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Abstract NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. Although the underlying mechanisms remain unclear, this form of LTD cannot be induced by low-frequency stimulation (LFS) in adult mice. In this study, we found that LFS-induced LTD was not easily induced in adult animals and was age dependent. Interestingly, the level of the 5-HT1A receptor was correspondingly increased and exhibited an inverse correlation with the magnitude of LFS-LTD during development. Knockout or pharmacological inhibition of the 5-HT1A receptor reversed impaired LFS-LTD in adult mice (P60), while activation or inhibition of this receptor disturbed or enhanced LFS-LTD in adolescent mice (P21), respectively. Furthermore, the astrocytic 5-HT1A receptor in the hippocampus predominantly mediated age-dependent LFS-LTD through enhancing GABAergic neurotransmission. Finally, fear memory extinction differed among the above conditions. These observations enrich our knowledge of LTD at the cellular level and suggest a therapeutic approach for LTD-related psychiatric disorders.

Abstract Background Ichang papeda (Citrus ichangensis), a wild perennial plant of the Rutaceae family, is a cold-hardy plant. WRKY transcription factors are crucial regulators of plant growth and development as well as abiotic stress responses. However, the WRKY genes in C. ichangensis (CiWRKY) and their expression patterns under cold stress have not been thoroughly investigated, hindering our understanding of their role in cold tolerance. Results In this study, a total of 52 CiWRKY genes identified in the genome of C. ichangensis were classified into three main groups and five subgroups based on phylogenetic analysis. Comprehensive analyses of motif features, conserved domains, and gene structures were performed. Segmental duplication plays a significant role in the CiWRKY gene family expansion. Cis-acting element analysis revealed the presence of various stress-responsive elements in the promoters of the majority of CiWRKYs. Gene ontology (GO) analysis and protein-protein interaction predictions indicate that the CiWRKYs exhibit crucial roles in regulation of both development and stress response. Expression profiling analysis demonstrates that 14 CiWRKYs were substantially induced under cold stress. Virus-induced gene silencing (VIGS) assay confirmed that CiWRKY31, one of the cold-induced WRKYs, functions positively in regulation of cold tolerance. Conclusion Sequence and protein properties of CiWRKYs were systematically analyzed. Among the 52 CiWRKY genes 14 members exhibited cold-responsive expression patterns, and CiWRKY31 was verified to be a positive regulator of cold tolerance. These findings pave way for future investigations to understand the molecular functions of CiWRKYs in cold tolerance and contribute to unravelling WRKYs that may be used for engineering cold tolerance in citrus.

The long-term safety and effectiveness of once-daily tadalafil is crucial, but limited data are available in Chinese patients with erectile dysfunction (ED). In this post-marketing, multicenter, randomized, open-label trial with 2-year follow-up, 635 ED cases were randomized to receive daily oral tadalafil 2.5 mg or 5 mg for 3 months, of whom 580 continued once-daily tadalafil 5 mg for 21 months. Treatment-emergent adverse events in the 12-month and 24-month period were similar, with the most common being viral upper respiratory tract infection, upper respiratory tract infection, and headache. Significant improvement from baseline in the International Index of Erectile Function-Erectile Function (IIEF-EF) score was detected at month 12 (least squares mean [LSM] change: 7.9, 95% confidence interval [CI]: 7.5–8.4, P < 0.001) and was maintained to month 24 (LSM change: 8.6, 95% CI: 8.1–9.0, P < 0.001). The proportions of patients regaining normal erectile function (IIEF-EF score ≥26) were 43.7% and 48.0% at months 12 and 24, respectively. Global Assessment Questionnaire results showed improved erection function in 97.5% of patients and improved ability to engage in sexual activity in 95.9% of patients at month 12; these values were 96.1% and 95.0% at month 24, respectively. The quality of sexual life score based on the Sexual Life Quality Questionnaire (SLQQ) was increased by 52.2% at month 12 and by 55.3% at month 24 (both P < 0.001). The treatment satisfaction score determined by SLQQ (mean ± standard deviation) was 62.4 ± 21.0 at month 12 versus 65.9 ± 20.2 at month 24. Two-year daily application of tadalafil 5 mg in Chinese men with ED showed a favorable safety profile and durable improvement in sexual performance and satisfaction.

Abstract DNA methylation serves as the primary mode of epigenetic regulation in prokaryotes, particularly through transcriptional regulation. With the rapid implementation of third‐generation sequencing technology, we are currently experiencing a golden age of bacterial epigenomics. However, there has been a lack of comprehensive research exploring the versatility and consequential impact of bacterial DNA methylome on cellular and physiological functions. There is a critical need for a user‐friendly bioinformatics tool that can effectively characterize DNA methylation modification features and predict the regulation patterns. To address this gap, the current study introduces Bacmethy, an innovative tool that utilizes SMRT‐seq data and offers a range of analytical modules. First, the tool classifies methylation sites in the genome, highlighting the distinct regulations present under varying modification fractions and location enrichment. Furthermore, this tool enables us to identify regulatory region methylation and potential cis and trans interactions between methylation sites and regulatory effectors. Using benchmark data sets and our data, we show that our tool facilitates the understanding of the distinctive traits of DNA methylation modifications and predicts transcriptional regulation effects on important physiological and pathological functions. Bacmethy code is freely available, and the Docker image is downloadable. Bacmethy has been made available as a user‐friendly web server interface at https://bacmethy.med.sustech.edu.cn.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), also known as National Institutes of Health (NIH) type III prostatitis, is a common disorder with an unclear etiology and no known curative treatments. Based on the presence or absence of leukocytes in expressed prostatic secretion (EPS), CP/CPPS is classified further into IIIa (inflammatory) and IIIb (noninflammatory) subtypes. However, the severity of symptoms is not entirely consistent with the white blood cell (WBC) count. Following the preliminary finding of a link between inflammatory cytokines and CP/CPPS, we performed this clinical study with the aim of identifying cytokines that are differentially expressed according to whether the prostatitis subtype is IIIa or IIIb. We found that granulocyte colony-stimulating factor (G-CSF), interleukin-18 (IL-18), and monocyte chemoattractant protein-1 (MCP-1) levels were significantly elevated and interferon-inducible protein-10 (IP-10) and platelet-derived growth factor-BB (PDGF-BB) levels were downregulated in the EPS of patients with type IIIa prostatitis. In a word, it is a meaningful study in which we investigate the levels of various cytokines in EPS according to whether prostatitis is the IIIa or IIIb subtype. The combination of G-CSF, IL-18, MCP-1, IP-10, and PDGF-BB expression levels could form a basis for classification, diagnosis, and therapeutic targets in clinical CP/CPPS.

