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ObjectiveTo evaluate the effectiveness of repetitive transcranial magnetic stimulation (rTMS) combined with repetitive peripheral magnetic stimulation (rPMS) on upper limb motor dysfunction after stroke.MethodsWe systematically searched databases up to May 2024, including PubMed, Embase, Cochrane Library, Web of Science, CNKI, VIP, Wanfang, and CBM. Randomized controlled trials (RCTs) examining the application of rTMS combined rPMS on upper limb motor dysfunction after stroke were included based on predefined inclusion criteria. We used Cochrane Risk of Bias 2 tool to assess bias risk of the included RCTs. Meta-analysis was conducted using RevMan 5.4 and Stata 17.0 software.ResultsA total of 9 RCTs involving 483 participants were included in this study. Compared with the control groups that used either conventional therapy or rTMS alone, the experimental group that used rTMS combined rPMS showed significant improvements in stroke patients' upper limb motor function [MD = 3.65, 95% CI (2.75, 4.54), P < 0.05], ability of daily living [MD = 4.50, 95% CI (3.50, 5.50), P < 0.05], and spasticity [MD = –0.34, 95% CI (−0.48, −0.20), P < 0.05]. Meanwhile, in terms of neurophysiological indicators, significant differences were found both for motor evoked potential latency [MD = −1.77, 95% CI (−3.19, −0.35), P < 0.05] and motor evoked potential amplitude [MD = 0.25, 95% CI (0.01, 0.49), P < 0.05].ConclusionThis study provides low-level evidence that the therapy of LF-rTMS or HF-rTMS combined with rPMS can improve the upper limb motor function and daily living ability of stroke patients. However, given that the low quality of the evidence for the evaluation results, further evidence from high-quality studies is needed to substantiate this conclusion.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024539195, PROSPERO Platform [CRD42024539195].

The Sophora alopecuroide - Taraxacum Decoction (STD) is a traditional Chinese herbal formulation that has demonstrated significant potential in combating tumors. Despite its apparent effectiveness, the specific mechanisms through which STD exerts its anti-tumor properties remain largely unexplored and are yet to be fully understood. In our study, we provided evidence that STD effectively inhibits cellular growth and movement, as well as halting the cell cycle at the G2/M checkpoint. Furthermore, our pharmacological network analysis indicated that STD might induce cell death through a process known as ferroptosis. This hypothesis was substantiated by observing important biochemical changes associated with ferroptosis, including a decrease in glutathione (GSH) levels, an increase in iron accumulation, and elevated levels of reactive oxygen species (ROS) and lipid peroxidation. Additionally, we noted a significant rise in the expression of pro-ferroptosis genes such as Keap1, Nrf2, and HO-1, further supporting our findings. Significantly, and in line with the in vitro results, STD also showed a strong ability to inhibit tumor growth by inducing ferroptosis in a subcutaneous tumor model. Additionally, STD treatment changed the tumor immune microenvironment (TIME), as seen by an increase in CD107a+ CD8 and NK cells within the tumor. These findings demonstrate that STD induces ferroptosis and alters TIME to combat tumors, suggesting that STD may be a viable alternative treatment for patients with NSCLC.

Objective: To validate the predictive power of newly developed magnetic resonance (MR) morphological and clinicopathological risk models in predicting low anterior resection syndrome (LARS) 6 months after anterior resection of middle and low rectal cancer (MLRC). Methods: From May 2018 to January 2021, 236 patients with MLRC admitted to two hospitals (internal and external validation) were included. MR images, clinicopathological data, and LARS scores (LARSS) were collected. Tumor morphology data included longitudinal involvement length, maximum tumor diameter, proportion of tumor to circumference of the intestinal wall, tumor mesorectal infiltration depth, circumferential margin status, and distance between the tumor and anal margins. Pelvic measurements included anorectal angle, mesenterial volume (MRV), and pelvic volume. Univariate and multivariate logistic regression was used to obtain independent risk factors of LARS after anterior resection Then, the prediction model was constructed, expressed as a nomogram, and its internal and external validity was assessed using receiver operating characteristic curves. Results: The uni- and multivariate analysis revealed distance between the tumor and anal margins, MRV, pelvic volume, and body weight as significant independent risk factors for predicting LARS. From the nomogram, the area under the curve (AUC), sensitivity, and specificity were 0.835, 75.0 %, and 80.4 %, respectively. The AUC, sensitivity, and specificity in the external validation group were 0.874, 83.3 %, and 91.7 %, respectively. Conclusion: This study shows that MR imaging and clinicopathology presented by a nomogram can strongly predict LARSS, which can then individually predict LARS 6 months after anterior resection in patients with MLRC and facilitate clinical decision-making. Clinical relevance statement: We believe that our study makes a significant contribution to the literature. This method of predicting postoperative anorectal function by preoperative measurement of MRV provides a new tool for clinicians to study LARS.

Abstract Aloperine (ALO), a quinolizidine‐type alkaloid isolated from a natural Chinese herb, has shown promising antitumor effects. Nevertheless, its common mechanism of action and specific target remain elusive. Here, it is demonstrated that ALO inhibits the proliferation and migration of non‐small cell lung cancer cell lines in vitro and the tumor development in several mouse tumor models in vivo. Mechanistically, ALO inhibits the fusion of autophagosomes with lysosomes and the autophagic flux, leading to the accumulation of sequestosome‐1 (SQSTM1) and production of reactive oxygen species (ROS), thereby inducing tumor cell apoptosis and preventing tumor growth. Knockdown of SQSTM1 in cells inhibits ROS production and reverses ALO‐induced cell apoptosis. Furthermore, VPS4A is identified as a direct target of ALO, and the amino acids F153 and D263 of VPS4A are confirmed as the binding sites for ALO. Knockout of VPS4A in H1299 cells demonstrates a similar biological effect as ALO treatment. Additionally, ALO enhances the efficacy of the anti‐PD‐L1/TGF‐β bispecific antibody in inhibiting LLC‐derived subcutaneous tumor models. Thus, ALO is first identified as a novel late‐stage autophagy inhibitor that triggers tumor cell death by targeting VPS4A.

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.

C16H24CoN4O8, triclinic, P1‾ $P\overline{1}$ (no. 2), a = 7.4371(8) Å, b = 7.6451(9) Å, c = 9.9156(12) Å, α = 69.830(6)°, β = 71.245(5)°, γ = 79.653(5)°, V = 499.60(10) Å3, Z = 1, R gt(F) = 0.0247, wR ref(F 2) = 0.0630, T = 293(2) K.

