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Abstract As testicular mesenchymal stromal cells, stem Leydig cells (SLCs) show great promise in the treatment of male hypogonadism. The therapeutic functions of mesenchymal stromal cells are largely determined by their reciprocal regulation by immune responses. However, the immunoregulatory properties of SLCs remain unclear. Here, we observe that SLCs transplantation restore male fertility and testosterone production in an ischemia‒reperfusion injury mouse model. SLCs prevent inflammatory cascades through mitochondrial transfer to macrophages. Reactive oxygen species (ROS) released from activated macrophages inducing mitochondrial transfer from SLCs to macrophages in a transient receptor potential cation channel subfamily member 7 (TRPM7)-mediated manner. Notably, knockdown of TRPM7 in transplanted SLCs compromised therapeutic outcomes in both testicular ischemia‒reperfusion and testicular aging mouse models. These findings reveal a new mechanism of SLCs transplantation that may contribute to preserve testis function in male patients with hypogonadism related to immune disorders.

Male ageing is always accompanied by decreased fertility. The forkhead O (FOXO) transcription factor FOXO4 is reported to be highly expressed in senescent cells. Upon activation, it binds p53 in the nucleus, preventing senescent cell apoptosis and maintaining senescent cells in situ. Leydig cells play key roles in assisting spermatogenesis. Leydig cell senescence leads to deterioration of the microenvironment of the testes and impairs spermatogenesis. In this study, we observed that FOXO4-DRI, a specific FOXO4- p53 binding blocker, induced apoptosis in senescent Leydig cells, reduced the secretion of certain Senescence-Associated Secretory Phenotype and improved the proliferation of cocultured GC-1 SPG cells. In naturally aged mice, FOXO4-DRI-treated aged mice exhibited increased sperm quality and improved spermatogenesis.

Cadmium, an environmental toxicant, severely impairs male reproductive functions and currently lacks effective clinical treatments. Mesenchymal stem cell-derived exosomes (MSC-Exos) are increasingly recognized as a potential alternative to whole-cell therapy for tissue injury and regeneration. This study aims to investigate the protective effects of MSC-Exos against cadmium toxicity on male reproduction. Our findings reveal that MSC-Exos treatment significantly promotes spermatogenesis, improves sperm quality, and reduces germ cell apoptosis in cadmium-exposed mice. Mechanistically, MSC-Exos dramatically mitigate cadmium-induced cell apoptosis in a spermatogonia cell line (GC-1 spg) in vitro by reducing DNA damage and promoting autophagic flux. These results suggest that MSC-Exos have a protective effect on cadmium-induced germ cell apoptosis by ameliorating DNA damage and autophagy flux, demonstrating the therapeutic potential of MSC-Exos for cadmium toxicity on male reproduction.

In this paper, we consider the following semilinear Schrödinger equation: $ \begin{eqnarray*} \left\{ \begin{array}{ll} -\Delta u+V(x)u = a(x)g(u)&{\mbox{for}}\; x\in \mathbb{R}^{N} ,\\ u(x)\rightarrow0&{\mbox{as}}\; |x|\rightarrow \infty , \end{array} \right. \end{eqnarray*} $ where $ a(x) > 0 $ for all $ \mathbb{R}^{N} $. Under some different superlinear conditions on $ g(u) $, we obtain the existence of solutions for the above problem. In order to regain the compactness of the Sobolev embedding, a competing condition between $ a(x) $ and $ V(x) $ is introduced.

Abstract Hereditary primary hypogonadism (HPH), caused by gene mutation related to testosterone synthesis in Leydig cells, usually impairs male sexual development and spermatogenesis. Genetically corrected stem Leydig cells (SLCs) transplantation may provide a new approach for treating HPH. Here, a novel nonsense‐point‐mutation mouse model (LhcgrW495X) is first generated based on a gene mutation relative to HPH patients. To verify the efficacy and feasibility of SLCs transplantation in treating HPH, wild‐type SLCs are transplanted into LhcgrW495X mice, in which SLCs obviously rescue HPH phenotypes. Through comparing several editing strategies, optimized PE2 protein (PEmax) system is identified as an efficient and precise approach to correct the pathogenic point mutation in Lhcgr. Furthermore, delivering intein‐split PEmax system via lentivirus successfully corrects the mutation in SLCs from LhcgrW495X mice ex vivo. Gene‐corrected SLCs from LhcgrW495X mice exert ability to differentiate into functional Leydig cells in vitro. Notably, the transplantation of gene‐corrected SLCs effectively regenerates Leydig cells, recovers testosterone production, restarts sexual development, rescues spermatogenesis, and produces fertile offspring in LhcgrW495X mice. Altogether, these results suggest that PE‐based gene editing in SLCs ex vivo is a promising strategy for HPH therapy and is potentially leveraged to address more hereditary diseases in reproductive system.

