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Background: Thrombospondin (THBS) 3 is an adhesive glycoprotein involved in cell-cell and cell-matrix interactions. The purpose of this study is to determine whether THBS3 expression in peripheral blood can be used as a biomarker to predict the risk of acute myocardial infarction (AMI)., Methods: The peripheral blood of 111 patients with stable coronary artery disease (SCAD) and 112 patients with AMI was obtained. The experimental and the control cohorts were the AMI and SCAD groups, respectively. The expression of THBS3 mRNA and protein in both groups was determined using reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay., Results: THBS3 expression (range) in the peripheral plasma of patients in the AMI group was lower than that of patients in the SCAD group (4.526 (3.748-5.521), 5.511 (4.726-6.334), respectively), which was 0.82 times lower than the control ( p < 0.001). Furthermore, THBS3 mRNA level in the peripheral blood mononuclear cells of patients with AMI was 0.47 times lower than that in patients with SCAD ( p < 0.05). AMI was associated with fasting blood glucose levels, platelet counts and low THBS3 expression. Logistic regression analysis revealed that decreased expression of THBS3 protein increased the probability of AMI by 4.076 times ( p < 0.01). Additionally, high fasting blood glucose and high platelet counts increased the risk of AMI by 2.819 and 6.515 times, respectively ( p < 0.05)., Conclusions: THBS3 mRNA and protein levels in the peripheral blood of patients in the AMI group were much lower compared with those of patients in the SCAD group. Low THBS3 expression in peripheral blood was related to AMI and was an independent risk factor for AMI. Thus, low THBS3 expression in peripheral blood may be a novel, suitable molecular marker for the early detection of AMI., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Chronic wound healing remains a challenging medical problem affecting society, which urgently requires anatomical and functional solutions. Adipose-derived stem cells (ADSCs), mesenchymal stem cells with self-renewal and multiple differentiation ability, play essential roles in wound healing and tissue regeneration. The exosomes from ADSCs (ADSC-EXOs) are extracellular vesicles that are essential for communication between cells. ADSC-EXOs release various bioactive molecules and subsequently restore tissue homeostasis and accelerate wound healing, by promoting various stages of wound repair, including regulating the inflammatory response, promoting wound angiogenesis, accelerating cell proliferation, and modulating wound remodeling. Compared with ADSCs, ADSC-EXOs have the advantages of avoiding ethical issues, being easily stored, and having high stability. In this review, a literature search of PubMed, Medline, and Google Scholar was performed for articles before August 1, 2022 focusing on exosomes from ADSCs, chronic wound repair, and therapeutic potential. This review aimed to provide new therapeutic strategies to help investigators explore how ADSC-EXOs regulate intercellular communication in chronic wounds., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Long, Wang, Gan, Qin, Yang and Chen.)

The fruit morphological structures of the Cornaceae of China and related taxa were studied using the wax GMA semi-thin section method and other methods to identify characters useful in delimiting clades circumscribed in previous molecular phylogenetic studies. Maximum parsimony analyses of 27 fruit structural characters resulted in a generally poorly resolved strict consensus tree, yet one whose major clades matched those revealed previously. Cornaceae of China and related taxa are recognized in four significant clades with the following fruit structural features: (1) Helwingia , fruits lack trichome, the abdominal vascular bundles are close to the endocarp, and the endocarp sclereid is elongated; (2) Aucuba , single-cell lanceolate trichomes, pericarp without secretory structure; (3) Torricellia , polygon and elongated sclereids in the endocarp, pericarp without crystal and tannin; and (4) Cornus sensu lato, the trichome is T-shaped, the abdominal ventral bundle is absent, and the endocarp sclereid is nearly round. In Cornus sensu lato, this document supported that the cornelian cherries (CC, subg. Cornus ) and the big-bracted dogwoods (BB, subg. Syncarpea ) are sister groups. The dwarf dogwoods (DW, subg. Arctocrania ) are sister to them, and the blue- or white-fruited dogwoods (BW, subg. Kraniopsis , subg. Yinquania , and subg. Mesomora ) are the base of the Cornus sensu lato clade. The number of cell layers of endocarps and the types of crystals afford sound evidence for identifying their relationship. This study indicated that the fruit structures of Cornaceae might provide morphological and anatomical evidence for molecular phylogeny.

Introduction: Due to the actual limitation of training conditions, the freestyle skiing aerials winter training term is short. Training tasks such as adaptability training and developing new skills are needed in summer training. When facing different training environments, freestyle skiing aerial athletes' executive control over their abilities could be affected, which can affect their performance. Therefore, we want to research the effect of training conditions on executive control in freestyle skiing aerials athletes and its neural mechanism., Materials and Methods: Thirty-two freestyle skiing aerials athletes were recruited. We evaluated their executive control and used fNIRS to measure oxygenated hemoglobin concentration changes in the prefrontal cortex during a rapid event-related design go/nogo task with different training condition-activated materials., Results: Athletes' behavior control in the summer condition has a lower accuracy than it is in the control condition. Athletes' behavior control in the summer and winter training conditions had a longer reaction time than that in the control condition. The activation of the bilateral dlPFC and orbitofrontal cortex had a significant main effect across training conditions when freestyle skiing aerial athletes completed executive control tasks. The activation of athletes' bilateral vlPFC and left dlPFC had an interaction between training conditions and behavioral control., Conclusion: Different training conditions can lead to freestyle skiing aerial athletes executive control ability to drop, players in different training conditions show less activation on both sides of the vlPFC and orbitofrontal. The bilateral vlPFC and left dlPFC have an integrated effect on behavior inhibition across training conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Zhang, Wang, Liu and Sun.)

Helicobacter pylori is associated with gastric disorders. In this study, the anti-H. pylori capacity of natural products from "Winter Red" crabapple flowers were evaluated, including flavonoids, organic acids, terpenoids, and phenolic acids. Among these products, kaempferol showed the highest antibacterial capacity. Structure-activity relationship assays indicated that all hydroxyls contributed to the antibacterial capacity of kaempferol, with the most important being hydroxyls in the A-ring. Kaempferol had comparable anti-H. pylori capacities to clarithromycin and amoxicillin. Both kaempferol and the two antibiotics might damage the cell membrane of H. pylori. However, the RNA-sequence assay demonstrated that their antibacterial mechanisms were different. The ATP-binding cassette transporters, flagellar assembly, and fatty acid metabolism were the major pathways in H. pylori cells responding to kaempferol treatment. We suggest that crabapple containing abundant kaempferol may benefit humans by inhibiting gastric H. pylori. PRACTICAL APPLICATIONS: The anti-Helicobacter pylori capacity of natural products including flavonoids, organic acids, terpenoids, and phenolic acids from "Winter Red" crabapple flowers were evaluated in the present study. Among these products, kaempferol showed the highest antibacterial capacity. More importantly, kaempferol had comparable anti-H. pylori capacities to clarithromycin and amoxicillin, but in a manner distinct from the antibiotics. We suggest that crabapple flowers containing abundant kaempferol may be processed into various products for the patients who have gastric disorders caused by H. pylori. Or the extracted kaempferol from crabapples or other plants could be tested for the clinical treatment of gastric H. pylori., (© 2022 Wiley Periodicals LLC.)

Cellular differentiation, the fundamental hallmark of cells, plays a critical role in homeostasis. And stem cells not only regulate the process where embryonic stem cells develop into a complete organism, but also replace ageing or damaged cells by proliferation, differentiation and migration. In characterizing distinct subpopulations of skin epithelial cells, stem cells show large heterogeneity and plasticity for homeostasis, wound healing and tumorigenesis. Epithelial stem cells and committed progenitors replenish each other or by themselves owing to the remarkable plasticity and heterogeneity of epidermal cells under certain circumstance. The development of new assay methods, including single-cell RNA sequence, lineage tracing assay, intravital microscopy systems and photon-ablation assay, highlight the plasticity of epidermal stem cells in response to injure and tumorigenesis. However, the critical mechanisms and key factors that regulate cellular plasticity still need for further exploration. In this review, we discuss the recent insights about the heterogeneity and plasticity of epithelial stem cells in homeostasis, wound healing and skin tumorigenesis. Understanding how stem cells collaborate together to repair injury and initiate tumor will offer new solutions for relevant diseases. Schematic abstract of cellular heterogeneity and plasticity of skin epithelial cells in wound healing and tumorigenesis., (© 2022. The Author(s).)

