Gasdermin D-mediated pyroptosis: mechanisms, diseases, and inhibitors.

Gasdermin D (GSDMD)-mediated pyroptosis and downstream inflammation are important self-protection mechanisms against stimuli and infections. Hosts can defend against intracellular bacterial infections by inducing cell pyroptosis, which triggers the clearance of pathogens. However, pyroptosis is a double-edged sword. Numerous studies have revealed the relationship between abnormal GSDMD activation and various inflammatory diseases, including sepsis, coronavirus disease 2019 (COVID-19), neurodegenerative diseases, nonalcoholic steatohepatitis (NASH), inflammatory bowel disease (IBD), and malignant tumors. GSDMD, a key pyroptosis-executing protein, is linked to inflammatory signal transduction, activation of various inflammasomes, and the release of downstream inflammatory cytokines. Thus, inhibiting GSDMD activation is considered an effective strategy for treating related inflammatory diseases. The study of the mechanism of GSDMD activation, the formation of GSDMD membrane pores, and the regulatory strategy of GSDMD-mediated pyroptosis is currently a hot topic. Moreover, studies of the structure of caspase-GSDMD complexes and more in-depth molecular mechanisms provide multiple strategies for the development of GSDMD inhibitors. This review will mainly discuss the structures of GSDMD and GSDMD pores, activation pathways, GSDMD-mediated diseases, and the development of GSDMD inhibitors.

Recycling spent masks to fabricate flexible hard carbon anode toward advanced sodium energy storage.

The massive discard of spent masks during the COVID-19 pandemic imposes great environmental anxiety to the human society, which calls for a reliable and sustainable outlet to mitigate this issue. In this work, we demonstrate a green design strategy of recycling the spent masks to fabricate hard carbon fabrics toward high-efficient sodium energy storage. After a simple carbonization treatment, flexible hard carbon fabrics composed of interwoven microtubular fibers are obtained. When serving as binder-free anodes of sodium-ion batteries, a large Na-ion storage capacity of 280 mAh g-1 is achieved for the optimized sample. More impressively, the flexible anode exhibits an initial coulombic efficiency of as high as 86% and excellent rate/cycling performance. The real-life practice of the flexible hard carbon is realized in the full-cells. The present study affords an enlightening approach for the recycling fabrication of high value-added hard carbon materials from the spent masks for advanced sodium energy storage.

Fortuitous somatic mutations during antibody evolution endow broad neutralization against SARS-CoV-2 Omicron variants.

Striking antibody evasion by emerging circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identify a clonally related antibody family from a convalescent individual. One of the members, XG005, exhibits potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members show significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface reveals how crucial somatic mutations endow XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality exhibits a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provide a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.

Multimodal representation learning for predicting molecule-disease relations.

MOTIVATION: Predicting molecule-disease indications and side effects is important for drug development and pharmacovigilance. Comprehensively mining molecule-molecule, molecule-disease and disease-disease semantic dependencies can potentially improve prediction performance. METHODS: We introduce a Multi-Modal REpresentation Mapping Approach to Predicting molecular-disease relations (M2REMAP) by incorporating clinical semantics learned from electronic health records (EHR) of 12.6 million patients. Specifically, M2REMAP first learns a multimodal molecule representation that synthesizes chemical property and clinical semantic information by mapping molecule chemicals via a deep neural network onto the clinical semantic embedding space shared by drugs, diseases and other common clinical concepts. To infer molecule-disease relations, M2REMAP combines multimodal molecule representation and disease semantic embedding to jointly infer indications and side effects. RESULTS: We extensively evaluate M2REMAP on molecule indications, side effects and interactions. Results show that incorporating EHR embeddings improves performance significantly, for example, attaining an improvement over the baseline models by 23.6% in PRC-AUC on indications and 23.9% on side effects. Further, M2REMAP overcomes the limitation of existing methods and effectively predicts drugs for novel diseases and emerging pathogens. AVAILABILITY AND IMPLEMENTATION: The code is available at https://github.com/celehs/M2REMAP, and prediction results are provided at https://shiny.parse-health.org/drugs-diseases-dev/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Impaired autophagy-accelerated senescence of alveolar type II epithelial cells drives pulmonary fibrosis induced by single-walled carbon nanotubes.

