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Abstract Background Dimethyl fumarate (DMF) is a fumaric acid ester that exhibits immunoregulatory and anti-inflammatory properties. However, the function of DMF in autoimmune uveitis (AU) is incompletely understood, and studies comprehensively exploring the impact of DMF on immune cells are still lacking. Methods To explore the function of DMF in uveitis and its underlying mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) on the cervical draining lymph node (CDLN) cells of normal, experimental autoimmune uveitis (EAU), and DMF-treated EAU mice. Additionally, we integrated scRNA-seq data of the retina and CDLNs to identify the potential impact of DMF on ocular immune cell infiltration. Flow cytometry was conducted to verify the potential target molecules of DMF. Results Our study showed that DMF treatment effectively ameliorated EAU symptoms. The proportional and transcriptional alterations in each immune cell type during EAU were reversed by DMF treatment. Bioinformatics analysis in our study indicated that the enhanced expression of Pim1 and Cxcr4 in EAU was reversed by DMF treatment. Further experiments demonstrated that DMF restored the balance between effector T (Teff) /regulatory T (Treg) cells through inhibiting the pathway of PIM1-protein kinase B (AKT)-Forkhead box O1 (FOXO1). By incorporating the scRNA-seq data of the retina from EAU mice into analysis, our study identified that T cells highly expressing Pim1 and Cxcr4 were enriched in the retina. DMF repressed the ocular infiltration of Teff cells, and this effect might depend on its inhibition of PIM1 and CXCR4 expression. Additionally, our study indicated that DMF might reduce the proportion of plasma cells by inhibiting PIM1 expression in B cells. Conclusions DMF effectively attenuated EAU symptoms. During EAU, DMF reversed the Teff/Treg cell imbalance and suppressed the ocular infiltration of Teff cells by inhibiting PIM1 and CXCR4 expression. Thus, DMF may act as a new drug option for the treatment of AU.

Abstract Asymmetric transformations and synthesis have garnered considerable interest in recent decades due to the extensive need for chiral organic compounds in biomedical, agrochemical, chemical, and food industries. The field of chiral inorganic catalysts, garnering considerable interest for its contributions to asymmetric organic transformations, has witnessed remarkable advancements and emerged as a highly innovative research area. Here, we review the latest developments in this dynamic and emerging field to comprehensively understand the advances in chiral inorganic nanocatalysts and stimulate further progress in asymmetric catalysis.

Background: Previous research on the association between serum albumin (ALB) and venous thromboembolism (VTE) has produced inconclusive results. The polygenic risk score is constructed from a set of independent risk variants associated with a disorder, enabling the identification of a larger fraction of the population at comparable or greater disease risk. It is still unknown whether ALB and genetic factors jointly contribute to the incidence of VTE. Objectives: The present study aimed to explore ALB, genetic susceptibility, and the risk of VTE. Methods: The present investigation was an analysis of prospectively collected data from UK Biobank, a population-based, longitudinal cohort. Cox proportional models were used to calculate hazard ratios and 95% CIs for VTE. The Kaplan–Meier curve was utilized to visualize the cumulative risk of VTE according to different serum ALB levels, and the restricted cubic spline model was leveraged to explore the exposure–response relationship among ALB levels and VTE risk. Results: During median follow-up of 13.5 years, 11,502 cases with VTE were diagnosed among 417,113 participants in the UK Biobank. The lower ALB levels were associated with a higher risk for VTE. Individuals with both a high genetic risk and lowest ALB level had the highest risk of VTE (hazard ratio, 3.89; 95% CI, 3.41-4.43), compared with those with low genetic risk and highest ALB level. The positive joint effects of low ALB and polygenic risk score increased the risk of VTE in individuals with high genetic risk. This study excluded non-European patients and primarily focused on the European population, which may limit the generalizability of the findings. Conclusion: Low serum ALB levels were linked to an increased risk of VTE, which was in accordance with a linear dose–response relationship. There was a positive additive effect of ALB and genetic susceptibility on the risk of VTE. ALB could serve as a biomarker for predicting the risk of VTE.

Abstract Objective To systematically analyze the accuracy of ultrasonic techniques in assessing the nature of gastric contents and their volume. Methods English-language articles that used ultrasonic techniques to assess the nature of gastric contents and their volume in patients were selected. In eligible studies, data were recalculated and analyzed for forest plots and subject summary curves of operating characteristics (SROC). Study quality was assessed using the diagnostic accuracy study quality assessment tool QUADAS-2. Publication bias was tested using funnel plots. Results Nine articles with a total of 523 study subjects were identified for this review. All studies were feasibility studies. The sensitivity of ultrasound assessment of gastric contents ranged from 53 to 100% and the specificity from 48 to 99%. The combined analysis yielded an area under the working characteristic curve for subjects of 97% (95% confidence interval (CI), 95–98%), a sensitivity of 95% (95% CI, 84–99%), and a specificity of 88% (95% CI, 72–95%). There was a high degree of heterogeneity among the studies due to inter-operator differences and small sample sizes. Conclusion Ultrasound techniques have high diagnostic accuracy in assessing the nature of gastric contents and their volume in patients. However, most of the studies were feasibility studies with small sample sizes, lacked standardization, and had high risk of bias. More studies are needed in the future to investigate the diagnostic performance of gastric ultrasound assessment techniques. Critical relevance statement Ultrasonography can be used to assess gastric contents, but standardized data integration and reporting are needed to account for the diagnostic capabilities of this technology. Key points • Ultrasound is a safe and feasible tool for assessing gastric contents. • Ultrasound has good diagnostic performance for gastric contents. • There is still a certain heterogeneity within our analysis process; more research is needed in the future to improve our results. Graphical Abstract

Background: To prospectively assess the individual and joint effects of birth weight and the life’s essential 8 (LE8)-defined cardiovascular health (CVH) on myocardial infarction (MI) risk in later life. Methods: In 144,803 baseline MI-free participants who were recruited in the UK Biobank cohort between 2006 and 2010, Cox proportional hazard models were used to estimate the associations of birth weight, LE8 score, and their interactions with incident MI. LE8 was defined on the basis of diet, physical activity, nicotine exposure, sleep health, body mass index, blood pressure, blood glucose, and blood lipids. Results: Low birth weight was associated with higher risk of MI [hazard ratio (HR) 1.17, 95% confidence interval 1.02–1.35, P = 0.025], while no significant correlation between high birth weight and MI was observed after adjustment. Low CVH was associated with higher MI risk [HR 6.43 (3.71–11.15), P

Emergence delirium is a common postoperative complication in patients undergoing general anesthesia, especially in children. In severe cases, it can cause unnecessary self-harm, affect postoperative recovery, lead to parental dissatisfaction, and increase medical costs. With the widespread use of inhalation anesthetic drugs (such as sevoflurane and desflurane), the incidence of emergence delirium in children is gradually increasing; however, its pathogenesis in children is complex and unclear. Several studies have shown that age, pain, and anesthetic drugs are strongly associated with the occurrence of emergence delirium. Alterations in central neurophysiology are essential intermediate processes in the development of emergence delirium. Compared to adults, the pediatric nervous system is not fully developed; therefore, the pediatric electroencephalogram may vary slightly by age. Moreover, pain and anesthetic drugs can cause changes in the excitability of the central nervous system, resulting in electroencephalographic changes. In this paper, we review the pathogenesis of and prevention strategies for emergence delirium in children from the perspective of brain electrophysiology—especially for commonly used pharmacological treatments—to provide the basis for understanding the development of emergence delirium as well as its prevention and treatment, and to suggest future research direction.

