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The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway serves as a paradigm for signal transduction from the extracellular environment to the nucleus. It plays a pivotal role in physiological functions, such as hematopoiesis, immune balance, tissue homeostasis, and surveillance against tumors. Dysregulation of this pathway may lead to various disease conditions such as immune deficiencies, autoimmune diseases, hematologic disorders, and cancer. Due to its critical role in maintaining human health and involvement in disease, extensive studies have been conducted on this pathway, ranging from basic research to medical applications. Advances in the structural biology of this pathway have enabled us to gain insights into how the signaling cascade operates at the molecular level, laying the groundwork for therapeutic development targeting this pathway. Various strategies have been developed to restore its normal function, with promising therapeutic potential. Enhanced comprehension of these molecular mechanisms, combined with advances in protein engineering methodologies, has allowed us to engineer cytokines with tailored properties for targeted therapeutic applications, thereby enhancing their efficiency and safety. In this review, we outline the structural basis that governs key nodes in this pathway, offering a comprehensive overview of the signal transduction process. Furthermore, we explore recent advances in cytokine engineering for therapeutic development in this pathway., (© 2024. The Author(s).)

Background: SARS-CoV-2 specific antibodies exist in human milk expressed by lactating parents after vaccination. In the existing research, the effects of vaccine types on human milk are inconsistent., Research Aim: This study aims to perform a systematic review and meta-analysis of the existing observational studies to compare the positive rates of SARS-CoV-2 specific antibodies in human milk according to mRNA and adenovector-based vaccination., Methods: PubMed, Web of Science, Elsevier Science Direct and Cochrane Library databases were systematically searched for relevant articles published from December 30, 2019 to February 15, 2023. Observational studies were considered eligible provided they reported data on SARS-CoV-2 specific antibodies in human milk. The risk of bias in non-randomized studies of interventions (ROBINS-I) tool, the Newcastle-Ottawa Scale (NOS), and the Agency for Healthcare Research and Quality (AHRQ) were used to assess risk of bias. Seven studies, including 511 lactating participants, were included in this review and meta-analysis., Results: The positive rate of SARS-CoV-2 IgA is higher in mRNA vaccine groups than in adenovector-based vaccine groups ( OR  = 4.80, 95% CI [3.04, 7.58], p  < 0.001). The positive rate of SARS-CoV-2 IgG was higher in mRNA vaccines than in adenovector-based vaccines., Conclusions: Compared to adenovector-based vaccines, mRNA vaccines present a higher positivity rate of IgA and IgG in human milk after vaccination. In other words, mRNA vaccinations may offer breastfed children a higher level of protection than adenovector-based vaccinations. Further high-quality data is still required to substantiate these findings., Competing Interests: Disclosures and Conflicts of InterestThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Xuan Li, Yan Hu, You Lv, Nathan Obore, and YiXiao Wang completed this student research, and Hong Yu was the faculty advisor on this project

Due to the rarity of primary cervical lymphoma (PCL), the long-term survival of patients with cervical lymphoma and factors influencing survival are unknown. This study aimed to compare the survivals of patients with PCL and those with other cervical tumors and construct a clinical prediction model to assess the prognosis of patients with PCL. Patients with PCL from the Surveillance, Epidemiology, and End Results database were allocated randomly in a 7:3 ratio to the training and validation sets. Cox proportional hazard and Fine-Gray models were used to verify independent factors influencing overall survival (OS) and disease-specific survival (DSS), and nomograms were constructed. Receiver operating characteristic curve analysis and decision curve analysis (DCA) were used to test the performance and clinical utility of the models, respectively. We included 206 patients with PCL. The areas under the curves (AUCs) and DCA showed that all models had clinical benefits; The models constructed in this study had a predictive performance for patients with PCL. It can guide clinicians to rationalize the treatment plan for patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway functions as a central hub for transmitting signals from more than 50 cytokines, playing a pivotal role in maintaining hematopoiesis, immune balance, and tissue homeostasis. Dysregulation of this pathway has been implicated in various diseases, including immunodeficiency, autoimmune conditions, hematological disorders, and certain cancers. Proteins within this pathway have emerged as effective therapeutic targets for managing these conditions, with various approaches developed to modulate key nodes in the signaling process, spanning from receptor engagement to transcription factor activation. Following the success of JAK inhibitors such as tofacitinib for RA treatment and ruxolitinib for managing primary myelofibrosis, the pharmaceutical industry has obtained approvals for over 10 small molecule drugs targeting the JAK-STAT pathway and many more are at various stages of clinical trials. In this review, we consolidate key strategies employed in drug discovery efforts targeting this pathway, with the aim of contributing to the collective understanding of small molecule interventions in the context of JAK-STAT signaling. We aspire that our endeavors will contribute to advancing the development of innovative and efficacious treatments for a range of diseases linked to this pathway dysregulation., Competing Interests: Declaration of Competing Interest The authors declare no competing interests was involved in this work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate the effects of astaxanthin (AST) on mouse osteoarthritis (OA) and lipopolysaccharide (LPS)-induced ATDC5 cell damage and to explore whether SIRT1 protein plays a role., Methods: In this study, some mouse OA models were constructed by anterior cruciate ligament transection (ACLT). Imaging, molecular biology and histopathology methods were used to study the effect of AST administration on traumatic OA in mice. In addition, LPS was used to stimulate ATDC5 cells to mimic the inflammatory response of OA. The effects of AST on the cell activity, inflammatory cytokines, matrix metalloproteinases and collagen type II levels were studied by CCK8 activity assay, reverse transcription polymerase chain reaction and protein imprinting. The role of SIRT1 protein was also detected., Results: In the mouse OA model, the articular surface collapsed, the articular cartilage thickness and cartilage matrix protein abundance were significantly decreased, while the expression of inflammatory cytokines and matrix metalloproteinases was increased; but AST treatment reversed these effects. Meanwhile, AST pretreatment could partially reverse LPS-induced ATDC5 cell damage and upregulate SIRT1 expression, but this protective effect of AST was attenuated by concurrent administration of the SIRT1 inhibitor Ex527., Conclusion: AST can protect against the early stages of OA by affecting SIRT1 signalling, suggesting that AST might be a potential therapeutic agent for OA treatment., 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 © 2024 Elsevier B.V. All rights reserved.)

Acevaltrate is a natural product isolated from the roots of Valeriana glechomifolia F.G.Mey. (Valerianaceae) and has been shown to exhibit anti-cancer activity. However, the mechanism by which acevaltrate inhibits tumor growth is not fully understood. We here demonstrated the effect of acevaltrate on hypoxia-inducible factor-1α (HIF-1α) expression. Acevaltrate showed a potent inhibitory activity against HIF-1α induced by hypoxia in various cancer cells. This compound markedly decreased the hypoxia-induced accumulation of HIF-1α protein dose-dependently. Further analysis revealed that acevaltrate inhibited HIF-1α protein synthesis and promoted degradation of HIF-1α protein, without affecting the expression level of HIF-1α mRNA. Moreover, the phosphorylation levels of mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6K), and eIF4E binding protein-1 (4E-BP1) were significantly suppressed by acevaltrate. In addition, acevaltrate promoted apoptosis and inhibited proliferation, which was potentially mediated by suppression of HIF-1α. We also found that acevaltrate administration inhibited tumor growth in mouse xenograft model. Taken together, these results suggested that acevaltrate was a potent inhibitor of HIF-1α and provided a new insight into the mechanisms of acevaltrate against cancers., 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 © 2024 Elsevier B.V. All rights reserved.)