BACKGROUND: The rapid increase in production and application of carbon nanotubes (CNTs) has led to wide public concerns in their potential risks to human health. Single-walled CNTs (SWCNTs), as an extensively applied type of CNTs, have shown strong capacity to induce pulmonary fibrosis in animal models, however, the intrinsic mechanisms remain uncertain. RESULTS: In vivo experiments, we showed that accelerated senescence of alveolar type II epithelial cells (AECIIs) was associated with pulmonary fibrosis in SWCNTs-exposed mice, as well as SWCNTs-induced fibrotic lungs exhibited impaired autophagic flux in AECIIs in a time dependent manner. In vitro, SWCNTs exposure resulted in profound dysfunctions of MLE-12 cells, characterized by impaired autophagic flux and accelerated cellular senescence. Furthermore, the conditioned medium from SWCNTs-exposed MLE-12 cells promoted fibroblast-myofibroblast transdifferentiation (FMT). Additionally, restoration of autophagy flux with rapamycin significantly alleviated SWCNTs-triggered senescence and subsequent FMT whereas inhibiting autophagy using 3-MA aggravated SWCNTs-triggered senescence in MLE-12 cells and FMT. CONCLUSION: SWCNTs trigger senescence of AECIIs by impairing autophagic flux mediated pulmonary fibrosis. The findings raise the possibility of senescence-related cytokines as potential biomarkers for the hazard of CNTs exposure and regulating autophagy as an appealing target to halt CNTs-induced development of pulmonary fibrosis.

From study abroad to study at home: Spontaneous neuronal activity predicts depressive symptoms in overseas students during the COVID-19 pandemic.

The objective of this study was to evaluate symptoms of depression and anxiety as well as changes in spontaneous neuronal activity in college students studying abroad during the coronavirus 2019 (COVID-19) pandemic. We examined functional brain changes using resting-state functional magnetic resonance imaging (fMRI), the amplitude of low-frequency fluctuations (ALFF), and regional homogeneity (ReHo) in overseas students with enforced isolation due to the COVID-19 pandemic. Additionally, emotional assessments were administered to determine the severity of depression and anxiety. The questionnaire results showed that anxiety and depressive symptoms differed between overseas students (i.e., those attending an overseas college virtually) and local students (i.e., those attending a local college in person). The fMRI data revealed higher ALFF values in the bilateral superior medial frontal gyrus, bilateral pre-central gyrus, left insula, and left superior temporal gyrus as well as lower ALFF values in the bilateral paracentral lobule (supplementary motor area) in overseas students. Moreover, ReHo analysis also revealed significant differences between overseas students and local students. Compared with local students, overseas students showed significantly increased ReHo in the right inferior frontal and superior temporal gyri and decreased ReHo in the bilateral paracentral lobule, bilateral superior medial frontal gyrus (supplementary motor area), and bilateral pre-central gyrus. In addition, in overseas students, altered ReHo in the cluster including the left superior and medial frontal gyri, pre-central gyrus, and paracentral lobule was significantly positively correlated with Self-Rating Depression Scale scores. Thus, spontaneous brain activity in overseas students changed during the COVID-19 pandemic. This change in brain function might be related to depression and anxiety symptoms. These results suggest that mental health services are needed to decrease the risk of anxiety and depression among college students studying abroad during the COVID-19 pandemic.

Time-course RNA-Seq profiling reveals isoform-level gene expression dynamics of the cGAS-STING pathway.

The cGAS-STING pathway, orchestrating complicated transcriptome-wide immune responses, is essential for host antiviral defense but can also drive immunopathology in severe COVID-19. Here, we performed time-course RNA-Seq experiments to dissect the transcriptome expression dynamics at the gene-isoform level after cGAS-STING pathway activation. The in-depth time-course transcriptome after cGAS-STING pathway activation within 12 h enabled quantification of 48,685 gene isoforms. By employing regression models, we obtained 13,232 gene isoforms with expression patterns significantly associated with the process of cGAS-STING pathway activation, which were named activation-associated isoforms. The combination of hierarchical and k-means clustering algorithms revealed four major expression patterns of activation-associated isoforms, including two clusters with increased expression patterns enriched in cell cycle, autophagy, antiviral innate-immune functions, and COVID-19 coronavirus disease pathway, and two clusters showing decreased expression pattern that mainly involved in ncRNA metabolism, translation process, and mRNA processing. Importantly, by merging four clusters of activation-associated isoforms, we identified three types of genes that underwent isoform usage alteration during the cGAS-STING pathway activation. We further found that genes exhibiting protein-coding and non-protein-coding gene isoform usage alteration were strongly enriched for the factors involved in innate immunity and RNA splicing. Notably, overexpression of an enriched splicing factor, EFTUD2, shifted transcriptome towards the cGAS-STING pathway activated status and promoted protein-coding isoform abundance of several key regulators of the cGAS-STING pathway. Taken together, our results revealed the isoform-level gene expression dynamics of the cGAS-STING pathway and uncovered novel roles of splicing factors in regulating cGAS-STING pathway mediated immune responses.

