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ABSTRACT The oomycete Pythium oligandrum is a potential biocontrol agent to control a wide range of fungal and oomycete-caused diseases, such as Pythium myriotylum-caused rhizome rot in ginger, leading to reduced yields and compromised quality. Previously, P. oligandrum has been studied for its plant growth-promoting potential by auxin production and induction of disease resistance by elicitors such as oligandrin. Volatile organic compounds (VOCs) play beneficial roles in sustainable agriculture by enhancing plant growth and resistance. We investigated the contribution of P. oligandrum-produced VOCs on plant growth and disease suppression by initially using Nicotiana benthamiana plants for screening. P. oligandrum VOCs significantly enhanced tobacco seedling and plant biomass contents. Screening of the individual VOCs showed that 3-octanone and hexadecane promoted the growth of tobacco seedlings. The total VOCs from P. oligandrum also enhanced the shoot and root growth of ginger plants. Transcriptomic analysis showed a higher expression of genes related to plant growth hormones and stress responses in the leaves of ginger plants exposed to P. oligandrum VOCs. The concentrations of plant growth hormones such as auxin, zeatin, and gibberellic acid were higher in the leaves of ginger plants exposed to P. oligandrum VOCs. In a ginger disease biocontrol assay, the VOC-exposed ginger plants infected with P. myriotylum had lower levels of disease severity. We conclude that this study contributes to understanding the growth-promoting mechanisms of P. oligandrum on ginger and tobacco, priming of ginger plants against various stresses, and the mechanisms of action of P. oligandrum as a biocontrol agent. IMPORTANCE Plant growth promotion plays a vital role in enhancing production of agricultural crops, and Pythium oligandrum is known for its plant growth-promoting potential through production of auxins and induction of resistance by elicitors. This study highlights the significance of P. oligandrum-produced VOCs in plant growth promotion and disease resistance. Transcriptomic analyses of leaves of ginger plants exposed to P. oligandrum VOCs revealed the upregulation of genes involved in plant growth hormone signaling and stress responses. Moreover, the concentration of growth hormones significantly increased in P. oligandrum VOC-exposed ginger plants. Additionally, the disease severity was reduced in P. myriotylum-infected ginger plants exposed to P. oligandrum VOCs. In ginger, P. myriotylum-caused rhizome rot disease results in severe losses, and biocontrol has a role as part of an integrated pest management strategy for rhizome rot disease. Overall, growth enhancement and disease reduction in plants exposed to P. oligandrum-produced VOCs contribute to its role as a biocontrol agent.

Most internal organs in humans and other vertebrates exhibit striking left-right asymmetry in position and structure. Variation of normal organ positioning results in left-right asymmetry disorders and presents as internal organ reversal or randomization. Up to date, at least 82 genes have been identified as the causative genetic factors of left-right asymmetry disorders. This study sought to discover potential pathogenic variants responsible for left-right asymmetry disorder present in a Han-Chinese family using whole exome sequencing combined with Sanger sequencing. Novel compound heterozygous variants, c.5690A>G (p.Asn1897Ser) and c.7759G>A (p.Val2587Met), in the dynein axonemal heavy chain 1 gene (DNAH1), were found in the proband and absent in unaffected family members. Conservation analysis has shown that the variants affect evolutionarily conserved residues, which may impact the tertiary structure of the DNAH1 protein. The novel compound heterozygous variants may potentially bear responsibility for left-right asymmetry disorder, which results from a perturbation of left-right axis coordination at the earliest embryonic development stages. This study broadens the variant spectrum of left-right asymmetry disorders and may be helpful for genetic counseling and healthcare management for the diagnosed individual, and promotes a greater understanding of the pathophysiology.

BackgroundThe causal relationship between hypertension, antihypertensive drugs and the risk of erectile dysfunction is still uncertain. We performed a univariable and multivariable Mendelian randomization study to investigate whether they are causally related to erectile dysfunction.MethodsGenetic variants associated with blood pressure were derived from the genome-wide association study meta-analysis of the UK Biobank and International Consortium of Blood Pressure (N = 757,601). Summary association data for hypertension were obtained from the UK Biobank (N = 463,010) and the FinnGen study (N = 356,077). The summary statistics of erectile dysfunction were obtained from the European ancestry with 223,805 subjects. The SNP instruments used to assess the effect of the protein targets of antihypertensive drugs on erectile dysfunction were obtained from previous studys. Causal effects were estimated using the univariate Mendelian randomization method (inverse variance weighted, MR-Egger, weighted median, MR-PRESSO and Wald ratios) and the multivariate Mendelian randomization method. Sensitivity analyses were implemented with the Cochran's Q-test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis.ResultsUnivariate MR found that elevated diastolic blood pressure may increase the occurrence of erectile dysfunction (odds ratio [OR] = 1.012; 95% confidence interval [CI]: 1.000–1.024; P = 0.047). Genetically predicted hypertension is also associated with ED (For the FinnGen, OR = 1.106; 95% CI: 1.027–1.191; P = 0.008. For the UK Biobank, OR = 3.832; 95% CI: 1.410–10.414; P = 0.008). However, after adjusting for systolic blood pressure, diastolic blood pressure and hypertension using multivariate Mendelian randomization, only hypertension was causally associated with ED occurrence (For the FinnGen, OR = 1.103; 95% CI: 1.018–1.195; P = 0.017. For the UK Biobank, OR = 5.037; 95% CI: 1.601–15.846; P = 0.006). We found no evidence that the use of angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and thiazide diuretic increased the risk of erectile dysfunction.ConclusionsGenetically predicted hypertension increases the risk of erectile dysfunction, but we found no causal relationship between elevated systolic/diastolic blood pressure and erectile dysfunction. We speculate that the relationship between elevated blood pressure and erectile dysfunction risk may be nonlinear. We found little evidence that antihypertensive drugs increase the risk of erectile dysfunction.

Objective: This meta-analysis aimed to determine the efficacy of curcumin in preventing myocardial ischemia/reperfusion (I/R) injury in animal models.Methods: Studies published from inception to January 2023 were systematically searched in databases including PubMed, Web of Science, Embase, China’s National Knowledge Infrastructure (CNKI), Wan-Fang database, and VIP database (VIP). The SYRCLE’s RoB tool was used to determine methodological quality. Sensitivity analysis and subgroup analysis were performed when there was high heterogeneity. Publication bias was assessed using a funnel plot.Results: Thirty-seven studies involving 771 animals were included in this meta-analysis with methodology quality scores ranging from 4 to 7. The results indicated that curcumin treatment significantly improved myocardial infarction size standard mean difference (SMD) = −5.65; 95% confidence interval (CI): 6.94, −4.36; p < 0.01; I2 = 90%). The sensitivity analysis for infarct size showed that the results were stable and reliable. However, the funnel plot was asymmetric. The subgroup analysis included species, animal model, dose, administration, and duration. The results showed that the subgroup dose was statistically significant between subgroups. In addition, curcumin treatment improved cardiac function, myocardial injury enzymes, and oxidative stress levels in animal models of myocardial I/R injury. The funnel plot revealed that there is publication bias for creatine kinase and lactate dehydrogenase. Finally, we performed a meta-analysis of inflammatory cytokines and apoptosis index. The results showed that curcumin treatment downregulated serum inflammatory cytokine levels and myocardial apoptosis index.Conclusion: This meta-analysis suggests that curcumin has excellent potential for the treatment of myocardial I/R injury in animal models. However, this conclusion needs to be further discussed and verified in large animal models and human clinical trials.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42022383901.

The regulation of plant biomass degradation by fungi is critical to the carbon cycle, and applications in bioproducts and biocontrol. Trichoderma harzianum is an important plant biomass degrader, enzyme producer, and biocontrol agent, but few putative major transcriptional regulators have been deleted in this species. The T. harzianum ortholog of the transcriptional activator XYR1/XlnR/XLR-1 was deleted, and the mutant strains were analyzed through growth profiling, enzymatic activities, and transcriptomics on cellulose. From plate cultures, the Δxyr1 mutant had reduced growth on D-xylose, xylan, and cellulose, and from shake-flask cultures with cellulose, the Δxyr1 mutant had ~90% lower β-glucosidase activity, and no detectable β-xylosidase or cellulase activity. The comparison of the transcriptomes from 18 h shake-flask cultures on D-fructose, without a carbon source, and cellulose, showed major effects of XYR1 deletion whereby the Δxyr1 mutant on cellulose was transcriptionally most similar to the cultures without a carbon source. The cellulose induced 43 plant biomass-degrading CAZymes including xylanases as well as cellulases, and most of these had massively lower expression in the Δxyr1 mutant. The expression of a subset of carbon catabolic enzymes, other transcription factors, and sugar transporters was also lower in the Δxyr1 mutant on cellulose. In summary, T. harzianum XYR1 is the master regulator of cellulases and xylanases, as well as regulating carbon catabolic enzymes.

