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Abstract Background Acute exacerbation of fibrosing interstitial lung diseases (AE-ILD) is a serious life-threatening event per year. Methylprednisolone and/or immunosuppressive agents (ISA) are a mainstay in any regimen, under the premise that pulmonary infection has been promptly identified and controlled. We investigated the value of bronchoalveolar lavage fluid (BALF) metagenomic next-generation sequencing (mNGS) on the treatment adjustment of AE-ILD. Methods We conducted a cross-sectional observational study. All data were collected prospectively and retrospectively analyzed. We included fifty-six patients with AE-ILD and nineteen stable ILD who underwent BALF mNGS at the beginning of admission. Results Patients with a variety of ILD classification were included. Connective–tissue disease related ILD (CTD-ILD) occupy the most common underlying non-idiopathic pulmonary fibrosis (non-IPF). The infection-triggered AE accounted for 39.29%, with the majority of cases being mixed infections. The microorganisms load in the AE-ILD group was significantly higher. After adjusted by mNGS, the therapy coverage number of pathogens was significantly higher compared to the initial treatment (p

Abstract Individuals’ continuous success in competitive interactions with conspecifics strongly affects their social hierarchy. Medial prefrontal cortex (mPFC) is the key brain region mediating both social competition and hierarchy. However, the molecular regulatory mechanisms underlying the neural ensemble in the mPFC remains unclear. Here, we demonstrate that in excitatory neurons of prelimbic cortex (PL), lncRNA Sera remodels the utilization of Pkm Exon9 and Exon10, resulting in a decrease in the Pkm1/2 ratio in highly competitive mice. By employing a tet-on/off system, we disrupt or rebuild the normal Pkm1/2 ratio by controlling the expression of Pkm2 in PL excitatory neurons. We find that long-term Pkm2 modulation induces timely competition alteration and hysteretic rank change, through phosphorylating the Ser845 site of GluA1. Together, this study uncovers a crucial role of lncRNA Sera/Pkm2 pathway in the transition of social competition to rank by remodeling neural ensemble in mPFC.

Abstract In the KEYNOTE-811 study, anti-HER2 and immunotherapy treatments resulted in longer survival in HER2-positive gastric cancer patients with CPS ≥ 1, whereas CPS

Abstract IL-33 belongs to the inflammatory factor family and is closely associated with the inflammatory response. However, its role in the development of intrauterine adhesions (IUAs) remains unclear. In this study, the role of IL-33 in the formation of IUAs after endometrial injury was identified via RNA sequencing after mouse endometrial organoids were transplanted into an IUA mouse model. Major pathological changes in the mouse uterus, consistent with the expression of fibrotic markers, such as TGF-β, were observed in response to treatment with IL-33. This finding may be attributed to activation of the phosphorylation of downstream MAPK signaling pathway components, which are activated by the release of IL-33 in macrophages. Our study provides a novel mechanism for elucidating IUA formation, suggesting a new therapeutic strategy for the prevention and clinical treatment of IUAs.

Abstract Background Dietary diversity has been suggested as a potential preventive measure against frailty in older adults, but the effect of changes in dietary diversity on frailty is unclear. This study was conducted to examine the association between the dietary diversity score (DDS) and frailty among older Chinese adults. Methods A total of 12,457 adults aged 65 years or older were enrolled from three consecutive and nonoverlapping cohorts from the Chinese Longitudinal Healthy Longevity Survey (the 2002 cohort, the 2005 cohort, and the 2008 cohort). DDS was calculated based on nine predefined food groups, and DDS changes were assessed by comparing scores at baseline and the first follow-up survey. We used 39 self-reported health items to assess frailty. Cox proportional hazard models were performed to examine the association between DDS change patterns and frailty. Results Participants with low-to-low DDS had the highest frailty incidence (111.1/1000 person-years), while high-to-high DDS had the lowest (41.1/1000 person-years). Compared to the high-to-high group of overall DDS pattern, participants in other DDS change patterns had a higher risk of frailty (HRs ranged from 1.25 to 2.15). Similar associations were observed for plant-based and animal-based DDS. Compared to stable DDS changes, participants with an extreme decline in DDS had an increased risk of frailty, with HRs of 1.38 (1.24, 1.53), 1.31 (1.19, 1.44), and 1.29 (1.16, 1.43) for overall, plant-based, and animal-based DDS, respectively. Conclusions Maintaining a lower DDS or having a large reduction in DDS was associated with a higher risk of frailty among Chinese older adults. These findings highlight the importance of improving a diverse diet across old age for preventing frailty in later life.

Abstract Compensation and intracellular storage of PD-L1 may compromise the efficacy of antibody drugs targeting the conformational blockade of PD1/PD-L1 on the cell surface. Alternative therapies aiming to reduce the overall cellular abundance of PD-L1 thus might overcome resistance to conventional immune checkpoint blockade. Here we show by bioinformatics analysis that colon adenocarcinoma (COAD) with high microsatellite instability (MSI-H) presents the most promising potential for this therapeutic intervention, and that overall PD-L1 abundance could be controlled via HSC70-mediated lysosomal degradation. Proteomic and metabolomic analyses of mice COAD with MSI-H in situ unveil a prominent acidic tumor microenvironment. To harness these properties, an artificial protein, IgP β, is engineered using pH-responsive peptidic foldamers. This features customized peptide patterns and designed molecular function to facilitate interaction between neoplastic PD-L1 and HSC70. IgP β effectively reduces neoplastic PD-L1 levels via HSC70-mediated lysosomal degradation, thereby persistently revitalizing the action of tumor-infiltrating CD8 + T cells. Notably, the anti-tumor effect of lysosomal-degradation-based therapy surpasses that of antibody-based immune checkpoint blockade for MSI-H COAD in multiple mouse models. The presented strategy expands the use of peptidic foldamers in discovering artificial protein drugs for targeted cancer immunotherapy.

Abstract Background Cancer-associated fibroblasts (CAFs) are the prominent cell type in the tumor microenvironment (TME), and CAF subsets have been identified in various tumors. However, how CAFs spatially coordinate other cell populations within the liver TME to promote cancer progression remains unclear. Methods We combined multi-region proteomics (6 patients, 24 samples), 10X Genomics Visium spatial transcriptomics (11 patients, 25 samples), and multiplexed imaging (92 patients, 264 samples) technologies to decipher the expression heterogeneity, functional diversity, spatial distribution, colocalization, and interaction of fibroblasts. The newly identified CAF subpopulation was validated by cells isolated from 5 liver cancer patients and in vitro functional assays. Results We identified a liver CAF subpopulation, marked by the expression of COL1A2, COL4A1, COL4A2, CTGF, and FSTL1, and named F5-CAF. F5-CAF is preferentially located within and around tumor nests and colocalizes with cancer cells with higher stemness in hepatocellular carcinoma (HCC). Multiplexed staining of 92 patients and the bulk transcriptome of 371 patients demonstrated that the abundance of F5-CAFs in HCC was associated with a worse prognosis. Further in vitro experiments showed that F5-CAFs isolated from liver cancer patients can promote the proliferation and stemness of HCC cells. Conclusions We identified a CAF subpopulation F5-CAF in liver cancer, which is associated with cancer stemness and unfavorable prognosis. Our results provide potential mechanisms by which the CAF subset in the TME promotes the development of liver cancer by supporting the survival of cancer stem cells.