Abstract Background Astragaloside IV (As-IV) and Tanshinone IIA (Ta-IIA) are the main ingredients of traditional Chinese medicinal Astragalus membranaceus (Fisch.) Bunge and Salvia miltiorrhiza Bunge, respectively, both of which have been employed in the treatment of cardiovascular diseases. Nevertheless, the efficacy of the combination (Co) of Ta-IIA and As-IV for cardiovascular diseases remain unclear and warrant further investigation. This study aimed to investigate the efficacy and the underlying molecular mechanism of Co in treating myocardial ischemia–reperfusion injury (MIRI). Methods In order to assess the efficacy of Co, an in vivo MIRI mouse model was created by temporarily blocking the coronary arteries for 30 min and then releasing the blockage. Parameters such as blood myocardial enzymes, infarct size, and ventricular function were measured. Additionally, in vitro experiments were conducted using HL1 cells in both hypoxia-reoxygenation model and oxidative stress models. The apoptosis rate, expression levels of apoptosis-related proteins, oxidative stress indexes, and release of inflammatory factors were detected. Furthermore, molecular docking was applied to examine the binding properties of Ta-IIA and As-IV to STING, and western blotting was performed to analyze protein expression of the STING pathway. Additionally, the protective effect of Ta-IIA, As-IV and Co via inhibiting STING was further confirmed in models of knockdown STING by siRNA and adding STING agonist. Results Both in vitro and in vivo data demonstrated that, compared to Ta-IIA or As-IV alone, the Co exhibited superior efficacy in reducing the area of myocardial infarction, lowering myocardial enzyme levels, and promoting the recovery of myocardial contractility. Furthermore, the Co showed more potent anti-apoptosis, antioxidant, and anti-inflammation effects. Additionally, the Co enhanced the inhibitory effects of Ta-IIA and As-IV on STING phosphorylation and the activation of STING signaling pathway. However, the administration of a STING agonist attenuated the protective effects of the Co, Ta-IIA, and As-IV by compromising their anti-apoptotic, antioxidant, and anti-inflammatory effects in MIRI. Conclusion Compared to the individual administration of Ta-IIA or As-IV, the combined treatment demonstrated more potent ability in inhibiting apoptosis, oxidative stress, inflammation, and the STING signaling pathway in the context of MIRI, indicating a more powerful protective effect against MIRI. Graphical Abstract

Abstract The Janus kinase-signal transducer and transcription activator pathway (JAK-STAT) serves as a cornerstone in cellular signaling, regulating physiological and pathological processes such as inflammation and stress. Dysregulation in this pathway can lead to severe immunodeficiencies and malignancies, and its role extends to neurotransduction and pro-inflammatory signaling mechanisms. Although JAK inhibitors (Jakinibs) have successfully treated immunological and inflammatory disorders, their application has generally been limited to diseases with similar pathogenic features. Despite the modest expression of JAK-STAT in the CNS, it is crucial for functions in the cortex, hippocampus, and cerebellum, making it relevant in conditions like Parkinson's disease and other neuroinflammatory disorders. Furthermore, the influence of the pathway on serotonin receptors and phospholipase C has implications for stress and mood disorders. This review expands the understanding of JAK-STAT, moving beyond traditional immunological contexts to explore its role in stress-related disorders and CNS function. Recent findings, such as the effectiveness of Jakinibs in chronic conditions such as rheumatoid arthritis, expand their therapeutic applicability. Advances in isoform-specific inhibitors, including filgotinib and upadacitinib, promise greater specificity with fewer off-target effects. Combination therapies, involving Jakinibs and monoclonal antibodies, aiming to enhance therapeutic specificity and efficacy also give great hope. Overall, this review bridges the gap between basic science and clinical application, elucidating the complex influence of the JAK-STAT pathway on human health and guiding future interventions. Graphical Abstract

Potential outcomes play a fundamental and important role in many causal inference problems. If the potential-outcome means are identifiable, a series of causal effect measures, including the risk difference, the risk ratio, and the treatment benefit rate, among others, can also be identified. However, current identification and estimation methods for these means often implicitly assume that the collected data for analysis are measured precisely. In many fields such as medicine and economics, the collected variables may be subject to measurement errors, such as medical diagnostic results and individual wage data. Misclassification, as a non-classic measurement error, can lead to severely biased estimates in causal inference. In this paper, we leverage a combined sample to study the identifiability of potential-outcome means corresponding to different treatment levers under a plausible misclassification assumption for the outcome, allowing the misclassification probability to depend on not only the true outcome but also the covariates. Furthermore, we propose the multiply-robust and semiparametric efficient estimators for the means, consistent even under partial misspecification of the observed data law, based on the semiparametric theory framework. The simulation studies and real data analysis demonstrate the satisfactory performance of the proposed method.

Abstract Background Circulating tumor cells (CTCs) have been a non-invasive technique which allows investigation of tumor characteristics. The purpose of this study was to investigate the relationship between circulating tumor cells and colorectal cancer. Methods The clinical data of 617 patients with colorectal cancer from October 2019 to March 2022 were retrospectively collected to analyze the correlation between CTCs and clinicopathologic characteristics. Results The CTCs value increased with the progression of Tumor(T) stage,Metastasis(M) stage and Tumor Node Metastasis(TNM) stage (P 0.05). Binary logistic regression analysis showed that CTCs, CEA, CA125 and CA199 were independent risk factors for CRC metastasis. Compared with CTCs, CEA, CA125 and CA199, the Logistic model had the highest AUC (AUC = 0.778,95%CI: 0.732–0.824), and the specificity and sensitivity were 82.9% and 63.2%, respectively. After operation, chemo-radiotherapy and other treatment for CRC, CTCs and CEA were significantly decreased compared with before treatment (P

Multiple myeloma is the second most common malignant hematologic malignancy which evolved different strategies for immune escape from the host immune surveillance and drug resistance, including uncontrolled proliferation of malignant plasma cells in the bone marrow, genetic mutations, or deletion of tumor antigens to escape from special targets and so. Therefore, it is a big challenge to efficiently treat multiple myeloma patients. Despite recent applications of immunomodulatory drugs (IMiDS), protease inhibitors (PI), targeted monoclonal antibodies (mAb), and even hematopoietic stem cell transplantation (HSCT), it remains hardly curable. Summarizing the possible evasion strategies can help design specific drugs for multiple myeloma treatment. This review aims to provide an integrative overview of the intrinsic and extrinsic evasion mechanisms as well as recently discovered microbiota utilized by multiple myeloma for immune evasion and drug resistance, hopefully providing a theoretical basis for the rational design of specific immunotherapies or drug combinations to prevent the uncontrolled proliferation of MM, overcome drug resistance and improve patient survival.

