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Abstract Background Despite the growing interest in the use of human genomic data for drug target identification and validation, the extent to which the spectrum of human disease has been addressed by genome-wide association studies (GWAS), or by drug development, and the degree to which these efforts overlap remain unclear. Methods In this study we harmonize and integrate different data sources to create a sample space of all the human drug targets and diseases and identify points of convergence or divergence of GWAS and drug development efforts. Results We show that only 612 of 11,158 diseases listed in Human Disease Ontology have an approved drug treatment in at least one region of the world. Of the 1414 diseases that are the subject of preclinical or clinical phase drug development, only 666 have been investigated in GWAS. Conversely, of the 1914 human diseases that have been the subject of GWAS, 1121 have yet to be investigated in drug development. Conclusions We produce target-disease indication lists to help the pharmaceutical industry to prioritize future drug development efforts based on genetic evidence, academia to prioritize future GWAS for diseases without effective treatments, and both sectors to harness genetic evidence to expand the indications for licensed drugs or to identify repurposing opportunities for clinical candidates that failed in their originally intended indication.

Lipid droplets (LDs) as spherical dynamic subcellular organelles, play an important role in various cellular functions such as protein degradation, lipid metabolism, energy storage, signal transduction, and membrane formation. Abnormal function of LDs will lead to a series of diseases and hence monitoring the status of LDs is particularly important. In this study, we synthesized a water-insoluble red fluorescent emitting small molecule fluorescent probe (TPE-TCF), which exhibited aggregation-induced emission (AIE) properties and enabled highly selective real-time imaging of LDs (Pearson's R value was 0.90). More interestingly, this probe was able to track the dynamic processes of LDs in living cells, including lipophagy, and monitor fatty liver disease in mice. Therefore, TPE-TCF with red fluorescence emission, good biocompatibility, large Stokes shift, AIE properties, LDs imaging, and fatty liver recognition capabilities can be practically used in more LDs-related 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 B.V. All rights reserved.)

Hypoxia can aggravate tumor occurrence, development, invasion, and metastasis, and greatly inhibit the photodynamic therapy (PDT) effect. Herein, carbon nitride (CNs)-based DNA and photosensitizer co-delivery systems (BPSCNs) with oxygen-producing functions are developed to address this problem. Selenide glucose (Seglu) is used as the dopant to prepare red/NIR-active CNs (SegluCNs). The tumor-targeting unit Bio-PEG 2000 is utilized to construct BPSCNs nanoparticles through esterification reactions. Furthermore, DNA hydrophobization is realized via mixing P53 gene with a positively charged mitochondrial-targeted near-infrared (NIR) emitting photosensitizer (MTTPY), which is encapsulated in non-cationic BPSCNs for synergistic delivery. Ester bonds in BPSCNs@MTTPY-P53 complexes can be disrupted by lipase in the liver to facilitate P53 release, upregulated P53 expression, and promoted HIF-1α degradation in mitochondria. In addition, the oxygen produced by the complexes improved the hypoxic microenvironment of hepatocellular carcinoma (HCC), synergistically downregulated HIF-1α expression in mitochondria, promoted mitochondrial-derived ferroptosis and enhanced the PDT effect of the MTTPY unit. Both in vivo and in vitro experiments indicated that the transfected P53-DNA, produced O 2 and ROS by these complexes synergistically led to mitochondrial-derived ferroptosis in hepatoma cells through the HIF-1α/SLC7A11 pathway, and completely avoiding PDT resistance caused by hypoxia, exerting a significant therapeutic role in HCC treatment., (© 2024 Wiley‐VCH GmbH.)

Herein, we introduce an electrochemical dehydrogenative [3 + 2]/[5 + 2] annulation of easily available N -arylacrylamides with γ,σ-unsaturated malonates through C(sp 3 )-H/C(sp 2 )-H functionalization. The employment of inexpensive ferrocene as the redox catalyst allows access to diverse benzo[ b ]azepin-2-ones in moderate to excellent yields without stoichiometric oxidants. This protocol features broad substrate scope and excellent selectivity, and mechanistic studies indicated that the reaction proceeded through the oxidation of a C(sp 3 )-H bond to generate an alkyl radical, radical addition across the C═C bond, [3 + 2]/[5 + 2] annulations, and C(sp 2 )-H functionalization cascades.

Hypoxia can lead to liver fibrosis and severely limits the efficacy of photodynamic therapy (PDT). Herein, carbon nitride (CN)-based hybrid nanoparticles (NPs) VPSGCNs@TSI for light-driven water splitting were utilized to solve this problem. CNs were doped with selenide glucose (Se-glu) to enhance their red/NIR region absorption. Then, vitamin A-poly(ethylene glycol) (VA-PEG) fragments and aggregation-induced emission (AIE) photosensitizers TSI were introduced into Se-glu-doped CN NPs (VPSGCNs) to construct VPSGCNs@TSI NPs. The introduction of VA-PEG fragments enhanced the targeting of the NPs to activated hepatic stellate cells (HSCs) and reduced their toxicity to ordinary liver cells. VPSGCN units could trigger water splitting to generate O 2 under 660 nm laser irradiation, improve the hypoxic environment of the fibrosis site, downregulate HIF-1α expression, and activate HSC ferroptosis via the HIF-1α/SLC7A11 pathway. In addition, generated O 2 could also increase the reactive oxygen species (ROS) production of TSI units in a hypoxic environment, thereby completely reversing hypoxia-triggered PDT resistance to enhance the PDT effect. The combination of water-splitting materials and photodynamic materials showed a 1 + 1 > 2 effect in increasing oxygen levels in liver fibrosis, promoting ferroptosis of activated HSCs and reversing PDT resistance caused by hypoxia.

Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality caused by various factor. The specific strategies for AKI are still lacking. GSK3β is widely expressed in the kidneys. In acute models of injury, GSK3β promotes the systemic inflammatory response, increases the proinflammatory release of cytokines, induces apoptosis, and alters cell proliferation. We screened a series of 3-(4-pyridyl)-5-(4-sulfamido-phenyl)-1,2,4-oxadiazole derivatives which are recognized as new GSK3β inhibitors, and found that 5n had the least toxicity and the best cell protection. We then tested the anti-inflammatory and reno-protective effect of 5n in cisplatin-treated tubular epithelial cells. 5n had anti-inflammation effect indicated by phosphor-NF-κB detection. Finally, we found that 5n ameliorated renal injury and inflammation in cisplatin-induced AKI mouse model. Silencing GSK3β inhibited cell injury and inflammation induced by cisplatin. We found that GSK3β interacted with PP2Ac to modulate the activity of NF-κB. In conclusion, 5n, the novel GSK3β inhibitor, protects against AKI via PP2Ac-dependent mechanisms which may provide a potential strategy for the treatment of AKI in clinic., Competing Interests: 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., (© 2024 The Authors.)

Background: Intervertebral disc degeneration (IDD) and atherosclerosis are two common age-related conditions that can cause significant morbidity. While previous studies have suggested an association between the two conditions, the nature of this association remains unclear., Methods: We used Mendelian randomization (MR) to investigate the causal relationship between IDD and atherosclerosis. We identified genetic variants associated with IDD using summary statistics from a large genome-wide association study (GWAS). These variants were then used as instrumental variables to infer causal relationships with atherosclerosis in summary statistics from a separate GWAS., Results: Our MR analysis provided evidence for a causal relationship between IDD and atherosclerosis. We found that the genetic predisposition to atherosclerosis was associated with a higher risk of IDD (odds ratio [OR] = 3.55, 95% confidence interval [CI]: 1.07-11.74, p  = 0.04). The IVW estimates were consistent with the observational findings and other robust MR methods. Sensitivity analyses suggested that our findings were robust to potential sources of bias., Conclusions: Our study provides evidence for a causal link between IDD and atherosclerosis, suggesting that interventions targeting atherosclerosis could have potential benefits for reducing the risk of IDD. Further research is needed to explore the underlying mechanisms that link these two conditions and to investigate potential therapeutic interventions., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Background: Most previous studies on women of childbearing age have focused on reproductive health and fertility intentions, and evidence regarding the comprehensive health status of women of childbearing age is limited. This study aimed to comprehensively examine the health status of women of childbearing age through a multi-method and multi-indicator evaluation, analyze the factors that influence their overall health, and provide sound recommendations for the improvement and promotion of healthy behaviors., Methods: Data on women of childbearing age living in Shanxi Province were collected between September 2021 and January 2022 through online and offline surveys. The k-means algorithm was used to assess health-related patterns in women, and multivariate nonconditional logistic regression was used to assess the influencing factors of women's overall health., Results: In total, 1,258 of 2,925 (43%) participants were classified as having a good health status in all five domains of the three health dimensions: quality of life, mental health, and illness. Multivariate logistic regression showed that education level, gynecological examination status, health status of family members, access to medical treatment, age, cooking preferences, diet, social support, hand washing habits, attitude toward breast cancer prevention, and awareness of reproductive health were significantly associated with different health patterns., Conclusions: The comprehensive health status of women of childbearing age in Shanxi Province is generally good; however, a large proportion of women with deficiencies in some dimensions remains. Since lifestyle greatly impacts women's health, health education on lifestyle and health-related issues should be strengthened., (© 2023. The Author(s).)