Abstract Background The health effects of different weight loss strategies vary greatly, and the relationship between weight loss strategies, especially the combination of multiple strategies, and death is still unclear. We aimed to examine the associations of various numbers and combinations of weight loss strategies with all-cause and specific-cause mortality and to further evaluate the associations of different total weight loss volumes with mortality. Methods Using data from NHANES (1999–2018) with 48,430 participants aged 20 and above, we collected fourteen self-reported weight loss strategies and identified five clusters using latent class analysis. Cox proportional hazards models were used to examine the association between the amounts and clusters of weight loss strategies and mortality. Results During a median follow-up of 9.1 years of 48,430 participants, 7,539 deaths were recorded (including 1,941 CVDs and 1,714 cancer). Participants who adopted 2, 3–4, and ≥ 5 weight loss strategies had a lower risk of all-cause mortality, with HRs of 0.88 (95% CI, 0.81 to 0.97), 0.89 (95% CI, 0.81 to 0.96) and 0.71 (95% CI, 0.61 to 0.82). Regardless of weight loss or weight gain categories, there was a significant trend toward reduced mortality as the number of weight loss strategies increased (P trend

Abstract Mesenchymal stem cells (MSCs) therapy is a highly researched treatment that has the potential to promote immunomodulation and anti-inflammatory, anti-apoptotic, and antimicrobial activities. It is thought that it can enhance internal organ function, reverse tissue remodeling, and achieve significant organ repair and regeneration. However, the limited infusion, survival, and engraftment of transplanted MSCs diminish the effectiveness of MSCs-based therapy. Consequently, various preconditioning methods have emerged as strategies for enhancing the therapeutic effects of MSCs and achieving better clinical outcomes. In particular, the use of natural small molecule compounds (NSMs) as a pretreatment strategy is discussed in this narrative review, with a focus on their roles in regulating MSCs for injury repair in vital internal organs. Additionally, the discussion focuses on the future directions and challenges of transforming mesenchymal stem cell research into clinical applications.

Abstract Feline mesenchymal stem cells (fMSCs) are well known for their robust differentiation capabilities and are commonly used in studying immune-related diseases in cats. Despite their importance, the susceptibility of fMSCs to viral infections remains uncertain. This study aimed to assess the susceptibility of feline adipose-derived mesenchymal stem cells (fAD-MSCs) and feline umbilical cord-derived mesenchymal stem cells (fUC-MSCs) to common feline viruses, including feline coronavirus (FCoV), feline herpesvirus type 1 (FHV-1), and feline panleukopenia virus (FPV). The results demonstrated that both FCoV and FHV-1 were able to infect both types of cells, while FPV did not exhibit cytopathic effects on fUC-MSCs. Furthermore, all three viruses were successfully isolated from fAD-MSCs. These findings suggest that certain feline viruses can replicate in fMSCs, indicating potential limitations in using fMSCs for treating viral diseases caused by these specific viruses. This study has important clinical implications for veterinarians, particularly in the management of viral diseases.

Abstract The nanoscale fibrillar morphology, featuring long-range structural order, provides abundant interfaces for efficient exciton dissociation and high-quality pathways for effective charge transport, is a promising morphology for high performance organic solar cells. Here, we synthesize a thiophene terminated non-fullerene acceptor, L8-ThCl, to induce the fibrillization of both polymer donor and host acceptor, that surpasses the 20% efficiency milestone of organic solar cells. After adding L8-ThCl, the original weak and less continuous nanofibrils of polymer donors, i.e. PM6 or D18, are well enlarged and refined, whilst the host acceptor L8-BO also assembles into nanofibrils with enhanced structural order. By adapting the layer-by-layer deposition method, the enhanced structural order can be retained to significantly boost the power conversion efficiency, with specific values of 19.4% and 20.1% for the PM6:L8-ThCl/L8-BO:L8-ThCl and D18:L8-ThCl/L8-BO:L8-ThCl devices, with the latter being certified 20.0%, which is the highest certified efficiency reported so far for single-junction organic solar cells.

Abstract To increase the efficiency of phytoremediation to clean up heavy metals in soil, assisted with alternating current (AC) electric field technology is a promising choice. Our experiments utilized the hyperaccumulator Sedum alfredii Hance and the fast-growing, high-biomass willow (Salix sp.). We investigated the efficiency of AC field combined with S. alfredii—willow intercropping for removing Cd from soils with different pH values. In the AC electric field treatment with S. alfredii—willow intercropping, the available Cd content in acidic soil increased by 50.00% compared to the control, and in alkaline soil, the increase was 100.00%. Furthermore, AC electric field promoted Cd uptake by plants in both acidic and alkaline soils, with Cd accumulation in the aboveground increased by 20.52% (P

Abstract Background Even with advances in primary health care, depressive disorders remain a major global public health problem. We conducted an in-depth analysis of global, regional and national trends in depressive disorders incidence over the past 30 years. Methods Data on the incidence of depressive disorders were obtained by sex (female, male, and both), location (204 countries), age (5–84 years), year (1990–2019) from the Global Burden of Disease Study (GBD) 2019. Further, age-period-cohort modeling was used to estimate the net drift, local drift, age, period and cohort effects between 1990 and 2019. Results In 2019, although the incidence of depressive disorders has increased by 59.3% to 290 million (95% UI: 256, 328), the age-standardized incidence rate has decreased by 2.35% to 3588.25 per 100,000 people (3152.71, 4060.42) compared to 1990. There was an emerging transition of incidences from the young and middle-aged population to the old population. From 1990 to 2019, the net drift of incidence rate ranged from −0.54% (−0.61%, −0.47%) in low-middle Socio-demographic Index (SDI) regions to 0.52% (0.25%, 0.79%) in high SDI regions. Globally, the incidence rate of depressive disorders increases with age, period effects showing a decreasing risk and cohort effects beginning to decline after the 1960s. Conclusions Our current findings reflect substantial health disparities and potential priority-setting of depressive disorders incidence in the three dimensions of age, period and cohort across SDI regions, countries. The scope of healthcare to improve the progression of depressive disorders events can be expanded to include males, females of all ages.

Abstract The relationship between tissue-specific DNA methylation and cancer risk remains inadequately elucidated. Leveraging resources from the Genotype-Tissue Expression consortium, here we develop genetic models to predict DNA methylation at CpG sites across the genome for seven tissues and apply these models to genome-wide association study data of corresponding cancers, namely breast, colorectal, renal cell, lung, ovarian, prostate, and testicular germ cell cancers. At Bonferroni-corrected P

Abstract Background With a considerable variety of cancer subtypes, Non-small cell lung cancer (NSCLC) poses a substantial threat to public health, affecting a large number of individuals and resulting in a high mortality rate. Circular RNA (circRNA) has been applied in various diseases, including cancers. This study aims to investigate the clinial significance and functional role of circPTP4A2 in NSCLC. Methods The serum and tissue samples were collected for detecting circPTP4A2 expression in NSCLC using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Actinomycin D was used to treat NSCLC cells to detect circPTP4A2 stability. The CCK-8 and Transwell assays were utilized to assess the effects of circPTP4A2 in NSCLC cells. The ELISA assay and cytotoxicity analysis were used to detect the roles of circPTP4A2 in immune escape. Results The serum and tissue circPTP4A2 expression was upregulated in NSCLC. The high circPTP4A2 had a relatively high value in differentiating NSCLC patients from healthy individuals. The proliferation, invasion, and immune escape were repressed by circPTP4A2 knockdown. Conclusions High circPTP4A2 has the potential to be a diagnostic biomarker in NSCLC. Silencing of circPTP4A2 receded the progression of NSCLC and enhanced antitumor immunity, which might provide potential targets and new ideas for improving the diagnosis and effect of immunotherapy in NSCLC patients.

