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Diabetes mellitus-induced erectile dysfunction (DMED) is one of the complications of diabetes and has a poor response to phosphodiesterase type 5 inhibitor, the first-line treatment for ED. Saxagliptin (Sax), a dipeptidyl peptidase-4 inhibitor (DPP-4i), has been officially used in the treatment of type 2 diabetes. Stromal cell-derived factor-1 (SDF-1) is one of the important substrates of DPP-4, and has been proven to be beneficial for several DM complications. However, it is unknown whether Sax contributes to the management of DMED.To explore the effect and possible underlying mechanisms of Sax in the treatment of DMED.The model of DM was established by intraperitoneal injection of streptozotocin. All rats were divided into three groups (n = 8 per group): control group, DMED group and DMED+Sax group. In cellular experiments, the corpus cavernosum smooth muscle cells (CCSMCs) were exposed to high glucose (HG), and treated with Sax and AMD3100 (SDF-1 receptor inhibitor). The penile tissue and CCSMCs were harvested for detection.We found that erectile function was impaired in DMED rats compared with the control group, which was partially relieved by Sax. Decreased expression of DPP-4 and increased level of SDF-1 were also observed in DMED+Sax group, together with elevation of PI3K/AKT pathway and inhibition of endothelial dysfunction, oxidative stress and apoptosis in corpus cavernosum. Moreover, Sax could also regulate oxidative stress and apoptosis in CCSMCs under HG condition, which was blocked in part by AMD3100.Sax could alleviate DMED through increasing SDF-1 and PI3K/AKT pathway, in company with moderation of endothelial dysfunction, oxidative stress and apoptosis. Our findings indicated that DPP-4 is may be beneficial to the management of DMED.

Objective: Asthenozoospermia (AZS) is one of the most common causes of male fertility, affecting family wellbeing and population growth. Chronic epididymitis (CE) is a common and lingering inflammatory disease in the scrotum. Inflammation in the epididymis has a severe impact on sperm motility. This study aimed to explore the genetic profile and critical pathways involved in the pathological mechanisms of AZS and CE, and discover potential biomarkers.Methods: Genomic datasets of AZS and CE were obtained from the Gene Expression Omnibus (GEO) database, and relevant differentially expressed genes (DEGs) were identified. GO and pathway enrichment analyses, construction of a protein-protein interaction network, and receiver operator characteristic curve analysis were conducted. The expression profile of hub genes was validated in immunohistochemical data and testicular cell data. Immune infiltration, miRNA-hub gene interactions, and gene-disease interactions were explored. The mRNA levels of hub genes were further measured by qRT-PCR.Results: A total of 109 DEGs were identified between the AZS/CE and healthy control groups. Pathways of the immune system, neutrophil degranulation, and interleukin-4 and interleukin-13 signaling were enriched in AZS and CE. Five hub genes (CD300LB, CMKLR1, CCR4, B3GALT5, and CTSK) were selected, and their diagnostic values were validated in AZS, CE, and independent validation sets (area under the curve >0.7). Furthermore, the five-hub gene signature was well characterized in testicular immunohistochemical staining and testicular cells from healthy controls. Immune infiltration analysis showed that infiltration of CD8+ cells and T helper cells was significantly related to the expression level of five hub genes. In addition, a miRNA-hub gene network and interaction of other diseases were displayed. The mRNA levels of hub genes (CD300LB, CMKLR1, CCR4, and B3GALT5) were significantly elevated in the patient group. The mRNA level of CTSK also showed a similar trend.Conclusion: Our study uncovered the genetic profile involved in AZS and CE, and elucidated enriched pathways and molecular associations between hub genes and immune infiltration. This finding provides novel insight into the common pathogenesis of both diseases as well as the potential biomarkers for CE-associated AZS.

The management of diabetes mellitus-induced erectile dysfunction (DMED) is progressively becoming tricky due to the surge in the number of patients and the poor efficiency of phosphodiesterase type 5 inhibitors in DMED. Paeonol (Pae), as a traditional Chinese medicine, has been more and more widely used in the treatment of diabetic complications. However, whether Pae could be a potential therapeutic drug of DMED needs to be further evaluated.To investigate the pharmacological effect and possible mechanism of Pae in the treatment of DMED.Intraperitoneal streptozotocin injection and an apomorphine test were used to construct the model of DMED. Seventeen DMED rats were divided into two groups: DMED group (n = 8) and DMED+Pae group (Pae; 100 mg/kg/d; oral administration; n = 9). In addition, there were still 10 normal age-matched male rats as control group. Four weeks later, the cavernous nerve electric stimulation was carried out to measure the erectile response. Moreover, the corpus cavernosum smooth muscle cells (CCSMCs) were primarily isolated and exposed to high glucose (HG) stimulation, Pae treatment and glycyrrhizin (GL; the selective inhibitor of HMGB1). After an incubation for 1 week, the CCSMCs were harvested for detection.The impairment of erectile function was observed in DMED rats compared with control samples, accompanied by the upregulation of HMGB1/RAGE/NF-κB Pathway. The lower nitric oxide and cGMP level and the higher level of inflammation, fibrosis, and apoptosis were also observed in DMED rats. It showed contrast that Pae treatment could improve the erectile function, as well as histologic alteration and related molecular changes. In addition, Pae could downregulate the HMGB1/RAGE/NF-κB pathway to regulate the apoptosis and inflammation levels of CCSMCs in high-glucose conditions, which is similar to the results of GL treatment.Pae alleviated ED in DMED rats, likely by inhibiting HMGB1/RAGE/NF-κB Pathway, inflammatory, apoptosis, and fibrotic activity, and moderating endothelial dysfunction. Our study provide evidence for a potential new therapy for DMED.

A photolabile protecting group (PPG) 2-(2-nitrophenyl)-propyloxycarbonyl (NPPOC) was explored in glycosylation and applied in the consecutive synthesis of oligosaccharides. NPPOC displays a strong neighboring group participation (NGP) effect to facilitate the construction of 1,2

Background Non-obstructive azoospermia (NOA) affects approximately 1% of the male population worldwide. The underlying mechanism and gene transcription remain unclear. This study aims to explore the potential pathogenesis for the detection and management of NOA. Methods Based on four microarray datasets from the Gene Expression Omnibus database, integrated analysis and weighted correlation network analysis (WGCNA) were used to obtain the intersected common differentially expressed genes (DESs). Differential signaling pathways were identified via GO and GSVA-KEGG analyses. We constructed a seventeen-gene signature model using least absolute shrinkage and selection operation (LASSO) regression, and validated its efficacy in another two GEO datasets. Three patients with NOA and three patients with obstructive azoospermia were recruited. The mRNA levels of seven key genes were measured in testicular samples, and the gene expression profile was evaluated in the Human Protein Atlas (HPA) database. Results In total, 388 upregulated and 795 downregulated common DEGs were identified between the NOA and control groups. ATPase activity, tubulin binding, microtubule binding, and metabolism- and immune-associated signaling pathways were significantly enriched. A seventeen-gene signature predictive model was constructed, and receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) values were 1.000 (training group), 0.901 (testing group), and 0.940 (validation set). The AUCs of seven key genes (REC8, CPS1, DHX57, RRS1, GSTA4, SI, and COX7B) were all > 0.8 in both the testing group and the validation set. The qRT-PCR results showed that consistent with the sequencing data, the mRNA levels of RRS1, GSTA4, and COX7B were upregulated, while CPS1, DHX57, and SI were downregulated in NOA. Four genes (CPS1, DHX57, RRS1, and SI) showed significant differences. Expression data from the HPA database showed the localization characteristics and trajectories of seven key genes in spermatogenic cells, Sertoli cells, and Leydig cells. Conclusions Our findings suggest a novel seventeen-gene signature model with a favorable predictive power, and identify seven key genes with potential as NOA-associated marker genes. Our study provides a new perspective for exploring the underlying pathological mechanism in male infertility.

