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BET inhibition has been shown to have a promising antitumor effect in multiple tumors. However, the impact of BET inhibition on antitumor immunity was still not well documented in HNSCC. In this study, we aim to assess the functional role of BET inhibition in antitumor immunity and clarify its mechanism. We show that BRD4 is highly expressed in HNSCC and inversely correlated with the infiltration of CD8sup+/supT cells. BET inhibition potentiates CD8sup+/supT cell-based antitumor immunity in vitro and in vivo. Mechanistically, BRD4 acts as a transcriptional suppressor and represses the expression of MHC class I molecules by recruiting G9a. Pharmacological inhibition or genetic depletion of BRD4 potently increases the expression of MHC class I molecules in the absence and presence of IFN-γ. Moreover, compared to PD-1 blocking antibody treatment or JQ1 treatment individually, the combination of BET inhibition with anti-PD-1 antibody treatment significantly enhances the antitumor response in HNSCC. Taken together, our data unveil a novel mechanism by which BET inhibition potentiates antitumor immunity via promoting the expression of MHC class I molecules and provides a rationale for the combination of ICBs with BET inhibitors for HNSCC treatment.

The present study aimed to systematically analyze the risk factors for RBD.A systematic review and meta-analysis of case-control studies, cohort studies, and cross-sectional studies derived from the articles published in eight electronic databases before December 1, 2021. The primary outcome was the odds ratio (OR) and 95% confidence interval (95% CI), and heterogeneity was quantified using IWe identified 26 studies (44,230 subjects) among 2022 citations, and 13 factors were considered. Male sex (OR = 1.36, 95% CI = 1.13-1.64), smoking (OR = 1.37, 95% CI: 1.26-1.50), depression (OR = 2.06, 95% CI = 1.66-2.56), antidepressant use (OR = 2.36, 95% CI = 1.98-2.82), duration of neuropsychiatric disorders(OR = 1.43, 95% CI = 1.13-1.73), levodopa equivalent daily dose (LEDD, OR = 60.15, 95% CI = 23.95-96.35) and observable motor dysfunction (OR = 2.43, 95% CI = 0.65-4.22) were associated with a higher risk of RBD. Tertiary education and above (OR = 0.58, 95% CI = 0.35-0.96) was associated with a lower RBD risk. Men (OR = 1.40, 95% CI: 1.10-1.78, ISix modifiable risk factors and one protective factor were associated with RBD. Further research is required to understand the mechanisms and to develop preventative strategies.

Dysfunction of cardiomyocytes contributes to the development of acute myocardial infarction (AMI). Nonetheless, the regulatory mechanism of lncRNA myocardial infarction-associated transcript (MIAT) in cardiomyocyte injury remains largely unclear. The cardiomyocyte injury was assessed via cell viability and apoptosis using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and flow cytometry, respectively. The levels of MIAT, microRNA (miR)-488-3p, and Wnt5a were detected via quantitative real-time polymerase chain reaction and Western blot. After bioinformatical analysis, the binding between miR-488-3p and MIAT or Wnt5a was confirmed via dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. Our results showed that MIAT expression was increased in AC16 cells after hypoxia treatment. Silencing of MIAT alleviated hypoxia-induced viability reduction, apoptosis increase, and Wnt/β-catenin pathway activation. MIAT directly targeted miR-488-3p. MiR-488-3p might repress hypoxia-induced cardiomyocyte injury, and its knockdown reversed the effect of MIAT depletion on cardiomyocyte injury. Wnt5a was validated as a target of miR-488-3p. Wnt5a expression restoration attenuated the influence of MIAT knockdown on hypoxia-triggered cardiomyocyte injury. Our findings demonstrated that downregulation of MIAT might mitigate hypoxia-induced cardiomyocyte injury partly through miR-488-3p mediated Wnt/β-catenin pathway.

Intervertebral disc degeneration (IDD) development is regulated by miRNA, including inflammatory reactions, cell apoptosis, and degradation of extracellular matrix. Nucleus pulposus cells apoptosis has a absolute influence in the development of IDD. This experiment explores the mechanism of miR-328-5p regulating IDD. Through the analysis of miRNA and mRNA microarray database, we screened the target genes miR-328-5p and WWP2. We verified the expression of miR-328-5p, WWP2, and related apoptotic genes in normal and degenerative nucleus pulposus tissues by qRT-PCR. The expressions of WWP2, Bcl-2, and Bax were detected by qRT-PCR and western blot after transfection to nucleus pulposus cell. The nucleus pulposus cell proliferation and apoptosis after transfection were confirmed by CCK8 and flow cytometry. Luciferase reporter assay and bioinformatics analyzed the targeting relationship between miR-328-5p and WWP2. Firstly, the qRT-PCR experiments confirmed the significant increase of miR-328-5p expression, while significant reduction of WWP2 in a degenerative tissues compared to the normal tissues. Surprisingly, miR-328-5p expression was positively, while that of WWP2 negatively correlated with the degeneration grade of IDD. And we also identified the high expression of Bax and Caspase3, while low expression of Bcl-2 in a degenerative tissues. After miR-328-5p mimic transfected into nucleus pulposus cell, qRT-PCR and western blot confirmed that WWP2 and Bcl-2 expressions were downregulated, while Bax and Caspase3 expressions were upregulated, and the same results were obtained by knocking down WWP2. CCK8 and flow cytometry confirmed that miR-328-5p inhibited the proliferation and induced apoptosis of nucleus pulposus cells. WWP2 is a target gene of miR-328-5p by bioinformatics and luciferase reporter assay. In summary, miR-328-5p targets WWP2 to regulate nucleus pulposus cells apoptosis and then participates in the development of IDD. Furthermore, this study may provide new references and ideas for IDD treatment.

Nostalgia is shown to relieve an individual's perception of pain evoked by cold water, pressure, and thermal stimuli. However, there is no direct evidence to show the analgesic effects of different nostalgia-inducing methods on various stimulus intensities. We conducted two studies to examine the analgesic effect, at different pain intensities, after inducing nostalgia either idiographically or nomothetically. Study 1 (N = 118) induced nostalgia through an idiographic approach (i.e., event reflection task) and found that nostalgia relieved both high and low thermal pain. Study 2 (N = 66) induced nostalgia through a nomothetic approach (i.e., viewing nostalgic pictures) and found that nostalgia relieved low but not high thermal pain. The findings verify the analgesic effect of nostalgia on thermal pain and suggest the potential moderating role of the nostalgia induction approach and pain intensity. Practically, these findings have implications for using nostalgia as a nonpharmacological treatment for pain.

The advent of macrocycle-based supramolecular chemistry can offer powerful strategies for regulating vital bioactivities in living systems and bring about emerging technology in biomedical science. Herein, we construct a supra-biomacromolecular nanosystem involving microtubules, cell-permeable porphyrins, and antimitotic peptide-decorated permethyl-β-cyclodextrins for promoting cell apoptosis in a cooperative manner. Through specific polypeptide-tubulin recognition, cyclodextrin moieties are capable of anchoring to the tubulin surface and providing abundant hydrophobic microenvironments to accommodate the photosensitive porphyrins. Consequently, spherical tubulin aggregates are formed, and reactive oxygen species can be efficiently generated via the host-guest complexation. The combined usage of complexation-promoted photodynamic efficacy and tubulin aggregation gives more serious cell apoptosis under light irradiation in vitro and in vivo. To be envisioned, this supramolecularly enhanced photodynamic performance together with controlled aggregation of natural biomacromolecules may be developed as an innovative approach to improve the therapeutic potency against many diseases.

