Corrigendum: Roles of ubiquitin-specific proteases in inflammatory diseases.

[This corrects the article DOI: 10.3389/fimmu.2024.1258740.].

SNORD45A Affects Content of HIF-1α and Promotes Endothelial Angiogenic Function.

To find out the differentially expressed small nucleolar RNAs (snoRNAs) in corneal neovascularization and their effect on angiogenesis. The rat model of corneal neovascularization induced by alkali burn was established, and the differentially expressed snoRNAs were sifted by high-throughput sequencing. Human genome homologs were screened and verified in cytopathological models. Polymerase chain reactions (PCRs) and Western blot assays were applied to detect mRNA and corresponding proteins affected by the differentially expressed snoRNA. In vitro, experiments were promoted to identify whether snoRNA affects endothelial cell migration and angiogenesis. Forty-seven differentially expressed snoRNAs were sifted from transparent cornea and neovascularization. According to sequencing and cytopathological model results, SNORD45A was selected for subsequent experiments. At mRNA and protein levels, SNORD45A affected the expression of HIF-1α. SNORD45A promoted endothelial angiogenesis through endothelial cell migration and tube formation regulation. The research suggested that SNORD45A partakes in the corneal neovascularization formation and can become one of the targets for corneal neovascularization therapy.

Full-Length Transcriptome Sequencing and Comparative Transcriptomic Analyses Provide Comprehensive Insight into Molecular Mechanisms of Flavonoid Metabolites Biosynthesis in Styphnolobium japonicum.

Styphnolobium japonicum L. is a commonly consumed plant in China, known for its medicinal and nutritional benefits. This study focuses on the medicinal properties influenced by flavonoid metabolites, which vary during flower development. Utilizing full-length transcriptome sequencing on S. japonicum flowers, we observed changes in gene expression levels as the flowers progressed through growth stages. During stages S1 and S2, key genes related to flavonoid synthesis (PAL, 4CL, CHS, F3H, etc.) exhibited heightened expression. A weighted gene co-expression network analysis (WGCNA) identified regulatory genes (MYB, bHLH, WRKY) potentially involved in the regulatory network with flavonoid biosynthesis-related genes. Our findings propose a regulatory mechanism for flavonoid synthesis in S. japonicum flowers, elucidating the genetic underpinnings of this process. The identified candidate genes present opportunities for genetic enhancements in S. japonicum, offering insights into potential applications for improving its medicinal attributes.

Identification of dihydroquinolizinone derivatives with nitrogen heterocycle moieties as new anti-HBV agents.

The sustained loss of HBsAg is considered a pivotal indicator for achieving functional cure of HBV. Dihydroquinolizinone derivatives (DHQs) have demonstrated remarkable inhibitory activity against HBsAg both in vitro and in vivo. However, the reported neurotoxicity associated with RG7834 has raised concerns regarding the development of DHQs. In this study, we designed and synthesized a series of DHQs incorporating nitrogen heterocycle moieties. Almost all of these compounds exhibited potent inhibition activity against HBsAg, with IC50 values at the nanomolar level. Impressively, the compound (S)-2a (10 µM) demonstrated a comparatively reduced impact on the neurite outgrowth of HT22 cells and isolated mouse DRG neurons in comparison to RG7834, thereby indicating a decrease in neurotoxicity. Furthermore, (S)-2a exhibited higher drug exposures than RG7834. The potent anti-HBV activity, reduced neurotoxicity, and favorable pharmacokinetic profiles underscore its promising potential as a lead compound for future anti-HBV drug discovery.

Flavonoid Compounds in Hippophae rhamnoides L. Protect Endothelial Cells from Oxidative Damage Through the PI3K/AKT-eNOS Pathway.