Abstract Fusarium oxysporum (Fo) is an important species complex of soil-borne pathogenic fungi that cause vascular wilt diseases of agricultural crops and some opportunistic diseases of humans. The fungicide phenamacril has been extensively reported to have antifungal activity against Fusarium graminearum and Fusarium fujikuroi. In this study, we found that the amino acid substitutions (V151A and S418T) in Type I myosin FoMyo5 cause natural low resistance to phenamacril in the plant pathogenic Fo isolates. Therefore, we compared the transcriptomes of two phenamacril-resistant Fo isolates FoII5, Fo1st and one phenamacril-sensitive isolate Fo3_a after 1 μg/mL phenamacril treatment. Among the 2728 differentially expressed genes (DEGs), 14 DEGs involved in oxidation–reduction processes and MFS transporters, were significantly up-regulated in phenamacril-resistant isolates. On the other hand, 14 DEGs involved in ATP-dependent RNA helicase and ribosomal biogenesis related proteins, showed significantly down-regulated expression in both phenamacril-resistant and -sensitive isolates. These results indicated that phenamacril not only seriously affected the cytoskeletal protein binding and ATPase activity of sensitive isolate, but also suppressed ribosome biogenesis in all the isolates. Hence, this study helps us better understand resistance regulation mechanism and fungicidal activity of phenamacril and provide reference for the development of new fungicides to control Fo.

ObjectiveThis meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors in patients with glioma.MethodsPubMed, EMBASE, Web of Science, and the Cochrane library were searched from inception to January 2023 without language restriction. Primary outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). The risk of bias was assessed by subgroup analysis, sensitivity analysis, and publication bias, including funnel plot, Egger’s test, and Begg’s test.ResultsA total of 20 studies involving 2,321 patients were included in this meta-analysis. In the analysis of the included phase III clinical trials, the forest plot showed that PD-1/PD-L1 inhibitors did not improve the OS (HR=1.15, 95% CI: 1.03-1.29, P=0.02, I2 = 14%) and PFS (HR=1.43, 95% CI: 1.03-1.99, P=0.03, I2 = 87%). In the single-arm analysis, the forest plot demonstrated that the 6-month OS was 71% (95% CI: 57%-83%, I2 = 92%), 1-year OS was 43% (95% CI: 33%-54%, I2 = 93%), and the 2-year OS was 27% (95% CI: 13%-44%, I2 = 97%). The pooled estimate of the median OS was 8.85 months (95% CI: 7.33-10.36, I2 = 91%). Furthermore, the result indicated that the 6-month PFS was 28% (95% CI: 18%-40%, I2 = 95%), 1-year PFS was 15% (95% CI: 8%-23%, I2 = 92%), and the 18-month PFS was 10% (95% CI: 3%-20%, I2 = 93%). The pooled estimate of the median PFS was 3.72 months (95% CI: 2.44-5.00, I2 = 99%). For ORR, the pooled estimate of ORR was 10% (95% CI: 2%-20%, I2 = 88%). We further analyzed the incidence of PD-1/PD-L1 inhibitor-related AEs, and the pooled incidence of AEs was 70% (95% CI: 58%-81%, I2 = 94%). The incidence of AEs ≥ grade 3 was 19% (95% CI: 11%-30%, I2 = 94%). The funnel plot for the median PFS and median OS was symmetric with no significant differences in Egger’s test and Begg’s test. The sensitivity analysis revealed that our results were stable and reliable.ConclusionThe results of this meta-analysis suggest that anti-PD-1/PD-L1 therapy is relatively safe but could not prolong survival in glioma. More randomized controlled trials are needed to confirm our results.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42023396057.

BackgroundPenile cancer is a malignant tumor of the genitourinary system that mostly occurs in middle-aged and elderly men aged 50–70 years, which can seriously affect physical, psychological, and sexual health. Hundreds of original articles and reviews on penile cancer are published each year. However, a bibliometric analysis of these publications has not been performed.ObjectiveThis study aimed to systematically analyze and visualize penile cancer-related publications through bibliometrics and reveal identified topics, hotspots, and knowledge gaps in related fields.MethodsBased on the Web of Science core collection database, we first analyzed the quantity and quality of publications in the field of penile cancer. Second, we profiled the publishing groups in terms of country, institution, author’s publication, and cooperation network. Then, we systematized and summarized the hot topics of research.ResultsThis bibliometric analysis was conducted from 2001 to 2022. The analysis identified 1,687 articles and reviews, which were published in 432 journals. The number of publications and citations on penile cancer-related research has steadily increased over the last two decades. Furthermore, academic institutions in Europe and the United States play a leading role in penile cancer research. The country, institution, journal, and author with the most publications were the United States (507), H Lee Moffitt Cancer Research Center (96), Journal of Urology (83), and Spiess P (87), respectively. The most frequently used keywords were penile cancer (743), squamous-cell carcinoma (717), cancer (380), carcinoma (232), lymphadenectomy (229). 16 keyword clustering information was obtained, including #0 male circumcision, #1 lichen sclerosus, #2 chemotherapy, #3 penile neoplasms, #4 targeted therapy, #5 resection margin, #6 cervical cancer, #7 lymph node dissection, #8 prognostic factor, #9 prostate cancer, #10 inguinal lymph node dissection, #11 human papillomavirus DNA, #12 gene, #13 penile intraepithelial neoplasia, #14 male sexual function, and #15 penile cancer.ConclusionMore and more scholars are devoted to the research on penile cancer. This bibliometric analysis revealed that the main research topics and hotspots in penile cancer included risk factors and surgical treatment plans.

BackgroundOveractive bladder, a syndrome marked by an urgent need to urinate, is a globally prevalent ailment. Human health and quality of life are seriously affected. Therefore, it is essential to investigate the current progress and trends in this field.ObjectiveNo bibliometric analysis of overactive bladder has been conducted. Through the use of bibliometrics and visualization, this study intends to examine the current progress and development trend of this field.MethodsGlobal publications on overactive bladder between January 2004 and August 2022 were extracted from the Web of Science core collection database. A bibliometric and visual analysis was carried out using VOSviewer software and CiteSpace.ResultsOver the last 20 years, publications have grown rapidly, but after 2019, they started to fall. According to the collaboration network, the United States, Univ Pittsburgh AND NEUROUROLOGY AND URODYNAMICS are the most active countries, institutes AND journals in the field, respectively. All keywords were categorized by the symbiosis analysis into four categories: experimental study, symptoms, clinical use, and quality of life. The most prevalent keyword across all clusters is “overactive bladder.”ConclusionYear after year, there have been more publications in the field of overactive bladder research in many countries, and there has been a deeper level of cooperation and exchange. Researchers will still be interested in overactive bladder in the future. Currently, the clinical application of the disease and the safety and effectiveness of medications are being investigated. However, radical innovation in relevant experimental technologies is a significant obstacle in this field.

IntroductionDiabetic erectile dysfunction (DMED) refers to erectile dysfunction secondary to diabetes. Erectile dysfunction is characterized by a persistent inability to achieve and maintain an erection sufficient to permit satisfactory sexual activity.MethodsBased on the Web of Science core collection database, we firstly analyzed the quantity and quality of publications in the field of DMED, secondly profiled the publishing groups in terms of country, institution, author’s publication and cooperation network, and finally sorted out and summarized the hot topics of research.ResultsFrom 2001 to 2022, a total of 1,403 articles relating to this topic were published in 359 journals. They represent the global research status, potential hotspots, and future research directions. The number of DMED-related publications and citations has steadily increased over the few past decades. Academic institutions from Europe and the United States have played a leading role in DMED research. The country, institution, journal, and author with the most publications were the United States (294), INHA University (39), the Journal of Sexual Medicine (156), and Ryu, Ji-Kan (29), respectively. The most common keywords were erectile dysfunction (796), men (256), diabetes (254), diabetes mellitus (239), prevalence (180), corpus cavernosum (171), dysfunction (155), mellitus (154), nitric-oxide synthase (153), and expression (140). The main keyword-based research topics and hotspots in the DMED field were oral sildenafil, smooth muscle relaxation, nitric oxide synthase, gene therapy, metabolic syndrome, cavernous nerve injury, stem cell, and penile prosthesis.DiscussionThe terms oral sildenafil, smooth muscle relaxation, nitric oxide synthase, gene therapy, metabolic syndrome, cavernous nerve injury, stem cell, and penile prosthesis will be at the forefront of DMED-related research.

IntroductionAssisted reproductive technology (ART) is a method that uses various techniques to process sperm or ova. Assisted reproductive technology involves removing ova from a woman's ovaries, combining them with sperm in the laboratory, and returning them to the woman's body or donating them to another woman.MethodsBased on the web of science core collection database, we firstly analyzed the quantity and quality of publications in the field of ART, secondly profiled the publishing groups in terms of country, institution, author's publication and cooperation network, and finally sorted out and summarized the hot topics of research.ResultsIn total, 6,288 articles on ART were published between 2001 and 2022 in 1,013 journals. Most of these published articles represent the global research status, potential hotspots and future research directions. Publications and citations of research on assisted reproductive technology have steadily increased over the past few decades. Academic institutions in Europe and the United States have been leading in assisted reproductive technology research. The countries, institutions, journals, and authors with the most published articles were the United States (1864), Harvard Univ (108), Fertility and Sterility (819), and Stern, Judy E. (64). The most commonly used keywords are Assisted reproductive technology (3303) and in-vitro Fertilization (2139), Ivf (1140), Pregnancy (1140), Women (769), Intracytoplasmic Sperm injection (644), In Fertilization (632), Risk (545), and Outcome (423).ConclusionFrozen embryo transfer, intracytoplasmic sperm injection, and in vitro fertilization are the main research topics and hotspots in the field of assisted reproductive technology.

