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Abstract Classical Zn2+-dependent deac(et)ylases play fundamental regulatory roles in life and are well characterized in eukaryotes regarding their structures, substrates and physiological roles. In bacteria, however, classical deacylases are less well understood. We construct a Generalized Profile (GP) and identify thousands of uncharacterized classical deacylases in bacteria, which are grouped into five clusters. Systematic structural and functional characterization of representative enzymes from each cluster reveal high functional diversity, including polyamine deacylases and protein deacylases with various acyl-chain type preferences. These data are supported by multiple crystal structures of enzymes from different clusters. Through this extensive analysis, we define the structural requirements of substrate selectivity, and discovered bacterial de-d-/l-lactylases and long-chain deacylases. Importantly, bacterial deacylases are inhibited by archetypal HDAC inhibitors, as supported by co-crystal structures with the inhibitors SAHA and TSA, and setting the ground for drug repurposing strategies to fight bacterial infections. Thus, we provide a systematic structure-function analysis of classical deacylases in bacteria and reveal the basis of substrate specificity, acyl-chain preference and inhibition.

Abstract Background The Interleukin-6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) pathway, along with the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, are critical contributors to neuroinflammation in Alzheimer’s disease (AD). Although previous research outside the context of AD has indicated that the IL-6-STAT3 pathway may regulate the cGAS-STING pathway, the exact molecular mechanisms through which IL-6-STAT3 influences cGAS-STING in AD are still not well understood. Methods The activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of 5×FAD and WT mice was analyzed using WB and qRT-PCR. To explore the effects of IL-6 deficiency, Il6 +/− mice were crossed with 5×FAD mice, and the subsequent impact on hippocampal STAT3 pathway activity, cGAS-STING pathway activation, amyloid pathology, neuroinflammation, and cognitive function was evaluated through WB, qRT-PCR, immunohistochemistry, ThS staining, ELISA, and behavioral tests. The regulatory role of STAT3 in the transcription of the Cgas and Sting genes was further validated using ChIP-seq and ChIP-qPCR on hippocampal tissue from 5×FAD and Il6 −/− : 5×FAD mice. Additionally, in the BV2 microglial cell line, the impact of STAT3 activation on the transcriptional regulation of Cgas and Sting genes, as well as the production of inflammatory mediators, was examined through WB and qRT-PCR. Results We observed marked activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of AD mice, which was attenuated in the absence of IL-6. IL-6 deficiency reduced beta-amyloid deposition and neuroinflammation in the hippocampus of AD mice, contributing to cognitive improvements. Further analysis revealed that STAT3 directly regulates the transcription of both the Cgas and Sting genes. These findings suggest a potential mechanism involving the STAT3-cGAS-STING pathway, wherein IL-6 deficiency mitigates neuroinflammation in AD mice by modulating this pathway. Conclusion These findings indicate that the STAT3-cGAS-STING pathway is critical in mediating neuroinflammation associated with AD and may represent a potential therapeutic target for modulating this inflammatory process in AD.

Abstract How the lung achieves immune homeostasis after a pulmonary infection is not fully understood. Here, we analyzed the spatiotemporal changes in the lungs over a 2-week natural recovery from severe pneumonia in a Syrian hamster model of SARS-CoV-2 infection. We find that SARS-CoV-2 infects multiple cell types and causes massive cell death at the early stage, including alveolar macrophages. We identify a group of monocyte-derived Slamf9 + macrophages, which are induced after SARS-CoV-2 infection and resistant to impairment caused by SARS-CoV-2. Slamf9 + macrophages contain SARS-CoV-2, recruit and interact with Isg12 + Cst7 + neutrophils to clear the viruses. After viral clearance, Slamf9 + macrophages differentiate into Trem2 + and Fbp1 + macrophages, contributing to inflammation resolution at the late stage, and finally replenish alveolar macrophages. These findings are validated in a SARS-CoV-2-infected hACE2 mouse model and confirmed with publicly available human autopsy single-cell RNA-seq data, demonstrating the potential role of Slamf9 + macrophages and their coordination with neutrophils in post-injury tissue repair and inflammation resolution.

Abstract How immune cells are spatiotemporally coordinated in the lung to effectively monitor, respond to, and resolve infection and inflammation in primed form needs to be fully illustrated. Here we apply immunocartography, a high-resolution technique that integrates spatial and single-cell RNA sequencing (scRNA-seq) through deconvolution and co-localization analyses, to the SARS-CoV-2-infected Syrian hamster model. We generate a comprehensive transcriptome map of the whole process of pulmonary infection from physiological condition, infection initiation, severe pneumonia to natural recovery at organ scale and single-cell resolution, with 142,965 cells and 45 lung lobes from 25 hamsters at 5 time points. Integrative analysis identifies that alveolar dendritic cell–T cell immunity hubs, where Ccr7 + Ido1 + dendritic cells, Cd160 + Cd8 + T cells, and Tnfrsf4 + Cd4 + T cells physiologically co-localize, rapidly expand during SARS-CoV-2 infection, eliminate SARS-CoV-2 with the aid of Slamf9 + macrophages, and then restore to physiological levels after viral clearance. We verify the presence of these cell subpopulations in the immunity hubs in normal and SARS-CoV-2-infected hACE2 mouse models, as well as in publicly available human scRNA-seq datasets, demonstrating the potential broad relevance of our findings in lung immunity.

Abstract Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton’s tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination.

Abstract The triglyceride-glucose (TyG) index is a novel marker of insulin resistance that has been strongly associated with many diseases related to metabolic disorders, such as diabetes, coronary heart disease, myocardial infarction, obesity, nonalcoholic fatty liver disease, and stroke. However, whether the TyG index is associated with the prevalence of gallstones has not been determined. Therefore, the purpose of this study was to evaluate the relationship between the TyG index and the prevalence of gallstones in American adults, as well as the age at which adults in America undergo their first gallstone surgery. We selected individuals from the National Health and Nutrition Examination Survey (NHANES) database from 2017 to March 2020. Based on the goal of our study, comprehensive inclusion and exclusion criteria were created. A logistic regression analysis, dose–response curve, and subgroup analysis were computed to assess the relationship between the TyG index and gallstone prevalence and age at first surgery for gallstone. A total of 3905 participants aged > 20 years were included in our study, of whom 421 had a self-reported history of gallstones. A total of 1884 (48.2%) males and 2021 (51.8%) females were included. After confounders adjustment, it was found single-unit increases in the TyG index were linked with a 25.0% increase in gallstone prevalence (odds ratio [OR] = 1.25, 95% confidence interval [95%CI]: 1.04, 1.51). After conversion of the TyG index values from continuous to categorical variables with tertiles, a marked 48% increase in gallstone incidence was found in tertile 3 relative to tertile 1 (OR = 1.48, 95% CI: 1.09, 1.99). The dose–response curve results indicated positive associations between gallstone prevalence and the TyG index, while the latter was negatively associated with age at first gallstone surgery. Based on subgroup analysis, the positive association between TyG index and high-incidence of gallstones was more significant in females (OR = 1.39, 95% CI: 1.09, 1.77), age