Hypoxia is an important feature, which can upregulate the hypoxia-inducible factor-1α (HIF-1α) expression and promote the activation of hepatic stellate cells (HSCs), leading to liver fibrosis. Currently, effective treatment for liver fibrosis is extremely lacking. Herein, a safe and effective method is established to downregulate the expression of HIF-1α in HSCs via targeted delivery of VA-PEG-modified CNs-based nanosheets-encapsulated (VA-PEG-CN@GQDs) HIF-1α small interfering RNA (HIF-1α-siRNA). Due to the presence of lipase in the liver, the reversible release of siRNA can be promoted to complete the transfection process. Simultaneously, VA-PEG-CN@GQD nanosheets enable trigger the water splitting process to produce O 2 under near-infrared (NIR) irradiation, thereby improving the hypoxic environment of the liver fibrosis site and maximizing the downregulation of HIF-1α expression to improve the therapeutic effect, as demonstrated in liver fibrosis mice. Such combination therapy can inhibit the activation of HSCs via HIF-1α-mediated TGF-β1/Smad pathway, achieving outstanding therapeutic effects in liver fibrosis mice. In conclusion, this study proposes a novel strategy for the treatment of liver fibrosis by regulating the hypoxic environment and the expression of HIF-1α at lesion site., (© 2023 Wiley-VCH GmbH.)

Background: Intervertebral disc degeneration (IDD) is a common musculoskeletal disorder that contributes significantly to disability and healthcare costs. Serum urate concentration has been implicated in the development of various musculoskeletal conditions. While previous observational studies have suggested an association between the two conditions, it might confound the effect of serum urate concentrations on IDD. This Mendelian randomization (MR) study aimed to investigate the causal relationship between serum urate concentration and IDD., Methods: We performed a two-sample MR analysis using summary-level data from genome-wide association studies (GWAS) of serum urate concentration ( n  = 13 585 994 European ancestry) and IDD ( n  = 16 380 337 European ancestry). Single nucleotide polymorphisms (SNPs) significantly associated with serum urate concentration ( p  < 5 × 10 -8 ) were selected as instrumental variables. The associations between genetically predicted serum urate concentration and IDD were estimated using the inverse-variance weighted (IVW) method, with sensitivity analyses employing the weighted median, MR-Egger, and MR-PRESSO approaches to assess the robustness of the findings., Results: In the primary IVW analysis, genetically predicted serum urate concentration was unrelated associated with IDD (odds ratio [OR] = 1.00, 95% confidence interval (CI): 1.00-1.00, p  = 0.17)). The results remained consistent across the sensitivity analyses, and no significant directional pleiotropy was detected (MR-Egger intercept: p  = 0.15)., Conclusions: This MR study provides evidence that there is no causal relationship between serum urate concentration and IDD. It suggests previous observational associations may be confounded. Serum urate levels are unlikely to be an important contributor to IDD., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Diabetes mellitus during pregnancy, which can be classified into pregestational diabetes and gestational diabetes, has become much more prevalent worldwide. Maternal diabetes fosters an intrauterine abnormal environment for fetus, which not only influences pregnancy outcomes, but also leads to fetal anomaly and development of diseases in later life, such as metabolic and cardiovascular diseases, neuropsychiatric outcomes, reproduction malformation, and immune dysfunction. The underlying mechanisms are comprehensive and ambiguous, which mainly focus on microbiota, inflammation, reactive oxygen species, cell viability, and epigenetics. This review concluded with the influence of intrauterine hyperglycemia on fetal structure development and organ function on later life and outlined potential mechanisms that underpin the development of diseases in adulthood. Maternal diabetes leaves an effect that continues generations after generations through gametes, thus more attention should be paid to the prevention and treatment of diabetes to rescue the pathological attacks of maternal diabetes from the offspring., 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 © 2023 Yan, Feng, Yu, Tian, Zhou, Huang, Cai, Chen, Zhu and Jin.)

N 6 -methyladenosine (m 6 A) has been demonstrated to regulate RNA metabolism and various biological processes, including gametogenesis and embryogenesis. However, the landscape and function of m 6 A at single cell resolution have not been extensively studied in mammalian oocytes or during pre-implantation. In this study, we developed a single-cell m 6 A sequencing (scm 6 A-seq) method to simultaneously profile the m 6 A methylome and transcriptome in single oocytes/blastomeres of cleavage-stage embryos. We found that m 6 A deficiency leads to aberrant RNA clearance and consequent low quality of Mettl3 Gdf9 conditional knockout (cKO) oocytes. We further revealed that m 6 A regulates the translation and stability of modified RNAs in metaphase II (MII) oocytes and during oocyte-to-embryo transition, respectively. Moreover, we observed m 6 A-dependent asymmetries in the epi-transcriptome between the blastomeres of two-cell embryo. scm 6 A-seq thus allows in-depth investigation into m 6 A characteristics and functions, and the findings provide invaluable single-cell resolution resources for delineating the underlying mechanism for gametogenesis and early embryonic development., (© 2023. The Author(s).)

The yellow catfish ( Pelteobagrus fulvidraco ) is a freshwater fish with high economic value in eastern China. Nevertheless, pathogens causing bacterial diseases in P. fulvidraco have brought about huge economic loss and high mortality in artificial aquaculture. For disease control, it is critical to further understand the immune system of yellow catfish and immune-related genes with which they respond to pathogenic infections. In this study, high-throughput sequencing methods were used to analyze the transcriptomic spectrum of the head kidney from P. fulvidraco challenged by Vibrio cholera . A total of 45,544 unique transcript fragments (unigenes) were acquired after assembly and annotation, with an average length of 1,373 bp. Additionally, 674 differentially expressed genes (DEGs) were identified after stimulation with V. cholerae , 353 and 321 genes were identified as remarkably up- or downregulated, respectively. To further study the immune-related DEGs, we performed KEGG enrichment and GO enrichment. The results showed gene regulation of response to stimulus, immune response, immune system progress, response to external stimuli and cellular response to stimuli. Analysis of KEGG enrichment is important to identify chief immune related pathways. Real-time quantitative reverse transcription-PCR (qRT-PCR) results indicated 10 immune response genes that were found to be upregulated compared to a control group after 6 h of V. cholerae challenging. In summary, the results of our study are helpful to determine the defense mechanisms and immune system responses of yellow catfish in reaction to bacterial challenges., 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 © 2023 Jiang, Wu, Cai, Ma, Zhang, Zhang, Tang, Liu and Dai.)

Background: Calcaneal fracture is common and carries high morbidity and disability. Its treatment is therefore of vital concern. Many topics concerning calcaneal fracture remain controversial, and the subject has not yet been well-researched. We aim to analyze and illustrate the trends in development, overall knowledge structure, "hotspots," and research frontiers on the topic of calcaneal fracture., Methods: Literature relating to calcaneal fracture published between 2000 and 2021 was retrieved from Science Citation Index Expanded (SCIE) database of the Web of Science. Three bibliometric tools (Bibliometrix, CiteSpace, and VOSviewer software) were used for analysis and the generation of knowledge maps. Annual trends in publication counts and the relative contributions of different countries, regions, institutions, authors, and journals, as well as keyword clusters, "hot topics," and research frontiers, were analyzed., Results: A total of 1,687 publications were included in the analysis. The number of calcaneal fracture articles published worldwide each year was highest in 2019, with a total of 128 articles. The United States has made the greatest contribution to the field, with the largest number of publications and the highest H-index. Foot & Ankle International was the most productive journal, publishing a total of 167 articles on calcaneal fracture during the study period. Hebei Medical University of China and the University of California, San Francisco were the most prolific institutions. Professors T. Schepers, S. Rammelt, H. Zwipp, and Y. Z. Zhang have made remarkable contributions to the field. However, the degree of collaboration between researchers and among institutions was relatively low, and took place mainly in Europe and the Americas. All relevant keywords could be categorized into three clusters: studies of internal fixation, studies of fractures, and studies of osteoporosis. A trend of balanced and diversified development could be seen within these clusters. Keywords with ongoing "citation bursts," such as sinus tarsi approach, wound complications, minimally invasive technique, extensile lateral approach, surgical treatment, and plate, may continue to be research "hotspots" in the near future., Conclusion: Based on current global trends, the number of publications on calcaneal fracture will continue to increase. Topics such as minimally invasive techniques and complications have become important hotspots of research. We recommend enhancing international communication and collaboration for future research in this field., 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., (© 2023 Cai, Song, He, He, Wei and He.)