BackgroundBladder cancer is one of the most common urological cancers. Non-muscle invasive bladder cancer (NMIBC) accounts for about 75-85% of all newly diagnosed bladder cancers. Globally, there are many NMIBC-related publications. However, a bibliometric analysis of these publications has not been performed.ObjectiveThis study aims to systematically analyze and visualize NMIBC-related publications through bibliometrics, and to reveal identified topics, hotspots, and knowledge gaps in related fields.MethodsBased on the Web of Science core collection database, we firstly analyzed the quantity and quality of publications in the field of NMIBC, secondly profiled the publishing groups in terms of country, institution, author’s publication and cooperation network, and finally sorted out and summarized the hot topics of research.ResultsThis bibliometric analysis was conducted from 2001 to 2022. The analysis identified 2,185 articles and reviews, which were published in 402 journals. The number of publications and citations on NMIBC-related research has steadily increased over the last two decades. Furthermore, academic institutions in Europe and the United States play a leading role in NMIBC research. The country, institution, journal, and author with the most publications were the United States (559), Radboud University Nijmegen (88), Urologic oncology: Seminars and Original Investigations (141), and Witjes J (74), respectively. The most frequently used keywords were Bladder cancer (793), Recurrence (671), Urothelial carcinoma (593), Progression (523), Bacillus-calmette-guerin (411), Transitional-cell carcinoma (401), Carcinoma (366), Risk (297), Transurethral resection (286), and Non-muscle-invasive bladder cancer (280).ConclusionMore and more scholars are devoted to the research of related NMIBC. This bibliometric analysis revealed that the main research topics and hotspots in NMIBC included pathological staging, clinical diagnosis and treatment, and bladder perfusion.

ABSTRACT The Pythium (Peronosporales, Oomycota) genus includes devastating plant pathogens that cause widespread diseases and severe crop losses. Here, we have uncovered a far greater arsenal of virulence factor-related genes in the necrotrophic Pythium myriotylum than in other Pythium plant pathogens. The genome of a plant-virulent P. myriotylum strain (~70 Mb and 19,878 genes) isolated from a diseased rhizome of ginger (Zingiber officinale) encodes the largest repertoire of putative effectors, proteases, and plant cell wall-degrading enzymes (PCWDEs) among the studied species. P. myriotylum has twice as many predicted secreted proteins than any other Pythium plant pathogen. Arrays of tandem duplications appear to be a key factor of the enrichment of the virulence factor-related genes in P. myriotylum. The transcriptomic analysis performed on two P. myriotylum isolates infecting ginger leaves showed that proteases were a major part of the upregulated genes along with PCWDEs, Nep1-like proteins (NLPs), and elicitin-like proteins. A subset of P. myriotylum NLPs were analyzed and found to have necrosis-inducing ability from agroinfiltration of tobacco (Nicotiana benthamiana) leaves. One of the heterologously produced infection-upregulated putative cutinases found in a tandem array showed esterase activity with preferences for longer-chain-length substrates and neutral to alkaline pH levels. Our results allow the development of science-based targets for the management of P. myriotylum-caused disease, as insights from the genome and transcriptome show that gene expansion of virulence factor-related genes play a bigger role in the plant parasitism of Pythium spp. than previously thought. IMPORTANCE Pythium species are oomycetes, an evolutionarily distinct group of filamentous fungus-like stramenopiles. The Pythium genus includes several pathogens of important crop species, e.g., the spice ginger. Analysis of our genome from the plant pathogen Pythium myriotylum uncovered a far larger arsenal of virulence factor-related genes than found in other Pythium plant pathogens, and these genes contribute to the infection of the plant host. The increase in the number of virulence factor-related genes appears to have occurred through the mechanism of tandem gene duplication events. Genes from particular virulence factor-related categories that were increased in number and switched on during infection of ginger leaves had their activities tested. These genes have toxic activities toward plant cells or activities to hydrolyze polymeric components of the plant. The research suggests targets to better manage diseases caused by P. myriotylum and prompts renewed attention to the genomics of Pythium plant pathogens.

The formation of left–right asymmetry of the visceral organs is a conserved feature of the human body, and the asymmetry specification of structure and function is precisely orchestrated by multiple regulatory mechanisms. The abnormal results of organ positioning situs arise from defective cilia structure or function during embryogenesis in humans. In this study, we recruited two unrelated Han-Chinese families with left–right asymmetry disorders. The combination of whole-exome sequencing and Sanger sequencing identified two compound heterozygous variants: c.4109C>T and c.9776C>T, and c.612C>G and c.8764C>T in the dynein axonemal heavy chain 17 gene (DNAH17) in two probands with left–right asymmetry disorders. We report for the first time a possible association between DNAH17 gene variants and left–right asymmetry disorders, which is known as a causal gene for asthenozoospermia. Altogether, the findings of our study may enlarge the DNAH17 gene variant spectrum in human left–right asymmetry disorders, pave a way to illustrate the potential pathogenesis of ciliary/flagellar disorders, and provide supplementary explanation for genetic counseling.

BackgroundT-cell large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder that starts in T cells and is usually indolent. Long-term use of immunosuppressants, combined with agranulocytosis, is a double-edged sword, as both can lead to serious infections, especially in patients with combined hematologic malignancies and immune defects.Case PresentationA 30-year-old female patient was admitted to the hospital because of agranulocytosis for five years, with chest tightness, fatigue, and fever for two days. Pathology and metagenomic next-generation sequencing (mNGS) detected Aspergillus. Although she received cyclosporine and methylprednisolone, the patient showed drug intolerance and progression with invasive pulmonary fungal infections. After a bone marrow aspiration biopsy and other related examinations, she was diagnosed with T-LGLL and invasive pulmonary aspergillosis (IPA). T-cell immunophenotype was CD45+CD3dim+CD5-CD4-CD8+CD7+CD57p+CD25-CD30-, TCRγδ+, transducer and activator of transcripton-3 (STAT3) Y640F mutation and fusion gene NPL-DHX9 rearrangement were confirmed, which has never been reported in hematological diseases. After voriconazole regimen adjustment during treatment based on therapeutic drug concentration monitoring (TDM) and improvement in lung infection, the patient finally treated with purine nucleoside analogues (PNA) cladribine as a single agent at 0.14 mg/kg/d for 5 days. Complete response was achieved after four-cycles cladribine treatment (WBC 2.1*109/L, HGB 117 g/L, PLT 196*109/L, ANC 1.6*109/L, and ALC 0.2*109/L).ConclusionsTo our knowledge, this is the first case of T-LGLL with a rare γδ type and fusion gene NPL-DHX9 rearrangement. The patient was successfully treated with cladribine, suggesting that this regimen could be a promising therapeutic strategy for patients with aggressive T-LGLL.

Context The leech and centipede granules have good curative effects on many diabetic vascular diseases, including diabetes-induced erectile dysfunction (DIED). Objective To explore the effect of leech and centipede on erectile function in rats with diabetes-induced erectile dysfunction and its possible mechanism. Materials and methods Thirty male Sprague–Dawley DIED rats were randomly divided into the model group (Group M), low-dose group (Group DD), high-dose group (Group DG) and tadalafil group (Group T) (n = 6); diabetic rats were induced by streptozotocin. Apomorphine was used to induce diabetic erectile dysfunction. The ‘leech-centipede’ granules (0.15 and 0.6 g/kg) were intragastrically administered in the DD and DG groups for 8 weeks. Blood glucose, serum insulin, testosterone, cGMP levels and protein expression changes were measured in each group. Results After 8 weeks, the erectile function of rats in the DG group significantly improved (1.26 ± 0.73). Penis tissue cGMP levels were higher in the DG group (1.48 ± 0.11) than in the M group (0.58 ± 0.15). Protein and mRNA expression levels of NOS were significantly higher (0.77 ± 0.05; 0.61 ± 0.02) but those of PDE5 (0.43 ± 0.05; 0.61 ± 0.03) were lower in the DG group than in the M group (0.37 ± 0.06; 0.51 ± 0.01; 0.78 ± 0.06; 0.81 ± 0.04). Conclusion The leech-centipede can improve erectile dysfunction in DIED rats by regulating the expression of cGMP, NOS, and PDE5-related molecules in the PDE5 pathway. This study provides a potential mechanism for the treatment of DIED with leech-centipede.