Abstract The AMP-forming acetyl-CoA synthetase is regulated by lysine acetylation both in bacteria and eukaryotes. However, the underlying mechanism is poorly understood. The Bacillus subtilis acetyltransferase AcuA and the AMP-forming acetyl-CoA synthetase AcsA form an AcuA•AcsA complex, dissociating upon lysine acetylation of AcsA by AcuA. Crystal structures of AcsA from Chloroflexota bacterium in the apo form and in complex with acetyl-adenosine-5′-monophosphate (acetyl-AMP) support the flexible C-terminal domain adopting different conformations. AlphaFold2 predictions suggest binding of AcuA stabilizes AcsA in an undescribed conformation. We show the AcuA•AcsA complex dissociates upon acetyl-coenzyme A (acetyl-CoA) dependent acetylation of AcsA by AcuA. We discover an intrinsic phosphotransacetylase activity enabling AcuA•AcsA generating acetyl-CoA from acetyl-phosphate (AcP) and coenzyme A (CoA) used by AcuA to acetylate and inactivate AcsA. Here, we provide mechanistic insights into the regulation of AMP-forming acetyl-CoA synthetases by lysine acetylation and discover an intrinsic phosphotransacetylase allowing modulation of its activity based on AcP and CoA levels.

Abstract Background Apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for late‐onset Alzheimer's disease, and it can aggravate depressive symptoms in non‐AD patients. However, the impact of ApoE4 on AD‐associated depression‐like behaviors and its underlying pathogenic mechanisms remain unclear. Methods This study developed a 5xFAD mouse model overexpressing human ApoE4 (E4FAD). Behavioral assessments and synaptic function tests were conducted to explore the effects of ApoE4 on cognition and depression in 5xFAD mice. Changes in peripheral and central lipid metabolism, as well as the levels of serotonin (5‐HT) and γ‐aminobutyric acid (GABA) neurotransmitters in the prefrontal cortex, were examined. In addition, the protein levels of 24‐dehydrocholesterol reductase/glycogen synthase kinase‐3 beta/mammalian target of rapamycin (DHCR24/GSK3β/mTOR) and postsynaptic density protein 95/calmodulin‐dependent protein kinase II/brain‐derived neurotrophic factor (PSD95/CaMK‐II/BDNF) were measured to investigate the molecular mechanism underlying the effects of ApoE4 on AD mice. Results Compared with 5xFAD mice, E4FAD mice exhibited more severe depression‐like behaviors and cognitive impairments. These mice also exhibited increased amyloid‐beta deposition in the hippocampus, increased astrocyte numbers, and decreased expression of depression‐related neurotransmitters 5‐HT and GABA in the prefrontal cortex. Furthermore, lipid metabolism disorders were observed in E4FAD, manifesting as elevated low‐density lipoprotein cholesterol and reduced high‐density lipoprotein cholesterol in peripheral blood, decreased cholesterol level in the prefrontal cortex, and reduced expression of key enzymes and proteins related to cholesterol synthesis and homeostasis. Abnormal expression of proteins related to the DHCR24/GSK3β/mTOR and PSD95/CaMK‐II/BDNF pathways was also observed. Conclusion This study found that ApoE4 overexpression exacerbates depression‐like behaviors in 5xFAD mice and confirmed that ApoE4 reduces cognitive function in these mice. The mechanism may involve the induction of central and peripheral lipid metabolism disorders. Therefore, modulating ApoE expression or function to restore cellular lipid homeostasis may be a promising therapeutic target for AD comorbid with depression. This study also provided a better animal model for studying AD comorbid with depression.

BackgroundThe aim of this study is to evaluate the association between triglyceride glucose-waist height ratio (TyG-WHtR) index and the prevalence of gallstone disease (GSD), alongside the age at first gallstone surgery among adult populations within the United States.MethodsWe screened participants using the National Health and Nutrition Examination Survey (NHANES). Logistic regression analysis, generalized additive modeling, smoothed curve fitting, and subgroup analysis were employed to assess the association between the TyG-WHtR index, prevalence of GSD, and the age at initial gallstone surgical intervention.ResultsIn this study, 3,728 participants were enrolled, among whom 395 individuals reported a prior history of GSD. The association between the TyG-WHtR index and the prevalence of GSD demonstrated a non-linear, positive association. After adjusting for all potential confounders, for each incremental unit rise in the TyG-WHtR index, there was a 47% escalation in the prevalence of GSD (OR = 1.47, 95% CI: 1.29, 1.68). Subgroup analyses indicated a more pronounced association between the TyG-WHtR index and the prevalence of GSD among individuals aged 20–80 years, females, non-Hispanic white population, non-Hispanic black population, other racial groups, and non-diabetic cohorts. Additionally, this study identified that the TyG-WHtR index may be negatively correlated with age at first surgical treatment of gallstones.ConclusionAn elevated TyG-WHtR index demonstrates a positive association with the prevalence of GSD. However, more prospective studies are needed to validate our findings.

BackgroundBenign tumors of the spleen are rare compared to those of other parenchymal organs, accounting for less than 0.007% of all tumors, and are often found incidentally. Splenolymphangiomas are much rarer, commonly occur in children, and tend to have multiple foci. Splenic lymphangiomas are rare in adults, and fewer than 20 adult patients with isolated splenic lymphangiomas have been reported. In this article, we report the case of a middle-aged female patient with isolated splenic lymphangioma who underwent laparoscopic anatomical hypophysectomy of the lower pole of the spleen. We also summarize the existing literature on splenic lymphangioma diagnosis and available treatment options.Case presentationA 58-year-old middle-aged woman was found to have a mass approximately 60 mm in diameter at the lower pole of the spleen during a health checkup that was not accompanied by other symptoms or examination abnormalities. After completing a preoperative examination with no contraindications to surgery, the patient underwent laparoscopic anatomical splenectomy of the lower extremity of the spleen. The patient recovered well without complications and was discharged from the hospital on the 7th postoperative day. Histopathological and immunohistochemical results confirmed the diagnosis of splenic lymphangioma. Prompt surgical intervention is safe and necessary when splenic lymphangiomas are large or associated with a risk of bleeding.ConclusionSplenic lymphangiomas are rare and require early surgical intervention in patients with large tumor diameters or those at risk of rupture and bleeding. After rigorous preoperative evaluation and preparation, laparoscopic anatomical partial splenectomy is safe and feasible for surgeons with experience in laparoscopic surgery.

Abstract. Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in the treatment of hematological malignancies. Based on the immunomodulatory capability of CAR-T cells, efforts have turned toward exploring their potential in treating autoimmune diseases. Bibliometric analysis of 210 records from 128 academic journals published by 372 institutions in 40 countries/regions indicates a growing number of publications on CAR-T therapy for autoimmune diseases, covering a range of subtypes such as systemic lupus erythematosus, multiple sclerosis, among others. CAR-T therapy holds promise in mitigating several shortcomings, including the indiscriminate suppression of the immune system by traditional immunosuppressants, and non-sustaining therapeutic levels of monoclonal antibodies due to inherent pharmacokinetic constraints. By persisting and proliferating in vivo, CAR-T cells can offer a tailored and precise therapeutics. This paper reviewed preclinical experiments and clinical trials involving CAR-T and CAR-related therapies in various autoimmune diseases, incorporating innovations well-studied in the field of hematological tumors, aiming to explore a safe and effective therapeutic option for relapsed/refractory autoimmune diseases.