Adipose-derived stem cells(ADSCs) have been used for anti-photo-aging. But the purification of ADSCs requires in vitro amplification and culture, there is considerable risk of direct treatment for patients. Stromal vascular fraction(SVF) is a biologically and clinically interesting heterogeneous cell population contains ADSCs. There are few reports on anti-aging effects of SVF in photo-aging skin. The present study investigated the anti-aging effect of stromal vascular fraction (SVF) and adipose-derived stem cells (ADSCs) injection in photo-aging skin. The relationship between the dosage of injection and effect was also discussed. Thirty healthy, 6-week-old, nude rats were randomly divided into the control and experimental groups. The experimental group needing ultraviolet B (UVB) irradiation five days per week, and a duration of 8 weeks. According to different dose regimens of SVF and ADSCs, experiment rats were randomly grouped as the model control group, low-dose (LD) treatment group, middle-dose (MD) treatment group and high-dose (HD) treatment group. At 7 and 28 days post-treatment, specimens were harvested for histological and immunohistochemical analysis. We found that certain concentrations of cells (MD and HD groups) could improve the texture of photoaged skin. Changes in the epidermal cell layer were clearly observed after 7 days of treatment. The epidermal layer becomes thinner and more tender. After 28 days of treatment, the dermal tissue was thickened and the collagen content and proportion were improved. All these indicators showed no significant difference between the same dosages in the two treatment groups. Our results demonstrate that SVF may have anti-aging potential in photo-aging skin and the ADSCs play an important role in SVF. SVF maybe a potential agent for photo-anging skin and the most effective dose of SVF was 10 6 cells /100 µl/injection point. The proper injection interval may be 1.5 cm., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Chen, He, Li, Chen and Liu.)

Hair follicle stem cells (HFSCs) reside in the bulge region of the outer root sheath of the hair follicle. They are considered slow-cycling cells that are endowed with multilineage differentiation potential and superior proliferative capacity. The normal morphology and periodic growth of HFSCs play a significant role in normal skin functions, wound repair and skin regeneration. The HFSCs involved in these pathophysiological processes are regulated by a series of cell signal transduction pathways, such as lymphoid enhancer factor/T-cell factor, Wnt/β-catenin, transforming growth factor-β/bone morphogenetic protein, Notch and Hedgehog. The mechanisms of the interactions among these signaling pathways and their regulatory effects on HFSCs have been previously studied, but many mechanisms are still unclear. This article reviews the regulation of hair follicles, HFSCs and related signaling pathways, with the aims of summarizing previous research results, revealing the regulatory mechanisms of HFSC proliferation and differentiation and providing important references and new ideas for treating clinical diseases., (© The Author(s) 2022. Published by Oxford University Press.)

BACKGROUND: Respiratory syncytial virus (RSV) is a common, contagious, and seasonal pathogen causing 64 million acute respiratory infections annually in adults and children worldwide. High-risk adults, including older adults and those with cardiopulmonary conditions or weakened immune systems, are more likely to be infected. However, limited information exists on RSV incidence and associated costs among adults, including high-risk patients. OBJECTIVE: To evaluate the annual incidence of medically attended, International Classification of Diseases (ICD)-coded RSV among commercially insured adults and assess health care costs among adults with ICD-coded RSV in the United States. METHODS: Optum's deidentified Clinformatics Data Mart Database (January 01, 2007, to June 30, 2020) and IBM's MarketScan Databases (January 01, 2000, to July 31, 2020) were used. Medically attended, ICD-coded RSV incidence among adults was assessed from July 1 of a given year to June 30 of the next year and reported per 100,000 population. Trends in all-cause mean weekly costs pre-RSV and post-RSV diagnosis were reported. Results were reported overall and among patients aged 60-64 years, 65 years or older, 85 years or older, and 18-59 years at high risk of severe RSV (defined as having cardiopulmonary conditions or a weakened immune system). RESULTS: Annual incidence of medically attended, ICD-coded RSV in adults overall was 22.0-52.9 in Optum and 23.4-63.6 in MarketScan. Incidence rates were higher among patients aged 60-64 years (Optum: 25.2-66.1; MarketScan: 31.9-82.1), 65 years or older (Optum: 37.3-75.5; MarketScan: 54.1-97.3), 85 years or older (Optum: 92.4-140.6; MarketScan: 79.4-234.7), and 18-59 years at high risk of severe RSV (Optum: 41.3-135.9; MarketScan: 46.3-112.4). Mean weekly costs increased during the week before (Optum: $2,325; MarketScan: $2,080) and post-RSV diagnosis (Optum: $9,523; MarketScan: $3,551), compared with those in weeks 2-8 pre-RSV diagnosis (Optum: $1,350; MarketScan: $872). The increases in mean weekly costs during the week before and the week following RSV diagnosis were higher among patients aged 60-64 years (mean weekly costs in weeks 2-8 pre-RSV, week 1 pre-RSV, week 1 post-RSV; Optum: $1,623, $2,690, $10,823; MarketScan: $1,259, $2,992, $5,069), 65 years or older (Optum: $1,731, $3,067, $12,866; MarketScan: $1,517, $3,571, $5,268), 85 years or older (Optum: $1,563, $2,430, $18,134; MarketScan: $1,613, $4,113, $6,231), and 18-59 years at high risk of severe RSV (only for MarketScan: $1,237, $3,294, $5,531; costs were similar for Optum). CONCLUSIONS: Incidence of medically attended, ICD-coded RSV in adults was 22.0-63.6 per 100,000 population, a likely underestimation since RSV was not systematically tested and only RSV-coded cases were observed. Incremental costs associated with RSV were substantial. Incidence rates and costs were higher among patients aged 60 years or older and patients at high risk of severe RSV. DISCLOSURES: This study was sponsored by Janssen Scientific Affairs, LLC. The sponsor was involved in the study design, interpretation of results, manuscript preparation, and publication decisions. B. Brookhart and D. Anderson are employees of Janssen Scientific Affairs, LLC, and are stockholders of Johnson & Johnson. C. Rossi, B. Emond, J. Wang, P. Lefebvre, and M.-H. Lafeuille are employees of Analysis Group, Inc., a consulting company that has provided paid consulting services to Janssen Scientific Affairs, LLC, which funded the development and conduct of this study and manuscript. M. Mesa-Frias. and S. Drummond are former employees of Janssen Scientific Affairs, LLC. L. Lamerato is an employee of Henry Ford Health System and received research funding from Janssen Scientific Affairs, LLC.

Plant species diversity (PSD) is essential in evaluating the function and developing the management and conservation strategies of grassland. However, over a large region, an efficient and high precision method to monitor multiscale PSD (α-, β-, and γ-diversity) is lacking. In this study, we proposed and improved an unmanned aerial vehicle (UAV)-based PSD monitoring method (UAV B ) and tested the feasibility, and meanwhile, explored the potential relationship between multiscale PSD and precipitation on the alpine grassland of the source region of the Yellow River (SRYR), China. Our findings showed that: (1) UAV B was more representative (larger monitoring areas and more species identified with higher α- and γ-diversity) than the traditional ground-based monitoring method, though a few specific species (small in size) were difficult to identify; (2) UAV B is suitable for monitoring the multiscale PSD over a large region (the SRYR in this study), and the improvement by weighing the dominance of species improved the precision of α-diversity (higher R 2 and lower P values of the linear regressions); and (3) the species diversity indices (α- and β-diversity) increased first and then they tended to be stable with the increase of precipitation in SRYR. These findings conclude that UAV B is suitable for monitoring multiscale PSD of an alpine grassland community over a large region, which will be useful for revealing the relationship of diversity-function, and helpful for conservation and sustainable management of the alpine grassland., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Yuan, Luo, Ji, Bian, Zhu, Wang, Qin, He, Li and Yi.)