Background: Testicular aging is associated with diminished fertility and certain age-related ailments, and effective therapeutic interventions remain elusive. Here, we probed the therapeutic efficacy of exosomes derived from human umbilical cord mesenchymal stem cells (hUMSC-Exos) in counteracting testicular aging. Methods: We employed a model of 22-month-old mice and administered intratesticular injections of hUMSC-Exos. Comprehensive analyses encompassing immunohistological, transcriptomic, and physiological assessments were conducted to evaluate the effects on testicular aging. Concurrently, we monitored alterations in macrophage polarization and the oxidative stress landscape within the testes. Finally, we performed bioinformatic analysis for miRNAs in hUMSC-Exos. Results: Our data reveal that hUMSC-Exos administration leads to a marked reduction in aging-associated markers and cellular apoptosis while promoting cellular proliferation in aged testis. Importantly, hUMSC-Exos facilitated the restoration of spermatogenesis and elevated testosterone synthesis in aged mice. Furthermore, hUMSC-Exos could attenuate inflammation by driving the phenotypic shift of macrophages from M1 to M2 and suppress oxidative stress by reduced ROS production. Mechanistically, these efficacies against testicular aging may be mediated by hUMSC-Exos miRNAs. Conclusions: Our findings suggest that hUMSC-Exos therapy presents a viable strategy to ameliorate testicular aging, underscoring its potential therapeutic significance in managing testicular aging.

Abstract The joint detection and re-identification (re-ID) strategy shares network features of detection and re-ID, sacrifices the complex probability graph model pairing strategy, and consolidates a two-stage video tracking process into a one-stage, making the multi-object tracking process simple, fast, and accurate. In dense scenes, identified transfer is a major challenge for joint detection and re-ID. To this end, a probability graph model suitable for joint detection and re-ID is presented. The proposed model abandons the idea of matching candidate detections with historical detections in a classical probability graph, uses a scheme to calculate the degree of matching between candidate detections and historical trajectories, and transforms task of ID matching in re-ID process into an energy minimization problem of a conditional random field (CRF). However, the solution space of general CRF is complex and requires an iterative search. To achieve efficient online tracking, the original CRF problem is approximately transformed into a combination of multiple CRF problems with closed-form solutions. Moreover, the proposed algorithm has been applied in practical applications using an edge-cloud model that maintains the balance between performance and efficiency. Extensive experiments on the well-known MOTchallenge benchmark demonstrate the superior performance of the proposed algorithm.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) seriously affects the physical and mental health of approximately 90% of males. Due to its complex and unclear etiology, the treatment methods that are currently available for chronic prostatitis/chronic pelvic pain syndrome are controversial, and their efficacy is unsatisfactory. At present, most researchers believe that this kind of prostatitis is caused by autoimmune inflammation. Chinese herbs, which are the essence of traditional Chinese medicine (TCM), are emerging treatment options for inflammation and immune diseases. In this experiment, we investigated the effect of Ningmitai capsules (a kind of traditional Chinese medicine widely used to treat lower urinary tract inflammation and pain in males) on chronic prostatitis/chronic pelvic pain syndrome in a non-obese diabetes-experimental autoimmune prostatitis (NOD-EAP) mouse model. First, by using bioinformatics analysis of data from the Encyclopedia of Traditional Chinese Medicine (ETCM) database, we found that quercetin, which is one of the main components of Ningmitai capsules, could reduce the secretion of CCL2 by inhibiting the MAPK pathway. In animal experiments, it was found that after Ningmitai treatment, the inflammation in mouse prostates was alleviated, the expression of CCL2, which is related to pain, and MAPK pathway components were downregulated, and the activation of the inflammatory NF–κB and STAT3 pathways was reduced. Pelvic pain and inflammation were relieved in mice with EAP. Due to the presence of the blood–prostate barrier, the drug may not completely reach the prostate directly and take effect locally. However, we found that after Ningmitai treatment, the proportions of proinflammatory CD11b+Ly6Chigh immune cells in the spleen, bloodstream (systemic immunity), and prostate (local immunity) were reduced. The infiltration of CD11b+ immune cells into the spleen and prostate was decreased. These findings suggested that Ningmitai can treat chronic prostatitis/chronic pelvic pain syndrome by affecting systemic and local immunities through the CCL2–MAPK pathway.