Sea buckthorn, a traditional medicinal plant, has been used for several years in China for the prevention and treatment of various diseases, a practice closely associated with its significant antioxidant activity. The aim of this study was to investigate the protective effects of sea buckthorn flavonoids on vascular endothelial cells in an oxidative stress environment. We isolated and extracted active compounds from sea buckthorn and investigated their impact on endothelial nitric oxide synthase (eNOS) activity through the PI3K/AKT-eNOS signaling pathway through a combination of network pharmacology and cellular experiments, elucidating the regulatory effects of these compounds on endothelial cell functions. Three flavonoids, named Fr.4-2-1, Fr.4-2-2 and Fr.4-2-3, were obtained from sea buckthorn. The results of network pharmacology indicated that they might exert their effects by regulating the PI3K-AKT signaling pathway. In vitro results showed that all three flavonoids were effective in alleviating the degree of oxidative stress in cells, among which Fr.4-2-1 exerted its antioxidant effects by modulating the PI3K/AKT-eNOS pathway. Flavonoids in sea buckthorn can effectively inhibit oxidative stress-induced cellular damage, preserving the integrity and functionality of endothelial cells, which is crucial for maintaining vascular health and function.

Roles of ubiquitin-specific proteases in inflammatory diseases.

Ubiquitin-specific proteases (USPs), as one of the deubiquitinating enzymes (DUBs) families, regulate the fate of proteins and signaling pathway transduction by removing ubiquitin chains from the target proteins. USPs are essential for the modulation of a variety of physiological processes, such as DNA repair, cell metabolism and differentiation, epigenetic modulations as well as protein stability. Recently, extensive research has demonstrated that USPs exert a significant impact on innate and adaptive immune reactions, metabolic syndromes, inflammatory disorders, and infection via post-translational modification processes. This review summarizes the important roles of the USPs in the onset and progression of inflammatory diseases, including periodontitis, pneumonia, atherosclerosis, inflammatory bowel disease, sepsis, hepatitis, diabetes, and obesity. Moreover, we highlight a comprehensive overview of the pathogenesis of USPs in these inflammatory diseases as well as post-translational modifications in the inflammatory responses and pave the way for future prospect of targeted therapies in these inflammatory diseases.

Ageing on the impact of distribution about preformed anti-HLA and anti-MICA antibody specificities in recipients prior to initial HSCT from East China.

BACKGROUND: With the development of Hematopoietic Stem Cell Transplantation (HSCT) technology, increasing numbers of elderly patients were undergoing allogeneic HSCT and elderly patients with hematologic malignancies could benefit most from it. Preformed donor-specific human leukocyte antigen (HLA) antibodies (DSA) were associated with graft failure in HLA-mismatched allogeneic HSCT and the absence of DSA was the main criterion of selecting the donor. Except for sensitization events such as transfusion, pregnancy or previous transplantation, ageing affects the humoral immune response both quantitatively and qualitatively. To evaluate the prevalence and distribution of anti-HLA and antibodies of MHC class I chain related antigens A (MICA) specificities in different age groups before initial HSCT would provide HLA and MICA specific antibody profiles under the impact of ageing, which could provide meaningful information in the process of selecting suitable HLA-mismatched donors by avoiding preformed DSA. RESULTS: There were no significant differences in the distribution of anti-HLA class I, class II and anti-MICA antibodies among the three age groups in this study except that a significant lower negative ratio of anti-HLA class I, class II antibodies and higher positive rate of MICA antibodies with maximum mean fluorescent intensity (MFI) > 5000 in the elderly than in young age group. The distribution of antibody specificities against HLA -A, -B, -C, -DR, -DQ, -DP and MICA antigens in the three age groups were generally consistent. The anti-HLA class I antibody specificities with higher frequencies were A80,A68;B76,B45;Cw17, which were unlikely to become DSA in Chinese. Anti-HLA class II antibody specificities were more likely to become potential DSA than class I.DR7, DR9, DQ7, DQ8 and DQ9 were most likely to become potential DSA. CONCLUSIONS: The prevalence of anti-HLA and anti-MICA antibodies increased slightly as age increased. While ageing had a small impact on the distribution of antibody specificity frequencies against HLA-A, -B, -C, -DR,-DQ, -DP and MICA antigens in recipients awaiting initial HSCT from East China. The risk of developing preformed DSA was basically consistent in the three age groups and the elderly group might be more favorable in HLA-mismatched HSCT due to higher positive rate of anti-MICA antibody.