Dental fluorosis, resulting from long-term environmental exposure to fluoride, is prevalent among diverse populations worldwide. Severe fluorosis not only compromises the aesthetic appeal of teeth but also impairs their functionality. This study aims to investigate the oral microbiome in dental fluorosis and the health individuals of adolescents living in the endemic fluorosis area of Guizhou, China through full-length 16S rDNA sequencing. Fourty-six individuals meet the sampling criteria, and we divided these samples into the following groups: a healthy group (H = 23) and a dental fluorosis group (F = 23), and two subgroups of Miao ethnicity: a healthy Miao group (Hm = 13) and a dental fluorosis Miao group (Fm = 15). A total of 660,389 high-quality sequences were obtained, and 12,007 Amplicon Sequence Variants (ASVs) were identified, revealing significant variations in oral microbiome between Fm and Hm groups. The composition of oral microbiota was similar between the H and F groups. At the genus level, Pseudopropionibacterium and at the species level, Streptococcus oralis_subsp.dentisani_clade_058 were less abundant in group F than in group H (P < 0.05). Further analysis revealed that the abundance of Capnocytophaga gingivalis and Kingella denitrificans was significantly lower in Fm fluorosis patients than in the Hm group (P < 0.05). Based on the LEfSe analysis, the potential core biomarkers in the oral of Fm fluorosis patients were identified at different taxonomic levels, ranging from phylum to species. These include Gammaproteobacteria, Prevotella sp_HMT_304, Gemella sanguinis, and Gracilibacteria_(GN02). Network analysis revealed that the microbiota in the fluorosis group exhibited more complex interactions with each other than the healthy group. Notably, within the Hm group, the potential biomarkers Capnocytophaga gingivalis and Kingella denitrificans exhibited a positive correlation. Finally, we employed PICRUSt2 analysis to explore the abundance clustering of the top 30 functional units in each sample, and we found that the metabolic pathway compositions of the four groups were similar. In summary, our findings suggest that the microbial composition of plaque in Hm patients with dental fluorosis is significantly altered, and we identified the potential marker microorganisms that contribute to these changes.

Abstract Background Inflammatory bone resorption is a prominent risk factor for implantation failure. Simvastatin (SIM) has anti‐inflammatory effects independent of cholesterol lowering and reduces osteoclastogenesis by decreasing both the number and activity of osteoclasts. However, the specific mechanism of inflammatory bone loss alleviation by SIM remains to be elucidated. We hypothesized that SIM relieves inflammatory bone loss by modulating autophagy and suppressing the NOD‐like receptor family pyrin domain‐containing protein 3 (NLRP3) signaling pathway. Methods and results RAW264.7 cells were stimulated by lipopolysaccharide (LPS) after being pretreated with various concentrations of SIM. Osteoclast (OC) differentiation, formation and activity were evaluated by tartrate‐resistant acid phosphatase staining, F‐actin ring staining and bone resorption pit assays, respectively. We observed autophagosomes by transmission electron microscopy. Then NLRP3 inhibitor MCC950 was used to further explore the corresponding molecular mechanism underlying anti‑inflammatory bone resorption, the expression of autophagy‐related proteins and NLRP3 signaling pathway factors in pre‐OCs were evaluated by western blot analysis, and the expression of OC‑specific molecules was analyzed using reverse transcription‑quantitative polymerase chain reaction. The results showed that SIM decreased the expression of tumor necrosis factor‐α, whereas increased Interleukin‐10. In addition, SIM inhibited LPS‐induced OC differentiation, formation, bone resorption activity, the level of autophagosomes, and OC‑specific markers. Furthermore, SIM significantly suppressed autophagy by downregulating LC3II, Beclin1, ATG7, and NLRP3‐related proteins expression while upregulating P62 under inflammatory conditions. Conclusions SIM may reduce autophagy secretion to attenuate LPS‐induced osteoclastogenesis and the NLRP3 signaling pathway participates in this process, thus providing theoretical basis for the application of this drug in peri‐implantitis.

The treatment options for multiple myeloma (MM) have undergone significant transformation with the advent of immunotherapy. Novel therapies that focus on tumor antigens now drive advances in MM research. Bispecific antibodies (bsAbs) leverage revolutionary advances in bioengineering techniques and embody the second generation of antibody-based tumor therapy. Recent studies on bsAbs in relapsed/refractory MM cases have revealed remarkable efficacy and acceptable safety profiles. The approval of elranatamab and teclistamab represents the next step in the development of bsAbs for the treatment of MM. This review article addresses the antigen targeting, efficacy, safety, and strategies in the application of bsAbs against treatment-resistant MM, with a focus on clinical trials and real-world data.

It is now understood that hemolysis and the subsequent release of heme into circulation play a critical role in driving the progression of various diseases. Hemopexin (HPX), a heme-binding protein with the highest affinity for heme in plasma, serves as an effective antagonist against heme toxicity resulting from severe acute or chronic hemolysis. In the present study, changes in HPX concentration were characterized at different stages of hemolytic diseases, underscoring its potential as a biomarker for assessing disease progression and prognosis. In many heme overload-driven conditions, such as sickle cell disease, transfusion-induced hemolysis, and sepsis, endogenous HPX levels are often insufficient to provide protection. Consequently, there is growing interest in developing HPX therapeutics to mitigate toxic heme exposure. Strategies include HPX supplementation when endogenous levels are depleted and enhancing HPX’s functionality through modifications, offering a potent defense against heme toxicity. It is worth noting that HPX may also exert deleterious effects under certain circumstances. This review aims to provide a comprehensive overview of HPX’s roles in the progression and prognosis of hematological diseases. It highlights HPX-based clinical therapies for different hematological disorders, discusses advancements in HPX production and modification technologies, and offers a theoretical basis for the clinical application of HPX.

Abstract Since the discovery of Stimulator of Interferon Genes (STING) as an important pivot for cytosolic DNA sensation and interferon (IFN) induction, intensive efforts have been endeavored to clarify the molecular mechanism of its activation, its physiological function as a ubiquitously expressed protein, and to explore its potential as a therapeutic target in a wide range of immune-related diseases. With its orthodox ligand 2’3’-cyclic GMP–AMP (2’3’-cGAMP) and the upstream sensor 2’3’-cGAMP synthase (cGAS) to be found, STING acquires its central functionality in the best-studied signaling cascade, namely the cGAS–STING–IFN pathway. However, recently updated research through structural research, genetic screening, and biochemical assay greatly extends the current knowledge of STING biology. A second ligand pocket was recently discovered in the transmembrane domain for a synthetic agonist. On its downstream outputs, accumulating studies sketch primordial and multifaceted roles of STING beyond its cytokine-inducing function, such as autophagy, cell death, metabolic modulation, endoplasmic reticulum (ER) stress, and RNA virus restriction. Furthermore, with the expansion of the STING interactome, the details of STING trafficking also get clearer. After retrospecting the brief history of viral interference and the milestone events since the discovery of STING, we present a vivid panorama of STING biology taking into account the details of the biochemical assay and structural information, especially its versatile outputs and functions beyond IFN induction. We also summarize the roles of STING in the pathogenesis of various diseases and highlight the development of small-molecular compounds targeting STING for disease treatment in combination with the latest research. Finally, we discuss the open questions imperative to answer.