Abstract Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) seriously affects patient health. Despite the elusiveness of innate therapeutic effects, mesenchymal stromal cells (MSCs) hold great promise for inflammation-related diseases. Recent evidence indicates that disease-specific inflammatory cytokines could enhance the therapeutic effects of MSCs. Methods By establishing a CP/CPPS mouse model and pretreating MSCs with the cytokine interleukin-1β (IL-1β), we studied the IL-1β-primed MSC immunoregulatory ability and targeted migration ability in vitro and in CP/CPPS mice. Results IL-1β levels significantly increased in the prostate tissue and serum of experimental autoimmune prostatitis (EAP) mice. Pretreatment with IL-1β enhanced the immunomodulatory potential and targeted migration of MSCs in vitro. Furthermore, intravenous infusion of IL-1β-primed MSCs dampened inflammation in prostate tissues and alleviated hyperalgesia in EAP mice. The infused MSCs inhibited monocyte infiltration and promoted regulatory T lymphocyte formation in prostate tissue, thus remodeling the local environment. Surprisingly, IL-1β-primed MSCs exhibited improved accumulation in the spleen but not in prostate tissue. Accordingly, infused MSCs reshaped systemic immunity by reducing the proportion of Ly6ChighCD11b+ monocytes and boosting the proportion of CD4+Foxp3+ regulatory T lymphocytes in the spleen and lung. Inflammatory chemokine (C–C motif) ligand 2 (CCL2) decreased through the downregulation of the NF-κB and JNK/MAPK pathways by inflammatory resolution via MSCs infusion to alleviate pain. Conclusion In summary, IL-1β-primed MSCs restored systemic immunologic homeostasis to alleviate CP/CPPS by modulating systemic immunity. These findings provide a novel strategy to boost the therapeutic effects of MSC-based therapy for CP/CPPS and reveal the essential role of systematic immunity in the treatment of CP/CPPS with MSC infusion.

Testicular torsion-detorsion is an ischaemia-reperfusion-induced male gonad injury that may lead to male infertility. Oxidative stress plays an important role in the ischaemia-reperfusion injury. Icariside II (ICA II) prevents oxidative stress and has obvious protective effects on spermatogenic function. The present study was aimed to investigate therapeutic potentials of ICA II on testicular torsion. 72 mice were randomly divided into three groups: sham-operated control group (n = 24), testicular ischemia-reperfusion + saline group (n = 24) and testicular ischemia-reperfusion + icariside II treated group (n = 24). Testicular ischemia-reperfusion was induced by the left testis rotated 360 degrees in a clockwise direction for 30 minutes followed by detorsion, the contralateral testis was removed. ICA II in saline (5 mg/kg/day) was administrated by gavage immediately after detorsion. The results demonstrated that ICA II alleviated testicular damage by mitigating spermatogenic cell injury and improving testosterone production in mouse models of testicular torsion. We revealed that ICA II alleviated oxidative stress and apoptosis in the testes, reduced inflammatory infiltration and accelerated angiogenesis. Briefly, ICA II administration ameliorated testicular damage by improving spermatogenic function and testosterone production, which supports its use as a pharmacological treatment of testicular torsion.

The elderly males undergo degenerative fertility and testicular endocrine function that jeopardize the reproductive health and well-being. However, the mechanisms underlying reproductive aging are unclear. Here, we tried to address this by investigating the phenotypes and transcriptomes of seven regions of the male mouse reproductive tract: the testis, efferent ductules, initial segment, caput, corpus and cauda epididymidis, and vas deferens, in adult (3 months) and aged (21 months) mice. Quantitative PCR, immunohistochemistry, immunofluorescent staining, and enzyme-linked immunosorbent assay were performed for the analysis of gene expression in mice, human tissues, and semen samples. Aged male mice showed both systematic and reproductive changes, and remarkable histological changes were detected in the testis and proximal epididymis. Transcriptomes of the male reproductive tract were mapped, and a series of region-specific genes were identified and validated in mouse and/or human tissues, including Protamine 1 (Prm2), ADAM metallopeptidase domain 28 (Adam28), Ribonuclease A family member 13 (Rnase13), WAP four-disulfide core domain 13 (Wfdc13), and Wfdc9. Meanwhile, age-related transcriptome changes of different regions of the male reproductive tract were characterized. Notably, increased immune response was functionally related to the male reproductive aging, especially the T cell activation. An immune response-associated factor, phospholipase A2 group IID (Pla2g2d), was identified as a potential biomarker for reproductive aging in mice. And the PLA2G2D level in human seminal plasma surged at approximately 35 years of age. Furthermore, we highlighted Protein tyrosine phosphatase receptor type C (Ptprc), Lymphocyte protein tyrosine kinase (Lck), Microtubule associated protein tau (Mapt), and Interferon induced protein with tetratricopeptide repeats 3 (Ifit3) as critical molecules in the aging of initial segment, caput, caput, and cauda epididymidis, respectively. This study provides an RNA-seq resource for the male reproductive system during aging in mice, and is expected to improve our understanding of male reproductive aging and infertility.