Mental health status of adolescents after family confinement during the COVID-19 outbreak in the general population: a longitudinal survey.

Few studies have examined the psychological impact on adolescents of family confinement and infection exposure during the COVID-19 pandemic. However, these surveys lacked follow-up data to determine how the family confinement affects participants' depression and anxiety. The purpose of this study was to evaluate the psychological status and related risk and protective factors of adolescents after two months of family confinement for preventing COVID-19 in China, and compare them with baseline data. We surveyed teenagers in January 2020 before the COVID-19 outbreak (T1) and after home confinement (T2). We used the Patient Health Questionnaire (PHQ), the Generalized Anxiety Disorder (GAD) Scale and the Childhood Trauma Questionnaire (CTQ). 13,637 valid questionnaires were collected at T1, of which 22.34% reported depressive symptoms (PHQ-9 ≥ 10) and 14.42% reported anxiety symptoms (GAD-7 ≥ 10). At T2, the rates decreased to 14.86 and 7.44%, respectively (all P < 0.0001). Of the adolescents, 223 reported potential risk of exposure to COVID-19. We then compared them to the 9639 non-risk adolescents using a propensity score matching analysis. The adolescents with potential exposure risk had higher rates of depression (26.91 vs 15.32%, P = 0.0035) and anxiety (14.80 vs 7.21%, P = 0.01) than risk-free adolescents. Among adolescents with an exposure risk, psychological resilience was protective in preventing depression and anxiety symptoms, while emotional abuse, a poor parent-child relationship were risk factors. Long-term home confinement had minimal psychological impact on adolescents, but COVID-19 infection rates accounted for 50% of the variance in depression and anxiety among adolescents even with low community rates.

Small change for big improvement in the preparation of the key intermediate N 1, N 3-disubstituted 1,3,5-triazone of ensitrelvir.

In this study, the key intermediate N 1, N 3-disubstituted 1,3,5-triazone of ensitrelvir fumaric acid, approved in Japan for the treatment of SARS-CoV-2 infection under the emergency regulatory approval system, was produced from S-ethylisothiourea hydrobromide and aminomethyl triazole with CDI by four-step telescoped strategy including CDI-activated, condensation, CDI-cyclization, and N 1-alkylation. The strategy with simple conditions and operations had a total yield of 53% on a gram scale. The strategy for synthesizing the key N 1, N 3-disubstituted 1,3,5-triazone intermediate of ensitrelvir might provide a new avenue for further research and development of ensitrelvir analogs.

Small change for big improvement in the preparation of the key intermediate N1, N3-disubstituted 1,3,5-triazone of ensitrelvir† † Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d2ra07844a

In this study, the key intermediate N1, N3-disubstituted 1,3,5-triazone of ensitrelvir fumaric acid, approved in Japan for the treatment of SARS-CoV-2 infection under the emergency regulatory approval system, was produced from S-ethylisothiourea hydrobromide and aminomethyl triazole with CDI by four-step telescoped strategy including CDI-activated, condensation, CDI-cyclization, and N1-alkylation. The strategy with simple conditions and operations had a total yield of 53% on a gram scale. The strategy for synthesizing the key N1, N3-disubstituted 1,3,5-triazone intermediate of ensitrelvir might provide a new avenue for further research and development of ensitrelvir analogs. A four-step telescoped strategy for synthesis of the key intermediate of ensitrelvir, approved in Japan for the treatment of SARS-CoV-2 infection under the emergency regulatory approval system, was developed.

