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Abstract Pancreatic cancer is one of the most malignant tumors with the highest mortality rates, and it currently lacks effective drugs. Aptamer-drug conjugates (ApDC), as a form of nucleic acid drug, show great potential in cancer therapy. However, the instability of nucleic acid-based drugs in vivo and the avascularity of pancreatic cancer with dense stroma have limited their application. Fortunately, VNP20009, a genetically modified strain of Salmonella typhimurium, which has a preference for anaerobic environments, but is toxic and lacks specificity, can potentially serve as a delivery vehicle for ApDC. Here, we propose a synergistic therapy approach that combines the penetrative capability of bacteria with the targeting and toxic effects of ApDC by conjugating ApDC to VNP20009 through straightforward, one-step click chemistry. With this strategy, bacteria specifically target pancreatic cancer through anaerobic chemotaxis and subsequently adhere to tumor cells driven by the aptamer’s specific binding. Results indicate that this method prolongs the serum stability of ApDC up to 48 h and resulted in increased drug concentration at tumor sites compared to the free drugs group. Moreover, the aptamer’s targeted binding to cancer cells tripled bacterial colonization at the tumor site, leading to increased death of tumor cells and T cell infiltration. Notably, by integrating chemotherapy and immunotherapy, the effectiveness of the treatment is significantly enhanced, showing consistent results across various animal models. Overall, this strategy takes advantage of bacteria and ApDC and thus presents an effective synergistic strategy for pancreatic cancer treatment.

Abstract Background Recent research has indicated that parental use of central nervous system-targeting medications during periconceptional periods may affect offspring across various developmental and behavioral domains. The present study sought to investigate the potential influence of paternal use of donepezil, a specific reversible central acetylcholinesterase inhibitor that activates the cholinergic system to promote cognition, on offspring. Results In this study, male rats were bred after 21 days of oral donepezil administration at a dose of 4 mg/kg to generate F1 offspring. Both male and female F₁ offspring displayed enhanced performance in learning and short-term memory tests, including novel object recognition, Y maze, and operant learning. Transcriptomic analysis revealed notable alterations in genes associated with the extracellular matrix in the hippocampal tissue of the F1 generation. Integration with genes related to intelligence identified potential core genes that may be involved in the observed behavioral enhancements. Conclusions These findings indicate that prolonged paternal exposure to donepezil may enhance the learning and memory abilities of offspring, possibly by targeting nonneural, extracellular regions. Further research is required to fully elucidate any potential transgenerational effects.

Abstract Background Acute necrotizing encephalopathy (ANE) and myocarditis are both acute, life-threatening conditions that can be triggered by COVID-19. We report a case of sequential ANE and myocarditis following a COVID-19 infection. Case presentation A 27-year-old female patient was brought to the emergency department due to episodes of fever for two days and a 9-h altered state of consciousness. Her condition rapidly developed into stuporous and hemodynamic instability within serval hours. Veno-arterial extracorporeal membrane oxygenation (ECMO) was rapidly initiated with other supportive treatments. The following-up MRI showed bilateral, symmetrically distributed lesions in the brainstem, bilateral hippocampal regions, and bilateral basal ganglia, consistent with ANE. The diagnosis was confirmed through the detection of SARS-CoV-2 and the exclusion of other potential causes. After weeks of medical treatment, her condition stabilized, and she was transferred for further rehabilitation treatment. Conclusions This case study indicates that COVID-19 may simultaneously and rapidly affect the central nervous system and cardiovascular system, leading to poor outcomes. Accurate diagnosis and timely invasive bridging therapy, when necessary, can be lifesaving. Further exploration of potential mechanisms underlying COVID-19 central nervous system (CNS) and cardiovascular system manifestations will be important.

Purpose: This study aims to compare the effectiveness of pencil push-up training and binocular vision training in treating post-operative mild under-correction in patients with intermittent exotropia. Methods: A prospective cohort study was conducted, including patients who underwent surgery for intermittent exotropia at Children’s Hospital of Nanjing Medical University between June 2022 and January 2023 and experienced post-operative mild under-correction (-8∆ to -15∆). Patients were divided into two groups: pencil push-up training group and binocular vision training group. All patients underwent measurements of exodeviation and stereoacuity at distance and near, sensory fusion, and fusion convergence amplitude. The data were analyzed using independent sample t-tests, repeated measures analysis of variance, and Chi-square tests. Results: There were no statistically significant differences in exodeviation at distance and near between the two training groups before the training. After 6 months of training, the exodeviation at distance and near achieved a significant decrease in both groups (P < 0.05), and the pencil push-up training group showed a similar distance and near exodeviation compared to the binocular vision training group (t = 1.58, P ＞ 0.05; t = 0.43, P ＞ 0.05). After 6 months of training, the binocular vision training group exhibited significantly superior stereoacuity and fusion convergence amplitude compared to the pencil push-up training group (P < 0.001). Conclusion: Both pencil push-up training and binocular vision training are effective in reducing exodeviation in patients with post-operative mild under-correction of intermittent exotropia. However, binocular vision training demonstrates superior efficacy in restoring stereopsis and fusion convergence amplitude compared to pencil push-up training.

Summary: It has been widely recognized that the microbiota has the capacity to shape host gene expression and physiological functions. However, there remains a paucity of comprehensive study revealing the host transcriptional landscape regulated by the microbiota. Here, we comprehensively examined mRNA landscapes in mouse tissues (brain and cecum) from specific-pathogen-free and germ-free mice using nanopore direct RNA sequencing. Our results show that the microbiome has global influence on a host’s RNA modifications (m6A, m5C, Ψ), isoform generation, poly(A) tail length, and transcript abundance in both brain and cecum tissues. Moreover, the microbiome exerts tissue-specific effects on various post-transcriptional regulatory processes. In addition, the microbiome impacts the coordination of multiple RNA modifications in host brain and cecum tissues. In conclusion, we establish the relationship between microbial regulation and gene expression. Our results help the understanding of the mechanisms by which the microbiome reprograms host gene expression.

BackgroundIn recent years, there has been significant research interest in immunotherapy for colorectal cancer (CRC). Specifically, immunotherapy has emerged as the primary treatment for patients with mismatch repair gene defects (dMMR) or microsatellite highly unstable (MSI-H) who have colorectal cancer. Yet, there is currently no data to support the practicality and safety of neoadjuvant immunotherapy for colorectal cancer with dMMR or MSI-H. Therefore, a study was conducted to identify the postoperative pathology, safety profile, and imaging features of patients with dMMR or MSI-H CRC following neoadjuvant immunotherapy.MethodsThe retrospective study was carried out on patients with locally advanced or metastatic CRC who received immunotherapy at Sichuan Cancer Hospital, with approval from the hospital’s ethics committee. The study aimed to assess the short-term effectiveness of immunotherapy by focusing on pathological complete response (pCR) as the primary outcome, while also considering secondary endpoints such as objective response rate, disease-free survival, and safety profile.ResultsTwenty patients with dMMR/MSI-H CRC who underwent neoadjuvant immunotherapy as part of the treatment were enrolled between May 2019 and February 2024 at Sichuan Cancer Hospital. Out of these patients, eight patients received PD-1 blockade monotherapy as neoadjuvant treatment, while 12 were administered a combined therapy of anti-CTLA-4 and anti-PD-1. 12 patients received Nivolumab plus Ipilimumab regimen and 8 patients received PD-1 blockades (2 patients were Pembrolizumab, 2 patients were Sintilimab, 4 patients were Tislelizumab) monotherapy. Additionally, 19 patients underwent surgery after immunotherapy and of these, 15 (75.0%) achieved complete pathological response (pCR), 8 (66.7%) achieved the same on Nivolumab plus Ipilimumab immunotherapy while 7 (87.5%) achieved on PD-1 antibody monotherapy. The overall response rate (ORR) was 75%, with 45.0% of patients experiencing grade I/II immunotherapy-related adverse events. The most frequent adverse event observed was increased ALT i.e. 20%. Notably, no postoperative complications were observed.ConclusionBased on the findings, neoadjuvant immunotherapy for colorectal cancer may be both safe and effective in clinical practice. Furthermore, the study suggested that dual immunotherapy could potentially increase the immunotherapy cycle and contribute to a superior pCR rate. However, the conclusion emphasized the need for further prospective clinical trials to validate these results.