Abstract Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes. Herein, we retrospectively analyzed pancreatic lesions in autopsy tissues from 67 SARS-CoV-2 infected non-human primates (NHPs) models and 121 vaccinated and infected NHPs from 2020 to 2023 and COVID-19 patients. Multi-label immunofluorescence revealed direct infection of both exocrine and endocrine pancreatic cells by the virus in NHPs and humans. Minor and limited phenotypic and histopathological changes were observed in adult models. Systemic proteomics and metabolomics results indicated metabolic disorders, mainly enriched in insulin resistance pathways, in infected adult NHPs, along with elevated fasting C-peptide and C-peptide/glucose ratio levels. Furthermore, in elder COVID-19 NHPs, SARS-CoV-2 infection causes loss of beta (β) cells and lower expressed-insulin in situ characterized by islet amyloidosis and necrosis, activation of α-SMA and aggravated fibrosis consisting of lower collagen in serum, an increase of pancreatic inflammation and stress markers, ICAM-1 and G3BP1, along with more severe glycometabolic dysfunction. In contrast, vaccination maintained glucose homeostasis by activating insulin receptor α and insulin receptor β. Overall, the cumulative risk of diabetes post-COVID-19 is closely tied to age, suggesting more attention should be paid to blood sugar management in elderly COVID-19 patients.

Background Stroke is a leading cause of death worldwide, with a lack of effective treatments for improving the prognosis. The aim of the present study was to identify novel therapeutic targets for functional outcome after ischemic stroke . Methods and Results Cis‐expression quantitative trait loci data for druggable genes were used as instrumental variables. The primary outcome was the modified Rankin Scale score at 3 months after ischemic stroke, evaluated as a dichotomous variable (3–6 versus 0–2) and also as an ordinal variable. Drug target Mendelian randomization, Steiger filtering analysis, and colocalization analysis were performed. Additionally, phenome‐wide Mendelian randomization analysis was performed to identify the safety of the drug target genes at the genetic level. Among >2600 druggable genes, genetically predicted expression of 16 genes (ABCC2, ATRAID, BLK, CD93, CHST13, NR1H3, NRBP1, PI3, RIPK4, SEMG1, SLC22A4, SLC22A5, SLCO3A1, TEK, TLR4, and WNT10B) demonstrated the causal associations with ordinal modified Rankin Scale (P

Abstract B-cell maturation antigen (BCMA), expressed in plasmablasts and plasma cells, could serve as a promising therapeutic target for autoimmune diseases. We reported here chimeric antigen receptor (CAR) T cells targeting BCMA in two patients with highly relapsed and refractory myasthenia gravis (one with AChR-IgG, and one with MuSk-IgG). Both patients exhibited favorable safety profiles and persistent clinical improvements over 18 months. Reconstitution of B-cell lineages with sustained reduced pathogenic autoantibodies might underlie the therapeutic efficacy. To identify the possible mechanisms underlying the therapeutic efficacy of CAR-T cells in these patients, longitudinal single-cell RNA and TCR sequencing was conducted on serial blood samples post infusion as well as their matching infusion products. By tracking the temporal evolution of CAR-T phenotypes, we demonstrated that proliferating cytotoxic-like CD8 clones were the main effectors in autoimmunity, whereas compromised cytotoxic and proliferation signature and profound mitochondrial dysfunction in CD8+ Te cells before infusion and subsequently defect CAR-T cells after manufacture might explain their characteristics in these patients. Our findings may guide future studies to improve CAR T-cell immunotherapy in autoimmune diseases.

The increasing penetration of renewable energy sources and energy storage in the power grid has led to an exponentially large number of possible power generation scenarios. This makes it difficult to analyze, plan, and operate the power system, and necessitates a scenario reduction method. This paper presents a smart sampling approach for identifying a subset of generation scenarios from one year of production cost modeling data. The approach takes into account the seasonal and diurnal variability of renewable energy sources, utilizing a hierarchical design followed by sliced Latin-hypercube sampling method to select a statistically representative subset of hours. A series of validation tests provides strong evidence that the sampled subset exhibits the same statistical characteristics as the original one-year data.

Farmland shelterbelts are aimed at farmland protection and productivity improvement, environmental protection and ecological balance, as well as land use planning and management. Farmland shelterbelts play a vital role in determining the structural integrity and overall effectiveness of farmland, and assessing the dynamic changes within these protective forests accurately and swiftly is essential to maintaining their protective functions as well as for policy formulation and effectiveness evaluation in relevant departments. Traditional methods for extracting farmland shelterbelt information have faced significant challenges due to the large workload required and the inconsistencies in the accuracy of existing methods. For example, the existing vegetation index extraction methods often have significant errors, which remain unresolved. Therefore, developing a more efficient extraction method with greater accuracy is imperative. This study focused on Youyi Farm in Heilongjiang Province, China, utilizing satellite data with spatial resolutions ranging from 0.8 m (GF-7) to 30 m (Landsat). By taking into account the growth cycles of farmland shelterbelts and variations in crop types, the optimal temporal window for extraction is identified based on phenological analysis. The study introduced a new index—the Re-Modified Anthocyanin Reflectance Index (RMARI)—which is an improvement on existing vegetation indexes, such as the NDVI and the improved original ARI. Both the accuracy and extraction results showed significant improvements, and the feasibility of the RMARI was confirmed. The study proposed four extraction schemes for farmland shelterbelts: (1) spectral feature extraction, (2) extraction using vegetation indexes, (3) random forest extraction, and (4) RF combined with characteristic index bands. The extraction process was implemented on the GEE platform, and results from different spatial resolutions were compared. Results showed that (1) the bare soil period in May is the optimal time period for extracting farmland shelterbelts; (2) the RF method combined with characteristic index bands produces the best extraction results, effectively distinguishing shelterbelts from other land features; (3) the RMARI reduces background noise more effectively than the NDVI and ARI, resulting in more comprehensive extraction outcomes; and (4) among the satellite images analyzed—GF-7, Planet, Sentinel-2, and Landsat OLI 8—GF-7 achieves the highest extraction accuracy (with a Kappa coefficient of 0.95 and an OA of 0.97), providing the most detailed textural information. However, comprehensive analysis suggests that Sentinel-2 is more suitable for large-scale farmland shelterbelt information extraction. This study provides new approaches and technical support for periodic dynamic forestry surveys, providing valuable reference points for agricultural ecological research.

Abstract Microglia, the major resident immune cells in the central nervous system, serve as the frontline soldiers against cerebral ischemic injuries, possibly along with metabolic alterations. However, signaling pathways involved in the regulation of microglial immunometabolism in ischemic stroke remain to be further elucidated. In this study, using single‐nuclei RNA sequencing, a microglial subcluster up‐regulated in ischemic brain tissues is identified, with high expression of Igf1 and Trem2, neuroprotective transcriptional signature and enhanced oxidative phosphorylation. Microglial depletion by PLX3397 exacerbates ischemic brain damage, which is reversed by repopulating the microglia with high Igf1 and Trem2 phenotype. Mechanistically, Igf1 serves as one of the major down‐stream molecules of Trem2, and Trem2‐Igf1 signaling axis regulates microglial functional and metabolic profiles, exerting neuroprotective effects on ischemic stroke. Overexpression of Igf1 and supplementation of cyclocreatine restore microglial glucometabolic levels and cellular functions even in the absence of Trem2. These findings suggest that Trem2‐Igf1 signaling axis reprograms microglial immunometabolic profiles and shifts microglia toward a neuroprotective phenotype, which has promising therapeutic potential in treating ischemic stroke.