In recent years, obesity has become one of the major diseases that affect human health and consume human health resources, especially when it causes comorbidities such as hypertension, diabetes, cardiovascular disease and kidney disease. Many studies have demonstrated that obesity is associated with the development of chronic kidney disease and can exacerbate the progression of end-stage renal disease. This review described the mechanisms associated with the development of obesity-associated nephropathy and the current relevant therapeutic modalities, with the aim of finding new therapeutic targets for obesity-associated nephropathy. The mechanisms of obesity-induced renal injury include, in addition to the traditional alterations in renal hemodynamics, the involvement of various mechanisms such as macrophage infiltration in adipose tissue, alterations in adipokines (leptin and adiponectin), and ectopic deposition of lipids. At present, there is no "point-to-point" treatment for obesity-induced kidney injury. The renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors and bariatric surgery described in this review can reduce urinary protein to varying degrees and delay the progression of kidney disease. In addition, recent studies on the therapeutic effects of intestinal flora on obesity may reduce the incidence of obesity-related kidney disease from the perspective of primary prevention. Both of these interventions have their own advantages and disadvantages, so the continuous search for the mechanism of obesity-induced related kidney disease will be extremely helpful for the future treatment of obesity-related kidney disease., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Hao et al.)

The development of highly selective Janus Kinase 1 (JAK1) inhibitors is crucial for improving efficacy and minimizing adverse effects in the clinical treatment of autoimmune diseases. In a prior study, we designed a series of C-5 4-pyrazol substituted pyrrolopyridine derivatives that demonstrated significant potency against JAK1, with a 10 ∼ 20-fold selectivity over Janus Kinase 2 (JAK2). Building on this foundation, we adopted orthogonal strategy by modifying the C-5 position with 3-pyrazol/4-pyrazol/3-pyrrol groups and tail with substituted benzyl groups on the pyrrolopyridine head to enhance both potency and selectivity. In this endeavor, we have identified several compounds that exhibit excellent potency and selectivity for JAK1. Notably, compounds 12b and 12e, which combined 4-pyrazol group at C-5 site and meta-substituted benzyl tails, displayed IC 50 value with 2.4/2.2 nM and high 352-/253-fold selectivity for JAK1 over JAK2 in enzyme assays. Additionally, both compounds showed good JAK1-selective in Ba/F3-TEL-JAK1/2 cell-based assays. These findings mark a substantial improvement, as these compounds are 10-fold more potent and over 10-fold more selective than the best compound identified in our previous study. The noteworthy potency and selectivity properties of compounds 12b and 12e suggest their potential utility in furthering the development of drugs for autoimmune diseases., 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 © 2024 Elsevier Masson SAS. All rights reserved.)

Osteoporosis results from an imbalance in a highly balanced physiological process called bone remodeling, in which osteoclast-mediated bone resorption and osteoblast-mediated bone formation play important roles. Osteoimmunology is a newly discovered interdisciplinary research field that focuses on the relationship between bone and the immune system. Specifically, bone and the immune system interact through cytokines, immune cells secrete cytokines, and cytokines finely regulate bone metabolism by mediating the differentiation and activity of osteoclasts and osteoblasts. Therefore, understanding the influence of cytokines on bone metabolism is conducive for the development of novel targeted drugs against immune-related bone diseases. This review summarizes the pathophysiological functions of various common cytokines in bone and discusses the potential clinical value of multiple cytokines in immune-mediated bone diseases., Competing Interests: Declaration of Competing Interest All the authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Developing new scaffolds for highly potent and selective inhibitors of human Monoamine Oxidase B (hMAO-B) is a crucial objective in enhancing the efficacy and safety in the clinical treatment of neurodegenerative diseases. In this study, we have identified a series of C-3 isoxazole-substituted thiochromone S,S-dioxide derivatives that exhibit strong inhibitory activity against hMAO-B. The strategy of oxidizing thiochromone to thiochromone S,S-dioxide solves the key defect of extreme insolubility observed for thiochromone analogues. In addition, the sulfone group contributes extra hydrogen(H)-bonding interactions with Tyr435, which significantly increases the activity of thiochromone S,S-dioxide derivatives against hMAO-B. Furthermore, the presence of isoxazole group provides potential H-bonding interaction and electrostatic interaction with the residue of Tyr326, while the rigid aryl ring introduces a potential steric conflict with Phe208 of hMAO-A to improve both potency and selectivity. In our investigations, several compounds (9c, 10c, 10e, 10g, 10l and 10m) demonstrate remarkable single-digit nanomolar potency. These compounds exhibit favorable cytotoxicity profiles in both differentiated SH-SY5Y and HVSMC cells, without apparent cardiotoxic effects. Moreover, compounds 10e and 10h do not lead to an increase in ROS levels in differentiated SH-SY5Y cells, further demonstrating their potential as safe and effective hMAO-B inhibitors. These findings indicate that the C-3 isoxazole substituted thiochromone S,S-dioxide analogues are potential leading compounds for the development of selective inhibitors with high potency., 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 © 2023 Elsevier Masson SAS. All rights reserved.)

Browning is one of the main phenomena limiting the production of fresh-cut sweetpotatoes. This study investigated the anti-browning effect of citrus peel extracts and the key components and modes of action associated with browning in fresh-cut sweetpotatoes. Five different concentrations of citrus peel extract (1, 1.5, 2, 2.5 and 3 g/L) were selected to ensure storage quality; and the physical and chemical properties of fresh-cut sweetpotato slices were analysed. A concentration of 2 g/L of citrus peel extract significantly inhibited the browning of fresh-cut sweetpotatoes. The results showed that the browning index and textural characteristics of fresh-cut sweetpotatoes improved significantly after treatment with citrus peel extract; all the citrus peel extract solutions inhibited browning to some extent compared to the control. In addition; LC-IMS-QTOFMS analysis revealed a total of 1366 components in citrus peel extract; the evaluation of citrus peel extract monomeric components that prevent browning in fresh-cut sweetpotato indicated that the components with better anti-browning effects were citrulloside, hesperidin, sage secondary glycosides, isorhamnetin and quercetin. The molecular docking results suggest that citrullosides play a key role in the browning of fresh-cut sweetpotatoes. In this study, the optimum amount of citrus peel extract concentration was found to be 2 g/L.

Developing new fungicides is always crucial to protecting crops. A series of 4-(3,4-dichloroisothiazol-5-yl)-7-(2-((5-(5-pyrimidin-4-yl)amino)ethoxy)-8-methyl) coumarin derivatives were designed and synthesized by Williamson ether condensation and substitution reactions. Structure determinations were clarified by 1 H NMR, 13 C NMR, and HRMS, and compound 4h crystallized by the fusion method for further structural confirmation. The in vitro bioassay results showed that the target compounds displayed good fungicidal activity against Alternaria solani , Botrytis cinerea , Cercospora arachidicola , Fusarium graminearum , Physalospora piricola , Rhizoctonia solani, and Sclerotinia sclerotiorum . Among them, compounds 4b and 4d showed higher inhibitory activity against R. solani , with EC 50 values of 11.3 and 13.7 μg/mL, respectively, and they were more active than the positive control diflumetorim with an EC 50 value of 19.8 μg/mL. Molecular docking suggested that compound 4b and diflumetorim may have similar interactions with complex I NADH oxidoreductase. Density functional theory calculation and pesticide-likeness analysis studies gave a rational explanation of their fungicidal activity. These results indicated that compounds 4b and 4d deserved further optimization according to the principle of pesticide-likeness., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Understanding the molecular mechanisms underlying osteoclast differentiation provides insights into bone loss and even osteoporosis. The specific mechanistic actions of cullin 4A (CUL4A) in osteoclast differentiation and resultant osteoporosis is poorly explored. We developed a mouse model of osteoporosis using bilateral ovariectomy (OVX) and examined CUL4A expression. It was noted that CUL4A expression was increased in the bone marrow of OVX mice. Overexpression of CUL4A promoted osteoclast differentiation, and knockdown of CUL4A alleviated osteoporosis symptoms of OVX mice. Bioinformatic analyses were applied to identify the downstream target genes of microRNA-340-5p (miR-340-5p), followed by interaction analysis. The bone marrow macrophages (BMMs) were isolated from femur of OVX mice, which were transfected with different plasmids to alter the expression of CUL4A, Zinc finer E-box binding homeobox 1 (ZEB1), miR-340-5p, and Toll-like receptor 4 (TLR4). ChIP assay was performed to detect enrichment of ZEB1 promoter by H3K4me3 antibody in BMMs. ZEB1 was overexpressed in the bone marrow of OVX mice. Overexpression of CUL4A mediated H3K4me3 methylation to increase ZEB1 expression, thus promoting osteoclast differentiation. Meanwhile, ZEB1 could inhibit miR-340-5p expression and upregulate HMGB1 to induce osteoclast differentiation. Overexpressed ZEB1 activated the TLR4 pathway by regulating the miR-340-5p/HMGB1 axis to induce osteoclast differentiation, thus promoting the development of osteoporosis. Overall, E3 ubiquitin ligase CUL4A can upregulate ZEB1 to repress miR-340-5p expression, leading to HMGB1 upregulation and the TLR4 pathway activation, which promotes osteoclast differentiation and the development of osteoporosis., (© 2023 Wiley Periodicals LLC.)