Context Achyranthes bidentata Blume (Amaranthaceae) (ABR) and semen vaccariae (SV) are used commonly in the clinical treatment of erectile dysfunction in males with diabetes mellitus (DMED) to strengthen the kidney and promote blood circulation, and often achieve good curative effects. Objective Explore mechanistic details of ABR + SV treatment against DMED. Materials and methods Prediction of key targets by network pharmacology. A rat model of DM was established by streptozotocin injection (55 mg/kg). Apomorphine (100 μg/kg) was injected into rats to screen the DMED model. Group C (n = 6) and group M (n = 6) were gavaged with deionized water; group T (n = 6) was given Achyranthis bidentatae radix–semen vaccariae granule suspension (2.5 g/kg). It lasted 8 weeks. Real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) were used to measure the expression of tissue-related proteins and mRNA. Results The predicted key targets are albumin (ALB), caspase-3 (CASP3), vascular endothelial growth factor A (VEGFA), angiotensin-converting enzyme (ACE), and endothelial nitric oxide synthase (eNOS). Compared with the M group (0.52 ± 0.04; 0.50 ± 0.03; 0.49 ± 0.02; 0.23 ± 0.03), CASP3, VEGFA, and ACE protein expression reduced in the T group (0.39 ± 0.06; 0.34 ± 0.03; 0.39 ± 0.03), and eNOS protein expression increased (0.34 ± 0.03). Conclusion ABR + SV can improve erectile function in DMED rats. This study provides a potential mechanism for the treatment of DMED with ABR + SV and can benefit from more patients.

Biological control is a promising approach to suppress diseases caused by Pythium spp. such as Pythium soft rot of ginger caused by P. myriotylum. Unusually for a single genus, it also includes species that can antagonize Pythium plant pathogens, such as Pythium oligandrum. We investigated if a new isolate of P. oligandrum could antagonize P. myriotylum, what changes occurred in gene expression when P. oligandrum (antagonist) and P. myriotylum (host) interacted, and whether P. oligandrum could control soft-rot of ginger caused by P. myriotylum. An isolate of P. oligandrum, GAQ1, recovered from soil could antagonize P. myriotylum in a plate-based confrontation assay whereby P. myriotylum became non-viable. The loss of viability of P. myriotylum coupled with how P. oligandrum hyphae could coil around and penetrate the hyphae of P. myriotylum, indicated a predatory interaction. We investigated the transcriptional responses of P. myriotylum and P. oligandrum using dual-RNAseq at a stage in the confrontation where similar levels of total transcripts were measured from each species. As part of the transcriptional response of P. myriotylum to the presence of P. oligandrum, genes including a subset of putative Kazal-type protease inhibitors were strongly upregulated along with cellulases, elicitin-like proteins and genes involved in the repair of DNA double-strand breaks. In P. oligandrum, proteases, cellulases, and peroxidases featured prominently in the upregulated genes. The upregulation along with constitutive expression of P. oligandrum proteases appeared to be responded to by the upregulation of putative protease inhibitors from P. myriotylum, suggesting a P. myriotylum defensive strategy. Notwithstanding this P. myriotylum defensive strategy, P. oligandrum had a strong disease control effect on soft-rot of ginger caused by P. myriotylum. The newly isolated strain of P. oligandrum is a promising biocontrol agent for suppressing the soft-rot of ginger. The dual-RNAseq approach highlights responses of P. myriotylum that suggests features of a defensive strategy, and are perhaps another factor that may contribute to the variable success and durability of biological attempts to control diseases caused by Pythium spp.

With the increase of development and utilization of coastal tidal flats, the desertification of intertidal zone is becoming more and more serious, which will inevitably lead to changes in the distribution and migration of heavy metals. This study reported the multiphase distribution and solid-liquid partitioning of Cr, Ni, Cu, Zn, Pb and Cd in typical sandy intertidal zones and predicted the migration of heavy metals with stepwise multiple linear regression. The distribution of heavy metals in surface water was comparable with that in pore water, while the content of heavy metals in suspended solids was obviously greater than that in sediments. Compared to non-sandy sediments, the bioavailability state of heavy metals extracted from sandy sediments by diethylene triamine penta-acetic acid was much smaller. The mean partitioning coefficient values (Kd) ranged from 21.56 to 166.18, which were 10–40 times lower than those of organic-rich sediments and 100–750 times lower than those of mineral soils. The dynamics in solid clay, SOC and ORP greatly affected the variations of Kd values. Clay had a significant positive correlation with bioavailability but did not have a significant correlation with logKd, indicating that the adsorption capacity of heavy metals in the intertidal zone is not the only factor controlling heavy metal migration. Stepwise multiple linear regression analysis confirmed that the prediction equations of heavy metals are composed of multiple physicochemical factors. All predicted and tested values were of the same order of magnitude, with R2 values ranging from 0.8223 to 0.9775. Although our data focus on a single species of sandy intertidal zone, characterizing the Kd value and its relationship with site-specific factors provides different tools for assessing the probability of heavy metal contamination and migration in sandy intertidal zones.

Heterotaxy (HTX), a condition characterized by internal organs not being arranged as expected relative to each other and to the left-right axis, is often accompanied with congenital heart disease (CHD). The purpose was to detect the pathogenic variants in a Chinese family with HTX and CHD. A non-consanguineous Han Chinese family with HTX and CHD, and 200 unrelated healthy subjects were enlisted. Exome sequencing and Sanger sequencing were applied to identify the genetic basis of the HTX family. Compound heterozygous variants, c.3426-1G>A and c.4306C>T (p.(Arg1436Trp)), in the dynein axonemal heavy chain 11 gene (DNAH11) were identified in the proband via exome sequencing and further confirmed by Sanger sequencing. Neither c.3426-1G>A nor c.4306C>T variant in the DNAH11 gene was detected in 200 healthy controls. The DNAH11 c.3426-1G>A variant was predicted as altering the acceptor splice site and most likely affecting splicing. The DNAH11 c.4306C>T variant was predicted to be damaging, which may reduce the phenotype severity. The compound heterozygous variants, c.3426-1G>A and c.4306C>T, in the DNAH11 gene might be the pathogenic alterations resulting in HTX and CHD in this family. These findings broaden the variant spectrum of the DNAH11 gene and increase knowledge used in genetic counseling for the HTX family.

Tribbles homolog 3 (TRIB3) mediating signaling pathways are closely related to blood pressure regulation. Our previous findings suggested a greater benefit on vascular outcomes in patients carrying TRIB3 (251, A > G, rs2295490) G allele with good glucose and blood pressure control. And TRIB3 (rs2295490) AG/GG genotypes were found to reduce primary vascular events in type 2 diabetic patients who received intensive glucose treatment as compared to those receiving standard glucose treatment. However, the effect of TRIB3 genetic variation on antihypertensives was not clear in essential hypertension patients. A total of 368 patients treated with conventional dosage of antihypertensives (6 groups, grouped by atenolol/bisoprolol, celiprolol, doxazosin, azelnidipine/nitrendipine, imidapril, and candesartan/irbesartan) were enrolled in our study. Genetic variations were successfully identified by sanger sequencing. A linear mixed model analysis was performed to evaluate blood pressures among TRIB3 (251, A > G) genotypes and adjusted for baseline age, gender, body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol and other biochemical factors appropriately. Our data suggested that TRIB3 (251, A > G) AA genotype carriers showed better antihypertensive effect than the AG/GG genotype carriers [P = 0.014 for DBP and P = 0.042 for mean arterial pressure (MAP)], with a maximal reduction of DBP by 4.2 mmHg and MAP by 3.56 mmHg after azelnidipine or nitrendipine treatment at the 4th week. Similar tendency of DBP-change and MAP-change was found for imidapril (ACEI) treatment, in which marginally significances were achieved (P = 0.073 and 0.075, respectively). Against that, we found that TRIB3 (251, A > G) AG/GG genotype carriers benefited from antihypertensive therapy of ARBs with a larger DBP-change during the period of observation (P = 0.036). Additionally, stratified analysis revealed an obvious difference of the maximal blood pressure change (13 mmHg for the MAP between male and female patients with AA genotype who took ARBs). Although no significant difference in antihypertensive effect between TRIB3 (251, A > G) genotypes in patients treated with α, β-ADRs was observed, we found significant difference in age-, sex-dependent manner related to α, β-ADRs. In conclusion, our data supported that TRIB3 (251, A > G) genetic polymorphism may serve as a useful biomarker in the treatment of hypertension.

Major depressive disorder (MDD) is one of the most serious diseases and now becomes a major public health problem in the world. The pathogenesis of depression remains poorly understood. Fibroblast growth factors (FGFs) belong to a large family of growth factors that are involved in brain development during early periods as well as maintenance and repair throughout adulthood. In recent years, studies have found a correlation between the members of the FGF system and depression. These signaling molecules may be expected to be biomarkers for the diagnosis and prognosis of MDD, and may provide new drug targets for the treatment of depression. Here, we reviewed the correlation between some members of the FGF system and depression.