Background: The TGF-β gene is a gemcitabine (GEM) resistance gene; however, the mechanism by which it regulates GEM resistance in pancreatic cancer remains unclear. Methods: The PANC-1 cell line was treated with GEM and then stimulated with TGF-β. Subsequently, we constructed GEM-resistant pancreatic cancer cell lines, knocked down TGF-β in these cell lines, and detected changes in the proliferation and apoptosis of drug-resistant cancer cells. In addition, the protein expression levels of KLF-4, GFI-1, and ZEB-1 were determined. The xenograft tumor models of nude mice were constructed by subcutaneously injecting GEM-resistant PANC-1 cells into mouse axilla. The tumors were removed, dissected, and weighed after 6 weeks. The protein levels of KLF-4, GFI-1, and ZEB-1 in tumor tissues were quantified. In addition, the percentage of M2 macrophages in tumor tissues was determined using flow cytometry. Results: The protein levels of TGF-β in pancreatic cancer cells were significantly decreased after GEM treatment. The protein expression of KLF-4 was downregulated, whereas the expressions of GFI-1 and ZEB-1 were upregulated after TGF-β stimulation. Apoptosis increased and proliferation decreased after TGF-β knockdown in GEM-resistant pancreatic cancer cells, moreover, silencing TGF-β promoted the expression of Caspase 3 and Cleaved caspase 3. In addition, the protein expression of KLF-4 was upregulated, whereas the expressions of GFI-1 and ZEB-1 were downregulated. Further, the volume and weight of the transplanted tumor decreased after TGF-β knockdown. The protein expression of KLF-4 was upregulated, whereas the expressions of GFI-1 and ZEB-1 were downregulated in tumor tissues. In addition, the percentage of M2 macrophages decreased in tumor tissues after TGF-β knockdown. Conclusions: The knockdown of TGF-β inhibits epithelial-to-mesenchymal transition, suppresses the proliferation and promotes the apoptosis of drug-resistant cancer cells, and decreases the macrophage polarization to the M2 phenotype, consequently ameliorating GEM resistance in pancreatic cancer.

The advent of social media has brought about significant changes in people’s lives.While social media allows for easy access and sharing of news, it has also become a breeding ground for the dissemination of fake news, posing a serious threat to social security and stability.Consequently, researchers have shifted their focus towards fake news detection.Although several deep learning-based solutions have been proposed, these methods heavily rely on large amounts of supporting data.Currently, there is a scarcity of existing datasets, particularly in Chinese, and the collected news articles are often limited to the same category.To enhance the detection of fake news, a new multi-modal fake news dataset (MFND) was developed, which comprised Chinese and English news data from ten diverse categories: politics, economy, entertainment, sports, international affairs, technology, military, education, health, and social life.The word frequencies and categories of the proposed fake news dataset were analyzed and compared with existing fake news datasets in terms of number of news, news categories, modal information and news languages.The results of the comparison demonstrate that the MFND dataset excels in terms of category information and news languages.Moreover, training and validating existing typical fake news detection methods with MFND dataset, the experimental results show an improvement of approximately 10% in model performance compared to existing mainstream fake news datasets.

Financial security, an important part of national security, is critical for the stable and healthy development of the economy.Digital image watermarking technology plays a crucial role in the field of financial information security, and the anti-screen watermarking algorithm has become a new research focus of digital image watermarking technology.The common way to achieve an invisible watermark in existing watermarking schemes is to modify the carrier image, which is not suitable for all types of images.To solve this problem, an end-to-end robust watermarking scheme based on deep learning was proposed.The algorithm achieved both visual quality and robustness of the watermark image.A random binary string served as the input of the encoder network in the proposed end-to-end network architecture.The encoder can generate the watermark information overlay, which can be attached to any carrier image after training.The ability to resist screen shooting noise was learned by the model through mathematical methods incorporated in the network to simulate the distortion generated during screen shooting.The visual quality of the watermark image was further improved by adding the image JND loss based on just perceptible difference.Moreover, an embedding hyperparameter was introduced in the training phase to balance the visual quality and robustness of the watermarked image adaptively.A watermark model suitable for different scenarios can be obtained by changing the size of the embedding hyperparameter.The visual quality and robustness performance of the proposed scheme and the current state-of-the-art algorithms were evaluated to verify the effectiveness of the proposed scheme.The results show that the watermark image generated by the proposed scheme has better visual quality and can accurately restore the embedded watermark information in robustness experiments under different distances, angles, lighting conditions, display devices, and shooting devices.

Abstract Background Pathological angiogenesis and blood–brain barrier damage may play an important role in Alzheimer's disease (AD). ACE2 is mainly expressed on the surface of endothelial cells in brain. Recent studies have shown that the expression of ACE2 in AD is reduced, but its role in AD is still unclear. Method We induced AD damage in endothelial cells using Aβ25‐35 and overexpressed ACE2 in bEend.3 cells through lentiviral transfection. We detected the effect of Aβ25‐35 on cell viability using the CCK‐8 assay and examined the effect of overexpressing ACE2 on angiogenesis using an angiogenesis assay. We used western blot and cell immunofluorescence to detect changes in the expression of the VEGF/VEGFR2 pathway, tight junction protein, and NF‐κB pathway. Results Aβ25‐35 treatment significantly decreased the expression of ACE2 and reduced cell viability. ACE2 overexpression (1) reduced the number of branches and junctions in tube formation, (2) inhibited the activation of the VEGF/VEGFR2 pathway induced by Aβ25‐35, (3) increased the expression of TJPs, including ZO‐1 and claudin‐5, and (4) restored Aβ25‐35‐induced activation of the NF‐κB pathway. Conclusion Overexpression of ACE2 can improve pathological angiogenesis and blood–brain barrier damage in AD models in vitro by inhibiting NF‐κB/VEGF/VEGFR2 pathway activity. ACE2 may therefore represent a therapeutic target for endothelial cell dysfunction in AD.