Abstract Methylmalonic acid (MMA), a biomarker of mitochondrial dysfunction, has been reported to be associated with depression in specific populations (i.e., older adults and postpartum women). Our study aimed to investigate to what extent MMA was associated with depressive symptoms and mortality in the general population, and assess whether depressive symptoms mediate the relationship between MMA and mortality. We analyzed cross-sectional data from 8343 participants from the US National Health and Nutrition Examination Survey. MMA was measured by liquid chromatography-tandem mass spectrometry, while depressive symptoms were measured by the Patient Health Questionnaire-9. Mortality data were obtained through linkage with National Death Index records. Linear regression models were performed to assess the association between MMA and depressive symptoms. The Cox proportional hazard regression model was utilized to assess the association of MMA and depressive symptoms with mortality. Mediation analysis was conducted within the counterfactual framework. In this general population, each SD (around 0.49 μmol/L) increase in MMA was associated with a 0.03 SD (approximately 0.15 score) increase in depressive symptoms (β = 0.033, 95% CI: 0.010, 0.055, p = 0.005). Notably, this association was more pronounced in men and participants over 60 years old. Higher levels of MMA and having more depressive symptoms were associated with a higher risk of mortality. However, depressive symptoms do not mediate the relationship between MMA and mortality. Elevated MMA levels were associated with depressive symptoms and an increased risk of mortality. These findings suggest that mitochondrial dysfunction may contribute to the multifactorial etiology of depression.

Abstract Introduction Immunoglobulin light chain (AL) amyloidosis presents a clinical spectrum characterized by diverse manifestations and involvement of multiple organs, posing a significant diagnostic challenge for physicians. Methods and results We present a case of a patient admitted to our hospital due to recurrent cough and sputum, which was initially diagnosed as refractory tuberculosis. Throughout his hospitalization, the patient experienced distressing symptoms, including uncontrollable chest tightness, hypotension, and fever. Noteworthy observations included a persistent elevation in cardiac biomarkers, indicative of cardiac damage. Bronchoalveolar lavage revealed the presence of various pathogenic microorganisms, while bone marrow flow cytometry demonstrated the existence of clonal plasma cells. Additionally, the urine free light chain assay detected the presence of M protein, and the positive congo red staining of the abdominal wall fat biopsy confirmed amyloid deposition in the tissues. Taking into account the patient’s clinical presentation and the examination findings, we reached a conclusive diagnosis of immunoglobulin light chain (AL) amyloidosis. Conclusion This case serves as a reminder for physicians to consider rare diseases like AL amyloidosis when patients present with symptoms involving multiple organ systems such as heart, lung and kidney that are unresponsive to conventional treatment options.

Objective(s): Gefitinib (GEF) is a targeted medicine used to treat locally advanced or metastatic non-small cell lung cancer (NSCLC). However, GEF’s hepatotoxicity limits its clinical use. This study aims to investigate the protective effect of naringin (NG) against GEF-induced hepatotoxicity. Materials and Methods: Fifty female ICR mice were randomly divided into 5 groups: Control, GEF (200 mg/kg), NG (50 mg/kg) + GEF (200 mg/kg), NG (100 mg/kg) +GEF (200 mg/kg), NG (200 mg/kg) +GEF (200 mg/kg). After 4 weeks of continuous administration, the mice were euthanized. The blood and liver tissue samples were collected. Results: The results indicated that the GEF group showed increased liver index, liver enzyme activities, and decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities. Some hepatocytes showed hydropic degeneration and focal necrosis. Cell apoptosis, Cleaved-caspase3, and Poly (ADP-ribose) polymerase 1 (PARP1) increased. Transmission electron microscopy revealed the presence of numerous autophagic lysosomes or autophagosomes around the cell nucleus. Compared to the GEF group, NG can reverse these changes. Conclusion: In summary, NG alleviates GEF-induced hepatotoxicity by anti-oxidation, inhibiting cell apoptosis, and autophagy. Therefore, this study suggests the use of NG to mitigate GEF’s toxicity to the liver.

Abstract Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, necessitating the identification of novel therapeutic targets. Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is involved in biological processes critical to cancer progression, such as regulation of solute carrier transporter proteins and metabolic pathways, including mTORC1. However, the metabolic processes governed by LAPTM4B and its role in oncogenesis remain unknown. In this study, we conducted unbiased metabolomic screens to uncover the metabolic landscape regulated by LAPTM4B. We observed common metabolic changes in several knockout cell models suggesting of a role for LAPTM4B in suppressing ferroptosis. Through a series of cell-based assays and animal experiments, we demonstrate that LAPTM4B protects tumor cells from erastin-induced ferroptosis both in vitro and in vivo. Mechanistically, LAPTM4B suppresses ferroptosis by inhibiting NEDD4L/ZRANB1 mediated ubiquitination and subsequent proteasomal degradation of the cystine-glutamate antiporter SLC7A11. Furthermore, metabolomic profiling of cancer cells revealed that LAPTM4B knockout leads to a significant enrichment of ferroptosis and associated metabolic alterations. By integrating results from cellular assays, patient tissue samples, an animal model, and cancer databases, this study highlights the clinical relevance of the LAPTM4B-SLC7A11-ferroptosis signaling axis in NSCLC progression and identifies it as a potential target for the development of cancer therapeutics.

Abstract High temperatures are a major stress factor that limit the growth of Pinellia ternata. WRKY proteins widely distribute in plants with the important roles in plant growth and stress responses. However, WRKY genes have not been identified in P. ternata thus far. In this study, five PtWRKYs with four functional subgroups were identified in P. ternata. One group III WRKY transcription factor, PtWRKY2, was strongly induced by high temperatures, whereas the other four PtWRKYs were suppressed. Analysis of transcription factor characteristics revealed that PtWRKY2 localized to the nucleus and specifically bound to W-box elements without transcriptional activation activity. Overexpression of PtWRKY2 increased the heat tolerance of Arabidopsis, as shown by the higher percentage of seed germination and survival rate, and the longer root length of transgenic lines under high temperatures compared to the wild-type. Moreover, PtWRKY2 overexpression significantly decreased reactive oxygen species accumulation by increasing the catalase, superoxide dismutase, and peroxidase activities. Furthermore, the selected heat shock-associated genes, including five transcription factors (HSFA1A, HSFA7A, bZIP28, DREB2A, and DREB2B), two heat shock proteins (HSP70 and HSP17.4), and three antioxidant enzymes (POD34, CAT1, and SOD1), were all upregulated in transgenic Arabidopsis. The study identifies that PtWRKY2 functions as a key transcriptional regulator in the heat tolerance of P. ternata, which might provide new insights into the genetic improvement of P. ternata.