Both sarcopenia and loss of teeth are associated with aging. The purpose of this study was to investigate potential relationships between tooth loss and sarcopenia and its components in suburban community-dwelling older adults of Shanghai and Tianjin, China. The subjects were 1494 people over 60 years of age (40.7% men; aged 71.64 ± 5.97 years) from Chongming District of Shanghai and Hangu District of Tianjin. Asian Working Group for Sarcopenia(AWGS) criteria were used to define sarcopenia. Muscle mass, muscle strength, and physical performance were assessed using a bioelectrical impedance analyzer, a grip strength test, and a four-meter walk test, respectively. The subjects were divided into groups depending on self-reported loss of teeth. Our studies found no correlation between tooth loss and sarcopenia or muscle mass. However, the walking speed of female participants with at least 10 teeth lost was 0.059 m/s slower than that of participants with fewer than 10 teeth lost (p < 0.001), and grip strength was 1.577 kg lower among male participants with at least 10 teeth lost than among males with fewer than 10 teeth lost (p = 0.023). These results are consistent with the importance of good oral hygiene in preventing declines of physical performance in older adults., (© 2022. The Author(s).)

Optical metasurfaces are researched more and more intensively for the possible realization of lightweight and compact optical devices with novel functionalities. In this paper, a new beam-steering system based on double metasurface lenses (metalenses) is proposed and developed. The proposed system is lightweight, small volume, low cost, and easy to integrate. The exact close-form forward and numerical inverse solutions are derived respectively using the generalized Snell's law of refraction. Given the orientations of the double metalenses, the pointing position can be accurately determined. If the desired pointing position is given, the required metalenses' orientations can be obtained by applied global optimization algorithms to solve nonlinear equations related to the inverse problem. The relationships of the scan region and blind zone with the system parameters are derived. The method to eliminate the blind zone is given. Comparison with double Risley-prism systems is also conducted. This work provides a new approach to control light beams., (© 2022. The Author(s).)

Tumor microenvironment (TME)-responsive intelligent photodynamic therapy (PDT) systems have attracted increasing interest in anticancer therapy, due to their potential to address significant and unsatisfactory therapeutic issues, such as limited tissue penetration, inevitable normal tissue damage, and excessive impaired vessels. Here, an H 2 O 2 -triggered intelligent LCL/ZnO PDT nanodelivery system is elaborately designed. LCL/ZnO can selectively regulate tumor-derived endothelial cells (TECs) and specifically kill tumor cells, by responding to different H 2 O 2 gradients in TECs and tumor cells. The LCL/ZnO is able to normalize tumor vessels, thereby resulting in decreased metastases, and ameliorating the immunosuppressive TME. Further analysis demonstrates that singlet oxygen ( 1 O 2 )-activated transient receptor potential vanilloid-4-endothelial nitric oxide synthase signals generated in TECs by LCL/ZnO induce tumor vascular normalization, which is identified as a novel mechanism contributing to the increased ability of PDT to promote cancer therapy. In conclusion, designing an intelligent PDT nanodelivery system response to the TME, that includes both selective TECs regulation and specific tumor-killing, will facilitate the development of effective interventions for future clinical applications., (© 2022 Wiley-VCH GmbH.)

Background and Aims: This study aimed atinvestigating the relationship between speech-frequency hearing loss (SFHL), high-frequency hearing loss (HFHL), and cognitive impairment (CI) and then to determine whether there are any differences in gender among older community dwellers in China., Methods: 1012 adults aged ≥ 60 years (428 males; average age, 72.61 ± 5.51 years) and living in Chongming District, Shanghai were enrolled in the study. We used the audiometric definition of hearing loss (HL) adopted by the World Health Organization (WHO). Speech-frequencies were measured at 0.5 kHz, 1 kHz, 2 kHz, and 4 kHz; high-frequencies were measured at 4 kHz and 8 kHz. Pure tone average (PTA) was measured as hearing sensitivity. Cognitive performance was measured using the mini mental state examination (MMSE)., Results: Our studies demonstrated a 37.6% prevalence of HL in males and a 36.0% prevalence of HL in females. Adjusted for confounding variables, the results from a multivariate analysis showed that SFHL was associated with CI in females (OR = 2.922, 95% Confidence Interval = 1.666-5.124) and males (OR = 2.559, 95% Confidence Interval = 1.252-5.232). However, HFHL was associated with CI only in females (OR = 3.490, 95% Confidence Interval = 1.834-6.643). HL was associated with poorer cognitive scores (P < 0.05). "Registration" (P < 0.05) in MMSE was associated with speech- and high-frequency hearing sensitivity., Conclusions: The associations between HL and CI varied according to gender in older community-dwellers, suggesting that different mechanisms are involved in the etiology of HL. Moreover, hearing sensitivity was negatively associated with cognition scores; therefore, early screening for HL and CI among older community-dwelling adults is advised., (© 2021. The Author(s).)

Kalidium foliatum (Pall.) Moq. is a dominant halophyte species of the desert ecosystem mainly distributed in Southeast Europe and Northwest Asia, and used as a major forage grass. Here, we report its complete chloroplast genome, assembled from the whole-genome resequencing data. The circular genome of K. foliatum is 153,773 bp in length, including a typical quadripartite structure consisting of a pair of inverted repeats (IRs; 24,991 bp) separated by large single-copy (LSC; 84,781 bp) and small single-copy (SSC; 19,010 bp) regions. The total GC content is 36.3%, and a total of 129 genes are annotated, including 84 protein-coding genes, 37 tRNAs, and eight rRNAs. The phylogenetic analysis has shown that K. foliatum is positioned as a sister taxon to the two Salicornia species, all belonging to the same tribe, Salicornieae., Competing Interests: No potential conflict of interest was reported by the authors., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Burn injury is an intractable problem in the field of surgery where screening relevant target genes and exploring pathological mechanisms through bioinformatic methods has become a necessity. Herein, we integrated three burn injury mRNA microarray datasets from the Gene Expression Omnibus database to analyze the hub differentially expressed genes (DEGs) between burn injury patient samples and healthy human samples; we conducted multiple functional enrichment analyses and constructed the protein-protein interaction (PPI) network. Finally, we evaluated the immune infiltration in the burn injury microenvironment. A total of 84 intersection DEGs (32 upregulated and 52 downregulated) were screened in burn injury patients via integrated analyses. Upregulated genes were primarily enriched in regulation of T cell activation, regulation of response to DNA damage stimulus, positive regulation of innate immune response, positive regulation of defense response. We also identified 10 hub genes from the PPI network (CCNB2, MYO10, TTK, POLQ, VASP, TIMP1, CDK16, MMP1, ZYX, and PKMYT1). Next, we found that 22 immune cells were substantially changed during the burn injury by CIBERSORT. In addition, we verified that VASP and POLQ are two novel diagnostic markers in burn processes with high diagnostic efficacy via immunohistochemistry. In summary, we identified several key genes involved in burn injury and provided a favorable basis for elucidating the molecular mechanisms of burn injury through comprehensive bioinformatic analysis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Wang, Wang, He, Zheng, Long, Chen and Yang.)

Migraine is a complex neurovascular disease, which seriously affects the quality of life in patients. This study aimed to evaluate the effect of Xiongmatang (XMT) extract on rats with migraine induced by inflammatory soup and the underlying mechanisms. First, 1 week after dural catheterization, inflammatory soup was injected through a microsyringe to stimulate the dura of rats for 6 times (12 days), once every 2 days, 10  μ L each time, to establish a migraine model. According to pain threshold analysis, behavioral change detection, and pathological analysis, the effects of XMT extract on rats with migraine were evaluated. The positive, mRNA and protein expression of related factors were detected by immunohistochemistry, RT-QPCR, and Western blot analysis to elucidate the underlying mechanism. XMT extract improved the behavioral performance of rats, and improve the pathological changes in the trigeminal nerve in rats. Further experimental results show that XMT extract regulated the expression of migraine-related factors in the trigeminal nerve, manifested as transient receptor potential vanilloid 1 (TRPV1), calcitonin-gene-related peptide (CGRP), calcitonin receptor-like receptor (CRLR), and receptor activity-modifying protein 1 (RAMP1) positive expression, mRNA expression, and protein expression reduction. XMT extract can significantly improved the behavioral performance of rats with migraine, and its mechanism of action might involve regulating the activity of TRPV1-CGRP/CGRP-R pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Chang, Wang, Zhu, Jiang, Azhar, Ahmed and Zeng.)

