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Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the TATA-box binding protein gene (TBP). The disease has a varied age at onset and clinical presentation. It is distinct from other SCAs for its association with dementia, psychiatric symptoms, and some patients presenting with chorea. For this reason, it is also called Huntington’s disease-like 4 (HDL-4). Here we examine the distribution of SCA17 allele repeat sizes in a United Kingdom-based cohort with ataxia and find that fully penetrant pathogenic alleles are very rare (5 in 1,316 chromosomes; 0.38%). Phenotype-genotype correlation was performed on 30 individuals and the repeat structure of their TBP genes was examined. We found a negative linear correlation between total CAG repeat length and age at disease onset and, unlike SCA1, there was no correlation between the longest contiguous CAG tract and age at disease onset. We were unable to identify any particular phenotypic trait that segregated with particular CAG/CAA repeat tract structures or repeat lengths. One individual within the cohort was homozygous for variable penetrance range SCA17 alleles. This patient had a similar age at onset to heterozygotes with the same repeat sizes, but also presented with a rapidly progressive dementia. A pair of monozygotic twins within the cohort presented 3 years apart with the sibling with the earlier onset having a more severe phenotype with dementia and chorea in addition to the ataxia observed in their twin. This appears to be a case of variable expressivity, possibly influenced by other environmental or epigenetic factors. Finally, there was an asymptomatic father with a severely affected child with an age at onset in their twenties. Despite this, they share the same expanded allele repeat sizes and sequences, which would suggest that there is marked difference in the penetrance of this 51-repeat allele. We therefore propose that the variable penetrance range extend from 48 repeats to incorporate this allele. This study shows that there is variability in the presentation and penetrance of the SCA17 phenotype and highlights the complexity of this disorder.

BackgroundThis study aimed to explore the mechanism of action of DiWuYangGan (DWYG) capsule in improving Immunological non-responder (INR) by analyzing the active ingredients of DWYG.MethodsThe study employed a randomized, controlled, double-blind, single-simulation method. Patients were randomly divided into control and trial groups and treated with the primal highly effective antiretroviral therapy. To demonstrate the effect of DWYG on INR, patients in the control group were administered simulated DWYG, whereas patients in the trial group were administered DWYG capsules (ChiCTR1900024673). The chemical composition of DWYG was analyzed using ultra-performance liquid chromatography-high-resolution mass spectrometry. Potential targets of DWYG in the treatment of INR were identified and predicted using network pharmacology and molecular docking. The molecular mechanisms underlying the effects of DWYG were validated using a peripheral blood monocyte model.ResultsThe CD4:CD8 ratio in the trial group was significantly higher than that in the control group (p < 0.01). A total of 210 DWYG compounds were identified and network pharmacology revealed 182 potential therapeutic targets for DWYG and INR. The results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the toll-like receptor signaling pathway is one of the key pathways. This study demonstrated that DWYG reduced the expression level of TLR4 and the levels of IL-2, IL-10, and TNF-α, which are important cytokines involved in the immune response.ConclusionThe efficacy of DWYG in the treatment of INR confirmed the potential practical components of DWYG. Moreover, the results of network pharmacology and experimental validation showed that DWYG could restore the immune function of acquired immune deficiency syndrome patients by inhibiting the expression of TLR4 and related signaling pathways and the overactivation of immune function.Clinical Trial Registration:https://www.chictr.org.cn/index.html, identifier ChiCTR1900024673.

IntroductionThe detection rate of benign thyroid nodules is increasing every year, with some affected patients experiencing symptoms. Ultrasound-guided thermal ablation can reduce the volume of nodules to alleviate symptoms. As the degree and speed of lesion absorption vary greatly between individuals, an effective model to predict curative effect after ablation is lacking. This study aims to predict the efficacy of ultrasound-guided thermal ablation for benign thyroid nodules using machine learning and explain the characteristics affecting the nodule volume reduction ratio (VRR).DesignProspective studyPatientsThe clinical and ultrasonic characteristics of patients who underwent ultrasound-guided thermal ablation of benign thyroid nodules at our hospital between January 2020 and January 2023 were recorded.MeasurementsSix machine learning models (logistic regression, support vector machine, decision tree, random forest, eXtreme Gradient Boosting [XGBoost], and Light Gradient Boosting Machine [LGBM]) were constructed to predict efficacy; the effectiveness of each model was evaluated, and the optimal model selected. SHapley Additive exPlanations (SHAP) was used to visualize the decision process of the optimal model and analyze the characteristics affecting the VRR.ResultsIn total, 518 benign thyroid nodules were included: 356 in the satisfactory group (VRR ≥70% 1 year after operation) and 162 in the unsatisfactory group. The optimal XGBoost model predicted satisfactory efficacy with 78.9% accuracy, 88.8% precision, 79.8% recall rate, an F1 value of 0.84 F1, and an area under the curve of 0.86. The top five characteristics that affected VRRs were the proportion of solid components < 20%, initial nodule volume, blood flow score, peripheral blood flow pattern, and proportion of solid components 50–80%.ConclusionsThe models, based on interpretable machine learning, predicted the VRR after thermal ablation for benign thyroid nodules, which provided a reference for preoperative treatment decisions.

Background and PurposeThe risk of skin injuries in space is increasing with longer space missions and a growing astronaut population. This highlights the importance of understanding the adverse effects of weightlessness on wound healing. The objective of this research was to examine the therapeutic potential of Low-Level Light Therapy (LLLT) on skin healing processes under simulated microgravity (SMG) conditions and uncover the underlying molecular mechanisms, thus providing innovative solutions and a sound theoretical basis for space skin injuries.MethodsHindlimb unloading (HU) mice models were used to simulate weightlessness conditions, with or without a complete management of LLLT for 14 days. A systematic testing consisting of HE, Masson and immunohistochemical staining was performed against the standardized mouse tissue specimens. In vitro assessment of cellular biological functions under SMG conditions was carried out in the rotation system of culture (RSOC) using HaCaT and NIH3T3 cell-lines.ResultsUnder SMG conditions, LLLT significantly reduced skin wound area in HU mice, especially on Days 10 (p < 0.001), accompanied by increased collagen deposition and elevated levels of Ki67 and CD31. Moreover, LLLT showed impressive anti-inflammatory effects represented by the reduced in pro-inflammatory markers including LY6G, F4/80 and CD86, as well as the decreased levels of IL-1β, IL-6 and TNF-α. Conversely, an elevation in the anti-inflammatory marker CD206 was observed. By employing bioinformatics technology, we further found the PI3K/AKT signaling was prominent in the KEGG pathway analysis and CCR2 acted as a hub gene in the interaction network. Therefore, we demonstrated that LLLT could enhance the phosphorylation of PI3K/AKT and reduce CCR2 expression under SMG conditions, while CCR2 knockdown promoted the phosphorylation of PI3K/AKT, suggesting an important role of CCR2/PI3K/AKT signal axis in LLLT-accelerated wound healing under SMG conditions.ConclusionLLLT induced activation of the PI3K/AKT signaling pathway through suppression of CCR2 expression, which significantly enhanced skin wound healing under SMG conditions.s.

IntroductionAnti-GBM diseases with IgA deposition in the mesangial region are rarely described.The factors influencing renal prognosis in patients with anti-GBM disease combined with mesangial IgA deposition are unknown.MethodsWe searched the pathological reports of the First Affiliated Hospital of Zhengzhou University from 2015 to 2023 and found that a total of 72 patients with the anti-GBM disease and 25 patients combined with mesangial IgA deposition. We studied the clinical and pathological features, renal prognosis, and the factors affecting renal prognosis in patients with anti-GBM disease combined with mesangial IgA deposition.ResultsTheir median age was 44 years, and their age distribution was unimodal. The proportion of oliguria or anuria in patients with anti-GBM disease combined with mesangial IgA deposition was significantly lower than that in patients with classic anti-GBM disease (13.04 vs. 42.31%, p=0.030). Their 24-hour urinary protein excretion was significantly higher [median:3.25 vs. 1.12g/24h, Interquartile range(IQR):1.032~3.945 vs. 0.63~1.79g/24h, p=0.020], serum creatinine (SCr) level at the initial diagnosis was lower(median:456.0 vs. 825.5μmol/L, IQR:270.0~702.0 vs. 515.8~1231.2μmol/L, p=0.002), peak SCr level was lower (median: 601.0 vs. 907.2μmol/L, IQR: 376.5~937.0 vs. 607.0~1361.2μmol/L, p=0.007), and their serum complement 3(C3) level was higher(median: 1.275 vs. 1.015g/L, IQR:1.097~1.462 vs. 0.850~1.220g/L, p=0.027). They had better renal outcomes during follow-up (p

The treatment of aseptic inflammation has always been a clinical challenge. At present, non-steroidal drug-loaded microspheres have been widely used in the treatment of aseptic inflammation due to their excellent injectable and sustained release capabilities. In this study, ketoprofen-loaded shellac microspheres (Keto-SLAC) were prepared by electrospray. Alterations of Keto-SLAC morphology was observed in response to changed shellac concentration in ethanol solution through electrospray. Further examination revealed that ketoprofen presented as amorphous solid dispersion in the shellac microspheres. Most importantly, it was also shown that ketoprofen can be slowly released from the shellac matrix for up to 3 weeks. In vitro cell experiments verified that the microspheres had favorable cell compatibility. We therefore proposed that the prepared microspheres, being readily available in use in a variety of clinical settings through topical application, have promising therapeutic potential for the treatment of aseptic inflammation.