Abstract Background Ultrasound-guided percutaneous axillary vein cannulation can reduce cannulation failure and mechanical complications, is as safe and effective as internal jugular vein cannulation, and is superior to subclavian vein cannulation using landmark technique. As far, reports of venovenous extracorporeal membrane oxygenation (VV-ECMO) with percutaneous axillary vein cannulation are rare. Case presentation A 64-year-old man presenting with dyspnea and chest tightness after aspirating sewage was admitted to the emergency department. Computed tomography (CT) showed diffuse exudation of both lungs and arterial blood gas analysis showed an oxygenation index of 86. He was diagnosed with aspiration pneumonia-induced acute respiratory distress syndrome (ARDS) and intubated for deteriorated oxygenation. Despite the combination therapy of protective mechanical ventilation and prone position, the patient’s oxygenation deteriorated further, accompanied with multiple organ dysfunction syndrome, which indicated the requirement of support with VV-ECMO. However, vascular ultrasound detected multiple thrombus within bilateral internal jugular veins. As an alternative, right axillary vein was chosen as the access site of return cannula. Subsequently, femoral-axillary VV-ECMO was successfully implemented under the ultrasound guidance, and the patient’s oxygenation was significantly improved. Unfortunately, the patient died of hyperkalemia-induced ventricular fibrillation after 36 h of VV-ECMO running. Despite the poor prognosis, the blood flow during ECMO run was stable, and we observed no bleeding complication, vascular injury, or venous return disorder. Conclusions Axillary vein is a feasible alternative access site of return cannula for VV-ECMO if internal jugular vein access were unavailable.

Abstract Organic electrochemical transistors (OECTs) are of great interest in low‐power bioelectronics and neuromorphic computing, as they utilize organic mixed ionic‐electronic conductors (OMIECs) to transduce ionic signals into electrical signals. However, the poor environmental stability of OMIEC materials significantly restricts the practical application of OECTs. Therefore, the non‐fused planar naphthalenediimide (NDI)‐dialkoxybithiazole (2Tz) copolymers are fine‐tuned through varying ethylene glycol (EG) side chain lengths from tri(ethylene glycol) to hexa(ethylene glycol) (namely P‐XO, X = 3–6) to achieve OECTs with high‐stability and low threshold voltage. As a result, the NDI‐2Tz copolymers exhibit ambipolarity, rapid response (

Abstract Gut microbiota can influence host gene expression and physiology through metabolites. Besides, the presence or absence of gut microbiome can reprogram host transcriptome and epitranscriptome as represented by N6‐methyladenosine (m6A), the most abundant mammalian mRNA modification. However, which and how gut microbiota‐derived metabolites reprogram host transcriptome and m6A epitranscriptome remain poorly understood. Here, investigation is conducted into how gut microbiota‐derived metabolites impact host transcriptome and m6A epitranscriptome using multiple mouse models and multi‐omics approaches. Various antibiotics‐induced dysbiotic mice are established, followed by fecal microbiota transplantation (FMT) into germ‐free mice, and the results show that bile acid metabolism is significantly altered along with the abundance change in bile acid‐producing microbiota. Unbalanced gut microbiota and bile acids drastically change the host transcriptome and the m6A epitranscriptome in multiple tissues. Mechanistically, the expression of m6A writer proteins is regulated in animals treated with antibiotics and in cultured cells treated with bile acids, indicating a direct link between bile acid metabolism and m6A biology. Collectively, these results demonstrate that antibiotic‐induced gut dysbiosis regulates the landscape of host transcriptome and m6A epitranscriptome via bile acid metabolism pathway. This work provides novel insights into the interplay between microbial metabolites and host gene expression.

Abstract Amphibians and reptiles, especially the critically endangered Chinese alligators, are vulnerable to climate change. Historically, the decline in suitable habitats and fragmentation has restricted the distribution of Chinese alligators to a small area in southeast Anhui Province in China. However, the effects of climate change on range‐restricted Chinese alligator habitats are largely unknown. We aimed to predict current and future (2050s and 2070s) Chinese alligator distribution and identify priority conservation areas under climate change. We employed species distribution models, barycenter migration analyses, and the Marxian model to assess current and future Chinese alligator distribution and identify priority conservation areas under climate change. The results showed that the lowest temperature and rainfall seasonality in the coldest month were the two most important factors affecting the distribution of Chinese alligators. Future predictions indicate a reduction (3.39%–98.41%) in suitable habitats and a westward shift in their distribution. Further, the study emphasizes that suitable habitats for Chinese alligators are threatened by climate change. Despite the impact of the Anhui Chinese Alligator National Nature Reserve, protection gaps persist, with 78.27% of the area lacking priority protected area. Our study provides crucial data for Chinese alligator adaptation to climate change and underscores the need for improved conservation strategies. Future research should refine conservation efforts, consider individual plasticity, and address identified limitations to enhance the resilience of Chinese alligator populations in the face of ongoing climate change.

Abstract Epidemiological investigations indicate that parental drug abuse experiences significantly influenced the addiction vulnerability of offspring. Studies using animal models have shown that paternal cocaine use and highly motivated drug-seeking behavior are important determinants of offspring addiction susceptibility. However, the key molecules contributing to offspring addiction susceptibility are currently unclear. The motivation for cocaine-seeking behavior in offspring of male rats was compared between those whose fathers self-administered cocaine (SA) and those who were yoked with them and received non-contingent cocaine administrations (Yoke). We found that paternal experience with cocaine-seeking behavior, but not direct cocaine exposure, could lead to increased lever-pressing behavior in male F1 offspring. This effect was observed without significant changes to the dose-response relationship. The transcriptomes of ventral tegmental area (VTA) in offspring were analyzed under both naive state and after self-administration training. Specific transcriptomic changes in response to paternal cocaine-seeking experiences were found, which mainly affected biological processes such as synaptic connections and receptor signaling pathways. Through joint analysis of these candidate genes and parental drug-seeking motivation scores, we found that gamma-aminobutyric acid receptor subunit gamma-3 (Gabrg3) was in the hub position of the drug-seeking motivation-related module network and highly correlated with parental drug-seeking motivation scores. The downregulation of Gabrg3 expression, caused by paternal motivational cocaine-seeking, mainly occurred in GABAergic neurons in the VTA. Furthermore, down-regulating GABAergic Gabrg3 in VTA resulted in an increase in cocaine-seeking behavior in the Yoke F1 group. This down-regulation also reduced transcriptome differences between the Yoke and SA groups, affecting processes related to synaptic formation and neurotransmitter transmission. Taken together, we propose that paternal cocaine-seeking behavior, rather than direct drug exposure, significantly influences offspring addiction susceptibility through the downregulation of Gabrg3 in GABAergic neurons of the VTA, highlighting the importance of understanding specific molecular pathways in the intergenerational inheritance of addiction vulnerability.