The development of new fungicides is vital for safeguarding crops and ensuring sustainable agriculture. Building on our previous finding that 4-(3,4-dichloroisothiazole)-7-hydroxy coumarins can be used as fungicidal leads, 44 novel coumarin ester derivatives were designed and synthesized to evaluate whether esterification could enhance their fungicidal activity. In vitro fungicidal bioassays indicated that compound 2ai displayed good activity against Alternaria solani , Botrytis cinereal , Cercospora arachidicola , Physalospora piricola and Sclerotinia sclerotiorum , with an EC 50 value ranging from 2.90 to 5.56 μg/mL, comparable to the lead compound 1a , with its EC 50 value ranging from 1.92 to 9.37 μg/mL. In vivo bioassays demonstrated that compounds 1a , 2ar and 2bg showed comparable, excellent efficacy against Pseudoperonospora cubensis at a dose of 25 µg/mL. Our research shows that the esterification of 4-(3,4-dichloroisothiazole) 7-hydroxycoumarins results in a fungicidal activity equivalent to that of its lead compounds. Furthermore, our density functional theory (DFT) calculations and 3D-QSAR modeling provide a rational explanation of the structure-activity relationship and offer valuable insights to guide further molecular design.

Antimony (Sb) is a toxic and carcinogenic element that often enters soil in the form of antimony trioxide (Sb 2 O 3 ) and coexists with manganese (Mn) in weakly alkaline conditions. Mn oxides such as birnessite have been found to promote the oxidative dissolution of Sb 2 O 3 , but few researches concerned the co-transformations of Sb 2 O 3 and Mn(II) in environment. This study investigated the mutual effect of abiotic oxidation of Mn(II) and the coupled oxidative dissolution of Sb 2 O 3 . The influencing factors, such as Mn(II) concentrations, pH and oxygen were also discussed. Furthermore, their co-transformed mechanism was also explored based on the analysis of Mn(II) oxidation products with or without Sb 2 O 3 using XRD, SEM and XPS. The results showed that the oxidative dissolution of Sb 2 O 3 was enhanced under higher pH and higher Mn(II) loadings. With a lower Mn(II) concentration such as 0.01 mmol/L Mn(II) at pH 9.0, the improved dissolution of Sb 2 O 3 was attributed to the generation of dissolved intermediate Mn(III) species with strong oxidation capacity. However, under higher Mn(II) concentrations, both amorphous Mn(III) oxides and intermediate Mn(III) species were responsible for promoting the oxidative dissolution of Sb 2 O 3 . Most released Sb (∼72%) was immobilized by Mn oxides and Sb(V) was dominant in the adsorbed and dissolved total Sb. Meanwhile, the presence of Sb 2 O 3 not only inhibited the removal of Mn(II) by reducing Mn(III) to Mn(II) but also affected the final products of Mn oxides. For example, amorphous Mn oxides were formed instead of crystalline Mn(III) oxides, such as MnOOH. Furthermore, rhodochrosite (MnCO 3 ) was formed with the high Mn(II)/Sb 2 O 3 ratio , but without being observed in the low Mn(II)/Sb 2 O 3 ratio. The results of study could help provide more understanding about the fate of Sb in the environment and the redox transformation of Mn., 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 article., (Copyright © 2022. Published by Elsevier B.V.)

Developing selective inhibitors for Janus kinase 1 (JAK1) is a significant focus for improving the efficacy and alleviating the adverse effects in treating immune-inflammatory diseases. Herein, we report the discovery of a series of C-5 pyrazole-modified pyrrolopyrimidine derivatives as JAK1-selective inhibitors. The potential hydrogen bond between the pyrazole group and E966 in JAK1 is the key point that enhances JAK1 selectivity. These compounds exhibit 10- to 20-fold JAK1 selectivity over JAK2 in enzyme assays. Compound 12b also exhibits excellent JAK1 selectivity in Ba/F3-TEL-JAK cellular assays. Metabolism studies and the results of the hair growth model in mice indicate that compound 12b may be a viable lead compound for the development of highly JAK1-selective inhibitors for immune and inflammatory diseases.

With the miniaturization of electronic devices, electronic packaging has become increasingly precise and complex, which presents a significant challenge in terms of heat dissipation. Electrically conductive adhesives (ECAs), particularly silver epoxy adhesives, have emerged as a new type of electronic packaging material, thanks to their high conductivity and stable contact resistance. However, while there has been extensive research on silver epoxy adhesives, little attention has been paid to improving their thermal conductivity, which is a critical requirement in the ECA industry. In this paper, we propose a straightforward method for treating silver epoxy adhesive with water vapor, resulting in a remarkable improvement in thermal conductivity to 9.1 W/(m·K), three times higher than the sample cured using traditional methods (2.7 W/(m·K)). Through research and analysis, the study demonstrates that the introduction of H 2 O into the gaps and holes of the silver epoxy adhesive increases the path of electron conduction, thereby improving thermal conductivity. Furthermore, this method has the potential to significantly improve the performance of packaging materials and meet the needs of high-performance ECAs.

Objective: To explore the correlation between the expression level of Desmoglein 2 (DSG2) and the epithelial-mesenchymal transition (EMT) progression in gallbladder cancer (GBC)., Method: 106 GBC tissue specimens and corresponding clinical information were collected to make a tissue microarray. Immunohistochemical method was used to test the expression level of DSG2 in GBC tissues. DSG2 was knocked down in the GBC cell line GBC-SD to detect the change of its invasion and metastasis ability. Then RT-qPCR and Western Blot were applied on the DSG2-knocked down GBC-SD cells to detect the expression level change of genes associated with EMT., Result: The high expression rate of DSG2 was significantly correlated with the N, M and TNM staging of patients (P<0.05). Survival analysis identified that GBC patients with high DSG2 expression level had significantly better survival (P<0.05). To further investigate the potential mechanism of DSG2 on regulating GBC tumor progression, we used knockdown DSG2 on GBC-SD cell lines. The results showed that GBC-SD cell lines with DSG2 knockdown showed a promotion of cell invasion and metastatic ability. The mRNA levels of EMT-related genes E-Cadherin, Snail, Twist, ZEB1, and β-catenin, which is a key protein in the Wnt signaling pathway, were also significantly altered. Besides, protein levels of E-cadherin and Snail showed consistent results., Conclusion: The downregulation of DSG2 in gallbladder cancer is hypothesized to be associated with the invasion and metastasis progression of gallbladder cancer cells by regulating EMT-related pathways. Its expression level can be a novel biomarker for gallbladder cancer, providing new perspectives for diagnosis and treatment strategies., (©The Author(s) 2023. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

A cross-sectional study was performed using metabolomics in overweight patients with Type 2 diabetes (T2D) at different stages of the disease. We aimed to identify potential metabolites for assessing islet β-cell function in order to investigate the correlation between islet β-cell dysfunction and metabolite changes in overweight patients with T2D. We selected 60 overweight adults (24 ≤ body mass index [BMI] < 28 kg/m2) with T2D who had been admitted to our hospital. The participants were equally divided into three groups according to disease duration: H1 (duration ≤ 5 years), H2 (5 years < duration ≤ 10 years), and H3 (duration > 10 years). Questionnaires, physical examinations, laboratory tests, and imaging studies were administered to all participants. The modified homeostasis model of assessment (HOMA) index was calculated using fasting C-peptide levels, and metabolite assays were performed using mass spectrometry. The results showed that HOMA-β and visceral fat area (VFA) were negatively correlated with diabetes duration. The VFA was positively correlated with arginine, cysteine, methionine, proline, and succinyl/methylmalonylcarnitine levels. The HOMA-β was negatively correlated with the serine and tetradecanoyldiacylcarnitine levels, and positively correlated with the aspartic acid, cysteine, homocysteine, piperamide, proline, and valine levels. The HOMA-IR was negatively correlated with hydroxypalmitoylcarnitine levels and positively correlated with the myristoylcarnitine levels. Thus, at different stages of T2D progression in overweight patients, serine, aspartic acid, cysteine, homocysteine, piperamide, proline, valine, and tetradecanoyldiacylcarnitine may be associated with HOMA-β and represent potential novel biomarkers for evaluating islet β-cell function., (© 2023 The Author(s).)

