Bispecific antibodies targeting two glycoproteins on SFTSV exhibit synergistic neutralization and protection in a mouse model.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high fatality rate of up to 30% caused by SFTS virus (SFTSV). However, no specific vaccine or antiviral therapy has been approved for clinical use. To develop an effective treatment, we isolated a panel of human monoclonal antibodies (mAbs). SF5 and SF83 are two neutralizing mAbs that recognize two viral glycoproteins (Gn and Gc), respectively. We found that their epitopes are closely located, and we then engineered them as several bispecific antibodies (bsAbs). Neutralization and animal experiments indicated that bsAbs display more potent protective effects than the parental mAbs, and the cryoelectron microscopy structure of a bsAb3 Fab-Gn-Gc complex elucidated the mechanism of protection. In vivo virus passage in the presence of antibodies indicated that two bsAbs resulted in less selective pressure and could efficiently bind to all single parental mAb-escape mutants. Furthermore, epitope analysis of the protective mAbs against SFTSV and RVFV indicated that they are all located on the Gn subdomain I, where may be the hot spots in the phleboviruses. Collectively, these data provide potential therapeutic agents and molecular basis for the rational design of vaccines against SFTSV infection.

The impact of public demands on local environmental governance performance: Evidence from civil environmental complaints placed on leaders at different government levels in China.

The joint participation of multiple subjects is crucial for environmental governance. Using panel data for 273 Chinese cities during 2013-2019, this study investigates the impact and mechanism of public demands on environmental pollution. The results demonstrate that public demands measured by the number of environmental complaints placed on government leaders significantly reduce environmental pollution. Furthermore, increases in the rate and speed of government responses improve the effect of public demands on environmental governance. Public demands placed on provincial leaders reduce local environmental pollution to a greater extent than public demands placed on prefectural and county leaders. Province-level governments are more willing to consider public opinions and attach more importance to environmental governance; Prefecture-level governments prioritize province-level governments' attention to the environment when implementing environmental governance. Moreover, strong political ties between provincial and prefectural leaders and long tenures among prefectural leaders strengthen the pollution reduction effect of public demands placed on provincial leaders. The reduction effect of environmental complaints on pollution emission is more significant in cities with high level of Internet construction and environmental disclosure. Our results illustrate the role of public demands in environmental governance, offering a reference for developing effective environmental policies.

Enhanced breast cancer treatment using phototherapy and RNS therapy with macrophage membrane-coated liposomes.

Breast cancer, the predominant malignancy afflicting women, continues to pose formidable challenges despite advancements in therapeutic interventions. This study elucidates the potential of phototherapy, comprising both photothermal and photodynamic therapy (PTT/PDT), as a novel and promising modality. To achieve this goal, we devised liposomes coated with macrophage cell membranes including macrophage-associated membrane proteins, which have demonstrated promise in biomimetic delivery systems for targeting tumors while preserving their inherent tumor-homing capabilities. This integrated biomimetic delivery system comprised IR780, NONOate, and perfluorocarbon. This strategic encapsulation aims to achieve a synergistic combination of photodynamic therapy (PDT) and reactive nitrogen species (RNS) therapy. Under near-infrared laser irradiation at 808 nm, IR780 demonstrates its ability to prolifically generate reactive oxygen species (ROS), including superoxide anion (O2•-), singlet oxygen, and hydroxyl radical (·OH). Simultaneously, NONOate releases nitric oxide (NO) gas upon the same laser irradiation, thereby engaging with IR780-induced ROS to facilitate the formation of peroxynitrite anion (ONOO-), ultimately inducing programmed cell death in cancer cells. Additionally, the perfluorocarbon component of our delivery system exhibits a notable affinity for oxygen and demonstrates efficient oxygen-carrying capabilities. Our results demonstrate that IR780-NO-PFH-Lip@M significantly enhances breast cancer cell toxicity, reducing proliferation and in vivo tumor growth through simultaneous heat, ROS, and RNS production. This study contributes valuable insights to the ongoing discourse on innovative strategies for advancing cancer therapeutics.