Non-pharmacological interventions for asthma prevention and management across the life course: Umbrella review.

BACKGROUND: The impact of non-pharmacological interventions (NPIs) on asthma prevention and management is insufficiently examined. We aim to comprehensively evaluate and synthesize existing evidence regarding the effectiveness of various NPIs throughout the life course. METHODS: We conducted a systematic search and screening of reviews that examined the effectiveness of various NPIs on asthma prevention and control in the Cochrane Library, PubMed, Embase, and Ovid databases. Data extraction was performed by considering the type of NPIs and the life course stages of the target population. Recommendations were provided by considering the quality of review assessed using the AMSTAR2 tool and the consistency of findings across reviews. RESULTS: We identified 145 reviews and mapped the evidence on the impact of 25 subtypes of NPIs on asthma prevention and control based on five stages of life course. Reviews indicated a shift of focus and various impacts of major NPIs on asthma prevention and control across life courses, while a few types of NPIs, such as physical exercise, appeared to be beneficial in children, adolescents and adults. Consistent and high-level evidence was observed only for psychological intervention on asthma control and quality of life among adults and older adults. Potential benefit with high-level evidence was reported on certain NPIs, such as vitamin D in reducing risk of developing asthma in offsprings in the prenatal stage, digital health interventions in improving asthma control from childhood to older adulthood, and breathing exercise in improving quality of life, asthma-related symptoms and lung function in adulthood and older adulthood. CONCLUSION: This study emphasizes the significance of delivering NPIs to improve asthma prevention and management and highlights the heterogeneity regarding the impact of NPIs across life courses. High-quality research is urgently needed to further strengthen the evidence base of NPIs and tailored interventions should be considered in guideline development.

Risk factors associated with functional decline in older hospital survivors with acute lower respiratory tract infections: a prospective cohort study.

OBJECTIVE: To evaluate the dynamics of basic activity of daily living (BADL) in older patients with acute lower respiratory tract infections (LRTIs) during acute phase and to investigate risk factors associated with decreased physical function at discharge. METHODS: We conducted a prospective cohort study of patients aged 65 years and older who were hospitalized for acute LRTIs between April 15, 2020 and January 15, 2023. All patients received geriatric assessment at admission, including emotion, cognition, frailty, physical function status and so on. The BADL was also evaluated by the Barthel Index (BI) at two weeks before admission by recall (baseline status), at admission and at discharge. Based on the BI grades at baseline and at discharge, patients were classified into two groups: ADL decline and no ADL decline. Multivariable adjusted logistic regression models were used to evaluate the risk factors of decreased physical function. RESULTS: A total of 364 older survivors with LRTIs were included in the analysis. The median age was 74 years (IQR 61.0-82.0), 231 (62.6%) were male, the median length of stay was 10 days. In the geriatric assessment, 139 patients (38.2%) were classified as frailty, 137 patients (37.6%) experienced insomnia, 60 patients (16.5%) exhibited cognitive impairments, and 37 patients (10.2%) were defined as malnutrition. Additionally, 30 patients (8.2%) dealt with emotional disorders. On average, patients were taking 3 medications, and Charlson Comorbidity Index score was 4. 72 patients (19.8%) had function decline at discharge. In the multivariable analysis, frailty status had an odds ratio of 4.25 (95% CI 1.31-19.26) for decreased physical function and cognitive impairment had an odds ratio of 2.58 (95% CI 1.27-5.19). CONCLUSIONS: About 20% older patients with LRTIs experienced functional decline at discharge. Compared to age, severity of diseases and length of stay, frailty and cognitive impairment performed better at predicting the function decline. The apply of geriatric assessment may contribute to enhance the quality of management and treatment for patients with the older with LRTIs.

The application of a 4D-printed chitosan-based stem cell carrier for the repair of corneal alkali burns.