Abstract Citrus plants routinely experience a broad range of biotic and abiotic stress that occur either concurrently or sequentially in the field, causing huge losses in yield. Hence, cultivated citrus plants that tolerate only one type of abiotic stress are insufficient to maintain citrus productivity as the climate changes. Plants primarily develop delicate regulatory mechanisms to detect, transduce and respond to adverse environmental conditions. Therefore, elucidating the physiological, biochemical and molecular mechanisms underlying the dynamic response to multiple abiotic stresses is a prerequisite for determining the targets for genetic improvement programs of citrus. In this review, we pinpoint the current understanding of the physiological basis of citrus tolerance to abiotic stress. Then, we discuss recent insights into the integrated molecular mechanisms that are involved in the citrus response to multiple types of abiotic stress. Finally, we discuss recent prospects for using modern molecular technologies to facilitate the genetic improvement of citrus.

Abstract Background Salicylic Acid (SA) is a pivotal phytohormone in plant innate immunity enhancement of triggered by various pathogens, such as Candidatus Liberibacter asiaticus (CLas), the causal agent of Huanglongbing (HLB). WRKY is a plant specific transcription factor (TF) family, which plays crucial roles in plant response to biotic stresses. So far, the evolutionary history, functions, and expression patterns under SA treatment and CLas infection of WRKY family are poorly understood in Citrus, despite the release of the genome of several Citrus species. A comprehensive genomic and expressional analysis is worth to conduct for this family. Results Here, a genome-wide identification of WRKY TFs was performed in two Citrus species: Citrus sinensis (HLB-sensitive) and Poncirus trifoliata (HLB-tolerant). In total, 52 CsWRKYs and 51 PtrWRKYs were identified, whose physical and chemical properties, chromosome locations, phylogenetic relationships and structural characteristics were comparatively analyzed. Especially, expression patterns of these WRKY genes before and after SA treatment and CLas infection were compared. Based on this result, seven pairs of orthologous WRKY genes showing opposite expression patterns in two Citrus species were screened out. Moreover, two pairs of orthologous WRKY genes with significant differences in the number or type of stress-responsive cis-elements in the promoter regions were discovered. Subcellular localization and transcriptional activation activity assays revealed that these two pairs of orthologous genes are classic WRKY TFs localize in the nucleus and could function as transcriptional activators. Conclusion In this study, we systematically analyzed the genomic characterization of WRKY family in two Citrus species, together with the analyses of expression patterns under SA signaling and CLas infection. Our study laid a foundation for further study on the function of WRKY TFs in HLB response and SA signaling of Citrus.

PIK3CA is a commonly mutated cancer-associated gene, making it an attractive therapeutic target. Here, the authors report the results of a first-in-human phase Ia trial to assess the safety and recommended phase II dose of CYH33, a PI3Kα inhibitor, in patients with advanced solid tumors.

Aim: To examine prenatal diagnosis strategies through fetal karyotype analysis for 3117 pregnant women with genetic amniocentesis indications. Materials & methods: According to the different indications for amniocentesis, the study was divided into 8 groups. The number of amniocentesis specimens, the number of abnormal karyotypes and the positive rate of each group were analyzed. Results: Compared with prenatal serum screening, noninvasive prenatal DNA testing is more accurate and can effectively improve screening efficiency.Multiple prenatal diagnosis indicators (37.349%) were more likely to be detected than single prenatal diagnosis indicators (11.091%). Conclusion: None of the screeningmethods can completely replace amniocentesis, and for pregnant womenwith genetic indications for amniocentesis, amniocentesis is strongly recommended.

Abstract Objective Currently, only a few studies have been conducted on the mental status recovery in elderly aortic stenosis (AS) patients after treatment. How transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) differentially impinge on the mental status of elderly AS patients is completely unknown. The present prospective study aims to investigate this question by comparing the post-treatment levels of depression and anxiety, quality of life and frailty. Methods A total of 120 elderly patients (age above 70) with symptomatic AS were included, where 78 of them were treated with TAVR and 42 of them were treated with SAVR. Levels of depression and anxiety, quality of life and frailty were assessed by the Chinese version of Hospital Anxiety and Depression Scale (HADS), World Health Organization Quality of Life Instrument-Older Adults Module (WHOQOL-OLD) and clinical frailty scale, respectively. Scores were recorded and compared at admission, 1 month, 4 months and 8 months after treatment. Results Before treatment, both patient groups had similar baseline characteristics and all mental parameters. During the follow-up period, patients in the TAVR group demonstrated significant improvement in all assessed mental parameters to certain extent compared to the SAVR group. Specifically, frailty was significantly improved in the TAVR-treated patients at all three follow-up time points. Levels of depression and anxiety were significantly improved 8 months after treatment, although the remaining patient number is limited. Quality of life was only significantly improved 1 month after treatment. Conclusion TAVR may provide a better mental recovery outcome in elderly AS patients.

Manual fruit thinning (MFT) in fruit trees has been previously shown to increase fruit size and enhance fruit quality, but the effect of MFT on Ponkan (Citrus reticulata Blanco) and the underlying mechanisms remain poorly understood. In this study, efforts were made to elucidate how MFT influences the fruit quality of Ponkan. The results showed that MFT substantially increased fruit size and elevated fruit total soluble solids in comparison with the fruit from the unthinned trees (used as control). Expression analyses demonstrated that mRNA abundance of three important sugar transporter genes, including CrSUT1, CrSTP1 and CrTMT1, was evidently elevated in the flesh of thinned fruit when compared with those of the control. In addition, MFT prominently up-regulated the transcript levels of various auxin and gibberellin (GA) biosynthesis and signaling genes, including CrYUC6, CrAUX/IAA, CrGA20ox1 and CrGA3ox1. Concurrently, the contents of endogenous IAA and GA3, measured at 90 d after fruit thinning, were notably elevated in the fruit from trees with the thinning treatment relative to the control, although no difference was detected in the two groups before the thinning manipulation. Taken together, these results indicate that manual fruit thinning could greatly improve fruit quality, which may be attributed to promoting fruit expansion due to the increased auxin levels and expediting sugar accumulation through the up-regulation of sugar transporter genes.