β-Thalassemia (β-thal) is one of the most common monogenic recessive inherited diseases worldwide. The mutation spectrum of β-thal has been increasingly broadened by various genetic testing methods. The discovery and identification of novel and rare pathogenic thalassemia variants enable better disease prevention, especially in high prevalence regions. In this study, a Chinese thalassemia family with an unclear etiology was recruited to the Thalassemia Screening Program. Blood samples collected from them were primarily screened by hematology analysis and clinical routine genetic screening. Subsequently, targeted next-generation sequencing (NGS) and Sanger sequencing were performed to find and identify a novel deletion variant. The deletion, discovered by targeted NGS, was validated through real-time quantitative polymerase chain reaction (qPCR). First, a large novel β-thal deletion (3488 bp) related to a high Hb F level, NC_000011.9: g.5245533_5249020del (Chongqing deletion) (GRCh37/hg19), was found and identified in the proband and her mother. The deletion removed the entire β-globin gene and led to absent β-globin (β

Although the association of dietary inflammatory potential, evaluated by the dietary inflammatory index (DII), with all-cause and cause-specific mortality has been reported, evidence remains equivocal, with no relevant dose–response meta-analysis having been conducted. To examine the dose–response association of dietary inflammatory potential with risk of all-cause, cancer, and cardiovascular disease (CVD) mortality, PubMed, Embase, and Web of Science were systematically searched up to August 9, 2021. Cohort studies were included if DII was reported as ≥3 levels or per incremental increase, and if the associations of DII with all-cause, cancer, and CVD mortality were assessed. Generalized least squares regression was used to estimate study-specific dose–response associations, and the random effect model was used to pool the RRs and 95% CIs of all-cause, cancer, and CVD mortality per 1-unit increase in DII. Restricted cubic splines were used to intuitively display the dose–response association between dietary inflammatory potential and mortality. Of the 1415 studies retrieved, 15 articles (17 cohort studies involving 397,641 participants) were included in this meta-analysis. With per 1-unit increase in DII, the risks were significantly increased for all-cause mortality (RR: 1.04; 95% CI: 1.03, 1.05, I(2) = 51.8%; P-heterogeneity = 0.009), cancer mortality (RR: 1.02; 95% CI: 1.00, 1.04, I(2) = 58.6%; P-heterogeneity = 0.013), and CVD mortality (RR: 1.04; 95% CI: 1.02, 1.06, I(2) = 85.7%; P-heterogeneity

Lung cancer is one of the most common malignant tumors with growing morbidity and mortality worldwide. Several treatments are used to manage lung cancer, including surgery, radiotherapy and chemotherapy, as well as molecular-targeted therapy. However, the current measures are still far from satisfactory. Therefore, the current research should focus on exploring the molecular mechanism and then finding an effective treatment. Interestingly, we and others have embarked on a line of investigations focused on the mechanism of lung cancer. Specifically, lncRNA small nucleolar RNA host gene has been shown to be associated with biological characteristics and therapeutic resistance of lung cancer. In addition, small nucleolar RNA host genes may be used as diagnostic biomarker in the future. Herein, we will provide a brief review demonstrating the importance of small nucleolar RNA host genes in lung cancer, especially non-small cell lung cancer. Although lncRNA has shown a crucial role in tumor-related research, a large number of studies are needed to validate its clinical application in the future.

Microorganisms are commonly detected in tumor tissues, and the species and abundance have been reported to affect cancer initiation, progression, and therapy. Host genetics have been associated with gut microbial abundances, while the relationships between genetic variants and the cancer microbiome still require systematic interrogation. Therefore, identification of cancer microbiome quantitative trait loci (mbQTL) across cancer types might elucidate the contributions of genetic variants to tumor development. Using genotype data from The Cancer Genome Atlas and microbial abundance levels from Kraken-derived data, we developed a computational pipeline to identify mbQTLs in 32 cancer types. This study systematically identified 38,660 mbQTLs across cancers, ranging 50 in endometrial carcinoma to 3,133 in thyroid carcinoma. Furthermore, a strong enrichment of mbQTLs was observed among transcription factor binding sites and chromatin regulatory elements, such as H3K27ac. Notably, mbQTLs were significantly enriched in cancer genome-wide association studies (GWAS) loci and explained an average of 2% for cancer heritability, indicating that mbQTLs could provide additional insights into cancer etiology. Correspondingly, 24,443 mbQTLs overlapping with GWAS linkage disequilibrium regions were identified. Survival analyses identified 318 mbQTLs associated with patient overall survival. Moreover, we uncovered 135,248 microbiome–immune infiltration associations and 166,603 microbiome–drug response associations that might provide clues for microbiome-based biomarkers. Finally, a user-friendly database, Cancer-mbQTL (http://canmbqtl.whu.edu.cn/#/), was constructed for users to browse, search, and download data of interest. This study provides a valuable resource for investigating the roles of genetics and microorganisms in human cancer. Significance: This study provides insights into the host–microbiome interactions for multiple cancer types, which could help the research community understand the effects of inherited variants in tumorigenesis and development.

Fragile X syndrome (FXS) is a leading form of inherited intellectual disability and single-gene cause of autism spectrum disorder (ASD) and is characterized by core deficits in cognitive flexibility, sensory sensitivity, emotion, and social interactions. Motor deficits are a shared feature of FXS and autism. The cerebellum has emerged as one of the target brain areas affected by neurodevelopmental diseases. Alterations in the cerebellar structure, circuits, and function may be the key drivers of impaired fine and gross motor skills in FXS and fragile X-associated tremor/ataxia syndrome (FXTAS). In this review, we briefly examined recent findings in FXS and present a discussion on the literature supporting motor skill deficits in FXS. Subsequently, we focused on neuropathological alterations in the cerebellum in FXS and FXTAS. We highlight studies that have directly examined the function of fragile X mental retardation protein and related epigenetic variations in the cerebellum. Overall, we obtained considerable supporting evidence for the hypothesis that cerebellar dysfunction is evident in FXS and FXTAS; however, compared with studies on other ASD models, studies on motor skills related to fragile X disorders are particularly rare and inconclusive. Hence, future research should address FXS-related motor and behavioral trajectories and examine the underlying mechanisms at both the cell and circuit levels.

Aging is the strongest risk factor for Parkinson's disease (PD), which is a clinically heterogeneous movement disorder with highly variable age at onset. DNA methylation age (DNAm age) is an epigenetic clock that could reflect biological aging.The aim was to evaluate whether PD age at onset is associated with DNAm-age acceleration (difference between DNAm age and chronological age).We used the genome-wide Infinium MethylationEPIC array to assess DNAm age in discovery (n = 96) and replication (n = 182) idiopathic PD cohorts and a unique longitudinal LRRK2 cohort (n = 220) at four time points over a 3-year period, comprising 91 manifesting and 129 nonmanifesting G2019S carriers at baseline. Cox proportional hazard regression and multivariate linear regression were used to evaluate the relation between DNAm-age acceleration and PD age at onset, which was highly variable in manifesting G2019S carriers (36-75 years) and both idiopathic PD cohorts (26-77 and 35-81 years).DNAm-age acceleration remained steady over the 3-year period in most G2019S carriers. It was strongly associated with age at onset in the LRRK2 cohort (P = 2.25 × 10This study is the first to demonstrate that DNAm-age acceleration is related to PD age at onset, which could be considered in disease-modifying clinical trials. Future studies should evaluate the stability of DNAm-age acceleration over longer time periods, especially for phenoconverters from nonmanifesting to manifesting individuals. © 2022 International Parkinson and Movement Disorder Society.