MYH9-related disorder (MYH9-RD) is autosomal dominant thrombocytopenia caused by mutations in the MYH9 gene, which codes for the non-muscle myosin-IIA heavy chain. We present a case of a 24-year-old Chinese man with MYH9-RD who was initially misdiagnosed with immune thrombocytopenia. Whole-exome sequencing and Sanger sequencing revealed a novel missense mutation in the MYH9 gene at the position of c.4550 G > T (p.G1517V) in exon 32. The same phenotype was observed in the proband, his mother, and his brother, in addition to macrothrombocytopenia and Dohle-like bodies in neutrophil granulocytes without non-hematologic manifestations. Following failed treatment with eltrombopag, avatrombopag, which was not mentioned before in the MYH9-RD treatment, was administered to the patient, and thrombocytopenia improved. In this case report, we present a novel pathogenic mutation and show the potential of avatrombopag for temporarily increasing the platelet count in patients with MYH9-RD.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease caused by many factors including colonic inflammation and microbiota dysbiosis. Previous studies have indicated that celastrol (CSR) has strong anti-inflammatory and immune-inhibitory effects. Here, we investigated the effects of CSR on colonic inflammation and mucosal immunity in an experimental colitis model, and addressed the mechanism by which CSR exerts the protective effects. We characterized the therapeutic effects and the potential mechanism of CSR on treating UC using histological staining, intestinal permeability assay, cytokine assay, flow cytometry, fecal microbiota transplantation (FMT), 16S rRNA sequencing, untargeted metabolomics, and cell differentiation. CSR administration significantly ameliorated the dextran sodium sulfate (DSS)-induced colitis in mice, which was evidenced by the recovered body weight and colon length as well as the decreased disease activity index (DAI) score and intestinal permeability. Meanwhile, CSR down-regulated the production of pro-inflammatory cytokines and up-regulated the amount of anti-inflammatory mediators at both mRNA and protein levels, and improved the balances of Treg/Th1 and Treg/Th17 to maintain the colonic immune homeostasis. Notably, all the therapeutic effects were exerted in a gut microbiota-dependent manner. Furthermore, CSR treatment increased the gut microbiota diversity and changed the compositions of the gut microbiota and metabolites, which is probably associated with the gut microbiota-mediated protective effects. In conclusion, this study provides the strong evidence that CSR may be a promising therapeutic drug for UC.

Purpose The aim of the current study was to identify the relationship between body composition changes during neoadjuvant therapy (NAT) and the treatment efficiency of NAT in gastrointestinal cancer (GC) patients. Methods From January 2015 to July 2020, 277 GC patients treated with NAT had included for retrospective analysis. The body mass index (BMI) and computed tomography (CT) imaging before and after NAT were recorded. The BMI change optimal cut-off value were calculated by ROC curve. Balancing essential characteristic variables using propensity score matching (PSM) method. Exploring the association between BMI changes and tumor response to NAT using logistic regression analysis. The survival outcome of matched patients between different BMI change groups was compared. Results A cutoff point of BMI change >2% during NAT was defined as BMI loss. Among the 277 patients, 110 (39.7%) patients showed BMI change with a loss after NAT. In total, 71 pairs of patients were selected for further analysis. The median follow-up time was 22 months (range 3 to 63 months). Univariate and multivariate logistic regression analyses in matched cohort showed that BMI change was a prognostic factor for tumor response after NAT in GC patients (odds ratio (OR), .471; 95% confidence interval (CI), .233-.953; P = .036). In addition, patients who experienced BMI loss after NAT showed worse overall survival than those who had BMI gain or stable. Conclusion BMI loss during NAT probably may has negative effects on NAT efficiency and survival for gastrointestinal cancer patients. It is necessary to monitor and maintain weight for patients during treatment.

As one of the world’s top three popular non-alcoholic beverages, tea is economically and culturally valuable. Xinyang Maojian, this elegant green tea, is one of the top ten famous tea in China and has gained prominence for thousands of years. However, the cultivation history of Xinyang Maojian tea population and selection signals of differentiation from the other major variety Camellia sinensis var. assamica (CSA) remain unclear. We newly generated 94 Camellia sinensis (C. sinensis) transcriptomes including 59 samples in the Xinyang area and 35 samples collected from 13 other major tea planting provinces in China. Comparing the very low resolution of phylogeny inferred from 1785 low-copy nuclear genes with 94 C. sinensis samples, we successfully resolved the phylogeny of C. sinensis samples by 99,115 high-quality SNPs from the coding region. The sources of tea planted in the Xinyang area were extensive and complex. Specifically, Shihe District and Gushi County were the two earliest tea planting areas in Xinyang, reflecting a long history of tea planting. Furthermore, we identified numerous selection sweeps during the differentiation of CSA and CSS and these positive selection genes are involved in many aspects such as regulation of secondary metabolites synthesis, amino acid metabolism, photosynthesis, etc. Numerous specific selective sweeps of modern cultivars were annotated with functions in various different aspects, indicating the CSS and CSA populations possibly underwent independent specific domestication processes. Our study indicated that transcriptome-based SNP-calling is an efficient and cost-effective method in untangling intraspecific phylogenetic relationships. This study provides a significant understanding of the cultivation history of the famous Chinese tea Xinyang Maojian and unravels the genetic basis of physiological and ecological differences between the two major tea subspecies.

The gasdermins (GSDM), a family of pore-forming proteins, consist of gasdermin A (GSDMA), gasdermin B (GSDMB), gasdermin C (GSDMC), gasdermin D (GSDMD), gasdermin E (GSDME) and DFNB59 (Pejvakin (PJVK)) in humans. These proteins play an important role in pyroptosis. Among them, GSDMD is the most extensively studied protein and is identified as the executioner of pyroptosis. Other family members have also been implicated in certain cancers. As a unique form of programmed cell death, pyroptosis is closely related to tumor progression, and the inflammasome, an innate immune mechanism that induces inflammation and pyroptosis. In this review, we explore the current developments of pyroptosis, the inflammasome, and especially we review the gasdermin family members and their role in inducing pyroptosis and the possible therapeutic values in antitumor effects.

Abstract While cadherin (CDH) genes are aberrantly expressed in cancers, the functions of CDH genes in gastric cancer (GC) remain poorly understood. The clinical significance and molecular mechanisms of CDH genes in GC were assessed in this study. Data from a total of 1226 GC patients included in The Cancer Genome Atlas (TCGA) and Kaplan–Meier plotter database were used to independently explore the value of CDH genes in clinical application. The TCGA RNA sequencing dataset was used to explore the molecular mechanisms of CDH genes in GC. Using enrichment analysis tools, CDH genes were found to be related to cell adhesion and calcium ion binding in function. In TCGA cohort, 12 genes were found to be differentially expressed between GC para-carcinoma and tumor tissue. By analyzing GC patients in two independent cohorts, we identified and verified that CDH2, CDH6, CDH7 and CDH10 were significantly associated with a poor GC prognosis. In addition, CDH2 and CDH6 were used to construct a GC risk score signature that can significantly improve the accuracy of predicting the 5-year survival of GC patients. The GSEA approach was used to explore the functional mechanisms of the four prognostic CDH genes and their associated risk scores. It was found that these genes may be involved in multiple classic cancer-related signaling pathways, such as the Wnt and phosphoinositide 3-kinase signaling pathways in GC. In the subsequent CMap analysis, three small molecule compounds (anisomycin, nystatin and bumetanide) that may be the target molecules that determine the risk score in GC, were initially screened. In conclusion, our current study suggests that four CDH genes can be used as potential biomarkers for GC prognosis. In addition, a prognostic signature based on the CDH2 and CDH6 genes was constructed, and their potential functional mechanisms and drug interactions explored.