During recent decades, the association between mutations in ubiquitin-specific protease 26 (USP26) and male infertility remains doubtful. We conducted this meta-analysis to evaluate the association between mutations in USP26 and male infertility according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. It was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42021225251). PubMed, Web of Science, and Scopus were systematically searched for comparative clinical studies, which were written in English and provided eligible data. Studies were included when they compared USP26 mutations in azoospermic, oligozoospermic, and asthenozoospermic patients with controls with normal sperm parameter values or whose partners had experienced spontaneous pregnancy. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated with random effect models. Overall, twelve studies with 3927 infertility patients and 4648 healthy controls were included. The association between overall USP26 mutations and infertility was not significant (OR = 1.60, 95% CI: 0.51–5.01). For specific mutations, the pooled ORs were 1.65 (95% CI: 1.02–2.69) for cluster mutation (including 370–371insACA, 494T>C, and 1423C>T), 1.80 (95% CI: 0.35–9.15) for c.576G>A, 1.43 (95% CI: 0.79–2.56) for c.1090C>T, and 3.59 (95% CI: 2.30–5.59) for c.1737G>A. Our results suggest that several mutations (cluster mutation, c.1737G>A) may play roles in male infertility, while others (c.576G>A and c.1090C>T) do not show notable associations with male infertility. More high-quality clinical researches are needed for validation.

Sugar transporter proteins (STPs) play vital roles in sugar transport and allocation of carbon sources in plants. However, the evolutionary dynamics of this important gene family and their functions are still largely unknown in citrus, which is the largest fruit crop in the world. In this study, fourteen non−redundant CgSTP family members were identified in pummelo (Citrus grandis). A comprehensive analysis based on the biochemical characteristics, the chromosomal location, the exon–intron structures and the evolutionary relationships demonstrated the conservation and the divergence of CgSTPs. Moreover, CgSTP4, 11, 13, 14 were proofed to be localized in plasma membrane and have glucose transport activity in yeast. The hexose content were significantly increased with the transient overexpression of CgSTP11 and CgSTP14. In addition, antisense repression of CgSTP4 induced the shorter pollen tube length in vitro, implying the potential role of CgSTP4 in pummelo pollen tube growth. Taken together, this work explored a framework for understanding the physiological role of CgSTPs and laid a foundation for future functional studies of these members in citrus species.

Abstract Background Sucrose (Suc) hydrolysis is directly associated with plants tolerance to multiple abiotic stresses. Invertase (INV) enzymes irreversibly catalyze Suc degradation to produce glucose (Glc) and fructose (Frc). However, genome-wide identification and function of individual members of the INV gene family in Poncirus trifoliata or its Citrus relatives in response to abiotic stresses are not fully understood. Results In this report, fourteen non-redundant PtrINV family members were identified in P. trifoliata including seven alkaline/neutral INV genes (PtrA/NINV1–7), two vacuolar INV genes (PtrVINV1–2), and five cell wall INV isoforms (PtrCWINV1–5). A comprehensive analysis based on the biochemical characteristics, the chromosomal location, the exon–intron structures and the evolutionary relationships demonstrated the conservation and the divergence of PtrINVs. In addition, expression analysis of INV genes during several abiotic stresses in various tissues indicated the central role of A/NINV7 among INV family members in response to abiotic stresses. Furthermore, our data demonstrated that high accumulation of Suc, Glc, Frc and total sugar contents were directly correlated with the elevated activities of soluble INV enzymes in the cold-tolerant P. trifoliata, C. ichangensis and C. sinensis, demonstrating the potential role of soluble INV enzymes for the cold tolerance of Citrus. Conclusions This work offered a framework for understanding the physiological role of INV genes and laid a foundation for future functional studies of these genes in response to abiotic stresses.

BACKGROUND Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here, we explored the safety, feasibility, and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous TILs (auto-TILs) following concurrent chemoradiotherapy (CCRT) in patients with CC who had locally advanced disease.METHODS Twenty-seven patients with CC with stage III–IV disease were recruited in this single-center, phase I study. TILs were isolated from lesions in the uterine cervix and generated under good manufacturing practice (GMP) conditions and then infused after CCRT plus i.m. IL-2 injections.RESULTS TILs from 20 of the 27 patients were successfully expanded, with a feasibility of 74.1%. Twelve patients received TILs following CCRT. Adverse events (AEs) were primarily attributable to CCRT. Only 1 (8.3%) patient experienced severe toxicity with a grade 3 hypersensitivity reaction after TIL infusion. No autoimmune AEs, such as pneumonitis, hepatitis, or myocarditis, occurred, and there were no treatment-related mortalities. Nine of 12 patients (75.0%) attained a complete response, with a disease control duration of 9–22 months. Translational investigation showed that the transcriptomic characteristics of the infused TIL products and some immune biomarkers in the tumor microenvironment and serum of patients with CC at baseline were correlated with the clinical response.CONCLUSION TIL-based ACT following CCRT was safe in an academic center setting, with potentially effective responses in patients with locally advanced CC. “Hot” inflammatory immune environments were beneficial to the clinical efficacy of TIL-based ACT as adjuvant therapy.TRIAL REGISTRATION ClinicalTrials.gov NCT04443296.FUNDING National Key R&D Program; Sci-Tech Key Program of the Guangzhou City Science Foundation; the Guangdong Province Sci-Tech International Key Program; the National Natural Science Foundation of China.

Astrocytes contribute to autism spectrum disorder (ASD) pathophysiology. Here, the authors show that IP3R2 conditional KO mice show ASD-like behaviours and identify astrocyte-derived ATP as a modulator of these behaviours in mice.