Abstract Kidney stones are a pervasive disease with notoriously high recurrence rates that require more effective treatment strategies. Herein, tartronic acid is introduced as an efficient inhibitor of calcium oxalate monohydrate (COM) crystallization, which is the most prevalent constituent of human kidney stones. A combination of in situ experimental techniques and simulations are employed to compare the inhibitory effects of tartronic acid with those of its molecular analogs. Tartronic acid exhibits an affinity for binding to rapidly growing apical surfaces of COM crystals, thus setting it apart from other inhibitors such as citric acid, the current preventative treatment for kidney stones. Bulk crystallization and in situ atomic force microscopy (AFM) measurements confirm the mechanism by which tartronic acid interacts with COM crystal surfaces and inhibits growth. These findings are consistent with in vivo studies that reveal the efficacy of tartronic acid is similar to that of citric acid in mouse models of hyperoxaluria regarding their inhibitory effect on stone formation and alleviating stone‐related physical harm. In summary, these findings highlight the potential of tartronic acid as a promising alternative to citric acid for the management of calcium oxalate nephropathies, offering a new option for clinical intervention in cases of kidney stones.

BackgroundOsteomyelitis is characterized by an inflammatory process initiated by microorganisms, leading to infection and subsequent degradation of bone tissue. Several studies have indicated a potential link between gut microbiota and the occurrence of osteomyelitis. Utilizing the benefits of Mendelian randomization, which mitigates issues of confounding and reverse causation, we employed this approach to ascertain the presence of a causal connection between gut microbiota and osteomyelitis. Additionally, we aimed to pinpoint gut microbiota that could potentially exert substantial influence.MethodsWe performed a rigorous screening of single nucleotide polymorphisms in GWAS summary statistics for gut microbiota and osteomyelitis. The 2,542 instrumental variables obtained after screening were subjected to MR analyses, including inverse variance weighting, weighted median, weighted mode, MR-Egger, and Mendelian randomization pleiotropy residual sum and outlier test. We then validated the reliability of the results by performing sensitivity analyses on the MR of 196 well-defined gut microbiota.ResultWe established a causal relationship between gut microbiota and osteomyelitis through MR analysis. Additionally, we identified a taxon of significant importance and six taxons with nominal significance. Specifically, the family Bacteroidales S24.7 group exhibited an association with a diminished risk of osteomyelitis development. Conversely, the class Bacilli, class Bacteroidia, order Bacteroidales, order Lactobacillales, family Streptococcaceae, and genus Coprococcus3 displayed an increased risk of developing osteomyelitis. The MR outcomes for these seven taxa remained stable throughout a series of sensitivity analyses.ConclusionThis study demonstrated a causal relationship between gut microbiota and osteomyelitis by Mendelian randomization. We hope that this study will provide a new direction for the treatment of osteomyelitis, which has a paucity of therapeutic options.

Abstract Background The molecular and immunological characteristics of primary tumors and positive lymph nodes in esophageal squamous cell carcinoma (ESCC) are unknown and the relationship with recurrence is unclear, which this study attempted to explore. Methods A total of 30 ESCC patients with lymph node positive (IIB‐IVA) were enrolled. Among them, primary tumor and lymph node specimens were collected from each patient, and subjected to 551‐tumor‐targeted DNA sequencing and 289‐immuno‐oncology RNA panel sequencing to identify the different molecular basis and immunological features, respectively. Results The primary tumors exhibited a higher mutation burden than lymph nodes (p

Immunoregulation and indoleamine 2,3-dioxygenase 1 (IDO1) play pivotal roles in the rejection of allogeneic organ transplantation. This study aims to elucidate the immune-related functional mechanisms of exosomes (Exos) derived from bone marrow–derived mesenchymal stem cells (BMSCs) overexpressing IDO1 in the context of allogeneic heart transplantation (HTx) rejection. A rat model of allogeneic HTx was established. Exos were extracted after transfection with oe-IDO1 and oe-NC from rat BMSCs. Exos were administered via the caudal vein for treatment. The survival of rats was analyzed, and reverse transcription qualitative PCR (RT-qPCR) and immunohistochemistry (IHC) were employed to detect the expression of related genes. Histopathological examination was conducted using hematoxylin and eosin (HE) staining, and flow cytometry was utilized to analyze T-cell apoptosis. Proteomics and RNA-seq analyses were performed on Exos. The data were subjected to functional enrichment analysis using the R language. A protein interaction network was constructed using the STRING database, and miRWalk, TargetScan, and miRDB databases predicted the target genes, differentially expressed miRNAs, and transcription factors (TFs). Exos from BMSCs overexpressing IDO1 prolonged the survival time of rats undergoing allogeneic HTx. These Exos reduced inflammatory cell infiltration, mitigated myocardial damage, induced CD4 T-cell apoptosis, and alleviated transplantation rejection. The correlation between Exos from BMSCs overexpressing IDO1 and immune regulation was profound. Notably, 13 immune-related differential proteins (Anxa1, Anxa2, C3, Ctsb, Hp, Il1rap, Ntn1, Ptx3, Thbs1, Hspa1b, Vegfc, Dcn, and Ptpn11) and 10 significantly different miRNAs were identified. Finally, six key immune proteins related to IDO1 were identified through common enrichment pathways, including Thbs1, Dcn, Ptpn11, Hspa1b, Il1rap, and Vegfc. Thirteen TFs of IDO1-related key miRNAs were obtained, and a TF-miRNA-mRNA-proteins regulatory network was constructed. Exosome miRNA derived from BMSCs overexpressing IDO1 may influence T-cell activation and regulate HTx rejection by interacting with mRNA.

Abstract Background The two-way communications along the gut-lung axis influence the immune function in both gut and lung. However, the shared genetic characteristics of lung function with gastrointestinal tract (GIT) diseases remain to be investigated. Methods We first investigated the genetic correlations between three lung function traits and four GIT diseases. Second, we illustrated the genetic overlap by genome-wide pleiotropic analysis (PLACO) and further pinpointed the relevant tissue and cell types by partitioning heritability. Furthermore, we proposed pleiotropic genes as potential drug targets by drug database mining. Finally, we evaluated the causal relationships by epidemiologic observational study and Mendelian randomization (MR) analysis. Results We found lung function and GIT diseases were genetically correlated. We identified 258 pleiotropic loci, which were enriched in gut- and lung-specific regions marked by H3K4me1. Among these, 16 pleiotropic genes were targets of drugs, such as tofacitinib and baricitinib targeting TYK2 for the treatment of ulcer colitis and COVID-19, respectively. We identified a missense variant in TYK2, exhibiting a shared causal effect on FEV1/FVC and inflammatory bowel disease (rs12720356, P PLACO =1.38 × 10− 8). These findings suggested TYK2 as a promising drug target. Although the epidemiologic observational study suggested the protective role of lung function in the development of GIT diseases, no causalities were found by MR analysis. Conclusions Our study suggested the shared genetic characteristics between lung function and GIT diseases. The pleiotropic variants could exert their effects by modulating gene expression marked by histone modifications. Finally, we highlighted the potential of pleiotropic analyses in drug repurposing.

AbstractMerkel cell carcinoma (MCC) is a primary cutaneous neoplasm of neuroendocrine carcinoma of the skin, which is characterized by molecular heterogeneity with diverse tumour microenvironment (TME). However, we are still lack knowledge of the cellular states and ecosystems in MCC. Here, we systematically identified and characterized the landscape of cellular states and ecotypes in MCC based on a machine learning framework. We obtained 30 distinct cellular states from 9 immune cell types and investigated the B cell, CD8 T cell, fibroblast, and monocytes/macrophage cellular states in detail. The functional profiling of cellular states were investigated and found the genes highly expressed in cellular states were significantly enriched in immune- and cancer hallmark-related pathways. In addition, four ecotypes were further identified which were with different patient compositions. Transcriptional regulation analysis revealed the critical transcription factors (i.e. E2F1, E2F3 and E2F7), which play important roles in regulating the TME of MCC. In summary, the findings of this study may provide rich knowledge to understand the intrinsic subtypes of MCCs and the pathways involved in distinct subtype oncogenesis, and will further advance the knowledge in developing a specific therapeutic strategy for these MCC subtypes.