Background: It has been reported that activation of glutamate kainate receptor subunit 2 (GluK2) subunit-containing glutamate receptors and the following Fas ligand(FasL) up-regulation, caspase-3 activation, result in delayed apoptosis-like neuronal death in hippocampus CA1 subfield after cerebral ischemia and reperfusion. Nitric oxide-mediated S-nitrosylation might inhibit the procaspase activation, whereas denitrosylation might contribute to cleavage and activation of procaspases., Objectives: The study aimed to elucidate the molecular mechanisms underlying procaspase-3 denitrosylation and activation following kainic acid (KA)-induced excitotoxicity in rat hippocampus., Methods: S-nitrosylation of procaspase-3 was detected by biotin-switch method. Activation of procaspase-3 was shown as cleavage of procaspase-3 detected by immunoblotting. FasL expression was detected by immunoblotting. Cresyl violets and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining were used to detect apoptosis-like neuronal death in rat hippocampal CA1 and CA3 subfields., Results: KA led to the activation of procaspase-3 in a dose- and time-dependent manner, and the activation was inhibited by KA receptor antagonist NS102. Procaspase-3 was denitrosylated at 3 h after kainic acid administration, and the denitrosylation was reversed by SNP and GSNO. FasL ASODNs inhibited the procaspase-3 denitrosylation and activation. Moreover, thioredoxin reductase (TrxR) inhibitor auranofin prevented the denitrosylation and activation of procaspase-3 in rat hippocampal CA1 and CA3 subfields. NS102, FasL AS-ODNs, and auranofin reversed the KAinduced apoptosis and cell death in hippocampal CA1 and CA3 subfields., Conclusions: KA led to denitrosylation and activation of procaspase-3 via FasL and TrxR. Inhibition of procaspase-3 denitrosylation by auranofin, SNP, and GSNO played protective effects against KA-induced apoptosis-like neuronal death in rat hippocampal CA1 and CA3 subfields. These investigations revealed that the procaspase-3 undergoes an initial denitrosylation process before becoming activated, providing valuable insights into the underlying mechanisms and possible treatment of excitotoxicity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The dorsal raphe nucleus (DRN) has previously been proved to be involved in the regulation of the sleep-wake behavior. DRN contains several neuron types, such as 5-HTergic and GABAergic neurons. GABAergic neurons, which are the second largest cell subtype in the DRN, participate in a variety of neurophysiological functions. However, their role in sleep-wake regulation and the underlying neural circuitry remains unclear. Herein, we used fiber photometry and synchronous electroencephalogram (EEG)/electromyography (EMG) recording to demonstrate that DRN GABAergic neurons exhibit high activities during wakefulness and low activities during NREM sleep. Short-term optogenetic activation of DRN GABAergic neurons reduced the latency of NREM-to-wake transition and increased the probability of wakefulness, while long-term optogenetic activation of these neurons significantly increased the amount of wakefulness. Chemogenetic activation of DRN GABAergic neurons increased wakefulness for almost 2 h and maintained long-lasting arousal. In addition, inhibition of DRN GABAergic neurons with chemogenetics caused a reduction in the amount of wakefulness. Finally, similar to the effects of activating the soma of DRN GABAergic neurons, optogenetic stimulation of their terminals in the ventral tegmental area (VTA) induced instant arousal and promoted wakefulness. Taken together, our results illustrated that DRN GABAergic neurons are vital to the induction and maintenance of wakefulness, which promote wakefulness through the GABAergic DRN-VTA pathway., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

During the first two years of the COVID-19 pandemic, the Chinese public consistently demonstrated a high level of compliance with some of the most restrictive infection control measures in the world. As a result, as of early 2022 China achieved remarkable control of a virus that had devastating effects in other parts of the world. In this article we take seriously the complexities of a simple question: Why did most urban Chinese citizens so willingly comply with the state's COVID-19 control measures for so long? Based on two years of ethnographic research conducted primarily in Shanghai, China between June 2020 and May 2022, we argue that the strong support the Chinese government enjoyed among China's self-described laobaixing ("ordinary people") in implementing its COVID-19 control measures emerged from a combination of self-interest, nationalistic pride, and "conscious indifference to transparency," rooted in ongoing critical evaluations of governmental competence. With these evaluations changing in the wake of new outbreaks in 2022, the future of China's zero-COVID policy is in jeopardy., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Sacha inchi (Plukenetia volubilis L.) tea has been used as an adjuvant treatment for diabetes in Pu'er, in the Yunnan province of China. The effects of sacha inchi tea on diabetes and the underlying mechanisms remain unknown. This study was conducted to investigate the influence of a water extract of sacha inchi (P. volubilis L.) leaves (PWE) on hypoglycemic activity and gut microbiota composition in mice with streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM). During the 6 weeks of the study, T1DM mice were administered PWE intragastrically at 400 mg kg -1 body weight (BW) per day., Results: Treatment with PWE reduced excessive loss of BW and excessive intake of food. It significantly decreased blood glucose levels and improved oral glucose tolerance. The treatment caused protective histopathological transformations in sections of the pancreas, leading to decreased insulin resistance and improved insulin sensitivity. Treatment with PWE also significantly ameliorated disorders of the gut microbiota structure and increased the richness and diversity of intestinal microbial species in T1DM mice. At the genus level, the populations of several crucial bacteria, such as Akkermansia, Parabacteroides, and Muribaculum increased in the PWE treatment group but the abundance of Ruminiclostridium and Oscillibacter decreased., Conclusions: Treatment with PWE can ameliorate hyperglycemic symptoms in STZ-induced T1DM mice, and the anti-diabetic effect of PWE was related to the amelioration of gut microbial structural disorder and the enrichment of functional bacteria. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

Objectives: The effects of body mass index (BMI) on the outcome of high ligation and stripping (HLS) in an ambulatory center remain unclear. This study aims to investigate the outcomes of HLS in an ambulatory center based on BMI in the Chinese population., Design: This was a prospective cohort study with mid-term follow-up., Materials and Methods: 170 eligible patients were included in the study and the data of Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) classification, Venous Clinical Severity Score (VCSS), Visual Analogue Score (VAS), Aberdeen Varicose Veins Questionnaire (AVVQ), Quality of Recovery (QoR-15), and postoperative complications at predetermined time points were collected., Results: A total of 170 patients (236 limbs) with a mean age of 53.87 ± 9.96 years (range, 24-80 years) and a mean BMI of 23.86 ± 2.96 kg/m 2 were included. Of the group, 50.6% were women, and 66 patients received bilateral procedures. Through curve fitting, a BMI less than 28 and a BMI of 28 or higher were found to have a negative [-0.1 (-0.3, 0.1) 0.296] and positive [0.7 (0.2, 1.2) 0.006] relationship trend, respectively, with the improvement of VCSS at 6 weeks after surgery. Through smooth curve fitting, BMI was shown to have a negative relationship trend on the improvement of VCSS at 6 months after surgery. After multivariable risk adjustment for potential confounding factors, BMI was not found to be associated with the improvement of VCSS and AVVQ at 6 weeks after surgery, as well as the improvement of AVVQ at 6 months after surgery (all p -values >0.05). Six months after surgery, BMI was shown to have a negative relationship trend on the improvement of VCSS, and obese patients showed lower VCSS improvement than patients of normal BMI [-1.3 (-1.9, -0.7) <0.0001]. Six weeks after surgery, postoperative complications such as paresthesia were found to be significantly higher in the obese group than in the non-obese group ( p  < 0.05). At 6 months after surgery, the obese group showed significantly higher complications of the legs compared with the normal BMI group ( p  < 0.05)., Conclusions: Our results showed that obesity is a risk factor for prognosis and postoperative complications following ambulatory HLS., 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 Chen, Cai, Wang, Wu, Liu, Huang, Yang, Yuan, Ma and Zhao.)