Introduction: Low anterior resection syndrome (LARS) is the most common complication after total mesorectal excision (TME) in patients with low rectal cancer and has been a challenge in colorectal surgery that severely impacts the quality of life of patients. This study aimed to introduce a revised surgical procedure which could effectively maintain rectal compliance and significantly improve LARS after the operation. Methods: We performed mesorectal reconstruction after routine Dixon TME using greater omental pedicle flap transplantation in 11 patients with low rectal cancer (5 cases of preoperative neoadjuvant chemoradiotherapy, 5 cases of preoperative neoadjuvant chemotherapy, and 1 case of postoperative adjuvant chemotherapy), thereby simulating the initial anatomical structure of the mesorectum and significantly reducing the postoperative anterior resection syndrome. The lars precision syndrome assessment scale (LARSS) was used to access the LARS. Results: At 12 weeks after the 11 patients recovered from the anal defecation function, the average score on the LARS questionnaire was 25.5 ± 1.5 (minor). The average time at which anal function began to recover was 6.2 ± 2.6 weeks after surgery. The recovery was rapid, as the rectal and anal function of all patients generally returned to normal levels within 12 weeks, and the quality of life was close to that before surgery. Conclusion: Greater omental flap transplantation can significantly improve LARS after Dixon TME in patients with low rectal cancer.

ZnO quantum dots (QDs) have received much attention as biomarkers and drug delivery systems in cancer treatment, due to their low cost, ease of preparation, and pH-responsive degradation. However, its applications are limited by the low quantum yield and light absorption. In this work, a lanthanum-doped zinc oxide (La-ZnO) QDs-based drug delivery platform was constructed. The results show that 4% La doping is the most beneficial for improving the fluorescent properties of the ZnO QDs. After loading the drug, the cell activity was 15% at ZnO@DOX and 12% at La-ZnO@DOX. According to in vitro and in vivo experiment results, the La-ZnO QDs show enhancement of the antitumor effect. Dual enhancement of fluorescence and anti-tumor effects make La-ZnO QDs promising as a drug delivery system in cancer treatment.

S-nitrosylation can influence many pathophysiological processes. Here the authors show that the coupling efficiency of GNAI2 with CXCR5 is enhanced by S-nitrosylation of GNAI2, leading to Hippo-YAP dysfunction in endothelium, and plays a role in diabetes-accelerated atherosclerosis.

BackgroundLeonurus japonicus Houtt has an obvious efficacy on cardiovascular diseases. As the most representative component in the herb, leonurine has attracted increasing attention for its potential in myocardial ischemia. However, its protective mechanism against myocardial ischemia remains incompletely elucidated.ObjectivesThe present study aimed to reveal the potential mechanism of leonurine in acute myocardial ischemia using a strategy combining metabolomics and network pharmacology.MethodsFirst, a metabolomics method was proposed to identify the differential metabolites of plasma in rats. Then, network pharmacology was performed to screen candidate targets of leonurine against acute myocardial ischemia. A compound-reaction-enzyme-gene network was thus constructed with the differential metabolites and targets. Finally, molecular docking was carried out to predict the binding capability of leonurine with key targets.ResultsA total of 32 differential metabolites were identified in rat plasma, and 16 hub genes were detected through network pharmacology. According to the results of compound-reaction-enzyme-gene network and molecular docking, what was screened included six key targets (GSR, CYP2C9, BCHE, GSTP1, TGM2, and PLA2G2A) and seven differential metabolites (glycerylphosphorylcholine, lysophosphatidylcholine, choline phosphate, linoleic acid, 13-HpODE, tryptophan and glutamate) with four important metabolic pathways involved: glycerophospholopid metabolism, linoleic acid metabolism, tryptophan metabolism and glutamate metabolism. Among them, glycerophospholipid and tryptophan metabolism were shown to be important, since the regulation of leonurine on these two pathways was also observed in our previous metabolomics study conducted on clinical hyperlipidemia patients.ConclusionThis is the first study of its kind to reveal the underlying mechanism of leonurine against acute myocardial ischemia through a strategy combining metabolomics and network pharmacology, which provides a valuable reference for the research on its future application.

Abstract Background The clinical characteristics and prognosis of primary intestinal diffuse large B‐cell lymphoma (PI‐DLBCL) are rarely reported. We aimed to explore the role of surgery in patients with PI‐DLBCL. Methods Adult PI‐DLBCL patients were included from the Surveillance, Epidemiology, and End Results database. The effect of surgery was evaluated by Kaplan–Meier and Cox proportional regression analyses. Propensity score matching (PSM) was used to reinforce our results. Lasso regression was utilized to determine independent risk factors of overall survival (OS) for a nomogram and a novel web‐based calculator. The performance of the model was measured via concordance index, receiver operating characteristic curve, and calibration plots in both cohorts. Results Overall, 1602 patients with PI‐DLBCL were analyzed. Surgery significantly improved survival in both univariate and multivariate analyses (p = 0.007, p

As one of the most lethal diseases, pancreatic cancer shows a dismal overall prognosis and high resistance to most treatment modalities. Furthermore, pancreatic cancer escapes early detection during the curable period because early symptoms rarely emerge and specific markers for this disease have not been found. Although combinations of new drugs, multimodal therapies, and adjuvants prolong survival, most patients still relapse after surgery and eventually die. Consequently, the search for more effective treatments for pancreatic cancer is highly relevant and justified. As a newly re-discovered mediator of gasotransmission, hydrogen sulfide (H2S) undertakes essential functions, encompassing various signaling complexes that occupy key processes in human biology. Accumulating evidence indicates that H2S exhibits bimodal modulation of cancer development. Thus, endogenous or low levels of exogenous H2S are thought to promote cancer, whereas high doses of exogenous H2S suppress tumor proliferation. Similarly, inhibition of endogenous H2S production also suppresses tumor proliferation. Accordingly, H2S biosynthesis inhibitors and H2S supplementation (H2S donors) are two distinct strategies for the treatment of cancer. Unfortunately, modulation of endogenous H2S on pancreatic cancer has not been studied so far. However, H2S donors and their derivatives have been extensively studied as potential therapeutic agents for pancreatic cancer therapy by inhibiting cell proliferation, inducing apoptosis, arresting cell cycle, and suppressing invasion and migration through exploiting multiple signaling pathways. As far as we know, there is no review of the effects of H2S donors on pancreatic cancer. Based on these concerns, the therapeutic effects of some H2S donors and NO–H2S dual donors on pancreatic cancer were summarized in this paper. Exogenous H2S donors may be promising compounds for pancreatic cancer treatment.