The enrichment of phosphorus (P) in groundwater (GW) has been regarded as one of the most important sources of water eutrophication, but its sources and mechanisms have remained unclear. This study focused on hydraulic change show that drove the migration of P in an agricultural groundwater system, Jianghan Plain, Central China. Based on four rounds of field investigation over different seasons and across two consecutive years. Seasonable water table fluctuations (WLFs) reached 1.6 m and 3.8 m in GW and surface water (SW), respectively. Moreover, the concentrations of P in GW were obviously higher than those in SW where 54.1% of all GW samples presented higher content of P than the World Health Organization (WHO) limit of 0.4 mg/L with the highest one arriving to 1.97 mg/L. Although the trends and amplitudes varied at different points and depths, the spatial and temporal distribution of P corresponded with the local WLFs that were responsible for the enrichment of GW P. On the one hand, WLFs changed hydraulic conditions to enhance the migration of soluble P in the unsaturated zone into the aquifer. On the other hand, WLFs resulted in changes to the redox conditions or to the GW hydrochemical compositions, which promoted the dissolution of Fe or Mn containing P. These caused the release and enrichment of P in GW. Therefore, this study helps understand the geochemical cycling of P and improves GW management in the local GW system, Jianghan Plain., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Recent studies have shown that the relationship between mercury exposure and diabetes is controversial. The aim of this study is to determine the relationship between mercury exposure and diabetes using a systematic review and meta-analysis approach., Methods: We systematically searched PubMed, Web of Science, Cochrane, and Embase databases for cross-sectional, case-control, or cohort studies assessing the correlation between mercury exposure and diabetes in any population. Details of each included study were extracted using a pre-designed Excel spreadsheet. Quality assessment of cohort and case-control studies used the Newcastle-Ottawa Scale (NOS), whereas cross-sectional studies were assessed by the Agency for Healthcare Research and Quality (AHRQ) scale. Meta-analyses were performed using random-effects models to calculate the pooled odds ratio (OR), standardized mean difference (SMD), and their 95% confidence intervals (CIs). Subgroup and sensitivity analyses were employed to assess heterogeneity sources. Begg's and Egger's tests were used to evaluate publication bias., Results: Our meta-analysis included 8 eligible articles, comprising a total of 40,891 subjects, reporting mercury OR and/or concentrations. Among the included studies, one was a case control, one was a cohort study, and the rest were cross-sectional studies. Two studies were rated as high quality and six as medium quality. The results revealed no link between mercury exposure and diabetes (OR: 1.11, 95% CI: 0.80, 1.55, n=6, I 2 =73.7%; and SMD: 0.41, 95% CI: -0.32, 1.14, n=3, I 2 =88.7%). In the stratified male and female subgroups, the pooled OR was 0.71 (95% CI: 0.57, 0.90, n=3, I 2 =0.0%), 1.11 (95% CI: 0.69, 1.79, n=3, I 2 =67.7%). The Begg's test results revealed no significant publication bias (P=0.06), but the Egger's test results did (P=0.013). The sensitivity analysis confirmed the stability of our results., Conclusions: No significant relationship was observed between mercury and diabetes mellitus. However, more well-designed studies on mercury exposure and diabetes risk are still needed, particularly on the type of mercury (i.e., elemental, inorganic, and organic), exposure time and dose, type of biological specimen, and the population's sex and age., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-6404/coif). The authors have no conflicts of interest to declare., (2023 Annals of Translational Medicine. All rights reserved.)

The Ångström method is a promising thermal diffusivity measurement method for microfibers. Based on the heat-loss Ångström method and micro-Ångström method, the FFT (Fast Fourier Transform) Ångström method can be used to shorten the testing time and enhance the testing robustness of thermal conductivity. The FFT Ångström uses multi-frequency superimposed input signals and then uses the FFT for frequency division analysis. Since different frequencies are input at the same time, the measuring time is greatly reduced. Moreover, because different frequencies are input in the same environment, the random and environmental perturbations of the frequencies are the same, enhancing the fitting robustness. In contrast, the single feeding strategy is relatively time-consuming, and its measurement homogeneity for different frequencies cannot be guaranteed. By comparing the measurement results from a multi-frequency input and separated single-frequency input, the FFT shows good feasibility and robustness. It may also have great potential in other types of thermal wave measurements.

The study aimed to evaluate the diagnostic and prognostic value of indexes detected by electrogastrography in Parkinson's disease patients. One hundred twenty early Parkinson's disease patients and 120 healthy controls were recruited, and underwent electrogastrography to detect dominant frequency (DF), instability coefficient of DF (ICDF), low frequency range (LFR), high frequency range (HFR), and normal frequency range (NFR). The receiver operating characteristic (ROC) curve was drawn for the diagnostic value analysis. The motor function was scored with the Unified Parkinson's Disease Rating Scale (UPDRS). Sniffin' Sticks test was used for the olfactory evaluation, and the TDI score consisting of odor threshold (T), odor discrimination (D) and odor identification (I) tests was calculated. The preprandial ICDF of Parkinson's disease patients was significantly higher than that of the control group, and decreased slowly during the late postprandial phase. The levels of LFR%, HFR% and NFR% in Parkinson's disease patients were higher than the control group during both the preprandial and late postprandial phase, and the changes of each index before and after meals were not obvious. Preprandial ICDF value and TDI score had the ability to distinguish Parkinson's disease patients with the AUC of 0.874 and 0.859 respectively. The ICDF detected by electrogastrography has high clinical value in the early diagnosis of Parkinson's disease, and the combination of ICDF and TDI can improve the diagnostic sensitivity and specificity of a single indicator. High ICDF levels during the preprandial phase are related to the poor prognosis of Parkinson's disease patients after treatment.