Optimal treatment strategies for patients with stage IVa-b hypopharyngeal squamous cell carcinoma (HSCC) remain controversial. This study aimed to examine the high-risk factors of postoperative tumor recurrence after surgical resection of HSCC and devise individualized postoperative adjuvant treatment (POAT).Overall, 218 patients with stage IVa-b HSCC who received surgery as initial treatment and with negative surgical margins were evaluated. Independent risk factors of recurrence were identified, and survival outcomes were compared according to recurrence risk and POAT use.POAT significantly improved recurrence-free survival (RFS) and overall survival (OS) only in the high-risk patients (p = 0.003 and 0.018, respectively). Compared with postoperative radiotherapy alone, postoperative chemoradiotherapy (pCRT) achieved significantly better RFS (p = 0.035) and OS (p = 0.048).POATs are recommended for high-risk patients with stage Iva-b HSCC, with pCRT achieving superior outcomes. Regular re-examination after tumor resection is sufficient for low-risk patients.

De novo systemic atypical hemolytic uremic syndrome (aHUS) post-kidney transplant is an uncommon entity associated with unfavorable outcome. We herein report a case of systemic and fulminant de novo aHUS accompanied by heart and respiratory failure in a 48-year-old male receiving ABO-incompatible living-related kidney transplant who was successfully treated with the anti-C5 monoclonal antibody eculizumab with complete recovery of allograft function. Genetic testing demonstrated a novel pathogenic heterozygous complement factor H-related 1 gene mutation in both the donor and the recipient. Our study highlights the high risks of post-transplant aHUS due to the complement gene mutations in both donor and recipient in living-related transplantation. Early intervention with eculizumab may be effective for reversing systemic aHUS in kidney transplant recipients.

Cytocapsular tubes (CTs) provide membranous channels for cancer cells interconnection and multidirectional locomotion, which facilitate cancer cell transportation and metastasis. However, the clinicopathological significance of CTs has not been documented in oral squamous cell carcinoma (OSCC). Herein, we aimed to identify CTs and assess their clinicopathological significance in OSCC.Operetta CLS™ high-content analysis system was used to detect the CTs originated from OSCC cells cultured in a 3D Matrigel matrix. Then, pan-cadherin and γ-actin immunostaining were performed to identify CTs in 4NQO-induced murine OSCC tissues, OSCC xenografts and 88 human primary OSCC samples. Finally, the prognostic value and clinicopathological significance of CTs in OSCC were further examined by using the Kaplan-Meier method and Cox regression analysis.CTs were observed in OSCC cells in a 3D Matrigel matrix. In vivo, CTs were frequently identified in 4NQO-induced murine OSCC tissues, OSCC xenografts and human primary OSCC samples. CTs density was significantly associated with T stage, lymph node metastasis, differentiation, invasive depth, tumor budding, TNM stage and tumor recurrence. Importantly, the high-CTs density indicated a decreased overall survival (OS) and progression-free survival (PFS) in OSCC patients. Cox regression models showed that CTs could serve as a prognostic factor for OS and PFS.CTs, which are correlated with the cell migration and invasion, can be readily identified in OSCC and appear to be a novel biomarker for patients at risk of metastasis.

Current evidence-based guidelines support stereotactic radiosurgery (SRS) for patients with up to four brain metastases (BMs). However, debate continues about how many tumors may be treated by SRS alone.This retrospective study included non-small cell lung cancer (NSCLC) patients with BMs treated with gamma knife as the initial treatment for cerebral lesions. The patients were followed up to obtain their survival information. The outcomes were statistically analyzed to compare the differences in survival between the5 BMs and ≥5 BMs groups and to identify prognostic factors.A total of 77 patients were divided into two groups (54 patients with5 BMs and 23 patients with ≥5 BMs). The median overall survival (OS) was 18.3 months in the5 BMs group and 17.7 months in the ≥5 BMs group. The median intracranial progression-free survival (IPFS) was 9.0 months in the5 BMs group and 9.9 months in the ≥5 BMs group. There was no significant difference in OS and IPFS between the two groups. The multivariate analysis demonstrated that adenocarcinoma, controlled primary cancer, higher Karnofsky Performance Scale (KPS), and salvage treatment were independent prognostic factors favoring longer OS.SRS alone as the initial treatment for NSCLC patients with more than four BMs was non-inferior to SRS for those with one to four BMs in terms of OS and IPFS.

The activation of platelets and proliferation of vascular smooth muscle cells (VSMCs) in the vascular intima play an essential role in the pathological mechanism of vascular restenosis (RS). Rosmarinic acid (RA) is a natural phenolic acid compound. However, its mechanism of action on platelets and VSMCs is still unclear. This study investigated the effects of RA on platelet function, VSMCs phenotypic conversion, proliferation, and migration in vascular remodeling with a specific focus on the Keap1-Nrf2-ARE signaling pathway. RA inhibited platelet aggregation and Ca

Few studies quantitatively investigated the degree of medial canthal tendon (MCT) laxity using three-dimensional (3D) stereophotography as two-dimensional (2D) imaging systems are still widely used in periocular anthropometry. Hence, in this study, we aimed to compare 2D and 3D technique in assessing MCT laxity and to investigate the correlation between them.A cross-sectional study was conducted in randomly recruited healthy volunteers with no history of eyelid disease and surgery. Predictor variables were the linear measurements derived from 2D and 3D images, respectively, and the outcome variable was MCT laxity. Covariates including age and sex were also included in our correlation observations. One-side measurements for each image were randomly selected for our study. Bivariate correlation was applied to evaluate the correlation between 2D and 3D measurements. Linear regression was used to investigate the correlation between the predictor and outcome variables.Ninety-five Caucasian volunteers (50 men and 45 women, 95 eyes) between 22 and 84 years of age (58.5 ± 16.0 years) were included in our study. The 2 sets of measurements for MCT laxity were 3.13 ± 0.75 and 2.62 ± 1.50 mm on 2D images (P = .18) and 2.49 ± 1.58 and 2.58 ± 1.72 mm on 3D images (P = .23). A significant correlation was observed between 3D measurements and MCT laxity (P .01), while no significant correlation was found between 2D measurements and MCT laxity (P = .64).Our results revealed that measurements on 3D images could be predictors of MCT laxity and might be applied as a base and a reference for speculating the 3D MCT laxity in further research and clinical evaluation.

Evidence has shown that multisensory integration benefits to unisensory perception performance are asymmetric and that auditory perception performance can receive more multisensory benefits, especially when the attention focus is directed toward a task-irrelevant visual stimulus. At present, whether the benefits of semantically (in)congruent multisensory integration with modal-based attention for subsequent unisensory short-term memory (STM) retrieval are also asymmetric remains unclear. Using a delayed matching-to-sample paradigm, the present study investigated this issue by manipulating the attention focus during multisensory memory encoding. The results revealed that both visual and auditory STM retrieval reaction times were faster under semantically congruent multisensory conditions than under unisensory memory encoding conditions. We suggest that coherent multisensory representation formation might be optimized by restricted multisensory encoding and can be rapidly triggered by subsequent unisensory memory retrieval demands. Crucially, auditory STM retrieval is exclusively accelerated by semantically congruent multisensory memory encoding, indicating that the less effective sensory modality of memory retrieval relies more on the coherent prior formation of a multisensory representation optimized by modal-based attention.