Ficus religiosa L., known as bodhi tree, is an ornamental tree and widely planted as an avenue and roadside tree due to ovate-rounded leaves with narrow, elongated tips. During 2018-2021, circular to oval-shaped leaf spots with pale white centers and brown-black edges surrounded by a chlorotic halo were observed on the leaves of more than 200 bodhi trees all year round in a park in Zhanjiang, Guangdong (N 21°15'22.29''; E110°23'1.03''). The leaf disease incidences were usually 15-80%, in severe cases, up to 100% in autumn and winter every year, and some trees shed all leaves(Fig S1). Repeated annual defoliation may weaken the tree and decrease the aesthetic value in the landscape. Diseased tissues (5 × 5 mm) of five symptomatic infected leaves were surface sterilized in 3% hydrogen peroxide solution for 3 min, rinsed thrice with sterile water, plated on potato dextrose agar (PDA) amended with ampicillin (50mg/L), and incubated at 25-28 ℃ in the dark for 3-7 days. Five strains with similar morphology were obtained by transferring hyphal tips of the colonies to fresh PDA and further isolating by single spore method. Fungal colonies were flat and spreading, with sparse, white aerial mycelium, and black pycnidial conidiomata semi-immersed in PDA after 30-days incubation at 25-28 ℃ in dark. Conidiophores were hyaline and α-conidia were single-celled, oval to fusiform, guttulate, 5.3 × 2.5 μm (n>50), similar to Diaporthe sp. (Crous et al. 2015), but no β and γ -conidia were observed. The internal transcribed spacer(ITS), large subunit ribosomal RNA gene(LSU), calmodulin (CAL) and β-tubulin(TUB) gene regions of a representative strain were amplified using specific primers reported by White et al. (1990), Gao et al (2017) and Gomes et al (2013), and submitted to GenBank (ITS: OM200852, LSU: OM228732, CAL: OM244761, TUB: OM244760). NCBI Blastn showed above 99% identity to D. tulliensis (anamorph: Phomopsis heveicola ) isolates of ITS (MT974186, MN393590 and KX457967), LSU (KR936131), CAL (MW759801), and TUB (KR936132 and MN399886), respectively (Crous et al. 2015; Huang et al. 2021; Gong et al. 2020; Bai et al. 2017). Based on the concatenated ITS, CAL, and TUB, a Maximum Likelihood phylogenetic analyses using MEGA 10.1.8 clustered the fungus with D. tulliensis in a clade with a 93% bootstrap support(Fig S2). Therefore, the fungus was identified as D. tulliensis based on morpho- molecular characteristics. Healthy detached leaves were sanitized thrice with 70% alcohol, and rinsed with sterile water. PDA plugs with actively growing 10-days-old mycelium were placed on predetermined sites, put into a sealed box with above 80% relative humidity and incubated at room temperature (25-28℃). Each isolate was inoculated at 25 needle-wounded and unwounded sites, PDA plugs without mycelium served as controls. Symptomatic spots appeared on all wounded leaves by 7 days post-inoculation (dpi) and on all unwounded leaves by 12 dpi. No symptoms appeared on controlled leaves. Pure cultures were recovered from inoculated leaves and showed identical morpho-molecular criteria to the original isolates. More than 70 pathogenic fungi are known to cause diseases on F. religiosa while there is no record of D. tulliensis infecting bodhi according to the U.S. National Fungus Collection (Farr and Rossman 2022). This report could provide basic understanding and alerting role for horticulturist in daily management.

Stratifin (SFN) is a member of the 14-3-3 family of highly conserved soluble acidic proteins, which regulates a variety of cellular activities such as cell cycle, cell growth and development, cell survival and death, and gene transcription. Acute kidney injury (AKI) is prevalent disorder characterized by inflammatory response, oxidative stress, and programmed cell death in renal tubular epithelial cells, but there is still a lack of effective therapeutic target for AKI. In this study, we investigated the role of SFN in AKI and the underlying mechanisms. We established ischemic and nephrotoxic AKI mouse models caused by ischemia-reperfusion (I/R) and cisplatin, respectively. We conducted proteomic and immunohistochemical analyses and found that SFN expression levels were significantly increased in AKI patients, cisplatin- or I/R-induced AKI mice. In cisplatin- or hypoxia/reoxygenation (H/R)-treated human proximal tubule epithelial cells (HK2), we showed that knockdown of SFN significantly reduced the expression of kidney injury marker Kim-1, attenuated programmed cell death and inflammatory response. Knockdown of SFN also significantly alleviated the decline of renal function and histological damage in cisplatin-caused AKI mice in vivo. We further revealed that SFN bound to RIPK3, a key signaling modulator in necroptosis, to induce necroptosis and the subsequent inflammation in cisplatin- or H/R-treated HK2 cells. Overexpression of SFN increased Kim-1 protein levels in cisplatin-treated MTEC cells, which was suppressed by RIPK3 knockout. Taken together, our results demonstrate that SFN that enhances cisplatin- or I/R-caused programmed cell death and inflammation via interacting with RIPK3 may serve as a promising therapeutic target for AKI treatment., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

MicroRNAs (miRNAs) consist of a large family of small, non-coding RNAs with the ability to result in gene silencing post-transcriptionally. With recent advances in research technology over the past several years, the physiological and pathological potentials of miRNAs have been gradually uncovered. MiR-149-5p, a conserved miRNA, was found to regulate physiological processes, such as inflammatory response, adipogenesis and cell proliferation. Notably, increasing studies indicate miR-149-5p may act as an important regulator in solid tumors, especially cancers in reproductive system and digestive system. It has been acknowledged that miR-149-5p can function as an oncogene or tumor suppressor in different cancers, which is achieved by controlling a variety of genes expression and adjusting downstream signaling pathway. Moreover, the levels of miR-149-5p are influenced by several newly discovered long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). However, there is blank about systematic function and mechanism of miR-149-5p in human cancers. In this review, we firstly summarize the present comprehension of miR-149-5p at the molecular level, its vital role in tumor initiation and progression, as well as its potential roles in monitoring diverse reproductive and digestive malignancies., 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 Ren, Yao, Cai, Cai, Su and Fang.)

This study aimed at the efficacy of sequential treatment of bone marrow-derived mesenchymal stem cell secretion for busulfan-treated azoospermia in mice. The conditioned media (CM) was obtained from bone marrow mesenchymal stem cells (MSCs) or 293 cells. Chemically induced azoospermia mice received 200 μl MSC-CM or 293-CM twice a week intravenously for three consecutive weeks. The histological assessment of spermatogenic recovery quantifying the expression of meiosis-associated genes, and Sertoli cell barrier functional factors were assessed. The characteristics of TM4 cells (Sertoli cell line) after pre-incubation of MSC-CM in vitro were also obtained. The MSC-CM group had the most spermatogenic colonies among the three groups (p < .05), but no spermatids were seen. Expressions of the meiosis-associated genes Dazl, Vasa, Miwi, Stra8, CyclinA1, Pgk2 and Scp3 in MSC-CM testis were remarkably higher compared with 293-CM and busulfan groups respectively (p < .05). The levels of Sertoli cell barrier functional factors, for example ICAM-1 and N-cadherin, were significantly increased during MSC-CM treatment (p < .05). Moreover, pre-incubation of MSC-CM particularly accelerated the CD54 (ICAM-1) and CD44 expressions of TM4 cells and promoted cell inherent adhesion. MSC-CM treatment can significantly improve the short-term restoration of spermatogonial structures of chemically induced azoospermia related to facilitating Sertoli cell adhesion integrity., (© 2021 Wiley-VCH GmbH.)