Abstract It has been previously established that paternal development of a strong incentive motivation for cocaine can predispose offspring to develop high cocaine-seeking behavior, as opposed to sole exposure to the drug that results in drug resistance in offspring. However, the adaptive changes of the reward circuitry have not been fully elucidated. To infer the key nuclei and possible hub genes that determine susceptibility to addiction in offspring, rats were randomly assigned to three groups, cocaine self-administration (CSA), yoked administration (Yoke), and saline self-administration (SSA), and used to generate F1. We conducted a comprehensive transcriptomic analysis of the male F1 offspring across seven relevant brain regions, both under drug-naïve conditions and after cocaine self-administration. Pairwise differentially expressed gene analysis revealed that the orbitofrontal cortex (OFC) exhibited more pronounced transcriptomic changes in response to cocaine exposure, while the dorsal hippocampus (dHip), dorsal striatum (dStr), and ventral tegmental area (VTA) exhibited changes that were more closely associated with the paternal voluntary cocaine-seeking behavior. Consistently, these nuclei showed decreased dopamine levels, elevated neuronal activation, and elevated between-nuclei correlations, indicating dopamine-centered rewiring of the midbrain circuit in the CSA offspring. To determine if possible regulatory cascades exist that drive the expression changes, we constructed co-expression networks induced by paternal drug addiction and identified three key clusters, primarily driven by transcriptional factors such as MYT1L, POU3F4, and NEUROD6, leading to changes of genes regulating axonogenesis, synapse organization, and membrane potential, respectively. Collectively, our data highlight vulnerable neurocircuitry and novel regulatory candidates with therapeutic potential for disrupting the transgenerational inheritance of vulnerability to cocaine addiction.

Abstract Background Osteoarthritis (OA) is a degenerative disease related to cholesterol metabolism disorders. However, current therapies for OA are insufficient and no convincing disease-modifying OA drugs exist. Therefore, we aimed to elucidate the mechanism by which borojoa iridoid glycoside (BIG) inhibits chondrocyte apoptosis in OA. Methods Borojoa pulp was heated to 70 °C, and the main active substance in borojoa, BIG, was extracted by fractionation at an ultraviolet 254-nm absorption peak. Chondrocytes were identified by immunohistochemistry and visualized by immunofluorescence confocal microscopy. The proliferation of chondrocytes cultured with BIG was determined by MTS assay. The apoptosis of chondrocytes cultured with BIG was tested by Annexin V-FITC/PI, and the cytokine, protein, and cholesterol levels in chondrocytes were detected by ELISA, RT‒qPCR, Western blot, and biochemistry analyses. Protein‒protein interactions were verified by a coimmunoprecipitation (Co-IP) assay. Results BIG promoted chondrocyte proliferation and reduced apoptosis in vitro. BIG induced an alteration of the total RNA profiles in chondrocytes, and bioinformatic analysis showed that BIG inhibited chondrocyte apoptosis by promoting c-MYC expression; KEGG analysis confirmed that BIG-inhibited apoptosis was enriched in the cell cycle pathway. Flow cell cycle experiments confirmed that BIG promoted chondrocyte proliferation by significantly increasing the S phase cell number. The c-MYC inhibitor 10058-F4 stimulated the increased expression of IL-1β, IL-6, TNF-α, and AGEs and suppressed the cholesterol metabolism, which promoted chondrocyte apoptosis and autophagy. Co-IP analysis showed that BIG promoted the interaction of c-MYC and CH25H, Bcl-2, which suggests that BIG could inhibit chondrocyte apoptosis in part by enhancing c-MYC-mediated cholesterol metabolism. Conclusions This study confirmed that BIG promotes chondrocyte proliferation and inhibits apoptosis and autophagy, and BIG improving OA is associated with cholesterol metabolism. The results identify a potential mechanism by which BIG enhances c-MYC-mediated CH25H regulation of cholesterol metabolism in vitro and suggest that BIG might be a promising new drug against OA.

Abstract Background There are few studies comparing robotic-assisted surgery (RAS) and laparoscopic-assisted surgery (LAS) in Hirschsprung’s disease (HSCR). This study aimed to compare intraoperative and postoperative outcomes between RAS and LAS performed during the same period. Methods All consecutive 75 patients with pathologically diagnosed as HSCR who underwent Swenson pull-through surgery from April 2020 to Nov 2022, were included. Patients were divided into RAS group and LAS group and a retrospective analysis was performed based on clinical indexes and prognosis. Results A total of 75 patients were included, among which, 31 patients received RAS and 44 received LAS. The RAS and LAS groups had similar ages, sex, weight, postoperative hospital stays, and fasting times. Compared with LAS, blood loss (p = 0.002) and the incidence of Hirschsprung-associated enterocolitis (p = 0.046) were significantly lower in the RAS group. The first onset of Hirschsprung-associated enterocolitis in patients younger than 3 months occurred significantly earlier (p = 0.043). Two patients experienced anastomotic leakage in the LAS group and one patient experienced incisional hernia in the RAS group. The cost of RAS was significantly higher than that of LAS (p 3 months) may improve outcomes.

Abstract The rising prevalence of metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM) poses a major challenge to global health. Existing therapeutic approaches have limitations, and there is a need for new, safe, and less invasive treatments. Interventional metabolic therapy is a new addition to the treatment arsenal for metabolic disorders. This review focuses on two interventional techniques: bariatric arterial embolization (BAE) and endovascular denervation (EDN). BAE involves embolizing specific arteries feeding ghrelin‐producing cells to suppress appetite and promote weight loss. EDN targets nerves that regulate metabolic organs to improve glycemic control in T2DM patients. We describe the current state of these techniques, their mechanisms of action, and the available safety and effectiveness data. We also propose a new territory called “Interventional Metabology” to encompass these and other interventional approaches to treating metabolic disorders.

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.

IntroductionDuring the de-escalation phase of circulatory shock, norepinephrine weaning may induce diverse arterial pressure responses in patients with different vasomotor tones. Dynamic arterial elastance (Eadyn) has been extensively studied to predict the arterial pressure response to interventions. We conducted this meta-analysis to systematically assess the predictive performance of Eadyn for the mean arterial pressure (MAP) response to norepinephrine weaning in mechanically ventilated patients with vasoplegic syndrome.Materials and methodsA systematic literature search was conducted on May 29, 2023 (updated on January 21, 2024), to identify relevant studies from electronic databases. The area under the hierarchical summary receiver operating characteristic curve (AUHSROC) was estimated as the primary measure of diagnostic accuracy because of the varied thresholds reported. Additionally, we observed the distribution of the cutoff values of Eadyn, while computing the optimal value and its corresponding 95% confidential interval (CI).ResultsA total of 5 prospective studies met eligibility, comprising 183 participants, of whom 67 (37%) were MAP responders. Eadyn possessed an excellent ability to predict the MAP response to norepinephrine weaning in patients with vasoplegic syndrome, with an AUHSROC of 0.93 (95% CI: 0.91–0.95), a pooled sensitivity of 0.94 (95% CI: 0.85–0.98), a pooled specificity of 0.73 (95% CI: 0.65–0.81), and a pooled diagnostic odds ratio of 32.4 (95% CI: 11.7–89.9). The cutoff values of Eadyn presented a nearly conically symmetrical distribution; the mean and median cutoff values were 0.89 (95% CI: 0.80–0.98) and 0.90 (95% CI: not estimable), respectively.ConclusionsThis meta-analysis with limited evidences demonstrates that Eadyn may be a reliable predictor of the MAP response to norepinephrine weaning in mechanically ventilated patients with vasoplegic syndrome.Systematic Review RegistrationPROSPERO CRD42023430362.