Background: It is crucial for older adults, especially those with mild cognitive impairment (MCI), to make profitable decisions routinely. However, the results regarding decision-making (DM) remain inconsistent. Objective: The present study assessed DM profiles under uncertainty conditions in individuals with MCI and their associations with multi-domain cognitive performance. Method: Fifty-three patients with MCI and forty-two age-, gender-, and education level-matched healthy controls (HCs) were administered a comprehensive neuropsychological battery test. The Iowa Gambling Task (IGT) and Game of Dice Task (GDT) were used to assess DM competence in conditions involving ambiguity and risk, respectively. In addition, Spearman’s correlations were used to examine relationships between GDT and multi-domain cognitive performance. Result: The final capital (FC) and frequency of utilization of negative feedback (FUNF) and positive feedback (FUPF) in the GDT were lower in MCI patients than in HCs. In addition, the number of shifts between safe and risky alternatives was significantly different across groups. However, IGT performance was comparable across groups. In the MCI patients, risky DM performance was associated with language, whereas in HCs was correlated with memory and executive functions. Besides, in MCI, performance on IGT was significantly correlated with social cognition. Conclusion: Individuals with mild cognitive impairment have difficulty utilizing feedback to make optimal decisions under risky situations. The association between decision-making performance and cognitive function is divergent regarding situational uncertainty and individuals’ cognitive status. In mild cognitive impairment and normal aging, decision-making under ambiguity needs further investigation.

This study investigated possible therapeutic effect mechanisms of exosomes from bone marrow-derived mesenchymal stem cells (BMSC) in neuronal and microglial cells and in a Parkinson disease (PD) model. Neuronal SH-SY5Y cells and microglial HMC3 cells were subjected to 1-methyl-4-phenylpyridinium (MPP+) or LPS, respectively. The mRNA and protein expression was assessed using qRT-PCR, Western blotting, and enzyme-linked immunosorbent assay. Cell viability and apoptosis of SH-SY5Y cells were examined using the MTT assay and flow cytometry. Chromatin immunoprecipitation assays were performed to assess the binding relationship between glioma-associated oncogene homolog 1 (Gli1) and the Sp1 transcription factor promoter. BMSC-derived exosomes promoted cell proliferation and inhibited apoptosis in MPP+-treated SH-SY5Y cells and suppressed inflammatory markers in LPS-treated HMC3 cells. Sp1 knockdown decreased SH-SY5Y cell damage and HMC3 immune activation. Gli1 carried by BMSC exosomes directly bound with Sp1 to inhibit Sp1-mediated LRRK2 activation whereas exosomes secreted by Gli1-knockdown in BMSC did not. In a PD mouse model induced with MPTP, BMSC exosomes decreased neuron loss injury and the inflammatory response by inhibiting Sp1 signaling. Thus, BMSC-derived exosomal Gli1 alleviates inflammatory damage and neuronal apoptosis by inhibiting Sp1 in vitro and in vivo. These findings provide the basis for the potential clinical use of BMSC-derived exosomes in PD.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado Joseph disease (MJD), is a common dominantly inherited ataxia, and has heterogeneous clinical features and variable age of onset, ranging from 10 to 78 years. Repeats variability of ATXN3, HTT, ATN1 and ATXN2 can explain partially but not fully SCA3 age of onset heterogeneity. Aging is a reported modifier of SCA3 severity and closely linked to DNA methylation (DNAm). DNAm age acceleration was associated with disease risk and/or variable disease phenotypes in several repeat associated neurodegenerative diseases (such as Huntington's disease and Amyotrophic lateral sclerosis). To understand if DNAm age acceleration is associated with SCA3 age of onset, we performed a genome-wide DNAm study of a Chinese SCA3 family with variable age of onset and clinical presentations. All patients showed unsteady gait, deterioration of extremities coordination, speech (dysarthria) and swallowing problems (dysphagia, choking on eating and/or drinking) and oculomotor abnormalities, with variable age of onset ranging from 27 to 52 years. We found that DNAm age acceleration is associated with age of onset (p-value = 0.0023, B = -1.26), suggesting that every 5 year increase in DNAm-age acceleration is corresponding to a 6.3 year earlier disease onset. This association remains significant after the adjustment to ATXN3 CAG repeats (adjusted p-value = 0.037, adjusted B = -1.0). In an independent SCA3 cohort (n = 40), we also observed the association between DNAm age acceleration and age of onset (adjusted p-value = 0.007, adjusted B = -0.69). Of note, we found no significant association between DNAm of single-CpG locus and/or CpG-SNPs and SCA3 age of onset in the current family or the SCA3 cohort. Our findings suggested that DNAm age acceleration might be a SCA3 age of onset modifier, and encourage further investigations in extended SCA3 cohorts to clarify the role of epigenetic aging in modifying disease onset.

Pairing a single visual stimulus with multiple auditory stimuli will lead to the illusory perception of multiple visual stimuli, which is known as sound-induced flash illusion (SIFI). The present study adopted the classic SIFI paradigm to investigate whether value-associated tasks could affect the SIFI. By adjusting the sequence of reward and nonreward conditions, we also examined the effect of reward history on SIFI. The results showed that the fission illusion was reduced when associated with momentary reward, demonstrating significantly higher accuracy and discriminability than the nonreward condition. However, the fusion illusion was not affected by the momentary reward, and the explanation was that the fusion illusion was not as stable as the fission illusion and disappeared across different trials and conditions. Moreover, the robustness of reward history in the present study was not as strong as previous studies have suggested, indicating that the effect of sound on the perceptual representation of visual stimuli is strong and robust to reward history. These findings demonstrated that the reward could reduce the SIFI and broaden the existing dichotomy of SIFI. New evidence for the operation of value-driven attention mechanisms is also provided, suggesting that the underlying value-driven attention operates across multiple sensory systems.

Hip fracture is the most common complication of osteoporosis, and its major contributor is compromised femoral strength. This study aimed to develop practical machine learning models based on clinical quantitative computed tomography (QCT) images for predicting proximal femoral strength. Eighty subjects with entire QCT data of the right hip region were randomly selected from the full MrOS cohorts, and their proximal femoral strengths were calculated by QCT-based finite element analysis (QCT/FEA). A total of 50 parameters of each femur were extracted from QCT images as the candidate predictors of femoral strength, including grayscale distribution, regional cortical bone mapping (CBM) measurements, and geometric parameters. These parameters were simplified by using feature selection and dimensionality reduction. Support vector regression (SVR) was used as the machine learning algorithm to develop the prediction models, and the performance of each SVR model was quantified by the mean squared error (MSE), the coefficient of determination (R

An association between cardiorespiratory fitness (CRF) and type 2 diabetes mellitus (T2DM) has not been established in the Chinese population. This study aimed to estimate the independent and joint associations of CRF and obesity with T2DM incidence in the rural Chinese population.We conducted a prospective study of 11,825 non-T2DM subjects among rural Chinese adults. Cox regression models were used to estimate the independent and joint associations between CRF and obesity exposure on T2DM. Restricted cubic splines were used to model the dose-response association. During a median follow-up of 6.01 years, 835 participants developed T2DM. In comparison to quartile 1 of CRF, the multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) of quartiles 2, 3, 4 were 0.75 (0.61-0.91), 0.54 (0.43-0.68), and 0.42 (0.32-0.55), respectively. When stratified by sex, the results were similar. Joint analyses showed that overweight/obesity-unfit individuals had a 2.28 times higher risk of developing T2DM than the normal weight-fit referent (HR 2.28, 95% CI 1.84-2.83; PA negative association was observed between CRF and risk of T2DM. Overweight/obese or abdominal obesity and unfit participants showed the highest risks of T2DM. It is therefore strongly recommended that fitness-enhancing be encouraged for the prevention of T2DM, especially among obesity participants.