Background: Chemotherapy is the basic treatment for colorectal cancer (CRC). However, colorectal cancer cells often develop resistance to chemotherapy drugs, leading to recurrence and poor prognosis. More and more studies have shown that the Homologous recombination (HR) pathway plays an important role in chemotherapy treatment for tumors. However, the relationship between HR pathway, chemotherapy sensitivity, and the prognosis of CRC patients is still unclear.Methods: We collected 35 samples of CRC patients after chemotherapy treatment from Guangxi Medical University Cancer Hospital, then collected mutation data and clinical prognosis data from the group. We also downloaded Mondaca-CRC, TCGA-CRC cohorts for chemotherapy treatment.Result: We found that HR mutant-type (HR-MUT) patients are less likely to experience tumor metastasis after receiving chemotherapy. Additionally, our univariate and multivariate cox regression models showed that HR-MUT can be used as an independent predictor of the prognosis of chemotherapy for CRC patients. The KM curve showed that patients with HR-MUT CRC had significantly prolonged overall survival (OS) time (log-rank p = 0.017; hazard ratio (HR) = 0.69). Compared to HR mutant-type (HR-WT), HR-MUT has a significantly lower IC50 value with several chemotherapeutic drugs. Pathway enrichment analysis further revealed that the HR-MUT displayed a significantly lower rate of DNA damage repair ability, tumor growth, metastasis activity, and tumor fatty acid metabolism activity than HR-WT, though its immune response activity was notably higher.Conclusion: These findings indicate that HR-MUT may be a relevant marker for CRC patients receiving chemotherapy, as it is closely related to improving OS time and reducing chemotherapy resistance.

Lung cancer is characterized by the most common oncological disease and leading cause of cancer death worldwide, of which a group of subtypes known as non-small cell lung cancer (NSCLC) accounts for approximately 85%. In the past few decades, important progression in the therapies of NSCLC has enhanced our understanding of the biology and progression mechanisms of tumor. The application of immunotherapy and small molecule tyrosine kinase inhibitors has brought significant clinical benefits in certain patients. However, early metastasis and the emergence of resistance to antitumor therapy have resulted in the relatively low overall cure and survival rates for NSCLC. Autophagy is a conserved process that allows cells to recycle unused or damaged organelles and cellular components. It has been reported to be related to the progression of NSCLC and resistance to targeted therapy and cytotoxic chemotherapy. Therefore, autophagy is considered as a potential therapeutic target for NSCLC. Mounting results have been reported about the combination of tyrosine kinase inhibitors and inhibitors of autophagy in models of NSCLC. This review aims to provide a comprehensive review on the roles of autophagy in NSCLC, focusing on related clinical data of agents that regulate autophagy in NSCLC. Furthermore, this study will provide a theoretical basis for further improvement of autophagy-based cancer therapy.

The SARS-CoV-2 and its variants are still hitting the world. Ever since the outbreak, neurological involvements as headache, ageusia, and anosmia in COVID-19 patients have been emphasized and reported. But the pathogenesis of these new-onset neurological manifestations in COVID-19 patients is still obscure and controversial. As difficulty always lay in the diagnosis of neurological infection, current reports to validate the presence of SARS-CoV-2 in cerebrospinal fluid (CSF) almost relied on the basic methods and warranted improvement. Here we reported a case series of 8 patients with prominent new-onset neurological manifestations, who were screened out from a patch of 304 COVID-19 confirmed patients. Next-generation sequencing (NGS) and proteomics were conducted in the simultaneously obtained CSF and serum samples of the selected patients, with three non-COVID-19 patients with matched demographic features used as the controls for proteomic analysis. SARS-CoV-2 RNA was detected in the CSF of four COVID-19 patients and was suspicious in the rest four remaining patients by NGS, but was negative in all serum samples. Proteomic analysis revealed that 185 and 59 proteins were differentially expressed in CSF and serum samples, respectively, and that only 20 proteins were shared, indicating that the proteomic changes in CSF were highly specific. Further proteomic annotation highlighted the involvement of complement system, PI3K-Akt signaling pathway, enhanced cellular interaction, and macrophages in the CSF proteomic alterations. This study, equipped with NGS and proteomics, reported a high detection rate of SARS-CoV-2 in the CSF of COVID-19 patients and the proteomic alteration of CSF, which would provide insights into understanding the pathological mechanism of SARS-CoV-2 CNS infection.

The model drift problem is an inevitable problem for online visual tracking. Model drift can amplify the false tracking result over time and lead to failed tracking finally. Background-aware correlation filter (BACF) tracker obtains the training samples from negative background patches instead of shifted foreground patches and can mitigate the drifting to some extent. However, in complex scenes, such as occlusion, deformation, the inappropriate update of BACF may lead to model drift. We propose an anti-drift background-aware correlation filter via introducing the temporal consistency constraint into BACF. That is, we combine the excellent ability of BACF to distinguish the foreground and background with the ability of the temporal consistency constraint to stabilize model changes, and improve anti-drift performance of BACF. To improve computation efficient, we offer a fast algorithm via alternative Direction Method of Multipliers (ADMM) in the frequency domain. Besides, we design a simple yet effective adaptive feature channel selection method, which can further improve the success rate and precision of the tracker in complex scenes. Our proposed tracker with hand-crafted features achieves a gain of 2.2%, 3.3%, and 5.3% in AUC success rate on OTB-2013, OTB-2015, and Temple Color-128 dataset, respectively. Our proposed tracker with deep features achieves AUC success rate of 69.1% on OTB-2013 dataset. Besides, our proposed tracker with hand-crafted features achieves a gain of 3.94% in EAO on VOT-2018 dataset. Moreover, the proposed tracker performs favorably against several representative state-of-the-art methods regarding precision and success rate.

The underwater vehicle-manipulator systems (UVMS) face significant challenges in trajectory tracking and motion planning because of external disturbance (current and payload) and kinematic redundancy. Former algorithms can finish the tracking of end-effector (EE) and free of singularity redundancy solution alone. However, only a few analytical studies have been conducted on coordinated motion planning of UVMS considering the dynamics controller. This article introduces a combined dynamics and kinematics networked fuzzy task priority motion planning method to solve the above problems. It avoids the assumption of perfect dynamic control. Firstly, to eliminate the kinematics error, a dynamic transformation method from joint space to task space is proposed. Without chattering, an outer loop sliding mode controller is designed for tracking EE’s trajectory. Further, to ensure the underwater vehicle’ posture stability and joint constraint, a task priority frame with kinematics error is used to planning the coordinated motion of UVMS, in which the posture and joint limits map into the null space of prioritized tasks, and weight gains are adopted to guarantee orthogonality of secondary tasks. On top of that, the gain weighted are updated by the networked fuzzy logic. The proposed algorithm achieves better coordinated motion planning and tracking performance. Effectiveness is validated by numerical simulation.

BackgroundSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) induced Coronavirus Disease 2019 (COVID-19) has posed a global threat to public health. The immune system is crucial in defending and eliminating the virus and infected cells. However, immune dysregulation may result in the rapid progression of COVID-19. Here, we evaluated the subsets, phenotypic and functional characteristics of natural killer (NK) and T cells in patients with COVID-19 and their associations with disease severity.MethodsDemographic and clinical data of COVID-19 patients enrolled in Wuhan Union Hospital from February 25 to February 27, 2020, were collected and analyzed. The phenotypic and functional characteristics of NK cells and T cells subsets in circulating blood and serum levels of cytokines were analyzed via flow cytometry. Then the LASSO logistic regression model was employed to predict risk factors for the severity of COVID-19.ResultsThe counts and percentages of NK cells, CD4+ T cells, CD8+ T cells and NKT cells were significantly reduced in patients with severe symptoms. The cytotoxic CD3-CD56dimCD16+ cell population significantly decreased, while the CD3-CD56dimCD16- part significantly increased in severe COVID-19 patients. More importantly, elevated expression of regulatory molecules, such as CD244 and programmed death-1 (PD-1), on NK cells and T cells, as well as decreased serum cytotoxic effector molecules including perforin and granzyme A, were detected in patients with COVID-19. The serum IL-6, IL-10, and TNF-α were significantly increased in severe patients. Moreover, the CD3-CD56dimCD16- cells were screened out as an influential factor in severe cases by LASSO logistic regression.ConclusionsThe functional exhaustion and other subset alteration of NK and T cells may contribute to the progression and improve the prognosis of COVID-19. Surveillance of lymphocyte subsets may in the future enable early screening for signs of critical illness and understanding the pathogenesis of this disease.

Complement, as a central immune surveillance system, can be activated within seconds upon stimulation, thereby displaying multiple immune effector functions. However, in pathologic scenarios (like in tumor progression), activated complement can both display protective effects to control tumor development and passively promotes the tumor growth. Clinical investigations show that patients with several hematological malignancies often display abnormal level of specific complement components, which in turn modulates complement activation or deregulated cascade. In the past decades, complement-dependent cytotoxicity and complement-dependent cell-mediated phagocytosis were fully approved to display vital roles in monoclonal antibody-based immunotherapies, especially in therapies against hematological malignancies. However, tumor-mediated complement evasion presents a big challenge for such a therapy. This review aims to provide an integrative overview on the roles of the complement in tumor promotion, highlights complement mediated effects on antibody-based immunotherapy against distinct hematological tumors, hopefully provides a theoretical basis for the development of complement-based cancer targeted therapies.

The complement system, originally classified as part of innate immunity, is a tightly self-regulated system consisting of liquid phase, cell surface, and intracellular proteins. In the blood circulation, the complement system, platelets, coagulation system, and fibrinolysis system form a close and complex network. They activate and regulate each other and jointly mediate immune monitoring and tissue homeostasis. The dysregulation of each cascade system results in clinical manifestations and the progression of different diseases, such as sepsis, atypical hemolytic uremic syndrome, C3 glomerulonephritis, systemic lupus erythematosus, or ischemia–reperfusion injury. In this review, we summarize the crosstalk between the complement system, platelets, and coagulation, provide integrative insights into how complement dysfunction leads to hemopathic progression, and further discuss the therapeutic relevance of complement in hemolytic and thrombotic diseases.

Background: Aquaporin 1 (AQP-1), a transmembrane water channel protein, has been proven to involve in many diseases' progression and prognosis. This research aims to explore the prognostic value of AQP-1 in elderly cytogenetically normal acute myeloid leukemia (CN-AML).Methods: Complete clinical and expression data of 226 elderly patients (aged > 60) with cytogenetically normal acute myeloid leukemia (CN-AML) were downloaded from the databases of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). We have explored prognostic significance of AQP-1, investigated the underlying mechanism, and developed a novel scoring system for the risk assessment of elderly patients with AML based on AQP1 methylation.Results: In the first and second independent group, AQP1 shows lower expression in CN-AML than normal people, while high AQP1 expression and AQP1 promoter hypomethylation were related to better overall survival (OS; P < 0.05). To understand the underlying mechanisms, we investigated differentially expressed genes (DEGs), miRNA and lncRNA associated with AQP1 methylation. A three-gene prognostic signature based on AQP1 methylation which was highly correlated with OS was established, and the performance was validated by Permutation Test and Leave-one-out Cross Validation method. Furthermore, an independent cohort was used to verify the prognostic value of this model.Conclusions: AQP1 methylation could serve as an independent prognostic biomarker in elderly CN-AML, and may provide new insights for the diagnosis and treatment for elderly CN-AML patients.

Summary: Plasma membrane damage and cell death during processes such as necroptosis and apoptosis result from cues originating intracellularly. However, death caused by pore-forming agents, like bacterial toxins or complement, is due to direct external injury to the plasma membrane. To prevent death, the plasma membrane has an intrinsic repair ability. Here, we found that repair triggered by pore-forming agents involved TMEM16F, a calcium-activated lipid scramblase also mutated in Scott’s syndrome. Upon pore formation and the subsequent influx of intracellular calcium, TMEM16F induced rapid “lipid scrambling” in the plasma membrane. This response was accompanied by membrane blebbing, extracellular vesicle release, preserved membrane integrity, and increased cell viability. TMEM16F-deficient mice exhibited compromised control of infection by Listeria monocytogenes associated with a greater sensitivity of neutrophils to the pore-forming Listeria toxin listeriolysin O (LLO). Thus, the lipid scramblase TMEM16F is critical for plasma membrane repair after injury by pore-forming agents. : Pore-forming agents like bacterial toxins or complement kill cells by attacking the plasma membrane. Wu et al. show that the calcium-activated lipid scramblase TMEM16F promotes plasma membrane repair after pore formation by enhancing membrane fluidity and facilitating release of extracellular vesicles containing damaged membranes. Keywords: TMEM16F, ANO6, scramblase, lipid scrambling, plasma membrane repair, pore forming, Listeria, listeriolysin O, phosphatidylserine exposure, extracellular vesicles, calcium

Two kinds of organic phosphate nucleating agent (NA-11 and NA-21) were used in PP with different molecular weights through the melt extrusion method. The dispersibility of the nucleating agents in PP, and the effect of the nucleating agents on the molecular weight, rheological behavior and crystallization behavior of PP were investigated. SEM and TEM analysis showed that the average radius of the dispersed particles (nucleating agents) was larger in LPP than that in HPP. The good dispersion of NA-21 also created more nucleation embryos for the adsorption of polypropylene molecules than the agglomerated NA-11. The gel permeation chromatography (GPC) analysis showed that the average molecular weight of HPP and LPP both decreased with the addition of a nucleating agent. The rotational rheometer and capillary rheometer analysis showed that the effect of NA-21 on reducing intermolecular entanglement was more significant, whether in HPP or LPP. The addition of NA-21 had less elastic energy storage and better flow stability, and could be processed at a higher speed. Simultaneously, the relaxation time in the blends with LPP was shorter than that with HPP. It was found that the crystallinity and nucleation efficiency of HPP/nucleating agent blends increased remarkably, while there was a barely perceptible increase in LPP/nucleating agent blends.