Two-stage one-pot synthetic strategy for the key triazone-triazole intermediate of ensitrelvir (S-217622), an oral clinical candidate for treating COVID-19.

Herein, the preparation of the key triazone-triazole intermediate of ensitrelvir (S-217622) via sequential cyclization and alkylation reaction is described. Firstly, chloromethyl triazole was synthesized through a one-pot tandem process (condensation and cyclization reaction) from commercially available chloroacetamide in a 72% yield. Then, the key triazone-triazole intermediate was obtained in a second one-pot process by N-alkylation with triazone followed by highly selective N 1-methylation with iodomethane in a 54% yield. In addition, two of the main process impurities were synthesized and identified. This novel alternative two-stage one-pot strategy for synthesizing the key triazone-triazole intermediate opens a new avenue for further research and development of ensitrelvir analogs.

Quality of online video resources concerning patient education for neck pain: A YouTube-based quality-control study.

Background: More than 70 percent of the world's population is tortured with neck pain more than once in their vast life, of which 50-85% recur within 1-5 years of the initial episode. With medical resources affected by the epidemic, more and more people seek health-related knowledge via YouTube. This article aims to assess the quality and reliability of the medical information shared on YouTube regarding neck pain. Methods: We searched on YouTube using the keyword "neck pain" to include the top 50 videos by relevance, then divided them into five and seven categories based on their content and source. Each video was quantitatively assessed using the Journal of American Medical Association (JAMA), DISCERN, Global Quality Score (GQS), Neck Pain-Specific Score (NPSS), and video power index (VPI). Spearman correlation analysis was used to evaluate the correlation between JAMA, GQS, DISCERN, NPSS and VPI. A multiple linear regression analysis was applied to identify video features affecting JAMA, GQS, DISCERN, and NPSS. Results: The videos had a mean JAMA score of 2.56 (SD = 0.43), DISCERN of 2.55 (SD = 0.44), GQS of 2.86 (SD = 0.72), and NPSS of 2.90 (SD = 2.23). Classification by video upload source, non-physician videos had the greatest share at 38%, and sorted by video content, exercise training comprised 40% of the videos. Significant differences between the uploading sources were observed for VPI (P = 0.012), JAMA (P < 0.001), DISCERN (P < 0.001), GQS (P = 0.001), and NPSS (P = 0.007). Spearman correlation analysis showed that JAMA, DISCERN, GQS, and NPSS significantly correlated with each other (JAMA vs. DISCERN, p < 0.001, JAMA vs. GQS, p < 0.001, JAMA vs. NPSS, p < 0.001, DISCERN vs. GQS, p < 0.001, DISCERN vs. NPSS, p < 0.001, GQS vs. NPSS, p < 0.001). Multiple linear regression analysis suggested that a higher JAMA score, DISCERN, or GQS score were closely related to a higher probability of an academic, physician, non-physician or medical upload source (P < 0.005), and a higher NPSS score was associated with a higher probability of an academic source (P = 0.001) than of an individual upload source. Conclusions: YouTube videos pertaining to neck pain contain low quality, low reliability, and incomplete information. Patients may be put at risk for health complications due to inaccurate, and incomplete information, particularly during the COVID-19 crisis. Academic groups should be committed to high-quality video production and promotion to YouTube users.

Insomnia mediates the effect of perceived stress on emotional symptoms during the first wave of the COVID-19 pandemic in China.

The outbreak of the 2019 coronavirus disease (COVID-19) has significant effects on stress, emotion and sleep in the general public. The aim of this study was to explore the relationship between perceived stress and emotional symptoms during the first wave of the COVID-19 pandemic in China and to further determine whether insomnia could serve as a mediator in this relationship. A total of 1178 ordinary citizens living in mainland China conducted anonymous online surveys. The 10-item Perceived Stress Scale, the Insomnia Severity Index, the 9-item Patient Health Questionnaire and the 7-item Generalized Anxiety Disorder scale were used to estimate perceived stress, insomnia, depression and anxiety symptoms, respectively. Of the 1171 valid respondents from 132 cities in China, 46.6 % and 33.0 % showed symptoms of depression and anxiety, respectively. Perceived stress and insomnia independently predicted the prevalence of emotional symptoms and were positively correlated with the severity of these emotional symptoms. The mediation analyses further revealed a partial mediation effect of insomnia on the relationship between perceived stress and emotional symptoms during the first wave of the COVID-19 outbreak in China. Our findings can be used to formulate early psychological interventions to improve the mental health of vulnerable groups, specifically those with insomnia, during the COVID-19 pandemic.