Abstract Erlotinib, an EGFR tyrosine kinase inhibitor, is used for treating patients with cancer exhibiting EGFR overexpression or mutation. However, the response rate of erlotinib is low among patients with gastric cancer (GC). The findings of this study illustrated that the overexpression of bromodomain PHD finger transcription factor (BPTF) is partially responsible for erlotinib resistance in GC, and the combination of the BPTF inhibitor AU‐1 with erlotinib synergistically inhibited tumor growth both in vivo and in vitro. AU‐1 inhibited the epigenetic function of BPTF and decreased the transcriptional activity of c‐MYC on PLCG1 by attenuating chromosome accessibility of the PLCG1 promoter region, thus decreasing the expression of p‐PLCG1 and p‐Erk and eventually improving the sensitivity of GC cells to erlotinib. In patient‐derived xenograft (PDX) models, AU‐1 monotherapy exhibited remarkable tumor‐inhibiting activity and is synergistic anti‐tumor effects when combined with erlotinib. Altogether, the findings illustrate that BPTF affects the responsiveness of GC to erlotinib by epigenetically regulating the c‐MYC/PLCG1/pErk axis, and the combination of BPTF inhibitors and erlotinib is a viable therapeutic approach for GC.

Abstract Objective The aim of this study is to evaluate the Chinese Version of the Tinnitus Primary Function Questionnaire (TPFQ). Methods One hundred and sixteen patients who had been suffering from tinnitus for over 3 months were included in this study. Those tinnitus patients were administered the TPFQ, the Tinnitus Handicap Inventory (THI), the Beck Anxiety Inventory (BAI), the Beck Depression Inventory (BDI), and the Pittsburgh Sleep Quality Index (PSQI). Additionally, the magnitude estimate of tinnitus loudness, pure tone audiogram, and tinnitus matching was obtained. The factor structure was measured using the Kaiser–Meyer–Olkin test. The internal consistency was examined using Cronbach's α coefficient. The relationships between the TPFQ scores and other measurements were compared using Spearman's rank correlation coefficient. Results The Cronbach's α of the 20‐item version of TPFQ was 0.94, and that of the 12‐item version of TPFQ was 0.92. Both the 20‐ and 12‐item versions of TPFQ were significantly correlated with magnitude estimation of tinnitus loudness, THI, PSQI, BDI, and BAI. The average pure tone hearing threshold was significantly correlated with the hearing subscale. Conclusion The 20‐ and 12‐item Chinese versions of TPFQ are reliable and valid measures of tinnitus. The TPFQ can be applied to the assessment and management of tinnitus among the Chinese‐speaking population.

Abstract The accurate delineation of the spatial extent of cold regions provides the basis for the study of global environmental change. However, attention has been lacking on the temperature-sensitive spatial changes in the cold regions of the Earth in the context of climate warming. In this study, the mean temperature in the coldest month lower than − 3 °C, no more than 5 months over 10 °C, and an annual mean temperature no higher than 5 °C were selected to define cold regions. Based on the Climate Research Unit land surface air temperature (CRUTEM) of monthly mean surface climate elements, the spatiotemporal distribution and variation characteristics of the Northern Hemisphere (NH) continental cold regions from 1901 to 2019 are analyzed in this study, by adopting time trend and correlation analyses. The results show: (1) In the past 119 years, the cold regions of the NH covered on average about 4.074 × 107 km2, accounting for 37.82% of the total land area of the NH. The cold regions can be divided into the Mid-to-High latitude cold regions and the Qinghai-Tibetan Plateau cold regions, with spatial extents of 3.755 × 107 km2 and 3.127 × 106 km2, respectively. The Mid-to-High latitude cold regions in the NH are mainly distributed in northern North America, most of Iceland, the Alps, northern Eurasia, and the Great Caucasus with a mean southern boundary of 49.48° N. Except for the southwest, the entire region of the Qinghai-Tibetan Plateau, northern Pakistan, and most of Kyrgyzstan are cold regions. (2) In the past 119 years, the rates of change in the spatial extent of the cold regions in the NH, the Mid-to-High latitude, and the Qinghai-Tibetan Plateau were − 0.030 × 107 km2/10 a, − 0.028 × 107 km2/10 a, and − 0.013 × 106 km2/10 a, respectively, showing an extremely significant decreasing trend. In the past 119 years, the mean southern boundary of the Mid-to-High latitude cold regions has been retreating northward at all longitudes. For instance, the mean southern boundary of the Eurasian cold regions moved 1.82° to the north and that of North America moved 0.98° to the north. The main contribution of the study lies in the accurate definition of the cold regions and documentation of the spatial variation of the cold regions in the NH, revealing the response trends of the cold regions to climate warming, and deepening the study of global change from a new perspective.

Currently, impacts of rapid cropland reclamation and its intense structural changes in internal paddy-upland on ecosystem service are insufficient in Sanjiang Plain, China. Further, land management systems of Sanjiang Plain consist of state-owned and private farms; however, exploring the impact of different land management systems on “land use–landscape–ecosystem service” is still lacking. To reveal this issue, the integrated methodology of “land dynamic tracking–landscape index–improved ecosystem service assessment” was established. Results are displayed below: From 1990 to 2020, land use was featured by decreases in forest (−3308.62 km2), grassland (−6030.86 km2), waters (−475.81 km2), and unused land (−3037.27 km2), with a slight increase in constructed land (+403.25 km2) and a rapid increase in cropland (+12,447.56 km2). Although nearly equal increments of cropland on state-owned and private farms (i.e., 6156.70 km2 vs. 6290.86 km2) were monitored, different cropland structure changes were still revealed, namely a drastic expansion of paddy fields (13,788.32 km2) and an acute decrease in upland crops (−7631.62 km2) on state-owned farms, but both a slight increments in paddy fields (5920.08 km2) and upland crops (370.78 km2) on private farms. For landscape, private farms were more fragmented (SHDI = +0.63%), causing a decrease in aggregation (AI = −0.56%) and a more complex shape (LSI = +23.3%), by contrast, state-owned farms displayed an increased integrity (SHDI = −9.88%), along with an increase in aggregation (AI = +0.43%) and simplified shape (LSI = −13.30%). Evaluated ecosystem service value changed from 338.62 to 296.25 billion yuan from 1990 to 2020, a loss rate of 12.58% in Sanjiang Plain. Then, a new finding showed a higher loss rate on state-owned than private farms (i.e., 30.15% vs. only 6.18%). This study revealed differentiated processes of “land use–landscape–ecosystem service” in different land management system regions in China, providing new findings in the fields of land management system, ecological landscape, and environment.