BackgroundCOVID-19 has spread widely across continents since 2019, causing serious damage to human health. Accumulative research uncovered that SARS-CoV-2 poses a great threat to male fertility, and male infertility (MI) is a common comorbidity for the COVID-19 pandemic. The aim of the study was to explore the cross-talk molecular mechanisms between COVID-19 and MI.Materials and methodsA total of four transcriptome data regarding COVID-19 and MI were downloaded from the Gene Expression Omnibus (GEO) repository, and were divided for two purposes (initial analysis and external validation). Differentially expressed genes (DEGs) analysis, GO and pathway annotation, protein-protein interaction (PPI) network, connectivity ranking, ROC analysis, immune infiltration, and translational and post-translational interaction were performed to gain hub COVID-19-related DEGs (CORGs). Moreover, we recorded medical information of COVID-19 patients with MI and matched healthy controls, and harvested their sperm samples in the university hospital. Expressions of hub CORGs were detected through the qRT-PCR technique.ResultsWe identified 460 overlapped CORGs in both the COVID-19 DEGs and MI DEGs. CORGs were significantly enriched in DNA damage and repair-associated, cell cycle-associated, ubiquitination-associated, and coronavirus-associated signaling. Module assessment of PPI network revealed that enriched GO functions were closely related to cell cycle and DNA metabolism processes. Pharmacologic agent prediction displayed protein-drug interactions of ascorbic acid, biotin, caffeine, and L-cysteine with CORGs. After connectivity ranking and external validation, three hub CORGs (ENTPD6, CIB1, and EIF3B) showed good diagnostic performance (area under the curve > 0.75). Subsequently, three types of immune cells (CD8+ T cells, monocytes, and macrophages M0) were dominantly enriched, and 24 transcription factor-CORGs interactions and 13 miRNA-CORGs interactions were constructed in the network. Finally, qRT-PCR analysis confirmed that there were significant differences in the expression of hub CORGs (CIB1 and EIF3B) between the patient and control groups.ConclusionThe present study identified and validated hub CORGs in COVID-19 and MI, and systematically explored molecular interactions and regulatory features in various biological processes. Our data provide new insights into the novel biomarkers and potential therapeutic targets of COVID-19-associated MI.

Background: Clinical associations between erectile dysfunction and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been noticed, but the common pathogenic mechanisms between them remain elusive. The aim of the study was to mine shared genetic alterations between ED and chronic prostatitis/chronic pelvic pain syndrome.Method: Transcriptome data of ED and chronic prostatitis/chronic pelvic pain syndrome-related genes (CPRGs) were retrieved from relevant databases and differentially expressed analysis was used to obtain significant CPRGs. Then function enrichment and interaction analyses were performed to show shared transcriptional signature, including gene ontology and pathway enrichment, the construction of protein-protein interaction (PPI) network, cluster analysis, and co-expression analysis. Hub CPRGs and key cross-link were selected by validating these genes in clinical samples, chronic prostatitis/chronic pelvic pain syndrome and ED-related datasets. Then the miRNA-OSRGs co-regulatory network was predicted and validated. Subpopulation distribution and disease association of hub CPRGs were further identified.Result: Differentially expressed analysis revealed 363 significant CPRGs between ED and chronic prostatitis/chronic pelvic pain syndrome, functioning in inflammatory reaction, oxidative stress, apoptosis, smooth muscle cell proliferation, and extracellular matrix organization. A PPI network containing 245 nodes and 504 interactions was constructed. Module analysis depicted that multicellular organismal process and immune metabolic process were enriched. 17 genes were screened in PPI via topological algorithms, and reactive oxygen species as well as interleukin-1 metabolism were regarded as the bridging interactive mechanism. After screening and validation, a hub-CPRG signature consisting of COL1A1, MAPK6, LPL, NFE2L2 and NQO1 were identified and associated miRNA were verified. These miRNAs played an important role in immune and inflammatory response likewise. Finally, NQO1 was identified as a key genetic link between ED and chronic prostatitis/chronic pelvic pain syndrome. It was predominately enriched in corpus cavernosum endothelial cell, and correlated with other male urogenital and immune system diseases tightly.Conclusion: We identified the genetic profiles as well as corresponding regulatory network underlying interaction between ED and chronic prostatitis/chronic pelvic pain syndrome via multi-omics analysis. These findings expanded a new understanding for the molecular mechanism of ED with chronic prostatitis/chronic pelvic pain syndrome.

Erectile dysfunction and atherosclerosis are common cardiovascular complications in diseases. Clinical associations between erectile dysfunction and atherosclerosis have been noticed, but the specific mechanisms are not illustrated adequately.The aim of the study was to further mine associated pathological mechanisms and genetic alterations of atherosclerosis in diabetes mellitus-related erectile dysfunction (DMED).Significant atherosclerosis-related genes (ASRGs) were identified from transcriptome data of DMED and ASRG sets from DisGeNET and GeneCard databases. Functional enrichment and immune infiltration analyses were performed to clarify the biological roles and pathways as well as immune responses of significant ASRGs. A protein-protein interaction (PPI) network was constructed and gene clusters were performed. Then, data of diabetic plaques and high-glucose cavernosum endothelial cells was analyzed for validation. And hub ASRGs were identified. Finally expressed pattern of hub ASRGs were explored by single-cell profiling and immune analysis.In total, 202 significant ASRGs including 100 up-regulated and 102 down-regulated genes were identified. These genes were related to endothelial cell migration, inflammatory response, regulation of oxidative stress and immune response. In immune infiltration, immature dendritic cell and monocyte showed differential expression between the DMED and control groups, A PPI network containing 135 nodes was constructed. A hub-ASRG signature consisting of HBEGF, LOX, NQO1 and VLDLR was obtained by multi-omics validation. In addition, Functional enrichment analysis revealed that hub ASRGs were involved in oxidoreductase activity and extracellular matrix organization.We explored atherosclerosis-related genetic changes and signaling pathways in DMED. HBEGF, LOX, NQO1 and VLDLR were identified as hub ASRGs. These may serve as potential biomarkers for the clinical management of atherosclerosis and preventing further cardiovascular risks in DMED. This article is protected by copyright. All rights reserved.

Erectile dysfunction (ED) is a common male sexual dysfunction disease, and it was predicted that the number of ED patients worldwide will reach 322 million by 2025. However, the pathogenesis of ED is complex and the current treatment options are still limited, so it is urgent to explore new treatment strategies. Recent studies have shown that microRNAs (miRNAs) play an important role in ED, and these single-stranded non-coding small RNA molecules are involved in key pathophysiological processes in the occurrence and development of ED. Therefore, miRNAs have remarkable potential as therapeutic targets in ED. Here, this review introduces the physiological basis of erectile function and the pathophysiological changes in ED and summarizes the current knowledge on the expression, biological functions, and molecular mechanisms of miRNAs in ED, especially the potential of miRNA-targeted therapies to improve ED. This review will provide a comprehensive view of the role of miRNAs in the pathogenesis of ED and the potential value of miRNAs in the treatment of ED.