The product warranty has become an indispensable facet of business operations. Burn-in is effective at eliminating infant mortality and improving operational reliability levels for consumers. This paper considers the influence of different failure states and different phases of product reliability and warranty policies on warranty costs from predelivery inspection to the end of the warranty period. We then propose a comprehensive warranty cost model that considers burn-in, free replacement warranty and pro-rata warranty as three phases for repairable products presenting two types of failure (minimal and catastrophic failure) that involve minimal repair and replacement, respectively. Warranty costs are the result of a combination of the three phases, where two types of failure occur individually or simultaneously. Moreover, we developed a framework for the modeling process of warranty costs, and the effects of various parameters, such as the burn-in time, warranty period, and distribution function on warranty costs, were analyzed. Finally, a practical case was examined by using a warranty cost model, and through an after-sales service data analysis, we obtained the failure rate distribution and optimal warranty length by minimizing the average warranty cost, which can serve as a reference for manufacturers when developing warranty policies.

Tertiary lymphoid organs (TLOs) frequently develop locally in adults in response to non-resolving inflammation. Chronic inflammation leads to the differentiation of stromal fibroblast cells toward lymphoid tissue organizer-like cells, which interact with lymphotoxin α1β2+ immune cells. The interaction initiates lymphoid neogenesis by recruiting immune cells to the site of inflammation and ultimately leads to the formation of TLOs. Mature TLOs harbor a segregated T-cell zone, B-cell follicles with an activated germinal center, follicular dendritic cells, and high endothelial venules, which architecturally resemble those in secondary lymphoid organs. Since CXCL13 and LTα1β2 play key roles in TLO neogenesis, they might constitute potential biomarkers of TLO activity. The well-developed TLOs actively regulate local immune responses and influence disease progression, and they are thereby regarded as the powerhouses of local immunity. In this review, we recapitulated the determinants for TLOs development, with great emphasis on the fundamental role of chronic inflammation and tissue-resident stromal cells for TLO neogenesis, hence offering guidance for therapeutic interventions in TLO-associated diseases.

Vascular smooth muscle cells (VSMCs) constitute the major cells in the media layer of arteries, and are critical to maintain the integrity of the arterial wall. They participate in arterial wall remodeling, and play important roles in atherosclerosis throughout all stages of the disease. Studies demonstrate that VSMCs can adopt numerous phenotypes depending on inputs from endothelial cells (ECs) of the intima, resident cells of the adventitia, circulating immune cells, hormones, and plasma lipoproteins. This plasticity allows them to perform multiple tasks in physiology and disease. In this minireview, we focus on a previously underappreciated activity of VSMCs, i.e., their impact on atherosclerosis immunity via formation of artery tertiary lymphoid organs (ATLOs).

The Discriminative Correlation Filter (DCF) has been universally recognized in visual object tracking, thanks to its excellent accuracy and high speed. Nevertheless, these DCF-based trackers perform poorly in long-term tracking. The reasons include the following aspects—first, they have low adaptability to significant appearance changes in long-term tracking and are prone to tracking failure; second, these trackers lack a practical re-detection module to find the target again after tracking failure. In our work, we propose a new long-term tracking strategy to solve these issues. First, we make the best of the static and dynamic information of the target by introducing the motion features to our long-term tracker and obtain a more robust tracker. Second, we introduce a low-rank sparse dictionary learning method for re-detection. This re-detection module can exploit a correlation among these training samples and alleviate the impact of occlusion and noise. Third, we propose a new reliability evaluation method to model an adaptive update, which can switch expediently between the tracking module and the re-detection module. Massive experiments demonstrate that our proposed approach has an obvious improvement in precision and success rate over these state-of-the-art trackers.

A new structural material named “steel fiber polymer structural concrete (SFPSC)” with features of both high strength and high toughness was developed by this research group and applied to the bridge superstructures in the hot-wet environments. In order to investigate the fatigue performance and durability of SFPSC under hot-wet environments, the environment and fatigue load uncoupling method and the coupling action of environment and fatigue load were used or developed. Three-point bending fatigue experiments with uncoupling action of environments and cyclic loads were carried out for SFPSC specimens which were pretreated under hot-wet environments, and the experiments with the coupling action of environments and cyclic loads for SFPSC specimens were carried out under hot-wet environments. Then, the effects of hot-wet environments and the experimental methods on the fatigue mechanism of SFPSC material were discussed, and the environmental fatigue equations of SFPSC material under coupling and uncoupling action of hot-wet environments and cyclic bending loads were established. The research results show that the fatigue limits of SFPSC under the coupling action of the environments and cyclic loads were lower about 15%. The proposed fatigue equations could be used to estimate the fatigue lives and fatigue limits of SFPSC material.

Candida albicans, the important human fungal pathogen uses multiple evasion strategies to control, modulate and inhibit host complement and innate immune attack. Clinical C. albicans strains vary in pathogenicity and in serum resistance, in this work we analyzed sequence polymorphisms and variations in the expression levels of two central fungal complement evasion proteins, Gpm1 (phosphoglycerate mutase 1) and Pra1 (pH-regulated antigen 1) in thirteen clinical C. albicans isolates. Four nucleotide (nt) exchanges, all representing synonymous exchanges, were identified within the 747-nt long GPM1 gene. For the 900-nt long PRA1 gene, sixteen nucleotide exchanges were identified, which represented synonymous, as well as non-synonymous exchanges. All thirteen clinical isolates had a homozygous exchange (A to G) at position 73 of the PRA1 gene. Surface levels of Gpm1 varied by 8.2, and Pra1 levels by 3.3 fold in thirteen tested isolates and these differences influenced fungal immune fitness. The high Gpm1/Pra1 expressing candida strains bound the three human immune regulators more efficiently, than the low expression strains. The difference was 44% for Factor H binding, 51% for C4BP binding and 23% for plasminogen binding. This higher Gpm1/Pra1 expressing strains result in enhanced survival upon challenge with complement active, Factor H depleted human serum (difference 40%). In addition adhesion to and infection of human endothelial cells was increased (difference 60%), and C3b surface deposition was less effective (difference 27%). Thus, variable expression levels of central immune evasion protein influences immune fitness of the human fungal pathogen C. albicans and thus contribute to fungal virulence.