Abstract Background Genome‐wide association studies (GWAS) have identified more than a thousand loci for blood pressure (BP). Functional genes in these loci are cell‐type specific. The aim of this study was to elucidate potentially functional genes associated with BP in the aorta through the utilization of RNA modification‐associated single‐nucleotide polymorphisms (RNAm‐SNPs). Methods Utilizing large‐scale genetic data of 757,601 individuals from the UK Biobank and International Consortium of Blood Pressure consortium, we identified associations between RNAm‐SNPs and BP. The association between RNAm‐SNPs, gene expression, and BP were examined. Results A total of 355 RNAm‐SNPs related to m6A, m1A, m5C, m7G, and A‐to‐I modification were associated with BP. The related genes were enriched in the pancreatic secretion pathway and renin secretion pathway. The BP GWAS signals were significantly enriched with m6A‐SNPs, highlighting the potential functional relevance of m6A in physiological processes influencing BP. Notably, m6A‐SNPs in CYP11B1, PDE3B, HDAC7, ACE, SLC4A7, PDE1A, FRK, MTHFR, NPPA, CACNA1D, and HDAC9 were identified. Differential methylation and differential expression of the BP genes in FTO‐overexpression and METTL14‐knockdown vascular smooth muscle cells were detected. RNAm‐SNPs were associated with ascending and descending aorta diameter and the genes showed differential methylation between aortic dissection (AD) cases and controls. In scRNA‐seq study, we identified ARID5A, HLA‐DPB1, HLA‐DRA, IRF1, LINC01091, MCL1, MLF1, MLXIPL, NAA16, NADK, RERG, SRM, and USP53 as differential expression genes for AD in aortic cells. Conclusion The present study identified RNAm‐SNPs in BP loci and elucidated the associations between the RNAm‐SNPs, gene expression, and BP. The identified BP‐associated genes in aortic cells were associated with AD.

Abstract Objective To investigate the anatomic risk factors of knee in patients with acute non-contact anterior cruciate ligament (aACL) ruptures to develop ramp lesions. Methods A total of 202 subjects were retrospectively divided into three groups: (1) aACL ruptures combined with ramp lesions group (n = 76); (2) isolated ACL ruptures group (n = 56) and (3) normal controls group (n = 70). Quantitative morphological parameters on MRI were measured including: diameter of medial femoral condyle (MFC), anterior-posterior length and depth of medial tibial plateau (MTP AP length and depth), lateral posterior tibial slope (LPTS) and medial posterior tibial slope (MTPS), asymmetry of LPTS and MPTS (LMPTS), lateral meniscal slope (LMS), and medial meniscal slope (MMS). Results The MTP AP length, MTP AP length/MFC diameter ratio, MTP depth, LPTS and the asymmetry of LMPTS showed significant differences among the three groups (p

For over two decades, the development of B-cell lymphoma-2 (Bcl-2) family therapeutics has primarily focused on anti-apoptotic proteins, resulting in the first-in-class drugs called BH3 mimetics, especially for Bcl-2 inhibitor Venetoclax. The pro-apoptotic protein Bcl-2-associated X protein (BAX) plays a crucial role as the executioner protein of the mitochondrial regulated cell death, contributing to organismal development, tissue homeostasis, and immunity. The dysregulation of BAX is closely associated with the onset and progression of diseases characterized by pathologic cell survival or death, such as cancer, neurodegeneration, and heart failure. In addition to conducting thorough investigations into the physiological modulation of BAX, research on the regulatory mechanisms of small molecules identified through biochemical screening approaches has prompted the identification of functional and potentially druggable binding sites on BAX, as well as diverse all-molecule BAX modulators. This review presents recent advancements in elucidating the physiological and pharmacological modulation of BAX and in identifying potentially druggable binding sites on BAX. Furthermore, it highlights the structural and mechanistic insights into small-molecule modulators targeting diverse binding surfaces or conformations of BAX, offering a promising avenue for developing next-generation apoptosis modulators to treat a wide range of diseases associated with dysregulated cell death by directly targeting BAX.

The 3D reconstruction and virtual display of wooden furniture cultural relics were investigated using laser scanning and CT scanning techniques. The suitability of different 3D reconstruction techniques and virtual display approaches were considered. The experiments demonstrated that digital models obtained from both laser scanning and CT scanning can be integrated seamlessly into virtual environments created with 3DMAX for exhibition purposes. Additionally, post-processing software, such as PR or AE, can be utilized to synthesize virtual display video. The resulting images exhibit self-adaptation capabilities, with clear and undistorted 3D model and texture image. Moreover, other types of scanned models are suitable for 3D micro-scale model printing, although CT-based models tend to achieve higher printing accuracy compared to those generated by laser scanning technology. However, the precision of 3D printing model is contingent upon factors such as the precision of digital model, the type of printer, and the printing material.

Abstract Accumulating evidence indicates that exosomal proteins are critical in diagnosing malignant tumors. To identify novel exosomal biomarkers for lung cancer diagnosis, we isolated plasma exosomes from 517 lung cancer patients and 168 healthy controls (NLs)—186 lung adenocarcinoma (LUAD) patients (screening (SN): 20, validation (VD): 166), 159 lung squamous carcinoma (LUSC) patients (SN: 20, VD: 139), 172 benign nodules (LUBN) patients (SN: 20, VD: 152) and 168 NLs (SN: 20, VD: 148)—and randomly assigned them to the SN or VD group. Proteomic analysis by LC–MS/MS and PRM were performed on all groups. The candidate humoral markers were evaluated and screened by a machine learning method. All selected biomarkers were identified in the VD groups. For LUAD, a 7-protein panel had AUCs of 97.9% and 87.6% in the training and test sets, respectively, and 89.5% for early LUAD. For LUSC, an 8-protein panel showed AUCs of 99.1% and 87.0% in the training and test sets and 92.3% for early LUSC. For LUAD + LUSC (LC), an 8-protein panel showed AUCs of 85.9% and 80.3% in the training and test sets and 87.1% for early LC diagnosis. The characteristics of the exosomal proteome make exosomes potential diagnostic tools.

Abstract Objectives To explore the relationship between different types of physical activity and female infertility. Methods This study analyzed data from 2,796 female participants aged 18–44 years in the United States, obtained from the National Health and Nutrition Examination Survey (NHANES) database spanning the years 2013 to 2020. Multiple logistic regression analyses and generalized linear models were used to explore the relationship between different types of physical activity and infertility after adjusting for potential confounding factors. Results We found a non-linear relationship between recreational activities and infertility with an inflection point of 5.83 h/week (moderate intensity), while work activities and traffic-related activities did not. On the left side of the inflection point, there was no significant association between recreational activity time and infertility (OR = 0.93, 95% CI: 0.86 to 1.02, P = 0.1146), but on the right side of the inflection point, there was a positive association between recreational activity time and the risk of infertility (OR = 1.04, 95% CI: 1.02 to 1.06, P = 0.0008). Conclusions The relationship between different types of physical activity and female infertility varies. We acknowledge the potential influence of confounding variables on this relationship. However, we have already adjusted for these potential variables in our analysis. Therefore, our findings suggest that appropriate recreational activity programs are essential for promoting reproductive health in women of reproductive age. Nevertheless, it is important to note that the observed association does not imply causality. Given the limitations of cross-sectional studies, further prospective cohort studies are needed to explore the causal relationship while accounting for additional confounding factors.