The aim of the study was to compare the magnetic resonance imaging (MRI) findings of intracranial haemorrhage (ICH) in the middle- and late trimesters and to explore the relationship between the MRI features of foetal ICH and postnatal outcomes. This was a retrospective study which recruited foetal ICH diagnosed by MRI in one tertiary centre from 2015 to 2019. The prenatal and postnatal medical records were reviewed. Of 39 ICH cases, 82.1% (32) had germinal matrix intraventricular haemorrhage (GM-IVH), and 18.9% (7) were diagnosed with non-GM-IVH. The cerebellum, corpus callosum and subdural space were affected in 5, 1 and 1 non-GM-IVH cases, respectively. MRI confirmed possible ICH on sonogram in 10 cases (35.7%) and the remaining 19 added ICH diagnoses that were not obtained on initial ultrasound imaging. Pregnancy outcome data were available in 82.1% of (32) cases, of which 21 were terminated pregnancies, 1 was foetal demise and 10 were delivered. One neonate died after birth and one infant suffered from hearing loss. The remaining eight patients had favourable outcome. In our study, evaluation of the relationship between MRI findings and outcomes remains challenging, depending on the timing of examination and the hematoma itself. MRI was an adjunct to US in diagnosing ICH in utero which helps to assess postnatal development.

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare genetically heterogeneous disease and characterized by incomplete or absent puberty and infertility. It is worth noting that partial IHH patients could recover reproductive endocrine function following treatment, which is termed reversal. This study aimed to investigate clinical and genetic characteristics of IHH reversal patients. A total of 141 IHH male patients were enrolled and followed up regularly. Their clinical and genetic features were collected and analysed to discover something in common in reversal cases. These IHH patients with a median age of 21 years (interquartile range: 18-24) were divided into reversal group (n = 13) and non-reversal group (n = 128). IL17RD, ERBB4, DLX5, EGFR, SEMA4D, B3GNT1 and CCKAR RSVs were demonstrated in reversal cases for the first time. Pathogenic/likely pathogenic (P/LP) RSVs consisted of 3 RSVs (one each patient, including PROKR2 p.W178S, EGFR p.G630R and CCKAR p.S291del) in reversal group. Reversal of IHH could not be ignored in clinical follow-up. Patients with high levels of basal LH and T may harbour more possibility of reversal and worthy extra attention to identify whether reversal occurs or not. Relapse after reversal also needs to be monitored.

Coronary angiography (CAG) is usually performed in patients with coronary heart disease (CHD) to evaluate the coronary artery stenosis. However, patients with iodine allergy and renal dysfunction are not suitable for CAG. We try to develop a radiomics machine learning model based on restEighty-four patients were included with the inclusion criteria: adult patients; suspected CHD; resting MPI and CAG were performed; and complete data. Coronary artery stenosis75% were considered to be significant stenosis. Patients were randomly divided into a training group and a testing group with a ratio of 1:1. Myocardial blood flow (MBF), perfusion defect extent (EXT), total perfusion deficit (TPD), and summed rest score (SRS) were obtained. Myocardial static images of the left ventricular (LV) coronary segments were segmented, and radiomics features were extracted. In the training set, the conventional parameter (MPI model) and radiomics (Rad model) models were constructed using the machine learning method and were combined to construct a nomogram. The models' performance was evaluated by area under the curve (AUC), accuracy, sensitivity, specificity, decision analysis curve (DCA), and calibration curves. Testing and subgroup analysis were performed.MPI model was composed of MBF and EXT, and Rad model was composed of 12 radiomics features. In the training set, the AUC/accuracy/sensitivity/specificity of the MPI model, Rad model, and the nomogram were 0.795/0.778/0.937/0.511, 0.912/0.825/0.760/0.936 and 0.911/0.865/0.924/0.766 respectively. In the testing set, the AUC/accuracy/sensitivity/specificity of the MPI model, Rad model, and the nomogram were 0.798/0.722/0.659/0.841, 0.887/0.810/0.744/0.932 and 0.900/0.849/0.854/0.841 respectively. The AUC of Rad model and nomogram were significantly higher than that of MPI model. The DCA curve also showed that the clinical net benefit of the Rad model and nomogram was similar but greater than that of MPI model. The calibration curve showed good agreement between the observed and predicted values of the Rad model. In the subgroup analysis of Rad model, there was no significant difference in AUC between subgroups.The Rad model is more accurate than the MPI model in predicting coronary stenosis. This noninvasive technique could help improve risk stratification and had good generalization ability.

Erectile dysfunction (ED) is a common andrological disorder that tends to afflict diabetic patients, among others. Pharmacological therapy of diabetes mellitus-induced ED (DMED) is ineffective, as it is linked with smooth muscle cell loss in the corpus cavernosum. Ferroptosis is a recently identified kind of cell death evoked by lipid peroxidation, and it is connected with a number of diabetic complications.To investigate the role of ferroptosis in DMED.We established the rat model of DMED and conducted a combined analysis of RNA sequencing (RNA-seq) and Gene Expression Omnibus (GEO) data to identify differentially expressed genes (DEGs). Next, DMED disease targets were determined by cross-referencing DEGs and DMED-related genes in the DisGeNET, GenCLiP3, and GeneCards databases. Additionally, these targets were analyzed using "clusterProfiler" in R utilizing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations. Immunohistochemistry (IHC) staining of rat penile tissues was used to validate several targets. Notably, the Cell Counting Kit-8 assay, Western blotting, oxidative stress (OS) level, and iron concentration were tested in corpus cavernosum smooth muscle cells (CCSMCs) stimulated with high glucose (HG), and treated with Ferrostatin-1 (Fer-1).Sixty-nine disease targets of DMED were identified. According to KEGG analysis, these targets were primarily enriched in the ferroptosis pathway. Additionally, IHC results revealed that the expression of GPX4, SLC7A11, and ACSL4 was deregulated in the DMED group compared to the control group. Significantly, HG decreased cell viability and increased OS and iron levels in CCSMCs, which could be reversed by Fer-1 treatment.Our study revealed that ferroptosis may indeed exist in DMED. GPX4, SLC7A11, and ACSL4 all have a role in controlling the viability of CCSMCs, making them potential therapeutic targets.