AbstractPerturbation of transcriptome in viral infection patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent transcriptome and identification of robust biomarkers is not complete. In this study, we manually collected 23 datasets related to 6,197 blood transcriptomes across 16 types of respiratory virus infections. We applied a comprehensive systems biology approach starting with whole-blood transcriptomes combined with multilevel bioinformatics analyses to characterize the expression, functional pathways, and protein-protein interaction (PPI) networks to identify robust biomarkers and disease comorbidities. Robust gene markers of infection with different viruses were identified, which can accurately classify the normal and infected patients in train and validation cohorts. The biological processes (BP) of different viruses showed great similarity and enriched in infection and immune response pathways. Network-based analyses revealed that a variety of viral infections were associated with nervous system diseases, neoplasms and metabolic diseases, and significantly correlated with brain tissues. In summary, our manually collected transcriptomes and comprehensive analyses reveal key molecular markers and disease comorbidities in the process of viral infection, which could provide a valuable theoretical basis for the prevention of subsequent public health events for respiratory virus infections.

Abstract Kidney stone disease (KSD) is a complex disorder with high heritability and prevalence. We performed a large genome-wide association study (GWAS) meta-analysis for KSD to date, including 720,199 individuals with 17,969 cases in European population. We identified 44 susceptibility loci, including 28 novel loci. Cell type-specific analysis pinpointed the proximal tubule as the most relevant cells where susceptibility variants might act through a tissue-specific fashion. By integrating kidney-specific omics data, we prioritized 223 genes which strengthened the importance of ion homeostasis, including calcium and magnesium in stone formation, and suggested potential target drugs for the treatment. The genitourinary and digestive diseases showed stronger genetic correlations with KSD. In this study, we generate an atlas of candidate genes, tissue and cell types involved in the formation of KSD. In addition, we provide potential drug targets for KSD treatment and insights into shared regulation with other diseases.

Abstract Background Craniopharyngiomas are low‐grade malignancies (WHO I) in the sellar region. Most cases of childhood‐onset craniopharyngioma are adamantinomatous craniopharyngioma, and neurosurgery is the treatment of choice. Affected patients have postoperative complications, including water and electrolyte disturbances, because these malignancies develop near the hypothalamus and pituitary gland. Determining postoperative serum sodium fluctuation patterns in these patients can reduce postoperative mortality and improve prognosis. Objective To measure changes in serum sodium levels in pediatric patients who underwent craniopharyngioma surgery and identify influencing factors. Methods This retrospective study measured the serum sodium levels of 202 patients aged 0–18 years who underwent craniopharyngioma resection in Beijing Tiantan Hospital and Beijing Children's Hospital and identified predictors of severe hyponatremia and hypernatremia. Results The mean age of the cohort was 8.35 ± 4.35 years. The prevalence of hypernatremia, hyponatremia, and their severe forms (serum Na+ > 150 mmol/L and serum Na+

Background: Prior pulmonary tuberculosis (PTB) might be associated with the development of chronic obstructive pulmonary disease (COPD). However, the impact of prior PTB on the risk of incident COPD has not been studied in a large prospective cohort study of the European population. Objectives: This study aimed to investigate the association of prior PTB with the risk of COPD. Design: Prospective cohort study. Methods: A multivariable Cox proportional model was used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) for the association of prior PTB with COPD. Subgroup analyses were further conducted among individuals stratified by age, sex, body mass index, smoking status, drinking status, physical activity, and polygenic risk score (PRS). Results: The study involved a total of 216,130 participants, with a median follow-up period of 12.6 years and 2788 incident cases of COPD. Individuals with a prior history of PTB at baseline had an 87% higher risk of developing incident COPD compared to those without such history [adjusted hazard ratio (aHR) = 1.87; 95% confidence interval (CI): 1.26–2.77; p = 0.002]. Subgroup analysis revealed that individuals having prior PTB history presented a higher risk of incident COPD among individuals who were aged from 50 to 59 years with aHR of 2.47 (1.02–5.95, p = 0.044), older than 59 years with aHR of 1.81 (1.16–2.81, p = 0.008), male with aHR of 2.37 (1.47–3.83, p

Lung diseases have become a major threat to human health worldwide. Despite advances in treatment and intervention in recent years, effective drugs are still lacking for many lung diseases. As a traditional natural medicine, Tibetan medicine has had a long history of medicinal use in ethnic minority areas, and from ancient times to the present, it has a good effect on the treatment of lung diseases and has attracted more and more attention. In this review, a total of 586 Tibetan medicines were compiled through literature research of 25 classical works on Tibetan medicine, drug standards, and some Chinese and English databases. Among them, 33 Tibetan medicines have been studied to show their effectiveness in treating lung diseases. To investigate the uses of these Tibetan medicines in greater depth, we have reviewed the ethnomedicinal, phytochemical and pharmacological properties of the four commonly used Tibetan medicines for lung diseases (rhodiola, gentian, sea buckthorn, liexiang dujuan) and the five most frequently used Tibetan medicines (safflower, licorice, sandalwood, costus, myrobalan). It is expected to provide some reference for the development of new drugs of lung diseases in the future.

Vector-like leptons (VLLs) as one kind of the most intriguing particles, have been widely concerned in several extensions of the Standard Model (SM). In this work, we explore the discovery potential of VLLs via pair production in the context of models that satisfy asymptotic safety at the International Linear Collider (ILC). The expected sensitivities of the ILC with the center of mass energy s=1 TeV and the integrated luminosity L=1 ab−1 to the parameter space of this kind of VLL models are derived. The results we obtained show that, for the VLL with mass MF in the region of MF∈[101 GeV,463 GeV], the Yukawa coupling κ can be as low as κ∈[0.032,0.098].

BackgroundPseudomonas aeruginosa (PA) is a prevalent opportunistic pathogen that has close associations with both acute and chronic infections. However, there exists an insufficiency of accurate and comprehensive data pertaining to the antimicrobial susceptibility patterns and clinical characteristics of both mucoid and non-mucoid strains of PA (mPA and non-mPA, respectively).MethodsFrom January 1, 2021 to December 31, 2022, a thorough retrospective study was carried out to examine and compare the antibiotic susceptibility test outcomes and clinical characteristics of hospitalized patients with mPA and non-mPA infections.ResultsThis study investigated a cohort of 111 patients who were diagnosed with mPA infections, as well as 792 patients diagnosed with non-mPA infections. Significant demographic disparities, including gender (p

IntroductionCurrently in China, there is a lack of well-defined and viable incentive mechanisms at the governmental and hospital levels to support the development of young medical talents, thereby hindering their growth Existing studies primarily investigate the current state and trajectory of incentives, yet they inadequately address the distinctive characteristics of various stakeholders involved in medical talent incentive processes, particularly the lack of research on incentive mechanisms with Chinese attributes.MethodsThis study adopts evolutionary game theory to investigate the dynamics of replication and the strategies for achieving evolutionary stability in the comprehensive development of young medical talents, considering both scenarios with and without supportive policies.ResultsIn the absence of any supportive policy measures, the evolutionarily stable strategy (ESS) point is O(0,0), the unstable equilibrium point is C(1,1), and the saddle points are A(0,1), B(1,0). The initial state of the system is at the unstable equilibrium point C(1,1), which means that the young medical talents and medical institutions adopt a combination of strategies (actively seeking comprehensive development and taking incentive measures). Under the scenario with supportive policies, the ESS point is C(1,1), the unstable equilibrium point is O(0,0), and the saddle points are A(0,1), B(1,0). The initial state of the system is at the unstable equilibrium point O(0,0), which means that young medical talents and medical institutions adopt (N,N) strategy combinations (inactively seeking comprehensive development, implementing no incentive measure).Discussion(1) Government incentives play a crucial role in motivating young medical talents to seek comprehensive development. (2) The level of government incentive support for young medical talents should exceed the cost increment of individual efforts. Additionally, the policy support provided by the government to medical institutions should surpass the incentive support offered by these institutions to young medical talents. This will enhance the motivation and encouragement efforts of medical institutions in actively promoting comprehensive development among young medical talents. (3) With the backing of certain government incentive policies, medical institutions implementing incentive measures and young medical talents actively seeking comprehensive development will establish a virtuous cycle of mutual promotion.