Abstract Background The flower colour of H. syriacus ‘Qiansiban’ transitions from fuchsia to pink–purple and finally to pale purple, thereby enhancing the ornamental value of the cultivars. However, the molecular mechanism underlying this change in flower colour in H. syriacus has not been elucidated. In this study, the transcriptomic data of H. syriacus ‘Qiansiban’ at five developmental stages were analysed to investigate the impact of flavonoid components on flower colour variation. Additionally, five cDNA libraries were constructed from H. syriacus ‘Qiansiban’ during critical blooming stages, and the transcriptomes were sequenced to investigate the molecular mechanisms underlying changes in flower colouration. Results High-performance liquid chromatography‒mass spectrometry detected five anthocyanins in H. syriacus ‘Qiansiban’, with malvaccin-3-O-glucoside being the predominant compound in the flowers of H. syriacus at different stages, followed by petunigenin-3-O-glucoside. The levels of these five anthocyanins exhibited gradual declines throughout the flowering process. In terms of the composition and profile of flavonoids and flavonols, a total of seven flavonoids were identified: quercetin-3-glucoside, luteolin-7-O-glucoside, Santianol-7-O-glucoside, kaempferol-O-hexosyl-C-hexarbonoside, apigenin-C-diglucoside, luteolin-3,7-diglucoside, and apigenin-7-O-rutinoside. A total of 2,702 DEGs were identified based on the selected reference genome. Based on the enrichment analysis of differentially expressed genes, we identified 9 structural genes (PAL, CHS, FLS, DRF, ANS, CHI, F3H, F3’5’H, and UFGT) and 7 transcription factors (3 MYB, 4 bHLH) associated with flavonoid biosynthesis. The qRT‒PCR results were in good agreement with the high-throughput sequencing data. Conclusion This study will establish a fundamental basis for elucidating the mechanisms underlying alterations in the flower pigmentation of H. syriacus.

Abstract Septated pleural effusion is very common. The presence of septations in pleural effusion determines the local treatment strategy for such patients. Therefore, there is a pressing need for imaging techniques to assess the presence of septations. The objective of this research was to assess the diagnostic efficacy of computed tomography (CT) and chest ultrasound in identifying septated pleural effusion. We delineated the ultrasound and enhanced chest CT manifestations for diagnosing septated pleural effusions, and subsequently, we conducted a comparative analysis to assess the diagnostic efficacy of enhanced chest CT and ultrasound in identifying septated pleural effusions. Medical thoracoscopy served as the gold standard for confirming the diagnosis of septated pleural effusions. Ultrasound demonstrated a sensitivity of 82.6% (95% CI 73.3–89.7%) and a specificity of 100.0% (95% CI 98.1–NaN) for diagnosing septated pleural effusion. In comparison, enhanced chest CT exhibited a sensitivity of 59.8% (95% CI 49.0–69.9%) and a specificity of 87.0% (95% CI 81.5–91.4%). The positive predictive value for ultrasound was 100.0% (95% CI 95.3–100.0%), while for enhanced chest CT, it was 68.8% (95% CI 59.0–77.4%). Ultrasound yielded a negative predictive value of 92.3% (95% CI 87.5–NaN), and enhanced chest CT had a negative predictive value of 82.0% (95% CI 74.6–87.8%) in diagnosing septated pleural effusion. Thoracic ultrasound exhibits superior sensitivity and specificity compared to enhanced chest CT in diagnosing septated pleural effusions. Therefore, chest ultrasound is highly recommended as an adjunct for determining septated pleural effusion.

Abstract Colorectal cancer (CRC) is a malignant tumor originating from epithelial cells of the colon or rectum, and its invasion and metastasis could be regulated by anoikis. However, the key genes and pathways regulating anoikis in CRC are still unclear and require further research. The single cell transcriptome dataset GSE221575 of GEO database was downloaded and applied to cell subpopulation type identification, intercellular communication, pseudo time cell trajectory analysis, and receptor ligand expression analysis of CRC. Meanwhile, the RNA transcriptome dataset of TCGA, the GSE39582, GSE17536, and GSE17537 datasets of GEO were downloaded and merged into one bulk transcriptome dataset. The differentially expressed genes (DEGs) related to anoikis were extracted from these data sets, and key marker genes were obtained after feature selection. A clinical prognosis prediction model was constructed based on the marker genes and the predictive effect was analyzed. Subsequently, gene pathway analysis, immune infiltration analysis, immunosuppressive point analysis, drug sensitivity analysis, and immunotherapy efficacy based on the key marker genes were conducted for the model. In this study, we used single cell datasets to determine the anoikis activity of cells and analyzed the DEGs of cells based on the score to identify the genes involved in anoikis and extracted DEGs related to the disease from the transcriptome dataset. After dimensionality reduction selection, 7 marker genes were obtained, including TIMP1, VEGFA, MYC, MSLN, EPHA2, ABHD2, and CD24. The prognostic risk model scoring system built by these 7 genes, along with patient clinical data (age, tumor stage, grade), were incorporated to create a nomogram, which predicted the 1-, 3-, and 5-years survival of CRC with accuracy of 0.818, 0.821, and 0.824. By using the scoring system, the CRC samples were divided into high/low anoikis-related prognosis risk groups, there are significant differences in immune infiltration, distribution of immune checkpoints, sensitivity to chemotherapy drugs, and efficacy of immunotherapy between these two risk groups. Anoikis genes participate in the differentiation of colorectal cancer tumor cells, promote tumor development, and could predict the prognosis of colorectal cancer.

Abstract Background White Sponge Nevus (WSN) is traditionally considered a benign genetic disorder affecting the oral mucosa, primarily caused by pathogenic mutations in keratin 4 (KRT4) or keratin 13 (KRT13). Despite its benign nature, recent evidence has begun to question the malignant potential of WSN. Case presentation We report a case involving a 70-year-old man who presented with a white lesion on the right floor of his mouth. Initial diagnostic evaluations confirmed the lesion as WSN. Over a one-year follow-up, the lesion underwent malignant transformation, evolving into local epithelial moderate-to-severe dysplasia. Exome sequencing identified a novel insertion mutation in exon 1 of the KRT4 gene, resulting in a deletion-insertion amino acid mutation involving glycine. Single-cell RNA sequencing further revealed altered epithelial proliferation and differentiation dynamics within the lesion. Conclusions This case not only expands the known genetic spectrum of KRT4 mutations associated with WSN but also provides preliminary evidence suggesting the malignant potential of WSN. The novel pathogenic mutation in KRT4 is postulated to alter epithelial proliferation and differentiation, thereby raising concerns about the malignant transformation of WSN. Further studies are warranted to confirm these findings.

Agrobacterium-mediated plant transformation is widely used in plant genetic engineering. However, its efficiency is limited by plant immunity against Agrobacterium. Chili pepper (Capsicum annuum L.) is an important vegetable that is recalcitrant to Agrobacterium-mediated transformation. In this work, Agrobacterium was found to induce a strong immune response in pepper, which might be the reason for T-DNA being difficult to express in pepper. An Agrobacterium mutant screen was conducted and a point mutation in the hisI gene was identified due to a weak immune response and enhanced transient expression mediated by this Agrobacterium mutant in pepper leaves. Further genetic analysis revealed that histidine biosynthesis deficiency caused by mutations in many genes of this pathway led to reduced pepper cell death, presumably due to reduced bacterial growth. However, mutation analysis of threonine and tryptophan biosynthesis genes showed that the biosynthesis of different amino acids may play different roles in Agrobacterium growth and stimulating the pepper immune response. The possible application of Agrobacterium amino acid biosynthesis mutations in plant biology was discussed.

Abstract Sleep, locomotor and social activities are essential animal behaviors, but their reciprocal relationships and underlying mechanisms remain poorly understood. Here, we elicit information from a cutting-edge large-language model (LLM), generative pre-trained transformer (GPT) 3.5, which interprets 10.2–13.8% of Drosophila genes known to regulate the 3 behaviors. We develop an instrument for simultaneous video tracking of multiple moving objects, and conduct a genome-wide screen. We have identified 758 fly genes that regulate sleep and activities, including mre11 which regulates sleep only in the presence of conspecifics, and NELF-B which regulates sleep regardless of whether conspecifics are present. Based on LLM-reasoning, an educated signal web is modeled for understanding of potential relationships between its components, presenting comprehensive molecular signatures that control sleep, locomotor and social activities. This LLM-aided strategy may also be helpful for addressing other complex scientific questions.