The forest experience is good for people’s physical and mental health. However, few studies on the effects of pure forest based on the duration and way of experience on people’s physical and mental recovery. In this study, we took 180 first-year college students as research objects and conducted experiments in Pinus sylvestris and Betula platyphylla and the control group of grass plot. The changes of physiological and psychological indexes of the subjects were compared by two perception methods (onsite perception, video perception) and three perception duration (10 min, 20 min, 30 min). The results indicated that: (1) Differences between the two pure forests were mainly reflected in short-term recovery of diastolic blood pressure (DBP) and long-term recovery of total mood disorder (TMD). (2) Video perception was more conducive to short-term recovery of systolic blood pressure (SBP) and diastolic blood pressure (DBP). (3) Viewing the Pinus sylvestris for 20 min in different ways was the best way to relieve stress. It is suggested that, Pinus sylvestris can be used as the rehabilitation perception material, and reasonable path length or perception time can be selected for landscape construction in future. These results can provide scientific reference for landscape design based on forest health and environmental perception.

IntroductionProtocadherin-19 (PCDH19)-Clustering Epilepsy (PCE) is a developmental and epileptic encephalopathy caused by loss-of-function variants of the PCDH19 gene on the X-chromosome. PCE affects females and mosaic males while male carriers are largely spared. Mosaic expression of the cell adhesion molecule PCDH19 due to random X-chromosome inactivation is thought to impair cell–cell interactions between mutant and wild type PCDH19-expressing cells to produce the disease. Progress has been made in understanding PCE using rodent models or patient induced pluripotent stem cells (iPSCs). However, rodents do not faithfully model key aspects of human brain development, and patient iPSC models are limited by issues with random X-chromosome inactivation.MethodsTo overcome these challenges and model mosaic PCDH19 expression in vitro, we generated isogenic female human embryonic stem cells with either HA-FLAG-tagged PCDH19 (WT) or homozygous PCDH19 knockout (KO) using genome editing. We then mixed GFP-labeled WT and RFP-labeled KO cells and generated human cortical organoids (hCOs).ResultsWe found that PCDH19 is highly expressed in early (days 20–35) WT neural rosettes where it co-localizes with N-Cadherin in ventricular zone (VZ)-like regions. Mosaic PCE hCOs displayed abnormal cell sorting in the VZ with KO and WT cells completely segregated. This segregation remained robust when WT:KO cells were mixed at 2:1 or 1:2 ratios. PCE hCOs also exhibited altered expression of PCDH19 (in WT cells) and N-Cadherin, and abnormal deep layer neurogenesis. None of these abnormalities were observed in hCOs generated by mixing only WT or only KO (modeling male carrier) cells.DiscussionOur results using the mosaic PCE hCO model suggest that PCDH19 plays a critical role in human VZ radial glial organization and early cortical development. This model should offer a key platform for exploring mechanisms underlying PCE-related cortical hyperexcitability and testing of potential precision therapies.

Introduction: Gene-edited pigs have become prominent models for studying human disease mechanisms, gene therapy, and xenotransplantation. CRISPR (clustered regularly interspaced short palindromic repeats)/CRISPR-associated 9 (CRISPR/Cas9) technology is a widely employed tool for generating gene-edited pigs. Nevertheless, delivering CRISPR/Cas9 to pre-implantation embryos has traditionally posed challenges due to its reliance on intricate micromanipulation equipment and specialized techniques, resulting in high costs and time-consuming procedures. This study aims to introduce a novel one-step approach for generating genetically modified pigs by transducing CRISPR/Cas9 components into pre-implantation porcine embryos through oviductal injection of recombinant adeno-associated viruses (rAAV).Methods: We first used rAAV-1, rAAV-6, rAAV-8, rAAV-9 expressing EGFP to screen for rAAV serotypes that efficiently target porcine embryos, and then, to achieve efficient expression of CRISPR/Cas9 in vivo for a short period, we packaged sgRNAs targeting the GHR genes to self-complementary adeno-associated virus (scAAV), and Cas9 proteins to single-stranded adeno-associated virus (ssAAV). The efficiency of porcine embryos -based editing was then validated in vitro. The feasibility of this one-step method to produce gene-edited pigs using rAAV-CRISPR/Cas9 oviductal injection into sows within 24 h of conception was then validated.Results: Our research firstly establishes the efficient delivery of CRISPR/Cas9 to pig zygotes, both in vivo and in vitro, using rAAV6. Successful gene editing in pigs was achieved through oviductal injection of rAAV-CRISPR/Cas9.Conclusion: This method circumvents the intricate procedures involved in in vitro embryo manipulation and embryo transfers, providing a straightforward and cost-effective approach for the production of gene-edited pigs.

BackgroundDocetaxel combined with prednisone plus androgen deprivation therapy (ADT) is the preferred treatment option for metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC). With the development of next-generation hormonal agents (NHAs) and poly (ADP-ribose) polymerase (PARP) inhibitors, more aggressive first-line or later-line treatment strategies have been added to the treatment of mHSPC and mCRPC. However, docetaxel rechallenge (DR) has special clinical significance in patients with “docetaxel-sensitive” prostate cancer. There are no reports on the efficacy and safety of the second DR in mCRPC patients.Case presentationWe report one patient diagnosed with mCRPC who showed progression-free survival (PFS) and overall survival (OS) benefits and safety and good lower urinary tract function after the second DR.ConclusionThe second DR as a potential alternative later-line treatment strategy should be considered for patients with mCRPC who worry about the high economic burden of multigene molecular testing and PARP inhibitors as well as repeated prostate needle biopsy.

Background and purposeRevascularization surgery for patients with moyamoya disease (MMD) is very complicated and has a high rate of postoperative complications. This pilot study aimed to prove the safety and efficacy of remote ischemic conditioning (RIC) in adult MMD patients undergoing revascularization surgery.MethodsA total of 44 patients with MMD were enrolled in this single-center, open-label, prospective, parallel randomized study, including 22 patients assigned to the sham group and 22 patients assigned to the RIC group. The primary outcome was the incidence of major neurologic complications during the perioperative period. Secondary outcomes were the modified Rankin Scale (mRS) score at discharge, at 90 days post-operation, and at 1 year after the operation. The outcome of safety was the incidence of adverse events associated with RIC. Blood samples were obtained to monitor the serum concentrations of cytokines (VEGF, IL-6).ResultsNo subjects experienced adverse events during RIC intervention, and all patients could tolerate the RIC intervention in the perioperative period. The incidence of major neurologic complications was significantly lower in the RIC group compared with the control group (18.2% vs. 54.5%, P = 0.027). The mRS score at discharge in the RIC group was also lower than the control group (0.86 ± 0.99 vs. 1.18 ± 1.22, P = 0.035). In addition, the serum IL-6 level increased significantly at 7 days after bypass surgery in the control group and the serum level of VEGF at 7 days post-operation in the RIC group.ConclusionIn conclusion, our study demonstrated the neuroprotective effect of RIC by reducing perioperative complications and improving cerebral blood flow in adult MMD patients undergoing revascularization surgery. Thus, RIC seems to be a potential treatment method for MMD.Clinical trial registrationClinicalTrials.gov, identifier: NCT05860946.

BackgroundInflammation is a factor that promotes tumor progression and immunosuppression. Lung immune prognostic index (LIPI) is a non-invasive and easily calculated indicator of inflammation. This study aimed to investigate whether continuous assessment of LIPI has predictive value for chemoimmunotherapy in non-small cell lung cancer (NSCLC) patients receiving first-line programmed cell death 1 (PD-1) inhibitor plus chemotherapy. In addition, the predictive value of LIPI in patients with the negative or low programmed death-ligand (PD-L1) expression level was also explored.MethodsTotally, 146 stage IIIB to IV or recurrent NSCLC patients who received first-line PD-1 inhibitor combined with chemotherapy were enrolled in this study. The LIPI scores were calculated at baseline (PRE-LIPI) and after two cycles of the combined administration (POST-LIPI). This study analyzed the relationship between good/intermediate/poor PRE (POST)-LIPI and objective response rate (ORR), as well as progression-free survival (PFS) using logistic and Cox regression models. In addition, the predictive value of LIPI in patients with the negative or low PD-L1 expression level was explored. To further assess the potential predictive value of continuous assessment of LIPI, the association of sum (LIPI) [sum(LIPI) = PRE-LIPI + POST-LIPI] and PFS was analyzed in the 146 patients.ResultsCompared with good POST-LIPI group, significantly lower ORRs were found in intermediate POST-LIPI (P = 0.005) and poor POST-LIPI (P = 0.018) groups. Moreover, intermediate POST-LIPI (P =0.003) and poor POST-LIPI (P < 0.001) were significantly associated with a shorter PFS than good POST-LIPI. Additionally, a higher POST-LIPI score was still significantly associated with poorer treatment efficacy in patients with the negative or low PD-L1 expression level. Moreover, a higher sum (LIPI) score was significantly correlated with a shorter PFS (P = 0.001).ConclusionContinuous assessment of LIPI might be an effective method for predicting the efficacy of PD-1 inhibitor plus chemotherapy in NSCLC patients. In addition, in patients with the negative or low PD-L1 expression level, it might also have a potential predictive value for therapeutic efficacy to continuously assess LIPI during the treatment.