BackgroundGrowing evidence links immunological responses to Multiple sclerosis (MS), but specific immune factors are still unclear.MethodsMendelian randomization (MR) was performed to investigate the association between peripheral hematological traits, MS risk, and its severity. Then, further subgroup analysis of immune counts and circulating cytokines and growth factors were performed.ResultsMR revealed higher white blood cell count (OR [95%CI] = 1.26 [1.10,1.44], P = 1.12E-03, P adjust = 3.35E-03) and lymphocyte count (OR [95%CI] = 1.31 [1.15,1.50], P = 5.37E-05, P adjust = 3.22E-04) increased the risk of MS. In further analysis, higher T cell absolute count (OR [95%CI] = 2.04 [1.36,3.08], P = 6.37E-04, P adjust = 2.19E-02) and CD4+ T cell absolute count (OR [95%CI] = 2.11 [1.37,3.24], P = 6.37E-04, P adjust = 2.19E-02), could increase MS risk. While increasing CD25++CD4+ T cell absolute count (OR [95%CI] = 0.75 [0.66,0.86], P = 2.12E-05, P adjust = 1.72E-03), CD25++CD4+ T cell in T cell (OR [95%CI] = 0.79[0.70,0.89], P = 8.54E-05, P adjust = 5.29E-03), CD25++CD4+ T cell in CD4+ T cell (OR [95%CI] = 0.80[0.72,0.89], P = 1.85E-05, P adjust = 1.72E-03), and CD25++CD8+ T cell in T cell (OR [95%CI] = 0.68[0.57,0.81], P = 2.22E-05, P adjust = 1.72E-03), were proved to be causally defensive for MS. For the disease severity, the suggestive association between some traits related to CD4+ T cell, Tregs and MS severity were demonstrated. Moreover, elevated levels of IL-2Ra had a detrimental effect on the risk of MS (OR [95%CI] = 1.22 [1.12,1.32], P = 3.20E-06, P adjust = 1.34E-04).ConclusionsThis study demonstrated a genetically predicted causal relationship between elevated peripheral immune cell counts and MS. Subgroup analysis revealed a specific contribution of peripheral immune cells, holding potential for further investigations into the underlying mechanisms of MS and its severity.

The awareness of protecting traditional culture and humanistic landscapes is increasing year by year, and the protection of ancient gardens is becoming more and more a consensus among people. This paper takes the architectural profile of Guyi Garden as the research basis, introduces the specific application of 3D laser scanning technology, plans the scope of architectural data acquisition in Guyi Garden, and designs the corresponding architectural data acquisition program. With respect to the acquired point cloud data of GuYiYuan, the bilateral filtering algorithm is used to reduce the noise of the data, the curvature thinning algorithm is combined to reduce the point cloud data of the buildings in GuYiYuan, the point cloud data are spliced based on the connection point, and the ICP algorithm with the introduction of the optimization of the rotational angle constraints is introduced to realize the alignment of the point cloud data. In addition, the shadows generated from the point cloud data are removed by combining the relighting method, and the linear transformation method is also used to globally correct the texture image generated from the point cloud data. The point cloud density was reduced from 0.95m² to 0.01m² when the thinning rate was increased from 8% to 96%, and the alignment error of the improved ICP algorithm under 25dB Gaussian white noise was only 0.083*10-4mm. The maximum error accuracy of the two-dimensional model of Yiyi Nodang generated based on the point cloud data was only 0.007m, and the error of the three-dimensional model was controlled to be within the range of ±9mm. Accurate architectural data can be obtained through the use of 3D laser scanning technology, leading to a new method for digitally preserving historical buildings.

Reversible data hiding with contrast enhancement (RDH-CE) enables contrast enhancement of the image and lossless recovery of host image after embedded data extraction. Although the current RDH-CE methods are effective in enhancing carrier images and ensuring reversibility, image quality control is still lacking, which may lead to poor image visualization. In more serious situations, the image detail information may be lost. The peak pair selection mechanism plays an extremely crucial role in image quality enhancement; however, existing work often neglects this. In this paper, we propose an RDH-CE algorithm that pursues high image quality maintenance, aiming to maintain image quality by guiding and controlling the selection of peaks and the direction of histogram shift through quality metrics. Specifically, instead of simply selecting only one pair of peaks at each peak selection stage, our algorithm selects several pairs of peaks that meet the requirements as candidate peak pairs. It then first performs simulated histogram equalization on these candidate peaks, followed by analyzing the situation of the quality metrics generated by each pair of peaks accordingly, and then selects the optimal peaks for the current iteration based on the performance of each pair of candidate peaks to be used in the equalization process. Our selection mechanism also dynamically changes the peak selection strategy based on before-and-after changes in the actual metrics, which can better ensure image quality stability over the iterations. Under the evaluations of a series of image quality metrics, the proposed method can still maintain high quality and visual effect under high iteration and has strong stability for image quality control, thus demonstrating the effectiveness and superiority of the proposed method.

ABSTRACTEmerging zoonoses of wildlife origin caused by previously unknown agents are one of the most important challenges for human health. The Qinghai-Tibet Plateau represents a unique ecological niche with diverse wildlife that harbours several human pathogens and numerous previously uncharacterized pathogens. In this study, we identified and characterized a novel arenavirus (namely, plateau pika virus, PPV) from plateau pikas (Ochotona curzoniae) on the Qinghai-Tibet Plateau by virome analysis. Isolated PPV strains could replicate in several mammalian cells. We further investigated PPV pathogenesis using animal models. PPV administered via an intraventricular route caused trembling and sudden death in IFNαβR-/- mice, and pathological inflammatory lesions in brain tissue were observed. According to a retrospective serological survey in the geographical region where PPV was isolated, PPV-specific IgG antibodies were detected in 8 (2.4%) of 335 outpatients with available sera. Phylogenetic analyses revealed that this virus was clearly separated from previously reported New and Old World mammarenaviruses. Under the co-speciation framework, the estimated divergence time of PPV was 77–88 million years ago (MYA), earlier than that of OW and NW mammarenaviruses (26-34 MYA).

Abstract Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disorder of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are activated and play a pivotal role in response to tissue injury. Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed by microglia and promotes microglial activation, survival and phagocytosis. Here, we identify a critical role for TREM2 in microglial activation and function during AQP4-IgG and complement-induced demyelination. TREM2-deficient mice had more severe tissue damage and neurological impairment, as well as fewer oligodendrocytes with suppressed proliferation and maturation. The number of microglia clustering in NMOSD lesions and their proliferation were reduced in TREM2-deficient mice. Moreover, morphology analysis and expression of classic markers showed compromised activation of microglia in TREM2-deficient mice, which was accompanied by suppressed phagocytosis and degradation of myelin debris by microglia. These results overall indicate that TREM2 is a key regulator of microglial activation and exert neuroprotective effects in NMOSD demyelination. Graphical Abstract

Abstract Computerized adaptive testing (CAT) targets to accurately assess the student’s proficiency in the required subject/area. The key issue is how to design a question selector that adaptively selects the best-suited questions for each student based on previous performance step by step. Most existing question selectors execute via greedy metric functions (e.g., question information and uncertainty), which can not effectively capture data characteristics. There also exist learning-based question selectors that redefine the CAT problem as a bilevel optimization problem, where the parameter learning of the question selector and the student proficiency estimation model are coupled, which is not flexible enough. To this end, in this paper, we propose a novel CAT framework with Decoupled Learning selector (DL-CAT). Specifically, we first use the currently estimated student ability and question characteristics as input and design a deep learning-based question selector to predict question selection scores. Then, to address the issue that there is no ground truth to measure the quality of the selected question, an approximate ground-truth and a pairwise rank loss function are specially designed to update the parameters of the question selector independently. Extensive experiments on two real datasets demonstrate that our proposed DL-CAT has certain advantages in effectiveness and significant advantages in efficiency.