Evodia rutaecarpa, the near-ripe fruit of Euodia rutaecarpa (Juss.) Benth, Euodia rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang, or Euodia rutaecarpa (Juss.) Benth. var. bodinieri (Dode) Huang, is a famous herbal medicine with several biological activities and therapeutic values, which has been applied for abdominalgia, abdominal distension, vomiting, and diarrhea as a complementary and alternative therapy in clinic. Indole alkaloids, particularly evodiamine (EVO), rutaecarpine (RUT), and dedhydroevodiamine (DHE), are received rising attention as the major bioactivity compounds in Evodia rutaecarpa. Therefore, this review summarizes the physicochemical properties, pharmacological activities, pharmacokinetics, and therapeutic effects on gastrointestinal diseases of these three indole alkaloids with original literature collected by PubMed, Web of Science Core Collection, and CNKI up to June 2023. Despite sharing the same parent nucleus, EVO, RUT, and DHE have different structural and chemical properties, which result in different advantages of biological effects. In their wide range of pharmacological activities, the anti-migratory activity of RUT is less effective than that of EVO, and the neuroprotection of DHE is significant. Additionally, although DHE has a higher bioavailability, EVO and RUT display better permeabilities within blood-brain barrier. These three indole alkaloids can alleviate gastrointestinal inflammatory in particular, and EVO also has outstanding anti-cancer effect, although clinical trials are still required to further support their therapeutic potential.

Retail banking is undergoing considerable product competitiveness and disruptions. New product development is necessary to tackle such challenges and reinvigorate product lines. This study presents an instrumental real-life banking case study, where marketing analytics was utilized to drive a product differentiation strategy. In particular, the study applied unsupervised machine learning techniques of link analysis, latent class analysis, and association analysis to undertake behavioral-based market segmentation, in view of attaining a profitable competitive advantage. To underpin the product development process with well grounded theoretical framing, this study asked the research question: “How may we establish a theory-driven approach for an analytics-driven process?” Findings of this study include a theoretical conceptual framework that underpinned the end-to-end segmentation-driven new product development process, backed by the empirical literature. The study hopes to provide: (i) for managerial practitioners, the use of case-based reasoning for practice-oriented new product development design, planning, and diagnosis efforts, and (ii) for researchers, the potentiality to test of the validity and robustness of an analytical-driven NPD process. The study also hopes to drive a wider research interest that studies the theory-driven approach for analytics-driven processes.

Approximately 20% of concentrate will be produced from coal gasification wastewater after reverse osmosis treatment. The organic matter contained in the concentrate affects its evaporation crystallisation; therefore, the refractory organics must be removed. In this study, Cu-Co-Mn/AC catalytic ozonation was used to treat reverse osmosis concentrate (ROC). With the addition of the Cu-Co-Mn/AC catalyst, the production of ·OH increased by 82 μmol/L, thereby enhancing the ozonation performance. The pH, ozone dosage, and catalyst dosage all affected the catalytic ozonation performance. By constructing a response surface model, it was found that the catalyst dosage had the most significant effect on the catalytic ozonation performance. The predicted optimal reaction conditions were pH = 9.02, ozone dosage = 1.08 g/L, and catalyst dosage = 1.33 g/L, under which the chemical oxygen demand (COD) removal reached a maximum of 81.49%. HIGHLIGHTS The Cu-Co-Mn/activated carbon catalyst enhanced the ozonation efficiency for treating reverse osmosis concentrate (ROC).; The removal of COD from ROC by catalytic ozonation could be about 80%.; A response surface model was established to determine the operating parameters of catalytic ozonation.;

A computational pipeline and webserver identify regulators of RNA-binding proteins (RBPs) at single-cell resolution and are applied to determine the role of RBP HNRNPK in cancer.

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.

Background To analyze the correlation between the inducing effect of Fusobacterium nucleatum (Fn) on the surface expression of the inhibitory receptor KIR2DL1 on CD8+ T cells in oesophageal squamous cell carcinoma (ESCC) and the clinicopathological features and survival prognosis and to explore its clinical significance. Methods The inducing effect of Fn on CD8+ T cell surface inhibitory receptor KIR2DL1 expression was analyzed in a coculture system of human CD8+ T cells and ESCC cells infected with Fn. Fn infection and the expression of KIR2DL1 on CD8+ T cells were detected by RNAscope and immunohistochemistry in ESCC tissues, and the correlations between the inducing effect of Fn on KIR2DL1 expression on CD8+ T cells and clinicopathological features were analyzed. COX regression was used to analyze the influence of each factor on the prognosis of ESCC. Survival curves were plotted by the Kaplan–Meier method, and the effect of KIR2DL1 induction on survival time was analyzed by the log-rank test. Results In the coculture system, KIR2DL1 expression on the surface of CD8+ T cells increased with increasing Fn infection time. In ESCC tissues, Fn infection was significantly correlated with high KIR2DL1 expression on CD8+ T cells. The Fn + CD8+KIR2DL1 positive patients were predominantly males who were smokers and alcohol drinkers. Moreover, patients with Fn infection were characterized by poor tumour differentiation, advanced clinical stage, and a short survival time. Meanwhile, Fn + CD8+KIR2DL1 positive group was independent risk factor affecting the prognosis of ESCC patients. Conclusions Long-term drinking and smoking lead to an extremely unhealthy oral environment in which Fn infection and colonization are more likely to occur, thus inducing high expression of KIR2DL1 on the surface of CD8+ T cells, which can weaken the antitumour immune response and promote the malignant progression of ESCC.HIGHLIGHTS Fn induced high expression of KIR2DL1 CD8+ T cells in a time-dependent manner. Fn can reduce the response of tumour cells to CDDP. The inducing effect of Fn on CD8+ T cell surface KIR2DL1 expression was significantly associated with the poor prognosis of ESCC patients.

Context The potential anti-inflammatory bioactivities of β-hydroxyisovalerylshikonin (β-HIVS) remain largely unknown.Objective This study investigated the anti-inflammatory effects and underlying mechanisms of β-HIVS.Materials and methods RAW 264.7 cells stimulated with LPS (100 ng/mL) for 24 h were treated with the non-cytotoxic doses of β-HIVS (0.5 or 1 μM, determined by MTT and Trypan blue staining), qRT-PCR and FCM assay were used to examine macrophage polarization transitions. Western blotting was used to evaluate the activation of the AMPK/Nrf2 pathway. In vivo, C57BL/6 mice were randomly divided into vehicle control, LPS (10 mg/kg), and β-HIVS (2.5 mg/kg) combined with LPS (10 mg/kg) groups, blood samples, BALF, and lung tissues of mice were subjected to ELISA, qRT-PCR, FCM, and H&E staining.Results β-HIVS (1 μM) inhibited LPS-induced expression of M1 macrophage markers (TNF-α: 0.29-fold, IL-1β: 0.32-fold), promoted the expression of M2 macrophage markers (CD206: 3.14-fold, Arginase-1: 3.98-fold) in RAW 264.7 cells; mechanistic studies showed that β-HIVS increased the expression of nuclear Nrf2 (2.04-fold) and p-AMPK (3.65-fold) compared with LPS group (p

Abstract In breast conserving surgery (BCS), specimen mammography is one of the most widely used intraoperative methods of assessing margin status. We performed a meta-analysis to evaluate the diagnostic accuracy of specimen mammography. Literature databases including PubMed, Cochrane Library, Web of Science, and EMBASE were searched prior to Jun 2022. A total of 1967 patients were included from 20 studies. A pooled analysis, heterogeneity testing, threshold effect testing, publication bias analysis, and subgroup analyses were performed from extracted data. The pooled weighted values were a sensitivity of 0.55 (95% confidence interval [CI], 0.47–0.63), a specificity of 0.85 (95% CI, 0.78–0.90), a diagnostic odds ratio of 7 (95% CI, 4–12), and a pooled positive likelihood ratio of 3.7 (95% CI 2.6–5.5). The area under the receiver operator characteristic curve was 0.75 (95% CI 0.71–0.78). In the subgroup analysis, the pooled specificity in the positive margin defined as tumor at margin subgroup was lower than the other positive margin definition subgroup (0.82 [95% CI: 0.71, 0.92] vs. 0.87 [95% CI: 0.80, 0.94], p = 0.01). Our findings indicated that specimen mammography was an accurate intraoperative imaging technique for margin assessment in BCS.