Understanding the genetic variation underlying transcript splicing is essential for fully dissecting the molecular mechanisms of common diseases. The available evidence from splicing quantitative trait locus (sQTL) studies using pancreatic ductal adenocarcinoma (PDAC) tissues have been limited to small sample sizes. Here we present a genome-wide sQTL analysis to identify SNP that control mRNA splicing in 176 PDAC samples from TCGA. From this analysis, 16,175 sQTLs were found to be significantly enriched in RNA-binding protein (RBP) binding sites and chromatin regulatory elements and overlapped with known loci from PDAC genome-wide association studies (GWAS). sQTLs and expression quantitative trait loci (eQTL) showed mostly nonoverlapping patterns, suggesting sQTLs provide additional insights into the etiology of disease. Target genes affected by sQTLs were closely related to cancer signaling pathways, high mutational burden, immune infiltration, and pharmaceutical targets, which will be helpful for clinical applications. Integration of a large-scale population consisting of 2,782 patients with PDAC and 7,983 healthy controls identified an sQTL variant rs1785932-T allele that promotes alternative splicing of ELP2 exon 6 and leads to a lower level of the ELP2 full-length isoform (ELP2_V1) and a higher level of a truncated ELP2 isoform (ELP2_V2), resulting in decreased risk of PDAC [OR = 0.83; 95% confidence interval (CI), 0.77–0.89; P = 1.16 × 10−6]. The ELP2_V2 isoform functioned as a potential tumor suppressor gene, inhibiting PDAC cell proliferation by exhibiting stronger binding affinity to JAK1/STAT3 than ELP2_V1 and subsequently blocking the pathologic activation of the phosphorylated STAT3 (pSTAT3) pathway. Collectively, these findings provide an informative sQTL resource and insights into the regulatory mechanisms linking splicing variants to PDAC risk.Significance:In pancreatic cancer, splicing quantitative trait loci analysis identifies a rs1785932 variant that contributes to decreased risk of disease by influencing ELP2 mRNA splicing and blocking the STAT3 oncogenic pathway.

Mitochondrial unfolded protein response plays an important role in the occurrence and development of breast cancer. However, the role of mitochondrial unfolded protein response (UPRmt) in the sensitivity of breast cancer to cisplatin chemotherapy has not yet been cleared. The purpose of this study is to explore the role of mitochondrial unfolded protein response in breast cancer sensitivity to cisplatin. In this study, qRT-PCR, Western blotting, Immunofluorescence, CCK-8, Colony formation, Transwell assay and TUNEL staining assay were used to confirm the role of UPRmt in breast cancer cells treated with cisplatin. Cisplatin increased the levels of UPRmt including CLPP, HSP60, LONP1 in MCF7 and MDA-MB-231 cells. UPRmt inducer Nicotinamide ribose (NR) could promote the proliferation and invasion of breast cancer cells treated with cisplatin. Importantly, SIRT3 was discovered to increase UPRmt in breast cancer cells and silencing of SIRT3 could inhibit the effect of NR in breast cancer. UPRmt regulated by SIRT3 could protect breast cancer cell from cisplatin. Controlling SIRT3-induced UPR may be a potential therapeutic target to increase the sensitivity of breast cancer chemotherapy.

Superb microvascular imaging (SMI) is among the latest doppler ultrasound methods. It uses an advanced clutter filter to eliminate artifacts caused by breathing, movement and retains the low-speed blood signals in microvessels. The great advantage of SMI is that it can intuitively detect very slow blood signals in microvessels, providing clinicians with more significant information about flow distribution in the target area. Therefore, it is speculated that SMI has important application value. The purpose of this article is to outline the application of SMI in different parts of the body.

Urban-rural income gap and haze pollution concerns are remained at top priority to achieve sustainable development objectives in China. Based on the panel data of 283 cities in China from 2008 to 2018, the quantile regression model is used to study the impact of haze pollution on the urban-rural income gap. In addition, we adopt ventilation coefficients as the instrumental variable of haze pollution to control for potential endogeneity. Findings obtained from the quantile regression estimator suggest that haze pollution can significantly increase the urban-rural income gap. The effect of haze pollution on urban-rural income gap is more significant in the low quantile than the high quantile state. After alleviating endogenous bias through instrumental variables, the promotion effect is more obvious. Furthermore, haze pollution affects the urban-rural income gap through healthy human capital. Our results shed new light on the relationship between haze pollution and urban-rural income gap and provide support for policymakers in tackling the dual tasks of urban-rural income gap and haze pollution. A less haze pollution, our findings suggest, may exert positive effects in relation to the mitigation of urban-rural income gap in China.

Accurate biomechanical properties of the human dura mater are required for computational models and to fabricate artificial substitutes for transplantation and surgical training purposes. Here, a systematic literature review was performed to summarize the biomechanical properties of the human dura mater that are reported in the literature. Furthermore, anthropometric data, information regarding the mechanically tested samples, and specifications with respect to the used mechanical testing setup were extracted. A meta-analysis was performed to obtain the pooled mean estimate for the elastic modulus, ultimate tensile strength, and strain at maximum force. A total of 17 studies were deemed eligible, which focused on human cranial and spinal dura mater in 13 and 4 cases, respectively. Pooled mean estimates for the elastic modulus (n = 448), the ultimate tensile strength (n = 448), and the strain at maximum force (n = 431) of 68.1 MPa, 7.3 MPa and 14.4% were observed for native cranial dura mater. Gaps in the literature related to the extracted data were identified and future directions for mechanical characterizations of human dura mater were formulated. The main conclusion is that the most commonly used elastic modulus value of 31.5 MPa for the simulation of the human cranial dura mater in computational head models is likely an underestimation and an oversimplification given the morphological diversity of the tissue in different brain regions. Based on the here provided meta-analysis, a stiffer linear elastic modulus of 68 MPa was observed instead. However, further experimental data are essential to confirm its validity.

As a predominately positive emotion, nostalgia serves various adaptive functions, including a recently revealed analgesic effect. The current fMRI study aimed to explore the neural mechanisms underlying the nostalgia-induced analgesic effect on noxious thermal stimuli of different intensities. Human participants' (males and females) behavior results showed that the nostalgia paradigm significantly reduced participants' perception of pain, particularly at low pain intensities. fMRI analysis revealed that analgesia was related to decreased brain activity in pain-related brain regions, including the lingual and parahippocampal gyrus. Notably, anterior thalamic activation during the nostalgia stage predicted posterior parietal thalamus activation during the pain stage, suggesting that the thalamus might play a key role as a central functional linkage in the analgesic effect. Moreover, while thalamus-PAG functional connectivity was found to be related to nostalgic strength, periaqueductal gray-dorsolateral prefrontal cortex (PAG-dlPFC) functional connectivity was found to be associated with pain perception, suggesting possible analgesic modulatory pathways. These findings demonstrate the analgesic effect of nostalgia and, more importantly, shed light on its neural mechanism.SIGNIFICANCE STATEMENTNostalgia is known to reduce individuals' perception of physical pain. The underlying brain mechanisms, however, are unclear. Our study found that the thalamus plays a key role as a functional linkage between nostalgia and pain, suggesting a possible analgesic modulatory mechanism of nostalgia. These findings have implications for the underlying brain mechanisms of psychological analgesia.