BackgroundMicroglia has gradually gained researchers’ attention in the past few decades and has shown its promising prospect in treating neuropathic pain. Our study was performed to comprehensively evaluate microglia-related neuropathic pain via a bibliometric approach.MethodsWe retrospectively reviewed publications focusing on microglia-related neuropathic pain from 2000 to 2021 in WoSCC. VOS viewer software and CiteSpace software were used for statistical analyses.ResultsA total of 2,609 articles were finally included. A steady increase in the number of relevant publications was observed in the past two decades. China is the most productive country, while the United States shares the most-cited and highest H-index country. The University of London, Kyushu University, and the University of California are the top 3 institutions with the highest number of publications. Molecular pain and Pain are the most productive and co-cited journals, respectively. Inoue K (Kyushu University) is the most-contributed researcher and Ji RR (Duke University) ranks 1st in both average citations per article and H-index. Keywords analyses revealed that pro-inflammatory cytokines shared the highest burst strength. Sex differences, neuroinflammation, and oxidative stress are the emerging keywords in recent years.ConclusionIn the field of microglia-related neuropathic pain, China is the largest producer and the United States is the most influential country. The signaling communication between microglia and neurons has continued to be vital in this field. Sexual dimorphism, neuroinflammation, and stem-cell therapies might be emerging trends that should be closely monitored.

Experiences in natural environments can enhance human wellbeing and promote the recovery of physiological and psychological health. During the COVID-19 pandemic, university students' activity off-campus was limited, thus, the campus environment was particularly important for the recovery of students' physiological and psychological health. Although the benefits of sustained natural exposure are obvious for people's physiological and psychological health, the effects of brief exposure on physiological and psychological are unclear. In the present study, four types of campus environments, including square space, dense forest space, sparse forest space, and waterfront space, were selected to explore the transient recovery effects of different types of campus environments. Sixty university students were recruited, measuring their systolic blood pressure, diastolic blood pressure, and heart rate as physical parameters to assess stress recovery. Respondents also reported scores about their personal feelings in questionnaires to evaluate their psychological states. Both physiological and psychological indicators responded to the brief natural exposure (5 min), and physiological and psychological health was restored. However, only the recovery amounts of psychological indicators were significantly different in waterfront space, dense forest space, and sparse forest space. These results indicate that being compare with other spaces, the brief exposure in the waterfront space was the most beneficial to students' psychological health recovery. This recovery was attributed to the great role played by the sense of escape, but after the brief exposure, the attraction and compatibility of the environment would hinder the psychological health recovery. In conclusion, according to tests on both physiological and psychological aspects, the waterfront environment on campus is the best choice for students' transient health recovery.

BackgroundTubridge flow diverter is a widely used device aimed at reconstructing parent arteries and occluding complex aneurysms in China. The experience of Tubridge in treating small and medium aneurysms is still limited. In this study, we aimed to evaluate the safety and efficacy of the Tubridge flow diverter for the treatment of the two types of aneurysms.MethodsWe reviewed the clinical records of aneurysms treated with a Tubridge flow diverter between 2018 and 2021 in a national cerebrovascular disease center. Cases were divided into small and medium aneurysms according to aneurysm size. The therapeutic process, occlusion rate, and clinical outcome were compared.ResultsIn total, 57 patients and 77 aneurysms were identified. The patients were divided into two groups: small aneurysms (39 patients, 54 aneurysms) and medium aneurysms (18 patients, 23 aneurysms). There were 19 patients with tandem aneurysms (a total of 39 aneurysms) in the two groups, among which 15 patients (30 aneurysms) were in the small aneurysm group and four patients (nine aneurysms) were in the medium aneurysm group. The results show that the mean maximal diameter/neck in the small and medium aneurysms was 3.68/3.25 and 7.61/6.24 mm, respectively. In total, 57 Tubridge flow diverters were successfully implanted without unfolding failure, and there were six patients with new mild cerebral infarction in the small aneurysm group. The complete occlusion rate on the last angiographic follow-up was achieved in 88.46% of the small aneurysms group and 81.82% of the medium aneurysms group. The complete occlusion rate of patients with tandem aneurysms in the last angiographic follow-up was 86.67% (13/15) of the small aneurysms group and 50% (2/4) of the medium aneurysm group. Intracranial hemorrhage was nonencountered in the two groups.ConclusionOur preliminary experience suggests that the Tubridge flow diverter might be a safe and effective treatment for small and medium aneurysms along the internal carotid artery. Long stents may increase the risk of cerebral infarction. Adequate evidence is required to clarify the definite indications and complications in a multicenter randomized controlled trial with a long-term follow-up.

ObjectivesImmune-checkpoint inhibitors (ICIs) combined with chemotherapy are more widely used than monotherapy and have shown better survival in patients with advanced non-small cell lung cancer (NSCLC) without oncogenic driver alterations. The monocyte-to-lymphocyte ratio (MLR) might predict the treatment outcomes of ICI therapy in advanced NSCLC patients but has not yet been investigated. In addition, the cutoff of MLR is controversial. Therefore, the present study aimed to explore the associations between changes in MLR at the initial stage of treatment and clinical outcomes in stage IIIB-IV NSCLC patients receiving first-line PD-1 inhibitor combined with chemotherapy.MethodsThe present study included 139 stage IIIB-IV NSCLC patients treated with first-line PD-1 inhibitor combined with chemotherapy. The blood results were assessed 10 days before initiation of PD-1 inhibitor-based combination therapy (time point 1, baseline) and before the third cycle of combined therapy (time point 2). Compared to altered MLR, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in baseline and in time point 2, patients were divided into decreased MLR/NLR/PLR and increased MLR/NLR/PLR groups. The objective response rate (ORR), progression-free survival (PFS), and the association with the changes in blood indicators were analyzed.ResultsA total of 48 patients were categorized in the decreased MLR group and 91 in the increased MLR group. Patients with decreased MLR had a significantly higher ORR in the univariate (P

BackgroundCardiac rehabilitation (CR) is an essential intervention after acute myocardial infarction (MI). However, it is still unclear whether patients with left ventricular aneurysm (LVA) formation after anterior MI would benefit from CR programs. This clinical trial is designed to assess the role of CR in patients with LVA formation after anterior MI.Trial designThe GRACE study is a single-center, single-blind, prospective, randomized controlled clinical trial in China. 100 subjects aged 18–75 years with LVA formation after anterior MI will be recruited and randomized 1:1 to the CR or control group. Both groups will receive standard drug treatment and routine health education according to the guidelines. Participants in the CR group will additionally receive tailored CR programs delivered over a period of 36 sessions. These participants will then be followed up for 1-year. The primary outcome is peak oxygen uptake measured by cardiopulmonary exercise testing after CR programs. The secondary outcomes are cardiac function and EuroQol 5-Dimension-3 Level index scores after CR program and 1-year and major adverse cardiac cerebrovascular events, a composite of cardiovascular mortality, non-fatal MI, non-fatal stroke, malignant arrhythmia or hospitalization for heart failure during the follow-up period.ConclusionsThis single-center, single-blind, prospective, randomized controlled clinical trial will determine whether CR improves physical capacity and clinical outcomes in patients with LVA formation after anterior MI.Trial registrationChinese Clinical Trial Registry ChiCTR2200058852. Registered on 18 April 2022.

IntroductionSocial anxiety disorder (SAD) and autism spectrum disorder (ASD) are highly overlapping in symptoms and have a high rate of comorbidity, posing challenges in diagnosis and intervention for both disorders. Both disorders are linked to abnormal attention to the eyes, yet how they interactively modulate the attentional process to the eyes remains unclear.MethodsIn this study, we explored how autistic traits and social anxiety in college students separately and together affected different temporal stages of attention to the eyes. Participants were instructed to view virtual faces for 10 s and make an emotional judgment, while their eye movements were recorded.ResultsWe found that social anxiety and autistic traits affected different temporal stages of eye-looking. Social anxiety only affected the first fixation duration on the eyes, while autistic traits were associated with eye avoidance at several time points in the later stage. More importantly, we found an interactive effect of autistic traits and social anxiety on the initial attention to the eyes: Among people scoring high on autistic traits, social anxiety was related to an early avoidance of the eyes as well as attention maintenance once fixated on the eyes.DiscussionOur study suggests the separate and interactive roles of social anxiety and autistic traits in attention to the eyes. It contributes to a deeper understanding of the mechanisms of social attention in both SAD and ASD and highlights the application of psychiatric diagnoses using eye-tracking techniques.