Imidacloprid reduces the mating success of males in bumblebees.

Bumblebees play a vital role in both natural and agricultural environments, but there has been a noticeable decline in their populations. Pesticides, particularly neonicotinoids, are widely regarded as a substantial contributing factor to the decline in bumblebee populations, as evidenced by the detrimental impacts documented across many stages of their life cycle. Mating is vital for the population maintenance of bumblebees. Nevertheless, there is a scarcity of research conducted on the effects of pesticides on the mating process. In this study, we individually examined the impact of imidacloprid on the mating behavior of bumblebee males and queens. A competitive mating experiment was conducted to evaluate the effect on the competitive prowess of male individuals and the mate selection behavior of female individuals. The study revealed that the mating rate of bumblebees exposed to a concentration of 10 ppb of imidacloprid was 3 %. This finding demonstrated a statistically significant impact when compared to the control group, which exhibited a mating rate of 58 % in the normal mating experiment. Furthermore, in the competitive mating experiment, we found that the competitive mating success rate of treated males (1 %) was significantly lower than that of untreated males (35 %). Hence, it provides evidence that neonicotinoid imidacloprid negatively affects bumblebee mating success and cautions us to protect bumblebees from pesticide exposure to prevent a severe impact on their populations.

Identification of biomimetic nanoplatform-mediated delivery of si-ISG15 for treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is recognized as the most malicious form of breast cancer and exhibits an alarming tendency for recurrence, a heightened propensity for metastasis, and an overwhelmingly grim prognosis. Therefore, effective therapy approaches for TNBC are urgently required. In this study, the interferon-stimulated gene 15 (ISG15) expression level was analyzed by bioinformatics and verified by Western blot analysis. The effects of ISG15 on the proliferation and metastasis of TNBC cells were assessed using MTT, Colony formation, EdU, Transwell, and Flow cytometry assays. We also developed a cancer cell-biomimetic nanoparticle delivery system and evaluated its therapeutic efficacy in vivo. In this study, we reported that ISG15 was upregulated in TNBC, and its high expression level correlated with an increased risk of tumorigenesis. Through in vitro and in vivo studies, we discovered that ISG15 knockdown drastically suppressed cell proliferation, invasion, and migration and induced apoptosis in TNBC cells. Our findings revealed that ISG15 was a candidate therapeutic target in TNBC because of its key role in malignant growth and invasion. Moreover, co-immunoprecipitation showed that ISG15 exerted oncogenic functions through its interaction with ATP binding cassette subfamily E member 1 and activated the Janus kinase/signal transducers and activators of the transcription signaling pathway. Furthermore, we created a nanoparticle-based siRNA camouflaged using a cancer cell membrane vesicle delivery system (the CM@NP complex) and confirmed its therapeutic effects in vivo. Our findings confirmed that ISG15 may play a pivotal oncogenic role in the development of TNBC and that CM@siRNA-NP complexes are an effective delivery system and a novel biological strategy for treating TNBC.

Repeated inoculation with rumen fluid accelerates the rumen bacterial transition with no benefit on production performance in postpartum Holstein dairy cows.