Male infertility is a major health issue with an estimated prevalence of 4.2% of male infertility worldwide. Oxidative stress (OS) is one of the main causes of male infertility, which is characterized by excessive reactive oxygen species (ROS) or lack of antioxidants. Meanwhile, it is reported that oxidative stress plays an important role in the spermatogenic impairment in Inner mitochondrial membrane peptidase 2-like (Immp2l) mutant mice. In this study, we focused on the potential mechanism of Guilingji in protecting the spermatogenic functions in Immp2l mutant mice. The results revealed that Immp2l mutant mice exhibit impaired spermatogenesis and histology shows seminiferous tubules with reduced spermatogenic cells. After administration of Guilingji [150 mg/kg per day intragastric gavage], however, alleviated spermatogenesis impairment and reversed testis histopathological damage and reduced apoptosis. What’s more, western blotting and the levels of redox classic markers revealed that Guilingji can markedly reduce reactive oxygen species. Moreover, Guilingji treatment led to inhibition of the phosphorylation of mitogen-activated protein kinase (MAPK), regulated apoptosis in the cells. In summary, Guilingji can improve spermatogenesis in Immp2l mutant mice by regulating oxidation-antioxidant balance and MAPK pathway. Our data suggests that Guilingji may be a promising and effective antioxidant candidate for the treatment of male infertility.

Irregular text recognition of natural scene is a challenging task due to large span of character angles and morphological diversity of a word. Recent work first rectifies curved word region, and then employ sequence algorithm to complete the recognition task. However, this strategy largely depends on rectification quality of the text region, and cannot be applied to large difference between tilt angles of character. In this work, a novel anchor-free network structure of rotating character detection is proposed, which includes multiple sub-angle domain branch networks, and the corresponding branch network can be selected adaptively according to character tilt angle. Meanwhile, a curvature Adaptive Text linking method is proposed to connect the discrete strings detected on the two-dimensional plane into words according to people's habits. We achieved state-of-the-art performance on two irregular texts (TotalText, CTW1500), outperforming state-of-the-art by 2.4% and 2.7%, respectively. The experimental results demonstrate the effectiveness of the proposed algorithm.

Due to high performance and low power consumption, heterogeneous processors are widely used in many real-time systems. In these systems, if tasks are not completed before deadline, it will cause disastrous consequences, and thus it is important to provide fault-tolerance. This paper proposes a novel, adaptive and transient fault-tolerant scheduling algorithm to solve the fault-tolerant problem in heterogeneous real-time systems, aiming to improve system reliability within a given deadline. Since task replication is efficient in improving system reliability, the proposed algorithm supports multiple replicas for each primary task and allows the primary tasks and their replicas to be scheduled on the same processor to increase reliability and lower latency. Also, the algorithm can dynamically adjust the number of replicas for each task to accommodate the deadline and ensure higher reliability. Simulated results show that the proposed algorithm can achieve higher reliability in comparison with existing and related fault-tolerant algorithms. To be specific, the proposed algorithm can obtain the reliability of 89.37% whereas the two existing algorithms DB-FTSA and FTSA obtain the reliability of 47.05% and 84.75% for the benchmark of sixty tasks, respectively, to be detailed in Fig. 4 in experiment.

Crowd behavior refers to a collective behavior composed of two or more individuals who influence, interact, and depend on each other for a specific goal. Compared with an ordinary crowd behavior, the probability of a dangerous crowd behavior is much smaller. Video-based crowd behavior recognition can be categorized as one multi-label classification task, which is characterized by complex scenes and imbalanced samples. Aimed at tackling problems of imbalanced samples and multi-label task, a classification method of associative subspace is proposed. For a single category (called main category) with fewer samples, this paper generates a special subspace wherein it is relatively easy to distinguish these samples by association with other categories. A classifier that can weaken the main category and strengthen relationship between the main category and other categories is designed in the subspace. Therefore, the main category can contribute to reducing dependence on the number of samples with the above-mentioned classifier in the corresponding subspace. In order to make full use of the relevant information concerning categories, multi-label information is further injected into spatio-temporal features of video action representation. Experiments on a challenging WWW dataset show that both the proposed subspace method and multi-label information fusion mechanism are efficient.