ObjectivesCerebral infarction is the major complication of revascularization surgery in patients with moyamoya disease (MMD), and we analyzed the possible causes of cerebral infarction after revascularization surgery for MMD.MethodsMMD patients who were admitted and underwent surgical revascularization at Shanghai Huashan Hospital from January 2019 to December 2021 were retrospectively analyzed.ResultsA total of 815 patients and 890 revascularization surgeries (677 first revascularization surgeries and 213 second revascularization surgeries) were included in this study; 453 (50.9%) were performed on the left side and 437 (49.1%) on the right side, with 779 (87.5%) combined procedures and 111 (12.5%) indirect bypasses included. The mean patient age at the time of these procedures was 44.6 ± 11.7 years (range 6–72 years). Postoperative cerebral infarctions were observed in 46 (5.17%) surgeries, among which 31 occurred after left hemisphere revascularization surgeries, with an incidence of 6.84%, and 15 occurred after right hemisphere revascularization surgeries, with an incidence of 3.43%. Of these, 30 (65.2%) occurred in the operated hemispheres, 2 (4.3%) in the contralateral hemisphere and 13 (28.3%) in the bilateral hemisphere. There were 11 cases of massive infarction (23.9%). The incidence of postoperative infarction in patients undergoing the first revascularization was 6% (41/677) and 2.3% (5/213) in the second revascularization surgeries. Initial presentation as infarction (P < 0.001), initial presentation as hemorrhage (P < 0.001), hypertension (P = 0.018), diabetes (P = 0.006), 1st or 2nd surgery and surgical side (P = 0.007) were found to be related to postoperative cerebral infarction. Initial presentation as infarction (OR = 2.934, 95% CI 1.453–5.928, P = 0.003), initial presentation as hemorrhage (OR = 0.149, 95% CI 0.035–0.641, P = 0.011), and 1st or 2nd surgery and surgical side (OR = 1.66, 95% CI 1.106–2.491, P = 0.014) were independently associated with cerebral infarction after revascularization surgeries.ConclusionsIn patients with MMD undergoing surgical revascularization, initial presentation as infarction and first revascularization surgery performed on the left hemisphere are independent risk factors for postoperative cerebral infarction, whereas initial presentation as hemorrhage is a protective factor.

The impact of waves on the morphological changes of sheltered mudflats is less well studied compared to that on open flats. To investigate the sensitivity of low-energy sheltered mudflats to hydrodynamics such as waves, we carried out in situ measurements of bed level, currents, and waves on the middle flat of a sheltered mudflat in a bay in southern China. Two 1-month measurements, March 26–26 April 2021, and July 8–8 August 2021, were performed for repetition. We found that the sheltered system was not as stable as it appeared. The maximum intratidal bed-level variation, ΔZ, was

The skin is the largest organ of the body that protects from mechanical, thermal, and physical injury. However, the function and appearance of skin visibly degenerates with age due to its frequent exposure to harmful effects of the environment, including ultraviolet irradiation and hazardous substances, in addition to the progression of oxidative stress in aging. These factors result in phenotypic changes in the skin, including wrinkling, pigmentation, reduced elasticity, and hydration during aging. Many natural antioxidant compounds have been studied extensively to reverse the signs of aging skin. Tocotrienols are a subfamily of vitamin E with potent antioxidant activity. Therefore, supplementation with vitamin E in the form of tocotrienol may efficiently protect skin from aging. In this review, the effects of tocotrienol on skin health, including pigmentation, moisture, and wrinkles during aging and UV exposure, were systematically evaluated based on a literature search of the PubMed and Scopus databases. The present data showed that tocotrienols protect the skin from inflammation, UV radiation and melanin accumulation. As the therapeutic value of tocotrienols grows, the potential of these vitamin E analogs to the skin requires further investigation.

Concern has been raised about how to effectively encourage industrial structure upgrading using green finance as a tool in the framework of sustainable development. This paper is based on the data from 2010 to 2019, the social network had been constructed using the gravitational model. Also, the spatial correlation of green finance development on industrial structure upgrading was studied through using the social network analysis method, as well as the detection analysis of the impact factor of green finance on industrial structure upgrading was conducted by using the geographic detector. The empirical results showed that: green finance and industrial optimization had entered a differentiated development stage in each province; green finance development would have an effect on upgrading industrial structure; and the overall network had established and maintained a benign development trend. This paper suggests that the government must improve the green finance management system as soon as possible, effectively use green finance to promote industrial optimization and introduce policies as per the characteristics of each province in order to promote the coordinated development of green finance in each province.

Background and aimsMaternal depression before and after delivery has dramatically increased in China. Therefore, this study aimed to examine the association between antepartum and postpartum depression and neonatal outcomes.DesignA population-based retrospective cohort study.SettingChina.ParticipantsData were obtained from China Family Panel Studies (CFPS). Different mother-child/infant samples were included in this study. Mother in CFPS2012 and CFPS2016 were linked with 1–2-year-old children in CFPS2014 and CFPS2018, respectively. Besides, and mothers in CFPS2012, CFPS2016, and CFPS2018 were linked with 0–1-year-old infants in CFPS2012, CFPS2016, and CFPS2018, respectively.MethodsMaternal depression was measured using the Center for Epidemiologic Studies Depression Scale. The neonatal outcomes included duration of gestational days, preterm birth, birth weight, birth weight z-score, weight, weight z-score, illness in the past month, and hospitalization in the past year. Propensity score matching was used to balance maternal, family, and infant/child characteristics between the maternal depression and non-maternal depression groups.ResultsMultivariable regression analysis of matched samples estimated that antepartum depression was associated with a shorter duration of gestation by 3.99 days (95% confidence interval [CI] = −7.21, −0.78). The association between antepartum depression and preterm birth, birth weight and birth weight z-score were not statistically significant. Postpartum depression was associated with more episodes of illness in the last month by 0.23 times (95% CI = 0.11, 0.36) and a higher odd of hospitalization in the previous year (OR = 1.59, 95% CI = 1.15, 2.20). The association between postpartum depression and weight or the weight z-score was not significant.ConclusionMaternal depression appears to be associated with worse neonatal outcomes.

Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the TATA-box binding protein gene (TBP). The disease has a varied age at onset and clinical presentation. It is distinct from other SCAs for its association with dementia, psychiatric symptoms, and some patients presenting with chorea. For this reason, it is also called Huntington's disease-like 4 (HDL-4). Here we examine the distribution of SCA17 allele repeat sizes in a United Kingdom-based cohort with ataxia and find that fully penetrant pathogenic alleles are very rare (5 in 1,316 chromosomes; 0.38%). Phenotype-genotype correlation was performed on 30 individuals and the repeat structure of their TBP genes was examined. We found a negative linear correlation between total CAG repeat length and age at disease onset and, unlike SCA1, there was no correlation between the longest contiguous CAG tract and age at disease onset. We were unable to identify any particular phenotypic trait that segregated with particular CAG/CAA repeat tract structures or repeat lengths. One individual within the cohort was homozygous for variable penetrance range SCA17 alleles. This patient had a similar age at onset to heterozygotes with the same repeat sizes, but also presented with a rapidly progressive dementia. A pair of monozygotic twins within the cohort presented 3 years apart with the sibling with the earlier onset having a more severe phenotype with dementia and chorea in addition to the ataxia observed in their twin. This appears to be a case of variable expressivity, possibly influenced by other environmental or epigenetic factors. Finally, there was an asymptomatic father with a severely affected child with an age at onset in their twenties. Despite this, they share the same expanded allele repeat sizes and sequences, which would suggest that there is marked difference in the penetrance of this 51-repeat allele. We therefore propose that the variable penetrance range extend from 48 repeats to incorporate this allele. This study shows that there is variability in the presentation and penetrance of the SCA17 phenotype and highlights the complexity of this disorder. [ABSTRACT FROM AUTHOR]

BackgroundOsteoporosis and atherosclerosis are common in the elderly population, conferring a heavy worldwide burden. Evidence links osteoporosis and atherosclerosis but the exact underlying common mechanism of its occurrence is unclear. The purpose of this study is to further explore the molecular mechanism between osteoporosis and atherosclerosis through integrated bioinformatic analysis.MethodsThe microarray data of osteoporosis and atherosclerosis in the Gene Expression Omnibus (GEO) database were downloaded. The Weighted Gene Co-Expression Network Analysis (WGCNA) and differentially expressed genes (DEGs) analysis were used to identify the co-expression genes related to osteoporosis and atherosclerosis. In addition, the common gene targets of osteoporosis and atherosclerosis were analyzed and screened through three public databases (CTD, DISEASES, and GeneCards). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Metascape. Then, the common microRNAs (miRNAs) in osteoporosis and atherosclerosis were screened out from the Human microRNA Disease Database (HMDD) and the target genes of whom were predicted through the miRTarbase. Finally, the common miRNAs–genes network was constructed by Cytoscape software.ResultsThe results of common genes analysis showed that immune and inflammatory response may be a common feature in the pathophysiology of osteoporosis and atherosclerosis. Six hub genes (namely, COL1A1, IBSP, CTSD, RAC2, MAF, and THBS1) were obtained via taking interaction of different analysis results. The miRNAs–genes network showed that has-let-7g might play an important role in the common mechanisms between osteoporosis and atherosclerosis.ConclusionThis study provides new sights into shared molecular mechanisms between osteoporosis and atherosclerosis. These common pathways and hub genes may offer promising clues for further experimental studies.