BACKGROUND: The dairy cow's postpartum period is characterized by dramatic physiological changes, therefore imposing severe challenges on the animal for maintaining health and milk output. The dynamics of the ruminal microbiota are also tremendous and may play a crucial role in lactation launch. We aim to investigate the potential benefits of early microbial intervention by fresh rumen microbiota transplantation (RMT) and sterile RMT in postpartum dairy cows. Twelve fistulated peak-lactation dairy cows were selected to be the donors for rumen fluid collection. Thirty postpartum cows were divided into 3 groups as the transplantation receptors respectively receiving 10 L fresh rumen fluid (FR), 10 L sterile rumen fluid (SR), or 10 L saline (CON) during 3 d after calving. RESULTS: Production performance, plasma indices, plasma lipidome, ruminal microbiome, and liver transcriptome were recorded. After fresh and sterile RMT, we found that the molar proportion of propionic acid was increased on d 7 in the FR and SR groups and the bacterial composition was also significantly changed when compared with the CON group. A similarity analysis showed that the similarities between the CON group and FR or SR group on d 7 were 48.40% or 47.85%, whereas the similarities between microbiota on d 7 and 21 in the FR and SR groups were 68.34% or 66.85%. Dry matter intake and feed efficiency were not affected by treatments. Plasma ß-hydroxybutyrate concentration in the FR group was decreased and significantly different lipids mainly included phosphatidylcholine and lysophosphatidylcholine containing polyunsaturated fatty acids. Hepatic transcriptomics analysis indicated acute-phase response pathways were upregulated in the SR group. CONCLUSIONS: Our study suggests that RMT can shorten the transition process of the ruminal microbiota of postpartum dairy cows with no benefit on dry matter intake or feed efficiency. Inoculation with rumen fluid may not be a useful approach to promote the recovery of postpartum dairy cows.

TMEM43 promotes the development of hepatocellular carcinoma by activating VDAC1 through USP7 deubiquitination.

Background: Transmembrane protein 43 (TMEM43), a member of the TMEM subfamily, is encoded by a highly conserved gene and widely expressed in most species from bacteria to humans. In previous studies, TMEM43 has been found to play an important role in a variety of tumors. However, the role of TMEM43 in cancer remains unclear. Methods: We utilized the RNA sequencing (RNA-seq) and The Cancer Genome Atlas (TGCA) databases to explore and identify genes that may play an important role in the occurrence and development of hepatocellular carcinoma (HCC), such as TMEM43. The role of TMEM43 in HCC was explored through Cell Counting Kit-8 (CCK-8) cloning, flow cytometry, and Transwell experiments. The regulatory relationship between TMEM43 and voltage-dependent anion channel 1 (VDAC1) was investigated through coimmunoprecipitation (co-IP) and western blot (WB) experiments. WB was used to study the deubiquitination effect of ubiquitin-specific protease 7 (USP7) on TMEM43. Results: In this study, we utilized the RNA-seq and TGCA databases to mine data and found that TMEM43 is highly expressed in HCC. The absence of TMEM43 in cancer cells was shown to inhibit tumor development. Further research detected an important regulatory relationship between TMEM43 and VDAC1. In addition, we found that USP7 affected the progression of HCC by regulating the ubiquitination level of TMEM43 through deubiquitination. Conclusions: Our study demonstrated that USP7 participates in the growth of HCC tumors through TMEM43/VDAC1.Our results suggest that USP7/TMEM43/VDAC1 may have predictive value and represent a new treatment strategy for HCC.

Brain eQTLs of European, African American, and Asian ancestry improve interpretation of schizophrenia GWAS.

Research on brain expression quantitative trait loci (eQTLs) has illuminated the genetic underpinnings of schizophrenia (SCZ). Yet, the majority of these studies have been centered on European populations, leading to a constrained understanding of population diversities and disease risks. To address this gap, we examined genotype and RNA-seq data from African Americans (AA, n=158), Europeans (EUR, n=408), and East Asians (EAS, n=217). When comparing eQTLs between EUR and non-EUR populations, we observed concordant patterns of genetic regulatory effect, particularly in terms of the effect sizes of the eQTLs. However, 343,737 cis-eQTLs (representing ∼17% of all eQTLs pairs) linked to 1,276 genes (about 10% of all eGenes) and 198,769 SNPs (approximately 16% of all eSNPs) were identified only in the non-EUR populations. Over 90% of observed population differences in eQTLs could be traced back to differences in allele frequency. Furthermore, 35% of these eQTLs were notably rare (MAF < 0.05) in the EUR population. Integrating brain eQTLs with SCZ signals from diverse populations, we observed a higher disease heritability enrichment of brain eQTLs in matched populations compared to mismatched ones. Prioritization analysis identified seven new risk genes ( SFXN2 , RP11-282018.3 , CYP17A1 , VPS37B , DENR , FTCDNL1 , and NT5DC2 ), and three potential novel regulatory variants in known risk genes ( CNNM2 , C12orf65 , and MPHOSPH9 ) that were missed in the EUR dataset. Our findings underscore that increasing genetic ancestral diversity is more efficient for power improvement than merely increasing the sample size within single-ancestry eQTLs datasets. Such a strategy will not only improve our understanding of the biological underpinnings of population structures but also pave the way for the identification of novel risk genes in SCZ.