To compare prospective ECG-gated multi-slice computed tomography (MSCT) and trans-thoracic echocardiography (TTE) in the diagnosis of complex congenital heart disease (CHD).This was a prospective study of consecutive patients with complex CHD (age

Camptodactyly is a digit deformity characterized by permanent flexion contracture of one or both fifth fingers at the proximal interphalangeal joints. Though over 60 distinct types of syndromic camptodactyly have been described, only one disease locus (3q11.2-q13.12) for nonsyndromic camptodactyly has been identified. To identify the genetic defect for camptodactyly in a four-generation Chinese Han family, exome and Sanger sequencings were conducted and a missense variant, c.1016C>T (p.S339L), in the talin 2 gene (TLN2) was identified. The variant co-segregated with disease in the family and was not observed in 12 unaffected family members or 1,000 normal controls, suggesting that p.S339L is a pathogenic mutation. Two asymptomatic carriers in the family indicated incomplete penetrance or more complicated compensated mechanism. Most of p.S339L carriers also have relatively benign cardiac phenotypes. Expression of wild and mutant TLN2 in HEK293 cells suggested the predominant localization in cytoplasm. Our data suggest a potential molecular link between TLN2 and camptodactyly pathogenesis.

In fungal cells, a phosphate (Pi) responsive signaling and metabolism (PHO) pathway regulates Pi-homeostasis. NUC-2/PHO81 and its homologs are one of the most important components in the regulation pathway. In soil-borne phytopathogenic fungus Verticillium dahliae, we identified a Neurospora crassa nuc-2 homolog gene VdNUC-2. VdNUC-2 is composed of 1,018 amino acids, and is highly conserved in tested filamentous fungi. Under conditions of Pi-starvation, compared with the wild-type strain and ectopic complementation strains, the VdNUC-2 knocked out mutants exhibited reduced radial growth, decreased production of conidia and microsclerotia, and were more sensitive to hydrogen peroxide stress. The virulence of VdNUC-2 defective mutants was significantly compromised, and that was unable to be restored by exogenous application of extra Pi. Additionally, the deletion mutants of VdNUC-1, a key transcription factor gene positively controlled by VdNUC-2 in the PHO pathway, showed the similar cultural phenotypes as VdNUC-2 mutants when both of them grew in Pi-limited conditions. However, the virulence of VdNUC-1 mutants was comparable to the wild-type strain. These evidences indicated that the virulence reduction in VdNUC-2 mutants is not due to the interruptions in the PHO pathway or the disturbance of Pi-homeostasis in V. dahliae cytoplasm. VdNUC-2 is not only a crucial gene in the PHO pathway in V. dahliae, but also is required for the full virulence during host-infection.

KCNH2 (hERG) potassium channels have an integral role in regulating the excitability of smooth muscle cells. Some pathways driven by angiotensin II, nitric oxide and adrenergic receptors blocker are involved in modulating the properties of KCNH2 potassium channels. And these pathways are closely related to blood pressure regulation. Therefore, we hypothesized that KCNH2 genetic polymorphisms may affect blood pressure response to the antihypertensive drug therapies.To evaluate the interactions between KCNH2 genetic polymorphisms and individual blood pressure response to antihypertensive drugs, 370 subjects with essential hypertension (EH) were studied. In evaluating the interactions between KCNH2 genetic polymorphisms and drug response to blood pressure, multivariable ANOVA analysis followed by Bonferroni correction were carried out.There were statistically significant interactions between KCNH2 (1956, C>T) polymorphism and DBP change (P = 0.010), MAP change (P = 0.014) on azelnidipine or nitrendipine therapy patients at the end of 6 weeks. We found that the KCNH2 (1956,C>T) polymorphism was associated with the hypotensive effects of α,β-ADR blockers of DBP change at the end of 4 and 6 weeks' treatment in an age- and gender-dependent manner (P = 0.007 and 0.019, respectively). Similar results were also observed for changes in MAP at the end of 4 and 6 weeks (P-values were 0.035 and 0.078, respectively). While patients who received imidapril, candesartan and irbesartan therapy, no significant difference in drug response among KCNH2(1956,C>T) genotype was observed.We have reported for the first time that KCNH2 (1956, C>T) polymorphism is associated with efficacy of antihypertensive drugs CCBs and ADR blockers, and may serve as a novel biomarker for individualized therapy for certain antihypertensive drugs.

Abstract Recurrence is one of the main causes of treatment failure in early-stage non-small cell lung cancer (NSCLC). However, there are no predictors of the recurrence of early-stage NSCLC, and the molecular mechanism of its recurrence is not clear. In this study, we used clinical sample analysis to demonstrate that low levels of expression of precursor surfactant protein B (pro-SFTPB) in primary NSCLC tissue compared to their adjacent tissues are closely correlated with recurrence and poor prognosis in early-stage NSCLC patients. In vitro and in vivo experiments showed that downregulation of pro-SFTPB expression activates the Akt pathway by upregulating PGK1, which promotes metastasis and tumorigenicity in NSCLC cells. We then demonstrated that pro-SFTPB suppresses the formation of the ADRM1/hRpn2/UCH37 complex by binding to ADRM1, which inhibits PGK1 deubiquitination, thus accelerating ubiquitin-mediated PGK1 degradation. In summary, our findings indicate that low expression of pro-SFTPB in primary NSCLC compared to their adjacent tissue has potential as a predictor of recurrence and poor prognosis in early-stage NSCLC. Mechanistically, downregulation of pro-SFTPB attenuates inhibition of ADRM1-deubiquitinated PGK1, resulting in elevated levels of PGK1 protein; this activates the Akt pathway, ultimately leading to the progression of early-stage NSCLC.

Abstract Cancer stem cells (CSCs), a rare subset of tumor cells, have been recognized as promotive role on tumor initiation and propagation. Among, aerobic glycolysis, widely clarified in multiple tumor cells, is the key for maintaining cancer stemness. Regrettably, it is largely unknown about the connection of cellular metabolic reprogramming and stemness in gastric carcinoma (GC). Two GC parental cells lines PAMC‐82 and SNU‐16 and their spheroids were obtained to determine the expression status of POU1F1 using quantitative real‐time PCR (qRT‐PCR) and western blotting analysis, respectively. Gain or loss‐of‐function assay was employed to assess its biological effects. Sphere formation and transwell assays were performed to evaluate the stem cell‐like traits, including self‐renewal capacity, migration and invasion. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted for determining the binding relationship of POU1F1 on ENO1 promoter region. Herein, aberrantly upregulated POU1F1 was observed in spheroids, compared with the parental PAMC‐82 and SNU‐16 cells, which promoted stem cell‐like traits, as representing increasing sphere formation, enhanced cell migration and invasion. Additionally, POU1F1 expression was positively with glycolytic signaling, as displaying increasing glucose consumption, lactic acid production, and extracellular acid ratio (ECAR). Furthermore, POU1F1 was identified to be a transcriptional activator of ENO1, of which overexpression remarkably abolished POU1F1 knockdown‐mediated blocking effects. Taken together, we draw a conclusion that POU1F1 facilitated the stem cell‐like properties of GC cells through transcriptionally augmenting ENO1 to enhance glycolysis.

In order to better understand the research status in the field of HVDC interference in buried pipelines by numerical simulation technology, the research results of HVDC interference in buried pipelines at home and abroad were summarized. The method of calculation of numerical simulation technology was introduced, the calculation principles of two numerical simulation and calculation softwares, CDEGS and Beasy, were analyzed, and their advantages and disadvantages were compared. In addition, the application status of numerical simulation technology in the study of HVDC interference in buried pipelines was summarized. On this basic, the current problems in numerical simulation technology were pointed out, and the future calculation direction of numerical simulation technique used for HVDC interference in buried pipelines was prospected, which would provide reference and inspiration for relevant researchers and engineers.

本研究關注10位母親在COVID-19疫情下在家學習，使用質性研究方法 瞭解母親與孩子一起進行活動、觀察孩子在家中的行為以及如何影響他們的孩子。在此背景下，記錄、蒐集與分析這些故事中的四個主題，包括母親成為代理老師、在家學習的表現、反思學習方式、覺察關係品質。結果發現，母親兼代教育者所思考到的是在師生期待和學校提供之間的不可預期性，包括線上學習對孩子的影響、創造理想的互動、直接參與課程、反思學校教育的意義、心智狀態、使用媒體的社會互動，以及在家學習產生的新體驗。母親們透過成為代理教育者，可以協助導引孩子自主學習，發展相應的技能與學校互動。母親在家與孩子一起合作，降低在線上學習的無聊並建立常規，創造互動的感受與積極的學習空間。 This study highlights the diverse voices of 10 mothers of homeschoolers. Qualitative research methods were used to understand the activities that parents performed with their children, what they observed in their children’s behavior at home, and how it affected their children. For this purpose, this study was conducted according to the autoethnography, a method used to describe and collect experiences. Within the context of this study, the opinions of mothers of their children receiving transformation of school education in the home school during their quarantine period were elicited. As a result of the analysis of the interviews conducted within the context of this study, four themes gathered under these stories were picked up, including “mother to be proxy educator,” “performance of learning from home,” “reflect on form of learning” and “awareness of quality of relationship.” As a conclusion, the thoughts for the mother instead of proxy educator were found to be “unpredictability between the teachers and student” expectations and what is offered by the school, including the effects of online education on the child, creating interactional ideals, engaging in curriculum directly, reflecting on educational meaning and mindful status, social interaction of media use, and their encounter with the new experience of homeschooling. Through being a proxy educator, mothers can help children navigate their own self-learning and promote positive coping skills and school interactions. Proxy educators working with children can reduce online boredom and establish a routine, which could create a sense of interaction, and a positive learning environment.