Addressing the current issue of limited control methods for badminton serving devices, this paper proposes a vision-based multimodal control system and method for badminton serving. The system integrates computer vision recognition technology with traditional control methods for badminton serving devices. By installing vision capture devices on the serving device, the system identifies various human body postures. Based on the content of posture information, corresponding control signals are sent to adjust parameters such as launch angle and speed, enabling multiple modes of serving. Firstly, the hardware design for the badminton serving device is presented, including the design of the actuator module through 3D modeling. Simultaneously, an embedded development board circuit is designed to meet the requirements of multimodal control. Secondly, in the aspect of visual perception for human body recognition, an improved BlazePose candidate region posture recognition algorithm is proposed based on existing posture recognition algorithms. Furthermore, mappings between posture information and hand information are established to facilitate parameter conversion for the serving device under different postures. Finally, extensive experiments validate the feasibility and stability of the developed system and method.

Gut microbes play a vital role in the health and disease of animals, especially in relation to pathogen infections. Chinchillas, ferrets, and marmots are commonly used as important laboratory animals for infectious disease research. Here, we studied the bacterial and fungal microbiota and discovered that chinchillas had higher alpha diversity and a higher abundance of bacteria compared to marmots and ferrets by using the metabarcoding of 16S rRNA genes and ITS2, coupled with co-occurrence network analysis. The dominant microbes varied significantly among the three animal species, particularly in the gut mycobiota. In the ferrets, the feces were dominated by yeast such as Rhodotorula and Kurtzmaniella, while in the chinchillas, we found Teunomyces and Penicillium dominating, and Acaulium, Piromyces, and Kernia in the marmots. Nevertheless, the dominant bacterial genera shared some similarities, such as Clostridium and Pseudomonas across the three animal species. However, there were significant differences observed, such as Vagococcus and Ignatzschineria in the ferrets, Acinetobacter and Bacteroides in the chinchillas, and Bacteroides and Cellvibrio in the marmots. Additionally, our differential analysis revealed significant differences in classification levels among the three different animal species, as well as variations in feeding habitats that resulted in distinct contributions from the host microbiome. Therefore, our data are valuable for monitoring and evaluating the impacts of the microbiome, as well as considering potential applications.

The lateral hypothalamus' orexinergic system has been associated with anxiety-related behaviors, and electroacupuncture (EA) modifies orexin neurons to control the anti-anxiety process. However, in a rat model of post-traumatic stress disorder (PTSD), the important role of LH orexin neurons (OXNs) in the anxiolytic effects induced by EA has not been explored. In this study, rats underwent modified single prolonged stress (MSPS) for seven days before developing EA. The rats were then subjected to elevated plus maze (EPM) and open field (OFT) tests, and western blot and c-Fos/orexin double labeling investigations were carried out to determine the functional activation of LH orexinergic neurons. Compared to MSPS model rats, it has been demonstrated that EA stimulation enhanced the amount of time spent in the central zone (TSCZ) in OFT and the amount of time spent in the open arm (TSOA) in EPM in MSPS model rats (P

The mechanical washing wastewater contained a large amount of oil, and the iron wrapped in the oil was slowly released into water. This caused the effluent quality to fluctuate, causing common polymeric aluminum chloride (PAC) to ineffectively remove the water-in-oil. The method uses Ca2+ to demulsify and ClOx− to destroy the water-in-oil structure, which releases Fe from the oil droplets. The active oxygen produced by NaClOx further converts Fe2+ into Fe3+ and then combines with NaOH to form Fe(OH)3-flocs core, which improves the flocculation efficiency of PAC. The optimal ratio was approximately 400 μL of NaClOx, 200 μL of 1 mol L−1 CaO, and 12 mL of 12.8 g L−1 PAC. The oil removal rate reached 99.88% and the residue density was 178.42 mg L−1. The maximum Fe and chemical oxygen demand (COD) removal rates were close to 49.2 and 99.89%, respectively. In field applications, wastewater should be acidified first, and acidification oxidation is more effective than direct oxidation. In short, a novel way for treating mechanically washed wastewater with iron-in-oil characteristics by changing the environmental fate of iron is provided. HIGHLIGHTS 49.2% of Fe and 99.89% of COD were removed by NaClOx + CaO + PAC.; The optimal ratio was 400 μL of NaClOx, 200 μL of 1 mol L−1 CaO, and 12 mL of 12.8 g L−1 PAC.; NaClOx destroys the water-in-oil and alters the environmental fate of Fe to Fe(OH)3 for promoting flocculation.; Acidification prior to NaClOx oxidation benefits the removal of COD and iron.;

Abstract Autophagy is one of the degradation pathways to remove proteins or damaged organelles in cells that plays an important role in neuroprotection. Different stages of autophagy are regulated by autophagy‐related genes, and many molecules such as transcription factor EB (TFEB) are involved. The complete autophagy process plays an important role in maintaining the dynamic balance of autophagy and is crucial to the homeostasis of intracellular substance and energy metabolism. Autophagy balance is disrupted in neurodegenerative diseases, accounting for a variety of degeneration disorders. These impairments can be alleviated or treated by the regulation of autophagy through molecules such as TFEB.

Abstract Background Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. Results Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. Conclusions Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.

There is a lot of interest in the policymakers’ plans to have grids run entirely on renewable energy in the upcoming years. As a result of the high renewable penetration, future large interconnected grids (LIGs) become more volatile and difficult to operate. To understand future grids better, the planning studies of future grids must consider a wide range of operating conditions and contingencies. In this paper, we propose a novel future grid planning framework that can simulate a wide range of operating conditions and contingencies while considering future policy and topology changes, production cost models, dynamics, steady state AC power flow, and cascade constraints. Using this proposed framework, we propose an approach to identify voltage stability critical locations in the future grid without assumptions on switching devices and load change trajectories during system collapse, while also considering the cascading/time-series behavior of future LIGs. The proposed future grid planning framework is used to generate 1.485 terabytes of dynamic simulation data for 2028 WECC system containing 4455 scenarios. The proposed voltage stability approach is demonstrated on the 2028 representation of the WECC system, and IEEE 30, 300-bus systems.

Abstract The Omicron variants of SARS-CoV-2, primarily authenticated in November 2021 in South Africa, has initiated the 5th wave of global pandemics. Here, we systemically examined immunological and metabolic characteristics of Omicron variants infection. We found Omicron resisted to neutralizing antibody targeting receptor binding domain (RBD) of wildtype SARS-CoV-2. Omicron could hardly be neutralized by sera of Corona Virus Disease 2019 (COVID-19) convalescents infected with the Delta variant. Through mass spectrometry on MHC-bound peptidomes, we found that the spike protein of the Omicron variants could generate additional CD8 + T cell epitopes, compared with Delta. These epitopes could induce robust CD8 + T cell responses. Moreover, we found booster vaccination increased the cross-memory CD8 + T cell responses against Omicron. Metabolic regulome analysis of Omicron-specific T cell showed a metabolic profile that promoted the response of memory T cells. Consistently, a greater fraction of memory CD8 + T cells existed in Omicron stimulated peripheral blood mononuclear cells (PBMCs). In addition, CD147 was also a receptor for the Omicron variants, and CD147 antibody inhibited infection of Omicron. CD147-mediated Omicron infection in a human CD147 transgenic mouse model induced exudative alveolar pneumonia. Taken together, our data suggested that vaccination booster and receptor blocking antibody are two effective strategies against Omicron.