Introduction: Biomarkers predicting tumor response to neoadjuvant immunochemotherapy in non-small cell lung cancer (NSCLC) are still lacking despite great efforts. We aimed to assess the effectiveness of the immune PET Response Criteria in Solid Tumors via SULmax (iPERCIST-max) in predicting tumor response to neoadjuvant immunochemotherapy and short-term survival in locally advanced NSCLC.Methods: In this prospective cohort study, we calculated SULmax, SULpeak, metabolic tumor volume (MTV), total lesion glycolysis (TLG) and their dynamic percentage changes in a training cohort. We then investigated the correlation between alterations in these parameters and pathological tumor responses. Subsequently, iPERCIST-max defined by the proportional changes in the SULmax response (△SULmax%) was constructed and internally validated using a time-dependent receiver operating characteristic (ROC) curve and the area under the curve (AUC) value. A prospective cohort from the Sun Yat-Sen University Cancer Center (SYSUCC) was also included for external validation. The relationship between the iPERCIST-max responsiveness and event-free survival in the training cohort was also investigated.Results: Fifty-five patients with NSCLC were included in this study from May 2019 to December 2021. Significant alterations in post-treatment SULmax (p < 0.001), SULpeak (p < 0.001), SULmean (p < 0.001), MTV (p < 0.001), TLG (p < 0.001), and tumor size (p < 0.001) were observed compared to baseline values. Significant differences in SULpeak, SULmax, and SULmean between major pathological response (mPR) and non-mPR statuses were observed. The optimal cutoff values of the SULmax response rate were −70.0% and −88.0% using the X-tile software. The univariate and multivariate binary logistic regression showed that iPERCIST-max is the only significant key predictor for mPR status [OR = 84.0, 95% confidence interval (CI): 7.84–900.12, p < 0.001]. The AUC value for iPERCIST-max was 0.896 (95% CI: 0.776–1.000, p < 0.001). Further, external validation showed that the AUC value for iPERCIST-max in the SYSUCC cohort was 0.889 (95% CI: 0.698–1.000, p = 0.05). Significantly better event-free survival (EFS) in iPERCIST-max responsive disease (31.5 months, 95% CI 27.9–35.1) than that in iPERCIST-max unresponsive disease (22.2 months, 95% CI: 17.3–27.1 months, p = 0.024) was observed.Conclusion: iPERCIST-max could better predict both early pathological tumor response and short-term prognosis of NSCLC treated with neoadjuvant immunochemotherapy than commonly used criteria. Furthermore, large-scale prospective studies are required to confirm the generalizability of our findings.

Occult breast cancer, commonly presenting with axillary lymphadenopathy, is an extremely rare entity of breast cancer. Metastasis to the spleen as a single site is rarely seen and has been little reported in literature. Herein we described a case of a 60-year-old patient who presented with an asymptomatic solitary splenic mass 19 months after axillary lymph node dissection, regional radiotherapy, and systemic therapy. Laparoscopic splenectomy was performed, and histopathological examination confirmed metastasis from occult breast cancer. Then, the patient was administered with oral vinorelbine and dual-targeted treatment. With over 10 months of follow-up, there is no evidence of recurrence or metastasis of malignancy. To our knowledge, this study reports the first case of solitary splenic metastasis from occult breast cancer and highlights the importance of considering splenic metastasis as the only site of recurrence during follow-up of primary cancer, regardless of its rarity. If possible, splenectomy may be a therapeutic strategy.

PurposeThe present study sets out to evaluate the feasibility, safety, and effectiveness of conversion surgery following induction immunochemotherapy for patients with initially unresectable locally advanced esophageal squamous cell carcinoma (ESCC) in a real-world scenario.Materials and MethodsIn this multi-center, real-world study (NCT04822103), patients who had unresectable ESCC disease were enrolled across eight medical centers in China. All patients received programmed death receptor-1 (PD-1) inhibitor plus chemotherapy every 3 weeks for at least two cycles. Patients with significant relief of cancer-related clinical symptoms and radiological responsive disease were deemed surgical candidates. Feasibility and safety profile of immunochemotherapy plus conversion surgery, radiological and pathological tumor responses, as well as short-term survival outcomes were evaluated. Moreover, data of an independent ESCC cohort receiving induction chemotherapy (iC) were compared.ResultsOne hundred and fifty-five patients were enrolled in the final analysis. Esophagectomy was offered to 116 patients, yielding a conversion rate of 74.8%. R0 resection rate was 94%. Among the 155 patients, 107 (69.0%) patients experienced at least one treatment-related adverse event (TRAE) and 45 (29.0%) patients reported grade 3 and above TRAEs. Significant differences in responsive disease rate were observed between iC cohort and induction immunochemotherapy (iIC) cohort [objective response rate: iIC: 63.2% vs. iC: 47.7%, p = 0.004; pathological complete response: iIC: 22.4% vs. iC: 6.7%, p = 0.001). Higher anastomosis fistula rate was observed in the iC group (19.2%) compared with the iIC group (4%). Furthermore, Significantly higher event-free survival was observed in those who underwent conversion surgery.ConclusionOur results supported that conversion surgery following immunochemotherapy is feasible and safe for patients with initially unresectable locally advanced ESCC. Both radiological and pathological response rates were significantly higher in the iIC cohort compared with those in the traditional iC cohort.

Structural superlubricity (SSL) is a state of contact between two sliding surfaces with no wear and ultralow friction. SSL has been characterized at contacts with van der Waals (vdW) layered materials, while its robustness under high pressure has not been assessed. Here we report experimental results showing that incommensurate vdW interfaces between graphite can maintain the state of SSL under the pressure of no lower than 9.45 GPa, and the vdW contact between a tungsten tip and graphite substrate remains stable up to 3.74 GPa, even higher than the strength of most solids. Beyond this critical pressure, wear is activated, signaling the breakdown of vdW contacts and SSL. This unexpected strong pressure resistance and wear-free feature of SSL signals a wear mechanism beyond the Archard law. Atomistic simulations reveal the microscopic processes of SSL breakdown, which originates from lattice destruction at the vdW contact by pressure-assisted bonding, triggering wear through shear-induced tearing of layered vdW materials. The correlation between the breakdown pressure and material parameters for a number of vdW contacts was analyzed. The results show that the bulk modulus and the first ionization energy, are the most relevant factors, which indicate the combined structural and electronic effects. The critical pressures of several metal/graphite contacts could exceed the strength of metals, demonstrating the robustness of SSL. These findings offer fundamental understandings of wear at the vdW contacts, and could guide the design of SSL-derived applications.

Background Idiopathic hypogonadotropic hypogonadism (IHH) is a rare genetic disease attributed to the disorder of hypothalamic-pituitary-gonadal axis. Mutations in the GNRHR gene are one of the most common genetic causes of IHH. Herein, we aimed to investigate GNRHR variants in a Chinese cohort with IHH, and to characterize them at the molecular level. Methods A total of 153 IHH patients were recruited, and variants were detected using a tailored next-generation sequencing panel. GNRHR rare sequencing variant (RSV) was verified using Sanger sequencing. Phenotypic features and therapeutic outcomes of patients were followed up. In order to examine the pathogenicity of the GNRHR RSV, we performed conservative analysis, crystal structure prediction, expression analysis as well as the assessment of ERK1/2 activation and IP3/Ca2+ response. Results The same heterozygous RSV (p.R240Q) in GNRHR was identified in four sporadic IHH patients. These patients exhibited different severity of testicular development and hormone profile. hCG treatment was effective in improving gonadal development, serum testosterone, and semen quality. The GNRHR RSV has no effect on the expression of mRNA and protein, whereas damaged ERK1/2 activation and inositol triphosphate/calcium signaling. Conclusions The study expands GNRHR mutation spectrum in IHH patients, and reveals that the GNRHR RSV is a partial loss-of-function mutation. Although this heterozygous RSV may not have a significant influence on the pathogenesis of IHH, but its homozygous/ compound status should be paid attention in this research field.