Purpose: High explosives are used to produce blast waves to study their biological effects. The lungs are considered as the critical target organ in blast-effect studies. The degree of lung hemorrhaging is related to both the explosive power and the increased lung weight. We studied the characteristics of the biological effects from an air explosion of a thermobaric bomb in a high-altitude environment and the lethality and lung injury severity of goats in different orientations and distances. Methods: Goats were placed at 2.5, 3, 4, and 5 m from the explosion center and exposed them to an air blast at an altitude of 4700-meter. A group of them standing oriented to the right side and the other group seated facing the explosion center vertically. The lung injuries were quantified according to the percentage of surface area contused, and using the pathologic severity scale of lung blast injury (PSSLBI) to score the 4 injury categories (slight, moderate, serious and severe) as 1, 2, 3, and 4, respectively. The lung coefficient (lung weight [g]/body weight [kg]) was the indicator of pulmonary edema and was related to lung injury severity. Blast overpressure data were collected using blast test devices placed at matching locations to represent loadings to goats. All statistical analyses were performed using SPSS, version 26.0, statistical software (SPSS, Inc., Chicago, IL, USA). Results: In total, 127 goats were involved in this study. Right-side-standing goats had a significantly higher mortality rate than those seated vertical-facing (p

Summary: In the human fungal pathogen Candida albicans, invasive hyphal growth is a well-recognized virulence trait. We employed transposon-mediated genome-wide mutagenesis, revealing that inactivating CTM1 blocks hyphal growth. CTM1 encodes a lysine (K) methyltransferase, which trimethylates cytochrome c (Cyc1) at K79. Mutants lacking CTM1 or expressing cyc1K79A grow as yeast under hyphae-inducing conditions, indicating that unmethylated Cyc1 suppresses hyphal growth. Transcriptomic analyses detected increased levels of the hyphal repressor NRG1 and decreased levels of hyphae-specific genes in ctm1Δ/Δ and cyc1K79A mutants, suggesting cyclic AMP (cAMP)-protein kinase A (PKA) signaling suppression. Co-immunoprecipitation and in vitro kinase assays demonstrated that unmethylated Cyc1 inhibits PKA kinase activity. Surprisingly, hyphae-defective ctm1Δ/Δ and cyc1K79A mutants remain virulent in mice due to accelerated proliferation. Our results unveil a critical role for cytochrome c in maintaining the virulence of C. albicans by orchestrating proliferation, growth mode, and metabolism. Importantly, this study identifies a biological function for lysine methylation on cytochrome c.

Animal experiments have shown that injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells can promote recovery from spinal cord injury. To investigate whether injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells can be used to treat spontaneous intracerebral hemorrhage, this non-randomized phase I clinical trial recruited patients who met the inclusion criteria and did not meet the exclusion criteria of spontaneous intracerebral hemorrhage treated in the Characteristic Medical Center of Chinese People’s Armed Police Force from May 2016 to December 2020. Patients were divided into three groups according to the clinical situation and patient benefit: control (n = 18), human umbilical cord-derived mesenchymal stem cells (n = 4), and combination (n = 8). The control group did not receive any transplantation. The human umbilical cord-derived mesenchymal stem cells group received human umbilical cord-derived mesenchymal stem cell transplantation. The combination group received injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells. Patients who received injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells had more remarkable improvements in activities of daily living and cognitive function and smaller foci of intracerebral hemorrhage-related encephalomalacia. Severe adverse events associated with cell transplantation were not observed. Injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells appears to have great potential treating spontaneous intracerebral hemorrhage.

Psychobiotics are a class of probiotics that confer beneficial effects on the mental health of the host. We have previously reported hypnotic effects of a psychobiotic strain, Lactobacillus fermentum PS150 (PS150), which significantly shortens sleep latency in experimental mice, and effectively ameliorate sleep disturbances caused by either caffeine consumption or a novel environment. In the present study, we discovered a L. fermentum strain, GR1009, isolated from the same source of PS150, and found that GR1009 is phenotypically distinct but genetically similar to PS150. Compared with PS150, GR1009 have no significant hypnotic effects in the pentobarbital-induced sleep test in mice. In addition, we found that heat-killed PS150 exhibited hypnotic effects and altered the gut microbiota in a manner similar to live bacteria, suggesting that a heat-stable effector, such as exopolysaccharide (EPS), could be responsible for these effects. Our comparative genomics analysis also revealed distinct genetic characteristics in EPS biosynthesis between GR1009 and PS150. Furthermore, scanning electron microscopy imaging showed a sheet-like EPS structure in PS150, while GR1009 displayed no apparent EPS structure. Using the phenol-sulfate assay, we found that the sugar content value of the crude extract containing EPS (C-EPS) from PS150 was approximately five times higher than that of GR1009, indicating that GR1009 has a lower EPS production activity than PS150. Through the pentobarbital-induced sleep test, we confirmed the hypnotic effects of the C-EPS isolated from PS150, as evidenced by a significant reduction in sleep latency and recovery time following oral administration in mice. In summary, we utilized a comparative approach to delineate differences between PS150 and GR1009 and proposed that EPS may serve as a key factor that mediates the observed hypnotic effect.

Abstract Background Cyclin-dependent kinase inhibitor 2C (CDKN2C) was identified to participate in the occurrence and development of multiple cancers; however, its roles in small cell lung carcinoma (SCLC) remain unclear. Methods Differential expression analysis of CDKN2C between SCLC and non-SCLC were performed based on 937 samples from multiple centers. The prognosis effects of CDKN2C in patients with SCLC were detected using both Kaplan–Meier curves and log-rank tests. Using receiver-operating characteristic curves, whether CDKN2C expression made it feasible to distinguish SCLC was determined. The potential mechanisms of CDKN2C in SCLC were investigated by gene ontology terms and signaling pathways (Kyoto Encyclopedia of Genes and Genomes). Based on 10,080 samples, a pan-cancer analysis was also performed to determine the roles of CDKN2C in multiple cancers. Results For the first time, upregulated CDKN2C expression was detected in SCLC samples at both the mRNA and protein levels (p of Wilcoxon rank-sum test 1, p

Abstract Recurrence is a challenge to survival after the initial treatment of esophageal squamous cell carcinoma (ESCC). But, its mechanism remains elusive and there are currently no biomarkers to predict postoperative recurrence. Here, the possibility of sterile alpha motif domain‐containing protein 9 (SAMD9) as a predictor of postoperative recurrence of ESCC is evaluated and the molecular mechanisms by which SAMD9 promotes ESCC recurrence are elucidated. The authors found that the high level of SAMD9 is correlated with postoperative recurrence and poor prognosis of ESCC. Overexpression of SAMD9 promotes tumor stemness, angiogenesis, and EMT, while downregulation of SAMD9 reduced these phenotypes. Mechanistically, it is found that SAMD9 stimulated ubiquitination‐mediated glycogen synthase kinase‐3 beta (GSK‐3β) degradation by interaction with myosin‐9 (MYH9) and TNF receptor‐associated factor 6 (TRAF6), which in turn activated Wnt/β‐catenin pathway. Further, the authors demonstrated that silencing SAMD9 inhibited lung metastasis and tumor formation in vivo. Finally, the authors found that silencing MYH9 or β‐catenin, or overexpressing GSK‐3β inhibited SAMD9‐stimulated ESCC cell stemness, EMT, angiogenesis, metastasis, and tumorigenicity. Together, the findings indicate that the SAMD9/MYH9/GSK3β/β‐catenin axis promotes ESCC postoperative recurrence and that SAMD9 is a crucial target for ESCC therapy. Additionally, SAMD9 has the potential as a predictor of postoperative recurrence in ESCC.

Different oil well tubes have different influences on CO2 corrosion.In order to optimize the materials with the best corrosion resistance to CO2, it is necessary to explore the corrosion of materials of conventional oil well tubes under different conditions.Therefore, taking the production well of CO2 composite flooding injection in Block nine six of Karamay oilfield as the research object, and simulating the actual service condition of oil well pipes, the corrosion weight loss experiments on N80, 3Cr, tungsten-plated heat insulation tube and P110 oil tube materials were carried out.The Potentiodynamic polarization curve and electrochemical impedance spectroscopy(EIS)were measured by three electrode system, scanning electron microscopy(SEM), energy dispersive spectroscopy(EDS)and X-ray diffraction(XRD)were used to observe the microstructure of corrosion products.Results showed that the corrosion rate of the four kinds of materials increased first and then decreased with the increase of temperature.With the increase of pressure, the corrosion rate of the four kinds of casing steels increased.The corrosion rate of tungsten-plated heat insulation tube and 3Cr was obviously lower than that of N80 and P110.According to the corrosion morphology, the four kinds of casing steels were corroded in varying degrees.The serious corrosion occurred on the surface of N80 and P110 whereas slight corrosion occurred on the surface of the tungsten-plated heat insulation tube and the 3Cr.Therefore, the corrosion law of four oil well tubes in CO2-driven environment was obtained, the suggestions on the design and selection of oil well tubes in CO2-driven environment were proposed to select the materials with the best corrosion resistance to CO2 optimally.