Identification of targets among known drugs plays an important role in drug repurposing and discovery. Computational approaches for prediction of drug-target interactions (DTIs)are highly desired in comparison to traditional biological experiments as its fast and low price. Moreover, recent advances of systems biology approaches have generated large-scale heterogeneous, biological information networks data, which offer opportunities for machine learning-based identification of DTIs. We present a novel Inductive Matrix Completion with Heterogeneous Graph Attention Network approach (IMCHGAN)for predicting DTIs. IMCHGAN first adopts a two-level neural attention mechanism approach to learn drug and target latent feature representations from the DTI heterogeneous network respectively. Then, the learned latent features are fed into the Inductive Matrix Completion (IMC)prediction score model which computes the best projection from drug space onto target space and output DTI score via the inner product of projected drug and target feature representations. IMCHGAN is an end-to-end neural network learning framework where the parameters of both the prediction score model and the feature representation learning model are simultaneously optimized via backpropagation under supervising of the observed known drug-target interactions data. We compare IMCHGAN with other state-of-the-art baselines on two real DTI experimental datasets. The results show that our method is superior to existing methods in term of AUC and AUPR. Moreover, IMCHGAN also shows it has strong predictive power for novel (unknown)DTIs. All datasets and code can be obtained from https://github.com/ljatynu/IMCHGAN/.

Background: A substantial proportion of patients with unresectable stage III non-small-cell lung cancer (NSCLC) cannot either tolerate or access concurrent chemoradiotherapy, so sequential chemoradiotherapy is commonly used. We assessed the efficacy and safety of sugemalimab, an anti-PD-L1 antibody, in patients with stage III NSCLC whose disease had not progressed after concurrent or sequential chemoradiotherapy., Methods: GEMSTONE-301 is a randomised, double-blind, placebo-controlled, phase 3 trial in patients with locally advanced, unresectable, stage III NSCLC, done at 50 hospitals or academic research centres in China. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 who had not progressed after concurrent or sequential chemoradiotherapy. We randomly assigned patients (2:1, using an interactive voice-web response system) to receive sugemalimab 1200 mg or matching placebo, intravenously every 3 weeks for up to 24 months. Stratification factors were ECOG performance status, previous chemoradiotherapy, and total radiotherapy dose. The investigators, trial coordination staff, patients, and study sponsor were masked to treatment allocation. The primary endpoint was progression-free survival as assessed by blinded independent central review (BICR) in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of assigned study treatment. The study has completed enrolment and the results of a preplanned analysis of the primary endpoint are reported here. The trial is registered with ClinicalTrials.gov, NCT03728556., Findings: Between Aug 30, 2018 and Dec 30, 2020, we screened 564 patients of whom 381 were eligible. Study treatment was received by all patients randomly assigned to sugemalimab (n=255) and to placebo (n=126). At data cutoff (March 8, 2021), median follow-up was 14·3 months (IQR 6·4-19·4) for patients in the sugemalimab group and 13·7 months (7·1-18·4) for patients in the placebo group. Progression-free survival assessed by BICR was significantly longer with sugemalimab than with placebo (median 9·0 months [95% CI 8·1-14·1] vs 5·8 months [95% CI 4·2-6·6]; stratified hazard ratio 0·64 [95% CI 0·48-0·85], p=0·0026). Grade 3 or 4 treatment-related adverse events occurred in 22 (9%) of 255 patients in the sugemalimab group versus seven (6%) of 126 patients in the placebo group, the most common being pneumonitis or immune-mediated pneumonitis (seven [3%] of 255 patients in the sugemalimab group vs one [<1%] of 126 in the placebo group). Treatment-related serious adverse events occurred in 38 (15%) patients in the sugemalimab group and 12 (10%) in the placebo group. Treatment-related deaths were reported in four (2%) of 255 patients (pneumonia in two patients, pneumonia with immune-mediated pneumonitis in one patient, and acute hepatic failure in one patient) in the sugemalimab group and none in the placebo group., Interpretation: Sugemalimab after definitive concurrent or sequential chemoradiotherapy could be an effective consolidation therapy for patients with stage III NSCLC whose disease has not progressed after sequential or concurrent chemoradiotherapy. Longer follow-up is needed to confirm this conclusion., Funding: CStone Pharmaceuticals and the National Key Research and Development Program of China., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests Y-LW reports advisory services for AstraZeneca, Boehringer Ingelheim, Novartis, and Takeda; personal fees from AstraZeneca, Beigene, Boehringer Ingelheim, Bristol Meyer Squibb, Eli Lilly, MSD, Pfizer, Roche, and Sanofi; grants from AstraZeneca, Boehringer Ingelheim, BMS, Hengrui, and Roche, outside of the submitted work. QZ reports honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Meyer Squibb, Eli Lilly, MSD, Pfizer, Roche, and Sanofi, outside the submitted work. NC, JW, QW, RZ, and JY are employed by CStone Pharmaceuticals and NC, JW, QW, and JY declare stock ownership in the company. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To investigate the clinical manifestations, laboratory and imaging examinations, and the treatment outcomes of autoimmune encephalitis (AE)., Methods: The clinical data of 13 patients with autoimmune encephalitis who were hospitalized in the department of neurology, Liaocheng People's Hospital from July 2016 to August 2018 were retrospectively analyzed., Results: The average age of onset of the 13 patients was 45 years, including 6 cases (46%) of anti-NMDAR encephalitis, 3 cases (23%) of anti-GABAB receptor encephalitis, and 4 cases (30%) of anti-LG11 encephalitis, and 4 of them showed abnormal signals of brain MRI (30%). 13 patients (100%) had cognitive impairment and psychiatric symptoms; seizures occurred in 12 patients (92%); lung cancer was found in 1 patient (7%). One case was given up because of the treatment of lung cancer, the other was controlled obviously in epilepsy, and cognitive impairment and abnormal mental behavior were also significantly improved., Conclusion: Patients with AE still need to be diagnosed early to avoid missed diagnosis and receive early immunosuppressive therapy, which could effectively reduce mortality and morbidity. A detailed history, clinical manifestations, and positive results for specific NSAbs tests can confirm the diagnosis, and the treatment is mainly done by immunosuppressive therapy., Competing Interests: We declare no conflict of interests., (Copyright © 2022 Anqi Huang et al.)

Objective: To explore the risk factors of postoperative cognitive dysfunction (POCD) in elderly patients with gastric cancer after radical resection and to establish a risk prediction model., Methods: A retrospective analysis of the clinicopathological data of 687 elderly patients who underwent radical gastric cancer surgery from January 2014 to January 2020 in the Third Department of Surgery, Fourth Hospital of Hebei Medical University was conducted. The degree of cognitive impairment was divided into POCD positive group (n=141, 20.52%) and POCD negative group (n=546, 79.48%). The general data of the two groups were compared. Multivariate logistic regression was used to analyze the risk factors for POCD in elderly gastric cancer patients after radical surgery. A risk prediction model was established. The receiver operating characteristic (ROC) curve was used to evaluate the effectiveness of the model., Results: Multivariate logistic regression analysis showed that preoperative ASA classification (OR=4.674, 95% CI: 1.610~12.651, P=0.020), age (OR=3.130, 95% CI: 1.307~8.669, P=0.001), operation time (OR=2.724, 95% CI: 1.232~7.234, P=0.031), preoperative PG-SGA score (OR=4.023, 95% CI: 1.011-10.883, P=0.048), and preoperative hemoglobin (OR=4.158, 95% CI: 2.255~8.227, P=0.001) were independent risk factors for POCD. Intraoperative application of dexmedetomidine (OR=0.172, 95% CI: 0.078~0.314, P=0.002) and maintaining a deeper anesthesia state (OR=0.151, 95% CI: 0.122~0.283, P=0.018) were protective factors. The area under the ROC curve of the POCD risk prediction model for elderly gastric cancer patients after surgery was 0.820 (95% CI: 0.742-0.899) (P<0.01)., Conclusion: The occurrence of postoperative POCD in elderly patients with gastric cancer is closely related to a variety of risk factors. By establishing a risk prediction model for the occurrence of POCD, high-risk patients can be effectively identified during the perioperative period, to intervene earlier., Competing Interests: None., (AJTR Copyright © 2022.)