To estimate human fetal brain MRI tissue properties including apparent T1 (T1app) and apparent proton density (PDapp) by using a rapid multi-contrast acquisition protocol called STrategically Acquired Gradient Echo (STAGE) imaging. STAGE data were collected using two flip angles (15° and 60°, with a TR = 600 ms) for 30 pregnant women at 1.5 T (15 healthy controls: gestational age (GA) range 19 + 1/7 weeks to 34 + 5/7 weeks; 11 abnormal subjects with ventriculomegaly: GA range 21 + 5/7 weeks to 31 + 5/7 weeks; 4 subjects with other abnormalities). Both T1app and PDapp maps of the fetal brain were calculated from the STAGE data. A region-of-interest-based approach was used to measure T1app and PDapp in the subplate/intermediate zone (SP/IZ), cortical plate (CP), and cerebrospinal fluid (CSF) in the fetal brain. The ratios of T1appSP/IZ/T1appCP and PDappSP/IZ/PDappCP were larger than unity while T1appSP/IZ/T1appCSF and PDappSP/IZ/PDappCSF were both less than unity. STAGE imaging provides a potential practical approach to estimate multi-parametric properties of the human fetal brain. • STAGE is feasible in measuring fetal brain tissue properties. • Water content in cortical plate and subplate/intermediate zone approaches that of cerebrospinal fluid in early gestational ages.

Prostate cancer is the third leading cause of new cancer cases and the second most common tumor type in men globally. LMO3 has been stated to play a vital role in some cancers; however, the prognostic value of LMO3 in PCa remains vague. Here, we utilized various web databases to elucidate in detail the prognostic value and molecular functions of LMO3 in PCa. LMO3 expression was significantly decreased in PCa. Low LMO3 expression was associated with gender, age, and TNM grade and predicted a poor prognosis in PCa patients. Functional enrichment analysis suggested that LMO3 is engaged in the extracellular matrix and immune response. Moreover, LMO3 was positively correlated with immune infiltration levels and numerous immune markers. LMO3 may function as a prospective biomarker of immune infiltration in PCa.

Neurogenic erectile dysfunction (NED) caused by cavernous nerve (CN) injury is a typical complication after pelvic surgery, which lacks efficient treatments. Acetyl-L-carnitine (ALCAR) has been proven to promote nerve repair.To investigate the effect and potential mechanism of ALCAR in the treatment of NED.Thirty-two rats were randomly divided into bilateral CN injury (BCNI) group, BCNI + lower-dose ALCAR (50 mg/kg/day) group, BCNI + higher-dose (100 mg/kg/day) group, and sham-operated group. Erectile function was assessed 14 days after daily intraperitoneal injection of ALCAR or placebo. The penile tissues were gathered for subsequent histological and molecular biological analysis. Rat Schwann cell (SC) line S16 was used to verify the mechanism of ALCAR in vitro.We found that the erectile function of the rats in the BCNI group was severely impaired, which was improved considerably in both BCNI+ALCAR-LD and BCNI+ALCAR-HD groups. Also, we observed decreased smooth muscle and increased collagen content in the corpus cavernosum in the BCNI group. The expressions of fibrosis markers transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), and Smad 2/3 were significantly up-regulated in the BCNI group. The above changes were alleviated after the administration of lower and higher-dose ALCAR. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate pathway (cGMP) was promoted and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was inhibited in the corpus cavernosum of BCNI rats after ALCAR treatment, accompanied by increased neuronal nitric oxide synthase (nNOS) and down-regulated tyrosine hydroxylase (TH). In vitro, ALCAR promoted the migration and proliferation of SC and increased the expression of 22-kD peripheral myelin protein and nerve growth factor (NGF). Further, rats treated with ALCAR had high expression of ATF3 and S100 in the distal nerve tissues of the CN extrusion site.ALCAR could promote nerve repair and regeneration, inhibit penile fibrosis, and improve penile erection by promoting the proliferation and migration of SC and the secretion of NGF. Our study confirms that ALCAR may be a potential treatment strategy for NED.

Erectile dysfunction (ED) is a major health issue among men with diabetes, and ED induced by diabetes mellitus (DMED) is particularly difficult to treat. Therefore, novel therapeutic approaches for the treatment of DMED are urgently needed. Exosomes, nanosized particles involved in many physiological and pathological processes, may become a promising tool for DMED treatment. In this study, we investigated the therapeutic effect of exosomes derived from corpus cavernosum smooth muscle cells (CCSMC‐EXOs) on erectile function in a rat model of diabetes and compared their effect with that of exosomes derived from mesenchymal stem cells (MSC‐EXOs). We incubated labelled CCSMC‐EXOs and MSC‐EXOs with CCSMCs and then observed uptake of the exosomes at different time points using laser confocal microscopy. CCSMC‐EXOs were more easily taken up by CCSMCs. The peak concentration and retention time of labelled CCSMC‐EXOs and MSC‐EXOs in the corpus cavernosum of DMED rats after intracavernous injection were compared by in vivo imaging techniques. Intracavernous injection of CCSMC‐EXOs was associated with a relatively high peak concentration and long retention time. Our data showed that CCSMC‐EXOs could improve erectile function in DMED rats. Meanwhile, CCSMC‐EXOs could exert antifibrotic effects by increasing the smooth muscle content and reducing collagen deposition. CCSMC‐EXOs also increased the expression of eNOS and nNOS, followed by increased levels of NO and cGMP. These findings initially identify the possible role of CCSMC‐EXOs in ameliorating DMED through inhibiting corporal fibrosis and modulating the NO/cGMP signalling pathway, providing a theoretical basis for a breakthrough in the treatment of DMED.

Purpose Intravoxel incoherent motion (IVIM) imaging is widely used to evaluate microcirculatory flow, which consists of diffusive and ballistic flow components. We proposed a joint use of flow-compensated (FC) and non-compensated (NC) diffusion gradients to probe the fraction and velocity of ballistic flow in the placenta. Methods Forty pregnant women were included in this study and scanned on a 1.5T clinical scanner. FC and NC diffusion MRI (dMRI) sequences were achieved using a pair of identical or mirrored bipolar gradients. A joint FC-NC model was established to estimate the fraction (fb ) and velocity (vb ) of the ballistic flow. Conventional IVIM parameters (f, D, and D*) were obtained from the FC and NC data, separately. The vb and f·D*, as placental flow velocity measurements, were correlated with the umbilical-artery Doppler ultrasound indices and gestational ages. Results The ballistic flow component can be observed from the difference between the FC and NC dMRI signal decay curves. vb fitted from the FC-NC model showed strong correlations with umbilical-artery impedance indices, the systolic-to-diastolic (SD) ratio and pulsatility index (PI), with correlation coefficients of 0.65 and 0.62. The f·D* estimated from the NC data positively correlated with SD and PI, while the FC-based f·D* values showed weak negative correlations. Significant gestational-age dependence was also found in the flow velocity measurements. Conclusion Our results demonstrated the feasibility of using FC and NC dMRI to noninvasively measure ballistic flow velocity in the placenta, which may be used as a new marker to evaluate placenta microcirculation.