Background: Emerging infectious diseases are a constant threat to the public's health and health care systems around the world. Coronavirus disease 2019 (COVID-2019), which was defined by the World Health Organization as pandemic, has rapidly emerged as a global health threat. Outbreak evolution and prevention of international implications require substantial flexibility of frontline health care facilities in their response., Aim: To explore the effect of the implementation and management strategy of pre-screening triage in children during COVID-19., Methods: The standardized triage screening procedures included a standardized triage screening questionnaire, setup of pre-screening triage station, multi-point temperature monitoring, extensive screenings, and two-way protection. In order to ensure the implementation of the pre-screening triage, the prevention and control management strategies included training, emergency exercise, and staff protection. Statistical analysis was performed on the data from all the children hospitalized from January 20, 2020 to March 20, 2020 at solstice during the pandemic period. Data were obtained from questionnaires and electronic medical record systems., Results: A total of 17561 children, including 2652 who met the criteria for screening, 192 suspected cases, and two confirmed cases without omission, were screened from January 20, 2020 to March 20, 2020 at solstice during the pandemic period. There was zero transmission of the infection to any medical staff., Conclusion: The effective strategies for pre-screening triage have an essential role in the prevention and control of hospital infection., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To evaluate the quality of the published breast cancer screening guidelines to provide a reference for domestic studies in the future. Methods: PubMed, Embase, Cochrane Library, Web of Science, SinoMed, China National Knowledge Infrastructure, VIP, and Wanfang Data were searched to identify breast cancer screening guidelines on until August 2020. Two reviewers screened literature and extracted data independently. The Appraisal of Guidelines for Research & Evaluation Ⅱ(AGREEⅡ) and Reporting Items for Practice Guidelines in Healthcare(RIGHT) tools were used to evaluate the quality of the included guidelines. Results: A total of 15 breast cancer screening guidelines were included, of which seven were published in the United States, with publication years focusing on 2015 to 2019, and 11 guidelines had updated versions. "Rigour of development" (47.0%±22.1%) and "Applicability" (44.0%±15.1%) of AGREEⅡ scored lower than other domains. "Review and quality assurance" (46.7%±39.9%) and "Funding, declaration, and management of interests" (41.7%±24.4%) of RIGHT were reported poorer than others. There were six guidelines recommended and another nine recommended with modifications based on the overall AGREEⅡ score. There were four guidelines with a good level, and another 11 were with a moderate level of RIGHT. The National Comprehensive Cancer Network published the best overall quality guidelines in 2018 (AGREEⅡ: 83.3%, RIGHT: 80.0%) and by the American Cancer Society in 2015 (AGREEⅡ: 83.3%, RIGHT: 85.7%). Conclusion: The quality of breast cancer screening guidelines was predominantly of moderate quality, and greater attention should be paid to the guideline development process and quality control of the guidelines.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) have a common pathology. Both diseases are characterized by local deposition of amyloid proteins in the brain or islet organ, but their phenotypes and clinical manifestation vary widely. Although the sources of islet amyloid polypeptide (IAPP) and amyloid beta (Aβ) are independent, their fibrillar sequences are highly homologous. The prevalence of AD in T2DM populations is considerably higher than that in the normal population, but a mechanistic linkage remains elusive. Therefore, the present study aimed to explore the effects of Aβ42 deposition in the brain on the persistently expression of human IAPP (hIAPP). Additionally, cognitive ability, synaptic plasticity, the state of neural stem cells and mitochondrial function were evaluated at 2 or 6 months after stereotaxically injected the oligomer Aβ 1-42 into the dentate gyrus of hIAPP (-/+) mice or the wild-type littermates. We found that Aβ 42 and amylin were co-located in hippocampus and Aβ 42 levels increased when Aβ 1-42 was injected in hIAPP transgenic mice compared with that of the wild-type littermates. Furthermore, at 6 months after Aβ 1-42 injection in hIAPP (-/+) mice, it exhibits exacerbated AD-related pathologies including Aβ 42 deposition, cognitive impairment, synapse reduction, neural stem cells exhaustion and mitochondrial dysfunction. Our present study suggested that hIAPP directly implicated the Aβ 42 production and deposition as an important linkage between T2DM and AD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

To present an evidence map for explicating research trends and gaps, we systematically review clinical practice guidelines (CPGs) on diabetic retinopathy (DR) and assess the quality of CPGs and consistency of recommendations. A literature search was performed in PubMed, Embase, Web of Science, CPG databases, and website of diabetes society to include the CPGs. The basic information, methodological quality, and reporting quality of CPGs, recommendations for DR were exacted by the Excel 2013. Methodological and reporting quality of DR CPGs were evaluated by AGREE II instrument and RIGHT checklist. The bubble plot format of evidence map was made by Excel 2013. Nineteen CPGs proved eligible, which included eight DR CPGs and 11 comprehensive diabetic CPGs. The identified CPGs were of mixed quality and they scored poorly in the rigor of development, applicability domains by AGREE II. Field two (background) had the highest reporting rate (86.31%) and field five (review and quality assurance) obtained the lowest reporting rate (31.58%) among the seven domains of RIGHT checklist. According to the recommendations of CPGs, there were three inconsistencies in the screening of DR, and CPGs recommendations for treatment were consistent on the whole. At the same time, recommendations for laser therapy were not accurate. Some recommendations were not specific and clear in some DR CPGs. This evidence map could collect and evaluate the characteristics of published CPGs, add to our knowledge and promote the development of trustworthy CPGs for DR.

Background: One of the major challenges in nursing and medical education is to foster the critical thinking ability and autonomous learning ability for students. But the effect of different teaching methods on these abilities of nursing or medical students has not been conclusive, and few studies have directly compared the differences in the effects of different teaching methods. As a result, it is necessary for students to evaluate the impact of different teaching methods on critical thinking ability and autonomous learning ability., Methods: A systematic search will be performed using Chinese National Knowledge Infrastructure, Wanfang Data (Chinese database), VIP Information (Chinese database), Chinese Biomedical Literature, and English language databases, including PubMed and Embase, Web of Science, CINAHL Complete (EBSCO0, Cochrane library to identify relevant studies from inception to July 10, 2020. We will include random controlled trials that evaluated the different teaching methods. The Quality Assessment of Diagnostic Accuracy Studies 2 quality assessment tool will be used to assess the risk of bias in each study. Standard pairwise meta-analysis and network meta-analysis will be performed using STATA V.12.0, MetaDiSc 1.40, and R 3.4.1 software to compare the diagnostic efficacy of different hormonal biomarkers., Results: The results of this study will be published in a peer-reviewed journal., Conclusion: This study will summarize the direct and indirect evidence to determine the effectiveness of different teaching methods for medical or nursing students and attempt to find the most effective teaching method., Ethics and Dissemination: Ethics approval and patient consent are not required, because this study is a meta-analysis based on published studies., Inplasy Registration Number: INPLASY202070017.

Acute kidney injury (AKI), characterized by a rapid decline in renal function, is triggered by an acute inflammatory response that leads to kidney damage. An effective treatment for AKI is lacking. Using in vitro and in vivo AKI models, our laboratory has identified a series of anti-inflammatory molecules and their derivatives. In the current study, we identified the protective role of rutaecarpine (Ru) on renal tubules. We obtained a series of 3-aromatic sulphonamide-substituted Ru derivatives exhibiting enhanced renoprotective and anti-inflammatory function. We identified Compound-6c(Cpd-6c) as having the best activity and examined its protective effect against cisplatin nephropathy both in vivo and in vitro in cisplatin-stimulated tubular epithelial cells (TECs). Our results showed that Cpd-6c restored renal function more effectively than Ru, as evidenced by reduced blood urea nitrogen and serum creatinine levels in mice. Cpd-6c alleviated tubular injury, as shown by PAS staining and molecular analysis of kidney injury molecule-1 (KIM-1), with both prevention and treatment protocols in cisplatin-treated mice. Moreover, Cpd-6c decreased kidney inflammation, oxidative stress and programmed cell death. These results have also been confirmed in cisplatin-treated TECs. Using web-prediction algorithms, molecular docking, and cellular thermal shift assay (CETSA), we identified phosphodiesterase 4B (PDE4B) as a Cpd-6c target. In addition, we firstly found that PDE4B was up-regulated significantly in the serum of AKI patients. After identifying the function of PDE4B in cisplatin-treated tubular epithelial cells by siRNA transfection or PDE4 inhibitor rolipram, we showed that Cpd-6c treatment did not protect against cisplatin-induced injury in PDE4B knockdown TECs, thus indicating that Cpd-6c exerts its renoprotective and anti-oxidative effects via the PDE4B-dependent pathway. Collectively, Cpd-6c might serve as a potential therapeutic agent for AKI and PDE4B may be highly involved in the initiation and progression of AKI., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The U.S. Food and Drug Administration (FDA), Office of Regulatory Affairs (ORA) oversees FDA field laboratories, monitoring the occurrence and levels of toxic mycotoxins in domestic and imported human and animal food products that have the potential to impact human and animal health when consumed. The mycotoxins being routinely monitored in human and animal foods and feeds by the Agency include aflatoxins (B1, B2, G1, G2, and M1), fumonisins (FB1, FB2, and FB3), deoxynivalenol, ochratoxin A, patulin, and zearalenone. There has been an ongoing expansion of the Sample Collection Operation Planning Effort (SCOPE) for the mycotoxin program to monitor more mycotoxins in a wider variety of food and feed matrices. To meet this pressing need, we are in the process of modernizing and harmonizing the FDA/ORA mycotoxin program in the field laboratories using approaches such as adopting new analytical technologies/methods to further advance the service. This short perspective gives an overview of the FDA mycotoxin program in the field laboratories and the current program status, discusses the need to advance the program, strategies for modernization and harmonization by implementing liquid chromatography-mass spectrometry technologies for multi-mycotoxin analysis, benefits of doing this, and challenges in taking this new approach. Perspectives on finding solutions to tackle challenges and addressing emerging issues are also discussed., (AOAC INTERNATIONAL 2020. This work is written by US Government employees and is in the public domain in the US.)