Quantum Nature of Charge Transport in Inkjet-Printed Graphene Revealed in High Magnetic Fields up to 60T.

Inkjet-printing of graphene, iGr, provides an alternative route for the fabrication of highly conductive and flexible graphene films for use in devices. However, the contribution of quantum phenomena associated with 2D single layer graphene, SLG, to the charge transport in iGr is yet to be explored. Here, the first magneto-transport study of iGr in high magnetic fields up to 60 T is presented. The observed quantum phenomena, such as weak localization and negative magnetoresistance, are strongly affected by the thickness of the iGr film and can be explained by a combination of intra- and inter-flake classical and quantum charge transport. The quantum nature of carrier transport in iGr is revealed using temperature, electric field, and magnetic field dependences of the iGr conductivity. These results are relevant for the exploitation of inkjet deposition of graphene, which is of particular interest for additive manufacturing and 3D printing of flexible and wearable electronics. It is shown that printed nanostructures enable ensemble averaging of quantum interference phenomena within a single device, thereby facilitating comparison between experiment and underlying statistical models of electron transport.

Pan-genome analysis highlights the role of structural variation in the evolution and environmental adaptation of Asian honeybees.

The Asian honeybee, Apis cerana, is an ecologically and economically important pollinator. Mapping its genetic variation is key to understanding population-level health, histories and potential capacities to respond to environmental changes. However, most efforts to date were focused on single nucleotide polymorphisms (SNPs) based on a single reference genome, thereby ignoring larger scale genomic variation. We employed long-read sequencing technologies to generate a chromosome-scale reference genome for the ancestral group of A. cerana. Integrating this with 525 resequencing data sets, we constructed the first pan-genome of A. cerana, encompassing almost the entire gene content. We found that 31.32% of genes in the pan-genome were variably present across populations, providing a broad gene pool for environmental adaptation. We identified and characterized structural variations (SVs) and found that they were not closely linked with SNP distributions; however, the formation of SVs was closely associated with transposable elements. Furthermore, phylogenetic analysis using SVs revealed a novel A. cerana ecological group not recoverable from the SNP data. Performing environmental association analysis identified a total of 44 SVs likely to be associated with environmental adaptation. Verification and analysis of one of these, a 330 bp deletion in the Atpalpha gene, indicated that this SV may promote the cold adaptation of A. cerana by altering gene expression. Taken together, our study demonstrates the feasibility and utility of applying pan-genome approaches to map and explore genetic feature variations of honeybee populations, and in particular to examine the role of SVs in the evolution and environmental adaptation of A. cerana.

How does early-life famine experience influence household energy transition?