MiRNA-disease association prediction plays an important role in identifying human disease-related miRNAs. This approach is helpful not only to formulate individualized diagnosis schemes, but also to understand the pathogenesis of diseases. Many studies have focused on enhancing the prediction performance using explicit side information, such as miRNA functional similarity and disease semantic similarity. The existing approaches, however, often ignore the higher-order implicit proximity among miRNAs and diseases. To this end, in this paper, we first propose a novel approach HOP&#95;MDA (Higher-Order Proximity based MiRNA and Disease Association Prediction) for predicting potential association between miRNA and disease. Both explicit interaction information and implicit higher-order proximity information between miRNA and disease are encoded with different order proximity matrices which are weightily combined into a parameterized prediction matrix. A supervised learning approach based on the known miRNAs-disease associations is proposed to determine the optimal weight parameters. The prediction matrix is then used to achieve effective prediction. Additionally, a higher-order proximity approximation technique (HOPA&#95;MDA) is presented to make more efficient predictions. 5-fold cross validation is used to evaluate the performance of our proposed method. The average AUC values of HOPA&#95;MDA for two real datasets are 0.921+/-0.002 and 0.944+/-0.0015, respectively. Our method can also predict potential miRNAs specific to new diseases with no known related miRNAs.

Background: Allergic asthma is a chronic airway inflammatory disease with a number of cytokines participating in its pathogenesis and progress. Interleukin (IL)-22, which is derived from lymphocytes, acts on epithelial cells and play a role in the chronic airway inflammation. However, the actual role of IL-22 in allergic asthma is still unclear. Therefore, we explored the effect of IL-22 on allergic airway inflammation and airway hyperresponsiveness (AHR) in an ovalbumin (OVA)-induced asthma mouse model., Methods: To evaluate the effect of IL-22 in an allergic asthma model, BALB/c mice were sensitized and challenged with OVA; then the recombinant mouse IL-22 was administered intranasally 24 h prior to each challenge. The IL-22 levels in lung homogenates and bronchoalveolar lavage fluid (BALF) were measured by enzyme linked immunosorbent assay, respectively. AHR was evaluated through indicators including airways resistance (Rrs), elastance (Ers) and compliance (Crs); the inflammatory cell infiltration was assessed by quantification of differential cells counts in BALF and lung tissues stained by hematoxylin and eosin (H&E); IL-22 specific receptors were determined by immunohistochemistry staining., Results: The concentration of IL-22 was significantly elevated in the OVA-induced mice compared with the control mice in lung homogenates and BALF. In the OVA-induced mouse model, IL-22 administration could significantly attenuate AHR, including Rrs, Ers and Crs, decrease the proportion of eosinophils in BALF and reduce inflammatory cell infiltration around bronchi and their concomitant vessels, compared with the OVA-induced group. In addition, the expression of IL-22RA1 and IL-10RB in the lung tissues of OVA-induced mice was significantly increased compared with the control mice, while it was dramatically decreased after the treatment with IL-22, but not completely attenuated in the IL-22-treated mice when compared with the control mice., Conclusion: Interleukin-22 could play a protective role in an OVA-induced asthma model, by suppressing the inflammatory cell infiltration around bronchi and their concomitant vessels and airway hyperresponsiveness, which might associate with the expression of its heterodimer receptors. Thus, IL-22 administration might be an effective strategy to attenuate allergic airway inflammation., (© 2021. The Author(s).)

A surface-plasmon-resonance-based fiber device is proposed for highly sensitive relative humidity (RH) sensing and human breath monitoring. The device is fabricated by using a polyvinyl alcohol (PVA) film and gold coating on the flat surface of a side-polished polymer optical fiber. The thickness and refractive index of the PVA coating are sensitive to environmental humidity, and thus the resonant wavelength of the proposed device exhibits a redshift as the RH increases. Experimental results demonstrate an average sensitivity of 4.98 nm/RH% across an ambient RH ranging from 40% to 90%. In particular, the sensor exhibits a linear response between 75% and 90% RH, with a sensitivity of 10.15 nm/RH%. The device is suitable for human breath tests and shows an average wavelength shift of up to 228.20 nm, which is 10 times larger than that of a silica-fiber-based humidity sensor. The corresponding response and recovery times are determined to be 0.44 s and 0.86 s, respectively. The proposed sensor has significant potential for a variety of practical applications, such as intensive care and human health analysis., Competing Interests: The authors declare no conflict of interest.

Cell apoptosis detection is vital for biological analysis and clinical application; some detection assays are already commercially available. However, it is still far from perfect and needs further improvement for less cost, time-consuming and operation demanding. TUNEL, a high market share cell apoptosis assay, depends on adulteration fluorescent labelling dUTP by terminal deoxynucleotidyl transferase(TdT) which randomly adds deoxyribonucleoside triphosphates (dNTPs) at the 3'-OH terminal of ssDNA with a template-free manner. Based on our previous work, we adopted a label-free strategy to reduce the cost and operation maintenance of TUNEL and developed a facile, rapid, convenient and in-situ assay for cell apoptosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Chronic inflammation increases cancer risk, and cancer development is characterized by stepwise accumulation of genetic and epigenetic alterations. During chronic inflammation, infectious agents and intrinsic mediators of inflammatory responses can induce genetic and epigenetic changes. This study tried to evaluate both the genetic and epigenetic influence of chronic inflammation on colon mucosa cells. Repetitive dextran sulfate sodium (DSS) treatment induced chronic colitis model. Whole-exome sequencing (WES) (200× coverage) was performed to detect somatic variations in colon mucosa cells. With the use of whole-genome bisulfite sequencing (BS) at 34-fold coverage (17-fold per strand), the methylome of both the colitis and control tissue was comparatively analyzed. Bioinformatics assay showed that there was no significant single-nucleotide polymorphism/insertion or deletion (SNP/InDel) mutation accumulation in colitis tissue, while it accumulated in aged mice. Forty-eight genes with SNP/InDel mutation were overlapped in the three colitis tissues, two (Wnt3a and Lama2) of which are in the cancer development-related signaling pathway. Differentially methylated region (DMR) assay showed that many genes in the colitis tissue are enriched in the cancer development-related signaling pathway, such as PI3K-AKT, Ras, Wnt, TGF-beta, and MAPK signaling pathway. Together, these data suggested that even though chronic inflammation did not obviously increase genetic mutation accumulation, it could both genetically and epigenetically alter some genes related to cancer development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JC declared a shared affiliation with the authors JH, JH, JL, XW to the handling editor at time of review., (Copyright © 2021 He, Han, Liu, Yang, Wang, Wang and Chen.)