Evaluating actual crop evapotranspiration (ETc) variations and their determining factors under changing climates is crucial for agricultural irrigation management and crop productivity improvement in non-humid regions. This study analyzed the spatiotemporal characteristics and detected the determining factors of ETc for winter wheat and summer maize rotation system from 2000 to 2017 in the North China Plain (NCP), by combining the FAO-56 dual crop coefficient approach with remotely sensed vegetation indices (VIs). The results indicated that daily air temperature increased in varying degrees while wind speed and sunshine hours decreased slightly during the growing season of winter wheat and summer maize over the study period. The trends of relative humidity and effective precipitation varied in crop growing seasons. Based on the validated relationship of dual crop coefficients and VIs, the estimated multi-year average ETc of winter wheat (370.29 ± 31.28 mm) was much higher than summer maize (281.85 ± 20.14 mm), and the rotation cycle was 652.43 ± 27.67 mm. Annual ETc of winter wheat and the rotation cycle increased by 2.96 mm a−1 and 1.77 mm a−1, respectively. However, the ETc of summer maize decreased with distinct spatial variation. Spatially, winter wheat ETc increased significantly in the northeast NCP, covering the Beijing-Tianjin-Hebei areas. Meanwhile, significant increases in summer maize ETc were detected in the southwest NCP. The sensitivity and contribution analysis showed that ETc of winter wheat and summer maize was positively sensitive to temperature, wind speed, and sunshine hours while negatively to relative humidity. Moreover, wind speed and sunshine hours contributed most to changes in ETc (around 20%–40%).

Abstract Background Toxicological problem associated with herbal medicine is a significant public health problem. Hence, it is necessary to elaborate on the safety of herbal medicine. Salvianolic acid A (SAA) is a major active compound isolated from Danshen, a popular herbal drug and medicinal food plant in China. The aim of the present study was to explore the toxicological profile of SAA. Methods The acute toxicity studies were performed in mice and Beagle dogs with single administration with SAA. A 4-week subchronic toxicity was test in dogs. SAA was intravenously administered at doses of 20, 80 and 300 mg/kg. Clinical observation, laboratory testing and necropsy and histopathological examination were performed. The genotoxic potential of SAA was evaluated by 2 types of genotoxicity tests: a reverse mutation test in bacteria and bone marrow micronucleus test in mice. Results In acute toxicities, the LD50 of SAA is 1161.2 mg/kg in mice. The minimum lethal dose (MLD) and maximal non-lethal dose (MNLD) of SAA were 682 mg/kg and 455 mg/kg in dogs, respectively. The approximate lethal dose range was 455–682 mg/kg. In the study of 4-week repeated-dose toxicity in dogs, focal necrosis in liver and renal tubular epithelial cell, the decrease in relative thymus weight, as well as abnormal changes in biochemical parameters, were observed in SAA 80 or 300 mg/kg group. The no observed adverse effect level (NOAEL) of SAA was 20 mg/kg. Thymus, liver and kidneys were the toxic targets. These toxic effects were transient and reversible. These results indicated that it should note examination of liver and kidney function during the administration of SAA in clinic. Furthermore, SAA had no mutagenic effect at any tested doses. Conclusion These results provide new toxicological information of SAA for its clinical application and functional food consumption.

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.

Ferroptosis, as a novel-induced programmed cell death, plays critical roles in the pathogenesis of cancers. However, the promising biomarkers of ferroptosis in gastrointestinal stromal tumor (GIST) remain to be elucidated. Herein, the expression of ferroptosis-related genes was analyzed in GIST. Among the 64 ferroptosis-related genes, transferrin receptor (TFRC) expression presented a remarkable upregulation in high-risk patients through Gene Expression Omnibus (GEO) dataset analysis, as well as its significant change after imatinib was treated. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of TFRC-relevant genes revealed that TFRC expression was closely associated with cell growth pathways and metabolism-related pathways. Furthermore, patients at high risk of recurrence were more likely to exhibit high TFRC expression by immunohistochemistry. Additionally, high TFRC expression indicated an undesirable state of patient relapse, which could serve as a powerful significant independent predictor of recurrence-free survival (RFS). In summary, we systematically summarize the expression characteristics and clinical relevance of TFRC and show that TFRC can be used as a prognostic factor, which can be considered a potential therapeutic target in GIST.

A 64-year-old man presented with headache and dizziness. A vertebrobasilar dissecting aneurysm was identified via computed tomography angiography and high resolution magnetic resonance imaging. Perioperatively, standard oral dual antiplatelet drugs were given. Two flow diverters were telespcoped for endovascular treatment of the aneurysm. Postoperatively, there were no signs of cerebral infarction and no new symptoms. At the 6-month follow-up, digital subtraction angiography showed that the aneurysm was almost completely occluded, with no other complications. This case serves as a reference for using the multiple telescoping flow diverter technique to treat vertebrobasilar dissecting aneurysm.

Introduction: A growing body of evidence suggests that parental substance abuse, even prior to conception, may induce phenotypic changes in offspring. Parental opioid exposure has been shown to affect developmental processes, induce memory deficits, and lead to psycho-emotional disorders in offspring. However, how parental, especially paternal, chronic drug exposure affects offspring remains unexplored.Methods: Adult male rats were subjected to 31 days of heroin self-administration followed by mating with naïve females. Litter size and body weight of F1 offspring were recorded. Object-based attention tests, cocaine self-administration tests, and hot plate tests were used to test for potential effects of chronic paternal heroin seeking on cognition, reward, or analgesic sensitivity in the offspring.Results: Body weight and litter size of the heroin F1 generation were not altered compared to the saline F1 generation. Furthermore, paternal chronic heroin self-administration experience had no significant effect on object-based attention tests or cocaine self-administration behavior in either sex. However, in the hot plate test, although no difference in basal latency was found between the two groups in either sex, a significant increase in the analgesic effect of heroin was observed in the male heroin F1 generation.Conclusions: Taken together, these data provide evidence that paternal chronic heroin self-administration experience could sex-dimorphically increase the analgesic effect of heroin in male offspring, but had no significant effect on response to cocaine reinforcement or attentional behavior.

In this paper, a completely new numerical method, named Finite Line Method (FLM), is proposed for solving general linear and non-linear high-order partial differential equations (PDEs) in science as well as engineering problems in heat conduction and mechanics. In this method, the computational domain is discretized into a number of collocation points as in the free element method (Gao et al., 2019; Liu et al., 2019), and at each collocation point a set of straight or curved lines crossing the point is formed, which is represented by a number of nodes distributed over lines. The shape functions for each line are constructed using the Lagrange interpolation formulation and the first and high order spatial partial derivatives of the shape functions with respect to global coordinates are derived through an ingenious technique. The derived partial derivatives can be directly substituted into the governing differential equations and related boundary conditions to set up the discretized system of equations.FLM is a type of collocation method, not needing any integration to establish the solution scheme. And since the Lagrange interpolation formulation is used to construct the shape functions, arbitrarily high order lines can be easily formulated for solving any types of linear and non-linear high order PDEs and engineering problems. A number of numerical examples for PDEs, heat conduction and solid mechanics problems are given to demonstrate the correctness and stability of the proposed method.