Social media spreads risk awareness about COVID-19. This study aimed to explore the experience of a college professor in incorporating media multiliteracies, reflecting teaching and learning as well as interpret how to make connections between social media and in-class activities during creations. Applying action research as the research method, twenty-three undergraduate students who took “media ethics” class participated in the study, with eight works created. The results show that students identified themes of familiar misinformation as mission, transforming them into a form of reflective creation. Students could communicate the reflective disinformation on COVID-19 through sharing of redesigned messages on social media beyond the classroom. For educators, social media might foster a participatory and creative environment that allows for exchange of information and creation of new networks and organizations, thereby providing a creative educational space for discussing topics related to disasters and pandemics. Creations involving controversial COVID-19 disinformation helped students develop critical thinking and science media literacy. Moreover, students developed the ability to apply multiliteracy in daily life and share their reflections with others. The contribution of this study shows that multiliteracies as mediums indeed helped the learners raise art-based learning skills and cross-disciplinary understanding, and the teacher and students were provided opportunities to improve their professional knowledge and competence about reflective information in a co-create process. Based on these contributions, some suggestions were proposed for further art-based cross-disciplinary education research.

Abstract Background Metastasis is a major challenge in cervical cancer treatment. Previous studies have shown that the dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) promotes tumor metastasis and is overexpressed in cervical cancer. However, the biological role and mechanism of APE1 in cervical cancer metastasis have rarely been studied. Methods We used gene set enrichment analysis (GSEA) to determine the APE1-related signaling pathways in cervical cancer. To investigate the role and mechanism of APE1 in cervical cancer metastasis and invasion, immunohistochemistry, immunofluorescence, western blotting, secondary structure prediction, coimmunoprecipitation, luciferase reporter, and electrophoretic mobility shift assays were performed. The inhibitory effects of the APE1 redox function inhibitor APX3330 on cervical cancer metastasis were evaluated using animal models. Results Clinical data showed that high expression of APE1 was associated with lymph node metastasis in cervical cancer patients. GSEA results showed that APE1 was associated with epithelial to mesenchymal transition (EMT) in cervical cancer. Ectopic expression of APE1 promoted EMT and invasion of cervical cancer cells, whereas inhibition of APE1 suppressed EMT and invasion of cervical cancer cells in a redox function-dependent manner. Notably, APE1 redox function inhibitor APX3330 treatment dramatically suppressed cervical cancer cell lymph node and distant metastasis in vivo. Furthermore, we found that APE1 enhanced the interaction between ZEB1 and the E-cadherin promoter by binding to ZEB1, thereby suppressing the expression of E-cadherin, a negative regulator of EMT. Conclusion Our findings help to elucidate the role played by APE1 in cervical cancer metastasis and targeting APE1 redox function may be a novel strategy for inhibiting cervical cancer metastasis.

One reason for the poor therapeutic effects of stem cell transplantation in traumatic brain injury is that exogenous neural stem cells cannot effectively migrate to the local injury site, resulting in poor adhesion and proliferation of neural stem cells at the injured area. To enhance the targeted delivery of exogenous stem cells to the injury site, cell therapy combined with neural tissue engineering technology is expected to become a new strategy for treating traumatic brain injury. Collagen/heparan sulfate porous scaffolds, prepared using a freeze-drying method, have stable physical and chemical properties. These scaffolds also have good cell biocompatibility because of their high porosity, which is suitable for the proliferation and migration of neural stem cells. In the present study, collagen/heparan sulfate porous scaffolds loaded with neural stem cells were used to treat a rat model of traumatic brain injury, which was established using the controlled cortical impact method. At 2 months after the implantation of collagen/heparan sulfate porous scaffolds loaded with neural stem cells, there was significantly improved regeneration of neurons, nerve fibers, synapses, and myelin sheaths in the injured brain tissue. Furthermore, brain edema and cell apoptosis were significantly reduced, and rat motor and cognitive functions were markedly recovered. These findings suggest that the novel collagen/heparan sulfate porous scaffold loaded with neural stem cells can improve neurological function in a rat model of traumatic brain injury. This study was approved by the Institutional Ethics Committee of Characteristic Medical Center of Chinese People’s Armed Police Force, China (approval No. 2017-0007.2) on February 10, 2019.

Abstract Background Portal hypertension is a severe complication caused by various chronic liver diseases. The standard methods for detecting portal hypertension (hepatic venous pressure gradient and free portal pressure) are available in only a few hospitals due to their technical difficulty and invasiveness; thus, non-invasive measuring methods are needed. This study aimed to establish and assess a novel model to calculate free portal pressure based on biofluid mechanics. Result Comparison of each dog’s virtual and actual free portal pressure showed that a biofluid mechanics-based model could accurately predict free portal pressure (mean difference: -0.220, 95% CI: − 0.738 to 0.298; upper limit of agreement: 2.24, 95% CI: 1.34 to 3.14; lower limit of agreement: -2.68, 95% CI: − 3.58 to − 1.78; intraclass correlation coefficient: 0.98, 95% CI: 0.96 to 0.99; concordance correlation coefficient: 0.97, 95% CI: 0.93 to 0.99) and had a high AUC (0.984, 95% CI: 0.834 to 1.000), sensitivity (92.3, 95% CI: 64.0 to 99.8), specificity (91.7, 95% CI: 61.5 to 99.8), positive likelihood ratio (11.1, 95% CI: 1.7 to 72.8), and low negative likelihood ratio (0.08, 95% CI: 0.01 to 0.6) for detecting portal hypertension. Conclusions Our study suggests that the biofluid mechanics-based model was able to accurately predict free portal pressure and detect portal hypertension in canines. With further research and validation, this model might be applicable for calculating human portal pressure, detecting portal hypertensive patients, and evaluating disease progression and treatment efficacy.

Currently, there is no effective strategy to promote functional recovery after a spinal cord injury. Collagen scaffolds can not only provide support and guidance for axonal regeneration, but can also serve as a bridge for nerve regeneration at the injury site. They can additionally be used as carriers to retain mesenchymal stem cells at the injury site to enhance their effectiveness. Hence, we hypothesized that transplanting human umbilical cord-mesenchymal stem cells on collagen scaffolds would enhance healing following acute complete spinal cord injury. Here, we test this hypothesis through animal studies and a phase I clinical trial. (1) Animal experiments: Models of completely transected spinal cord injury were established in rats and canines by microsurgery. Mesenchymal stem cells derived from neonatal umbilical cord tissue were adsorbed onto collagen scaffolds and surgically implanted at the injury site in rats and canines; the animals were observed after 1 week–6 months. The transplantation resulted in increased motor scores, enhanced amplitude and shortened latency of the motor evoked potential, and reduced injury area as measured by magnetic resonance imaging. (2) Phase I clinical trial: Forty patients with acute complete cervical injuries were enrolled at the Characteristic Medical Center of Chinese People’s Armed Police Force and divided into two groups. The treatment group (n = 20) received collagen scaffolds loaded with mesenchymal stem cells derived from neonatal umbilical cord tissues; the control group (n = 20) did not receive the stem-cell loaded collagen implant. All patients were followed for 12 months. In the treatment group, the American Spinal Injury Association scores and activities of daily life scores were increased, bowel and urinary functions were recovered, and residual urine volume was reduced compared with the pre-treatment baseline. Furthermore, magnetic resonance imaging showed that new nerve fiber connections were formed, and diffusion tensor imaging showed that electrophysiological activity was recovered after the treatment. No serious complication was observed during follow-up. In contrast, the neurological functions of the patients in the control group were not improved over the follow-up period. The above data preliminarily demonstrate that the transplantation of human umbilical cord-mesenchymal stem cells on a collagen scaffold can promote the recovery of neurological function after acute spinal cord injury. In the future, these results need to be confirmed in a multicenter, randomized controlled clinical trial with a larger sample size. The clinical trial was approved by the Ethics Committee of the Characteristic Medical Center of Chinese People’s Armed Police Force on February 3, 2016 (approval No. PJHEC-2016-A8). All animal experiments were approved by the Ethics Committee of the Characteristic Medical Center of Chinese People’s Armed Police Force on May 20, 2015 (approval No. PJHEC-2015-D5).

Potassium (K) use efficiency in Paris polyphylla var. yunnanensis production is relatively low, and the excessive use of K fertilization has negative environmental impacts. Bacterial isolates can effectively alleviate this situation. The present work aimed to analyze the effects of different combinations of three potassium-solubilizing bacteria (KSB) (Bacillus thuringiensis, B. polymyxa, and Paenibacillus amylolyticus) on K in soil and P. polyphylla var. yunnanensis. The results showed that the contents of different forms of K were increased after the application of KSB. Compared with the control group, the maximum increases of slow-acting K, available K, quick-acting K, exchangeable K, and water-soluble K were 32.6% under inoculation with both P. amylolyticus and B. polymyxa, 73.5% with B. thuringiensis, 114.0% with B. thuringiensis, 83.2% with P. amylolyticus, and 210.0% with B. thuringiensis, respectively. This promoted the conversion of soil K to the form of K with high plant availability. Pseudo-protodiosgenin and diosgenin H contents were improved by KSB inoculations, which promoted medicinal quality of P. polyphylla var. yunnanensis. Correlation analysis showed that there were significantly positive correlations among the five forms of K in the soil in all experimental groups. In conclusion, the inoculation of KSB effectively improved the plant availability of soil K and medicinal quality of P. polyphylla var. yunnanensis, providing a path for sustainable production of P. polyphylla var. yunnanensis.