SARS-CoV-2 is the causative agent for the global COVID-19 pandemic; however, the interaction between virus and host is not well characterized. Natural killer cells play a key role in the early phase of the antiviral response, and their primary functions are dependent on signaling through the killer cell immunoglobulin-like receptor (KIR). This study measured the association between KIR/HLA class I ligand pairings and the occurrence and development of COVID-19. DNA of blood samples from 257 COVID-19 patients were extracted and used to detect KIR and HLA-C gene frequencies using single strain sequence-specific primer (SSP) PCR. The frequency of these genes was compared among 158 individuals with mild COVID-19, 99 with severe disease, and 98 healthy controls. The frequencies of KIR2DL2 (P=0.04, OR=1.707), KIR2DS3 (P=0.047, OR=1.679), HLA-C1C1 (P

Root border cells (RBCs) are a group of cells that originated from the root cap meristem, which are developed by genetic regulation and play a variety of biological functions. Being composed of a homologous single cell population with high metabolic activity and intact cell walls, RBCs represent a highly useful tool for studying various aspects of plant mineral absorption and utilization, as well as plant-soil-microbiome interactions in the rhizosphere. Research on RBCs also promise to become a hotspot in the context of understanding root adaptive responses to hostile environments. In order to take advantage of RBCs as an ideal single cell system in plant-environmental interactions, we summarized the production and function of RBCs and built-up the methodology for RBCs culturing, purification, and quantity control for plant research. The latter is done by using a case study of the application of RBCs to study mechanisms of Al toxicity in plants. This work offers plant scientists a new cognition of adopting RBCs as a convenient single cell system for the multidisciplinary research including (but not limited to) plant physiology, development and genetics, nutrition, and stress and adaptation. Root border cells (RBCs) are derived from the root cap and represent a population of living cells with special physiological activity and biological roles that are different from the root cap cells per se. After being separated from the root cap, RBCs become more active in metabolism than the progenitor root cap cells; for example, they incorporate labeled amino acids into protein 2.6-fold more efficiently than the cells of the root cap. In addition, mRNA and protein were differentially expressed between root cap cells and RBCs. Since the production of RBCs is genetically regulated and RBCs played a variety of biological functions in resistance to biotic and abiotic stresses occurred in the rhizosphere, RBCs were suggested as an ideal single cell system for the study the response of plant root cells to nutrient availability, environmental stresses, and in plant-microbial interactions. Some studies revealed that RBCs, which development is regulated by endogenous and exogenous signals, are biologically viable in the majority of higher plant species. This work reviews the research on RBCs in plant environment interaction and describes the case study of RBCs as a convenient single cell system to study plant responses to Al toxicity.

IntroductionAssociation of peritoneal protein clearance (Pcl) with outcomes in patients with peritoneal dialysis (PD) is uncertain. Thus, we aimed to investigate its impact on cardiovascular events and all-cause mortality in patients with PD and factors associated with Pcl.MethodsPrevalent patients with PD from January 2014 to April 2015 in the center of Renji Hospital were enrolled. At the time of enrollment, serum and dialysate samples were collected to detect biochemical parameters and Angiopoietin-2-Tie2 system cytokines. Mass transfer area coefficient of creatinine (MTACcr) and Pcl were calculated. Patients were dichotomized into two groups by the median Pcl level (68.5 ml/day) and were followed up prospectively until the end of the study (1 October 2018).ResultsA total of 318 patients with PD [51.2% men, mean age 56.7 ± 14.3 y, median PD duration 31.5 (12.1–57.2) months] were enrolled. Among them, 25.7% were comorbid with diabetes and 28.6% had a history of cardiovascular disease (CVD). After being followed up for up to 43.9 (24.2–50.3) months, 63 had developed cardiovascular events, and 81 patients were died. Among them, the high Pcl group had occurred 39 cardiovascular events and 51 deaths, and the low Pcl group had 24 cardiovascular events and 30 deaths. Kaplan-Meier analysis showed that both the occurrence of cardiovascular events and all-cause mortality were increased in patients with high Pcl. However, after adjusting for important confounders and serum Angiopoietin-2 (Angpt-2) level, Pcl was still an independent risk factor for cardiovascular events [hazard ratio (HR) = 1.006 (1.000–1.012), p = 0.038] but not mortality. On multivariate regression analysis, serum albumin, MTACcr, and body mass index (BMI) were found to be independently associated with Pcl.ConclusionHigh Pcl is an independent risk factor for cardiovascular events but not all-cause mortality. The prediction of cardiovascular events by Pcl was independent of serum Angpt-2.

BackgroundSerum uric acid (SUA) levels was associated with cardiovascular diseases and cardiovascular events. However, the relationship between SUA levels and traditional cardiovascular risk factors has not been well-established among Xiamen residents. Our study aimed to estimate the relationship between SUA levels and cardiovascular risk factors among Xiamen residents using real-world data.MethodsParticipants were enrolled from eight community health service centers in Xiamen, China. Participants were divided into four groups according to quartiles of the SUA levels. The history of diseases, the use of medications and the levels of laboratory parameters were collected. The China-PAR equation was used to evaluate the 10-year atherosclerotic cardiovascular disease (ASCVD) risk.ResultsA total of 1,322 participants were enrolled. About 568 (43.0%) were men and 754 (57.0%) were women. The prevalences of hypertension, elderly, current smokers, and obesity were higher in the quartile 4 (Q4) group than the quartile 1 (Q1) group (all p < 0.001). Multivariable logistic regression analysis showed the OR for hypertension was 2.671 (95% CI 1.777–4.015, p < 0.001) in the Q4 group compared with that in the Q1 group. Further logistic regression showed the OR for hypertension was 3.254 (95% CI 1.756–6.031, p < 0.001) in men and 2.314 (95% CI 1.354–3.955, p = 0.002) in women in the Q4 group compared with that in the Q1 group, respectively. In addition, the percentage of participants with low 10-year ASCVD risk calculated by China-PAR was higher in the Q1 group than that in the Q4 group (55.86 vs. 31.82%, p < 0.001). The percentage of participants with high 10-year ASCVD risk was lower in the Q1 group compared with the Q4 group (15.32 vs. 25.45%, p < 0.001). Multiple linear logistic regression showed the 10-year China-PAR ASCVD risk scores was positively correlated with SUA after adjusting for various factors (β = 0.135, p = 0.001).ConclusionSerum uric acid was associated with several cardiovascular risk factors in Xiamen residents. The percentage of high 10-year ASDVD risk was higher in participants with hyperuricemia. Participants with hyperuricemia may experience cardiovascular benefit from uric acid-lowering therapy.

Sheep are gregarious animals that can form close inter-individual relationships. Social bonds are affected by environmental and within-animal factors, but there is limited understanding of individual factors that influence social relationships, in part due to the challenges of accurately measuring individual social proximity within a group. This study used geospatially precise RTK-GNSS localization devices (Real-Time-Kinematic Global Navigation Satellite System) to evaluate social proximity between individuals with different personality traits in small sheep flocks. First, unsupervised clustering algorithms were used to categorize 78 individual Merino sheep (from a research flock of 108 grazed together for 11 months prior) based on their behavior measured in four behavioral tests: arena, novel object, flight speed, and isolation box. Sixty-five sheep were then categorized into five cohorts of 13 individuals each (clustered into three bold, six bold/fearful, and four fearful animals per cohort). Bold/fearful animals were bold toward a novel object but fearful of a human. Sheep within a single cohort were released into a 0.70 Ha test paddock with RTK-GNSS devices attached to their backs for 3 days to monitor relative positions. All cohorts were tested sequentially over a 5-week period. Social network analyses of GNSS locational data with a distance threshold of up to 30 m for all cohorts together showed no significant effect of personality traits (P = 0.11). There were, however, some significant but inconsistent differences in distances based on personality traits within separate cohorts [i.e., cohorts 1, 3, 4 (P ≤ 0.02), cohorts 2, 5 (P ≥ 0.44)]. When GNSS locational data were analyzed with a distance threshold of up to 2 m (day 2 excluded from all cohorts due to missing values), there was a significant effect of personality traits (P = 0.01) across all cohorts combined. The bold animals showed greater distances from each other relative to their distances from fearful or bold/fearful individuals. Additionally, regardless of personality traits, the average distance between animals decreased 2.2 m over the 3 test days. Social interactions in sheep flocks may be influenced by personality traits of fearfulness and boldness, but further research with larger numbers of sheep across varying environments is needed.