Background: Pressure ulcers (PU) bring a considerable physical and mental burden on patients and their families, and have put families and government under tremendous pressure to cover the cost for treatment. Therefore, this protocol proposes to evaluate the quality of existing PU clinical practice guidelines (CPGs) and compare the similarities and differences between its recommendations in order to improve the treatment efficacy and reduce the PU treatment cost., Methods: Electronic databases and specific databases of CPGs will be searched. Study selection and data collection will be performed independently by two reviewers. The Appraisal of Guidelines for Research & Evaluation II (AGREE II) Instrument and Reporting Items for Practice Guidelines in Healthcare (RIGHT) will be used to assess the methodological quality and reporting quality of included CPGs. Bubble plot will be used to describe the difference of the quality, and mind mapping will be plotted to illustrate the comparison of recommendations of a guideline when needed. R software, MindMaster and Excel will be used., Results: The results of this study will be submitted to a peer-reviewed journal for publication., Conclusion: This systematic review will provide comprehensive evidence of CPGs of PU., Prospero Registration Number: CRD42020149176.

The incidence and severity of acute kidney injury (AKI) is increased yearly in diabetic patients. Although the mechanisms for this remain unclear, the prevention of AKI in diabetic nephropathy is feasible and of value. As we detected highly activation of TGF-β/Smad3 signaling in both human biopsy and mouse model of diabetic nephropathy, we hypothesized that Smad3 activation in diabetic kidneys may increase AKI sensitivity. We tested our hypothesis in vitro using TGF-β type II receptor (TGF-βRII) disrupted tubular epithelial cells (TECs) and in vivo in mice with streptozotocin (STZ)-induced diabetic nephropathy before the induction of ischemia/reperfusion (I/R) injury. We found that high glucose (HG)-cultured TECs showed increased inflammation, apoptosis and oxidative stress following hypoxia/reoxygenation (H/R) injury. Disruption of TGF-βRII attenuated cell injury induced by H/R in HG-treated TECs. Consistently, Smad3 knockdown in diabetic kidney attenuated I/R-induced AKI. Mechanistically, Smad3 binds to p53 and enhances p53 activity in cells treated with HG and H/R, which may lead to TECs apoptosis. Additionally, ChIP assay showed that Smad3 bound with the promoter region of NOX4 and induced ROS production and inflammation. In conclusion, our results demonstrate that Smad3 promotes AKI susceptibility in diabetic mice by interacting with p53 and NOX4., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Mitogenomes are useful in analyzing phylogenetic relationships and also appear to influence energy metabolism, thermoregulation and osmoregulation. Much evidence has accumulated for positive selection acting on mitochondrial genes associated with environmental adaptation. Hence, the mitogenome is a likely target for environmental selection. The family Bufonidae (true toads) has only nine complete and four partial mitogenomes published compared to the 610 known species of this family. More mitogenomes are needed in order to obtain a clearer understanding of the phylogenetic relationships within Bufonidae that are currently controversial. To date, no mitogenomes have been reported from the genera Anaxyrus and Bufotes . Anaxyrus americanus can live in low temperature environments and Bufotes pewzowi can live in high salinity environments. We sequenced the mitogenomes of these two species to discuss the phylogenetic relationships within Bufonidae and the selection pressures experienced by specimens living in low temperature or saline environments. Like other toads, the circular mitogenomes of both species contained the typical 37 genes. Anaxyrus americanus had the highest A+T content of the complete mitogenome among the Bufonidae. In addition, A. americanus showed a negative AT-skew in the control region, whereas Bufotes pewzowi showed a positive AT-skew. Additionally, both toad species had unique molecular features in common: an ND1 gene that uses TTG as the start codon, an extra unpaired adenine (A) in the anticodon arm of trnS (AGY), and the loss of the DHU loop in trnC . The monophyly of Bufonidae was corroborated by both BI and ML trees. An analysis of selective pressure based on the 13 protein coding genes was conducted using the EasyCodeML program. In the branch model analysis, we found two branches of A. americanus and Bufotes pewzowi that were under negative selection. Additionally, we found two positively selected sites (at positions 115 and 119, BEB value > 0.90) in the ND6 protein in the site model analysis. The residue D (119) was located only in A. americanus and may be related to adaptive evolution in low temperature environments. However, there was no evidence of a positively selected site in Bufotes pewzowi in this study., Competing Interests: Jia-Yong Zhang is an Academic Editor for PeerJ. Kenneth B. Storey is an Academic Editor for PeerJ., (©2020 Cai et al.)

The motor and nonmotor symptoms of PD involve several brain regions. However, whether α -syn pathology originating from the SNc can directly lead to the pathological changes in distant cerebral regions and induce PD-related symptoms remains unclear. Here, AAV9-synapsin-mCherry-human SNCA (A53T) was injected into the unilateral SNc of mice. Motor function and olfactory sensitivity were evaluated. Our results showed that AAV9-synapsin-mCherry-human SNCA was continuously expressed in SNc. The animals showed mild motor and olfactory dysfunction at 7 months after viral injection. The pathology in SNc was characterized by the loss of dopaminergic neurons accompanied by ER stress. In the striatum, h α -syn expression was high, CaMK β -2 and NR2B expression decreased, and active synapses reduced. In the olfactory bulb, h α -syn expression was high, and aging cells in the mitral layer increased. The results suggested that h α -syn was transported in the striatum and OB along the nerve fibers that originated from the SNc and induced pathological changes in the distant cerebral regions, which contributed to the motor and nonmotor symptoms of PD., 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 Qing-Jun Wang et al.)

Background: As a significantly important part of clinical practice, the professional nursing process can be advanced in many ways. Despite the fact that case reports are regarded to be of a lower quality grade in the hierarchy of evidence, one of the principles of evidence-based medicine is that decision-making should be based on a systematic summary of evidence. However, the evidence on the reporting characteristics of case reports in the nursing field is deficient., Aim: To use the CARE guidelines to assess reporting quality and factors influencing the quality of case reports in the nursing field., Methods: Nursing science citation indexed (SCI-indexed) journals were identified from the professional website. Each of the identified journals was searched on their website for articles published before December 2017. Twenty-one sub-items on the CARE checklist were recorded as "YES", "PARTLY", or "NO" according to information reported by the included studies. The responses were assigned corresponding scores of 1, 0.5, and 0, respectively. The overall score was the sum of the 21 sub-items and was defined as "high" (more than 15), "medium" (10.5 to 14.5), and "low" (less than 10). The means, standard deviations, odds ratios (OR), and the associated 95% confidence interval (CI) were determined using Stata 12.0 software., Results: Ultimately, 184 case reports from 16 SCI-indexed journals were identified, with overall scores ranging from 6.5 to 18 (mean = 13.6 ± 2.3). Of the included case reports, 10.3% were regarded low-quality, 52.7% were considered middle-quality, and 37% were regarded high-quality. There were statistical differences in the mean overall scores of the included case reports with funding versus those without funding (14.2 ± 1.7 vs 13.6 ± 2.4, respectively; P = 0.4456) and journal impact factor < 1.8 versus impact factor ≥ 1.8 (13.3 ± 2.3 vs 13.6 ± 2.4, respectively; P = 0.4977). Five items from the CARE guidelines, 5a (Patient), 6 (Clinical findings), 8c (Diagnostic reasoning), 9 (Therapeutic intervention), and 11d (The main take-away lessons) were well-reported (Reporting rate more than 90%) in most of the included case reports. However, only three items, 2 (Keywords, OR = 0.42, 95%CI: 0.19-0.92, P = 0.03), 4 (Introduction, OR = 0.35, 95%CI: 0.15-0.83, P = 0.017), and 11b (The relevant medical literature, OR = 0.19, 95%CI: 0.06-0.56, P = 0.003) were considered better-reported after the CARE guidelines published in 2013., Conclusion: The reporting quality of case reports in the nursing field apparently has not improved since the publication of the CARE guidelines., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