The transition of households towards cleaner energy is crucial for achieving sustainable development goals. However, the impacts and associated mechanisms of early-life experiences on household energy transition have not been considered. Based on data from the 2015 Chinese General Social Survey, this study aimed to investigate whether people experiencing China's Great Famine (1959-1961) in their early life promoted household energy transition in adulthood. The varying severity of the Great Famine in different provinces was characterised as a quasi-natural experiment and was used to perform difference-in-differences (DID) estimation analysis for birth cohorts. The results showed that the transitions from firewood, agricultural waste, and animal waste to liquefied petroleum gas and electricity were significant in households with the Great Famine experiences. Specifically, the long-term energy transition effect of the famine was exhibited mostly in those who experienced the famine during childhood (4-11 years old) and adolescence (12-17 years old). Besides, early-life famine experiences led to poor physical health, and more modern forms of energy, such as electricity, were consumed to avoid further deteriorating health. Early-life famine experience also brought psychological trauma to people at that time, which led them to increase Internet use to gain emotional support, and the increased Internet use provided better access to information about the energy transition. Moreover, the household energy transition influenced by early-life famine experience occurred more in female-headed, rural, more educated, and low-income households. Our results illustrated the role of early-life famine experience in household energy transition and provided new insights into developing effective energy policies.

Defining a de novo non-RBM antibody as RBD-8 and its synergistic rescue of immune-evaded antibodies to neutralize Omicron SARS-CoV-2.

Currently, monoclonal antibodies (MAbs) targeting the SARS-CoV-2 receptor binding domain (RBD) of spike (S) protein are classified into seven classes based on their binding epitopes. However, most of these antibodies are seriously impaired by SARS-CoV-2 Omicron and its subvariants, especially the recent BQ.1.1, XBB and its derivatives. Identification of broadly neutralizing MAbs against currently circulating variants is imperative. In this study, we identified a "breathing" cryptic epitope in the S protein, named as RBD-8. Two human MAbs, BIOLS56 and IMCAS74, were isolated recognizing this epitope with broad neutralization abilities against tested sarbecoviruses, including SARS-CoV, pangolin-origin coronaviruses, and all the SARS-CoV-2 variants tested (Omicron BA.4/BA.5, BQ.1.1, and XBB subvariants). Searching through the literature, some more RBD-8 MAbs were defined. More importantly, BIOLS56 rescues the immune-evaded antibody, RBD-5 MAb IMCAS-L4.65, by making a bispecific MAb, to neutralize BQ.1 and BQ.1.1, thereby producing an MAb to cover all the currently circulating Omicron subvariants. Structural analysis reveals that the neutralization effect of RBD-8 antibodies depends on the extent of epitope exposure, which is affected by the angle of antibody binding and the number of up-RBDs induced by angiotensin-converting enzyme 2 binding. This cryptic epitope which recognizes non- receptor binding motif (non-RBM) provides guidance for the development of universal therapeutic antibodies and vaccines against COVID-19.

Ferroptosis induction via targeting metabolic alterations in triple-negative breast cancer.

Triple-negative breast cancer (TNBC), the most aggressive form of breast cancer, presents severe threats to women's health. Therefore, it is critical to find novel treatment approaches. Ferroptosis, a newly identified form of programmed cell death, is marked by the buildup of lipid reactive oxygen species (ROS) and high iron concentrations. According to previous studies, ferroptosis sensitivity can be controlled by a number of metabolic events in cells, such as amino acid metabolism, iron metabolism, and lipid metabolism. Given that TNBC tumors are rich in iron and lipids, inducing ferroptosis in these tumors is a potential approach for TNBC treatment. Notably, the metabolic adaptability of cancer cells allows them to coordinate an attack on one or more metabolic pathways to initiate ferroptosis, offering a novel perspective to improve the high drug resistance and clinical therapy of TNBC. However, a clear picture of ferroptosis in TNBC still needs to be completely revealed. In this review, we provide an overview of recent advancements regarding the connection between ferroptosis and amino acid, iron, and lipid metabolism in TNBC. We also discuss the probable significance of ferroptosis as an innovative target for chemotherapy, radiotherapy, immunotherapy, nanotherapy and natural product therapy in TNBC, highlighting its therapeutic potential and application prospects.

The impact of common variants on gene expression in the human brain: from RNA to protein to schizophrenia risk.