The mediating role of personal values between COVID-19-related posttraumatic growth and life satisfaction among Chinese college students: A two-wave longitudinal study.

Despite considerable disruption of social order caused by the COVID-19 pandemic, it has also been said to contribute to positive psychological changes and influence on the perception of public life satisfaction. The present study aimed to explore the association between the COVID-19 related posttraumatic growth and life satisfaction and the mediating role of personal values. A two-wave longitudinal design was used. 226 self-quarantined Chinese college students (58.8% male) completed post traumatic growth inventory (Time 1), satisfaction with life scale (Time 2), personal values questionnaire (Time 2) between February 2020 and May 2021. Results showed that more than half of self-quarantined Chinese college students reported moderate to high levels of the COVID-19 related posttraumatic growth. A structural equation model revealed that COVID-19 related posttraumatic growth was positively associated to life satisfaction, and self-transcendence and self-enhancement values partially mediated this association. These findings shed light on whether and how pandemic-related posttraumatic growth influenced personal life satisfaction, supporting the outcome and process perspectives of posttraumatic growth as well as Schwartz's value theory. Based on the findings, some positive psychology interventions, such as online rumination activities and mindfulness practice, were proposed to enhance self-quarantined college students' posttraumatic growth and life satisfaction.

Combating the SARS-CoV-2 Omicron (BA.1) and BA.2 with potent bispecific antibodies engineered from non-Omicron neutralizing antibodies.

The highly mutated and transmissible Omicron (BA.1) and its more contagious lineage BA.2 have provoked serious concerns over their decreased sensitivity to the current COVID-19 vaccines and evasion from most anti-SARS-CoV-2 neutralizing antibodies (NAbs). In this study, we explored the possibility of combating the Omicron and BA.2 by constructing bispecific antibodies based on non-Omicron NAbs. We engineered 10 IgG-like bispecific antibodies with non-Omicron NAbs named GW01, 16L9, 4L12, and REGN10987 by fusing the single-chain variable fragments (scFvs) of two antibodies through a linker and then connecting them to the Fc region of IgG1. Surprisingly, 8 out of 10 bispecific antibodies showed high binding affinities to the Omicron receptor-binding domain (RBD) and exhibited extreme breadth and potency against pseudotyped SARS-CoV-2 variants of concern (VOCs) including Omicron and BA.2, with geometric mean of 50% inhibitory concentration (GM IC50) values ranging from 4.5 ng/mL to 103.94 ng/mL, as well as the authentic BA.1.1. Six bispecific antibodies containing the cross-NAb GW01 not only neutralized Omicron and BA.2, but also neutralized the sarbecoviruses including SARS-CoV and SARS-related coronaviruses (SARSr-CoVs) RS3367 and WIV1, with GM IC50 ranging from 11.6 ng/mL to 103.9 ng/mL. Mapping analyses of 42 spike (S) variant single mutants of Omicron and BA.2 elucidated that these bispecific antibodies accommodated the S371L/F mutations, which were resistant to most of the non-Omicron NAbs. A cryo-electron microscopy (cryo-EM) structure study of the representative bispecific antibody GW01-16L9 (FD01) in its native full-length IgG form in complex with the Omicron S trimer revealed 5 distinct trimers and one novel trimer dimer conformation. 16L9 scFv binds the receptor-binding motif (RBM), while GW01 scFv binds a epitope outside the RBM. Two scFvs of the bispecific antibody synergistically induced the RBD-down conformation into 3 RBD-up conformation, improved the affinity between IgG and the Omicron RBD, induced the formation of trimer dimer, and inhibited RBD binding to ACE2. The trimer dimer conformation might induce the aggregation of virions and contribute to the neutralization ability of FD01. These novel bispecific antibodies are strong candidates for the treatment and prevention of infection with the Omicron, BA.2, VOCs, and other sarbecoviruses. Engineering bispecific antibodies based on non-Omicron NAbs could turn the majority of NAbs into a powerful arsenal to aid the battle against the pandemic.

A prospective clinical study on the mechanisms underlying critical illness myopathy-A time-course approach.