To systematically review clinical practice guidelines (CPGs) on diabetes foot and assess the consistency of recommendations, quality of CPGs and to present an evidence-map for explicating research trends and gaps. We performed a literature search on PubMed, Embase, and Web of Science, guideline databases and websites of diabetes society to include the diabetic CPGs. The basic information, recommendations for the diabetic foot, methodological quality and reporting quality of diabetic CPGs were exacted by the Excel. Four researchers evaluated the methodological and reporting quality of diabetic foot CPGs by AGREE II instrument and RIGHT checklist. R3.5.1 software was used to create all bubble plots. A total of 22 diabetic CPGs were included, eight CPGs were from different professional diabetes societies. Recommendations on diabetic foot complications involve Diabetic foot ulcer (DFU), Charcot neuropathy (CN) and Osteomyelitis (OM). Eight DFU diagnostic systems presented in 22 CPGs. According to the recommendations of diabetic CPGs, the treatment of DFU can be summarized in four major items; six recommendations on CN diagnosis and six recommendations on treatment of CN were consistent among studies. However, there were inconsistencies in three OM diagnosis recommendations and four OM treatment recommendations. Some recommendations in CPGs were not very specific and clear, and hence they were not reliable for OM diagnosis and treatment. Once these inconsistencies are resolved, validated, accurate and effective diagnosis and treatment of diabetes foot will lead to reduced costs and adverse complications. The results of this review add to our knowledge and promote the development of trustworthy CPGs on diabetes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Induced pluripotent stem cells (iPSCs) show huge variations in their differentiation potential, even in the same condition. However, methods for predicting these differentiation tendencies, especially in the early stage of differentiation, are still scarce. This study aimed to establish a simple and practical system to predict the differentiation tendency of iPSC lines using embryoid bodies (EBs) with identified parameters in the early stage. We compared four human iPSC lines in terms of the morphology and maintenance of EBs and their gene expression levels of specific markers for three germ-layers. Furthermore, the differentiation potentials of these iPSC lines into melanocytes, which are ectoderm-derived cells, were also compared and correlated with the above parameters. The results showed that iPSC lines forming regular, smooth, and not cystic EBs, which could be maintained in culture for a relatively longer time, also expressed higher levels of ectoderm-specific markers and lower levels of mesoderm/endoderm markers. Additionally, these iPSC lines showed greater potential in melanocyte differentiation using EB-based protocol, and the induced melanocytes expressed melanocytic markers and presented characteristics that were similar to those of normal human melanocytes. By contrast, iPSC lines that formed cystic EBs with bright or dark cavities and expressed relatively lower levels of ectoderm-specific markers failed in the melanocyte differentiation. Collectively, the differentiation tendency of human iPSC lines may be predicted by specific parameters in the EB stage. The formation and maintenance of optimal EBs and the expression of germ layer-specific markers are particularly important and practical for the prediction assay in the early stage., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) is a destructive clinical condition induced by multiple insults including ischemic reperfusion, nephrotoxic drugs and sepsis. It is characterized by a sudden decline in renal function, in addition to excessive inflammation, oxidative stress and programmed cell death of renal tubular epithelial cells. RIPK1-mediated necroptosis plays an important role in AKI. In the present study, we evaluated the treatment effects of Compound-71 (Cpd-71), a novel RIPK1 inhibitor, by comparing with Necrostatin-1 (Nec-1), a classic RIPK1 inhibitor, which has several drawbacks like the narrow structure-activity relationship (SAR) profile, moderate potency and non-ideal pharmacokinetic properties, in vivo and in vitro Our results showed that pretreatment of Cpd-71 attenuated cisplatin-induced renal injury, restored renal function and suppressed renal inflammation, oxidative stress and cell necroptosis. In addition, Cpd-71 inhibited renal damage while reducing the up-regulated serum creatinine (Cr) and blood urea nitrogen (BUN) levels in established AKI mice model. Consistently, we confirmed that Cpd-71 exhibited more effectively suppressive effect on cisplatin-induced renal tubular cell necroptosis than Nec-1, by physically binding to the allosteric type III ligand binding site of RIPK1, thereby reduced RIPK1 kinase activity, RIPK1/RIPK3 complex formation and phosphor-MLKL membrane translocation by molecular docking, Western blot, co-immunoprecipitation and cellular thermal shift assay (CETSA). Taken together, we currently showed that targeting RIPK1 with Cpd-71 may serve as a promising clinical candidate for AKI treatment., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

The present study was designed to investigate the therapeutic effect of bone marrow MSC-derived factors on gonadotropic toxicity induced by busulfan in vivo. The conditioned media (CM) was obtained from MSCs in serum-free incubation for 48 hr and concentrated ~25-fold by ultrafiltration. The CM of HEK 293 cells was treated as control (293-CM). MSC-CM was injected into busulfan mice via caudal veins after 1 day of busulfan treatment for 2 weeks (200 μl per dose/twice weekly）. Compared to the 293-CM group, testicular injury was delayed in MSC-CM group, including reduced vacuolations of cells in the basal compartment of the seminiferous epithelium and detachment of cells from basement membrane. Apoptotic spermatogenic cells were significantly decreased in MSC-CM group (p ＜ 0.05). Interesting N-cadherin，ICAM-1 and P-cadherin expressions significantly increased in MSC-CM group, while occludin, ZO-1 and connexin 43 expressions showed no difference among MSC-CM, 293-CM and busulfan groups. Present results suggest MSC-secreted factors protect spermatogenesis impairment after busulfan treatment by reducing the apoptosis of spermatogenic cells and enhancing intercellular adhesion molecule expressions., (© 2019 Blackwell Verlag GmbH.)

Background: Recent studies have revealed that vitamin D deficiency may increase the risk of Alzheimer's disease, and vitamin D supplementation may be effective strategy to ameliorate the neurodegenerative process in Alzheimer's disease patients. Paricalcitol (PAL), a low-calcemic vitamin D receptor agonist, is clinically used to treat secondary hyperparathyroidism. However, the potential application of PAL for treating neurodegenerative disorders remains unexplored., Methods: The APP/PS1 mice were intraperitoneally injected with PAL or vehicle every other day for 15 weeks. The β-amyloid (Aβ) production was confirmed using immunostaining and enzyme linked immunosorbent assay. The underlying mechanism was verified by western blot and immunostaining in vivo and in vitro., Findings: Long-term PAL treatment clearly reduced β-amyloid (Aβ) generation and neuronal loss in APP/PS1 transgenic mouse brains. PAL stimulated the expression of low-density lipoprotein receptor-related protein 1 (LRP1) possibly through inhibiting sterol regulatory element binding protein-2 (SREBP2); PAL also promoted LRP1-mediated β-site APP cleavage enzyme 1 (BACE1) transport to late endosomes, thus increasing the lysosomal degradation of BACE1. Furthermore, PAL diminished 8-hydroxyguanosine (8-OHdG) generation in neuronal mitochondria via enhancing base excision repair (BER), resulting in the attenuation of calpain-1-mediated neuronal loss., Interpretation: The present data demonstrate that PAL can reduce Aβ generation through accelerating BACE1 lysosomal degradation and can inhibit neuronal loss through suppressing mitochondrial 8-OHdG generation. Hence, PAL might be a promising agent for treating Alzheimer's disease. FUND: This study was financially supported by the Natural Science Foundation of China (U1608282)., (Copyright © 2019. Published by Elsevier B.V.)