Abstract Background We report a rare case of Gardnerella vaginalis found in the cerebrospinal fluid of a young boy. Case presentation A 14-year-old boy was admitted to hospital with headache, vomiting, fever, drowsiness and positive meningeal irritation signs on examination. Cerebrospinal fluid (CSF) shows white blood cell and protein were elevated, and glucose was low. Traditional aerobic and anaerobic culture of CSF did not grow any organisms. However, metagenomic next-generation sequencing (mNGS) reveals G. vaginalis in his CSF. The patient was diagnosed with purulent meningitis, and treated with intravenous meropenem and linezolid for a week, followed by oral administration of amoxicillin for two weeks. He recovered without sequelae. Conclusions Purulent meningitis caused by Gardnerella vaginalis is extremely rare. Metagenomic next-generation sequencing of CSF should be highlighted for early diagnosis. With effective antibiotic treatment, the prognosis was excellent.

Abstract Background Semaphorins have been found to play important roles in multiple malignancy-related processes. However, the role of Semaphorin 4B (SEMA4B) in lung cancer remains unclear. Here, we aimed to explore the biological functions of SEMA4B in through bioinformatic analysis, in vitro and in vivo assays. In the present study, the possible mechanism by which SEMA4B affected the tumor growth and microenvironment of lung adenocarcinoma (LUAD) were investigated. Methods The expression of SEMA4B in LUAD was analyzed by bioinformatic analysis and verified by the immunohistochemistry staining. The prognostic value of SEMA4B in LUAD was investigated using the Kaplan-Meier survival and Cox’s regression model. After silencing SEMA4B expression, the functions of SEMA4B in LUAD cells were investigated by in vitro experiments, including CCK-8 and plate clone formation. And the effect of SEMA4B on tumor growth and immune infiltration was explored in C57BL/6 mice tumor-bearing models. Results SEMA4B expression was upregulated in LUAD tissues and correlated with later pathological stages and poor prognosis of LUAD patients. Further study found that SEMA4B silencing suppressed the proliferation of lung cancer cells both in vitro and in vivo. Bioinformatic analysis showed that SEMA4B expression was correlated with the increased infiltration of myeloid-derived suppressor cells (MDSCs), T-regs and the decreased infiltration of CD8+ T cell in LUAD. Importantly, in vivo study verified that the infiltration of T-regs and MDSCs in tumor microenvironment (TME) of Xenograft tissues was decreased after SEMA4B silencing. Conclusions These findings demonstrated SEMA4B might play an oncogenic role in LUAD progression, and be a promising therapeutic target for lung cancer.

Abstract In order to realize the comprehensive utilization of multiple energy sources in renewable energy ships and improve the utilization rate of renewable energy and system economy, this paper studies the matching and optimization of renewable energy power generation system and ship power system. Firstly, the structure of renewable energy ship power system is introduced. Considering the natural conditions and the actual situation of the ship for the first time, the wind power generation, photovoltaic power generation and energy storage devices are configured in the ship power system. The objective function including system annual average cost and system reliability index is established. The constraint conditions are determined, and the system energy scheduling strategy is proposed. Then, the influence of the introduction of renewable energy generation system and energy storage device on the ship power system is analyzed. Finally, particle swarm optimization and improved algorithm are used to optimize and solve the configuration problem. The relationship between the loss of power supply probability and energy excess percentage in ship power system is analyzed for the first time, which provides a reference for the optimal allocation scheme of actual ship. The results are helpful to improve the economy and system reliability of renewable energy ships.

Abstract The gut microbiota of amphibians plays a crucial role in maintaining health and adapting to various developmental stages. The composition of gut microbial community is influenced by the phylogeny, habitat, diet, and developmental stage of the host. The present study analyzed the microbiota in the intestine of O. tormota at 11 developmental stages (from the tadpole at Gosner stage 24 to the 3‐year‐old adult) using high‐throughput 16S rRNA sequencing. Alpha diversity index analysis of the microbiota revealed that the index decreased from tadpole at Gosner stage 24 to adult frog stage, remained stable during the adult frog stages, but increased significantly at the early metamorphosis and hibernation preparation stages. The gut microbiota structure is similar in adult frogs but differs significantly in other developmental stages. Furthermore, the dominant phyla of gut microbiota in tadpoles were Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes, whereas those in adult frogs were Proteobacteria, Firmicutes, Bacteroidetes, and Verrucomicrobia. Host and environmental factors jointly affected the gut microbial diversity and community composition of O. tormota, but developmental stage, feeding habit, and habitat type had a more significant influence. The microbial community in the gut varies with the developmental stage of the host and constantly adapts to the survival requirements of the host. These findings advance our understanding of the evolutionary mechanism of amphibian gut microbiota in maintaining health homeostasis and adaptation.

BackgroundMulti system symptoms such as gastrointestinal tract and respiratory tract exist in coronavirus disease 2019 (COVID-19) patients. There is a lack of reliable evidence to prove that probiotics are effective in improving these symptoms. In this study, we aimed to evaluate the efficacy of probiotics in meta-analysis.MethodsWe systematically searched PubMed, Embase, Web of Science, and Cochrane Library up to February 15, 2023. Randomized controlled trials or high quality retrospective studies comparing the efficacy of probiotics as supplementation with non-probiotics in improving symptoms for patients with COVID-19 were included. This meta-analysis assessed endpoints using Review Manager 5.3.ResultTen citations comprising 1198 patients with COVID-19 were included. The results showed that probiotics could increase the number of people with overall symptom improvement (RR = 1.62, 95% CI [1.10, 2.38], P = 0.01) and shorten the duration (days) of overall symptoms (MD = −1.26, 95% CI [−2.36, −0.16], P = 0.02). For the duration (days) of specific symptoms, probiotics could improve diarrhea (MD = −2.12, 95% CI [−2.41, −1.83], P < 0.00001), cough (MD = −2.21, 95% CI [-4.56, 0.13], P = 0.06) and shortness of breath (MD = −1.37, 95% CI [-2.22, −0.53], P = 0.001). Probiotics had no obvious effect on fever, headache and weakness. For inflammation, probiotics could effectively reduce C-reactive Protein (CRP) serum level (mg/L) (MD = −4.03, 95% CI [−5.12, −2.93], P < 0.00001). Regarding hospital stay (days), probiotics group was shorter than non-probiotics group (MD = −0.98, 95% CI [−1.95, −0.01], P = 0.05).ConclusionTo some extent probiotics could improve the overall symptoms, inflammatory reaction and shorten hospital stay of patients with COVID-19. Probiotics may improve gastrointestinal symptoms (such as improving intestinal flora and reducing the duration of diarrhea) and further improve respiratory symptoms through the gut-lung axis.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=398309, identifier: CRD42023398309.