Mild traumatic brain injury (mTBI) is an important but less recognized public health concern. Research shows that altered subcortical structures mediate cognitive impairment in patients with mTBI. This has been performed mostly using voxel-based morphometry methods and traditional volume measurement methods, which have certain limitations. In this study, we conducted a vertex-wise shape analysis to understand the aberrant patterns of caudate subregions and recovery from mTBI. The study involved 36 patients with mTBI and 34 matched healthy controls (HCs) observed at seven days (acute phase) and followed up for one month (subacute phase) post-injury. Different aberrant shapes of the caudate subregions were observed at the acute phase, which revealed atrophy in the bilateral dorsal medial caudate, and increase in the size of the right ventral anterior caudate in patients with mTBI related to HCs. Moreover, specific and significant shape restoration of right dorsal medial caudate in mTBI was observed at the subacute phase, which significantly associated with the cognitive function improvement of the patients. These findings suggest that the restoration of the aberrant shape atrophy of the right dorsal medial caudate plays a vital role in the improvement of cognitive function of patients with mTBI, providing an alternative clinical target for these patients.

Aim: This study aims to provide reliable prognostic factors for patients with cryptococcal meningitis (CM). Patients & methods: Clinical characteristics and laboratory findings of CM patients were retrospectively reviewed. Results: Sixty-three patients with CM were enrolled and 38/63 were confirmed to be HIV serology positive. Among clinical characteristics, headache, nausea and/or vomiting, and fever were the most common symptoms. Among cerebrospinal fluid (CSF) parameters, changes in leukocyte count, lactate dehydrogenase and chloride were significantly associated with the outcome. An increased CSF/serum albumin quotient (QAlb) was indicative of an unfavorable outcome in HIV-negative patients. Conclusion: CSF lactate dehydrogenase and QAlb may improve the prediction of outcomes in patients with CM.

We developed and validated a set of composite scores that combine quantitative magnetic resonance imaging (MRI)-based measurements of hyaline cartilage damage, bone marrow lesions (BMLs), and effusion-synovitis into composite scores.We selected 300 participants (n = 100 for development cohort; n = 200 for validation cohort) from the Osteoarthritis Initiative with complete clinical, radiographic, and MRI data at baseline and 24 months. We used semiautomated programs to quantify tibiofemoral and patellar cartilage damage, BML volume, and whole-knee effusion-synovitis volume. The candidate composite scores were formed by summing changes from baseline to 24 months based on prespecified methods. We evaluated the candidate composite scores for 1) the ability to differentiate groups with and without knee osteoarthritis progression (17 radiographic and patient-reported definitions), 2) sensitivity to change (standardized response means), and 3) relative performance relating to legacy outcome measures of knee osteoarthritis progression.Three of 13 developed composite scores qualified for testing in the validation cohort (ranked by sensitivity to change): whole-knee cumulative cartilage damage, unweighted total knee score, and BML plus effusion-synovitis volume. Change in cumulative cartilage damage associated with radiographic progression (Kellgren/Lawrence grade: odds ratio [OR] 1.84; joint space width progression: OR 2.11). Changes in the unweighted total knee score (OR 1.97) and BML plus effusion-synovitis score (OR 1.92) associated with Western Ontario and McMaster Universities Osteoarthritis Index knee pain progression.Two composite scores emerged, reflecting discrete domains of knee osteoarthritis progression. First, cumulative damage, which is measured by a whole-knee cartilage damage score, reflects the damage accrued over time. Second, dynamic disease activity, which is measured by a BML plus effusion-synovitis score, relates to changes in a patient's state of disease and symptoms.

Rapalogs (everolimus and temsirolimus) are allosteric mTORC1 inhibitors and approved agents for advanced clear cell renal cell carcinoma (ccRCC), although only a subset of patients derive clinical benefit. Progress in genomic characterization has made it possible to generate comprehensive profiles of genetic alterations in ccRCC; however, the correlations between recurrent somatic mutations and rapalog efficacy remain unclear. Here, we demonstrate by using multiple patient-derived ccRCC cell lines that compared to PTEN-proficient cells, PTEN-deficient cells exhibit hypersensitivity to rapalogs. Rapalogs inhibit cell proliferation by inducing G

Background LINC00152 (long intergenic non-protein coding RNA 152) was identified as an oncogenic lncRNA in multiple cancers. In the current study, we aimed to explore the transcriptional profile of LINC00152 in oral squamous cell carcinoma (OSCC) and its regulations at the transcriptional level. Methods Bioinformatic analysis was performed by extracting the OSCC subset from The Cancer Genome Atlas (TCGA)-Head and Neck Squamous Cell Carcinoma (HNSC). LINC00152 subcellular localization and its interacting transcriptional factors (TFs) were explored. Dual-luciferase assay and ChIP-qPCR were applied to study transcriptional regulation. In vitro and in-vivo tumor cell growth models were used for functional assays. Results NR_024206.2 was the dominant isoform that accounts for 80% of all transcripts of LINC00152. LINC00152 upregulation was associated with unfavorable survival of patients with OSCC. LINC00152 knockdown significantly impaired OSCC cell growth in vitro and in vivo. RNA FISH assay confirmed nuclear and cytoplasmic distribution of LINC00152. It physically interacted with Upstream Transcription Factor 1 (USF1), a common transcription factor in mammalian cells. USF1 could bind to the promoter region of MRPL52 (Mitochondrial Ribosomal Protein L52) and activate its transcription. LINC00152 could enhance the binding, thereby indirectly elevating MRPL52 expression. USF1 or MRPL52 knockdown slowed the proliferation of OSCC cells and partly canceled LINC00152 mediated growth-promoting effects. Conclusion This study revealed a novel LINC00152-USF1/MRPL52 axis promoting OSCC tumor growth.

Purpose The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. Experimental design The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity. Results Significant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1). Conclusions Our study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.

Summary Introduction To analyze the clinicopathological characteristics, immunohistochemistry, genotyping and prognosis of patients in the multicenter GIST data in Inner Mongolia, China. Methods Retrospective analysis was performed on GIST data from January 2013 to January 2018 in Inner Mongolia. Descriptive statistics were used to analyze the clinical characteristics of GIST patients. The Chi-square test was performed on the modified NIH criteria by age distribution, and Kaplan-Merie method was used for survival analysis. Results A total of 804 patients were included in the GIST database in Inner Mongolia, with a male to female ratio of 1.1102:1. The most common location was the gastric (465). Mitotic count ≤5/50HPFs was found in 67.3 % patients. There were 276 patients with tumor diameter of 2–5 cm and 354 patients with tumor diameter of 5.1–10 cm.The modified NIH criteria was mainly of intermediate risk (210) and high risk (342). The recurrence and metastasis of patients were related to the tumor location, mitotic index, tumor size, and modified NIH criteria. All patients were followed up for 1–10 years, in which 63.1 % of them were followed up for at least three years. The 3-year survival rates of patients with modified NIH criteria of very low risk, low risk, intermediate risk, and high risk were 100 %, 100 %, 100 %, and 96.3 %, respectively. Conclusions The incidence of GIST in middle-aged and elder people in Inner Mongolia is high, and the long-term prognosis of patients after surgical treatment is good, which can objectively reflect the incidence, diagnosis and treatment of GIST in Inner Mongolia.