Abstract Chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA) have great potentials in autoimmune diseases and could be novel therapeutics for relapsed/refractory neuromyelitis optica spectrum disorder (NMOSD). To evaluate the safety and efficacy of the CT103A, a self-developed BCMA-targeting CAR construct against BCMA, in patients with AQP4-IgG seropositive NMOSD, an ongoing, investigator-initiated, open-label, single-arm, phase 1 clinical trial is conducted at our center. In total, 12 patients were administered with a CAR-BCMA infusion. Ten of the 12 patients dosed were women (83.3%), with a median age of 49.5 years (range, 30–67). were The most common events of grade 3 or higher were hematologic toxic effects. Seven patients (58%) developed infections, but no grade 4 infections occurred. Cytokine release syndrome was reported in all patients with only events of grade 1 or 2 observed. During the follow-up of a median 5.5 months, 11 patients had no relapse; all patients generally reported improvement in disabilities and quality-of-life outcomes; 11 patients’ AQP-4 antibodies in serum showed a downward trend by the cutoff date. CAR T-cell expansion was associated with responses, and persisted more than 6 months post-infusion in 17% of the patients. In summary, CAR T-cell therapy shows a manageable safety profile and therapeutic potentials for patients with relapsed/refractory AQP4-IgG seropositive NMOSD. Another expansion phase is currently underway to determine the safety and efficacy of CAR T-BCMA infusion in patients with other neuro-inflammatory diseases.

Abstracts The COVID-19 pandemic, caused by the SARS-CoV-2 virus and its variants, has posed unprecedented challenges worldwide. Existing vaccines have limited effectiveness against SARS-CoV-2 variants. Therefore, novel vaccines to match mutated viral lineages by providing long-term protective immunity are urgently needed. We designed a recombinant adeno-associated virus 5 (rAAV5)-based vaccine (rAAV-COVID-19) by using the SARS-CoV-2 spike protein receptor binding domain (RBD-plus) sequence with both single-stranded (ssAAV5) and self-complementary (scAAV5) delivery vectors and found that it provides excellent protection from SARS-CoV-2 infection. A single-dose vaccination in mice induced a robust immune response; induced neutralizing antibody (NA) titers were maintained at a peak level of over 1:1024 more than a year post-injection and were accompanied by functional T-cell responses. Importantly, both ssAAV- and scAAV-based RBD-plus vaccines produced high levels of serum NAs against the circulating SARS-CoV-2 variants, including Alpha, Beta, Gamma and Delta. A SARS-CoV-2 virus challenge showed that the ssAAV5-RBD-plus vaccine protected both young and old mice from SARS-CoV-2 infection in the upper and lower respiratory tracts. Whole genome sequencing demonstrated that AAV vector DNA sequences were not found in the genomes of vaccinated mice one year after vaccination, demonstrating vaccine safety. These results suggest that the rAAV5-based vaccine is safe and effective against SARS-CoV-2 and several variants as it provides long-term protective immunity. This novel vaccine has a significant potential for development into a human prophylactic vaccination to help end the global pandemic.

Abstract We searched a database of single-gene knockout (KO) mice produced by the International Mouse Phenotyping Consortium (IMPC) to identify candidate ciliopathy genes. We first screened for phenotypes in mouse lines with both ocular and renal or reproductive trait abnormalities. The STRING protein interaction tool was used to identify interactions between known cilia gene products and those encoded by the genes in individual knockout mouse strains in order to generate a list of “candidate ciliopathy genes.” From this list, 32 genes encoded proteins predicted to interact with known ciliopathy proteins. Of these, 25 had no previously described roles in ciliary pathobiology. Histological and morphological evidence of phenotypes found in ciliopathies in knockout mouse lines are presented as examples (genes Abi2, Wdr62, Ap4e1, Dync1li1, and Prkab1). Phenotyping data and descriptions generated on IMPC mouse line are useful for mechanistic studies, target discovery, rare disease diagnosis, and preclinical therapeutic development trials. Here we demonstrate the effective use of the IMPC phenotype data to uncover genes with no previous role in ciliary biology, which may be clinically relevant for identification of novel disease genes implicated in ciliopathies.

Mouse bone marrow mesenchymal stem cells (mBM‐MSCs) are important for preclinical tissue regeneration and repair studies. In the present study, we isolated mBM‐MSCs using three easy‐to‐perform methods (whole bone marrow‐adherent culture, density‐gradient centrifugation, and bone digestion), and then compared the morphology, proliferation, differentiation, and paracrine factor profiles of the isolated mBM‐MSCs. Of these three isolation methods, the bone digestion method resulted in the highest quantity of mBM‐MSCs with high growth potential and moderate differentiation. Conversely, the mBM‐MSCs isolated through the whole bone marrow‐adherent method exhibited the lowest potency for proliferation and differentiation. The differentially expressed factors between mBM‐MSCs were primarily those involved in immune responses. The highly expressed secreted factors included cytokines/members of the chemokine family, growth factors, and protein binding/proteinase activity. These findings provide a fundamental reference for development of MSC isolation methods.

Abstract COVID‐19 patients can develop clinical and histopathological features associated with fibrosis, but the pathogenesis of fibrosis remains poorly understood. CD147 has been identified as a universal receptor for SARS-CoV-2 and its variants, which could initiate COVID-19-related cytokine storm. Here, we systemically analyzed lung pathogenesis in SARS-CoV-2- and its delta variant-infected humanized CD147 transgenic mice. Histopathology and Transmission Electron Microscopy revealed inflammation, fibroblast expansion and pronounced fibrotic remodeling in SARS-CoV-2-infected lungs. Consistently, RNA-sequencing identified a set of fibrosis signature genes. Furthermore, we identified CD147 as a crucial regulator for fibroblast activation induced by SARS-CoV-2. We found conditional knockout of CD147 in fibroblast suppressed activation of fibroblasts, decreasing susceptibility to bleomycin-induced pulmonary fibrosis. Meplazumab, a CD147 antibody, was able to inhibit the accumulation of activated fibroblasts and the production of ECM proteins, thus alleviating the progression of pulmonary fibrosis caused by SARS-CoV-2. In conclusion, we demonstrated that CD147 contributed to SARS-CoV-2-triggered progressive pulmonary fibrosis and identified CD147 as a potential therapeutic target for treating patients with post-COVID-19 pulmonary fibrosis.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the causative agent of coronavirus disease 2019 (COVID‐19), the most consequential pandemic of this century, threatening human health and public safety. SARS‐CoV‐2 has been continuously evolving through mutation of its genome and variants of concern have emerged. The World Health Organization R&D Blueprint plan convened a range of expert groups to develop animal models for COVID‐19, a core requirement for the prevention and control of SARS‐CoV‐2 pandemic. The animal model construction techniques developed during the SARS‐CoV and MERS‐CoV pandemics were rapidly deployed and applied in the establishment of COVID‐19 animal models. To date, a large number of animal models for COVID‐19, including mice, hamsters, minks and nonhuman primates, have been established. Infectious diseases produce unique manifestations according to the characteristics of the pathogen and modes of infection. Here we classified animal model resources around the infection route of SARS‐CoV‐2, and summarized the characteristics of the animal models constructed via transnasal, localized, and simulated transmission routes of infection.