This paper selected Vanke as the case to study the governance problems of Vanke and the protection of the interests of small and medium shareholders under the situation of equity disputes. At the same time, the study further explored the advantages and disadvantages of the dispersed ownership structure, the long-term impact on the company’s development and the choice of the involved corporate governance methods under the current Chinese capital market conditions. This paper adopted the event research method and selected the period from June 2015 to June 2017 (24 months) as the observation period to analyze the market performance impact of Vanke in the equity disputes. At the same time, this paper also measured Vanke’s individual stock rate of return (Rit) and market rate of return (Rmt), and calculated Vanke’s normal rate of return [E(Ri,t)], abnormal rate of return (ARi,t), and cumulative abnormal rate of return (CARi) during different event windows ([−3,10]). Vanke’s shareholding was too dispersed and the stock price had been sluggish for a long time, which had greatly reduced the acquisition difficulty and cost of Baoneng, thus triggering the “barbarian invasion” of Baoneng. In the struggle for control, whether it was Vanke’s anti-takeover measures or China Resources, Baoneng, and Evergrande’s competition for equity, their actions had harmed the interests of small and medium shareholders. The market supervision department was too lenient to supervise and punish the interests of small and medium shareholders, and opportunism made behaviors that infringe on the interests of others more reckless. However, small and medium shareholders cannot actively participate in the company’s management decision-making to safeguard their legitimate rights and interests, which intensifies the violations of all parties in the equity disputes, thus forming a vicious circle. Therefore, the protection of the interests of small and medium shareholders required the joint efforts and consciousness of regulators, small and medium shareholders, and acquirers.

With the development of economic globalization and the policy guidance of International Financial Reporting Standards (IFRS), the overseas investment of Chinese enterprises has been greatly affected. To study the overseas investment risks of Chinese enterprises, this paper applies a risk analysis model to summarize and analyze the results of overseas investment of Haier from 2008 to 2020. This paper defines the risk analysis model as risk identification, risk assessment, and risk response, and studies overseas investment risks including political, economic, cultural, legal, cost, epidemic, and business risks. (1) The existence of various risks is identified in the company’s overseas investment projects; (2). The overseas investment risks of Haier are evaluated, through a comprehensive evaluation method combining qualitative and quantitative, financial data, and market response; (3). In view of the deficiencies of the existing risk prevention measures in the overseas investment of enterprises, some reasonable suggestions are purposed. The innovation of this paper are: This paper combines IFRS 9, IFRS 15, and IFRS 16, selects theories, and combines cases to evaluate the risks of overseas investment that are difficult to quantify, and analyzes the risks of overseas investment by Z-value models and market effects. This research method has pertinence and applicability to enterprises investing overseas.

Background: Anlotinib is a novel anti-angiogenesis drug. In non-small cell lung cancer (NSCLC), high body mass index (BMI) was not associated with worse survival in patients treated with bevacizumab compared with those with normal or low BMI. However, it remains unknown whether such an association still exists in NSCLC patients receiving anlotinib therapy. Hence, we conducted this study to investigate whether BMI is associated with clinical outcomes in patients treated with anlotinib for advanced NSCLC.Methods: Data of 554 patients from the ALTER-0302 and the ALTER-0303 trials were analyzed in this study. The patients were classified into non-obesity (BMI

Growing evidence indicates that gut microbiota factors cannot be viewed as independent in the occurrence of obesity. Because the gut microbiome is highly dimensional and complex, studies on interactions between gut microbiome and host in obesity are still rare. To explore the relationship of gut microbiome–host interactions with obesity, we performed multi-omics associations of gut metagenome, intestinal transcriptome, and host obesity phenotypes in divergently selected obese–lean broiler lines. Metagenomic shotgun sequencing generated a total of 450 gigabases of clean data from 80 intestinal segment contents of 20 broilers (10 of each line). The microbiome comparison showed that microbial diversity and composition in the duodenum, jejunum, ileum, and ceca were altered variously between the lean- and fat-line broilers. We identified two jejunal microbes (Escherichia coli and Candidatus Acetothermia bacterium) and four cecal microbes (Alistipes sp. CHKCI003, Ruminococcaceae bacterium CPB6, Clostridiales bacterium, and Anaeromassilibacillus sp. An200), which were significantly different between the two lines (FDR < 0.05). When comparing functional metagenome, the fat-line broilers had an intensive microbial metabolism in the duodenum and jejunum but degenerative microbial activities in the ileum and ceca. mRNA-sequencing identified a total of 1,667 differentially expressed genes (DEG) in the four intestinal compartments between the two lines (| log2FC| > 1.5 and FDR < 0.05). Multi-omics associations showed that the 14 microbial species with abundances that were significantly related with abdominal fat relevant traits (AFRT) also have significant correlations with 155 AFRT-correlated DEG (p < 0.05). These DEG were mainly involved in lipid metabolism, immune system, transport and catabolism, and cell growth-related pathways. The present study constructed a gut microbial gene catalog of the obese–lean broiler lines. Intestinal transcriptome and metagenome comparison between the two lines identified candidate DEG and differential microbes for obesity, respectively. Multi-omics associations suggest that abdominal fat deposition may be influenced by the interactions of specific gut microbiota abundance and the expression of host genes in the intestinal compartments in which the microbes reside. Our study explored the interactions between gut microbiome and host intestinal gene expression in lean and obese broilers, which may expand knowledge on the relationships between obesity and gut microbiome.

BackgroundDiabetes mellitus (DM) is a frequent comorbidity in patients with cancer. This study aimed to evaluate the prognosis of advanced non-small cell lung cancer (NSCLC) patients with DM and to assess whether an optimal glycemic control improves overall survival (OS).MethodsA total of 1279 advanced NSCLC patients including 300 (23.5%) with preexisting DM were retrospectively reviewed. The continuous relationship between glycated hemoglobin A1C (HbA1c) level and OS was analyzed by restricted cubic spline (RCS) function. Optimal HbA1c cut-off point was determined using X-tile analysis. Survival was analyzed with the Kaplan–Meier method and compared among groups stratified by diabetes status and HbA1c. Multivariable Cox proportional hazards regression analysis was employed to identify prognostic factors for OS after adjusting for baseline characteristics.ResultsDM and non-DM patients had similar OS (median (95% CI): 22.85 (20.05-26.73) vs. 22.22 (20.35-24.76) months, P=0.950). The multivariate Cox regression analyses showed that DM status was not a prognostic factor for OS (HR: 0.952, 95% CI: 0.808-1.122, P=0.559). However, there existed a non-linear but generally positive relationship between the elevated HbA1c level and increased risk of overall mortality. HbA1c > 6.6% was a negative prognostic factor for OS (HR: 1.593, 95% CI: 1.113-2.280, P=0.011). The median OS (95% CI) for nondiabetic patients, DM patients with HbA1c ≤6.6% and those with HbA1c > 6.6% was 22.22 (20.01-24.43), 25.28 (21.79-28.77) and 15.45 (7.57-23.33) months, respectively. Well-controlled DM patients had a comparable crude OS (HR (95% CI): 0.90 (0.76-1.08), P=0.273] compared to nondiabetic patients while patients with HbA1c>6.6% had a worse crude OS than patients without DM (HR (95% CI): 1.70 (1.24-2.34), P=0.001]. The survival benefit of good HbA1c control was prominent in all subgroups.ConclusionImpaired glycemic level negatively affects survival for patients with advanced NSCLC while proper glycemic control with HbA1c ≤6.6% improves the OS.

The blood flow in the coronary artery (CA) is pulsatile and much higher than that measured in the brain, retina, and skin before. Its quantitative measurement is medically significant in the coronary artery bypass grafting (CABG). Here, to the best of our knowledge, we first detect the pulsatile flow using the laser speckle contrast imaging technique. Since the factors influencing the flow rate in the CA are complex, we developed a comprehensive model, a speckle triangle assessment (STA), to assess the characteristics of the flow: the speckle flow index (SFI), mean flow index (MFI), and pulsatility index (PI). The phantom experiment was performed and found that our customized setup possessed high dynamic range of the velocity measurement with good sensitivity. It also indicated that the pulsatile flow estimated by the speckle triangle assessment is promising to obtain a more accurate assessment of a coronary artery’s patency in the CABG.