In attentional orienting, researchers have proposed that reward history is a component of attentional control, as the reward value might enhance the spatial attention process to achieve more efficient goal-directed behavior and to improve target-detection performance. Although the effect of reward–induced motivation on attentional orienting has been studied in two–dimensional (2-D) space, the specific mechanisms underlying the influence of reward on inhibition of return (IOR) of attentional orienting in three-dimensional space (3-D) remain unclear. In the present study, by incorporating the Posner spatial-cueing paradigm into a virtual 3-D environment, we aimed to investigate the influence of reward on IOR in 3-D space. The results showed the following: (1) IOR size in the rewarded conditions was smaller than IOR size in the unrewarded condition in the near depth plane, resulting in an IOR difference with or without reward. (2) Reward weakened IOR in the near depth plane because the response to the uncued location was delayed, not because the response to the cued location was accelerated. The present study indicated that the different depth planes of the target location in 3-D space could influence the interaction between reward and IOR, and reward weakened IOR in the near depth plane.

Fluid-attenuated inversion recovery vascular hyperintensity (FVH) is frequently observed in patients with acute ischemic stroke (AIS). FVH is associated with functional outcome at 3 months in AIS patients receiving endovascular thrombectomy. In the present study, we assessed whether FVH predicted early neurological deterioration (END) and hemorrhagic transformation (HT) within 72 h in AIS patients receiving endovascular thrombectomy. We retrospectively analyzed 104 patients with acute internal-carotid-artery or proximal middle-cerebral-artery occlusion within 16 h after symptom onset. Before thrombectomy, all patients underwent brain magnetic resonance imaging. END was defined as an increase of 4 points or more from baseline National Institutes of Health Stroke Scale (NIHSS) during 72 h following onset. HT was assessed by brain computed tomography. Statistical analyses were performed to predict END and HT. The proportion of high FVH score, high American Society of Intervention and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grade in non-END group was higher than that in END group (p 0.001, p 0.001, respectively). FVH score was positively correlated with ASITN/SIR grade (r = 0.461, p 0.001). FVH score was a predictor factor for END (adjusted OR, 13.552; 95% CI, 2.408-76.260; p = 0.003), while FVH score was not a predictor factor for HT. Furthermore, NIHSS at admission (adjusted OR, 1.112; 95% CI, 1.006-1.228; p = 0.038) and high-density lipoprotein cholesterol (adjusted OR, 18.865; 95% CI, 2.998-118.683; p = 0.002) were predictor factors for HT. To assess FVH score before thrombectomy might be useful for predicting END in AIS patients receiving endovascular thrombectomy.

Intraoperative conversion to laparotomy is a challenge during laparoscopic hepatectomy; however, the risk factors of conversion have been poorly elucidated.In this systematic review and meta-analysis, we computed pooled odds ratios (ORs) with 95% confidence intervals (CIs) for each risk factor and evaluated heterogeneity using a L'Abbe plot, Galbraith radial plot, Cochran's Q test, and IA total of 25 eligible studies were enrolled in the meta-analysis. Higher body mass index (OR 1.346, 95% CI 1.055-1.717), hypertension (OR 1.387, 95% CI 1.100-1.749), male sex (OR 1.278, 95% CI 1.072-1.523), cirrhosis (OR 1.378, 95% CI 1.062-1.788), major resection (OR 2.041, 95% CI 1.748-2.382), posterosuperior tumor location (OR 2.420, 95% CI 1.923-3.044), and larger tumor diameter (OR 1.618, 95% CI 1.270-2.061) were found to be significantly related to intraoperative conversion during laparoscopic hepatectomy. Malignant tumor (OR 1.253, 95% CI 0.970-1.619), higher American Society of Anesthesiologists stage (OR 1.186, 95% CI 0.863-1.631), multiple tumors (OR 1.273, 95% CI 0.866-1.871), and abdominal surgery history (OR 1.236, 95% CI 0.589-2.597) were not associated with conversion. A history of abdominal surgery showed significant heterogeneity with an IIn this systematic review and meta-analysis, we identified a number of factors associated with intraoperative conversion during laparoscopic hepatectomy. Our findings can help patient risk evaluation to reduce the laparotomy conversion rate in laparoscopic hepatectomy.

Background To preliminary evaluate the application of SaCoVLM™ video laryngeal mask airway in airway management of general anesthesia. Methods We recruited 100 adult patients (ages 18–78 years, male 19, female 81, weight 48–90 kg) with normal predicted airway (Mallampati I ~ II, unrestricted mouth opening, normal head and neck mobility) and ASA I-II who required general anaesthesia. The SaCoVLM™ was inserted after anesthesia induction and connected with the anesthesia machine for ventilation. Our primary outcome was glottic visualization grades. Secondary outcomes included seal pressure, success rate of insertion, intraoperative findings (gastric reflux and contraposition), gastric drainage and 24-h complications after operation. Results The laryngeal inlet was exposed in all the patients and shown on the video after SaCoVLM™ insertion. The status of glottic visualization was classified: grade 1 in 55 cases, grade 2 in 23 cases, grade 3 in 14 cases and grade 4 in 8 cases. The first-time success rate of SaCoVLM™ insertion was 95% (95% CI = 0.887 to 0.984), and the total success rate was 96% (95% CI = 0.901 to 0.989). The sealing pressure of SaCoVLM™ was 34.1 ± 6.2 cmH2O and the gastric drainage were smooth. Only a small number of patients developed mild complications after SaCoVLM™ was removed (such as blood stains on SaCoVLM™ and sore throat). Conclusions The SaCoVLM™ can visualize partial or whole laryngeal inlets during the surgery, with a high success rate, a high sealing pressure and smooth gastroesophageal drainage. SaCoVLM™ could be a promise new effective supraglottic device to airway management during general anesthesia. Trial registration ChiCTR,ChiCTR2000028802.Registered 4 January 2020.

Periplaneta americana L. (PA), a type of animal medicine, has been widely used for wound healing in clinical settings. In order to further investigate the bioactive wound healing substances in PA, crude PA protein-polysaccharide complexes were further purified by cellulose DE-52 and Sephadex G100 chromatography in succession. Among these isolated fractions, two fractions eluted by 0.3 M and 0.5 M NaCl with the higher yield, respectively named PaPPc2 and PaPPc3 respectively, were chosen for the wound healing experiments. Mediated by HPGPC, amino acid and monosaccharide composition analysis, circular dichroism spectrum, glycosylation type, FT-IR, and

Objective To evaluate the effects of Transcutaneous Electric Nerve Stimulation (TENS) on pain, function, walking ability and stiffness in people with Knee osteoarthritis (KOA). Design Systematic review and meta-analysis of randomized controlled trials. Methods We searched MEDLINE, EMBASE, PubMed, Cochrane Central Register of Controlled Trials, Physiotherapy Evidence Database (PEDro), clinicaltrials.gov and Web of Science (last search November 2021) for randomized controlled trials. The Cochrane Risk of Bias Tool was used for the included studies, and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used to interpret the certainty of results. Standardized Mean Differences (SMDs) and 95% confidence interval (CI) were calculated for meta-analysis. Results Twenty-nine studies were found (1398 people, age range 54-85, 74% are female) and fourteen were included in this review. Intervention duration was divided as short term (immediately after intervention), medium term (Conclusion TENS could significantly relieve pain, decrease dysfunction and improve walking ability in people with KOA, but it is not effective for stiffness.