We aimed to confirm the predictive ability of the presence of intraductal carcinoma of the prostate (IDC-P) for prognosis and the associations between IDC-P and clinicopathological parameters. Studies were identified in PubMed, Cochrane Library, EMBASE, Web of Science, and SCOPUS up to December 1, 2019. Hazard ratios (HRs) for survival data and odds ratios for clinicopathological data with 95% confidence intervals (CIs) were extracted. Heterogeneity was evaluated by the I[2] value, and quality was assessed by the Newcastle–Ottawa Scale criteria. A total of 4179 patients from 13 studies were included. The results showed that IDC-P presence was significantly associated with poor progression-free survival (PFS; HR = 2.31; 95% CI: 1.96–2.73), cancer-specific survival (HR = 1.89; 95% CI: 1.28–2.77), and overall survival (HR = 2.14; 95% CI: 1.53–3.01). In the subgroup analysis, IDC-P presence was significantly associated with poor PFS in prostate cancer treated by radical prostatectomy (HR = 2.48; 95% CI: 2.05–3.00) and treated by radiotherapy (HR = 2.83; 95% CI: 1.65–4.85). Regarding clinicopathological characteristics, patients with IDC-P presence had significantly higher tumor clinical stages, Gleason scores, probabilities of lymph node invasion, positive surgical margins, and positive extraprostatic extension. Our meta-analysis indicates that the presence of IDC-P is closely associated with poor prognosis and adverse clinicopathological characteristics. Our data support the value and clinical utility of the routine detection of IDC-P by pathological examination. These conclusions need further validation, and prospective studies are needed to find better treatment modalities other than traditional first-line therapy for patients with IDC-P.

Acute administration of EPA impairs learning and memory and hippocampal LTP in mice that was mediated through enhancing GABAergic transmission via the 5-HT6R. DHA can prevent EPA-induced impairments at a ratio of EPA to DHA similar to that in marine fish oil via the 5-HT2CR.

The spatial-temporal baseline threshold method is commonly used to select interferograms for the Small BAseline Subset interferometric synthetic aperture radar (SBAS-InSAR) technique. However, this selection strategy is rather empirical and prone to including highly contaminated interferograms or excluding those with high quality. To overcome these limitations, this study first derives the relationship between the measurement accuracy of unknown parameters and the number of selected interferograms with their corresponding qualities. Subsequently, an adaptive interferogram selection method is proposed on the basis of Graph Theory (GT) and the turbulence atmospheric effects of interferogram. This proposed method first identifies and deletes the SAR image that is severely polluted by atmospheric phase. Second, high-quality interferograms are selected for SBAS-InSAR based on their corresponding turbulence atmospheric variance. Compared with the traditional selection method, this approach can significantly reduce the effect of turbulence atmosphere on SBAS-InSAR. A set of simulated experiments and real Sentinel-1A data in Hawaii, United States, validate the good performance of the proposed method.

Abstract Background The majority of death-related ovarian cancer is epithelial ovarian cancer (EOC). Regarding the Federation of Gynecology and Obstetrics (FIGO) stage IV EOC, the 5-year overall survival (OS) has not changed in last decades. Platelet (PLT) count and CA125 level are both prognostic markers that related to inflammation and immune evasion in EOC. This study intended to assess the prognostic value of pretreatment PLT count and CA125 level in FIGO stage IV EOC. Methods The study included 108 patients diagnosed with FIGO stage IV EOC and treated with surgery and/or chemotherapy between January 1995 and December 2016. The PLT counts and CA125 levels of the patients before any treatment were analysed with clinical and pathological parameters, OS and progression-free survival (PFS). The survival of different groups was analyzed using the Kaplan-Meier method. The PLT-CA125 scores (0, 1, and 2) were defined basing on the presence of thrombocytosis (PLT count > 400,000/μL), an elevated CA125 level (CA125 > 1200 U/mL), or both. The prognostic value of PLT-CA125 was assessed with a Cox regression model. Results Median OS, but not median PFS, was significantly decreased in patients with thrombocytosis or elevated CA125 levels when compared with the others (p = 0.011 & p = 0.004). The median OS was significantly decreased in patients with a PLT-CA125 score of 2 [37.8 months; 95% confidence interval (CI) 20.6–54.9] compared with patients with a PLT-CA125 score of 0 (70.0 moths, 95% CI 38.0–101.9, p

Gonadotropin therapy is commonly used to induce virilization and spermatogenesis in male isolated hypogonadotropic hypogonadism (IHH) patients. In clinical practice, 5.6%–15.0% of male IHH patients show poor responses to gonadotropin treatment; therefore, testosterone (T) supplementation can serve as an alternative therapy to normalize serum T levels and promote virilization. However, treatment with exogenous T impairs spermatogenesis and suppresses intratesticular T levels. This retrospective study aimed to determine whether oral testosterone undecanoate (TU) supplementation together with human chorionic gonadotropin (hCG) would negatively affect spermatogenesis in IHH patients compared with hCG alone. One hundred and seven IHH patients were included in our study. Fifty-four patients received intramuscular hCG and oral TU, and 53 patients received intramuscular hCG alone. The median follow-up time was 29 (range: 12–72) months in both groups. Compared with the hCG group, the hCG/TU group required a shorter median time to normalize serum T levels (P < 0.001) and achieve Tanner stage (III and V) of pubic hair and genital development (P < 0.05). However, there were no significant differences in the rate of seminal spermatozoa appearance, sperm concentration, or median time to achieve different sperm concentration thresholds between the groups. In addition, there were no significant differences in side effects, such as acne and gynecomastia, observed in both groups. This study indicates that oral TU supplementation together with hCG does not impair spermatogenesis in treated IHH patients compared with hCG alone, and it shortens the time to normalize serum T levels and promote virilization.