Abstract Seven undescribed compounds, including three flavones (1–3), one phenylpropanoid (19), three monoaromatic hydrocarbons (27–29), were isolated from the twigs of Mosla chinensis Maxim together with twenty-eight known compounds. The structures were characterized by HRESIMS, 1D and 2D NMR, and ECD spectroscopic techniques. Compound 20 displayed the most significant activity against A/WSN/33/2009 (H1N1) virus (IC50 = 20.47 μM) compared to the positive control oseltamivir (IC50 = 6.85 µM). Further research on the anti-influenza mechanism showed that compound 20 could bind to H1N1 virus surface antigen HA1 and inhibit the early attachment stage of the virus. Furthermore, compounds 9, 22, 23, and 25 displayed moderate inhibitory effects on the NO expression in LPS inducing Raw 264.7 cells with IC50 values of 22.78, 20.47, 27.66, and 30.14 µM, respectively. Graphical Abstract

The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with emotions. Specifically, astrocytes in the basolateral amygdala have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which basolateral amygdala astrocytes regulate chronic stress–induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2 agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal mice. After knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was obviously mitigated. Additionally, administration of an excitatory amino acid transporter 2 inhibitor in the basolateral amygdala yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that basolateral amygdala astrocytic excitatory amino acid transporter 2 plays a role in in the regulation of unpredictable chronic mild stress-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting excitatory amino acid transporter 2 in the basolateral amygdala holds therapeutic promise for addressing anxiety disorders.

Abstract Background The S100 protein family is a group of small molecular EF-hand calcium-binding proteins that play critical roles in various biological processes, including promotion of growth, metastasis and immune evasion of tumor. However, the potential roles of S100 protein family expression in tumor microenvironment (TME) cell infiltration in pan-cancer remain elusive. Methods Herein, we conducted a comprehensive assessment of the expression patterns of the S100 protein family in pan-cancer, meticulously examining their correlation with characteristics of TME cell infiltration. The S100 score was constructed to quantify S100 family expression patterns of individual tumors. Results The S100 family was a potent risk factor in many cancers. Clustering analysis based on the transcriptome patterns of S100 protein family identified two cancer clusters with distinct immunophenotypes and clinical characteristics. Cluster A, with lower S100 expression, exhibited lower immune infiltration, whereas, Cluster B, with higher S100 expression, featured higher immune infiltration. Interestingly, Cluster B had a poorer prognosis, likely due to an immune-excluded phenotype resulting from stromal activation. The analysis revealed robust enrichment of the TGFb and EMT pathways in the cohort exhibiting high S100 score, alongside a positive correlation between the S100 score and Treg levels, suggesting the manifestation of an immune-excluded phenotype in this group. Moreover, S100 families were associated with the prognosis of 22 different cancers and a noteworthy association was observed between high S100 score and an unfavorable response to anti-PD-1/L1 immunotherapy. Consistent findings across two independent immunotherapy cohorts substantiated the advantageous therapeutic outcomes and clinical benefits in patients displaying lower S100score. Conclusion Our analysis demonstrated the role of S100 family in formation of TME diversity and complexity, enabling deeper cognition of TME infiltration characterization and the development of personalized immunotherapy strategies targeting S100 family for unique tumor types.

Abstract Coronavirus disease (COVID-19) and pulmonary hypertension (PH) are closely correlated. However, the mechanism is still poorly understood. In this article, we analyzed the molecular action network driving the emergence of this event. Two datasets (GSE113439 and GSE147507) from the GEO database were used for the identification of differentially expressed genes (DEGs).Common DEGs were selected by VennDiagram and their enrichment in biological pathways was analyzed. Candidate gene biomarkers were selected using three different machine-learning algorithms (SVM-RFE, LASSO, RF).The diagnostic efficacy of these foundational genes was validated using independent datasets. Eventually, we validated molecular docking and medication prediction. We found 62 common DEGs, including several ones that could be enriched for Immune Response and Inflammation. Two DEGs (SELE and CCL20) could be identified by machine-learning algorithms. They performed well in diagnostic tests on independent datasets. In particular, we observed an upregulation of functions associated with the adaptive immune response, the leukocyte-lymphocyte-driven immunological response, and the proinflammatory response. Moreover, by ssGSEA, natural killer T cells, activated dendritic cells, activated CD4 T cells, neutrophils, and plasmacytoid dendritic cells were correlated with COVID-19 and PH, with SELE and CCL20 showing the strongest correlation with dendritic cells. Potential therapeutic compounds like FENRETI-NIDE, AFLATOXIN B1 and 1-nitropyrene were predicted. Further molecular docking and molecular dynamics simulations showed that 1-nitropyrene had the most stable binding with SELE and CCL20.The findings indicated that SELE and CCL20 were identified as novel diagnostic biomarkers for COVID-19 complicated with PH, and the target of these two key genes, FENRETI-NIDE and 1-nitropyrene, was predicted to be a potential therapeutic target, thus providing new insights into the prediction and treatment of COVID-19 complicated with PH in clinical practice.

A new repeated freeze-thaw extraction was employed to extract crude polysaccharide from Ganoderma lucidum, named as GLPf, in order to improve its extraction yield and bioactivity. Single-factor tests and response surface experiment were used to obtain the optimal extraction conditions. Three novel G. lucidum polysaccharide fractions (GLPf30, GLPf60, and GLPf80) were isolated and purified from GLPf by stepwise alcohol precipitation. Results showed that the optimal parameters were as follows: Swelling ratio 1:14 (g/mL), free-ze-thaw time 140 min, and free-ze-thaw times was 3. Under these conditions, its extraction rate was 2.71%, which was significantly higher than that of polysaccharide extrcted by traditional water extraction (GLP, 2.36%). The preliminary structural features of all polysaccharide fractions were determined by highperformance anion-exchange chromatography with pulsed-amperometric detection (HPAEC-PAD) and Fourier transform infrared spectrophotometer (FT-IR) analyses, which showed that all sugar fractions were acidic polysaccharides, and they all were composed of six monosaccharides (fucose, glucosamine, galactose, glucose, xylose and mannose) with pyranose as the backbone. However, there were significant differences in both monosaccharide composition and physicochemical property, and GLPf30 had the highest percentage of GlcN (up to 37.66%). The results of antioxidant activity assays showed that antioxidant power of GLPf30 was significantly higher than that of the other two polysaccharides (GLPf60 and GLPf80) and their precursors GLPf. These findings would provide scientific basis for the rational development and high value utilization of G. lucidum polysaccharides.

Abstract Despite the high therapeutic response achieved with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory multiple myeloma (R/R MM), primary resistance and relapse exist with single-target immunotherapy. Here, we design bispecific BC19 CAR T cells targeting BCMA/CD19 and evaluate antimyeloma activity in vitro and in vivo. Preclinical results indicate that BC19 CAR specifically recognize target antigens, and BC19 CAR T cells mediate selective killing of BCMA or CD19-positive cancer cells. BC19 CAR T cells also exhibit potent antigen-specific anti-tumor activity in xenograft mouse models. We conduct an open-label, single-arm, phase I/II study of BC19 CAR T cells in 50 patients with R/R MM (ChiCTR2000033567). The primary endpoint was safety. BC19 CAR T cells are well tolerated with grade 3 or higher cytokine release syndrome in 8% of patients and grade 1 neurotoxic events in 4% of patients, which meet the pre-specified primary endpoint. Secondary endpoints include overall response rate (92%), median progression-free survival (19.7 months), median overall survival (19.7 months) and median duration of response (not reached). Our study demonstrates that bispecific BC19 CAR T cells are feasible, safe and effective in treating patients with R/R MM.