BACKGROUND: Corneal alkali burns can lead to ulceration, perforation, and even corneal blindness due to epithelial defects and extensive cell necrosis, resulting in poor healing outcomes. Previous studies have found that chitosan-based in situ hydrogel loaded with limbal epithelium stem cells (LESCs) has a certain reparative effect on corneal alkali burns. However, the inconsistent pore sizes of the carriers and low cell loading rates have resulted in suboptimal repair outcomes. In this study, 4D bioprinting technology was used to prepare a chitosan-based thermosensitive gel carrier (4D-CTH) with uniform pore size and adjustable shape to improve the transfer capacity of LESCs. METHODS: Prepare solutions of chitosan acetate, carboxymethyl chitosan, and ß-glycerophosphate sodium at specific concentrations, and mix them in certain proportions to create a pore-size uniform scaffold using 4D bioprinting technology. Extract and culture rat LESCs (rLESCs) in vitro, perform immunofluorescence experiments to observe the positivity rate of deltaNp63 cells for cell identification. Conduct a series of experiments to validate the cell compatibility of 4D-CTH, including CCK-8 assay to assess cell toxicity, scratch assay to evaluate the effect of 4D-CTH on rLESCs migration, and Calcein-AM/PI cell staining experiment to examine the impact of 4D-CTH on rLESCs proliferation and morphology. Establish a severe alkali burn model in rat corneas, transplant rLESCs onto the injured cornea using 4D-CTH, periodically observe corneal opacity and neovascularization using a slit lamp, and evaluate epithelial healing by fluorescein sodium staining. Assess the therapeutic effect 4D-CTH-loaded rLESCs on corneal alkali burn through histological evaluation of corneal tissue paraffin sections stained with hematoxylin and eosin, as well as immunofluorescence staining of frozen sections. RESULTS: Using the 4D-CTH, rLESCs were transferred to the alkali burn wounds of rats. Compared with the traditional treatment group (chitosan in situ hydrogel encapsulating rLESCs), the 4D-CTH-rLESC group had significantly higher repair efficiency of corneal injury, such as lower corneal opacity score (1.2 ± 0.4472 vs 0.4 ± 0.5477, p < 0.05) and neovascularization score (5.5 ± 1.118 vs 2.6 ± 0.9618, p < 0.01), and significantly higher corneal epithelial wound healing rate (72.09 ± 3.568% vs 86.60 ± 5.004%, p < 0.01). CONCLUSION: In summary, the corneas of the 4D-CTH-rLESC treatment group were similar to the normal corneas and had a complete corneal structure. These findings suggested that LESCs encapsulated by 4D-CTH significantly accelerated corneal wound healing after alkali burn and can be considered as a rapid and effective method for treating epithelial defects.

Response of microbial communities to the changes in grazing intensity and season in a typical steppe.

Livestock grazing is an influencing factor playing a key role in shaping the plant community, microbial community, and soil properties in grassland ecosystems. Northern China's Loess Plateau has been used for livestock grazing for centuries and is a vulnerable ecosystem. In this study, the fates of bacterial and fungal communities of the typical steppe of the Loess Plateau were investigated under increasing grazing intensities practiced in summer and winter seasons. The results revealed changes in soil physiochemical properties, plant community properties, and microbial diversity in response to alterations in the grazing intensity. The alpha diversity of microbial communities (including bacteria and fungi) exhibited an uneven trend during summer grazing due to an increase in grazing intensity, but it decreased during winter grazing; however, the observed changes were not significant. The beta diversity of the bacterial community was highly influenced by grazing intensity, the summer community clustered near nongrazing, and the winter community presented significantly different results. The beta diversity of the fungal community was not influenced by grazing intensity or season. Grazing induced the growth of fast-growing bacteria (such as Actinobacteria and Firmicutes) and saprophytic fungi and a reduction in overall pathogenic traits. Co-occurrence network analysis and a structural equation model revealed changes in soil and plant properties (such as soil nitrogen level, soil organic carbon level, aboveground biomass, and litter biomass), with an increase in grazing intensity contributing to alterations in bacterial and fungal diversities. This finding demonstrates that grazing intensity can directly affect soil microbes and play an indirect role by modifying soil nutrients and reducing plant biomass, which eventually contributes to changes in microbial communities. Overall, implementing low grazing intensity is suggested for maintaining the microbial community structure the same as that of the native microbiome (ungrazed) in the steppe ecosystems.