Once-daily tadalafil administration has been well established; however, studies about tadalafil once-daily treatment in the Chinese population are lacking. In this phase 4, postmarketing study, we ascertained the long-term safety and effectiveness of tadalafil 2.5 mg and 5.0 mg once daily in Chinese men with erectile dysfunction (n = 635). The primary endpoint of the study was safety at 12 months as assessed by the proportion of patients experiencing at least one treatment-emergent adverse event (serious or nonserious). The secondary endpoints included safety and effectiveness, measured by the International Index of Erectile Function-Erectile Function (IIEF-EF) domain scores. Similar adverse events to the known safety profile of tadalafil, such as nasopharyngitis, upper respiratory tract infection, headache, and dizziness, were detected. No new cardiovascular safety concerns were observed. After 3 months of treatment, significant increases in IIEF-EF domain scores were detected for both 2.5-mg (least squares [LS] mean change: 6.3; 95% confidence interval [CI]: 5.4–7.1; P < 0.001) and 5.0-mg (LS mean change: 7.4; 95% CI: 6.8–7.9; P < 0.001) tadalafil doses, and significance was maintained up to 12 months. In addition, approximately 40% of patients regained normal erectile function (IIEF-EF ≥26) following 1 year of tadalafil once-daily treatment. The findings in this study provide evidence for the extended effectiveness and tolerability of tadalafil, demonstrating no new safety concerns, in a Chinese population and make once-daily tadalafil administration a viable option for improving sexual performance and satisfaction in Chinese men with erectile dysfunction.

We performed this meta-analysis to evaluate the predictive value of different parameters in the sperm retrieval rate (SRR) of microdissection testicular sperm extraction (TESE) in patients with nonobstructive azoospermia (NOA). All relevant studies were searched in PubMed, Web of Science, EMBASE, Cochrane Library, and EBSCO. We chose three parameters to perform the meta-analysis: follicle-stimulating hormone (FSH), testicular volume, and testicular histopathological findings which included three patterns: hypospermatogenesis (HS), maturation arrest (MA), and Sertoli-cell-only syndrome (SCOS). If there was a threshold effect, only the area under the summary receiver operating characteristic curve (AUSROC) was calculated. Otherwise, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and the diagnostic odds ratio (DOR) were also calculated. Twenty-one articles were included in our study finally. There was a threshold effect among studies investigating FSH and SCOS. The AUSROCs of FSH, testicular volume, HS, MA, and SCOS were 0.6119, 0.6389, 0.6758, 0.5535, and 0.2763, respectively. The DORs of testicular volume, HS, and MA were 1.98, 16.49, and 1.26, respectively. The sensitivities of them were 0.80, 0.30, and 0.27, while the specificities of them were 0.35, 0.98, and 0.76, respectively. The PLRs of them were 1.49, 10.63, and 1.15, respectively. And NLRs were 0.73, 0.72, and 0.95, respectively. All the investigated factors in our study had limited predictive value. However, the histopathological findings were helpful to some extent. Most patients with HS could get sperm by microdissection TESE.

Calpain activation contributes to hyperglycemia-induced endothelial dysfunction and apoptosis. This study was designed to investigate the role of calpain inhibition in improving diabetic erectile dysfunction (ED) in mice. Thirty-eight-week-old male C57BL/6J mice were divided into three groups: (1) nondiabetic control group, (2) diabetic mice + vehicle group, and (3) diabetic mice + MDL28170 (an inhibitor of calpain) group. Type 1 diabetes was induced by intraperitoneal injection of streptozotocin at 60 mg kg−1 body weight for 5 consecutive days. Thirteen weeks later, diabetic mice were treated with MDL28170 or vehicle for 4 weeks. The erectile function was assessed by electrical stimulation of the cavernous nerve. Penile tissues were collected for measurement of calpain activity and the endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. Terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) staining was used to evaluate apoptosis. Caspase-3 expression and activity were also measured to determine apoptosis. Our results showed that erectile function was enhanced by MDL28170 treatment in diabetic mice compared with the vehicle diabetic group. No differences in calpain-1 and calpain-2 expressions were observed among the three groups. However, calpain activity was increased in the diabetic group and reduced by MDL28170. The eNOS-NO-cGMP pathway was upregulated by MDL28170 treatment in diabetic mice. Additionally, MDL28170 could attenuate apoptosis and increase the endothelium and smooth muscle levels in corpus cavernosum. Inhibition of calpain could improve erectile function, probably by upregulating the eNOS-NO-cGMP pathway and reducing apoptosis.

Previous studies have shown that oxidative stress and corporal fibrosis in penile tissues of rats were key pathological factors of erectile dysfunction induced by diabetic mellitus (DMED). Lipoxin A4 (LXA4) was reported to inhibit oxidative stress and fibrosis diseases, while whether it could exert a protective role on erectile function was not clear. Type I diabetic mellitus (DM) was induced in thirty male 10-week-old Sprague-Dawley rats using streptozotocin. Ten weeks later, twenty-two rats with DMED confirmed by an apomorphine test were divided into two groups: the DMED group (n = 11) and the DMED + LXA4 group (n = 11; LXA4 injection daily for 4 weeks). In addition, another ten age-matched rats formed the Control group. We found that erectile function was significantly impaired in the DMED group compared with the Control group, but was improved in the DMED + LXA4 group. Similarly, the over-activated oxidative stress and impaired endothelial function in the DMED group were both improved in the DMED + LXA4 group. Moreover, the DMED group showed serious corporal fibrosis, which was also inhibited by the treatment of LXA4 in the DMED + LXA4 group. Taken together, LXA4 could exert an inhibition role on oxidative stress and fibrosis to improve DMED effectively.