Objective: To explore the correlates of sexual dysfunction and lower urinary tract symptoms (LUTS) in male patients with urinary bladder stones and to determine the effect of stone extraction on recovery of sexual function.Materials and Methods: A total of 87 male patients with primary bladder stones were studied from January 2015 to May 2016. All patients underwent pneumatic lithotripsy for bladder stones. Sexual dysfunction was assessed based on sexual function assessment scales. The relationship of bladder stones with sexual dysfunction or LUTS was assessed using a two-sample t-test. Postoperative improvement of sexual function was assessed by repeated measures Analysis of Variance (ANOVA).Results: Forty-one patients had primary bladder stones and 46 had secondary stones from the kidneys. Eighty-three of 87 patients (95%) had sexual dysfunction; 79 patients (91%) had both sexual dysfunction and LUTS. There was a significant association between bladder stones and sexual dysfunction, between sexual dysfunction and LUTS, and between bladder stone and LUTS (p < 0.05). There was no significant association between the course of illness, size and number of bladder stones, or urinary tract infection with sexual function (p > 0.05). In addition, among 83 patients with both bladder stone and sexual dysfunction, 61 patients (73%) had benign prostatic hyperplasia (BPH) and 22 patients (27%) had no BPH. On postoperative evaluation at 3 months, sexual dysfunction scores were significantly improved in 77 patients (88.5%)Conclusion: Patients with bladder stones have a high incidence of sexual dysfunction, particularly those with co-existing LUTS and BPH. About 1/3 patients without BPH had sexual dysfunction and surgical removal of bladder stones significantly improved sexual function and LUTS.

Introduction: Stem cell therapies represent a promising new frontier for the treatment of refractory diabetic erectile dysfunction (DED). The use of stem cell-derived extracellular vesicles (EVs) is a novel strategy for cell-free stem cell therapy. We have reported that urine-derived stem cells (USCs) can improve DED; however, the therapeutic effects of EVs secreted by USCs (USC-EVs) remain unknown. Aim: To determine the therapeutic effects of USC-EVs on DED in a rat model. Methods: USC-EVs were isolated from conditioned medium by ultracentrifugation. DED was induced in male Sprague–Dawley rats via an intraperitoneal injection of streptozotocin. Sixteen DED rats were divided into phosphate-buffered saline (PBS) and USC-EV groups. Eight normal rats served as the normal control group. PBS or USC-EVs were transplanted into the corpora cavernosa in the corresponding groups. Main Outcome Measure: Intracavernosal pressure (ICP), mean arterial pressure (MAP), expression of endothelial markers (CD31), endothelial nitric oxide synthase (eNOS), phospho-eNOS, and neural nitric oxide synthase (nNOS) were assessed in each group. Masson’s trichrome staining was used to determine the collagen deposition and ratio of smooth muscle cells to collagen. The microRNA (miRNA) cargo of USC-EVs was characterized by high-throughput RNA sequencing. Results: Recovery of erectile function was observed in the USC-EV group, as represented by improved ICP and ICP/MAP ratio. CD31, eNOS, phospho-eNOS, and nNOS expression in the penis was significantly improved in the USC-EV group. In addition, the ratio of smooth muscle to collagen was significantly increased in the USC-EV group. RNA sequencing revealed that USC-EVs were enriched for distinct classes of miRNA (miR-21-5p, let-7 family, miR-10 family, miR-30 family, and miR-148a-3p) that promote angiogenesis. Conclusion: USC-EV transplantation can ameliorate DED in rats. Its mechanism may involve the delivery of proangiogenic miRNA.Ouyang B, Xie Y, Zhang C, et al. Extracellular Vesicles From Human Urine-Derived Stem Cells Ameliorate Erectile Dysfunction in a Diabetic Rat Model by Delivering Proangiogenic MicroRNA. Sex Med 2019;7:241–250. Key Words: Erectile Dysfunction, Sexual Dysfunction, Stem Cells, Extracellular Vesicles, Diabetes, Endothelial Dysfunction

Male infertility has become an important health problem that is primarily caused by testicular dysfunction with abnormal spermatogenesis. In this study, we demonstrated that the neuropeptide, substance P (SP), is essential for spermatogonia proliferation in a seminiferous tubule culture system. In addition, SP (5 nmol/kg) treatment markedly restored spermatogenesis, improved sperm quality, and increased the number of ZBTB16+ or LIN28+ undifferentiated spermatogonia as well as STRA8+ differentiated spermatogonia in a busulfan-induced non-obstructive azoospermic mouse model. Furthermore, 100 nM SP treatment in vitro significantly stimulated the proliferation of GC-1 spg cells (a spermatogonia cell line) via activation of the Erk1/2 signaling pathway. Moreover, the sperm quality and the number of spermatogonia were significantly reduced after treatment with RP67580, a selective NK-1 receptor antagonist, suggesting that SP-NK1R signaling plays an important role in spermatogenesis. Taken together, these results suggest that SP may be a potential therapeutic agent for male infertility by accelerating the restoration of spermatogenesis.