Background: The impact of genetic variants on gene expression has been intensely studied at the transcription level, yielding in valuable insights into the association between genes and the risk of complex disorders, such as schizophrenia (SCZ). However, the downstream impact of these variants and the molecular mechanisms connecting transcription variation to disease risk are not well understood. Results: We quantitated ribosome occupancy in prefrontal cortex samples of the BrainGVEX cohort. Together with transcriptomics and proteomics data from the same cohort, we performed cis-Quantitative Trait Locus (QTL) mapping and identified 3,253 expression QTLs (eQTLs), 1,344 ribosome occupancy QTLs (rQTLs), and 657 protein QTLs (pQTLs) out of 7,458 genes quantitated in all three omics types from 185 samples. Of the eQTLs identified, only 34% have their effects propagated to the protein level. Further analysis on the effect size of prefrontal cortex eQTLs identified from an independent dataset showed clear post-transcriptional attenuation of eQTL effects. To investigate the biological relevance of the attenuated eQTLs, we identified 70 expression-specific QTLs (esQTLs), 51 ribosome-occupancy-specific QTLs (rsQTLs), and 107 protein-specific QTLs (psQTLs). Five of these omics-specific QTLs showed strong colocalization with SCZ GWAS signals, three of them are esQTLs. The limited number of GWAS colocalization discoveries from omics-specific QTLs and the apparent prevalence of eQTL attenuation prompted us to take a complementary approach to investigate the functional relevance of attenuated eQTLs. Using S-PrediXcan we identified 74 SCZ risk genes, 34% of which were novel, and 67% of these risk genes were replicated in a MR-Egger test. Notably, 52 out of 74 risk genes were identified using eQTL data and 70% of these SCZ-risk-gene-driving eQTLs show little to no evidence of driving corresponding variations at the protein level. Conclusion: The effect of eQTLs on gene expression in the prefrontal cortex is commonly attenuated post-transcriptionally. Many of the attenuated eQTLs still correlate with SCZ GWAS signal. Further investigation is needed to elucidate a mechanistic link between attenuated eQTLs and SCZ disease risk.

Investigation on preventive inerting approach of coal spontaneous combustion in gob considering adsorption effect.

Coal spontaneous combustion in the gob poses a significant threat to coal mining operations. Designing optimal process parameters for nitrogen injection to prevent and control fires efficiently is crucial. To achieve this, a multi-field coupling equation was established, considering the adsorption of coal to gas. The model's accuracy was verified on-site, and the effects of nitrogen injection at different locations and flow rates were simulated. The optimal injection parameters were determined by analyzing temperature and inerting time. The results showed that the coal spontaneous combustion hazardous zone in the gob tested on-site was consistent with the simulation from the perspective of physisorption. Nitrogen injection had three stages: gas expansion, rapid oxygen dilution, and complete inerting. The nitrogen injection effect presented a nonlinear change in injection location and flow rate. The optimal nitrogen injection location for the Tingnan Coal Mine in Shaanxi was determined to be 90 m behind the working face on the inlet side, with an optimal flow rate of 800 m3/min. This study focused on gas adsorption and offered valuable insights for creating high-efficiency fire-fighting techniques that involve inserting in the gob.

Airway Microbiome Composition and Co-Occurrence Network Are Associated with Inflammatory Phenotypes of Asthma.