Osimertinib, an orally administered third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is widely approved for the first-line and second-line treatment of advanced non-small-cell lung cancer (NSCLC) with EGFR mutations. However, the rapid development of osimertinib resistance renders the unsustainable treatment benefit. Patients with EGFR -mutated NSCLC who develop osimertinib resistance, especially those acquiring relatively rare and 'off-target' resistance mutations, still lack effective therapeutic options for postosimertinib therapy. Herein, we reported a 73-year-old woman diagnosed with T1N3M1 lung adenocarcinoma harboring EGFR L858R mutation, who acquired two GNAS mutations (R201C and R201H) and lost the EGFR L858R mutation after progression on icotinib and osimertinib. The patient was subsequently treated with trametinib and there was no obvious tumor increase. Our study revealed that GNAS R201 can confer the osimertinib resistance in EGFR -positive NSCLC, and present the first report of the prevalence of GNAS R201C and R201H mutants in NSCLC which response to trametinib treatment. Our case suggests that trametinib could be a treatment option in NSCLC patients harboring GNAS -activating mutations., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aims: Potassium (K + ) channels have been demonstrated to play a prominent involvement in nociceptive processing. Kir7.1, the newest members of the Kir channel family, has not been extensively studied in the CNS, and its function remains largely unknown. The present study investigated the role of spinal Kir7.1 in the development of pathological pain., Methods and Results: Neuropathic pain was induced by spared nerve injury (SNI). The mechanical sensitivity was assessed by von Frey test. Immunofluorescence staining assay revealed that Kir7.1 was predominantly expressed in spinal neurons but not astrocytes or microglia in normal rats. Western blot results showed that SNI markedly decreased the total and membrane expression of Kir7.1 in the spinal dorsal horn accompanied by mechanical hypersensitivity. Blocking Kir7.1 with the specific antagonist ML418 or knockdown kir7.1 by siRNA led to mechanical allodynia. Co-IP results showed that the spinal kir7.1 channels were decorated by SUMO-1 but not SUMO-2/3, and Kir7.1 SUMOylation was upregulated following SNI. Moreover, inhibited SUMOylation by GA (E1 inhibitor) or 2-D08 (UBC9 inhibitor) can increase the spinal surface Kir7.1 expression., Conclusion: SUMOylation of the Kir7.1 in the spinal cord might contribute to the development of SNI-induced mechanical allodynia by decreasing the Kir7.1 surface expression in rats., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: This retrospective study aims to explore the effect of silver nanoparticles with thermoplastic polyurethane (TPU/NS) on the rehabilitation of diabetic patients with open fracture of lower extremities., Methods: Diabetic patients ( n  = 98) with open fracture of lower extremities treated in our hospital were analyzed retrospectively from June 2015 to December 2021. TPU/NS nanocomposites were prepared for postoperative treatment of diabetic patients with open fracture of lower extremities. First, the cultured Staphylococcus aureus and Escherichia coli were used to test the antibacterial effect of TPU/NS dressing in vitro . After using TPU/NS dressing (observation group) and traditional dressing (control group), the inflammatory reaction, clinical treatment, functional rehabilitation, and adverse reactions in patients were compared., Results: TPU/NS dressing effectively inhibited the growth of bacteria with a minimum inhibitory concentration of 2 μg/mL. The usage of TPU/NS dressing reduced the inflammatory reaction by reducing positive rate of bacteria after the dressing on the seventh day postoperatively. Besides, the times of dressing, stopping time of wound exudation, wound healing time, length of hospital stay, and VAS score in the observation group were lower than those in the control group; the incidence of adverse reactions after treatment was lower in the observation group as compared with the control group (17.07% vs. 35.09%). Meanwhile, the functional rehabilitation and life quality of patients in the observation group were better TPU/NS dressing treatment., Conclusion: TPU/NS dressing has the function of promoting the postoperative recovery of patients by inhibiting the bacterial infection of the wound, thus improving the limb function and life quality. As a result, there was a tremendous potential to apply the constructed TPU/NS membrane to diabetic patients with open fractures, especially those with soft tissue injury., 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 Zhang, Yao, Ma, Nan, Lv, Zhu and Zhu.)

Chemotherapy-induced neuropathic pain is a major clinical problem with limited treatment options. Here, we show that metformin relieves bortezomib (BTZ)-evoked induction and maintenance of neuropathic pain by preventing the reduction in the expression of Beclin-1, an autophagy marker, in the spinal dorsal horn. Application of rapamycin or 3-methyladenine, autophagy inducer and inhibitor, respectively, affected the mechanical allodynia differently. Co-application of 3-methyladenine and metformin partially inhibited the effect of metformin in recovering Beclin-1 expression and in reducing the pain behavior in rats subjected to BTZ treatment. BTZ treatment also reduced the expression of AMPKa2 in the dorsal horn, which was recovered by metformin treatment. Overexpression of AMPKa2 attenuated the BTZ-evoked reduction in Beclin-1 expression and mechanical allodynia, whereas intrathecal injection of AMPKa2 siRNA decreased the Beclin-1 expression and induced mechanical allodynia in naive rats. Moreover, BTZ treatment increased the GATA3 expression in the dorsal horn, and GATA3 siRNA attenuated the AMPKa2 downregulation and mechanical allodynia induced by BTZ. Chromatin immunoprecipitation further showed that BTZ induced an increased recruitment of GATA3 to multiple sites in the AMPKa2 promoter region. Furthermore, decreased acetylation and increased methylation of histone H3 in the AMPKa2 promoter in the spinal dorsal horn was detected after BTZ treatment. Our findings suggest that metformin may regulate AMPKa2-mediated autophagy in the dorsal horn and alleviate the behavioral hypersensitivity induced by BTZ., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In many living phenomena, the behavior of social animals (such as ants, fish stocks, and birds) has attracted great attention, and many theories and models have emerged to simulate the behavior of biological communities. These studies are important in theory and practice and have wide application potential in optimization methods and product design, which leads to the so-called cluster intelligence. Development of the 3D animation system can be closely combined with cluster intelligence, and the full application of cluster intelligence is conducive to continuously improve the stability of animation system design, for animation system design to bring continuous design inspiration. The purpose of the development platform is to promote the development of enterprise projects, record each stage of the animation process in 3D, form a complete industrial chain, ensure the traceability and resilience of the whole process, and provide a comprehensive and effective solution for 3D animation production., Competing Interests: The author declares no conflicts of interest., (Copyright © 2022 You Lv.)

Creating gradients of nanostructure on the surface has found broad applications such as enhanced optical spectroscopy, optical storage of information, and broadband solar energy harvesting. Here, a facile strategy is presented for fabricating gradient nanoparticle arrays with tunable size. It takes a ZnO:Ga microwire as the starting material, and the Ga 3+ doping gradient along the microwire is induced by the high voltage applied. Such a doping gradient facilitates the formation of a temperature gradient in a Joule heating process. And this temperature gradient produced by this technique can be as high as 800 °C/mm, which could be later used for gradient annealing of thin metal films. After annealing, the thin metal films turn to gradient nanoparticle arrays. The obtained gradient nanoparticle arrays are confirmed effective in multi-wavelength surface enhanced Raman scattering enhancement., (© 2022. The Author(s).)

Purpose: Both percutaneous endoscopic lumbar discectomy (PELD) and open fenestration discectomy (OFD) are effective and safe surgical procedures for the treatment of LDH. The purpose of this retrospective study was to compare the surgical outcomes of percutaneous endoscopic interlaminar discectomy (PEID) and OFD for single-segment huge lumbar disc herniation (HLDH)., Patients and Methods: We retrospectively analyzed 91 patients diagnosed with single-segment HLDH and treated with OFD or PEID. Visual analog scale (VAS), modified Japanese orthopedic association (mJOA) and Oswestry disability index (ODI) were used to assess clinical outcomes at preoperation and postoperatively at 3, 6, 12, and 24months. Modified Macnab criteria were applied to evaluate clinically satisfaction at the final follow-up., Results: In both groups, the VAS and ODI scores at 3, 6, 12, and 24months postoperatively showed a significant decrease and the mJOA score at 3, 6, 12, and 24months postoperatively was significantly increased compared to preoperative results ( P <0.001). According to Macnab criteria at the final follow-up, the overall clinically satisfactory rate was 86.67% in the OFD group and 86.96% in the PEID group. There were no significant differences in VAS, ODI, and mJOA scores between the two groups at preoperation and postoperative 3, 6, 12, and 24months, respectively. In the PEID group, the length of hospitalization and the length of incision were significantly shorter than that in the OFD group ( P <0.0001). However, there was no significant difference in operative time between groups ( P =0.81)., Conclusion: Collectively, postoperative clinical results were equally favorable for both procedures, with no statistically significant difference between PEID and OFD at the two-year of follow-up. No serious complication was observed in two groups. Compared with the traditional surgery, PEID has the following benefits: less trauma, less bleeding, speedy recovery, and shorter hospitalization. Therefore, PEID may be a promising alternative to traditional surgery., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Ma et al.)