BACKGROUND: Critical illness myopathy (CIM) is a consequence of modern critical care resulting in general muscle wasting and paralyses of all limb and trunk muscles, resulting in prolonged weaning from the ventilator, intensive care unit (ICU) treatment and rehabilitation. CIM is associated with severe morbidity/mortality and significant negative socioeconomic consequences, which has become increasingly evident during the current COVID-19 pandemic, but underlying mechanisms remain elusive. METHODS: Ten neuro-ICU patients exposed to long-term controlled mechanical ventilation were followed with repeated muscle biopsies, electrophysiology and plasma collection three times per week for up to 12 days. Single muscle fibre contractile recordings were conducted on the first and final biopsy, and a multiomics approach was taken to analyse gene and protein expression in muscle and plasma at all collection time points. RESULTS: (i) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro-ICU patients during the observation period (myosin:actin ratio decreased from 2.0 in the first to 0.9 in the final biopsy, P < 0.001). The myosin loss was coupled to a general transcriptional downregulation of myofibrillar proteins (P < 0.05; absolute fold change >2) and activation of protein degradation pathways (false discovery rate [FDR] <0.1), resulting in significant muscle fibre atrophy and loss in force generation capacity, which declined >65% during the 12 day observation period (muscle fibre cross-sectional area [CSA] and maximum single muscle fibre force normalized to CSA [specific force] declined 30% [P < 0.007] and 50% [P < 0.0001], respectively). (ii) Membrane excitability was not affected as indicated by the maintained compound muscle action potential amplitude upon supramaximal stimulation of upper and lower extremity motor nerves. (iii) Analyses of plasma revealed early activation of inflammatory and proinflammatory pathways (FDR < 0.1), as well as a redistribution of zinc ions from plasma. CONCLUSIONS: The mechanical ventilation-induced lung injury with release of cytokines/chemokines and the complete mechanical silencing uniquely observed in immobilized ICU patients affecting skeletal muscle gene/protein expression are forwarded as the dominant factors triggering CIM.

Field measurements of indoor and community air quality in rural Beijing before, during, and after the COVID-19 lockdown.

The coronavirus (COVID-19) lockdown in China is thought to have reduced air pollution emissions due to reduced human mobility and economic activities. Few studies have assessed the impacts of COVID-19 on community and indoor air quality in environments with diverse socioeconomic and household energy use patterns. The main goal of this study was to evaluate whether indoor and community air pollution differed before, during, and after the COVID-19 lockdown in homes with different energy use patterns. Using calibrated real-time PM2.5 sensors, we measured indoor and community air quality in 147 homes from 30 villages in Beijing over 4 months including periods before, during, and after the COVID-19 lockdown. Community pollution was higher during the lockdown (61 ± 47 µg/m3 ) compared with before (45 ± 35 µg/m3 , p < 0.001) and after (47 ± 37 µg/m3 , p < 0.001) the lockdown. However, we did not observe significantly increased indoor PM2.5 during the COVID-19 lockdown. Indoor-generated PM2.5 in homes using clean energy for heating without smokers was the lowest compared with those using solid fuel with/without smokers, implying air pollutant emissions are reduced in homes using clean energy. Indoor air quality may not have been impacted by the COVID-19 lockdown in rural settings in China and appeared to be more impacted by the household energy choice and indoor smoking than the COVID-19 lockdown. As clean energy transitions occurred in rural households in northern China, our work highlights the importance of understanding multiple possible indoor sources to interpret the impacts of interventions, intended or otherwise.

The role of parental conflict in predicting adolescent depression symptoms during the COVID-19 pandemic: A longitudinal study.

The present study was designed to investigate the association and the underlying mechanism between parental conflict and adolescent depression during the COVID-19 pandemic. In a longitudinal study, a total of 655 Chinese adolescents ranging from 13 to 16 years old completed a three-wave survey (W1, W2, W3) via a survey website. The data was collected three times: March 15-20, 2020 (W1, the outbreak period of the COVID-19 pandemic in Mainland China), June 20-25, 2020 (W2, the trough stage), and December 15-20, 2020 (W3, six months after the trough stage). The SPSS 16.0 software was used to investigate the relationships among study variables. The findings showed that a double-hump effect was found for depression detection among adolescents during the pandemic, with depression rates in W1 (26.9%) and W3 (29%) were higher than that in W2 (21.9%). The parental conflict subscales of content and resolution had a greater impact on adolescent adjustment than other subscales. The parental conflict had direct and indirect impacts (through reducing family support and increasing burdensomeness) on adolescent depression symptoms in W3. It was concluded that when the COVID-19 pandemic was in a trough curve for more than six months, adolescent adjustment was significantly impacted by the pandemic, and parental conflict was an important risk factor in predicting individual adjustment. Therefore, family intervention is recommended when improving adolescent adjustment during the COVID-19 pandemic.