Xylanase is a member of an important family of enzymes that has been used in many biotechnological processes. However, the overall cost of enzyme production has been the main problem in the industrial application of enzymes. To obtain maximum xylanase production, statistical approaches based on the Plackett–Burman design and response surface methodology were employed. The results of the statistical analyses demonstrated that the optimal conditions for increased xylanase production were the following: inoculum size, 3.8%; maize meal, 4.5%; histidine, 0.6%; methanol, 1%; culture volume, 20%; bean pulp, 30 g L−1; and Tween‐80, 0.8%; and pH 5.0. Verification of the optimization demonstrated that 3273 U mL−1 xylanase was observed under the optimal conditions in shake flask experiments. SDS–PAGE results showed that the size of xylanase protein was about 23 kDa. The results showed that the xylanase produced by fermentation came from Aspergillus Niger by MALDI‐TOF‐MS. The optimized medium resulted in 2.1‐ and 1.4‐fold higher the activity of xylanase compared with the unoptimized medium (the main nutrients are maize meal and bean pulp) and laboratory medium (the main nutrients are yeast extract and peptone), respectively. The optimization of fermentation conditions is an effective means to reduce production cost and improve xylanase activity.

Cavernous nerve injury induced erectile dysfunction (ED) is a refractory complication with high incidence in person under radical prostatectomy. Studies have shown that relaxin-2 (RLX-2) plays a vital role of endothelial protection, vasodilation, anti-fibrosis and neuroprotection in a variety of diseases. However, whether penile cavernous erection can benefit from RLX-2 remains unknown. The purpose of the experiment was to explore the effects of RLX-2 on ED in the rat suffering with bilateral cavernous nerve injury (BCNI).The rats were divided into three groups: Sham group was underwent sham operation, BCNI+RLX group or BCNI group was underwent bilateral cavernous nerve crush and then randomly treated with RLX-2 (0.4 mg/kg/d) or saline by continuous administration using a subcutaneously implanted micro pump for 4 weeks respectively. Then, erectile function was evaluated by electrical stimulation of cavernous nerves. Cavernous nerves and penile tissues and were collected for histological evaluation.Erectile function of rats with BCNI was partially improved after RLX-2 treatment. The BCNI group had lower expression of relaxin family peptide receptor (RXFP) 1, p-AKT/AKT, p-eNOS/eNOS ratios than sham operation rats, but RLX-2 could partially reversed these changes. Histologically, the BCNI+RLX group had a significant effect on preservation of neurofilament, neuronal glial antigen 2 of penile tissue and nNOS of cavernous nerves when compared with BCNI group. RLX-2 could inhibited the lever of BCNI induced corporal fibrosis and apoptosisRLX-2 could improve erectile function of BCNI rats by protecting cavernous nerve and endothelial function and suppressing corporal fibrosis and apoptosis

BACKGROUND The population with diabetes mellitus-induced erectile dysfunction is increasing rapidly, but current drugs are not effective in treating erectile dysfunction. Studies of the traditional Chinese medicine extract berberine on diabetes and its complications provide us with new ideas. OBJECTIVES To evaluate the therapeutic effect and potential mechanism of berberine on the erectile function of diabetic rats. MATERIALS AND METHODS Fifty male Sprague-Dawley rats were randomly grouped, and 42 rats were injected intraperitoneally with streptozotocin to establish a diabetes model. Erectile dysfunction rats were screened out through the apomorphine test and randomly divided into the diabetes mellitus and berberine groups, and these animals were administered berberine (200 mg/kg/day) and normal saline by gavage for 4 weeks. Primary corpus cavernous smooth muscle cells from healthy rats were cultured and treated with berberine. RESULTS Fasting blood glucose in the diabetes mellitus group was significantly increased, while berberine showed no significant effect on glucose. Erectile function was obviously impaired in the diabetes mellitus group, and berberine administration partially rescued this impairment. The expression of sphingosine kinase 1, S1PR2, and sphingosine-1-phosphate in the diabetes mellitus group was increased. Berberine partially inhibited the expression of sphingosine kinase 1 and S1PR2, but the decrease in sphingosine-1-phosphate was not significant. Moreover, mitogen-activated protein kinase pathway factor expression was upregulated and eNOS activity was decreased in the diabetes mellitus group. Berberine treatment could partially reverse these alterations. Severe fibrosis and apoptosis were detected in diabetic rats, accompanied by higher expression of TGFβ1, collagen I/IV, Bax/Bcl-2, and caspase 3 than in the other groups. However, supplementation with berberine inhibited the expression of these proteins and attenuated fibrosis and apoptosis. CONCLUSIONS Berberine ameliorated erectile dysfunction in rats with diabetes mellitus, possibly by improving endothelial function and inhibiting apoptosis and fibrosis by suppressing the sphingosine kinase 1/sphingosine-1-phosphate/S1PR2 and mitogen-activated protein kinase pathways.

As a kind of energy storage device, supercapacitors have attracted the attention of researchers, and the development of high-performance electrode materials is also the focus of attention. In this paper, template synthesis and pyrolysis were combined to prepare high performance porous carbon electrode materials. The carbonized electrode material effectively increased the capacitance storage capacity and charge transfer rate. The results revealed that the derivative had a relatively low charge-transfer resistance and high specific capacitance of 1059 F·g−1 at a current density of 1.0 A·g−1 in a three-electrode system. To further exploring practical application, a device based on the derivative and hemp-activated carbon asymmetric supercapacitor was assembled in 0.1 M Na2SO4 neutral electrolyte, which exhibited an energy density of 20.35 Wh·kg−1 at a power density of 400 W·kg−1. Interestingly, it showed capability retention of nearly of 91.7% and columbic efficiency of 100% even after 10000 charging/discharging cycles in the neutral electrolyte.

Background Oxidative stress is a significant contributor to the poor treatment efficacy on erectile dysfunction induced by diabetes mellitus (DMED). Thus, understanding the mechanism underlying oxidative stress will aid in the identification of novel therapeutic targets. Aim To define the role of Janus kinase 2 (JAK2) in mediating oxidative stress in the corpus cavernosum smooth muscle cells (CCSMCs) and to investigate the therapeutic effect of monomeric berberine (BB), which inhibits JAK2, in the pathogenesis of DMED. Methods Streptozotocin was used to establish type I diabetic rat models and apomorphine tests were conducted to determine DMED rats. Eighteen DMED rats were divided into the DMED group and the DMED+BB group, whereas another 10 age-matched rats formed the control group. CCSMCs were isolated from the corpus cavernosum of rats and were treated with the JAK2 inhibitor alpha cyanano-(3,4-hydroxyl)N-benzophenylamine (AG490) and/or BB. Outcomes Metabolic parameters; erectile function; histologic and molecular alterations. Results Erectile function was impaired and excessive oxidative stress was found in the DMED group. Excessive oxidative stress led to decreased expression level of phosphorylated endothelial nitric oxide synthase at serine 1177/endothelial nitric oxide synthase and increased expression level of Ras homolog gene family and Rho kinase 1/2. Meanwhile, the relative expression ratio of phosphorylated JAK2/JAK2 was significantly greater in the DMED group than that in the other groups. In vitro, oxidative stress was significantly reduced along with reduced intracellular calcium upon treatment with the JAK2 inhibitor, AG490. Moreover, the CCSMCs treated with BB showed changes similar to those upon treatment with AG490. In vivo experiments also confirmed that the erectile function of the DMED+BB group was improved, accompanied by decreased phosphorylated JAK2/JAK2 and decreased oxidative stress. Clinical Translation JAK2 can be used as a therapeutic target and BB can be used as a potential drug for the clinical treatment of DMED. Strengths and Limitations This study examines the promoting effect of JAK2 on oxidative stress occurrence in the corpus cavernosum and on the development of DMED in both animal experiments and cell experiments, as well evaluates the inhibitory effect of BB on JAK2 and its therapeutic effect on DMED. The main limitation of our current study is the lack of an appropriate means for activating JAK2. Conclusions JAK2 can induce DMED by enhancing oxidative stress and BB can play a role in treating DMED by inhibiting JAK2 and reducing oxidative stress. Our study provides an option and an idea for further studies on the pathogenesis and treatment of DMED.