Herein, we conducted a study of the Zhangsanxi karst groundwater system in Zhangjiajie, Hunan Province, China, and used the results to develop a method for identifying the aquifer medium and its structural characteristics. To begin, rainfall, underground river flow dynamics, and groundwater level dynamics in the Zhangsanxi karst groundwater system were subjected to high-resolution monitoring to elucidate the groundwater system's rainfall-hydrological response characteristics under varying rainfall amounts and intensities. Next, an exponential attenuation curve was employed to analyze how the law of attenuation applies to underground river discharge and groundwater level during a typical rainfall event. Finally, we determined the degree of karst development at different depths, so the data can serve as a reference for local decision makers regarding karst water disaster prevention and water resource utilization. The results show that the flow response lag time in the karst groundwater system depicts good correlation with the rainfall amount but is also affected by the rainfall intensity. Thus, under conditions of identical rainfall, increasing rainfall intensity corresponds to a progressively shorter underground river flow lag time. The area's rainfall can be divided into four types, based on its concentration and intensity characteristics. The underground river flow generally has no evident response to type I rainfall, while the flow response lag time to types II III and IV rainfall is approximately 110, 60, and 40 h, respectively. Furthermore, the Zhangsanxi karst system's water-bearing medium is dominated by karst fissures and pores, which account for about 2/3 of its open space. Large karst conduits and caves account for the remaining 1/3. The degree of karst development in this system depicts evident depth variation but, overall, tends to increase as a function of burial depth.Responsible editor: Xianliang Yi., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Twenty-one novel 3,4-dichloroisothiazolocoumarin-containing strobilurins were rationally designed and synthesized. Preliminary bioassay showed that compounds 7c, 7h and 7l exhibited over 80% inhibitory rate against Sclerotinia sclerotiorum at 50 μg/mL, 7c exhibited good activity against S. sclerotiorum with median effective concentration (EC 50 ) of 4.08 μg/mL, while the positive control coumoxystrobin showed EC 50 of 1.00 μg/mL. In addition, 7d showed better fungicidal activity with a lower EC 50 value of 7.65 μg/mL against Botrytis cinerea than that of positive control trifloxystrobin with its EC 50 value of 21.96 μg/mL. This study indicated that 3,4-dichloroisothiazolocoumarin-containing strobilurin was a promising fungicide lead deserved for further study., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

New targeted chemotherapy agents greatly improved five-year survival in NSCLC patients, but which were susceptible to drug resistance. NVP-AUY922, terminated in phase II clinical trials, exhibited promising anti-NSCLC (non-small-cell lung cancer) activity targeting to Hsp90 N (heat shock protein), which demonstrated advantages in overcoming drug resistance as a broad-spectrum anti-cancer target. It was expected to develop novel anti-NSCLC drugs to overcome drug resistance by the structural optimization of NVP-AUY922. However, the absence of high-resolution complex crystal structure of Hsp90 N -NVP-AUY922 blocked the way. Herein, 1.59 Å-resolution complex crystal structure of Hsp90 N -NVP-AUY922 (PDB ID 6LTI) was successfully determined by X-ray diffraction. Meanwhile, there was a strong binding capability between NVP-AUY922 and its target Hsp90 N verified by TSA (ΔTm, -15.56 ± 1.78°C) and ITC ( K d , 5.10 ± 2.10 nM). Results by the complex crystal structure, TSA and ITC verified that NVP-AUY922 well accommodated in the ATP-binding pocket of Hsp90 N to disable the molecular chaperone activity of Hsp90. Therefore, NVP-AUY922 exhibited approving inhibitory activity on NSCLC cell line H1299 (IC 50 , 2.85 ± 0.06 μM) by inhibiting cell proliferation, inducing cell cycle arrest and promoting cell apoptosis. At the basis of the complex crystal structure and molecular interaction analysis, thirty-two new NVP-AUY922 derivatives were further designed, and among which twenty-eight new ones display enhanced binding force with Hsp90 N by molecular docking evaluation. The results would promote anti-NSCLC new drug development to overcome drug resistance based on the lead compound NVP-AUY922., 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 He, Lv, Guo, Zhou, Qin, Zhao, Li, Xing, Zhou, Li, Yu, He and Cao.)

Twenty-one novel pyrazole-thiazole carboxamide derivatives were rationally designed and synthesized. Bioassay results indicated that 6d (EC 50  = 5.11 μg/mL) and 6j (EC 50  = 8.14 μg/mL) exhibited better in vitro activities than fluxapyroxad (EC 50  = 11.93 μg/mL) and thifluzamide (EC 50  = 22.12 μg/mL) against Rhizoctonia cerealis. Particularly, compound 6j showed promising in vivo protective activity against Rhizoctonia solani and Puccinia sorghi Schw. with 80% and 90% inhibition at 10 μg/mL, respectively. Our studies found that pyrazole-thiazole is a promising fungicide lead deserving for further derivation., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To evaluate the curative efficacy by comparing perioperative characteristics and 1.5-year observational outcomes in 1-segment lumbar spondylolisthesis between traditional minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) and optimized Endoscopic TLIF techniques., Methods: The study was a single-center, randomized controlled trial comparing two different treatment approaches for 1-segment lumbar spondylolisthesis. 102 patients treated by MIS-TLIF (48 cases) or Endo-TLIF (54 cases) were included from March 2018 to April 2019. Perioperative parameters and clinical outcomes were evaluated. Degree of slip were measured, and fusion rates were determined at 18 months after surgery., Results: The Endo-TLIF group had similar return to work time and rate. Blood loss, left bed time, analgesic ratio were significantly less in Endo-TLIF group. The Endo-TLIF group had a significantly longer operative time. Significant postoperative reduction in %slip was showed in both groups. The VAS and ODI improved significantly in both groups after surgery. Significant decreases in low-back pain in Endo-TLIF group were found at postoperative day 1 and 3 months. The fusion rate in the two groups was similar., Conclusion: Endo-TLIF surgery with a C-shaped working tube and a visualization system may be regarded as an efficient alternative surgery for 1-segment lumbar spondylolisthesis. It is a safe and minimally invasive way to perform this surgery and has shown satisfactory clinical outcomes., Trial Registration: ChiCTR1800015197, 13 March 2018., Trial Registry: Chinese Clinical Trial Registry. Registered 13 March 2018. http://www.chictr.org.cn/showproj.aspx?proj=25865., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To explore the functional connectivity (FC) between the bilateral thalamus and the other brain regions in patients with vestibular migraine (VM)., Methods: Resting-state fMRI and 3D-T1 data were collected from 37 patients with VM during the interictal period and 44 age-, gender-, and years of education-matched healthy controls (HC). The FC of the bilateral thalamus was analyzed using a standard seed-based whole-brain correlation method. Furthermore, the correlations between thalamus FC and clinical characteristics of patients were investigated using Pearson's partial correlation., Results: Compared with HC, VM patients showed decreased FC between the left thalamus and the left anterior cingulate cortex (ACC), bilateral insular and right supplementary motor cortex. We also observed decreased FC between the right thalamus and the left insular and ACC in VM patients. Furthermore, patients with VM also exhibited increased FC between the left thalamus and the right precuneus and middle frontal gyrus, between the right thalamus and superior parietal lobule. FC between the right thalamus and the left insular was negatively correlated with disease duration (p = 0.019, r =  - 0.399), FC between the left thalamus and the left ACC was negatively correlated with HIT-6 score (p = 0.004, r =  - 0.484)., Conclusion: VM patients showed altered FC between thalamus and brain regions involved in pain, vestibular and visual processing, which are associated with specific clinical features. Specifically, VM patients showed reduced thalamo-pain and thallamo-vestibular pathways, while exhibited enhanced thalamo-visual pathway, which provided first insight into the underlying functional brain connectivity in VM patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The lesions besides lateral ventricle and motor recovery following rehabilitation have hardly been studied., Objective: To explore the relationship between the size, location of infarction beside the lateral ventricle and motor recovery following rehabilitation., Methods: A prospective cohort of 55 patients submitted to a Rehabilitation Medical Center between January 2015 and June 2019 who suffered a single cerebral infarction beside the lateral ventricle were included in the study. The size and distance between the posterior margin and the frontal-middle line (FML) of the lesion were measured. Follow-up was conducted until the recovery was no longer progressing. Barthel index and Brunstrom stages were used to evaluate the outcome (full recovery, partial recovery and poor recovery). Variance analysis and nonparametric test were used for the comparison between groups. Multivariate logistic regression analysis was used to screen the factors affecting the outcomes. The Pearson correlation coefficient was used to compare the volume of infarction, behind the FML and the outcomes., Results: Among the 55 patients, the outcome was full recovery (n = 28), partial recovery (n = 13) and poor recovery (n = 14). Multivariate logistic regression analysis showed that volume and location of the infarction were significantly correlated with the outcome (p = 0.039, 0.050). The lesion volume in the full recovery patients was significantly smaller than that in the poor recovery patients (p < 0.01). The posterior edge of the lesion in the full recovery patients behind the FML was statistically significant compared with that in the poor recovery patients (p < 0.01). Spearman correlation analysis showed that the motor recovery was negative correlation to lesion volume (r = -0.508, P < 0.01) and location (r = -0.450, P < 0.01) of the infarction., Conclusion: The motor recovery of patients with cerebral infarction beside lateral ventricle is related to the volume and location of the lesion. The larger the volume of the lesion, and the farther the posterior margin of the lesion to the FML, the worse the motor recovery.