Proteomic analysis and identification reveal the anti-inflammatory mechanism of clofazimine on lipopolysaccharide-induced acute lung injury in mice.

BACKGROUND AND OBJECTIVE: Acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) was increasingly recognized as one of the most severe acute hyperimmune response of coronavirus disease 2019 (COVID-19). Clofazimine (CFZ) has attracted attention due to its anti-inflammatory property in immune diseases as well as infectious diseases. However, the role and potential molecular mechanism of CFZ in anti-inflammatory responses remain unclear. METHODS: We analyze the protein expression profiles of CFZ and LPS from Raw264.7 macrophages using quantitative proteomics. Next, the protective effect of CFZ on LPS-induced inflammatory model is assessed, and its underlying mechanism is validated by molecular biology analysis. RESULTS: LC-MS/MS-based shotgun proteomics analysis identified 4746 (LPS) and 4766 (CFZ) proteins with quantitative information. The key proteins and their critical signal transduction pathways including TLR4/NF-κB/HIF-1α signaling was highlighted, which was involved in multiple inflammatory processes. A further analysis of molecular biology revealed that CFZ could significantly inhibit the proliferation of Raw264.7 macrophages, decrease the levels of TNF-α and IL-1ß, alleviate lung histological changes and pulmonary edema, improve the survival rate, and down-regulate TLR4/NF-κB/HIF-1α signaling in LPS model. CONCLUSION: This study can provide significant insight into the proteomics-guided pharmacological mechanism study of CFZ and suggest potential therapeutic strategies for infectious disease.

Structural Study of SARS-CoV-2 Antibodies Identifies a Broad-Spectrum Antibody That Neutralizes the Omicron Variant by Disassembling the Spike Trimer.

The continuous emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses new challenges in the fight against the coronavirus disease 2019 (COVID-19) pandemic. The newly emerging Omicron strain caused serious immune escape and raised unprecedented concern all over the world. The development of an antibody targeting a conserved and universal epitope is urgently needed. A subset of neutralizing antibodies (NAbs) against COVID-19 from convalescent patients were isolated in our previous study. In this study, we investigated the accommodation of these NAbs to SARS-CoV-2 variants of concern (VOCs), revealing that IgG 553-49 neutralizes pseudovirus of the SARS-CoV-2 Omicron variant. In addition, we determined the cryo-electron microscopy (cryo-EM) structure of the SARS-CoV-2 spike (S) protein complexed with three monoclonal antibodies targeting different epitopes, including 553-49, 553-15, and 553-60. Notably, 553-49 targets a novel conserved epitope and neutralizes the virus by disassembling S trimers. IgG 553-15, an antibody that neutralizes all of the VOCs except Omicron, cross-links two S trimers to form a trimer dimer, demonstrating that 553-15 neutralizes the virus by steric hindrance and virion aggregation. These findings suggest the potential to develop 553-49 and other antibodies targeting this highly conserved epitope as promising therapeutic reagents for COVID-19. IMPORTANCE The emergence of the Omicron strain of SARS-CoV-2 caused higher immune escape, raising unprecedented concerns about the effectiveness of antibody therapies and vaccines. In this study, we identified a SARS-CoV-2 neutralizing antibody, 553-49, which neutralizes all variants by targeting a completely conserved novel epitope. In addition, we revealed that IgG 553-15 neutralizes SARS-CoV-2 by cross-linking virions and that 553-60 functions by blocking receptor binding. Comparison of different receptor binding domain (RBD) epitopes revealed that the 553-49 epitope is hidden in the S trimer and keeps a high degree of conservation during SARS-CoV-2 evolution, making 553-49 a promising therapeutic reagent against the emerging Omicron and future variants of SARS-CoV-2.