Cancer pain is one of the main complications in advanced cancer patients, and its management is still challenging. Therefore, there is an urgent need to develop novel pharmacotherapy for cancer pain. Several natural products have attracted the interest of researchers. In previous studies, curcumin has proved to exhibit antitumor, antiviral, antioxidant, anti-inflammatory, and analgesic effects. However, the analgesic mechanism of curcumin has not been elucidated. Thus, in this study, we aimed to elucidate the antinociceptive potency and analgesic mechanism of curcumin in cancer-induced bone pain. Our results showed that consecutive curcumin treatment (30, 60, 120 mg/kg, i.p., twice daily for 11 days) produced significant analgesic activity, but had no effect on the progress of the bone cancer pain. Notably, pretreatment with naloxone, a non-selective opioid receptor antagonist, markedly reversed the antinociceptive effect induced by curcumin. Moreover, in primary cultured rat dorsal root ganglion (DRG) neurons, curcumin significantly up-regulated the expression of proopiomelanocortin (Pomc) and promoted the release of β-endorphin and enkephalin. Furthermore, pretreatment with the antiserum of β-endorphin or enkephalin markedly attenuated curcumin-induced analgesia in cancer-induced bone pain. Our present study, for the first time, showed that curcumin attenuates cancer-induced bone pain. The results also suggested that stimulation of expression of DRG neurons β-endorphin and enkephalin mediates the antinociceptive effect of curcumin in pain hypersensitivity conditions.

The presence of comutations (co-mut+) in DNA damage response and repair (DDR) pathways was associated with improved survival for immune checkpoint inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC). However, it remains unknown whether co-mut+ status could be a predictive biomarker for immunotherapy. We aimed to explore the predictive role of co-mut+ status in the efficacy of ICIs. A total of 853 NSCLC patients from OAK and POPLAR trials were included in the analyses for the relationship between co-mut status and clinical outcomes with atezolizumab treatment. In co-mut+ NSCLC patients, significantly prolonged progression-free survival (PFS) (p = 0.004) and overall survival (OS) (p < 0.001) were observed in atezolizumab over docetaxel. The interaction between co-mut status and treatment was significant for PFS (p for interaction = 0.010) and OS (p for interaction = 0.017). In patients with negative or low programmed death receptor-ligand 1 expression, co-mut+ status still predicted improved clinical outcomes from atezolizumab therapy. These findings suggested that co-mut status may be a promising predictor of ICI therapy in NSCLC.

Bovine Viral Diarrhea Virus (BVDV) is the main pathogen of bovine viral diarrhea disease (BVD), which leads to enormous economic losses in the cattle industry. A sensitive and specific detection for BVDV is advantageous to the control of BVDV. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas systems have been used for detecting virus RNA. In this study, the expression and purification of LwCas13a protein was optimized and the RNase activity of LwCas13a in vitro was verified. CRISPR-LwCas13a system could detect BVDV virus and BVDV RNA with high specificity and simplicity. The detection limit of the LwCas13a system was 103 pM, and there were no cross-reactions with HEK293T and MDBK. In summary, a sensitive, specific, and simple nucleic acid detection method based on CRISPR-Cas13a was developed for BVDV. This method provides a new detection strategy for early diagnosis of BVDV.

Microvascular imaging based on indocyanine green is an important tool for surgeons who carry out extracranial–intracranial arterial bypass surgery. In terms of blood perfusion, indocyanine green images contain abundant information, which cannot be effectively interpreted by humans or currently available commercial software. In this paper, an automatic processing framework for perfusion assessments based on indocyanine green videos is proposed and consists of three stages, namely, vessel segmentation based on the UNet deep neural network, preoperative and postoperative image registrations based on scale-invariant transform features, and blood flow evaluation based on the Horn–Schunck optical flow method. This automatic processing flow can reveal the blood flow direction and intensity curve of any vessel, as well as the blood perfusion changes before and after an operation. Commercial software embedded in a microscope is used as a reference to evaluate the effectiveness of the algorithm in this study. A total of 120 patients from multiple centers were sampled for the study. For blood vessel segmentation, a Dice coefficient of 0.80 and a Jaccard coefficient of 0.73 were obtained. For image registration, the success rate was 81%. In preoperative and postoperative video processing, the coincidence rates between the automatic processing method and commercial software were 89 and 87%, respectively. The proposed framework not only achieves blood perfusion analysis similar to that of commercial software but also automatically detects and matches blood vessels before and after an operation, thus quantifying the flow direction and enabling surgeons to intuitively evaluate the perfusion changes caused by bypass surgery.

Reverse transcription quantitative real-time PCR is the most commonly used method to detect gene expression levels. In experiments, it is often necessary to correct and standardize the expression level of target genes with reference genes. Therefore, it is very important to select stable reference genes to obtain accurate quantitative results. Although application examples of reference genes in mammals have been reported, no studies have investigated the use of reference genes in studying the growth and development of adipose tissue and the proliferation and differentiation of preadipocytes in chickens. In this study, GeNorm, a reference gene stability statistical algorithm, was used to analyze the expression stability of 14 candidate reference genes in the abdominal adipose tissue of broilers at 1, 4, and 7 weeks of age, the proliferation and differentiation of primary preadipocytes, as well as directly isolated preadipocytes and mature adipocytes. The results showed that the expression of the TATA box binding protein (TBP) and hydroxymethylbilane synthase (HMBS) genes was most stable during the growth and development of abdominal adipose tissue of broilers, the expression of the peptidylprolyl isomerase A (PPIA) and HMBS genes was most stable during the proliferation of primary preadipocytes, the expression of the TBP and RPL13 genes was most stable during the differentiation of primary preadipocytes, and the expression of the TBP and HMBS genes was most stable in directly isolated preadipocytes and mature adipocytes. These results provide reference bases for accurately detecting the mRNA expression of functional genes in adipose tissue and adipocytes of chickens.

BackgroundStudies have shown that autoimmune response contributes to chronic hepatitis B (CHB) development.AimThis study aimed to identify autoantibodies in the sera of patients with CHB and to investigate the association of autoimmune response with disease severity in CHB.MethodsProteins from human liver carcinoma cell line HepG2 were separated by two-dimensional electrophoresis. The candidate autoantigens were recognized by serum autoantibodies from Chinese CHB patients. Immunohistochemical staining was performed to determine the hepatic expression of the autoantigen in CHB patients with different inflammatory grades. Enzyme-linked immunosorbent assay (ELISA) was conducted to measure the prevalence and the levels of serum autoantibody in CHB patients with different disease severity. Flow cytometry analysis was carried out to assess the autoreactive T cell response in the peripheral circulation of CHB patients.ResultsErbB-3-binding protein-1 (EBP-1) was identified as an autoantigen of serum autoantibodies in CBP patients. EBP-1 protein expression was upregulated in the liver of CHB patients with high-grade hepatic inflammation. The prevalence and levels of serum anti-EBP1 IgG were significantly increased in CHB patients with severe diseases compared with those with mild or moderate diseases, but none was detectable in the healthy controls. EBP-1 peptides induced proinflammatory cytokine expression in CD4+ T cells from CHB patients.ConclusionOur results demonstrate the presence of an autoantibody against EBP-1 in the sera as well as EBP-1-reactive T cells in the peripheral blood of CHB patient. EBP-1-induced autoimmune response is positively associated with the disease severity, suggesting that EBP-1-induced autoimmune response possibly contributes to progressive liver failure.

Objective: Vascular cognitive impairment (VCI) is a common complication in adult patients with moyamoya disease (MMD), and is reversible by surgical revascularization in its early stage of mild VCI. However, accurate diagnosis of mild VCI is difficult based on neuropsychological examination alone. This study proposed a method of dynamic resting-state functional connectivity (FC) network to recognize global cognitive impairment in MMD.Methods: For MMD, 36 patients with VCI and 43 patients with intact cognition (Non-VCI) were included, as well as 26 normal controls (NCs). Using resting-state fMRI, dynamic low-order FC networks were first constructed with multiple brain regions which were generated through a sliding window approach and correlated in temporal dimension. In order to obtain more information of network interactions along the time, high-order FC networks were established by calculating correlations among each pair of brain regions. Afterwards, a sparse representation-based classifier was constructed to recognize MMD (experiment 1) and its cognitive impairment (experiment 2) with features extracted from both low- and high-order FC networks. Finally, the ten-fold cross-validation strategy was proposed to train and validate the performance of the classifier.Results: The three groups did not differ significantly in demographic features (p > 0.05), while the VCI group exhibited the lowest MMSE scores (p = 0.001). The Non-VCI and NCs groups did not differ significantly in MMSE scores (p = 0.054). As for the classification between MMD and NCs, the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity of the classifier reached 90.70, 88.57, 93.67, and 73.08%, respectively. While for the classification between VCI and Non-VCI, the AUC, accuracy, sensitivity, and specificity of the classifier reached 91.02, 84.81, 80.56, and 88.37%, respectively.Conclusion: This study not only develops a promising classifier to recognize VCI in adult MMD in its early stage, but also implies the significance of time-varying properties in dynamic FC networks.