Objective: To explore the effect of butylphthalide soft capsules combined with modified tonic exercise therapy on neurologic function and the abilities of daily living in patients with stroke hemiplegia., Methods: In this retrospective trial, a total of 90 patients with stroke hemiplegia admitted to our hospital from January 2019 to January 2020 were enrolled and divided into a control group and an experimental group according to different treatment methods. The two groups were both treated with butylphthalide soft capsules, and the experimental group was additionally treated by modified tonic exercise therapy. The clinical efficacy, endothelial injury indicators, molecular indicators of oxidative stress, and adverse reactions of the two groups were compared. Generic Quality of Life Inventory-74 (GQOLI-74) was used to assess the quality of life of patients after treatment. The Fugl-Meyer Upper Extremity Assessment (FMA) was used to evaluate their limb function before and after treatment, the National Institute of Health Stroke Scale (NIHSS) was used to evaluate their brain nerve function before and after the treatment, and the activities of daily living (ADL) were employed to assess their activities of daily living before and after treatment., Results: After treatment, the experimental group outperformed the control group in terms of total clinical efficacy (P<0.05). The experimental group had significantly lower endothelial injury indicators and higher molecular indicators of oxidative stress than the control group (all P<0.001). The incidence of adverse reactions in the experimental group was lower than that in the control group (P<0.05). Higher GQOLI-74, FMA, and ADL scores and a significantly lower NIHSS score were obtained in the experimental group than the control group after treatment (P<0.001)., Conclusion: For patients with stroke hemiplegia, butylphthalide soft capsule combined with modified tonic exercise therapy effectively improves their neurologic function, abilities of daily living, and quality of life., Competing Interests: None., (AJTR Copyright © 2021.)

An ultra-thin vapor chamber (UTVC) is an efficient heat transfer component that meets the heat dissipation requirement of miniaturized electronic devices. Heat dissipation is one of the most important issues for UTVCs. With decreasing thickness, the mechanical strength of heat pipes and vapor chambers drops dramatically, and inevitable surface damage occurs during conventional contact thermal testing. Here, we demonstrate a non-contact thermal testing method using laser heating and infrared temperature measurement to evaluate the thermal performance of UTVCs. This non-contact method allows UTVCs to reach a steady-state sooner than traditional contact methods. Use of the characteristic thermal resistance is proposed for more straightforward evaluation of the UTVC thermal performance in non-contact testing setups. This non-contact thermal testing method has proved to be an efficient testing method for UTVCs due to its rapidity, accuracy, and non-destructiveness.

Surfaces with desirable cytocompatibility and bactericidal ability are favoured for orthopaedic implants to stimulate osteogenic activity and to prevent implant-associated infection. In this work, we creatively introduce ultrasonic vibration (UV) to micro-arc oxidation (MAO) process and explore its influence on the microstructure, corrosion property and biological responses of Zn-modified TiO 2 coating. With the introduction of UV, a uniform surface layer with homogeneously-distributed clusters could be produced as the outer layer, which possesses a fusion band with the underlying TiO 2 . The microstructural modification associated with UV results in the enhanced corrosion resistance, increased adhesive strength and improved biological performances of the resultant coating relative to that with the absence of UV. Hence, the ultrasonic auxiliary micro-arc oxidation (UMAO) is regarded as a promising surface modification method to produce Ti-based orthopaedic implants of high quality., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Itaconic acid (IA), an important five-carbon unsaturated dicarboxylic acid, is one of the top 12 renewable chemicals with an urgent need to reduce industrial production costs. Halomonas bluephagenesis, which possesses the potential for cost-effective bioproduction of chemicals and organic acids due to its ability to grow under open nonsterile conditions and high tolerance to organic acid salts, was genetically engineered and used to produce IA from citrate by a cell catalytic strategy. Here, two essential genes ( cis -aconitate decarboxylase encoding gene cadA and aconitase (ACN) encoding gene acn ) were introduced into H. bluephagenesis to construct an IA biosynthesis pathway. Further engineering modifications including coexpression of molecular chaperones GroESL, increasing the copy number of the gene encoding rate-limiting enzyme ACN, and weakening the competing pathway were implemented. Under the optimized condition for the cell catalytic system, the engineered strain TAZI-08 produced 451.45 mM (58.73 g/L) IA from 500 mM citrate, with 93.24% conversion in 36 h and a productivity of 1.63 g/(L h). An intermittent feeding strategy further increased the IA titer to 488.86 mM (63.60 g/L). The IA titer and citrate conversion in H. bluephagenesis are the highest among heterologous hosts reported so far, demonstrating that this strain is a suitable chassis for hyperproduction of IA.

Three yeast strains, namely Cryptococcus albidus (Ca63), Cryptococcus albidus (Ca64), and Candida parapsilosis (Yett1006), and their combinations, including single yeast agent, two combined yeast strains, single yeast agent + NaHCO 3 , single yeast agent + chitosan, single yeast agent + ascorbic acid, and single yeast agent + konjac powder, were evaluated for their activity against Botrytis cinerea , the most economically important fungal pathogens causing postharvest disease of snap beans. In in vitro tests, no inhibition zone was observed in dual cultures of three yeast strains and B. cinerea. The mycelial growth inhibition rates of B. cinerea for Ca63, Ca64, and Yett1006 were 97%, 95%, and 97%, respectively. In in vivo tests, the optimal combination of the lowest disease index of snap beans with B. cinerea was Ca63 + Ca64, with a preventing effect of 75%. The decay rate and rust spots index of Ca64 + ascorbic acid combination were 25% and 20%, respectively, which were the lowest. The activities of defense-related enzymes increased, while malondialdehyde (MDA) content was suppressed in snap beans after different treatments. Our results highlight the potential of the three yeast strains and their combinations as new nonpolluting agents for the integrated control of B. cinerea on snap beans.

Background: X-linked inhibitor of apoptosis protein (XIAP) is the strongest member of the family of inhibitor of apoptosis protein. Studies found that the expression of XIAP in colon cancer tissue was significantly higher than that in adjacent tissues. Studies have shown that the expression of microRNA-215 (miR-215) was significantly lower than that of the adjacent tissues. This study investigated whether dysregulated miR-215 and XIAP play important roles in colon cancer cell apoptosis and the incidence of colon cancer. Materials and Methods: Forty-two patients with colorectal cancer (CRC) diagnosed and treated in the authors' hospital were selected. Human CRC cell line HCT116 and normal colonic mucosal epithelial cells (CMECs) were used. Luciferase reporter gene vector was constructed and dual-luciferase reporter gene assay was performed. HCT116 cells were cultured in vitro and divided into five groups: mimic normal control (NC) group, miR-215 mimic group, si-NC group, si-XIAP group, and miR-215 mimic + si-XIAP group. Western blot and polymerase chain reaction were conducted to examine XIAP and caspase-3. Apoptosis was detected by flow cytometry and cell proliferation was detected by cell counting kit-8 assay. Results: Compared with the adjacent tissues, the expression of miR-215 in colon cancer tissue was significantly lower, whereas the expression of XIAP in colon cancer tissue was significantly higher. The apoptosis rate and miR-215 expression level of HCT116 cells were lower than that of normal CMECs, whereas XIAP expression was significantly higher than that in normal colon mucosa epithelial cells. MiR-215 targeted the 3'-untranslated regions of XIAP and inhibited its expression. Overexpressing miR-215 and (or) silencing XIAP expression could significantly enhance the activity of caspase-9 and caspase-3, and promote the apoptosis of HCT116 cells. Conclusion: MiR-215 inhibited the expression of XIAP and promoted the apoptosis of HCT116 cells.