Objective: To explore the anti-aging function and mechanism of pond turtle protein-derived peptides (PTPDP) on Drosophila melanogaster. Methods: PTPDP were obtained by enzymatic hydrolysis of turtle meat. Nutrients content, molecular weight distribution and amino acid composition of PTPDP were determined. D. melanogaster were fed with 0.2%, 0.4%, and 0.8% PTPDP. The activities of superoxide dismutase (SOD) and catalase (CAT), along with the content of malondialdehyde (MDA) were determined to analyze the anti-aging function of PTPDP. The anti-aging mechanism was explored by measuring the expression of antioxidant genes (Sod1, Sod2 and Cat) and lifespan-related genes (mth and Rpn11) in female D. melanogaster fed with 0.8% PTPDP. Results: The enzymatic hydrolysis products of turtle meat were mainly composed of small molecule peptides less than 1000 Da. PTPDP were rich in amino acids with antioxidant activity, such as glycine, glutamic acid and proline. In the survival experiment, the average lifespans of female and male D. melanogaster were significantly prolonged by 18.92% and 9.37% (P

Cabernet Sauvignon grape pomace contains carbohydrates and various amino acids that could be used as substrates for lactic acid (LA) production. In this study, a mutant strain of L. plantarum with deletion of the D-lactate synthesis gene was developed and used to produce optical pure L-LA from grape pomace. The highest optical purity of the L-LA produced by this mutant strain was 99.61%. The direct bioconversion of the raw substrate showed a low LA yield. Several pretreatment methods were applied to improve the LA yield, including ball milling, hydrothermal, dilute acid pretreatment, alkaline pretreatment, and combined wet alkaline mechanical pretreatment. Due to the efficient delignification, alkaline pretreatment achieved the highest lactic acid yield of 96.26% at 15% solid loading, with corresponding LA concentration and volumetric productivity of 18.45 g/L and 2.30 g/L·h, respectively.

Neuromyelitis optica spectrum disorders (NMOSD) are demyelinating diseases of the central nervous system, have drawn the attention of many researchers due to the relapsing courses and cumulative disability. A first bibliometric analysis of NMOSD was conducted to identify the research hotspots and emerging trends. Articles relevant to NMOSD published in the core collection of Web of Science were retrieved and analyzed through visualized analysis using CiteSpace and VOSviewer, focusing on annual publication trends, countries, institutions, authors, journals, and keywords. The analysis showed that over the past 30 years, publications related to NMOSD had shown steady growth with slight fluctuations. The United States played an important part in this field, with the highest outputs and the greatest number of citations. Research hotspots of NMOSD had gradually shifted from the definition, biomarkers, and diagnostic criteria to diagnosis and treatment, particularly immunotherapy. This bibliometric analysis provides researchers with a theoretical basis for studying NMOSD and offers guidance for future research directions.

Abstract Objective The aim of this study was to establish and validate a clinical prediction model for assessing the risk of metastasis and patient survival in Ewing's sarcoma (ES). Methods Patients diagnosed with ES from the Surveillance, Epidemiology and End Results (SEER) database for the period 2010-2016 were extracted, and the data after exclusion of vacant terms was used as the training set (n=767). Prediction models predicting patients' overall survival (OS) at 1 and 3 years were created by cox regression analysis and visualized using Nomogram and web calculator. Multicenter data from four medical institutions were used as the validation set (n=51), and the model consistency was verified using calibration plots, and receiver operating characteristic (ROC) verified the predictive ability of the model. Finally, a clinical decision curve was used to demonstrate the clinical utility of the model. Results The results of multivariate cox regression showed that age, , bone metastasis, tumor size, and chemotherapy were independent prognostic factors of ES patients. Internal and external validation results: calibration plots showed that the model had a good agreement for patient survival at 1 and 3 years; ROC showed that it possessed a good predictive ability and clinical decision curve proved that it possessed good clinical utility. Conclusions The tool built in this paper to predict 1- and 3-year survival in ES patients ( https://drwenleli0910.shinyapps.io/EwingApp/ ) has a good identification and predictive power.

Abstract Background Experimental animals are used to study physiological phenomena, pathological mechanisms, and disease prevention. The gut microbiome is known as a potential confounding factor for inconsistent data from preclinical studies. Although many gut microbiome studies have been conducted in recent decades, few have focused on gut microbiota fluctuation among representative mouse strains. Methods A range of frequently used mouse strains were selected from 34 isolation packages representing disease‐related animal (DRA), immunity defect animal (IDA), or gene‐editing animal (GEA) from the BALB/c and C57BL/6J backgrounds together with normal mice, and their microbial genomic DNA were isolated from mouse feces to sequence for the exploration of gut microbiota. Results Mouse background strain, classification, introduced source, introduced year, and reproduction type significantly affected the gut microbiota structure (p

Abstract In this paper, we completely characterize the boundedness and compactness of the Volterra integration operators J g $J_{g}$ acting from the Hardy-type tent spaces HT q , α p ( B n ) to the Hardy spaces H t ( B n ) in the unit ball of C n for all 0 < p , q , t < ∞ $0< p,q,t − n − 1 $\alpha >-n-1$ . The duality and factorization techniques for tent spaces of sequences play an important role in the proof of the main results.

Abstract Ischemic stroke is caused primarily by an interruption in cerebral blood flow, which induces severe neural injuries, and is one of the leading causes of death and disability worldwide. Thus, it is of great necessity to further detailly elucidate the mechanisms of ischemic stroke and find out new therapies against the disease. In recent years, efforts have been made to understand the pathophysiology of ischemic stroke, including cellular excitotoxicity, oxidative stress, cell death processes, and neuroinflammation. In the meantime, a plethora of signaling pathways, either detrimental or neuroprotective, are also highly involved in the forementioned pathophysiology. These pathways are closely intertwined and form a complex signaling network. Also, these signaling pathways reveal therapeutic potential, as targeting these signaling pathways could possibly serve as therapeutic approaches against ischemic stroke. In this review, we describe the signaling pathways involved in ischemic stroke and categorize them based on the pathophysiological processes they participate in. Therapeutic approaches targeting these signaling pathways, which are associated with the pathophysiology mentioned above, are also discussed. Meanwhile, clinical trials regarding ischemic stroke, which potentially target the pathophysiology and the signaling pathways involved, are summarized in details. Conclusively, this review elucidated potential molecular mechanisms and related signaling pathways underlying ischemic stroke, and summarize the therapeutic approaches targeted various pathophysiology, with particular reference to clinical trials and future prospects for treating ischemic stroke.

Abstract Object Early‐life neglect has irreversible emotional effects on the central nervous system. In this work, we aimed to elucidate distinct functional neural changes in medial prefrontal cortex (mPFC) of model rats. Methods Maternal separation with early weaning was used as a rat model of early‐life neglect. The excitation of glutamatergic and GABAergic neurons in rat mPFC was recorded and analyzed by whole‐cell patch clamp. Results Glutamatergic and GABAergic neurons of mPFC were distinguished by typical electrophysiological properties. The excitation of mPFC glutamatergic neurons was significantly increased in male groups, while the excitation of mPFC GABAergic neurons was significant in both female and male groups, but mainly in terms of rest membrane potential and amplitude, respectively. Conclusions Glutamatergic and GABAergic neurons in medial prefrontal cortex showed different excitability changes in a rat model of early‐life neglect, which can contribute to distinct mechanisms for emotional and cognitive manifestations.