Background: Obesity and maternal age are the two most important factors independently affecting the risk of gestational diabetes mellitus (GDM). However, the age differences in the association between obesity and GDM remain unclear. The objectives of this cohort study included: (1) to determine the current incidence of GDM in Qingdao; and (2) to evaluate the risk factors for GDM, such as the interaction between pre-pregnancy body mass index (BMI) and age.Methods: The cohort included 17,145 pregnant women who registered at 15 to 20 gestational weeks from August 1, 2018, to March 1, 2019. A 75-g 2-h oral glucose tolerance test (OGTT) was conducted for each participant at 24–28 gestational weeks. The age-adjusted incidence of GDM was calculated using logistic regression. Multivariate logistic regression analysis was used to identify risk factors. Interaction between age (reference group

Ethnopharmacological RelevanceIn Traditional Chinese medicine (TCM) theory, ulcerative colitis (UC) is associated with damp-heat, blood stasis, and intestinal vascular ischemia. Kuijieyuan decoction (KD) is a traditional Chinese medicine based on the above theory and used clinically to alleviate UC injury.MethodsThe main components of KD were analyzed by using high-pressure liquid chromatography (HPLC) and confirmed by UPLC-MS/MS. A UC model was established in rats by using dextran sulfate sodium (DSS) and dead rats (caused by DSS) were excluded from the study. Forty-eight rats were divided into 6 groups, health control (CG), UC model (UG), sulfasalazine (SG), low-dose KD (LG), middle-dose KD (MG), and high-dose KD (HG) groups. UC damage was assessed by hematoxylin and eosin staining and scan electron microscopy. We measured Toll-like receptor 4 (TLR4), p-phosphatidylinositol 3-kinase (PI3K), PI3K, p-Protein kinase B (AKT), AKT, p-nuclear factor kappa B (NF-κB), NF-κB, oxidative stress marker (superoxidase dismutase (SOD), catalase (CAT), glutathione peroxidases (GPx), and malondialdehyde) and inflammatory markers (tumor necrosis factor α (TNFα), interleukin (IL)-1, IL-6 and IL-10) in UC tissues. Gut microbiota was analyzed through16S rRNA sequencing.ResultsThe main components of KD consist of gallic acid, paeoniflorin, emodin, berberine, coptisine, palmatine, jatrorrhizine, baicalein and baicalin. The UC model was successfully established by causing intestinal barrier injury with the loss of intestinal villi and destructed mitochondria of intestinal epithelial cells. Both sulfasalazine and KD treatment repaired UC injury, reduced the levels of malondialdehyde, TNFα, IL-1, IL-6, TLR4, p-PI3K, p-AKT, and p-NF-κB, and increased the levels of SOD, GPx, CAT, and IL-10. KD showed a protective function for the UC model in a dose-dependent way. The serum levels of paeoniflorin and baicalin had a strong relationship with the levels of inflammatory and oxidative stress biomarkers. KD treatment increased the proportion of Alloprevotella, Treponema, Prevotellaceae, and Prevotella, and reduced the proportion of Escherichia_Shigella and Desulfovibrio in gut microbiota.ConclusionsKD improved intestinal barrier injury of ulcerative colitis, antioxidant and anti-inflammatory properties by affecting TLR4-dependent PI3K/AKT/NF-κB signaling possibly through the combination of its main compounds, and improving gut microbiota.

The number of vertebrae, especially thoracic vertebrae, is an important economic trait that may influence carcass length and meat production in animals. However, the genetic basis of vertebrae number in sheep is still poorly understood. To detect the candidate genes, 400 increased number of thoracic vertebrae (T14L6) and 200 normal (T13L6) Kazakh sheep were collected. We generated and sequenced 60 pools of genomic DNA (each pool prepared by mixing genomic DNA from 10 sheep with the same thoracic traits), with an average depth of coverage of 25.65×. We identified a total of 42,075,402 SNPs and 11 putatively selected genomic regions, including the VRTN gene and the HoxA gene family that regulate vertebral development. The most prominent areas of selective elimination were located in a region of chromosome 7, including VRTN, which regulates spinal development and morphology. Further investigation indicated that the expression level of the VRTN gene during fetal development was significantly higher in sheep with more thoracic vertebrae than in those with a normal number of thoracic vertebrae. A genome-wide comparison between sheep with increased and normal numbers of thoracic vertebrae showed that the VRTN gene is the major selection locus for the number of thoracic vertebrae in sheep and has the potential to be utilized in sheep breeding in the future.

Background: The aim of the present study was to identify the potential long non-coding (lnc.)-RNA and its associated molecular mechanisms involved in the regulation of the radiosensitivity of esophageal squamous cell cancer (ESCC) in order to assess whether it could be a biomarker for the prediction of the response to radiotherapy and prognosis in patients with ESCC.Methods: Microarrays and bioinformatics analysis were utilized to screen the potential lncRNAs associated with radiosensitivity in radiosensitive (n = 3) and radioresistant (n = 3) ESCC tumor tissues. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed in 35 ESCC tumor tissues (20 radiosensitive and 15 radioresistant tissues, respectively) to validate the lncRNA that contributed the most to the radiosensitivity of ESCC (named the candidate lncRNA). MTT, flow cytometry, and western blot assays were conducted to assess the effect of the candidate lncRNA on radiosensitivity in vitro in ECA109/ECA109R ESCC cells. A mouse xenograft model was established to confirm the function of the candidate lncRNA in the radiosensitivity of ESCC in vivo. The putative downstream target genes regulated by the candidate lncRNA were predicted using Starbase 2.0 software and the TargetScan database. The interactions between the candidate lncRNA and the putative downstream target genes were examined by Luciferase reporter assay, and were confirmed by PCR.Results: A total of 113 aberrantly expressed lncRNAs were identified by microarray analysis, of which family with sequence similarity 201-member A (FAM201A) was identified as the lncRNA that contributed the most to the radiosensitivity of ESCC. FAM201A was upregulated in radioresistant ESCC tumor tissues and had a poorer short-term response to radiotherapy resulting in inferior overall survival. FAM201A knockdown enhanced the radiosensitivity of ECA109/ECA109R cells by upregulating ataxia telangiectasia mutated (ATM) and mammalian target of rapamycin (mTOR) expression via the negative regulation of miR-101 expression. The mouse xenograft model demonstrated that FAM201A knockdown improved the radiosensitivity of ESCC.Conclusion: The lncRNA FAM201A, which mediated the radiosensitivity of ESCC by regulating ATM and mTOR expression via miR-101 in the present study, may be a potential biomarker for predicting radiosensitivity and patient prognosis, and may be a therapeutic target for enhancing cancer radiosensitivity in ESCC.

Tumor necrosis factor-alpha (TNF-alpha) triggers activation of cytosolic phospholipase A2 (cPLA2) and then enhancing the synthesis of prostaglandin (PG) in inflammatory diseases. However, the detailed mechanisms of TNF-alpha induced cPLA2 expression were not fully defined in human pulmonary alveolar epithelial cells (HPAEpiCs). We found that TNF-alpha-stimulated increases in cPLA2 mRNA (5.2 folds) and protein (3.9 folds) expression, promoter activity (4.3 folds), and PGE2 secretion (4.7 folds) in HPAEpiCs, determined by Western blot, real-time PCR, promoter activity assay and PGE2 ELISA kit. These TNF-alpha-mediated responses were abrogated by the inhibitors of NADPH oxidase [apocynin (APO) and diphenyleneiodonium chloride (DPI)], ROS [N-acetyl cysteine, (NAC)], NF-kappaB (Bay11-7082) and transfection with siRNA of ASK1, p47phox, TRAF2, NIK, IKKalpha, IKKbeta, or p65. TNF-alpha markedly stimulated NADPH oxidase activation and ROS including superoxide and hydrogen peroxide production which were inhibited by pretreatment with a TNFR1 neutralizing antibody, APO, DPI or transfection with siRNA of TRAF2, ASK1, or p47phox. In addition, TNF-alpha also stimulated p47phox phosphorylation and translocation in a time-dependent manner. On the other hand, TNF-alpha induced TNFR1, TRAF2, ASK1, and p47phox complex formation in HPAEpiCs, which were attenuated by a TNF-alpha neutralizing antibody. We found that pretreatment with NAC, DPI, or APO also attenuated the TNF-alpha-stimulated IKKalpha/beta and NF-kappaB p65 phosphorylation, NF-kappaB (p65) translocation, and NF-kappaB promoter activity in HPAEpiCs. Finally, we observed that TNF-alpha-stimulated NADPH oxidase activation and ROS generation activates NF-kappaB through the NIK/IKKalpha/beta pathway. Taken together, our results demonstrated that in HPAEpiCs, up-regulation of cPLA2 by TNF-alpha is, at least in part, mediated through the cooperation of TNFR1, TRAF2, ASK1, and NADPH oxidase leading to ROS generation and ultimately activates NF-kappaB pathway.