Background The optimal dosages, timing, and treatment sequencing for standard-of-care neoadjuvant chemoradiotherapy necessitate re-evaluation when used in conjunction with immune checkpoint inhibitors for patients with resectable, locally advanced esophageal squamous cell carcinoma (RLaESCC). The SCALE-1 phase Ib study aimed to evaluate the safety and efficacy of short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab in this patient population.Methods RLaESCC patients with clinical stages cT3-4aN0M0/cT1-4aN+M0 received neoadjuvant paclitaxel (135 mg/m2), carboplatin (area under the curve=5), and toripalimab (240 mg) every 3 weeks for two cycles. Short-course neoadjuvant radiotherapy (30 Gy in 12 fractions; 5 days per week) was administered between neoadjuvant immune-chemotherapy (nICT) doses. Esophagectomies were scheduled 4–6 weeks after completing neoadjuvant treatment. The primary endpoint was safety, with secondary endpoints including pathological complete response (pCR) rate, postoperative complications, progression-free survival (PFS), and overall survival (OS). Exploratory biomarker analysis used gene expression profiles via the nCounter platform.Results Of the 23 patients enrolled, all completed neoadjuvant radiotherapy, while 21 cases finished full nICT doses and cycles. Common grade 3/4 adverse events included neutropenia (57%), leukopenia (39%), and skin rash (30%). No grade 3 or higher esophagitis or pneumonitis occured. Twenty patients underwent surgery, and 11 achieved pCR (55%). Two patients (10%) experienced grade IIIb surgical complications. At the database lock, a 2-year PFS rate of 63.8% (95% CI 43.4% to 84.2%) and 2-year OS rate was 78% (95% CI 64.9% to 91.1%) were achieved. Tumor immune microenvironment analysis indicated that tumors with pCR exhibited significantly higher pretreatment T-cell-inflamed score and post-treatment reshaping of antitumor immunity.Conclusions Combining short-course neoadjuvant radiotherapy with chemotherapy and toripalimab demonstrated favorable safety and promising efficacy in RLaESCC patients.Trial registration number ChiCTR2100045104.

IntroductionPseudomonas aeruginosa (P. aeruginosa) is a common pathogen associated with biofilm infections, which can lead to persistent infections. Therefore, there is an urgent need to develop new anti-biofilm drugs. DZ2002 is a reversible inhibitor that targets S-adenosylhomocysteine hydrolase and possesses anti-inflammatory and immune-regulatory activities. However, its anti-biofilm activity has not been reported yet.Methods and resultsTherefore, we investigated the effect of DZ2002 on P. aeruginosa PAO1 biofilm formation by crystal violet staining (CV), real-time quantitative polymerase chain reaction (RT-qPCR) and confocal laser scanning microscopy (CLSM). The results indicated that although DZ2002 didn’t affect the growth of planktonic PAO1, it could significantly inhibit the formation of mature biofilms. During the inhibition of biofilm formation by DZ2002, there was a parallel decrease in the synthesis of alginate and the expression level of alginate genes, along with a weakening of swarming motility. However, these results were unrelated to the expression of lasI, lasR, rhII, rhIR. Additionally, we also found that after treatment with DZ2002, the biofilms and extracellular DNA content of PAO1 were significantly reduced. Molecular docking results further confirmed that DZ2002 had a strong binding affinity with the active site of S-adenosylhomocysteine hydrolase (SahH) of PAO1.DiscussionIn summary, our results indicated that DZ2002 may interact with SahH in PAO1, inhibiting the formation of mature biofilms by downregulating alginate synthesis, extracellular DNA production and swarming motility. These findings demonstrate the potential value of DZ2002 in treating biofilm infections associated with P. aeruginosa.

Background/AimsPhaeodactylum tricornutum, a model organism of diatoms, plays a crucial role in Earth’s primary productivity. Investigating its cellular response to grazing pressure is highly significant for the marine ecological environment. Furthermore, the integration of multi-omics approaches has enhanced the understanding of its response mechanism.MethodsTo assess the molecular and cellular responses of P.tricornutum to grazer presence, we conducted transcriptomic, proteomic, and metabolomic analyses, combined with phenotypic data from previous studies. Sequencing data were obtained by Illumina RNA sequencing, TMT Labeled Quantitative Proteomics and Non-targeted Metabolomics, and WGCNA analysis and statistical analysis were performed.ResultsAmong the differentially expressed genes, we observed complex expression patterns of the core genes involved in the phenotypic changes of P.tricornutum under grazing pressure across different strains and multi-omics datasets. These core genes primarily regulate the levels of various proteins and fatty acids, as well as the cellular response to diverse signals.ConclusionOur research reveals the association of multi-omics in four strains responses to grazing effects in P.tricornutum. Grazing pressure significantly impacted cell growth, fatty acid composition, stress response, and the core genes involved in phenotype transformation.

Summary: Deficiency of DNA repair pathways drives the development of colorectal cancer. However, the role of the base excision repair (BER) pathway in colorectal cancer initiation remains unclear. This study shows that Nei-like DNA glycosylase 1 (NEIL1) is highly expressed in colorectal cancer (CRC) tissues and associated with poorer clinical outcomes. Knocking out neil1 in mice markedly suppresses tumorigenesis and enhances infiltration of CD8+ T cells in intestinal tumors. Furthermore, NEIL1 directly forms a complex with SATB2/c-Myc to enhance the transcription of COL17A1 and subsequently promotes the production of immunosuppressive cytokines in CRC cells. A NEIL1 peptide suppresses intestinal tumorigenesis in ApcMin/+ mice, and targeting NEIL1 demonstrates a synergistic suppressive effect on tumor growth when combined with a nuclear factor κB (NF-κB) inhibitor. These results suggest that combined targeting of NEIL1 and NF-κB may represent a promising strategy for CRC therapy.

Abstract Background Perioperative brain protection in older patients has been the focus of research recently; meanwhile, exploring the relationship between regional cerebral oxygen saturation (rSO2) and brain function in the perioperative period has been an emerging and challenging area—the difficulties related to the real-time monitoring of rSO2 and the choice of feasible interventions. As an advanced instrument for intraoperative rSO2 monitoring, the clinical application of near-infrared spectrum (NIRS) cerebral oxygen monitoring has gradually increased in popularity and is being recognized for its beneficial clinical outcomes in patients undergoing cardiac and noncardiac surgery. In addition, although sufficient evidence to support this hypothesis is still lacking, the effect of permissive hypercapnia (PHC) on rSO2 has expanded from basic research to clinical exploration. Therefore, monitoring intraoperative rSO2 in older patients with NIRS technology and exploring possible interventions that may change rSO2 and even improve postoperative cognitive performance is significant and clinically valuable. Methods This study is a single-center randomized controlled trial (RCT). 76 older patients are enrolled as subjects. Patients who meet the screening criteria will be randomly assigned 1:1 to the control and intervention groups. PHC-based mechanical ventilation will be regarded as an intervention. The primary outcome is the absolute change in the percent change in rSO2 from baseline to the completion of surgery in the intervention and control groups. Secondary outcomes mainly include observations of intraoperative cerebral oxygenation and metabolism, markers of brain injury, and assessments of patients' cognitive function using scale through postoperative follow-up. Discussion The findings of this RCT will reveal the effect of PHC on intraoperative rSO2 in older patients with nonacute fragile brain function (NFBF) and the approximate trends over time, and differences in postoperative cognitive function outcomes. We anticipate that the trial results will inform clinical policy decision-makers in clinical practice, enhance the management of intraoperative cerebral oxygen monitoring in older patients with comorbid NFBF, and provide guidance for clinical brain protection and improved postoperative cognitive function outcomes. Trial registration ChiCTR, ChiCTR2200062093, Registered 9/15/2022.