A high rate of thromboembolism and a high risk of death have been reported regarding hospitalized patients with coronavirus disease 2019 (COVID-19). Recently, we noticed that clinicians in some comparative studies used direct oral anticoagulants (DOACs) to prevent thromboembolism in patients with COVID-19. However, it is uncertain whether DOACs are better than recommended heparin for hospitalized patients with COVID-19. Therefore, a direct comparison of the prophylactic effects and safety between DOACs and heparin is needed. We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library from 2019 to December 1, 2022. Randomized controlled trials or retrospective studies comparing the efficacy or safety of DOACs with that of heparin in preventing thromboembolism for hospitalized patients with COVID-19 were included. We assessed endpoints and publication bias using Stata 14.0. Five studies comprising 1360 hospitalized COVID-19 patients with mild to moderate cases were identified in the databases. Comparing the embolism incidence, we found that DOACs had a better effect than heparin, mainly low-molecular-weight heparin (LMWH), in preventing thromboembolism (risk ratio [RR] = 0.63, 95% confidence interval [CI] [0.43-0.91], P = 0.014). Considering safety, DOACs resulted in less bleeding than heparin during hospitalization (RR = 0.52, 95% CI [0.11-2.44], P = 0.411). Similar mortality was discovered in the 2 groups (RR = 0.94, 95% CI [0.59-1.51], P = 0.797). In noncritically hospitalized patients with COVID-19, DOACs are superior to heparin, even LMWH, in preventing thromboembolism. Compared with heparin, DOACs have a lower trend of bleeding and yield a similar mortality rate. Therefore, DOACs may be a better alternative for patients with mild to moderate COVID-19.

BackgroundHepatoid adenocarcinoma of the stomach (HAS) is a highly malignant subtype of gastric carcinoma with specific clinicopathological features and extremely poor prognosis. We present an exceedingly rare case of complete response after chemo-immunotherapy.Case DescriptionA 48-year-old woman with highly elevated serum alpha-fetoprotein (AFP) level was found to have HAS verified by pathological examination based on gastroscopy. Computed tomography scan was done and TNM staging of the tumor was T4aN3aMx. Programmed cell death ligand-1 (PD-L1) immunohistochemistry was performed, revealing a negative PD-L1 expression. Chemo-immunotherapy including oxaliplatin plus S-1 and PD-1 inhibitor terelizumab was given to this patient for 2 months until the serum AFP level decreased from 748.5 to 12.9 ng/mL and the tumor shrank. D2 radical gastrectomy was then performed and histopathology of the resected specimen revealed that the cancerous cells had disappeared. Pathologic complete response (pCR) was achieved and no evidence of recurrence has been found after 1 year of follow-up.ConclusionsWe, for the first time, reported an HAS patient with negative PD-L1 expression who achieved pCR from the combined chemotherapy and immunotherapy. Although no consensus has been reached regarding the therapy, it might provide a potential effective management strategy for HAS patient.

Meningitis-like infectious disease (MID) (also known as frog cataract and torticollis) is a disease prone to occur in amphibians and reptiles. It is highly contagious and has a high mortality rate. In this study, we sampled and sequenced microbiomes from oral and intestinal samples of five normal and five diseased bullfrogs. The analysis found that the richness, uniformity, and abundance of the microbial community of the diseased bullfrogs were significantly higher than those of the normal bullfrogs in both the oral cavity and the gut. In the diseased group, the abundance of Elizabethkingia significantly increased and that of Lactococcus significantly decreased. It showed that the structure of the microbial community had changed a lot in diseased frogs. After the pathogenic bacteria infected the body, it might be make the decline in the immune function of the body declined, and resulting in some conditional pathogenic bacteria in the water body further infecting the body. As a result, the richness and composition of the microbial community significantly changed. This study can provide a theoretical basis for the control of MID of bullfrogs.

Summary: Background: Vacuolar protein sorting-associated protein 35 (VPS35) is a core component of the retromer complex which mediates intracellular protein transport. It is well known that dysfunctional VPS35 functions in the accumulation of pathogenic proteins. In our previous study, VPS35 was found to be a potential gene related to poor prognosis in gastric cancer. However, the biological functions of VPS35 in gastric cancer remain unclear. Methods: Cell viability assays were performed to examine whether VPS35 affected cell proliferation. Immunoprecipitation and biotin assays showed that VPS35 bound to epidermal growth factor receptor (EGFR) in the cytoplasm and recycled it to the cell surface. Patient-derived xenografts and organoids were used to evaluate the effect of VPS35 on the response of gastric cancer to EGFR inhibitors. Findings: VPS35 expression levels were upregulated in tumour tissues and correlated with local tumour invasion and poor survival in patients with gastric cancer. VPS35 promoted cell proliferation and increased tumour growth. Mechanistically, VPS35 selectively bound to endocytosed EGFR in early endosomes and recycled it back to the cell surface, leading to the downstream activation of the ERK1/2 pathway. We also found that high VPS35 expression levels increased the sensitivity of the xenograft and organoid models to EGFR inhibitors. Interpretation: VPS35 promotes cell proliferation by recycling EGFR to the cell surface, amplifying the network of receptor trafficking. VPS35 expression levels are positively correlated with gastric cancer sensitivity to EGFR inhibitors, which offers a potential method to stratify patients for EGFR inhibitor utilisation. Funding: National Natural Science Foundation of China.

Abstract Transient-receptor potential (TRP) channels comprise a diverse family of ion channels, which play important roles in regulation of intracellular calcium. Emerging evidence has revealed the critical roles of TRP channels in tumor development and progression. However, we still lack knowledge about the genetic and pharmacogenomics landscape of TRP genes across cancer types. Here, we comprehensively characterized the genetic and transcriptome alterations of TRP genes across >10,000 patients of 33 cancer types. We revealed prevalent somatic mutations and copy number variation in TRP genes. In particular, mutations located in transmembrane regions of TRP genes were likely to be deleterious mutations (p-values

This paper develops a multiplex RNA-seq method that reports tRNA abundance, modification, charging, and fragmentation. Results show stress-induced regulation in translational elongation and association of modification and tRNA fragment biogenesis.

Abstract Background Thalassemia is a genetic blood disorder characterized by decreased hemoglobin production. Severe anemia can damage organs and severe threat to life safety. Allogeneic transplantation of bone marrow-derived hematopoietic stem cell (HSCs) at present represents a promising therapeutic approach for thalassemia. However, immune rejection and lack of HLA-matched donors limited its clinical application. In recent years, human-induced pluripotent stem cells (hiPSCs) technology offers prospects for autologous cell-based therapy since it could avoid the immunological problems mentioned above. Methods In the present study, we established a new hiPSCs line derived from amniotic cells of a fetus with a homozygous β41-42 (TCTT) deletion mutation in the HBB gene and a heterozygous Westmead mutation (C > G) in the HBA2 gene. We designed a CRISPR-Cas9 to target these casual mutations and corrected them. Gene-corrected off-target analysis was performed by whole-exome capture sequencing. The corrected hiPSCs were analyzed by teratoma formation and erythroblasts differentiation assays. Results These mutations were corrected with linearized donor DNA through CRISPR/Cas9-mediated homology-directed repair. Corrections of hiPSCs were validated by sequences. The corrected hiPSCs retain normal pluripotency. Moreover, they could be differentiated into hematopoietic progenitors, which proves that they maintain the multilineage differentiation potential. Conclusions We designed sgRNAs and demonstrated that these sgRNAs facilitating the CRISPR-Cas9 genomic editing system could be applied to correct concurrent α- and β-thalassemia in patient-derived hiPSCs. In the future, these corrected hiPSCs can be applied for autologous transplantation in patients with concurrent α- and β-thalassemia.