Experimental autoimmune prostatitis (EAP) is a well-established model induced by an autoimmune response to prostate antigen. The symptomatic, pathological, and immunological characteristics of EAP animals are highly consistent with human chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), which makes EAP an ideal model for this disease. Here, we investigate the influence of EAP on male rat sexual function and the efficacy of anti-inflammatory therapy with celecoxib. EAP rat models were established using male Wistar rats. Rats were randomly assigned to a normal control group, an EAP model group, or an EAP model with celecoxib treatment group (celecoxib group). Behavioral changes, sexual behavioral changes, and erectile function were estimated using an open-field test, a sucrose consumption test, mating experiments, and by intracavernous pressure/mean arterial pressure ratio (ICP/MAP). Histological changes in the prostate were observed by HE staining, and the serum inflammatory factors IL-1β and TNF-α levels were measured by enzyme-linked immunosorbent assay. In addition, serotonin (5-hydroxytryptamine, 5-HT), 5-HT1A receptor, 5-HT2C receptor, and serotonin transporter (SERT) expression levels in the hippocampus and spinal cord (T13–L1, L5–S2) were examined by immunohistochemistry and western blot analysis. Results showed that EAP rats exhibited characteristics of depression, decreased sexual drive, premature ejaculation, and increased threshold of penile erection. Moreover, all these changes were effectively alleviated by celecoxib. Significant increases in prostatic interstitial infiltration by inflammatory cells and in serum IL-1β and TNF-α levels were observed in EAP rats, and these were partially reduced by celecoxib. Additionally, the expression pattern of serotonin system regulators in the hippocampus and spinal cord were altered in EAP model rats, including a decrease in 5-HT levels and an increase in 5-HT1A receptor levels. In conclusion, autoimmune prostatitis impaired rat sexual function, and this was effectively prevented by anti-inflammatory therapy with celecoxib. Moreover, a serotonin system disorder in the central nervous system was likely mediated via inflammation in EAP rats.

Background. There are no proven effective treatments that can reduce the mortality in heart failure with preserved ejection fraction (HFpEF), probably due to its heterogeneous nature which will weaken the effect of therapy in clinical studies. We evaluated the effect of beta-blocker treatment in HFpEF patients associated with atrial fibrillation (AF), which is a homogeneous syndrome and has seldom been discussed. Methods. This retrospective cohort study screened 955 patients diagnosed with AF and HFpEF. Patients with a range of underlying heart diseases or severe comorbidities were excluded; 191 patients were included and classified as with or without beta-blocker treatment at baseline. The primary outcome was all-cause mortality and rehospitalization due to heart failure. Kaplan-Meier curves and multivariable Cox proportional-hazards models were used to evaluate the differences in outcomes. Results. The mean follow-up was 49 months. After adjustment for multiple clinical risk factors and biomarkers for prognosis in heart failure, patients with beta-blocker treatment were associated with significantly lower all-cause mortality (hazard ratio (HR) = 0.405, 95% confidence interval (CI) = 0.233–0.701, p=0.001) compared with those without beta-blocker treatment. However, the risk of rehospitalization due to heart failure was increased in the beta-blocker treatment group (HR = 1.740, 95% CI = 1.085–2.789, p=0.022). There was no significant difference in all-cause rehospitalization between the two groups (HR = 1.137, 95% CI = 0.803–1.610, p=0.470). Conclusions. In HFpEF patients associated with AF, beta-blocker treatment is associated with significantly lower all-cause mortality, but it increased the risk of rehospitalization due to heart failure.