Abstract Binary drug combination usually targets different pathways to achieve cooperative therapy, but the exploitation of synergistic cooperativity between crystal growth modifiers that bind to the same site for preventing pathological biomineralization has yet to be realized. Here, we report that the binary inhibitor combinations of citrate with natural polyphenols can boost the inhibitory efficacy of calcium oxalate monohydrate crystallization, a primary component of kidney stones, up to four-fold greater than citrate alone. A combination of experimental and simulation techniques shows a strong synergy of four citrate-polyphenol inhibitor pairs on suppressing calcium oxalate monohydrate growth with minimal amounts of inhibitor, resulting from the reduction of growth kinetic constant paralleled with suppressing the crystallization driving force. Further, the inhibitor pairs demonstrated both in vitro and in vivo synergistic reductions of crystal-cell interactions, renal calcium oxalate deposition, and kidney injury, collectively presenting an effective therapeutic strategy for preventing calcium oxalate stones by boosting the inhibition efficacy of potent inhibitor pairs.

Abstract Background Diabetes and hyperlipidaemia are both risk factors for coronary artery disease, and both are associated with a high triglyceride-glucose index (TyG index). The TyG index has been presented as a marker of insulin resistance (IR). Its utility in predicting and detecting cardiovascular disease has been reported. However, few studies have found it to be a helpful marker of atherosclerosis in patients with symptomatic coronary artery disease (CAD). The purpose of this study was to demonstrate that the TyG index can serve as a valuable marker for predicting coronary and carotid atherosclerosis in symptomatic CAD patients, regardless of diabetes mellitus and hyperlipidaemia. Methods This study included 1516 patients with symptomatic CAD who underwent both coronary artery angiography and carotid Doppler ultrasound in the Department of Cardiology at Tianjin Union Medical Center from January 2016 to December 2022. The TyG index was determined using the Ln formula. The population was further grouped and analysed according to the presence or absence of diabetes and hyperlipidaemia. The Gensini score and carotid intima-media thickness were calculated or measured, and the patients were divided into four groups according to TyG index quartile to examine the relationship between the TyG index and coronary or carotid artery lesions in symptomatic CAD patients. Results In symptomatic CAD patients, the TyG index showed a significant positive correlation with both coronary lesions and carotid plaques. After adjusting for sex, age, smoking, BMI, hypertension, diabetes, and the use of antilipemic and antidiabetic agents, the risk of developing coronary lesions and carotid plaques increased across the baseline TyG index. Compared with the lowest quartile of the TyG index, the highest quartile (quartile 4) was associated with a greater incidence of coronary heart disease [OR = 2.55 (95% CI 1.61, 4.03)] and carotid atherosclerotic plaque [OR = 2.31 (95% CI 1.27, 4.20)] (P

Abstract Determining the diverse cell types in the tumor microenvironment (TME) and their organization into cellular communities, is critical for understanding the biological heterogeneity and therapy of cancer. Here, we deeply immunophenotype the colorectal cancer (CRC) by integrative analysis of large-scale bulk and single cell transcriptome of 2350 patients and 53,137 cells. A rich landscape of 42 cellular states and 7 ecosystems in TMEs is uncovered and extend the previous immune classifications of CRC. Functional pathways and potential transcriptional regulators analysis of cellular states and ecosystems reveal cancer hallmark-related pathways and several critical transcription factors in CRC. High-resolution characterization of the TMEs, we discover the potential utility of cellular states (i.e., Monocytes/Macrophages and CD8 T cell) and ecosystems for prognosis and clinical therapy selection of CRC. Together, our results expand our understanding of cellular organization in TMEs of CRC, with potential implications for the development of biomarkers and precision therapies.

Abstract Background MicroRNAs (miRNAs) of plasma-derived small extracellular vesicles (sEVs) have been proven to be associated with metastasis in several types of cancer. This study aimed to detect miRNAs of plasma-derived sEVs as potential biomarkers for metastatic non-small cell lung cancer (NSCLC). Methods We assessed the miRNA profiles of plasma-derived sEVs from healthy individuals as the control group (CT group), NSCLC patients without distant organ metastasis as the NM-NSCLC group and patients with distant organ metastasis as the M-NSCLC group. Next-generation sequencing (NGS) was performed on samples, and differentially expressed miRNAs (DEMs) of the three groups were screened. Kyoto Encyclopedia of Genes and Genomes (KEGG) and ClueGO were used to predict potential pathways of DEMs. MiRNA enrichment analysis and annotation tool (miEAA) was used to understand changes in the tumour microenvironment in NSCLC. Quantitative reverse transcription polymerase chain reaction (qRT‒PCR) analysis was used to validate target miRNAs. Result NGS was performed on 38 samples of miRNAs of plasma-derived sEVs, and DEMs were screened out between the above three groups. Regarding the distribution of DEMs in the NM-NSCLC and M-NSCLC groups, KEGG pathway analysis showed enrichment in focal adhesion and gap junctions and ClueGO in the Rap1 and Hippo signaling pathways; miEAA found that fibroblasts were over-represented. From our screening, miRNA-200c-3p and miRNA-4429 were found to be predictive DEMs among the CT, NM-NSCLC and M-NSCLC groups, and qRT‒PCR was applied to verify the results. Finally, it was revealed that expression levels of miR-200c-3p and miR-4429 were significantly upregulated in M-NSCLC patients. Conclusion This study identified miRNA-200c-3p and miRNA-4429 as potential biomarkers for NSCLC metastasis.

This study investigated the effects of irrigation with a fully inorganic nutrient solution (control; NNNN) and an organic instead of an inorganic nutrient solution (OIINS) at the flowering–fruit setting (ONNN), fruit expanding (NONN), color turning (NNON), and harvest (NNNO) stages of the first spike on the type and content of tomato fruit volatiles to provide a theoretical basis for tomato aroma improvement and high-quality cultivation. Compared with the control (NNNN), the results showed that all OIINS-related treatments decreased the number of fruit volatiles and increased the relative content of common volatile compounds, characteristic effect compounds, aldehydes, and cis-3-hexenal. In particular, the relative order of performance of the OIINS-related treatments was NNNO > NNON > ONNN > NONN in terms of the relative content of characteristic compounds. For all treatments, the relative cis-3-hexenal and trans-2-hexenal percentages were 20.99–51.49% and 20.22–27.81%, respectively. Moreover, hexanal was only detected in tomato fruits under the NNNN and NNNO treatments. The effects of irrigation with OIINS on tomato fruit volatiles were related to the fruit developmental stage. At the mature stage, the organic nutrient solution was conducive to the accumulation of characteristic compounds and improved the fruit aroma quality.

Abstract Background Colorectal cancer (CRC) is a fatal malignant tumor with poor prognosis. Cancer stem cells (CSCs) can cause metastasis, recurrence and drug resistance in CRC. This research aimed to analyze stemness‐related prognostic genes of CRC based on single‐cell RNA‐sequencing (scRNA‐seq) data. Methods DESeq2 was applied to analyze the differentially expressed genes (DEGs). The mRNA stemness index (mRNAsi) was calculated by one‐class logistic regression (OCLR). The stemness‐related cells were analyzed based on scRNA‐seq dataset GSE166555. Monocle 2 algorithm was used for stemness‐related cells pseudotime trajectory analysis. The stemness‐related prognostic genes were analyzed by clusterProfiler and survival package. The stemness of CRC cells was detected by spheroid formation assay, and the expression of stemness‐related prognostic genes was verified by qRT‐PCR and Western blot. Results 7916 DEGs between the CRC and normal tissues were obtained. The mRNAsi of the CRC tissues was shown to be significantly higher than that of the normal tissues. 7 and 8 cell types were annotated respectively in the normal and CRC tissues through analysis of the scRNA‐seq data. Cell–cell interactions (CCIs) in the tumor tissues were revealed to be significantly enhanced than that in the normal tissues. By calculating the ‘stemness score’, CSCs, epithelial cells (EPCs) and cancer‐associated fibroblasts (CAFs) were defined as stemness‐related cells. Through pseudotime trajectory analysis, 2111 genes were identified as state 2‐specific genes. Then, 41 genes were obtained by taking intersection of the up‐regulated genes with state 2‐specific genes and marker genes of CSCs, EPCs and CAFs. The univariate COX regression analysis revealed 5 stemness‐related prognostic genes (TIMP1, PGF, FSTL3, SNAI1 and FOXC1). Kaplan–Meier curve analysis indicated that the higher the expression of 5 genes, the lower the survival rate. In vitro cell experiment confirmed that the expression of TIMP1, PGF and SNAI1 was consistent with that revealed by bioinformatics analysis. Conclusions TIMP1, PGF and SNAI1 were identified as stemness‐related prognostic genes of CRC, and possibly potential therapeutic targets for CRC.