Background: Currently available evaluation criteria for penile tumescence and rigidity have been fraught with controversy. In this study, we sought to establish normative Chinese evaluation criteria for penile tumescence and rigidity by utilizing audiovisual sexual stimulation and RigiScan™ test (AVSS-Rigiscan test) with the administration of phosphodiesterase-5 inhibitor. Methods: A total of 1169 patients (aged 18–67 years) complained of erectile dysfunction (ED) underwent AVSS-RigiScan test with the administration of phosphodiesterase-5 inhibitor. A total of 1078 patients whose final etiological diagnosis was accurate by means of history, endocrine, vascular, and neurological diagnosis, International Index of Erectile Function 5 questionnaire, and erection hardness score were included in the research. Logistic regression model and receiver operating characteristic curve analysis were performed to determine the cutoff value of the RigiScan™ data. Then, the multivariable logistic analysis was used in the selected variables. Results: A normal result is defined as one erection with basal rigidity over 60% sustained for at least 8.75 min, average event rigidity of tip at least 43.5% and base at least 50.5%, average maximum rigidity of tip at least 62.5% and base at least 67.5%, △tumescence (increase of tumescence or maximum−minimum tumescence) of tip at least 1.75 cm and base at least 1.95 cm, total tumescence time at least 29.75 min, and times of total tumescence at least once. Most importantly, basal rigidity over 60% sustained for at least 8.75 min, average event rigidity of tip at least 43.5%, and base at least 50.5% would be the new normative Chinese evaluation criteria for penile tumescence and rigidity. By multivariable logistic regression analysis, six significant RigiScan™ parameters including times of total tumescence, duration of erectile episodes over 60%, average event rigidity of tip, △tumescence of tip, average event rigidity of base, and △tumescence of base contribute to the risk model of ED. In logistic regression equation, predict value P < 0.303 was considered as psychogenic ED. The sensitivity and specificity of the AVSS-RigiScan test with the administration of phosphodiesterase-5 inhibitor in discriminating psychogenic from organic ED was 87.7% and 93.4%, respectively. Conclusions: This study suggests that AVSS-RigiScan test with oral phosphodiesterase-5 inhibitors can objectively assess penile tumescence and rigidity and seems to be a better modality in differentiating psychogenic from organic ED. However, due to the limited sample size, bias cannot be totally excluded.

Objective: This study aims to explore the effects of the exogenous hydrogen sulfide (H2S)-mediated scavenger receptor A (SR-A) signaling pathway on renal ischemia/reperfusion injury (IRI) by regulating endoplasmic reticulum (ER) stress-induced autophagy in rats. Methods: A total of 48 normal Sprague-Dawley (SD) rats and SR-A knockout rats were selected and divided into six groups (n = 8): wild-type (WT) + sham, WT + ischemia-reperfusion (I/R), WT + I/R + NaHS, SR-A-/- + sham, SR-A-/- + I/R and SR-A-/- + I/R + NaHS. The concentrations of urinary protein, blood urea nitrogen (BUN), serum creatinine (SCR), malondialdehyde (MDA) and H2S in renal tissue were detected. qRT-PCR and Western blotting were used to detect the mRNA and protein levels of IL-6, TGF-β, SR-A, LC3I, LC3II, P62, PERK, ATF6 and IRE1 pathway-related genes. A TUNEL assay was used to detect cell apoptosis. Electron microscopy was applied to observe the structure of renal autophagosomes. Results: Compared with the WT + sham group, in the rates of the WT + I/R group, the urine volume, urinary protein, BUN, SCR and MDA concentrations, the mRNA and protein expression of IL-6, TGF-β, LC3II/I, and ER stress pathway-related genes, the cell apoptosis index, and the number of autophagosomes were significantly increased 24 h after I/R, while P62 and SR-A protein expression and SOD and H2S concentrations were significantly decreased (all P < 0.05). The levels of renal injury, autophagy and ER stress pathway-related genes were decreased in the WT + I/R + NaHS group but were increased in the SR-A-/- + I/R group relative to the WT + I/R group. No significant differences were observed in the urine volume; the concentrations of urinary protein, BUN, SCR and MDA; the SOD activity; the mRNA and protein expression of IL-6, TGF-β, SR-A, GRP78, SR-A, GPR94, ATF4, IRE1, XBP1, ATF6, and eIF2α; the cell apoptosis index; or the number of autophagosomes in rats of the SR-A-/- + I/R and SR-A-/- + I/R + NaHS groups (all P > 0.05). Conclusion: These results demonstrate that the exogenous H2S-mediated SR-A signaling pathway reduces renal IRI injury by up-regulating ER stress-induced autophagy in rats.

Our previous studies have demonstrated that erectile function was preserved in aged transgenic rats (TGR) harboring the human tissue kallikrein 1 (hKLK1), while the molecular level of hKLK1 on corporal fibrosis to inhibit age-related erectile dysfunction (ED) is poorly understood. Male wild-type Sprague-Dawley rats (WTR) and TGR harboring the hKLK1 gene were fed to 4- or 18-month-old and divided into three groups: young WTR (yWTR) as the control, aged WTR (aWTR), and aged TGR (aTGR). Erectile function of all rats was assessed by cavernous nerve electrostimulation method. Masson′s trichrome staining was used to evaluate corporal fibrosis in the corpus cavernosum. We found that the erectile function of rats in the aWTR group was significantly lower than that of other two groups. Masson′s trichrome staining revealed that compared with those of the yWTR and aTGR groups, the ratio of smooth muscle cell (SMC)/collagen (C) was significantly lower in the aWTR group. Immunohistochemistry and Western blotting analysis were performed, and results demonstrated that expression of α-SMA was lower, while expressions of transforming growth factor-β 1 (TGF-β1), RhoA, ROCK1, p-MYPT1, p-LIMK2, and p-cofilin were higher in the aWTR group compared with those in other two groups. However, LIMK2 and cofilin expressions did not differ among three groups. Taken together, these results indicated that the RhoA/ROCK1/LIMK/cofilin pathway may be involved in the corporal fibrosis caused by advanced age, and hKLK1 may reduce this corporal fibrosis by inhibiting the activation of this pathway to ameliorate age-related ED.

Polyamine (PA) catabolic processes are performed by copper-containing amine oxidases (CuAOs) and flavin-containing PA oxidases (PAOs). So far, several CuAOs and PAOs have been identified in many plant species. These enzymes exhibit different subcellular localization, substrate specificity, and functional diversity. Since PAs are involved in numerous physiological processes, considerable efforts have been made to explore the functions of plant CuAOs and PAOs during the recent decades. The stress signal transduction pathways usually lead to increase of the intracellular PA levels, which are apoplastically secreted and oxidized by CuAOs and PAOs, with parallel production of hydrogen peroxide (H2O2). Depending on the levels of the generated H2O2, high or low, respectively, either programmed cell death (PCD) occurs or H2O2 is efficiently scavenged by enzymatic/nonenzymatic antioxidant factors that help plants coping with abiotic stress, recruiting different defense mechanisms, as compared to biotic stress. Amine and PA oxidases act further as PA back-converters in peroxisomes, also generating H2O2, possibly by activating Ca2+ permeable channels. Here, the new research data are discussed on the interconnection of PA catabolism with the derived H2O2, together with their signaling roles in developmental processes, such as fruit ripening, senescence, and biotic/abiotic stress reactions, in an effort to elucidate the mechanisms involved in crop adaptation/survival to adverse environmental conditions and to pathogenic infections.