Erectile dysfunction (ED) is a common complication in men suffered with diabetic mellitus. Stem cell transplantation is a promising strategy for the treatment of diabetic ED (DED). In this study, we evaluated whether combined transplantation of adipose tissue-derived stem cells (ADSCs) and endothelial progenitor cells (EPCs) could improve the erectile function of the DED rat model. DED rats were induced via intraperitoneal injection of streptozotocin (50 mg/kg), and ED was screened by apomorphine (100 mg/kg). DED rats were divided into 4 groups (n=14 each): DED, ADSC, EPC, and ADSC/EPC group. Another 14 age-matched male SD rats with normal erectile function were served as the normal group. The normal group and the DED group were received intracavernous injection with phosphate-buffered saline (PBS). And the other groups were received intracavernous injection with ADSCs (1×106), EPCs (1×106), and ADSCs/EPCs (0.5×106/0.5×106), respectively. The total intracavernous pressure (ICP) and mean arterial pressure (MAP) were recorded at day 28 after injection. The endothelium, smooth muscle, and penile dorsal nerves were assessed within cavernoursal tissue. On day 28 after injection, the ADSC/EPC group displayed more significantly enhanced ICP and ICP/MAP than the DED or ADSC or EPC group (p

Abstract Endothelial cells (ECs) play a key role in revascularization within regenerating tissue. Stem cells are often used as an alternative cell source when ECs are not available. Several cell types have been used to give rise to ECs, such as umbilical cord vessels, or differentiated from somatic stem cells, embryonic, or induced pluripotent stem cells. However, the latter carry the potential risk of chronic immune rejection and oncogenesis. Autologous endothelial precursors are an ideal resource, but currently require an invasive procedure to obtain them from the patient's own blood vessels or bone marrow. Thus, the goal of this study was to determine whether urine‐derived stem cells (USCs) could differentiate into functional ECs in vitro. Urine‐derived cells were then differentiated into cells of the endothelial lineage using endothelial differentiation medium for 14 days. Changes in morphology and ultrastructure, and functional endothelial marker expression were assessed in the induced USCs in vitro. Grafts of the differentiated USCs were then subcutaneously injected into nude mice. Induced USCs expressed significantly higher levels of specific markers of ECs (CD31, vWF, eNOS) in vitro and in vivo, compared to nondifferentiated USCs. In addition, the differentiated USC formed intricate tubular networks and presented similar tight junctions, and migration and invasion ability, as well as ability to produce nitric oxide (NO) compared to controls. Using USCs as autologous EC sources for vessel, tissue engineering strategies can yield a sufficient number of cells via a noninvasive, simple, and low‐cost method suitable for rapid clinical translation. Stem Cells Translational Medicine 2018 Stem Cells Translational Medicine 2018;7:686–698

Abstract By introducing a new superquadratic condition, we obtain the existence of two nontrivial homoclinic solutions for a class of perturbed second order Hamiltonian systems which are obtained by the mountain pass theorem and Ekeland’s variational principle.

Aims. Cavernosal endothelial dysfunction is one of the factors in developing diabetic erectile dysfunction (DED), but the mechanism of cavernosal endothelial dysfunction is unclear. The present study is aimed at determining the contribution of autophagy in cavernosal endothelial dysfunction of DED rats and explaining the therapeutic effect of urine-derived stem cells (USCs). Methods. After rat corpus cavernosal vascular endothelial cells (CCECs) were isolated and cultured in vitro, CCECs were treated with advanced glycation end products (AGEs) to mimic the diabetic situation. Autophagy flux, proliferation, and apoptosis of CCECs were determined by mRFP-GFP-LC3 adenovirus infection combined with fluorescence observation and western blot analysis. USCs were isolated from the urine of six healthy male donors, and coculture systems of USCs and CCECs were developed to assess the protective effect of USCs for CCECs in vitro. The contribution of autophagy to the cellular damage in CCECs was evaluated by the autophagic inhibitor, 3-methyladenine (3-MA). Then, DED rats were induced by streptozotocin (50 mg/kg) and screened by apomorphine test (100 μg/kg). In DED rats, USCs or PBS as vehicle was administrated by intracavernous injection (n=15 per group), and another 15 normal rats served as normal controls. Four weeks after injection, erectile function was evaluated by measuring the intracavernosal pressure (ICP) and mean arterial pressure (MAP). Cavernosal endothelial function and autophagic activity were examined by western blot, immunofluorescence, and transmission electron microscopy. Results. In vitro, AGE-treated CCECs displayed fewer LC3 puncta formation and expressed less LC3-II, Beclin1, and PCNA but expressed more p62 and cleaved-caspase3 than controls (p

We study the planar symmetric central configurations of the 1 + 4-body problem where the symmetry axis does not contain any infinitesimal masses. Under certain assumptions, we find analytically some central configurations for suitable positive masses and also get some numerical results of symmetric central configurations where infinitesimal masses are not necessarily equal.