Brown adipose tissue (BAT) is an exclusive tissue of nonshivering thermogenesis. It is fueled by lipids and glucose and involved in energy and metabolic homeostasis. Intrauterine exposure to hyperglycemia during gestational diabetes mellitus may result in abnormal fetal development and metabolic phenotypes in adulthood. However, whether intrauterine hyperglycemia influences the development of BAT is unknown. In this study, mouse embryos were exposed to the intrauterine hyperglycemia environment by injecting streptozocin into pregnant mice at 1 d post coitum (dpc). The structure of BAT was examined by hematoxylin and eosin staining and immunohistochemical analysis. The glucose uptake in BAT was measured in vivo by [ 18 F]-fluoro-2-deoxyglucose-micro-positron emission tomography. The gene expression in BAT was determined by real-time PCR, and the 5'-C-phosphate-G-3' site-specific methylation was quantitatively analyzed. Intrauterine hyperglycemia exposure resulted in the impaired structure of BAT and decreased glucose uptake function in BAT in adulthood. The expressions of the genes involved in thermogenesis and mitochondrial respiratory chain in BAT, such as Ucp1, Cox5b, and Elovl3, were down-regulated by intrauterine hyperglycemia exposure at 18.5 dpc and at 16 wk of age. Furthermore, higher methylation levels of Ucp1, Cox5b, and Elovl3 were found in offspring of mothers with streptozotocin-induced diabetes. Our results provide the evidence for enduring inhibitory effects of intrauterine hyperglycemia on BAT development in offspring. Intrauterine hyperglycemia is associated with increased DNA methylation of the BAT specific genes in offspring, which support an epigenetic involvement.-Yu, D.-Q., Lv, P.-P., Yan, Y.-S., Xu, G.-X., Sadhukhan, A., Dong, S., Shen, Y., Ren, J., Zhang, X.-Y., Feng, C., Huang, Y.-T., Tian, S., Zhou, Y., Cai, Y.-T., Ming, Z.-H., Ding, G.-L., Zhu, H., Sheng, J.-Z., Jin, M., Huang, H.-F. Intrauterine exposure to hyperglycemia retards the development of brown adipose tissue.

Background: Magnesium (Mg)-deficiency is one of the most prevalent physiological disorders causing a reduction in Citrus yield and quality. 'Xuegan' (Citrus sinensis) seedlings were irrigated for 16 weeks with nutrient solution containing 2 mM (Mg-sufficiency) or 0 mM (Mg-deficiency) Mg(NO 3 ) 2 . Thereafter, we investigated the Mg-deficient effects on gas exchange and chlorophyll a fluorescence in the upper and lower leaves, and Mg, reactive oxygen species (ROS) and methylglyoxal (MG) metabolisms in the roots, lower and upper leaves. The specific objectives were to corroborate the hypothesis that the responses of ROS and MG metabolisms to Mg-deficiency were greater in the lower leaves than those in the upper leaves, and different between the leaves and roots., Results: Mg level was higher in the Mg-deficient upper leaves than that in the Mg-deficient lower leaves. This might be responsible for the Mg-deficiency-induced larger alterations of all the measured parameters in the lower leaves than those in the upper leaves, but they showed similar change patterns between the Mg-deficient lower and upper leaves. Accordingly, Mg-deficiency increased greatly their differences between the lower and upper leaves. Most of parameters involved in ROS and MG metabolisms had similar variation trends and degrees between the Mg-deficient lower leaves and roots, but several parameters (namely glutathione S-transferase, sulfite reductase, ascorbate and dehydroascorbate) displayed the opposite variation trends. Obviously, differences existed in the Mg-deficiency-induced alterations of ROS and MG metabolisms between the lower leaves and roots. Although the activities of most antioxidant and sulfur metabolism-related enzymes and glyoxalase I and the level of reduced glutathione in the Mg-deficient leaves and roots and the level of ascorbate in the leaves were kept in higher levels, the levels of malonaldehyde and MG and/or electrolyte leakage were increased in the Mg-deficient lower and upper leaves and roots, especially in the Mg-deficient lower leaves and roots., Conclusions: The ROS and MG detoxification systems as a whole did not provide sufficient detoxification capacity to prevent the Mg-deficiency-induced production and accumulation of ROS and MG, thus leading to lipid peroxidation and the loss of plasma membrane integrity, especially in the lower leaves and roots.

Citrus are mainly grown in low pH soils with high active aluminum (Al). 'Xuegan' (Citrus sinensis (L.) Osbeck) and 'Shatian pummelo' (Citrus grandis (L.) Osbeck) seedlings were fertilized for 18 weeks with nutrient solution containing either 0 mM (control) or 1 mM (Al toxicity) AlCl3·6H2O. Aluminum induced decreases of biomass, leaf photosynthesis, relative water content and total soluble protein levels, and increases of methylglyoxal levels only occurred in C. grandis roots and leaves. Besides, the Al-induced decreases of pigments and alterations of chlorophyll a fluorescence transients and fluorescence parameters were greater in C. grandis leaves than those in C. sinensis leaves. Aluminum-treated C. grandis had higher stem and leaf Al levels and similar root Al levels relative to Al-treated C. sinensis, but lower Al distribution in roots and Al uptake per plant. Aluminum toxicity decreased nitrogen, phosphorus, potassium, calcium, magnesium and sulfur uptake per plant in C. grandis and C. sinensis seedlings, with the exception of Al-treated C. sinensis seedlings exhibiting increased sulfur uptake per plant and unaltered magnesium uptake per plant. Under Al-stress, macroelement uptake per plant was higher in C. sinensis than that in C. grandis. Aluminum toxicity decreased the ratios of reduced glutathione/(reduced + oxidized glutathione) and of ascorbate/(ascorbate + dehydroascorbate) only in C. grandis roots and leaves. The activities of most antioxidant enzymes, sulfur metabolism-related enzymes and glyoxalases and the levels of S-containing compounds were higher in Al-treated C. sinensis roots and leaves than those in Al-treated C. grandis ones. Thus, C. sinensis displayed higher Al tolerance than C. grandis did. The higher Al tolerance of C. sinensis might involve: (i) more Al accumulation in roots and less transport of Al from roots to shoots; (ii) efficient maintenance of nutrient homeostasis; and (iii) efficient maintenance of redox homeostasis via detoxification systems of reactive oxygen species and methylglyoxal.

The mitochondrial genome of Fejervarya kawamurai is a circular molecule of 17,650 bp in length, containing 13 protein-coding genes, two rRNA genes, 23 tRNA genes (including an extra tRNA-Met), and the control region. The AT content of the whole genome is 56.9%. In Bayesian inference (BI) and Maximum likelihood (ML) analyses, we found that F. kawamurai is a sister clade to F. multistriata and F. limnocharis . The monophyly of Fejervarya , Quasipaa , Nanorana was well supported (1.00 in BI and 100% in ML)., Competing Interests: The authors declare no conflict of interest., (© 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

The complete mitochondrial genome sequence of the hybrid of Hoplobatrachus chinensis (♀) ×  H. rugulosus (♂) was obtained in this study. The circular mitochondrial genome was 20,282 bp in length (including extra ND5 genes). Compared with the complete mitogenome of the parents, the results indicated that the mitochondria of the hybrid tiger frog was consistent with a maternal inheritance. Phylogenetic analyses using concatenated nucleotide sequences of the 11 protein-coding genes with two different methods (maximum likelihood and MrBayes analysis) both highly supported a close relationship of the hybrid frogs with the Chinese tiger frog (= H. chinensis )., Competing Interests: The authors declare no conflict of interest., (© 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Objectives: The aim of this study was to perform an updated systematic review and meta-analysis to assess the clinical efficacy, safety, and cost-effectiveness of negative-pressure wound therapy (NPWT) in the treatment of diabetic foot ulcers (DFUs)., Methods: We searched the Cochrane Library, MEDLINE, EMBASE, Ovid, and Chinese Biological Medicine databases up to June 30, 2016. We also manually searched the articles from reference lists of the retrieved articles, which used the NPWT system in studies of vacuum-assisted closure therapy. Studies were identified and selected, and two independent reviewers extracted data from the studies., Results: A total of eleven randomized controlled trials, which included a total of 1,044 patients, were selected from 691 identified studies. Compared with standard dressing changes, NPWT had a higher rate of complete healing of ulcers (relative risk, 1.48; 95% confidence interval [CI]: 1.24-1.76; P <0.001), shorter healing time (mean difference, -8.07; 95% CI: -13.70- -2.45; P =0.005), greater reduction in ulcer area (mean difference, 12.18; 95% CI: 8.50-15.86; P <0.00001), greater reduction in ulcer depth (mean difference, 40.82; 95% CI: 35.97-45.67; P <0.00001), fewer amputations (relative risk, 0.31; 95% CI: 0.15-0.62; P =0.001), and no effect on the incidence of treatment-related adverse effects (relative risk, 1.12; 95% CI: 0.66-1.89; P =0.68). Meanwhile, many analyses showed that the NPWT was more cost-effective than standard dressing changes., Conclusion: These results indicate that NPWT is efficacious, safe, and cost-effective in treating DFUs., Competing Interests: Disclosure The authors report no conflicts of interest in this work.