INTRODUCTION: The composition and co-occurrence network of the airway microbiome might influence the asthma inflammatory phenotype. Airway microbiota change with asthma phenotypes, and the structure of the bacterial community in the airway might differ between different asthma inflammatory phenotypes and may also influence therapy results. Identifying airway microbiota can help to investigate the role that microbiota play in the asthma inflammatory process. METHODS: Induced sputum from 55 subjects and 12 healthy subjects from Beijing, China, was collected and analyzed for bacterial microbiota. Microbiome diversity, composition, co-occurrence networks, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were predicted and compared between the study groups. RESULTS: Significant differences in the sputum microbiome composition, co-occurrence network, and predicted functional pathways were observed between the two inflammatory phenotypes. Asthmatics in the low FeNO group exhibited lower α-diversity in the sputum microbiota and had higher abundance of the phylum Proteobacteria compared with that of the high FeNO group. The network in the high FeNO group was more "closed" and "connected" compared with that of the low FeNO group, and an alteration in the abundance of keystone species T. socranskii was found. Significantly different predicted metabolic subfunctions including nucleotide metabolism, lipid metabolism, energy metabolism, replication and repair, and drug resistance antimicrobial and carbohydrate metabolism between the two studied phenotypes were also observed. CONCLUSION: Our findings confirm that the airway microbiota is associated with the asthma inflammation process. The differences in the airway microbiome composition and co-occurrence network may affect distinct asthma inflammatory phenotypes, suggesting the possibility that more targeted therapies could be applied based on the airway bacterial genera.

ERα promotes SUMO1 transcription by binding with the ERE and enhances SUMO1-mediated protein SUMOylation in breast cancer.

Background: Estrogen plays a crucial role in the tumorigenesis of breast cancer (BC), and epigenetic modification by SUMOylation is essential for cancer development. However, the mechanism underlying estrogen's actions on protein SUMOylation and its effect on BC development are still incompletely understood. Methods: SUMO1 in BC cell lines was verified via real-time quantitative PCR (RT-qPCR) and western blot. Cell proliferation and colony formation assays was also performed to evaluate SUMOylation as mediated by SUMO1. Luciferase activity to examine whether E2 promoted the transcription of SUMO1, and chromatin immunoprecipitation (ChIP) assay to determine the binding of estrogen receptor alpha (ERα) to SUMO1 were conduction, and an animal model was used to evaluate the effects of E2-ERα-enhanced SUMO1 transcription. Results: E2 promoted SUMO1 mRNA and protein expression levels in a dose- and time-dependent manner in ER-positive BC cells; it exerted no influence on SUMO2/3 expression; in E2-induced SUMO1 transcription, ERα, but not ERß, was essential to the process. In addition, E2-ERα upregulated the transcription of SUMO1 by binding with an estrogen-response element half-site (1/2ERE, in the -134 to -123 bp region) of the SUMO1 promoter, and E2-ERα induced SUMO1 transcription-enhanced cellular viability in ER-positive BC cells. To further determine SUMOylation as mediated by SUMO1 in ER-positive BC, we evaluated novel SUMO1 target proteins such as Ras and demonstrated that E2 increased Ras SUMOylation and cellular proliferation by affecting downstream signaling-pathway transduction. Finally, our data revealed that E2-ERα enhanced SUMO1 transcription to promote tumor growth in a BC orthotopic tumor model. Conclusions: Collectively, our results showed that E2 promoted the transcription and protein expression of SUMO1 via ERα binding to a 1/2ERE in the SUMO1 promoter, and that E2-ERα also augmented SUMO1-mediated Ras SUMOylation and mediated cellular responses in ER-positive BC. We therefore achieved significant insights into the mechanism involved in ER-positive BC development and provided a novel target for its treatment.

Omalizumab for Chinese patients with moderate-to-severe allergic asthma in real-world clinical setting: a prospective, observational study.