Duhaldea nervosa (Wallich ex Candolle) Anderberg has been widely used as medicine and food additive in China for a long history. Its roots, known as Xiaoheiyao, are the mainly used medicinal part, while the other tissues of D. nervosa are ignored as non-medicinal parts despite their high biomass, resulting in a huge waste of resources. To mine and expand the medicinal values of different parts of D. nervosa, metabolic analysis by GC/LC-MS and bioactivity evaluation were performed. Based on the antioxidant activity and correlation analysis, a metabolite-related network was constructed. A total of 45 volatile and 174 non-volatile compounds were identified. Among them, caffeoylquinic acids and derivatives were more abundant in roots and flowers, while coumaroyltartaric acids and derivatives were mainly present in stems and leaves. By multivariate analysis, 13 volatile and 37 non-volatile differential metabolites were found, respectively. In the bioactivity evaluation of different parts, the order of antioxidant capacity was flowers > roots > leaves or stems. The flowers showed the highest FRAP value (354.47 μM TE/g DW) and the lowest IC50 values in the DPPH (0.06 mg/mL) and ABTS (0.19 mg/mL) assay, while higher inhibitory activity against α-glucosidase was exhibited by flowers and leaves. This study first established the similarities and differences of phytochemicals and bioactivities in D. nervosa, providing a scientific basis for developing non-medicinal parts and guiding the clinical application of this medicinal and edible herb.

ObjectiveHypothalamic-pituitary axis dysfunction is a common complication in post-operative craniopharyngioma(CP) patients, and it greatly impacts the long-term quality of life of such patients. To better understand the effects of postoperative hypothalamic-pituitary dysfunction and long-term hormone replacement therapy in patients with childhood CP, we assessed approximately 200 patients with childhood-onset CP postoperatively.MethodsClinical details of patients with childhood-onset CP who underwent sellar tumor resection in Beijing Children’s Hospital and Beijing Tiantan Hospital from 2018 to 2019 were retrieved retrospectively. The participants were followed up to assess the effects of post-operative long-term hormone replacement therapy and assess the tumor recurrence rate.ResultsThe median age of admission was 8.1 (1.8, 14.3) years. Headache (45.5%), visual impairment (39.5%), and nausea (33.0%) were the most common clinical manifestations. ACP accounted for 95% of all CP cases. The incidence of central adrenal insufficiency and central hypothyroidism within the first week after surgery was 56.2% and 70.3%, respectively. At the same time 85.5% of the patients required at least one dose of desmopressin to control urine output. Total survival and tumor recurrence rates were 98.6% and 26.1%, respectively, with a median follow-up time of 29.7 (19.0, 40.3) months. During the follow-up period, 28.1% patients met the diagnostic criteria for short stature, while 54.4% fit the criteria for obesity. In addition, 94.4% of the patients were taking at least one kind of hormone substitution, and 74.7% were taking three or more. The prevalence of levothyroxine, glucocorticoid, desmopressin, and growth hormone replacement therapy was 87.3%, 77.5%, 78.9% and 31.0%, respectively. The proportion of patients treated with the substitutive combination of levothyroxine, hydrocortisone, and desmopressin was 54.9%.ConclusionThis study is a large-sample systematic postoperative endocrine function evaluation of patients with childhood-onset CP. Due to the high prevalence of post-operative hypothalamic-pituitary dysfunction, patients with CP usually require long-term multiple hormone substitution therapy. Individualized management and accurate hormone replacement dosage for postoperative childhood-onset CP patients are of great importance.

BackgroundPatients with advanced chronic kidney disease (CKD), end-stage kidney disease (ESKD), and kidney transplants (KT) are at an elevated risk for COVID-19 infection, hospitalization, and mortality. A comprehensive comparison of morbidity and mortality between these populations with kidney disease and individuals without any kidney disease is lacking.MethodsWe analysed the 2020 Nationwide Inpatient Sample (NIS) database for non-elective adult COVID-19 hospitalizations, categorizing patients into advanced CKD, ESKD, KT, and kidney disease-free cohorts. Our analysis included a description of the distribution of comorbidities across the entire spectrum of CKD, ESKD, and KT. Additionally, we investigated in-hospital mortality, morbidity, and resource utilization, adjusting for potential confounders through multivariable regression models.ResultsThe study included 1,018,915 adults hospitalized for COVID-19 in 2020. The incidence of advanced CKD, ESKD, and KT in this cohort was 5.8%, 3.8%, and 0.4%, respectively. Patients with advanced CKD, ESKD, and KT exhibited higher multimorbidity burdens, with 90.3%, 91.0%, and 75.2% of patients in each group having a Charlson comorbidity index (CCI) equal to or greater than 3. The all-cause in-hospital mortality ranged from 9.3% in kidney disease-free patients to 20.6% in advanced CKD, 19.4% in ESKD, and 12.4% in KT patients. After adjusting for potential confounders at both the patient and hospital levels, CKD stages 3–5; ESKD; and KT were found to be associated with increased odds of mortality, with adjusted odds ratios (aOR) of 1.34, 1.80, 2.66, 1.97, and 1.69, respectively.ConclusionPatients hospitalized for COVID-19 with advanced CKD, ESKD, or KT demonstrated a higher burden of comorbidities and increased mortality rates compared to those without kidney disease. After adjusting for confounders, CKD stages 3–5; ESKD; and KT were identified as independent risk factors for in-hospital mortality, illustrating a dose-response relationship between the odds of mortality and adverse outcomes as CKD progressed from stages 3 to 5. Our study highlights the necessity for enhanced management of comorbidities, targeted interventions, and vigorous vaccination efforts to mitigate the risk of adverse outcomes in the vulnerable populations of patients with CKD, ESKD, and KT.

In order to generate high-quality single-photon emission computed tomography (SPECT) images under low-dose acquisition mode, a sinogram denoising method was studied for suppressing random oscillation and enhancing contrast in the projection domain. A conditional generative adversarial network with cross-domain regularization (CGAN-CDR) is proposed for low-dose SPECT sinogram restoration. The generator stepwise extracts multiscale sinusoidal features from a low-dose sinogram, which are then rebuilt into a restored sinogram. Long skip connections are introduced into the generator, so that the low-level features can be better shared and reused, and the spatial and angular sinogram information can be better recovered. A patch discriminator is employed to capture detailed sinusoidal features within sinogram patches; thereby, detailed features in local receptive fields can be effectively characterized. Meanwhile, a cross-domain regularization is developed in both the projection and image domains. Projection-domain regularization directly constrains the generator via penalizing the difference between generated and label sinograms. Image-domain regularization imposes a similarity constraint on the reconstructed images, which can ameliorate the issue of ill-posedness and serves as an indirect constraint on the generator. By adversarial learning, the CGAN-CDR model can achieve high-quality sinogram restoration. Finally, the preconditioned alternating projection algorithm with total variation regularization is adopted for image reconstruction. Extensive numerical experiments show that the proposed model exhibits good performance in low-dose sinogram restoration. From visual analysis, CGAN-CDR performs well in terms of noise and artifact suppression, contrast enhancement and structure preservation, particularly in low-contrast regions. From quantitative analysis, CGAN-CDR has obtained superior results in both global and local image quality metrics. From robustness analysis, CGAN-CDR can better recover the detailed bone structure of the reconstructed image for a higher-noise sinogram. This work demonstrates the feasibility and effectiveness of CGAN-CDR in low-dose SPECT sinogram restoration. CGAN-CDR can yield significant quality improvement in both projection and image domains, which enables potential applications of the proposed method in real low-dose study.