A polarization-sensitive, high on/off ratio and self-powered photodetector based on Nb2CTxand Nd2CTx@MoS2.

MXene two-dimensional materials have been widely used in energy storage, catalysis, sensing and other fields, Nb2C as a typical two-dimensional MXene material, its exploration in the field of optoelectronics is still in its infancy, especially Nb2C-based photodetectors are still to be developed. This paper demonstrates that two-dimensional films based on few-layer Nb2C have a photoelectric response in the wavelength range from visible to near-infrared. We have found that the light response performance can be easily adjusted by controlling the thickness of the spin-coated film, and that Nb2C photodetectors show great advantages in terms of wide bandwidth, polarization response, high switching ratio, etc. By adjusting the material concentration and sample thickness, the photocurrent can reach up to 330 nA, the switching ratio can reach 410, and the responsivity can reach 8.3 × 10-4A W-1. In the polarization characteristic test, an extinction ratio of 7.6 can be obtained. By adjusting the content of that doped MoS2quantum dot, the dark current can reach 7.6 × 10-13A, and the switching ratio can reach 3 × 105, which can be increased by 700 times. The above results show that the few-layer Nb2C nanosheets can be used as optoelectronic detectors in the visible to near-infrared bands, which further broadens the application prospects of two-dimensional MXene.

Deficiency of FRMD5 results in neurodevelopmental dysfunction and autistic-like behavior in mice.

The pathophysiology of autism spectrum disorders (ASDs) is causally linked to postsynaptic scaffolding proteins, as evidenced by numerous large-scale genomic studies [1, 2] and in vitro and in vivo neurobiological studies of mutations in animal models [3, 4]. However, due to the distinct phenotypic and genetic heterogeneity observed in ASD patients, individual mutation genes account for only a small proportion (<2%) of cases [1, 5]. Recently, a human genetic study revealed a correlation between de novo variants in FERM domain-containing-5 (FRMD5) and neurodevelopmental abnormalities [6]. In this study, we demonstrate that deficiency of the scaffolding protein FRMD5 leads to neurodevelopmental dysfunction and ASD-like behavior in mice. FRMD5 deficiency results in morphological abnormalities in neurons and synaptic dysfunction in mice. Frmd5-deficient mice display learning and memory dysfunction, impaired social function, and increased repetitive stereotyped behavior. Mechanistically, tandem mass tag (TMT)-labeled quantitative proteomics revealed that FRMD5 deletion affects the distribution of synaptic proteins involved in the pathological process of ASD. Collectively, our findings delineate the critical role of FRMD5 in neurodevelopment and ASD pathophysiology, suggesting potential therapeutic implications for the treatment of ASD.

A sensitive coumarin fluorescence sensor designed for isoprene detection and imaging research in plants.

The release of isoprene by plants is considered to be an adaptation to the environment. Herein, a highly selective coumarin fluorescent probe (DMIC) was designed for detecting isoprene. When isoprene came into contact with the maleimide of DMIC, an electrophilic addition process took place. The powerful push-pull effect of DMIC was disrupted. Simultaneously, intramolecular charge transfer was initiated. This enabled DMIC to achieve rapid detection of isoprene within 5 min. Furthermore, excellent linearity was observed in the concentration range of 1-560 ppm (R2 = 0.996). A limit of detection is 1.6 ppm. DMIC was applied to in vitro studies of plant release of liberated isoprene. By monitoring the release of isoprene from different tree species throughout the day, the dynamics of isoprene release from plants throughout the day have been successfully revealed. In addition, the release of isoprene varied considerably among different tree species. In particular, the biocompatibility of DMIC allowed for the in vivo detection of isoprene using fluorescence imaging. The results successfully revealed the dynamics of isoprene release in plants under stress. The amount of isoprene that a plant produced increased with the severity of the stress it experienced. This suggested that the level of isoprene content in plants could be used as a preliminary indicator of the physiological health status of plants. This research demonstrates great potential for clarifying signal transduction in biological systems. It provided ideas for further understanding the biology of isoprene.