Abstract Background Diabetic macular edema (DME) is a leading cause of vision loss in patients with diabetes. This study aimed to develop and evaluate an OCT-omics prediction model for assessing anti-vascular endothelial growth factor (VEGF) treatment response in patients with DME. Methods A retrospective analysis of 113 eyes from 82 patients with DME was conducted. Comprehensive feature engineering was applied to clinical and optical coherence tomography (OCT) data. Logistic regression, support vector machine (SVM), and backpropagation neural network (BPNN) classifiers were trained using a training set of 79 eyes, and evaluated on a test set of 34 eyes. Clinical implications of the OCT-omics prediction model were assessed by decision curve analysis. Performance metrics (sensitivity, specificity, F1 score, and AUC) were calculated. Results The logistic, SVM, and BPNN classifiers demonstrated robust discriminative abilities in both the training and test sets. In the training set, the logistic classifier achieved a sensitivity of 0.904, specificity of 0.741, F1 score of 0.887, and AUC of 0.910. The SVM classifier showed a sensitivity of 0.923, specificity of 0.667, F1 score of 0.881, and AUC of 0.897. The BPNN classifier exhibited a sensitivity of 0.962, specificity of 0.926, F1 score of 0.962, and AUC of 0.982. Similar discriminative capabilities were maintained in the test set. The OCT-omics scores were significantly higher in the non-persistent DME group than in the persistent DME group (p

Abstract Riemerella anatipestifer infection is characterized by meningitis with neurological symptoms in ducklings and has adversely affected the poultry industry. R. anatipestifer strains can invade the duck brain to cause meningitis and neurological symptoms, but the underlying mechanism remains unknown. In this study, we showed that obvious clinical symptoms, an increase in blood‒brain barrier (BBB) permeability, and the accumulation of inflammatory cytokines occurred after intravenous infection with the Yb2 strain but not the mutant strain Yb2ΔsspA, indicating that Yb2 infection can lead to cerebrovascular dysfunction and that the type IX secretion system (T9SS) effector SspA plays a critical role in this pathological process. In addition, we showed that Yb2 infection led to rapid degradation of occludin (a tight junction protein) and collagen IV (a basement membrane protein), which contributed to endothelial barrier disruption. The interaction between SspA and occludin was confirmed by coimmunoprecipitation. Furthermore, we found that SspA was the main enzyme mediating occludin and collagen IV degradation. These data indicate that R. anatipestifer SspA mediates occludin and collagen IV degradation, which functions in BBB disruption in R. anatipestifer-infected ducks. These findings establish the molecular mechanisms by which R. anatipestifer targets duckling endothelial cell junctions and provide new perspectives for the treatment and prevention of R. anatipestifer infection.

Abstract The Amur tiger is currently confronted with challenges of anthropogenic development, leading to its population becoming fragmented into two geographically isolated groups: smaller and larger ones. Small and isolated populations frequently face a greater extinction risk, yet the small tiger population’s genetic status and survival potential have not been assessed. Here, a total of 210 samples of suspected Amur tiger feces were collected from this small population, and the genetic background and population survival potentials were assessed by using 14 microsatellite loci. Our results demonstrated that the mean number of alleles in all loci was 3.7 and expected heterozygosity was 0.6, indicating a comparatively lower level of population genetic diversity compared to previously reported studies on other subspecies. The genetic estimates of effective population size (Ne) and the Ne/N ratio were merely 7.6 and 0.152, respectively, representing lower values in comparison to the Amur tiger population in Sikhote-Alin (the larger group). However, multiple methods have indicated the possibility of genetic divergence within our isolated population under study. Meanwhile, the maximum kinship recorded was 0.441, and the mean inbreeding coefficient stood at 0.0868, both of which are higher than those observed in other endangered species, such as the African lion and the grey wolf. Additionally, we have identified a significant risk of future extinction if the lethal equivalents were to reach 6.26, which is higher than that of other large carnivores. Further, our simulation results indicated that an increase in the number of breeding females would enhance the prospects of this population. In summary, our findings provide a critical theoretical basis for further bailout strategies concerning Amur tigers.

Abstract Metal-organic frameworks (MOFs) with diverse chemistry, structures, and properties have emerged as appealing materials for miniaturized solid-state devices. The incorporation of MOF films in these devices, such as the integrated microelectronics and nanophotonics, requires robust patterning methods. However, existing MOF patterning methods suffer from some combinations of limited material adaptability, compromised patterning resolution and scalability, and degraded properties. Here we report a universal, crosslinking-induced patterning approach for various MOFs, termed as CLIP-MOF. Via resist-free, direct photo- and electron-beam (e-beam) lithography, the ligand crosslinking chemistry leads to drastically reduced solubility of colloidal MOFs, permitting selective removal of unexposed MOF films with developer solvents. This enables scalable, micro-/nanoscale (≈70 nm resolution), and multimaterial patterning of MOFs on large-area, rigid or flexible substrates. Patterned MOF films preserve their crystallinity, porosity, and other properties tailored for targeted applications, such as diffractive gas sensors and electrochromic pixels. The combined features of CLIP-MOF create more possibilities in the system-level integration of MOFs in various electronic, photonic, and biomedical devices.

Abstract Background Sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease, is a rare, self-limiting disease that predominantly affects children and young adults. Moreover, the disease is characterized by painless bilateral cervical lymphadenopathy in 95% of the patients. However, few reports are available on the Rosai-Dorfman disease of the thymus. Case presentation We report a rare case of thymic Rosai-Dorfman disease detected using computed tomography. During a medical examination, a 50-year-old man underwent a chest computed tomography scan, which revealed an anterior mediastinal single mass with fat in the thymus. A thymectomy was performed to completely remove the tumor using a thoracoscopic technique due to a clinical suspicion of thymoma. Furthermore, Rosai-Dorfman disease was confirmed using histological and immunohistochemical analyses. Conclusions To the best of our knowledge, this is the sixth case of thymus-affecting solitary Rosai-Dorfman disease with histological and immunohistochemical evidence. Fat in the thymus, as was present in this case, has never been described in Rosai-Dorfman disease previously. Our results highlight the challenge of diagnosing this uncommon tumor before surgery, and more cases need to be reported to help with the preoperative diagnosis of such a rare tumor.