BACKGROUND: We aimed to investigate the effectiveness of omalizumab, a monoclonal anti-immunoglobulin E antibody, in Chinese patients with moderate-to-severe allergic asthma in real-world clinical practice. METHODS: This single-centre, prospective, observational study included Chinese patients aged 14-75 years with moderate-to-severe allergic asthma according to the Global Initiative for Asthma criteria. Omalizumab was administered subcutaneously, and the investigator collected real-world data on exacerbations, steroid exposure, pulmonary function and laboratory assessments at weeks 16, 24, 52, 104 and 156 after treatment initiation. The primary outcome was reduced exacerbations, measured as the proportion of patients with exacerbations in the year following omalizumab initiation. Bowker's test for paired proportions was performed to compare exacerbation rates before and after treatment initiation. A generalised linear mixed model was used to compare the number of exacerbations. RESULTS: The mean treatment duration was 46.6 weeks for the full analysis set (n=398). The proportion of patients with exacerbations in the year before and after omalizumab initiation was 80.4% (181/225) and 18.7% (42/225) (difference: -61.8%, 95% CI -68.5 to -54.0, p<0.0001), respectively. At week 52, 67.4% of patients discontinued oral corticosteroids, and 19.5% reduced inhaled corticosteroids. The Asthma Control Test scores increased by 4.6 at week 52 from baseline (p<0.001). Forced expiratory volume in 1 s increased by 11.2% and 9.0% at weeks 24 and 52, respectively, from baseline (p<0.01). Injection site reactions (5.2%) were the most frequently reported adverse event. CONCLUSIONS: In real-world clinical practice, omalizumab treatment remarkably reduced exacerbations in Chinese patients with moderate-to-severe asthma. Omalizumab reduced the use of oral corticosteroids and improved asthma control and pulmonary function.

Alternative splicing in mouse brains affected by psychological stress is enriched in the signaling, neural transmission and blood-brain barrier pathways.

Psychological stress increases the risk of major psychiatric disorders. Psychological stress on mice was reported to induce differential gene expression (DEG) in mice brain regions. Alternative splicing is a fundamental aspect of gene expression and has been associated with psychiatric disorders but has not been investigated in the stressed brain yet. This study investigated changes in gene expression and splicing under psychological stress, the related pathways, and possible relationship with psychiatric disorders. RNA-seq raw data of 164 mouse brain samples from 3 independent datasets with stressors including chronic social defeat stress (CSDS), early life stress (ELS), and two-hit stress of combined CSDS and ELS were collected. There were more changes in splicing than in gene expression in the ventral hippocampus and medial prefrontal cortex, but stress-induced changes of individual genes by differential splicing and differential expression could not be replicated. In contrast, pathway analyses produced robust findings: stress-induced differentially spliced genes (DSGs) were reproducibly enriched in neural transmission and blood-brain barrier systems, and DEGs were reproducibly enriched in stress response-related functions. The hub genes of DSG-related PPI networks were enriched in synaptic functions. The corresponding human homologs of stress-induced DSGs were robustly enriched in AD-related DSGs as well as BD and SCZ in GWAS. These results suggested that stress-induced DSGs from different datasets belong to the same biological system throughout the stress response process, resulting in consistent stress response effects.

Ionic-Nanophase Hybridization of Nafion by Supramolecular Patching for Enhanced Proton Selectivity in Redox Flow Batteries.

Nafion, as the mostly used proton exchange membrane material in vanadium redox flow batteries (VRFBs), encounters serious vanadium permeation problems due to the large size difference between its anionic nanophase (3-5 nm) and cationic vanadium ions (∼0.6 nm). Bulk hybridization usually suppresses the vanadium permeation at the expense of proton conductivity since conventional additives tend to randomly agglomerate and damage the nanophase continuity from unsuitable sizes and intrinsic incompatibility. Here, we report the ionic-nanophase hybridization strategy of Nafion membranes by using fluorinated block copolymers (FBCs) and polyoxometalates (POMs) as supramolecular patching additives. The cooperative noncovalent interactions among Nafion, interfacial-active FBCs, and POMs can construct a 1 nm-shrunk ionic nanophase with abundant proton transport sites, preserved continuity, and efficient vanadium screeners, which leads to a comprehensive enhancement in proton conductivity, selectivity, and VRFB performance. These results demonstrate the intriguing potential of the supramolecular patching strategy in precisely tuning nanostructured electrolyte membranes for improved performance.