RAB27B-regulated exosomes mediate LSC maintenance via resistance to senescence and crosstalk with the microenvironment.

The fate of leukaemia stem cells (LSCs) is determined by both their inherent mechanisms and crosstalk with their niches. Although LSCs were confirmed to be eradicated by restarting senescence, the specific key regulators of LSC resistance to senescence and remodelling of the niche to obtain a microenvironment suitable for stemness remain unknown. Here, we found that RAB27B, a gene regulating exosome secretion, was overexpressed in LSCs and associated with the poor prognosis of acute myeloid leukaemia (AML) patients. The increased RAB27B in LSCs prevented their senescence and maintained their stemness in vitro and in vivo. Mechanically, the increased RAB27B expression in LSCs selectively promoted the loading and release of exosomes rich in senescence-inducing proteins by direct combination. Furthermore, RAB27B-regulated LSC-derived exosomes remodelled the niche and induced senescence of mesenchymal stem cells (MSCs) with increased RAB27B expression ex vivo and in vivo. The increased RAB27B in the senescent MSCs conversely promoted LSC maintenance ex vivo and in vivo via selective excretion of exosomes rich in stemness-promoting proteins. Therefore, we identified the specifically increased RAB27B in LSCs and their educated senescent MSCs as a hub molecule for LSC resistance to senescence and maintenance through crosstalk with its niche via selective exosome excretion.

Regulation and mechanism of pyrite and humic acid on the toxicity of arsenate in lettuce.

Pyrite and humic acid are common substances in nature, and the combined effects of pyrite and humic acid on arsenic phytotoxicity are more widespread in the actual environments than that of a single substance, but have received less attention. In this study, the interaction between pyrite and humic acid in arsenate solution was studied, and the effects of pyrite and humic acid on plant toxicity of arsenate were evaluated. The results showed that arsenate + pyrite + fulvic acid (V-PF) treatment immobilized more arsenic by forming chemical bonds such as AsS and Fe-As-O and reduced the migration of arsenic to plants. Compared to the arsenate + fulvic acid (VF), arsenate + pyrite (VP) and arsenate (V) group, the inorganic arsenic content of lettuce leaves in the V- PF group was reduced by 19.8 %, 13.4 % and 13.4 %, respectively. In addition, the V-PF group increased the absorption of Ca, Fe and Cu in plant roots, and improved the activity of superoxide dismutase (SOD) in plant leaves. Compared to the VF group, SOD and MDA in the V-PF group increased by 34.1 % in 30 days and decreased by 47.3 % in 40 days, respectively. The biomass of lettuce in V-PF group was increased by 29.3 % compared with that in VF group on day 50. The protein content of the V-PF group was 58.3 % higher than that of the VF group and 23.1 % higher than that of the VP group. Furthermore, metabolomics analysis showed that the V-PF group promoted glycolysis by up-regulating glyoxylic acid and dicarboxylic acid metabolism, thus reducing carbohydrate accumulation. Phosphocreatine metabolism was also up-regulated, which decreased the oxidative damage in lettuce induced by arsenic. This study will provide new ideas for scientifically and rationally assessing the ecological environmental risks of arsenic and regulating its toxicity.

Grazing-driven shifts in soil bacterial community structure and function in a typical steppe are mediated by additional N inputs.