Target identification is one of the most important bases for novel pesticide development; pyruvate kinase (PK) was discovered as a potent fungicide target in our previous studies. To continue the PK-based fungicide development, novel isothiazole-purine derivatives were rationally designed and synthesized. Bioassay results showed that compound 5ai displayed excellent in vitro activity against Rhizoctonia solani with an EC 50 of 1.5 μg/mL, which was superior to those of positive controls diflumetorim with its EC 50 of 19.8 μg/mL and PK-based lead YZK - C22 with its EC 50 of 4.2 μg/mL. Compounds 3b (5.2 μg/mL) and 3c (4.5 μg/mL) displayed better activities against Gibberella zeae with their EC 50 s falling between 4.0 and 5.5 μg/mL, while YZK-C22 showed an EC 50 of 6.4 μg/mL. In addition, 5ah exhibited promising in vivo activity against Erysiphe graminis and Puccinia sorghi Schw. with 100% efficacy at 10 μg/mL and 90% efficacy at 2 μg/mL against P. sorghi Schw. Compound 5ai showed good PK inhibitory activity with an IC 50 of 38.8 μmol/L, and it was well docked into the active site of the target enzyme PK, which was slightly more active than YZK-C22 with its IC 50 of 42.4 μmol/L. Our studies discovered that isothiazole-purines were PK-based fungicidal leads deserving of further study.

Background: People living with HIV/AIDS not only require effective treatment for the alleviation of physical discomfort but also require social support to help them address difficulties in life and relieve their psychological anxiety and uneasiness. The social support network is of tremendous importance in helping people living with HIV/AIDS maintain good physical and mental health. This study aims to analyse the social support status among people living with HIV/AIDS in Kunming and explore associated factors., Method: The Social Support Rating Scale (SSRS) was used, and a questionnaire survey was conducted using convenience sampling to select people living with HIV/AIDS from 14 counties of Kunming. It collected information on general demographic information and social support status. Univariate and multivariate linear regression models were used to explore the associated factors., Results: A total of 990 valid questionnaires were completed. Data from all participants were analysed. Univariate analysis suggested that the factors associated with social support may include marital status, monthly income, and antiretroviral therapy. On the other hand, factors including monthly income and antiretroviral therapy accounted for the social support total score in the multivariate analysis., Conclusion: Social support among people living with HIV/AIDS in Kunming was generally low. This study identified a number of factors associated with social support among people living with HIV/AIDS. Based on our findings, appropriate interventions should be introduced to provide social support for those living with HIV/AIDS., (© 2021. The Author(s).)

Natural products are one of the resources for discovering novel fungicidal leads. As a natural fungicide, osthole was used as a coumarin-based lead compound for the development of novel fungicides. Here, a series of 3,4-dichloroisothiazole-containing 7-hydroxycoumarins were rationally designed, synthesized, and characterized by introducing a bioactive substructure, 3,4-dichloroisothiazole, into the coumarin skeleton. In vitro bioassay indicated that compound 7g displayed good activity against Rhizoctonia solani , Physalospora piricola , Sclerotinia sclerotiorum , and Botrytis cinerea . Its median effective concentration (EC 50 ) value against each of these fungi fell between 0.88 and 2.50 μg/mL, which was much lower than that of osthole against the corresponding pathogen (between 7.38 and 74.59 μg/mL). In vivo screening validated that 7k exhibited 100%, 60%, and 20% efficacy against R. solani Kühn at 200, 100, and 50 μg/mL, respectively. RNA sequence analysis implied that growth inhibition of R. solani by 7k might result from potential disruptions of fungal membrane formation and intracellular metabolism. Furthermore, a field experiment with cucumber plants indicated that 7b showed 62.73% and 74.03% efficacy against Pseudoperonospora cubensis (Berk. & Curt.) Rostov. at rates of 12.5 g a.i./ha and 25 g a.i./ha, respectively, which showed no significant difference between 7b and osthole at 30 g a.i./ha. Our studies suggested that 7b , 7g , and 7k might be used as fungicidal leads for further optimization.

Manganese oxides (MnO 2 ), important environmental oxides, have drawn significant attention in areas such as detoxification of micro-hazardous organic contaminants with electron-donating functional groups such as -OH. However, studies on whether these oxidized processes might further impact the fate of some esters like organophosphorus pesticide (OPPs) remain poorly understood. Herein, we propose a new mechanism involved in the enhanced removal of methyl parathion in mixtures of MnO 2 and phenol. Specifically, the removal of methyl parathion (up to 73.7%) was significantly higher for a binary system than for MnO 2 alone (approximately 9.3%) and was primarily due to adsorption rather than degradation. The extent of methyl parathion adsorption was dependent significantly on pH, reactant loading and metal ion co-solutes (such as Ca 2+ , Mg 2+ , Fe 3+ and Mn 2+ ). Both spectroscopic (FT-IR, SEM-EDX and XPS) and chromatographic (LC/HRMS) analyses showed that the remarkable increase in the number of organics (e.g., polymers) onto the MnO 2 surface dominated methyl parathion adsorption via hydrogen bonding, n-π and π-π interactions, van der Waals forces and pore-diffusion. The results from this study provided evidence for the role of manganese oxides in adsorption of methyl parathion in soil-aquatic environments involving phenolic compounds., Competing Interests: Declaration of competing interest The authors declared that they have no conflicts of interest to this work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Nitrogen- or oxygen-containing organic compounds which have significant antifungal activity, twenty one novel nitrogen or oxygen-containing (E)-3-acyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one analogues were designed and synthesized, and their structures were confirmed by 1 H NMR, 13 C NMR and HRMS. Preliminary bioassay showed that most of them exhibited certain-to-good antifungal activity. Compounds 5k-2, 5n, 5p and 5r exhibited over 80% inhibitory rate against Sclerotinia sclerotiorum at 50 μg/mL, and 5r exhibited good antifungal activity against S. sclerotiorum with EC 50 of 7.21 μg/mL. Compounds 5a and 5r also showed over 90% inhibition against Botrytis cinerea. In particular, 5r showed significant higher activity with the lowest EC 50 of 7.92 μg/mL than the positive control trifloxystrobin (21.96 μg/mL) and azoxystrobin (9.43 μg/mL). Providing a practical method for the synthesis of new scaffolds 1,2-Benzoxazepinone and systematically investigate their antifungal activity.

Since December 2019, COVID-19 has aroused global attention. Studies show the link between obesity and severe outcome of influenza and COVID-19. Thus, we aimed to compare the impacts of obesity on the severity and mortality of influenza and COVID-19 by performing a meta-analysis. A systematic search was performed in MEDLINE, EMASE, ClinicalTrials.gov, and Web of Science from January 2009 to July 2020. The protocol was registered onto PROSPERO (CRD42020201461). After selection, 46 studies were included in this meta-analysis. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were analyzed. We found obesity was a risk factor for the severity and mortality of influenza (ORsevere outcome = 1.56, CI: 1.28-1.90; ORmortality = 1.99, CI: 1.15-3.46). For COVID-19, obesity was a significant risk factor only for severe outcome (OR = 2.07, CI: 1.53-2.81) but not for mortality (OR = 1.57, CI: 0.85-2.90). Compared with obesity, morbid obesity was linked with a higher risk for the severity and mortality of both influenza (OR = 1.40, CI: 1.10-1.79) and COVID-19 (OR = 3.76, CI: 2.67-5.28). Thus, obesity should be recommended as a risk factor for the prognosis assessment of COVID-19. Special monitoring and earlier treatment should be implemented in patients with obesity and COVID-19., 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 © 2020 Zhao, Gang, He, Li, Lv, Han and Wang.)