Abstract Background CREG1 (cellular repressor of E1A‐stimulated genes 1) is a protein involved in cellular differentiation and homeostasis regulation. However, its role in skeletal muscle satellite cells differentiation and muscle regeneration is poorly understood. This study aimed to investigate the role of CREG1 in myogenesis and muscle regeneration. Methods RNA sequencing data (GSE8479) was analysed from the Gene Expression Omnibus database (GEO, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi). We generated Creg1 knockdown and skeletal muscle satellite cells specific Creg1 overexpression mice mediated by adeno‐associated virus serotype 9 (AAV9), skeletal muscle mature myofibre Creg1 knockout mice (myoblast/Creg1MKO), and control mice Creg1flox/flox (Creg1fl/fl) as in vivo models. The mice were injected into tibialis anterior (TA) muscle with 100 μL of 10 μM cardiotoxin to establish a muscle regeneration model. Creg1fl/fl and Creg1MKO mice were treated with AAV‐sh‐C‐Cbl (2 × 1010 genomic copies/mouse) to silence C‐Cbl in the TA muscle. 293T and C2C12 cells were transfected with plasmids using lipofectamine RNAi MAX in vitro. Mass spectrometry analyses and RNA sequencing transcriptomic assay were performed. Results We analysed the transcriptional profiles of the skeletal muscle biopsies from healthy older (N = 25) and younger (N = 26) adult men and women in GSE8479 database, and the results showed that Creg1 was associated with human sarcopenia. We found that Creg1 knockdown mice regenerated less newly formed fibres in response to cardiotoxin injection (~30% reduction, P

Ovaries are essential for healthy female reproduction, with the follicles as their fundamental functional units, which consist of an oocyte and surrounding granulosa cells. The development and formation of follicles in the ovaries are closely linked to reproductive health. Oxylipins refer to oxidative metabolites produced from the oxidation of polyunsaturated fatty acids, either through automatic oxidation or with the help of specific enzymes. They play crucial regulatory roles in the immune system, oxidative stress, and inflammatory reactions and are intimately linked to the development of numerous illnesses, such as diabetes, heart disease, asthma, and Alzheimer’s disease. Furthermore, oxylipins have a complex relationship with ovarian function, and both prostaglandins and leukotrienes produced by arachidonic acid affect processes such as follicle growth and development, ovulation, and hormone regulation. The synthesis and metabolism of oxylipins in the ovaries are finely regulated. Oxylipin dysregulation has been linked to various ovarian diseases, including endometriosis, polycystic ovary syndrome, ovarian cancer, and premature ovarian insufficiency. In addition, potential therapeutic targets and interventions targeting the oxylipin pathway for the treatment of ovarian diseases have become a prominent research focus, including regulating the enzymes responsible for oxylipin synthesis, using anti-inflammatory agents, and regulating lipid metabolism. Recent research has been directed towards improving the reproductive outcomes of women with ovarian diseases through this series of interventions. An overview of the role of oxylipins in ovarian function and disease is provided in this article, which will aid researchers in understanding the current state of the field and in identifying future directions.

Objective: Doxorubicin (DOX)-induced cardiotoxicity limits the application of DOX in cancer patients. Currently, there is no effective prevention or treatment for DOX-induced cardiotoxicity. The cellular repressor of E1A-stimulated genes (CREG1) is a cardioprotective factor that plays an important role in the maintenance of cardiomyocytes differentiation and homeostasis. However, the role and mechanism of CREG1 in DOX-induced cardiotoxicity has not yet been elucidated. Methods: In vivo, C57BL/6J mice, CREG1 transgenic and cardiac-specific CREG1 knockout mice were used to establish a DOX-induced cardiotoxicity model. H&E staining, Masson’s trichrome, WGA staining, real-time PCR, and western blotting were performed to examine fibrosis and ferroptosis in the myocardium. In vitro, neonatal mouse cardiomyocytes (NMCMs) were cultured and stimulated with DOX, CREG1-overexpressed adenovirus, and small interfering RNA was used to establish CREG1 overexpression or knockdown cardiomyocytes. Transcriptomics, real-time PCR, western blotting, and immunoprecipitation were used to examine the roles and mechanisms of CREG1 in cardiomyocytes ferroptosis. Results: The mRNA and protein levels of CREG1 were reduced in the hearts and NMCMs after DOX treatment. CREG1 overexpression alleviated myocardial damage and inhibited DOX-induced ferroptosis in the myocardium. CREG1 deficiency in the heart aggravated DOX-induced cardiotoxicity and ferroptosis. In vitro, CREG1 overexpression inhibited cardiomyocytes ferroptosis induced by DOX, and CREG1 knockdown aggravated DOX-induced cardiotoxicity. Mechanistically, CREG1 inhibited the mRNA and protein expression of pyruvate dehydrogenase kinase 4 (PDK4) by regulating the F-box and WD repeat domain containing 7 (FBXW7)-forkhead box O1 (FOXO1) pathway. PDK4 deficiency reversed the effects of CREG1 knockdown on cardiomyocytes ferroptosis following DOX treatment. Conclusion: CREG1 alleviated DOX-induced cardiotoxicity by inhibiting ferroptosis in cardiomyocytes. Our findings may help clarify the new roles of CREG1 in the development of DOX-induced cardiotoxicity.

Ferroptosis, driven by an imbalance in redox homeostasis, has recently been identified to regulate macrophage function and inflammatory responses. SENP3 is a redox-sensitive de-SUMOylation protease that plays an important role in macrophage function. However, doubt remains on whether SENP3 and SUMOylation regulate macrophage ferroptosis. For the first time, the results of our study suggest that SENP3 sensitizes macrophages to RSL3-induced ferroptosis. We showed that SENP3 promotes the ferroptosis of M2 macrophages to decrease M2 macrophage proportion in vivo. Mechanistically, we identified the ferroptosis repressor FSP1 as a substrate for SUMOylation and confirmed that SUMOylation takes place mainly at its K162 site. We found that SENP3 sensitizes macrophages to ferroptosis by interacting with and de-SUMOylating FSP1 at the K162 site. In summary, our study describes a novel type of posttranslational modification for FSP1 and advances our knowledge of the biological functions of SENP3 and SUMOylation in macrophage ferroptosis.

Abstract Background Chronic obstructive pulmonary disease (COPD) contributes to the incidence and prognosis of lung cancer. The presence of COPD significantly increases the risk of lung squamous cell carcinoma (LSCC). COPD may promote an immunosuppressive microenvironment in LSCC by regulating the expression of immune‐inhibitory factors in T cells, although the mechanisms remain unclear. In this study, we aimed to decipher the tumour microenvironment signature for LSCC with COPD at a single‐cell level. Methods We performed single‐cell RNA sequencing on tumour tissues from LSCC with or without COPD, then investigated the features of the immune and tumour cells. We employed multiple techniques, including multispectral imaging, flow cytometry, tissue microarray analysis, survival analysis, co‐culture systems and in vitro and in vivo treatment experiments, to validate the findings obtained from single‐cell analyses. Results LSCC with COPD showed increased proportions of tumour‐associated macrophages (TAMs) and higher levels of CD8+ T cell exhaustion molecules, which contributed to an immunosuppressive microenvironment. Further analysis revealed a critical cluster of CD74+ tumour cells that expressed both epithelial and immune cell signatures, exhibited a stronger capacity for tumorigenesis and predicted worse overall survival. Notably, migration inhibitory factor (MIF) secreted by TAMs from LSCC with COPD may promote the activation of CD74. MIF‐CD74 may interact with CD8+ T cells and impair their anti‐tumour activity by regulating the PI3K‐STAT3‐programmed cell death‐1 ligand 1 signalling pathway, facilitating tumour proliferation and immune evasion. Conclusions Our comprehensive picture of the tumour ecosystem in LSCC with COPD provides deeper insights into relevant immune evasion mechanisms and potential targets for immunotherapy. Highlight Our results demonstrated higher proportions of tumour‐associated macrophages (TAMs) and higher levels of exhaustion molecules in CD8+ T cells in the microenvironment of LSCC with COPD. CD74+tumour cells were associated with poor disease prognosis. Migration inhibitory factor (MIF)‐CD74 may interact with CD8+ T cells and impair their anti‐tumour activity by regulating the PI3K‐STAT3‐PD‐L1 signalling pathway, facilitating immune evasion.