Herbivore grazing and nitrogen (N) fertilization affect soil microbial diversity and community composition both in direct and indirect pathways (e.g., via alterations in soil microenvironment and plant communities); however, their combination effects are still largely unexplored. We carried out a field study to investigate how soil abiotic properties, plant community composition and functional traits altered soil bacterial community structure and function in response to a long-term herbivore grazing (17-year sheep grazing with four stocking rates) and anthropogenic N inputs (6-year N addition with four levels) experiment. We show that a high stocking rate of 8.7 sheep ha-1 (SR8.7) decreased soil bacterial α- and ß-diversity, while α- and ß-diversity showed hump-shaped and saddle-shaped responses, respectively, with increasing N addition rate, reaching tipping points at the N application rate of 10 g N m-2 year-1 (N10). The synergistic effects of grazing and N addition induced the highest soil bacterial α-diversity at SR2.7 with N10. The contrasting effects of grazing and N addition induced higher soil bacterial ß-diversity at SR8.7 with N20. Plant factors (e.g., aboveground biomass of Stipa bungeana and community-weighted mean carbon [CWM_C]), edaphic factors (e.g., soil moisture, pH, NO3--N, and C:nutrients ratios) and their interactions were the most significant factors affecting the diversity and community composition of bacteria. Our structure equation model (SEM) shows that grazing-induced negative effects on soil pH and plant community composition indirectly increased the ß-diversity of soil bacteria, while grazing-induced decreased CWM_C had positive effects on bacterial α-diversity and community structure. However, N addition indirectly increased ß-diversity of soil bacteria via changes in soil NO3--N and plant community composition, while N addition had negative impacts on bacterial α-diversity and community structure via variations in CWM_C. The interaction of grazing and N addition increased the complexity and stability of the bacterial network. Based on the KEGG database, grazing and N addition could accelerate the soil functional potential of C and N cycling. Our findings suggest that N application at a rate of <10 g N m-2 year-1 with a stocking rate of <5.3 sheep ha-1 could maintain the development of soil bacteria in supporting the most important ecosystem functions and services. Complex responses of soil microbes to grazing and N addition indicate the need for deeper investigations of the impacts of global change on microbial involvement in biogeochemical cycles.

Ozone exposure affects corneal epithelial fate by promoting mtDNA leakage and cGAS/STING activation.

Ozone is a common air pollutant associated with various human diseases. The human ocular surface is frequently exposed to ozone in the troposphere, but the mechanisms by which ozone affects the ocular surface health remain unclear. This study aimed to establish a mouse model to investigate the effects of ozone exposure on the ocular surface and the corneal epithelium. The findings revealed that ozone exposure disrupted corneal epithelial homeostasis and differentiation, resulting in corneal squamous metaplasia. Further, ozone exposure induced oxidative damage and cytoplasmic leakage of mitochondrial DNA (mtDNA), thereby activating the cGAS/STING signaling pathway. The activation of the cGAS/STING signaling pathway triggered the activation of downstream NF-κB and TRAF6 signaling pathways, causing corneal inflammation, thereby promoting corneal inflammation and squamous metaplasia. Finally, C-176, a selective STING inhibitor, effectively prevented and treated corneal inflammation and squamous metaplasia caused by ozone exposure. This study revealed the role of mtDNA leakage-mediated cGAS/STING activation in corneal squamous epithelial metaplasia caused by ozone exposure. It also depicted the abnormal expression pattern of corneal epithelial keratin using three-dimensional images, providing new targets and strategies for preventing and treating corneal squamous metaplasia and other ocular surface diseases.

A multicenter single-arm trial of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer.

The objective of this multicenter, single-arm trial (ChiCTR1900022293) was to explore the efficacy and safety of neoadjuvant therapy with epirubicin, cyclophosphamide, and pyrotinib followed by docetaxel, trastuzumab, and pyrotinib (ECPy-THPy) in the treatment of patients with stage II-III HER2-positive breast cancer. The present study enrolled patients with stage II-III HER2-positive breast cancer. Epirubicin and cyclophosphamide were administrated for four 21-day cycles, followed by four cycles of docetaxel and trastuzumab. Pyrotinib was taken orally once per day throughout the treatment period. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate in the modified intention-to-treat (mITT) population. In total, 175 patients were included. The tpCR rate was 68.6% (95% CI, 60.7-75.8%), while the objective response rate was 89.1%. In the post-hoc subgroup analysis, no association between clinical characteristics and the tpCR rate was observed. The most common grade ≥3 adverse events were diarrhea (54.3%), followed by white blood cell count decreased (5.1%), and neutrophil count decreased (4.6%). In conclusion, the neoadjuvant regimen with ECPy-THPy showed promising pathological response and clinical benefits with an acceptable safety profile in patients with stage II-III HER2-positive breast cancer.