In the rapid serial visual presentation (RSVP) paradigm, response accuracy for the target decreases when it appears within a short time window (200~500 ms) after the previous target. This phenomenon is termed the attentional blink (AB). Although mechanisms of cross-modal processing that reduce the AB have been documented, researchers have not explored the differences across modal attentional conditions. In the present study, we used the RSVP paradigm to investigate the effect of auditory-driven visual target perceptual enhancement on the AB under modality-specific selective attention (Experiment 1) and bimodal-divided attention (Experiment 2). The results showed that cross-modal attentional enhancement was not moderated by stimulus salience. Moreover, the results also showed that accuracy was higher when the attended sound appeared simultaneously with the target. These results indicated that audiovisual enhancement reduced AB and that stronger attentional enhancement in the bimodal-divided attentional condition led to the disappearance of AB.

Increasing evidence suggests that hypothyroidism aggravates atherosclerosis. Macrophage apoptosis plays a significant role in the development of atherosclerotic plaque. We aimed to explore the effect of thyroid hormones on macrophage apoptosis induced by oxidized low-density lipoprotein (oxLDL). Peripheral blood samples from 20 patients (normal group, hypothyroidism group, coronary artery disease [CAD] group, hypothyroidism + CAD group) were collected to perform messenger RNA microarray analysis. Bioinformatics analysis identified apoptosis and mitogen-activated protein kinase (MAPK) signaling as differentially expressed pathways between CAD and hypothyroidism + CAD group. In vitro, thyroid hormones concentration-dependently promoted cell survival and inhibited apoptosis in oxLDL-treated RAW264.7 macrophages, along with elevated extracellular signal-regulated kinases 1 and 2 (Erk1/2) phosphorylation. The STRING database showed an interaction of thyroid hormone receptor alpha1 (TRα1) and MAPK pathway. TRα1 knockdown increased cell apoptosis and decreased Erk1/2 phosphorylation. Erk1/2 inhibitor aggravated macrophage apoptosis. Moreover, thyroid hormones inhibited oxidative stress in oxLDL-treated macrophages. The study indicates that thyroid hormones concentration-dependently attenuate oxLDL-induced macrophage apoptosis through activating TRα1-Erk1/2 pathway and inhibiting oxidative stress, which implies a potential mechanism of hypothyroid-accelerated atherosclerosis.

Background Recurrence of nasopharyngeal carcinoma (NPC) after chemoradiotherapy is common, but submucosal recurrence of NPC is rare. The final pathological results determine the optimal therapeutic schedule for treatment of NPC recurrence, but tissue retrieval from submucosal lesions is usually difficult. The present study aimed to assess the safety and efficacy of a novel approach of endonasopharyngeal ultrasound-guided transnasopharyngeal needle aspiration (ENUS-TNNA) for submucosal neoplasms in patients with suspected NPC recurrence. Methods Between March 2017 and June 2021, 11 post-chemoradiotherapy patients with suspected magnetic resonance imaging (MRI) findings of submucosal recurrence of NPC underwent ENUS-TNNA. The safety and effectiveness of using ENUS-TNNA to sample submucosal neoplasms were evaluated. Results Needle aspiration biopsies were performed without any incidences in all cases. Out of the 11 patients, nine were diagnosed with submucosal recurrence of NPC via histopathological or cytological evaluations. Of the two puncture-negative cases, one patient had atypical imaging findings and clinical manifestations and was therefore followed-up using MRI. After follow-up for 3 years, this patient was still considered to be cancer-free due to the shrinking diameters of the submucosal lesions. For the other puncture-negative patient, submucosal biopsy samples were obtained using a surgical method. Pathological examination of these biopsies revealed that an angiosarcoma had developed after radiotherapy. There were no severe complications that occurred during the ENUS-TNNA procedure. Conclusion ENUS-TNNA is a safe, effective, and minimally invasive approach to obtain tissue samples from the submucosal region of the nasopharynx for patients with suspected NPC recurrence.

Messenger RNA (mRNA) vaccine technology has shown its power in preventing the ongoing COVID-19 pandemic. Two mRNA vaccines targeting the full-length S protein of SARS-CoV-2 have been authorized for emergency use. Recently, we have developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor-binding domain (RBD) of SARS-CoV-2 (termed ARCoV), which confers complete protection in mouse model. Herein, we further characterized the protection efficacy of ARCoV in nonhuman primates and the long-term stability under normal refrigerator temperature. Intramuscular immunization of two doses of ARCoV elicited robust neutralizing antibodies as well as cellular response against SARS-CoV-2 in cynomolgus macaques. More importantly, ARCoV vaccination in macaques significantly protected animals from acute lung lesions caused by SARS-CoV-2, and viral replication in lungs and secretion in nasal swabs were completely cleared in all animals immunized with low or high doses of ARCoV. No evidence of antibody-dependent enhancement of infection was observed throughout the study. Finally, extensive stability assays showed that ARCoV can be stored at 2–8 °C for at least 6 months without decrease of immunogenicity. All these promising results strongly support the ongoing clinical trial.

Although it is often assumed that spatial attention exists in the form of a unitary focus, the split-attention hypothesis proposes that attention can be simultaneously divided into two spatially noncontiguous positions and that the space in between can be ignored. However, whether split attention occurs directly based on the generation of attentional benefit or whether it requires a gradual divide from a unitary focus over time has not been clarified. In the present study, by using two spatial salient cues to direct the attention allocation of participants, we aimed to investigate whether attention requires time to divide from a unitary focus and whether the appearance time of split attention varies when the task difficulty level increases between experiments. The results showed that attention required time to divide from a unitary focus, and the position between the two cued positions was not excluded by attention when the stimulus-onset asynchrony (SOA) was 60 ms. However, as the task difficulty increased between experiments, the appearance time of split attention was earlier. These findings suggest that the appearance time of split attention has a certain flexibility and can be changed according to the task requirement, thus implying that split attention and unitary attention present some common attention mechanisms and that a split or unitary mode can be flexibly selected for an attention system.

Background: Affiliate stigma of family caregivers may severely influence family caregiving, early treatment, and recovery of people with mental illness (PMI), and it may be impacted by the knowledge of mental illness and contact with PMI. However, little is known about the correlation between affiliate stigma of family caregivers of PMI and contact in Hong Kong. Aims: This study aimed to investigate affiliate stigma and its influencing factors among family caregivers of PMI in Hong Kong. Methods: A total of 106 family caregivers in Hong Kong participated in the study. The measurements included affiliate stigma, contacts (quantity, quality, and level), knowledge, prejudice, and discriminatory behaviors. Multiple regression analyses were employed. Results: The mean score of affiliate stigma scale (ASS) in family caregivers was 2.17 ( SD = 0.65). In regression analyses, the results showed that contact quantity and contact level were significantly associated with higher affiliate stigma and its cognitive domain, while contact quality (e.g. positive contact) were significantly associated with lower affiliate stigma and its all domains among family caregivers. The positive relationship between prejudicial attitudes and affiliate stigma was also found. Conclusions: Affiliate stigma is severe among family caregivers of PMI in Hong Kong. The results of this study indicate that contact, especially positive contact, contributes to reducing affiliate stigma among family caregivers of PMI. The results of this study are important for development of health policy on reducing stigma in family caregivers of PMI. The effectiveness of Enhancing Contact Model (ECM) should be examined in future anti-stigma interventions.