The tumorigenesis of skin cutaneous melanoma (SKCM) remains unclear. The tumor microenvironment (TME) is well known to play a vital role in the onset and progression of SKCM. However, the dynamic mechanisms of immune regulation are insufficient. We conducted a comprehensive analysis of immune cell infiltration in the TME. Based on the differentially expressed genes (DEGs) in clusters grouped by immune infiltration status, a set of hub genes related to the clinical prognosis of SKCM and tumor immune infiltration was explored. Methods: We analyzed immune cell infiltration in two independent cohorts and assessed the relationship between the internal pattern of immune cell infiltration and SKCM characteristics, including clinicopathological features, potential biological pathways, and gene mutations. Genes related to the infiltration pattern of TME immune cells were determined. Furthermore, the unsupervised clustering method (k-means) was used to divide samples into three different categories according to TME, which were defined as TME cluster-A, -B, and -C. DEGs among three groups of samples were analyzed as signature genes. We further distinguished common DEGs between three groups of samples according to whether differences were significant and divided DEGs into the Signature gene-A group with significant differences and the Signature gene-B group with insignificant differences. The Signature gene-A gene set mainly had exon skipping in SKCM, while the Signature gene-B gene set had no obvious alternative splicing form. Subsequently, we analyzed genetic variations of the two signatures and constructed a competing endogenous RNA (ceRNA) regulatory network. LASSO Cox regression was used to determine the immune infiltration signature and risk score of SKCM. Finally, we obtained 13 hub genes and calculated the risk score based on the coefficient of each gene to explore the impact of the high- and low-risk scores on biologically related functions and prognosis of SKCM patients further. The correlation between the risk score and clinicopathological characteristics of SKCM patients indicated that a low-risk score was associated with TME cluster-A classification ( p < 0.001) and metastatic SKCM ( p < 0.001). Thirteen hub genes also showed different prognostic effects in pan-cancer. The results of univariate and multivariate Cox analyses revealed that risk score could be used as an independent risk factor for predicting the prognosis of SKCM patients. The nomogram that integrated clinicopathological characteristics and immune characteristics to predict survival probability was based on multivariate Cox regression. Finally, 13 hub genes that showed different prognostic effects in pan-cancers were obtained. According to immunohistochemistry staining results, Ube2L6 , SRPX2 , and IFIT2 were expressed at higher levels, while CLEC4E , END3 , and KIR2DL4 were expressed at lower levels in 25 melanoma specimens. Conclusion: We performed a comprehensive assessment of the immune-associated TME. To elucidate the potential development of immune-genomic features in SKCM, we constructed an unprecedented set of immune characteristic genes ( EDN3 , CLEC4E , SRPX2 , KIR2DL4 , UBE2L6 , and IFIT2 ) related to the immune landscape of TME. These genes are related to different prognoses and drug responses of SKCM. The immune gene signature constructed can be used as a robust prognostic biomarker of SKCM and a predictor of an immunotherapy effect., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhou, Sun, Chen, Wang, He, Lyu, Shen, Chen and Yang.)

Background: Currently, biotherapy is mainly administered to treat patients with severe asthma with the Type 2 (T2) inflammation phenotype. The variability of T2 inflammatory markers remains poorly understood., Objective: We aimed to describe the individual distributions of different biomarkers at varying thresholds and their variation patterns in participants with severe asthma., Methods: We retrospectively reviewed the data of participants who had completed 2 or more fraction of exhaled nitric oxide (FeNO) and peripheral blood eosinophil counts in our centre within 5 years. The individual distribution of biomarkers (blood or sputum eosinophils, FeNO, and serum total IgE) with repeated measurements at different thresholds was analysed. The varied patterns of biomarkers were analysed by cluster analysis., Results: A total of 241 eligible participants were screened. Through long-term longitudinal multiple measurements, we found that approximately 50% of severe asthmatics had blood eosinophil levels fluctuating around the threshold defined by biological agents. FeNO persisted at levels >19.5 ppb or 25 ppb in more than half of patients; about 30% of participants crossed this threshold. In our centre, 47.4% of participants consistently exceeded sputum eosinophils >3%, and 47.4% of patients crossed this threshold. Approximately 66.7% of participants had more than 50% alterations of serum total IgE, and 98.1% of participants continued to have IgE levels greater than 30 IU/mL. We used cluster analysis to classify variability and levels of FeNO and blood eosinophils and identified 4 patient clusters. Cluster 1 can be summarised as T2 severe asthma with low blood eosinophil levels and stability. Cluster 2 can be summarised as asthma with continuous increase and small fluctuations in various T2 inflammatory markers. Cluster 3 can be summarised as a non/low-T2 inflammatory phenotype. Cluster 4 can be summarised as a stable, moderate T2 inflammatory phenotype., Conclusion: We identified the distributions and variable patterns of the T2 inflammatory markers currently used to guide asthma biotherapy in clinical practice. The longitudinal comprehensive multiple assessments of T2 inflammatory markers provide support for initiating biologic therapy patients with severe asthma whose biomarker levels vary., Competing Interests: The authors declare that they have no relevant conflicts of interest., (© 2021 Published by Elsevier Inc. on behalf of World Allergy Organization.)

Asthma is driven by group 2 innate lymphoid cells, antigen-specific CD4+ T helper type 2 cells and their cytokines such as interleukin (IL)-4, IL-5, IL-13. IL-37 is decreased in asthma and negatively related to Th2 cytokines and other pro-inflammatory cytokines. Our study showed that IL-37 level in asthmatic peripheral blood mononuclear cells was lower than in healthy. Further, IL-37 was negatively correlated with exhaled nitric oxide, asthma control test score, atopy and rhinitis history in asthmatics. Then an OVA-induced asthma mice model treated with rhIL-37 was established. An antibody array was employed to uncover altered cytokines induced by IL-37 in mice lung tissue. 20 proteins differentially expressed after rhIL-37 treatment and five of them were validated in asthmatic peripheral blood mononuclear cells. Consistent with cytokine antibody array, CCL3, CCL4, CCL5 decreased after IL-37 administration. While CXCL9 and CXCL13 were no change. We concluded that IL-37 reduce asthmatic symptoms by inhibit pro-inflammatory cytokine such as CCL3, CCL4, CCL5.

Motivation: There is growing evidence showing that the dysregulations of miRNAs cause diseases through various kinds of the underlying mechanism. Thus, predicting the multiple-category associations between microRNAs (miRNAs) and diseases plays an important role in investigating the roles of miRNAs in diseases. Moreover, in contrast with traditional biological experiments which are time-consuming and expensive, computational approaches for the prediction of multicategory miRNA-disease associations are time-saving and cost-effective that are highly desired for us., Results: We present a novel data-driven end-to-end learning-based method of neural multiple-category miRNA-disease association prediction (NMCMDA) for predicting multiple-category miRNA-disease associations. The NMCMDA has two main components: (i) encoder operates directly on the miRNA-disease heterogeneous network and leverages Graph Neural Network to learn miRNA and disease latent representations, respectively. (ii) Decoder yields miRNA-disease association scores with the learned latent representations as input. Various kinds of encoders and decoders are proposed for NMCMDA. Finally, the NMCMDA with the encoder of Relational Graph Convolutional Network and the neural multirelational decoder (NMR-RGCN) achieves the best prediction performance. We compared the NMCMDA with other baselines on three experimental datasets. The experimental results show that the NMR-RGCN is significantly superior to the state-of-the-art method TDRC in terms of Top-1 precision, Top-1 Recall, and Top-1 F1. Additionally, case studies are provided for two high-risk human diseases (namely, breast cancer and lung cancer) and we also provide the prediction and validation of top-10 miRNA-disease-category associations based on all known data of HMDD v3.2, which further validate the effectiveness and feasibility of the proposed method., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: We examined the association between obesity and physical performance under different metabolic status., Methods: The sample included 1395 Chinese community-dwelling participants (mean age, 71.88 ± 5.87 years; 40.9% men). Being metabolically healthy was defined as having the presence of < 3 of 5 components of metabolic syndrome (MetS); obesity was defined as having a BMI > 28 kg/m 2 . Participants were divided into four groups based on BMI (non-obese/obese) and metabolic health (healthy/unhealthy). Physical performance was measured by grip strength, 4-m walking speed, and the timed up and go test (TUGT)., Results: After multiple adjustments, compared with metabolically healthy non-obese group, the metabolically unhealthy obese group showed lower relative grip strength, lower 4-m walking speed, and higher TUGT ( P all < 0.05), and only relative grip strength of the metabolically healthy obese group was significantly lower than that of metabolically healthy non-obese ( P < 0.01). Relative grip strength was negatively associated with impaired fasting glucose (β = -0.071), elevated triglycerides (β = -0.062), abdominal obesity (β = -0.230) and general obesity (β = -0.225) ( P all < 0.01). Walking speed and TUGT were only associated with general obesity, rather than other metabolic components. The associations of MetS with physical performance were mainly driven by abdominal obesity., Conclusion: Even in those who are metabolically healthy, obesity (especially general obesity) increases the risk of poor physical performance. Elderly people with general obesity and MetS, whether in combination or alone, have an increased risk of muscle dysfunction, and that combination produces a higher risk of impaired mobility., Competing Interests: The authors declare no conflicts of interest., (© 2021 Ma et al.)