Abstract Multi-agent multi-target search strategies can be utilized in complex scenarios such as post-disaster search and rescue by unmanned aerial vehicles. To solve the problem of fixed target and trajectory, the current multi-agent multi-target search strategies are mainly based on deep reinforcement learning (DRL). However, the training of agents by the DRL tend to be brittle due to their sensitivity to the training environment, which makes the strategies learned by the agents fall into local optima frequently, resulting in poor system robustness. Additionally, sparse rewards in DRL will lead to the problems such as difficulty in system convergence and low utilization efficiency of the sampled data. To address the problem that the robustness of the agents is weakened and the sparse rewards exist in the multi-objective search environment, we propose a MiniMax Multi-agent Deep Deterministic Policy Gradient based on the Parallel Hindsight Experience Replay (PHER-M3DDPG) algorithm, which adopts the framework of centralized training and decentralized execution in continuous action space. To enhance the system robustness, the PHER-M3DDPG algorithm employs a minimax learning architecture, which adaptively adjusts the learning strategy of agents by involving adversarial disturbances. In addition, to solve the sparse rewards problem, the PHER-M3DDPG algorithm adopts a parallel hindsight experience replay mechanism to increase the efficiency of data utilization by involving virtual learning targets and batch processing of the sampled data. Simulation results show that the PHER-M3DDPG algorithm outperforms the existing algorithms in terms of convergence speed and the task completion time in a multi-target search environment.

Objective: Establishing a simple and convenient method for the analysis of inorganic arsenic in mineral water and tea beverages. Methods: Amino-functioned polyacrylonitrile nanofibers (NH2-PAN nanofibers) was fabricated and used as adsorbent for pipette-tip solid-phase extraction (PT-SPE) of inorganic arsenic in mineral water and tea beverages followed by hydride generation-atomic fluorescence spectrometry (HG-AFS) analysis. Results: The optimal extraction conditions of pipette-tip solid phase extraction were that the pH of the sample solution was 8, the adsorbent was 12 mg NH2-PAN nanofibers, and the elution solution was 5 mL HCl with a concentration of 0.01 mol/L. Under the optimum conditions, the established method showed good linearity in the range of 0.0235~60 μg/L with correlation coefficient greater than 0.994 and a precision of less than 6%. The spiked recoveries of inorganic arsenic were above 85% for both mineral water and tea beverages at two levels of spiked concentrations. Conclusion: The established NH2-PAN nanofibers based PT-SPE/HG-AFS method is simple, accurate and expected to provide a prospective solution for the detection of inorganic arsenic.

This study sought to investigate the anti-amyloid β (Aβ) and anti-neuroinflammatory effects of catalpol in an Alzheimer’s disease (AD) mouse model. Methods: The effects of catalpol on Aβ formation were investigated by thioflavin T assay. The effect of catalpol on generating inflammatory cytokines from microglial cells and the cytotoxicity of microglial cells on HT22 hippocampal cells were assessed by real-time quantitative PCR, ELISA, redox reactions, and cell viability. APPswe/PS1ΔE9 mice were treated with catalpol, and their cognitive ability was investigated using the water maze and novel object recognition tests. Immunohistochemistry and immunofluorescence were used to probe for protein markers of microglia and astrocyte, Aβ deposits, and NF-κB pathway activity. Aβ peptides, neuroinflammation, and nitric oxide production were examined using ELISA and redox reactions. Results: Catalpol potently inhibited Aβ fibril and oligomer formation. In microglial cells stimulated by Aβ, catalpol alleviated the expression of the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and inducible nitric oxide synthase (iNOS) but promoted the expression of the anti-inflammatory cytokine IL-10. Catalpol alleviated the cytotoxic effects of Aβ-exposed microglia on HT22 cells. Treatment with catalpol in APPswe/PS1ΔE9 mice downregulated neuroinflammation production, decreased Aβ deposits in the brains and alleviated cognitive impairment. Catalpol treatment decreased the number of IBA-positive microglia and GFAP-positive astrocytes and their activities of the NF-κB pathway in the hippocampus of APPswe/PS1ΔE9 mice. Conclusion: The administration of catalpol protected neurons by preventing neuroinflammation and Aβ deposits in an AD mouse model. Therefore, catalpol may be a promising strategy for treating AD.

Summary: Meiotic crossovers are required for the faithful segregation of homologous chromosomes and to promote genetic diversity. However, it is unclear how crossover formation is regulated, especially on the XY chromosomes, which show a homolog only at the tiny pseudoautosomal region. Here, we show that ATF7IP2 is a meiosis-specific ortholog of ATF7IP and a partner of SETDB1. In the absence of ATF7IP2, autosomes show increased axis length and more crossovers; however, many XY chromosomes lose the obligatory crossover, although the overall XY axis length is also increased. Additionally, meiotic DNA double-strand break formation/repair may also be affected by altered histone modifications. Ultimately, spermatogenesis is blocked, and male mice are infertile. These findings suggest that ATF7IP2 constraints autosomal axis length and crossovers on autosomes; meanwhile, it also modulates XY chromosomes to establish meiotic sex chromosome inactivation for cell-cycle progression and to ensure XY crossover formation during spermatogenesis.

Abstract The application of single-cell RNA sequencing (scRNA-seq) in biomedical research has advanced our understanding of the pathogenesis of disease and provided valuable insights into new diagnostic and therapeutic strategies. With the expansion of capacity for high-throughput scRNA-seq, including clinical samples, the analysis of these huge volumes of data has become a daunting prospect for researchers entering this field. Here, we review the workflow for typical scRNA-seq data analysis, covering raw data processing and quality control, basic data analysis applicable for almost all scRNA-seq data sets, and advanced data analysis that should be tailored to specific scientific questions. While summarizing the current methods for each analysis step, we also provide an online repository of software and wrapped-up scripts to support the implementation. Recommendations and caveats are pointed out for some specific analysis tasks and approaches. We hope this resource will be helpful to researchers engaging with scRNA-seq, in particular for emerging clinical applications.

Abstract Background The tripartite motif (TRIM) proteins function as important regulators in innate immunity, tumorigenesis, cell differentiation and ontogenetic development. However, we still lack knowledge about the genetic and transcriptome alterations landscape of TRIM proteins across cancer types. Methods We comprehensively reviewed and characterized the perturbations of TRIM genes across > 10,000 samples across 33 cancer types. Genetic mutations and transcriptome of TRIM genes were analyzed by diverse computational methods. A TRIMs score index was calculated based on the expression of TRIM genes. The correlation between TRIMs scores and clinical associations, immune cell infiltrations and immunotherapy response were analyzed by correlation coefficients and gene set enrichment analysis. Results Alterations in TRIM genes and protein levels frequently emerge in a wide range of tumors and affect expression of TRIM genes. In particular, mutations located in domains are likely to be deleterious mutations. Perturbations of TRIM genes are correlated with expressions of immune checkpoints and immune cell infiltrations, which further regulated the cancer- and immune-related pathways. Moreover, we proposed a TRIMs score index, which can accurately predict the clinical outcome of cancer patients. TRIMs scores of patients are correlated with clinical survival and immune therapy response across cancer types. Identifying the TRIM genes with genetic and transcriptome alterations will directly contribute to cancer therapy in the context of predictive, preventive, and personalized medicine. Conclusions Our study provided a comprehensive analysis and resource for guiding both mechanistic and therapeutic analyses of the roles of TRIM genes in cancer.

Abstract Hereditary breast and ovarian cancer (HBOC) syndrome has increased predisposition to breast and/or ovarian cancer, and 24% of families with HBOC were associated with the germline pathogenic variants in BRCA1/2. Timely diagnosis and identification of mutation carriers is of utmost importance to improve survival benefit and quality of life. Cancers that have been included into screening of BRCA1/2 associated HBOC included prostate and pancreatic cancers etc. In this case, we reported a patient who firstly presented symptoms of CRC and was finally diagnosed as BRCA1 associated HBOC with advanced peritoneal carcinoma. With strategies of cetuximab based treatment and olaparib, and debulking surgeries, she has achieved an overall survival (OS) > 35 months. The aim was to indicate that HBOC might also first present as CRC, and comprehensive next-generation sequencing analysis might be a key complement for screening and diagnose of HBOC.