Lanelate navel orange (Citrus sinensis Osbeck) is a late-ripening citrus cultivar increasingly planted in China. The physiological disorder juice sac granulation often occurs in the fruit before harvest, but the physiological and molecular mechanisms underlying this disorder remain elusive. In this study, we found that fruit granulation of the late-ripening navel orange in the Three Gorges area is mainly caused by the low winter temperature in high altitude areas. Besides, dynamic changes of water content in the fruit after freezing were clarified. The granulation of fruit juice sacs resulted in increases in cell wall cellulose and decreases in soluble solid content, and the cells gradually became shrivelled and hollow. Meanwhile, the contents of pectin, cellulose, and lignin in juice sac increased with increasing degrees of fruit granulation. The activities of pectin methylesterase (PME) and the antioxidant enzymes peroxidase (POD), superoxide dismutase, and catalase increased, while those of polygalacturonase (PG) and cellulose (CL) decreased. Furthermore, a total of 903 differentially expressed genes were identified in the granulated fruit as compared with non-disordered fruit using RNA-sequencing, most of which were enriched in nine metabolic pathways, and qRT-PCR results suggested that the juice sac granulation is closely related to cell wall metabolism. In addition, the expression of PME involved in pectin decomposition was up-regulated, while that of PG was down-regulated. Phenylalanine ammonia lyase (PAL), cinnamol dehydrogenase (CAD), and POD related to lignin synthesis were up-regulated, while CL involved in cellulose decomposition was down-regulated. The expression patterns of these genes were in line with those observed in low-temperature treatment as revealed by qRT-PCR, further confirming that low winter temperature is associated with the fruit granulation of late-ripening citrus. Accordingly, low temperature would aggravate the granulation by affecting cell wall metabolism of late-ripening citrus fruit.

Banana is an important tropical fruit with high economic value. One of the main cultivars (‘Cavendish’) is susceptible to low temperatures, while another closely related specie (‘Dajiao’) has considerably higher cold tolerance. We previously reported that some membrane proteins appear to be involved in the cold tolerance of Dajiao bananas via an antioxidation mechanism. To investigate the early cold stress response of Dajiao, here we applied comparative membrane proteomics analysis for both cold-sensitive Cavendish and cold-tolerant Dajiao bananas subjected to cold stress at 10°C for 0, 3, and 6 h. A total of 2,333 and 1,834 proteins were identified in Cavendish and Dajiao, respectively. Subsequent bioinformatics analyses showed that 692 Cavendish proteins and 524 Dajiao proteins were predicted to be membrane proteins, of which 82 and 137 differentially abundant membrane proteins (DAMPs) were found in Cavendish and Dajiao, respectively. Interestingly, the number of DAMPs with increased abundance following 3 h of cold treatment in Dajiao (80) was seven times more than that in Cavendish (11). Gene ontology molecular function analysis of DAMPs for Cavendish and Dajiao indicated that they belong to eight categories including hydrolase activity, binding, transporter activity, antioxidant activity, etc., but the number in Dajiao is twice that in Cavendish. Strikingly, we found peroxidases (PODs) and aquaporins among the protein groups whose abundance was significantly increased after 3 h of cold treatment in Dajiao. Some of the PODs and aquaporins were verified by reverse-transcription PCR, multiple reaction monitoring, and green fluorescent protein-based subcellular localization analysis, demonstrating that the global membrane proteomics data are reliable. By combining the physiological and biochemical data, we found that membrane-bound Peroxidase 52 and Peroxidase P7, and aquaporins (MaPIP1;1, MaPIP1;2, MaPIP2;4, MaPIP2;6, MaTIP1;3) are mainly involved in decreased lipid peroxidation and maintaining leaf cell water potential, which appear to be the key cellular adaptations contributing to the cold tolerance of Dajiao. This membrane proteomics study provides new insights into cold stress tolerance mechanisms of banana, toward potential applications for ultimate genetic improvement of cold tolerance in banana.

We performed a meta-analysis to compare treatment with a combination of solifenacin plus tamsulosin oral controlled absorption system (TOCAS) with placebo or TOCAS monotherapy. The aim of the meta-analysis was to clarify the efficacy and safety of the combination treatments method for lower urinary tract symptoms (LUTS). We searched for trials of men with LUTS that were randomized to combination treatment compared with TOCAS monotherapy or placebo. We pooled data from three placebo-controlled trials meeting inclusion criteria. Primary outcomes of interest included changes in International Prostate Symptom Score (IPSS) and urinary frequency. We also assessed postvoid residual, maximum urinary flow rate, incidence of urinary retention (UR), adverse events. Data were pooled using random or fixed effect models for continuous outcomes and the Mantel-Haenszel method to generate risk ratio. Reductions in IPSS storage subscore and total urgency and frequency score (TUFS) were observed with solifenacin 6 mg plus TOCAS compared with placebo (P< 0.0001 and P< 0.0001, respectively). Reductions in IPSS storage subscore and TUFS were observed with solifenacin 9 mg plus TOCAS compared with placebo (P = 0.003 and P= 0.0006, respectively). Reductions in TUFS was observed with solifenacin 6 mg plus TOCAS compared with TOCAS (P = 0.01). Both combination treatments were well tolerated, with low incidence of UR. Solifenacin 6 mg plus TOCAS significantly improved total IPSS, storage and voiding symptoms compared with placebo. Solifenacin 6 mg plus TOCAS also improved storage symptoms compared with TOCAS alone. There was no additional benefit of solifenacin 9 mg compared with 6 mg when used in combination with TOCAS.