Background: Due to endogenous neuronal deficiency and glial scar formation, spinal cord injury (SCI) often leads to irreversible neurological loss. Accumulating evidence has shown that a suitable scaffold has important value for promoting nerve regeneration after SCI. Collagen/heparin sulfate scaffold (CHSS) has shown effect for guiding axonal regeneration and decreasing glial scar deposition after SCI. The current research aimed to evaluate the utility of the CHSSs adsorbed with mesenchymal stem cells (MSCs) on nerve regeneration, and functional recovery after acute complete SCI. Methods: CHSSs were prepared, and evaluated for biocompatibility. The CHSSs adsorbed with MSCs were transplanted into these canines with complete SCI. Results: We observed that MSCs had good biocompatibility with CHSSs. In complete transverse SCI models, the implantation of CHSS co-cultured with MSCs exhibited significant improvement in locomotion, motor evoked potential, magnetic resonance imaging, diffusion tensor imaging, and urodynamic parameters. Meanwhile, nerve fibers were markedly improved in the CHSS adsorbed with MSCs group. Moreover, we observed that the implantation of CHSS combined with MSCs modulated inflammatory cytokine levels. Conclusions: The results preliminarily demonstrated that the transplantation of MSCs on a CHSS could improve the recovery of motor function after SCI. Thus, implanting the MSCs-laden CHSS is a promising combinatorial therapy for treatment in acute SCI.

A numerical study on cavitation in the centrifugal pump during the transportation of pure water and diesel is carried out. An improved cavitation model based on the Zwart–Gerber–Belamri Model is employed in the simulation. A Cash–Karp fourth–fifth order Runge–Kutta method was used to solve the original Rayleigh-Plesset equation to get the numerical solution. The effects from viscosity and surface tension on bubbles’ expansion and compression are taken into account in the improved model instead of the traditional simplification in which the bubble radius is just a function of pressure and density. The coefficients got by fitting the numerical solution are added to the constant pre-multiplier of the Zwart-Gerber-Belrami cavitation model and finally enhance the model. The vapor volume fraction was predicted to be larger in diesel compared to water. The distribution of pressure in diesel is more homogenous than that in pure water. Keywords: Pump, Cavitation, Viscosity, Surface tension, Simulation

An epigenetic transition between white cells and opaque cells influences several properties of Candida albicans biology, including cellular morphology, biofilm formation, virulence, and sexual mating. In particular, these two cell types exhibit marked differences in their ability to undergo sex. A previous study identified the transcriptional regulator of pheromone response in both the white and opaque states as Cph1 because deletion of this gene abolished both pheromone-induced cell adhesion in white cells and sexual mating in opaque cells. To further explore how these cell types exhibit distinct biological outputs upon pheromone stimulation, we selected five Cph1-regulated genes with significant expression during the pheromone response in the white state but not the opaque state. These phase-specific pheromone-induced genes are ORF19.1539, ORF19.1725, ORF19.2430, ORF19.2691 and ORF19.5557. Deletion of each gene revealed that orf19.1539Δ, orf19.1725Δ, orf19.2430Δ and orf19.5557Δ showed significant decreases in pheromone-stimulated cell adhesion in the white state but retained normal mating competency in the opaque state, indicating that a particular role in white cell pheromone response is mediated by these four genes. Interestingly, the defects of orf19.1725Δ in pheromone-stimulated cell adhesion also abolished conventional biofilms and hyphal growth. Zebrafish egg infection assays further demonstrated that ORF19.1725 is involved in cell adhesion, penetration and virulence. Overall, four Cph1-regulated downstream targets were identified in the regulation of white cell pheromone response. We also clarified the roles of C. albicans ORF19.1725 in cell adhesion, hyphal growth, biofilm formation and virulence.

To improve the stress state of traditional antislide pile and utilize the stable soil on both sides of a landslide and slope foot, a spatial arc antislide pile supporting structure was proposed. Based on numerical calculation, a parametric study was conducted to assess the influence of the rise-span ratio on the stress state of the supporting structure, the displacement of the pile top, and the earth pressure in the front of the pile. The optimal rise-span ratio was 3-16 according to the numerical simulation results. An indoor model test at the optimal rise-span ratio was carried out, recording the pile strain and the earth pressure in front of the pile. The results showed that some indices increased with the increase in rise-span ratio, such as the load transferred to the pile at the arch foot, the bending moment of the piles, the displacement of the pile top, and the earth pressure; within a certain depth near the pile top, the soil in front of the pile is loose during the loading processes, and the earth pressure at the range was zero. The overall safety factors of the four supporting models were 2.42, 2.66, 2.78, and 2.84, respectively, which can satisfy the requirements for practical engineering. The test results verify the feasibility and rationality of the spatial arc antislide pile supporting structure, which can provide a new idea for landslide treatment.

This study examines the roles, the functions as well as the significance of images for communication with the public on global warming issues by analyzing image representations of popular science publications on global warming. According to the present study, the “cause images” represent scientific consensus, the “effect images” correspond to catastrophic events and uncertainties resulted from global warming, and the “resolution images” signify the descriptions of technologies and norms of behaviors. Under current defined role of images for upporting text, following characteristics were observed: First, when describing scientific facts and the cause-and-effect relationships in the content, the represented images of the symbols which are commonly used by the science culture circle, which include models, numbers, figures/tables and historical photos, can eliminate doubt and allow construction of significant and credible knowledgeable narratives. Second, when explaining the impact of global warming, the represented images often lean towards showing the shifting and changing uncertainties caused by the disasters that are occurring in order to signify the chain reactions produced by the crisis of global warming. Lastly, the study also explores the key roles of sustainable energy technologies for solving the problems of warming crisis. The most common images cited are of solar energy and wind energy. Following analysis of the above mentioned findings, practical suggestions as well as innovative insight for scientific image design from a public participation.

本研究以臺灣教育脈絡為始、個人心智乃社會產物的前提下，將個人創作學習視為教育創新的途徑。研究者以G. Kress的素養論為基礎，運用多模態溝通觀點，進一步理解，創作者學習者如何描繪實務經驗與意義的轉化。本研究招募20位藝術創作碩士生，以分組團體（媒體藝術、表演藝術、視覺藝術）進行創作學習的自我敘說，以相似性原則分別從「前備經驗」、「時間醞釀」、「團體心智」與「創造連結」四個面向做討論。研究發現，自我探索特別重要，故能為作品忍受未知的境遇，並善用積極等待的狀態，在意圖中找到作品中的歧義性、聯想與探索的自由度，意圖則交織在表現中，在自我分析中轉化為創作材料。建議未來教育能將創作視為培養獨創性與社會心智的媒介，深度認識自我與世界關係的行動。 Set within the context of Taiwanese education, and based on the premise of individual mentality being a social consequence, this study poses individual creative learning as an approach to educational creativity. Based on Gunther Kress’s theory of literacy, the perspective of multimodality was employed to gain better understanding of how creative learners portray practical experience and recognize meaning in transformation. The study recruited 20 master’s students studying creative arts. They were divided into discussion groups (media arts, performance arts and visual arts), in which they engaged in self-narratives related to creative learning. Then, the similarity principle was used in the paper to identify four dimensions: “preparatory experience,” “the brewing of ideas through time,” “group mentality,” and “creative association”. The research results revealed that self-exploration was particularly important, as was enduring uncertainty in the creative process and making productive use of the positive waiting state. During this phase they were able to find ambiguities in their intent as well as freedom to associate ideas and explore creatively. Their intent is woven into their expression, which is transformed into creative materials during their self-analysis. It is proposed that education in the future should consider the creative act as a medium for cultivating innovation and social mentality, through which one can contemplate at a deeper level and become acquainted with one’s actions arising from one’s relationship with the world.

The genus Maytenus is a member of the Celastraceae family, of which several species have long been used in traditional medicine. Between 1976 and 2021, nearly 270 new compounds have been isolated and elucidated from the genus Maytenus. Among these, maytansine and its homologues are extremely rare in nature. Owing to its unique skeleton and remarkable bioactivities, maytansine has attracted many synthetic endeavors in order to construct its core structure. In this paper, the current status of the past 45 years of research on Maytenus, with respect to its chemical and biological activities are discussed. The chemical research includes its structural classification into triterpenoids, sesquiterpenes and alkaloids, along with several chemical synthesis methods of maytansine or maytansine fragments. The biological activity research includes activities, such as anti-tumor, anti-bacterial and anti-inflammatory activities, as well as HIV inhibition, which can provide a theoretical basis for the better development and utilization of the Maytenus.