Upon starvation, cells rewire their metabolism, switching from glucose-based metabolism to mitochondrial oxidation of fatty acids, which require the transfer of FAs from lipid droplets (LDs) to mitochondria at mitochondria-LD membrane contact sites (MCSs). However, factors responsible for FA transfer at these MCSs remain uncharacterized. Here, we demonstrate that vacuolar protein sorting-associated protein 13D (VPS13D), loss-of-function mutations of which cause spastic ataxia, coordinates FA trafficking in conjunction with the endosomal sorting complex required for transport (ESCRT) protein tumor susceptibility 101 (TSG101). The VPS13 adaptor-binding domain of VPS13D and TSG101 directly remodels LD membranes in a cooperative manner. The lipid transfer domain of human VPS13D binds glycerophospholipids and FAs in vitro. Depletion of VPS13D, TSG101, or ESCRT-III proteins inhibits FA trafficking from LDs to mitochondria. Our findings suggest that VPS13D mediates the ESCRT-dependent remodeling of LD membranes to facilitate FA transfer at mitochondria-LD contacts.

Objective: This study aimed to examine the relationship between physical performance and mild cognitive impairment (MCI) in Chinese older adults., Methods: The sample comprised 956 relatively healthy and aged ≥65 years old Chinese community-dwelling participants (mean age, 72.56 ± 5.43 years; 56.8% female), which did not include those with dementia, severe cognitive impairment, mental illness etc. The Mini-Mental State Examination (MMSE) and the Instrumental Activities of Daily Living (IADL) scale were used for the initial classification of patients with MCI. Physical performance was measured via hand grip, Timed Up and Go Test (TUGT), and 4-m walking speed., Results: The physical performance (grip strength, TUGT, and 4-m walking speed) correlated with MCI. The grip strength [odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.93-0.99] and 4-m walking speed (OR = 0.25, 95% CI = 0.10-0.64) correlated negatively with MCI, while TUGT (OR = 1.08, 95% CI = 1.03-1.13) and MCI correlated positively., Conclusion: The physical performance (grip strength, TUGT, and 4-m walking speed) correlated with MCI. Further analysis showed that the grip strength was associated with overall cognition, time orientation, recall, and language, while TUGT and 4-m walking speed were associated with overall cognition and various cognitive domains, except recall., Competing Interests: The authors declare that they have no conflicts of interest for this work., (© 2021 Liu et al.)

Protein palmitoylation is a fundamental and reversible post-translational lipid modification that involves a series of biological processes. Although a large number of experimental studies have explored the molecular mechanism behind the palmitoylation process, the computational methods has attracted much attention for its good performance in predicting palmitoylation sites compared with expensive and time-consuming biochemical experiments. The prediction of protein palmitoylation sites is helpful to reveal its biological mechanism. Therefore, the research on the application of machine learning methods to predict palmitoylation sites has become a hot topic in bioinformatics and promoted the development in the related fields. In this review, we briefly introduced the recent development in predicting protein palmitoylation sites by using machine learningbased methods and discussed their benefits and drawbacks. The perspective of machine learning-based methods in predicting palmitoylation sites was also provided. We hope the review could provide a guide in related fields., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cyclin D1 is one of the most important oncoproteins that drives cancer cell proliferation and associates with tamoxifen resistance in breast cancer. Here, we identify a lncRNA, DILA1, which interacts with Cyclin D1 and is overexpressed in tamoxifen-resistant breast cancer cells. Mechanistically, DILA1 inhibits the phosphorylation of Cyclin D1 at Thr286 by directly interacting with Thr286 and blocking its subsequent degradation, leading to overexpressed Cyclin D1 protein in breast cancer. Knocking down DILA1 decreases Cyclin D1 protein expression, inhibits cancer cell growth and restores tamoxifen sensitivity both in vitro and in vivo. High expression of DILA1 is associated with overexpressed Cyclin D1 protein and poor prognosis in breast cancer patients who received tamoxifen treatment. This study shows the previously unappreciated importance of post-translational dysregulation of Cyclin D1 contributing to tamoxifen resistance in breast cancer. Moreover, it reveals the novel mechanism of DILA1 in regulating Cyclin D1 protein stability and suggests DILA1 is a specific therapeutic target to downregulate Cyclin D1 protein and reverse tamoxifen resistance in treating breast cancer.

In order to reveal the mechanism of galvanic pitting corrosion initiation induced by typical complex inclusions in Al-Ti-Mg deoxidized high strength pipeline steel, first-principles calculations, combining with immersion tests, scanning electron microscopy was used to study the correlation between electronic work function and galvanic corrosion of Al-Ti-Mg killed steel. The results show that MnS inclusions act as anodes in the electrochemical environment, preferentially corroding and dissolving; MgAl 2 O 4 and Al 2 O 3 inclusions act as cathodes, leading to the corrosion of Fe matrix; different end planes of MgTiO 3 and MgTi 2 O 4 act as both anodes and cathodes, but they have little effect on pitting corrosion. Microcrevices on the MgTiO 3 and MgTi 2 O 4 inclusions boundary are the main cause of matrix dissolution., (Copyright © 2020. Published by Elsevier Ltd.)

Pediocin PA-1 (PA-1) is a membrane-targeting bacteriocin from lactic acid bacteria, which shows antimicrobial activity against a wide range of Gram-positive pathogens. However, the outer membrane of Gram-negative bacteria does not allow pediocin access to its target. In this work, the synergistic inhibitory mechanism of PA-1 with L-lactic acid against Gram-negative aquaculture and food pathogen Aeromonas hydrophila (A. hydrophila) was analyzed. The combined treatment of 3.5 mmol/L L-lactic acid and 50 μmol/L (or 30 μmol/L) PA-1 had strong bacteriostatic and bactericidal activity against A. hydrophila. Full wavelength scanning and ELISA assay revealed the release of lipopolysaccharide (LPS) from the outer membrane of A. hydrophila caused by L-lactic acid treatment. Laser confocal microscopic imaging of A. hydrophila with FITC-labeled pediocin PA-1 proved the accumulation of PA-1 on lactic acid-treated bacterial cells. PA-1 then caused a rapid dissipation of membrane potential (Δψ) and a proton gradient difference (ΔpH) in lactic acid-treated A. hydrophila. Pediocin PA-1 also caused an increase in the extracellular ATP level. Morphology revealed by SEM and TEM showed that combined treating with lactic acid and PA-1 induced vesicles on the cell surface, the outer and inner membrane disruption, and even cytoplasm leakage and cell lysis. The results proved a potential mechanism of the synergistic inhibition of lactic acid and PA-1 against A. hydrophila, by which L-lactic acid released the outer membrane LPS, making it possible for PA-1 to contact the plasma membrane of A. hydrophila, resulting in the dissipation of proton-motive force in the inner membrane and cell death., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cardiac hypoxia plays a significant role in various types of heart disease, and improper treatment of hypoxia often leads to myocardial cell damage or even death. Transcriptome profiling and open chromatin mapping have been used as powerful tools to understand the development of heart disease, but the interplay between gene expression and chromatin accessibility has not been extensively investigated in hypoxia-induced cardiac damage. In this study, with HL-1 cardiomyocytes as a model, we performed temporal profiling of transcriptome and chromatin accessibility to show the cardiac responses to hypoxia (for 4 and 8 hr) and reoxygenation (for 24 hr). With RNA-seq and ATAC-seq, we identified a total of 2,912 differentially expressed genes and 3,004 differential peaks across the whole genome and showed that these data were in good agreement with each other. For hypoxia-related genes, we also discovered high correlations between their ATAC-seq signals and mRNA levels, such as VEGF, Angpt1, Slc2a1, Bnip3, and Casp3 with Pearson correlations >0.7. Interestingly, after 24 hr reoxygenation, the expression levels of 235 genes were still significantly different from the counterparts in the control, suggesting that these genes need a longer recovery time after reoxygenation. In conclusion, our study shows the close relationship between alterations of transcriptome and chromatin accessibility after hypoxia exposure and reoxygenation, emphasizing the importance of open chromatin profiling in related studies. In addition, the profiled molecular responses here will be valuable resources for better understanding of the mechanisms responsible for hypoxia-induced heart disease in future., (© 2020 International Union of Biochemistry and Molecular Biology.)