Context Swertia mussotii Franch. (Gentianaceae) is a source of the traditional Tibetan medicine, ZangYinChen, and is used to treat chronic hepatitis and many types of jaundice.Objective This study explored the therapeutic effects and mechanism of S. mussotii on non-alcoholic fatty liver disease in diet-induced hypercholesterolaemia.Materials and methods After a week of adaptive feeding, 32 Sprague-Dawley rats were divided into four groups: (1) Control, (2) Control-S, (3) Model, and (4) Model-S. During the 12 experimental weeks, we established the Model using a high-fat diet. Control-S and Model-S were given 1.0 g/kg S. mussotii water extract via gavage starting in the fifth week until the end of experiment.Results When compared with Model rats, the S. mussotii water extract led to a reduction in high-density lipoproteins (43.9%) and albumin (13.9%) and a decrease in total cholesterol (54.0%), triglyceride (45.6%), low-density lipoproteins (8.6%), aspartate aminotransferase (11.0%), alanine aminotransferase (15.5%), alkaline phosphatase (19.1%), total protein (6.4%), and glucose (20.8%) in serum. A reduction in three cytokines (IL-1β, IL-6, and TNFα) was detected. Histopathological examination showed that liver steatosis was significantly relieved in S. mussotii-treated high-fat diet rats. S. mussotii also caused a downregulation in the expression of TLR4 (43.2%), MyD88 (33.3%), and a decrease in phosphorylation of NF-κB.Discussion and conclusions Our findings indicate that S. mussotii may act as a potential anti-inflammation drug via inhibition of the TLR4/MyD88/NF-κB pathway. Further in vivo and in vitro studies are needed to validate its potential in clinical medicine.

Abstract Background Hybrid total hip replacement (THR) is commonly used in the management of proximal femur fractures in elderly individuals. However, in the context of the revision, the literature on hybrid THR is limited, and differences in the long-term survival outcomes reported in the literature are obvious. This retrospective study aimed to evaluate the long-term survival of hybrid THR for failed proximal femoral nail antirotation (PFNA) in elderly individuals aged ≥ 75 years. Methods An observational cohort of 227 consecutive individuals aged ≥ 75 years who experienced hybrid THRs following prior primary PFNAs was retrospectively identified from the Joint Surgery Centre, the First Affiliated Hospital, Sun Yat-sen University. Implant survival was estimated using the Kaplan–Meier method. The primary end point was the implant survivorship calculated using the Kaplan–Meier method with revision for any reason as the end point; secondary end points were the function score measured using the modified Harris Hip Score (mHHS) and the incidence of main orthopaedic complications. Results In total, 118 individuals (118 THRs) were assessed as available. The median follow-up was 10 (3–11) years. The 10-year survivorship with revision for any reason as the endpoint was 0.914 (95% confidence interval [CI], 0.843–0.960). The most common indication for revision was aseptic loosening (70.0%), followed by periprosthetic fracture (30.0%). At the final follow-up, the median functional score was 83.6 (79.0–94.0). Among the 118 patients included in this study, 16 experienced 26 implant-related complications. The overall incidence of key orthopaedic complications was 13.5% (16/118). Conclusion For patients aged ≥ 75 years old with prior failed PFNAs, hybrid THR may yield satisfactory long-term survival, with good functional outcomes and a low rate of key orthopaedic complications.

Abstract Background Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and play fundamental roles in various types of cancer. Current developments in transcriptome analyses unveiled the existence of lncRNAs; however, their functional characterization remains a challenge. Methods A bioinformatics screen was performed by integration of multiple omics data in hepatocellular carcinoma (HCC) prioritizing a novel oncogenic lncRNA, LINC01132. Expression of LINC01132 in HCC and control tissues was validated by qRT-PCR. Cell viability and migration activity was examined by MTT and transwell assays. Finally, our results were confirmed in vivo mouse model and ex vivo patient derived tumor xenograft experiments to determine the mechanism of action and explore LINC01132-targeted immunotherapy. Results Systematic investigation of lncRNAs genome-wide expression patterns revealed LINC01132 as an oncogene in HCC. LINC01132 is significantly overexpressed in tumor and associated with poor overall survival of HCC patients, which is mainly driven by copy number amplification. Functionally, LINC01132 overexpression promoted cell growth, proliferation, invasion and metastasis in vitro and in vivo. Mechanistically, LINC01132 acts as an oncogenic driver by physically interacting with NRF and enhancing the expression of DPP4. Notably, LINC01132 silencing triggers CD8+ T cells infiltration, and LINC01132 knockdown combined with anti-PDL1 treatment improves antitumor immunity, which may prove a new combination therapy in HCC. Conclusions LINC01132 functions as an oncogenic driver that induces HCC development via the NRF1/DPP4 axis. Silencing LINC01132 may enhance the efficacy of anti-PDL1 immunotherapy in HCC patients.

Abstract Background Given the unremitting growth in the volume of failed fixations of proximal femoral fractures (PFFs) in recent years, it is predictable that total hip replacements (THRs) will be the preferred surgical procedure. The long-term survival of cemented THR (CTHR) revisions remains controversial in patients aged 30–60 years. The goal of this retrospective review was to evaluate the 10-year survival of CTHRs following prior failed primary fixations of PFFs in patients aged 30–60 years. Methods We retrospectively identified CTHR revisions implemented at four medical centres during 2008–2017 for a failed primary fixation of PFFs in consecutive patients aged 30–60 years. The primary endpoint was implant survival calculated using the Kaplan–Meier method with 95% confidence intervals (CIs); secondary endpoints included functional scores assessed by Harris hip scores (HHS) and main revision-related orthopaedic complications. Follow-up was executed at 1, 2, 3, and 8 years following revision and then at 1-year intervals until the revision, death, or study deadline, whichever occurred first. Results In total, 120 patients (120 hips) who met the eligibility criteria were eligible for follow-up. The median follow-up was 10.2 years (range, 8–12 years). Kaplan–Meier survivorship showed that implant survival with revision for any reason as the endpoint was 95% at 5 years (CI: 93–97%), 89% at 8 years (CI: 86–92%), and 86% at 10 years (CI: 83–89%). Patients treated with three hollow screws had better revision-free survival than patients treated with proximal femoral nail antirotation (PFNA), dynamic hip screw (DHS) or titanium plate plus screws (three p

Single-photon emission computed tomography (SPECT) is a widely used diagnostic tool, but radioactive radiation during imaging poses potential health risks to subjects. Accurate low-dose single-photon emission computed tomography reconstruction is crucial in clinical applications of single-photon emission computed tomography. However, it remains a challenging problem due to the high noise and low spatial resolution of the low-dose reconstructed single-photon emission computed tomography images. The aim of the study is to develop a deep learning based framework for high quality low-dose single-photon emission computed tomography reconstruction. In the proposed framework, the conditional generative adversarial network (CGAN) was used as backbone structure and a Residual Attention CSwin Transformer (RACT) block was introduced as the basic building block for the generator of conditional generative adversarial network. The proposed residual attention CSwin transformer block has a dual-branch structure, which integrates the local modeling capability of CNN and the global dependency modeling capability of Transformer to improve the quality of single-photon emission computed tomography reconstructed images. More importantly, a novel loss term based on the geometric tight framelet (GTF) was designed to better suppress noise for the single-photon emission computed tomography reconstructed image while preserving the details of image to the greatest extent. Monte Carlo simulation software SIMIND was used to produce low-dose single-photon emission computed tomography images dataset to evaluate the performance of the proposed method. The simulation results showed that the proposed method can reduce more noise and preserve more details of various situations compared to several recent methods. To further validate the performance of the proposed method, we also verified the generalization ability of the proposed method, which is more adaptable to different noise level scenarios than other methods. Our results indicated that the proposed framework has the potential to reduce the tracer dose required for single-photon emission computed tomography imaging without compromising the quality of the reconstructed images.