We created a simple electrodeposition method of preparing Ni3S2 nanosheets deposited on 3D hemp-activated carbon supported by a Ni foam. We selected three optimized deposition cycles because of high capacitances of 3D hemp-activated carbon/Ni3S2 electrodes (2,797.43 F g−1 at 1 A g−1) in a 6 M KOH solution. Meanwhile, the capacitances' retention rate is 82.13%, indicating an excellent cyclic stability. To evaluate the further performance of 3D hemp-activated carbon/Ni3S2 electrodes materials in a full cell, the self-assembled all-solid-state supercapacitors device 3D hemp-activated carbon//3D hemp-activated carbon-Ni3S2 have the energy density of 55.32 Wh kg−1 at a current density of 1 A g−1, and a great cycle ability (it retain approximately 83.47% of the initial capacitance after 10,000 charge/discharge cycles).

The T9W is a variant of pig myeloid antimicrobial peptide-36 (PMAP 36) that displays efficient and specific activity against Pseudomonas aeruginosa. It may represent a promising agent for anti-pseudomonas therapies, so a large quantity of T9W is needed for pharmacological study and clinical use. Recombinant T9W was successfully produced by Bacillus subtilis WB800 N using the maltose-inducible promoter Pglv. After 36 h of induction by 5% maltose, 6×His-SUMO-T9W was directly secreted into culture medium. Then, 6×His-SUMO-T9W was purified by Ni-NTA affinity chromatography, and then 32 mg/L of fusion peptide was obtained. Then, the purified 6×His-SUMO-T9W was digested by SUMO protease, thus releasing the recombinant T9W. Recombinant T9W showed high antimicrobial activity against Pseudomonas aeruginosa and extremely weak activity against other gram-negative (Escherichia coli, Salmonella typhimurium) and gram-positive bacteria (Staphylococcus epidermidis, Staphylococcus aureus). When the concentration of recombinant T9W reached the maximum (256 μM), no hemolytic activity was observed. Recombinant T9W has similar activity to synthetic T9W. These results suggested that this method provided an economical and environmentally friendly approach to producing anti-pseudomonas agent T9W in Bacillus subtilis.

This paper is the first study of the application of non-metallic element modified metal-organic frameworks in supercapacitors. Three-dimensional metal-organic frameworks modified by non-metallic element have a novel flower cluster structure, which effectively improve the structural stability and the electrochemical performance of the supercapacitors. The electrochemical performances of the materials modified by the vulcanizing agent are particularly significant with a high specific capacitance of 1453.5F g−1 at a current density of 1 A g−1 and excellent cycle stability (retention rate of 89.23% after 5000 cycles). In addition, the assembled asymmetric supercapacitor S@Ni-MOF//AC also shows a high energy density of 56.85 Wh kg−1 at power density of 480 W kg−1 and good cycle stability with a capacitance retention of 86.67% after 20,000 cycles at current density 5 A g−1. As a result, metal-organic frameworks materials modified by the non-metallic element make up for the crystal defects, which can be used as promising electrode materials for practical applications.

In this work, a Co-ZIF material and the derived nanoporous cobalt-rich carbons by direct carbonization of this Co-ZIF material were synthesized and used as electrode materials for supercapacitors. This ZIF material exhibited a high specific capacitance of 160.3 F g−1 at 0.5 A g−1, an excellent rate capability (73.72 F g−1 at 10 A g−1), and a good cycling stability with 100% of its initials specific capacitance after 8000 cycles. In addition, the obtained derived nanoporous carbons displayed ideal capacitor behaviors and were promising electroactive materials for supercapacitors at low current density. The nanoporous carbon obtained at 650 °C possessed a highest specific capacitance of 393 F g−1 at 0.5 A g−1 and a wide potential application range of −1.0–0.33 V. In addition, a symmetric supercapacitor device consisting of Z-C-650 and activated carbon exhibited a maximum energy density of 61.23 Wh Kg−1 at a power density of 700 W kg−1 and predicted that Z-C-650 could be used as a potential energy storage material.

A novel tetrahydroxy-anthraquinone zeolitic framework (TZM) with a Viburnum blossom-like structure is synthesized via a simple solvothermal method by using tetrahydroxy-anthraquinone to substitute imidazolate without carbonization at high temperature. Considering the excellent electrochemical performance of the TZM, including a high specific capacitance of 2030 F g−1 at a current density of 1 A g−1, and good cycling stability with a capacitance retention of 94% of the initial capacitance after 1000 cycling charge/discharge measurements, an aqueous TZM//AC asymmetric supercapacitor (ASC) in 1 M KOH electrolyte is successfully fabricated by using the resultant TZM as the positive electrode and activated carbon nanosheets (ACS) as the negative electrode, respectively. The as-assembled aqueous ASC delivers a high energy density of 47.7 W h kg−1 at a power density of 750 W kg−1 with a high potential window of 0–1.5 V. Moreover, for the purpose of exploring the practical application of the active materials, an all-solid-state ASC TZM//ACS device with PVA-KOH gel electrolyte and separator is assembled and connected, which can light up a red light-emitting diode (LED). Its good performance demonstrates that the TZM//ACS ASC is a promising energy-storage system.

High-performance electrode materials were obtained by isomorphism and intercalation methods, resulting in multi-types of redox reaction centers and a bridge for charge transfer. Some of the Co ions (clusters) were replaced by Ni ions with little difference in radius and different types of redox reactions were constructed. At the same time, the introduction of 2-methylbenzimidazole in the intercalation of two-dimensional (2D) Ni/Co-MOF accelerated the charge transfer. The synthetic composite electrode material exhibited high specific capacitance of 2422.7 F g−1 at a current density of 1.0 A g−1 in three systems and cycle retention of 86% after 3000 cycles. An asymmetric supercapacitor device assembled with the composite material and activated carbon exhibited a maximum energy density of 82.8 W h kg−1 at a power density of 700 W kg−1, showing that the composite has good potential application value.

Pharmacological therapy of diabetes mellitus-induced erectile dysfunction (DMED) is intractable owig to the poor response to phosphodiesterase type 5 inhibitors (PDE5i). The surge in the number of diabetic patients makes it extremely urgent to find a novel therapy for DMED. Ferroptosis is a recently discovered form of cell death evoked by lipid peroxidation and is related to several diabetic complications. GPX4, an important phospholipid hydroperoxidase, can alleviate ferroptosis and maintain redox balance via reducing lipid peroxides. However, whether GPX4 can be a prospective target of DMED needs to be determined. Fifty rats were randomly divided into control group, DMED group, DMED + negative control group (DMED + NC group), DMED + low-dose group (1 × 106 infectious units), and DMED + high-dose group (2 × 106 infectious units). Erectile function was assessed 4 weeks after intracavernous injection of GPX4 or negative control lentivirus. The penile shafts were collected for subsequent molecular biological and histological analysis. The results demonstrated that erectile function of the rats in DMED and DMED + NC groups was extremely impaired and was improved in a dose-dependent manner with GPX4 lentivirus (GPX4-LV) injection. Additionally, upregulation of the ACSL4-LPCAT3-LOX pathway, iron overload, oxidative stress, fibrosis, and decreased endothelial and smooth muscle cell numbers were observed in the corpus cavernosum of DMED group. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway was inhibited, and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was promoted in DMED rats. The above histologic alterations and related molecular changes were alleviated after GPX4-LV injection. The results revealed that GPX4 improved erectile function by modulating ferroptosis during DMED progression. This finding is of paramount significance in deciphering the molecular mechanism of hyperglycemia-induced ferroptosis, thereby providing a prospective target for preventing the development of DMED.