Objective: To observe the effects of artesunate on eosinophil (EOS) apoptosis and Fas and Bcl-2 protein expressions in asthmatic mice., Methods: Thirty female BALB/c mice aged 6-8 weeks were randomly divided into control group, asthma group and artesunate group. Except for those in the control group, all the mice were sensitized with aerosolized ovalbumin to establish mouse models of asthma. In artesunate group, the rats were intraperitoneally injected with artesunate 1 h before ovalbumin inhalation from the 21st day of modeling. The lung tissues were harvested for staining 24 h after the last challenge. Flow cytometry was used to analyze the percentage and apoptosis rate of EOS in the alveolar lavage fluid (BALF). The apoptosis of EOS in the lung tissue was detected with TUNEL method, and Fas and Bcl-2 protein expressions were detected using immunohistochemistry., Results: Compared with those in asthma group, the artesunate-treated mice had significantly decreased percentage of EOS in the BALF ( P < 0.05) with increased apoptosis rate of EOS in the BALF and the lung tissue ( P < 0.05). The Fas-positive area and IOD of Fas protein in the lung tissue increased ( P < 0.05) while the Bcl-2-positive area and IOD of Bcl-2 protein decreased significantly in artesunate-treated mice as compared with the asthmatic mice ( P < 0.05)., Conclusions: Artesunate regulates the protein expressions of Fas and Bcl-2 to reduce EOS infiltration in the lung tissue and promote EOS apoptosis in asthmatic mice.

Skin stem cells distributed in the basal layer of the epidermis and hair follicles are important cell sources for skin development, metabolism, and injury repair. At present, great progress has been made in the study of epidermal stem cells at the cellular and molecular levels. Stem cell transplantation is reported to promote skin healing, endothelial cell transformation, and vascular formation. Local stem cells can also be transformed into keratinocytes, sebaceous gland, and other skin-associated tissues. However, the mechanism of action of epidermal stem cells on wound healing and regeneration is not completely clear. This review is aimed at briefly summarizing the biological characteristics of epidermal stem cells and their clinical application in wound healing and tissue regeneration. It further discussed the mechanism of action and the development direction in the future., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2020 Ronghua Yang et al.)

De novo variants (DNVs) are one of the most significant contributors to severe early-onset genetic disorders such as autism spectrum disorder, intellectual disability, and other developmental and neuropsychiatric (DNP) disorders. Presently, a plethora of DNVs have been identified using next-generation sequencing, and many efforts have been made to understand their impact at the gene level. However, there has been little exploration of the effects at the isoform level. The brain contains a high level of alternative splicing and regulation, and exhibits a more divergent splicing program than other tissues. Therefore, it is crucial to explore variants at the transcriptional regulation level to better interpret the mechanisms underlying DNP disorders. To facilitate a better usage and improve the isoform-level interpretation of variants, we developed NeuroPsychiatric Mutation Knowledge Base (PsyMuKB). It contains a comprehensive, carefully curated list of DNVs with transcriptional and translational annotations to enable identification of isoform-specific mutations. PsyMuKB allows a flexible search of genes or variants and provides both table-based descriptions and associated visualizations, such as expression, transcript genomic structures, protein interactions, and the mutation sites mapped on the protein structures. It also provides an easy-to-use web interface, allowing users to rapidly visualize the locations and characteristics of mutations and the expression patterns of the impacted genes and isoforms. PsyMuKB thus constitutes a valuable resource for identifying tissue-specific DNVs for further functional studies of related disorders. PsyMuKB is freely accessible at http://psymukb.net., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Alternaria is a major outdoor allergen. Immunotherapy with Alternaria extracts has been documented to be effective in the sensitized patients. However, Alternaria extracts are notoriously difficult to standardize. Our aim is to screen the B cell mimotopes of Alternaria and to evaluate the therapeutic effects of B cell mimotope peptides on a BALB/c mouse model of Alternaria allergy. After a human sera pool from Alternaria monosensitized patients was established, B cell mimotopes were screened by a phage-displayed random heptamer peptide library that was identified via mixed Alternaria -specific IgE in the sera pool. B cell mimotopes with phage as a carrier were used to perform immunotherapy in an Alternaria allergy mouse model. Serological Ab levels, lung histology, and cytokine profiles were compared in the mimotope immunotherapy group, natural extract immunotherapy group, irrelevant phage control group, Alternaria -sensitized model group, and saline-blank group. Two mimotopes (MISTSRK and QKRNTIT) presented high binding ability with the sera of the Alternaria -allergic patients and mice and, therefore, were selected for immunotherapy in the mouse model. Compared with irrelevant phage control, model, and natural extract immunotherapy group, mimotope immunotherapy group significantly reduced serum IgE levels, inflammatory cells infiltration in the lung tissue, and IL-4 levels in bronchoalveolar lavage fluid, whereas serum IgG1 and IFN-γ levels in bronchoalveolar lavage fluid were increased. Our results indicate that B cell mimotopes of Alternaria alleviates allergic response in a mouse model and have potential as novel therapeutic agents for IgE-mediated Alternaria -allergic diseases., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Background: Transcription factors (TFs) play important roles in the regulation of gene expression. They can activate or block transcription of downstream genes in a manner of binding to specific genomic sequences. Therefore, motif discovery of these binding preference patterns is of central significance in the understanding of molecular regulation mechanism. Many algorithms have been proposed for the identification of transcription factor binding sites. However, it remains a challengeable problem., Results: Here, we proposed a novel motif discovery algorithm based on support vector machine (MD-SVM) to learn a discriminative model for TF binding sites. MD-SVM firstly obtains position weight matrix (PWM) from a set of training datasets. Then it translates the MD problem into a computational framework of multiple instance learning (MIL). It was applied to several real biological datasets. Results show that our algorithm outperforms MI-SVM in terms of both accuracy and specificity., Conclusions: In this paper, we modeled the TF motif discovery problem as a MIL optimization problem. The SVM algorithm was adapted to discriminate positive and negative bags of instances. Compared to other svm-based algorithms, MD-SVM show its superiority over its competitors in term of ROC AUC. Hopefully, it could be of benefit to the research community in the understanding of molecular functions of DNA functional elements and transcription factors.

Objective: GPR142 agonists are being pursued as novel diabetes therapies by virtue of their insulin secretagogue effects. But it is undetermined whether GPR142's functions in pancreatic islets are limited to regulating insulin secretion. The current study expands research on its action., Methods and Results: We demonstrated by in situ hybridization and immunostaining that GPR142 is expressed not only in β cells but also in a subset of α cells. Stimulation of GPR142 by a selective agonist increased glucagon secretion in both human and mouse islets. More importantly, the GPR142 agonist also potentiated glucagon-like peptide-1 (GLP-1) production and its release from islets through a mechanism that involves upregulation of prohormone convertase 1/3 expression. Strikingly, stimulation of insulin secretion and increase in insulin content via GPR142 engagement requires intact GLP-1 receptor signaling. Furthermore, GPR142 agonist increased β cell proliferation and protected both mouse and human islets against stress-induced apoptosis., Conclusions: Collectively, we provide here evidence that local GLP-1 release from α cells defines GPR142's beneficial effects on improving β cell function and mass, and we propose that GPR142 agonism may have translatable and durable efficacy for the treatment of type 2 diabetes., (Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Fresh-cut water fennel was treated with a novel complex chemical solution and subsequently packaged prior to refrigerated storage. Chlorophyll degradation and lignification were investigated. The complex solution consisted of 1.16 g/L calcium lactate, 150 mg/L zinc acetate, and 15.29 mg/L salicylic acid. Chlorophyllase, Mg-dechelatase, and chlorophyll-degrading peroxidase activities of water fennel decreased after immersion in the complex solution, which delayed chlorophyll degradation and increased L * and a * values. Complex solution treatment also reduced phenylalanine ammonia-lyase (PAL) activity and, thus, inhibited accumulation of lignin. After the complex solution treatment, packaging in high-density polypropylene plastic bags further retained chlorophylls and alleviated lignification of water fennel. Treatment with a complex chemical solution and subsequent packaging can maintain the quality, delay senescence, and improve the shelf life of water fennel.