The study was to compare treatment preference, efficacy, and tolerability of sildenafil citrate (sildenafil) and tadalafil for treating erectile dysfunction (ED) in Chinese men naοve to phosphodiesterase 5 (PDE5) inhibitor therapies. This multicenter, randomized, open-label, crossover study evaluated whether Chinese men with ED preferred 20-mg tadalafil or 100-mg sildenafil. After a 4 weeks baseline assessment, 383 eligible patients were randomized to sequential 20-mg tadalafil per 100-mg sildenafil or vice versa for 8 weeks respectively and then chose which treatment they preferred to take during the 8 weeks extension. Primary efficacy was measured by Question 1 of the PDE5 Inhibitor Treatment Preference Questionnaire (PITPQ). Secondary efficacy was analyzed by PITPQ Question 2, the International Index of Erectile Function (IIEF) erectile function (EF) domain, sexual encounter profile (SEP) Questions 2 and 3, and the Drug Attributes Questionnaire. Three hundred and fifty men (91%) completed the randomized treatment phase. Two hundred and forty-two per 350 (69.1%) patients preferred 20-mg tadalafil, and 108/350 (30.9%) preferred 100-mg sildenafil (P < 0.001) as their treatment in the 8 weeks extension. Ninety-two per 242 (38%) patients strongly preferred tadalafil and 37/108 (34.3%) strongly the preferred sildenafil. The SEP2 (penetration), SEP3 (successful intercourse), and IIEF-EF domain scores were improved in both tadalafil and sildenafil treatment groups. For patients who preferred tadalafil, getting an erection long after taking the medication was the most reported reason for tadalafil preference. The only treatment-emergent adverse event reported by > 2% of men was headache. After tadalafil and sildenafil treatments, more Chinese men with ED naοve to PDE5 inhibitor preferred tadalafil. Both sildenafil and tadalafil treatments were effective and safe.

The interplay between polyamines (PAs) and nitrogen (N) is emerging as a key factor in plant response to abiotic and biotic stresses. The PA/N interplay in plants connects N metabolism, carbon (C) fixation, and secondary metabolism pathways. Glutamate, a pivotal N-containing molecule, is responsible for the biosynthesis of proline (Pro), arginine (Arg) and ornithine (Orn) and constitutes a main common pathway for PAs and C/N assimilation/incorporation implicated in various stresses. PAs and their derivatives are important signaling molecules, as they act largely by protecting and preserving the function/structure of cells in response to stresses. Use of different research approaches, such as generation of transgenic plants with modified intracellular N and PA homeostasis, has helped to elucidate a plethora of PA roles, underpinning their function as a major player in plant stress responses. In this context, a range of transgenic plants over-or under-expressing N/PA metabolic genes has been developed in an effort to decipher their implication in stress signaling. The current review describes how N and PAs regulate plant growth and facilitate crop acclimatization to adverse environments in an attempt to further elucidate the N-PAs interplay against abiotic and biotic stresses, as well as the mechanisms controlling N-PA genes/enzymes and metabolites.

A response surface method based on the all sample point interpolation approach (ASPIA) is proposed to improve the efficiency of reliability computation. ASPIA obtains new sample points through linear interpolation. These new sample points are occasionally extremely dense, thus easily generating an ill-conditioned problem for approximation functions. A mobile most probable failure point strategy is used to solve this problem. The advantage of the proposed method is proven by two numerical examples. With the ASPIA, the approximated process can rapidly approach the actual limit equation with accuracy. Additionally, there are no difficulties in applying the proposed ASPIA to the response surface model with or without cross terms. Solution results for the numerical examples indicate that the use of the response surface function with cross terms increases time cost, but result accuracy cannot be improved significantly. Finally, the proposed method is successfully used to analyze the reliability of the hydraulic cylinder of a forging hydraulic press by combining MATLAB and ANSYS software. The engineering example confirms the practicality of this method.

The effect of polysaccharide extract isolated from Ganoderma lucidum (Gl-PS) on rat cortical neuronal cultures exposed to hypoxia/reoxygenation (H/R) was studied in vitro. Gl-PS (1, 10, 100 μg/ml) increased neuron viability following H/R as measured by the inhibition of MTT reduction. Gl-PS also significantly reduced malondialdehyde content and reactive oxygen species production and increased the manganese superoxide dismutase (Mn-SOD) activity; furthermore, the translocation of nuclear factor-kappa B induced by H/R was blocked. These findings suggest that Gl-PS might be useful in treating H/R-induced oxidative stress and Mn-SOD might play a critical role in the neuroprotective effect of Gl-PS against H/R injury. Keywords:: polysaccharide extract isolated from Ganoderma lucidum, cultured rat cortical neuron, hypoxia/reoxygenation

Citrus canker disease caused by Xanthomonas citri subsp. citri (Xcc) is one of the most devastating biotic stresses affecting the citrus industry. Meiwa kumquat (Fortunella crassifolia) is canker-resistant, while Newhall navel orange (Citrus sinensis Osbeck) is canker-sensitive. To understand the molecular mechanisms underlying the differences in responses to Xcc, transcriptomic profiles of these two genotypes following Xcc attack were compared by using the Affymetrix citrus genome GeneChip. A total of 794 and 1324 differentially expressed genes (DEGs) were identified as canker-responsive genes in Meiwa and Newhall, respectively. Of these, 230 genes were expressed in common between both genotypes, while 564 and 1094 genes were only significantly expressed in either Meiwa or Newhall. Gene ontology (GO) annotation and Singular Enrichment Analysis (SEA) of the DEGs showed that genes related to the cell wall and polysaccharide metabolism were induced for basic defense in both Meiwa and Newhall, such as chitinase, glucanase and thaumatin-like protein. Moreover, apart from inducing basic defense, Meiwa showed specially upregulated expression of several genes involved in the response to biotic stimulus, defense response, and cation binding as comparing with Newhall. And in Newhall, abundant photosynthesis-related genes were significantly down-regulated, which may be in order to ensure the basic defense. This study revealed different molecular responses to canker disease in Meiwa and Newhall, affording insight into the response to canker and providing valuable information for the identification of potential genes for engineering canker tolerance in the future.