Polygonatum sibiricum, known as "Huangjing" in Chinese traditional medicine, of which functions include invigorating Qi and nourishing Yin, tonifying spleen and kidney, which are considered to replenish energy, and strengthen immunity. However, both the active components and mechanism of the immune-enhancing effect of Polygonatum sibiricum have not been clarified.To evaluate the immunoregulation effects of PSE30 (Polygonatum sibiricum ethanol 30) and PSE75 (Polygonatum sibiricum ethanol 75). The gut microbial and activation of RAW264.7 cells were also evaluated for exploring the mechanism of PSE75.Female ICR mice were randomly divided into different groups, which were pretreated with 0.9% saline, Yupingfeng granules, different dosage of PSE30 or PSE75. And the immunosuppressed mice model was constructed using cyclophosphamide. And the total duration of the experiment was 15 d. After that, the serum Immunoglobulins G (IgG) and Immunoglobulins M (IgM) antibody, regular blood testing, assessment of natural killer cell activity, and histological observation of spleen in immunosuppressed mice were measured to evaluate the immunoregulation effects of PSE30 and PSE75. Besides, effects of PSE75 on gut microbial were evaluated using 16s rRNA sequence. And the mRNA expression and cytokine secretion of RAW264.7 cell were evaluated to analyze the immunoregulation mechanism of PSE75.The content of serum IgG, IgM was significantly elevated by PSE75 (P＜0.05, P＜0.001). The NK cells killing activity in splenocytes against K562 cells induced by PSE30, and PSE75 was pronounced higher than that of the model group (P 0.05). Both mRNA expression of Th1 molecular markers including interleukin (IL)-2, interferon (IFN)-γ, and signal transducers and activators of transcription (STAT) 4, and Th2 molecular markers including IL-4 in splenocytes were markedly enhanced by PSE30, and PSE75 (P 0.05, P 0.01, or P 0.001). Besides, the result of 16s rRNA sequence indicated that PSE75 could recover the gut microbial community disturbed by cyclophosphamide. PSE75 could markedly promote the secretion of IL-6, IL-10, and IL-12 p40 from RAW264.7 cell (P＜0.01, or P＜0.001).PSE75 was proved to be a more promising immunomodulation agent, of which may enhance the immunity of immunosuppressed mice by improving gut microbial and activating macrophages. And PSE75 could be developed as a good immune booster in the future.

Intravoxel Incoherent Motion (IVIM) imaging has been used to assess placental microcirculatory flows. We proposed a joint analysis of flow-compensated (FC) and non-compensated (NC) diffusion MRI to estimate the fraction and velocity of ballistic microcirculatory flow (fGestational diabetes mellitus (GDM, n = 15) pregnancies and fetal growth restriction (FGR, n = 12), along with gestational age matched normal controls (n = 19 for GDM and 15 for FGR) underwent FC and NC-encoded IVIM scans at 1.5 T. fvv

Alternanthera philoxeroides (Mart.) Griseb. (Alternanthera philoxeroides) is an important herbage species, which could provide high-quality feed for livestock and poultry breeding. This paper is the first to report the A. philoxeroides’s chloroplast genomes, which were detected by de novo sequencing. The results showed that the length of A. philoxeroides’ chloroplast genome sequence was 152,255 bp, including a large single-copy (LSC) region (84,670 bp), a small single-copy (SSC) region (17,343 bp), and two inverted repeat (IR) regions (25,121 bp). Alternanthera philoxeroides’ chloroplast genome encoded 132 genes including 8 rRNA, 38 tRNA, and 86 protein-coding genes. After phylogenetic and cluster analysis, A. philoxeroides was closest to Amaranthaceae, and the relationship between Amaranthus and Achyranthes was closest.

BACKGROUND: Idiopathic hypogonadotropic hypogonadism (IHH) is a rare genetic disease attributed to the disorder of hypothalamic-pituitary-gonadal axis. Mutations in the GNRHR gene are one of the most common genetic causes of IHH. Herein, we aimed to investigate GNRHR variants in a Chinese cohort with IHH, and to characterize them at the molecular level. METHODS: A total of 153 IHH patients were recruited, and variants were detected using a tailored next-generation sequencing panel. GNRHR rare sequencing variant (RSV) was verified using Sanger sequencing. Phenotypic features and therapeutic outcomes of patients were followed up. In order to examine the pathogenicity of the GNRHR RSV, we performed conservative analysis, crystal structure prediction, expression analysis as well as the assessment of ERK1/2 activation and IP3/Ca(2+) response. RESULTS: The same heterozygous RSV (p.R240Q) in GNRHR was identified in four sporadic IHH patients. These patients exhibited different severity of testicular development and hormone profile. hCG treatment was effective in improving gonadal development, serum testosterone, and semen quality. The GNRHR RSV has no effect on the expression of mRNA and protein, whereas damaged ERK1/2 activation and inositol triphosphate/calcium signaling. CONCLUSIONS: The study expands GNRHR mutation spectrum in IHH patients, and reveals that the GNRHR RSV is a partial loss-of-function mutation. Although this heterozygous RSV may not have a significant influence on the pathogenesis of IHH, but its homozygous/ compound status should be paid attention in this research field.

In magnetic resonance imaging (MRI) studies of fetal brain development, structural brain atlases usually serve as essential references for the fetal population. Individual images are usually normalized into a common or standard space for analysis. However, the existing fetal brain atlases are mostly based on MR images obtained from Caucasian populations and thus are not ideal for the characterization of the fetal Chinese population due to neuroanatomical differences related to genetic factors. In this paper, we use an unbiased template construction algorithm to create a set of age-specific Chinese fetal atlases between 21-35 weeks of gestation from 115 normal fetal brains. Based on the 4D spatiotemporal atlas, the morphological development patterns, e.g., cortical thickness, cortical surface area, sulcal and gyral patterns, were quantified. The fetal brain abnormalities were detected when referencing the age-specific template. Additionally, a direct comparison of the Chinese fetal atlases and Caucasian fetal atlases reveals dramatic anatomical differences, mainly in the medial frontal and temporal regions. After applying the Chinese and Caucasian fetal atlases separately to an independent Chinese fetal brain dataset, we find that the Chinese fetal atlases result in significantly higher accuracy than the Caucasian fetal atlases in guiding brain tissue segmentation. These results suggest that the Chinese fetal brain atlases are necessary for quantitative analysis of the typical and atypical development of the Chinese fetal population in the future. The atlases with their parcellations are now publicly available at https://github.com/DeepBMI/FBA-Chinese.