations between RAR and the risk of all-cause and cause-specific mortality were evaluated using Cox proportional hazards regression models. Restricted cubic spline regressions were applied to estimate possible nonlinear associations. Results: In NHANES, 50 622 participants 18 years of age or older years were included (mean [SD] age, 48.6 [18.7] years; 26 136 [51.6%] female), and their mean (SD) RAR was 3.15 (0.51). In the UK Biobank, 418 950 participants 37 years of age or older (mean [SD], 56.6 [8.1] years; 225 038 [53.7%] female) were included, and their mean RAR (SD) was 2.99 (0.31). The NHANES documented 7590 deaths over a median (IQR) follow-up of 9.4 (5.1-14.2) years, and the UK Biobank documented 36 793 deaths over a median (IQR) follow-up of 13.8 (13.0-14.5) years. According to the multivariate analysis, elevated RAR was significantly associated with greater risk of all-cause mortality (NHANES: hazard ratio [HR], 1.83 [95% CI, 1.76-1.90]; UK Biobank: HR, 2.08 [95% CI, 2.03-2.13]), as well as mortality due to malignant neoplasm (NHANES: HR, 1.89 [95% CI, 1.73-2.07]; UK Biobank: HR, 1.93 [95% CI, 1.86-2.00]), heart disease (NHANES: HR, 1.88 [95% CI, 1.74-2.03]; UK Biobank: HR, 2.42 [95% CI, 2.29-2.57]), cerebrovascular disease (NHANES: HR, 1.35 [95% CI, 1.07-1.69]; UK Biobank: HR, 2.15 [95% CI, 1.91-2.42]), respiratory disease (NHANES: HR, 1.99 [95% CI, 1.68-2.35]; UK Biobank: HR, 2.96 [95% CI, 2.78-3.15]), diabetes (NHANES: HR, 1.55 [95% CI, 1.27-1.90]; UK Biobank: HR, 2.83 [95% CI, 2.35-3.40]), and other causes of mortality (NHANES: HR, 1.97 [95% CI, 1.86-2.08]; UK Biobank: HR, 2.40 [95% CI, 2.30-2.50]) in both cohorts. Additionally, a nonlinear association was observed between RAR levels and all-cause mortality in both cohorts. Conclusions and Relevance: In this cohort study, a higher baseline RAR was associated with an increased risk of all-cause and cause-specific mortality in the general population. These findings suggest that RAR may be a simple, reliable, and inexpensive indicator for identifying individuals at high risk of mortality in clinical practice.

Analysis of an Aqueous Extract from Turkish Galls Based on Multicomponent Qualitative and Quantitative Analysis Combined with Network Pharmacology and Chemometric Analysis.

The current quality control method for Turkish gall (TG) is limited to assessing total tannin or gallic acid (GA), which offers a basic level of quality control but does not fully capture the true quality of TG. Therefore, it is essential to establish a comprehensive method that utilizes multiple indicators to assess the intrinsic quality of TG. This research utilized UPLC-Q-TOF-MS/MS technology to qualitatively analyze the chemical composition of TG. Subsequently, the potential main active ingredients, targets, and pathways of TG in treating recurrent aphthous ulcers (RAU) were explored and analyzed using network pharmacology technology. Quantitative analysis of multicomponents by single marker (QAMS) was then employed to quantify the primary pharmacodynamic components in TG. Finally, chemometrics analysis was utilized to interpret the measured results and identify the markers of scavenging quality. The study identified 36 chemical components in TG, highlighting ellagic acid (EA), GA, and so on as key components in treating RAU. A method for simultaneously determining GA, EA, 1,2,3,6-tetra-O-galloyl-ß-D-glucose (TEGG) and 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (PEGG) in TG was established. Statistical analysis revealed significant differences in the content of these 4 components across 14 batches of TG, with GA and PEGG identified as the primary contributors to the variations. This study determined a quality index for TG, providing a reference for quality evaluation and introducing a cost-effective and efficient quality control method. Furthermore, it addressed the challenge of developing new Chinese medicine by overcoming the lack of reference substances.

Dopamine and its precursor levodopa inactivate SARS-CoV-2 main protease by forming a quinoprotein.

Many studies show either the absence, or very low levels of, SARS-CoV-2 viral RNA and/or antigen in the brain of COVID-19 patients. Reports consistently indicate an abortive infection phenomenon in nervous cells despite the fact that they contain the SARS-CoV-2 receptor, ACE2. Dopamine levels in different brain regions are in the range of micromolar to millimolar concentrations. We have shown that sub-micromolar to low micromolar concentrations of dopamine or its precursor (levodopa) time- and dose-dependently inhibit the activity of SARS-CoV-2 main protease (Mpro), which is vital for the viral life cycle, by forming a quinoprotein. Thiol detection coupled with the assessment of Mpro activity suggests that among the 12 cysteinyl thiols, the active site, Cys145-SH, is preferentially conjugated to the quinone derived from the oxidation of dopamine or levodopa. LC-MS/MS analyses show that the Cys145-SH is covalently conjugated by dopamine- or levodopa-o-quinone. These findings help explain why SARS-CoV-2 causes inefficient replication in many nerve cell lines. It is well recognized that inhaled pulmonary drug delivery is the most robust therapy pathway for lung diseases. CVT-301 (orally inhaled levodopa) was approved by the FDA as a drug for Parkinson's patients prior to the outbreak of COVID-19 in 2018. Based on the fact that SARS-CoV-2 causes inefficient replication in the CNS with abundant endogenous Mpro inhibitor in addition to the current finding that levodopa has an Mpro-inhibitory effect somewhat stronger than dopamine, we should urgently investigate the use of CVT-301 as a lung-targeting, COVID-19, Mpro inhibitor.

Sex-Specific Association Between Childhood Adversity and Accelerated Biological Aging.

Is childhood adversity associated with biological aging, and if so, does sex modify the association, and do lifestyle and mental health mediate the association? A lifespan analysis is conducted using data on 142 872 participants from the UK Biobank to address these questions. Childhood adversity is assessed through the online mental health questionnaire (2016), including physical neglect, physical abuse, emotional neglect, emotional abuse, sexual abuse, and a cumulative score. Biological aging is indicated by telomere length (TL) measured from leukocyte DNA using qPCR, and the shorter TL indicates accelerated biological aging; a lifestyle score is constructed using body mass index, physical activity, drinking, smoking, and diet; mental disorder is assessed using depression, anxiety, and insomnia at the baseline survey. The results reveal a sex-specific association such that childhood adversity is associated with shorter TL in women after adjusting for covariates including polygenic risk score for TL, but not in men. Unhealthy lifestyle and mental disorder partially mediate the association in women. The proportions of indirect effects are largest for sexual and physical abuse. These findings highlight the importance of behavioral and psychological interventions in promoting healthy aging among women who experienced childhood adversity, particularly sexual and physical abuse.