The aim of this study was to investigate whether intracavernous injection of urine-derived stem cells (USCs) or USCs genetically modified with pigment epithelium-derived factor (PEDF) could protect the erectile function and cavernous structure in a bilateral cavernous nerve injury-induced erectile dysfunction (CNIED) rat model. USCs were cultured from the urine of six healthy male donors. Seventy-five rats were randomly divided into five groups ( n = 15 per group): sham, bilateral cavernous nerve (CN) crush injury (BCNI), USC, USC GFP+ , and USC GFP/PEDF+ groups. The sham group received only laparotomy without CN crush injury and intracavernous injection with phosphate-buffered saline (PBS). All of the other groups were subjected to BCNI and intracavernous injection with PBS, USCs, USCs GFP+ , or USCs GFP/PEDF+ , respectively. The total intracavernous pressure (ICP) and the ratio of ICP to mean arterial pressure (ICP/MAP) were recorded. The penile dorsal nerves, the endothelium, and the smooth muscle were assessed within the penile tissue. The USC and USC GFP/PEDF+ groups displayed more significantly enhanced ICP and ICP/MAP ratio ( p < 0.05) 28 days after cell transplantation. Immunohistochemistry (IHC) and Western blot analysis demonstrated that the protection of erectile function and the cavernous structure by USCs GFP/PEDF+ was associated with an increased number of nNOS-positive fibers within the penile dorsal nerves, improved expression of endothelial markers (CD31 and eNOS) and a smooth muscle marker (smoothelin), an enhanced smooth muscle to collagen ratio, decreased expression of transforming growth factor-β1 (TGF-β1), and decreased cell apoptosis in the cavernous tissue. The paracrine effect of USCs and USCs GFP/PEDF+ prevented the destruction of erectile function and the cavernous structure in the CNIED rat model by nerve protection, thereby improving endothelial cell function, increasing the smooth muscle content, and decreasing fibrosis and cell apoptosis in the cavernous tissue.

The paracrine effect is the major mechanism of stem cell therapy. However, the details of the effect’s mechanism remain unknown. The aim of this study is to investigate whether adipose tissue-derived stem cells (ADSCs) can ameliorate cavernous nerve injury-induced erectile dysfunction (CNIED) rats and to determine its mechanism. Twenty-eight days after intracavernous injection of 5-ethynyl-2-deoxyuridine- (EdU-) labeled ADSCs, the erectile function of all the rats was evaluated by intracavernosal pressure (ICP). The ADSCs steadily secreted detectable pigment epithelium-derived factor (PEDF) in vitro. The expression of PEDF increased in the penis of the bilateral cavernous nerve injury (BCNI) group for 14 days and then gradually decreased. On day 28 after the intracavernous injection, the ADSCs group exhibited a significantly increased ICP compared with the phosphate buffered saline- (PBS-) treated group. Moreover, the neuronal nitric oxide synthase (nNOS) and S100 expression in penile dorsal nerves and the smooth muscle content to collagen ratio in penile tissues significantly increased. Furthermore, elevated PEDF, p-Akt, and p-eNOS were identified in the ADSCs group. This study demonstrated that intracavernous injection of ADSCs improved erectile function, repaired the nerve, and corrected penile fibrosis. One potential mechanism is the PEDF secretion of ADSCs and subsequent PI3K/Akt pathway activation.

The aim of this study was to investigate the prevalence of erectile dysfunction (ED) in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and explore the influence of UPOINT domains, National Institutes of Health-CP symptom index (NIH-CPSI) and other factors on ED prevalence. This was a prospective study of consecutive patients with CP/CPPS seen at 11 tertiary hospitals during January-July 2014. ED was diagnosed as a score of

Robertsonian translocations (ROBs) have an estimated incidence rate of 1/1000 births, making this type of rearrangement the most common structural chromosomal abnormalities seen in the general population. In this study, we reports 872 cases of ROBs from 205,001 specimens karyotyped postnatally in a single accredited laboratory in China, including 583 balanced ROBs, 264 unbalanced ROBs, 9 mosaic ROBs, and 18 complex ROBs. Ninety-three percent of the balanced ROBs observed were adults with infertility, miscarriage, or offspring(s) with known chromosomal abnormalities. Significant excess of females were found to be carriers of balanced ROBs with an adjusted male/female ratio of 0.77. Ninety-eight percent of the unbalanced ROBs observed were children with variable referral reasons. Almost all of the unbalanced ROBs involved chromosome 21 except a single ROB with [46,XX,der(13;14),+13] identified in a newborn girl with multiple congenital anomalies. Multiple novel ROB karyotypes were reported in this report. This study represents the largest collections of ROBs in Chinese population.

AIM: The aim of this study was to determine the possibility of improving erectile dysfunction using cell therapy with either human urine-derived stem cells (USCs) or USCs genetically-modified with FGF2 in a type 2 diabetic rat model. METHODS: Human USCs were collected from 3 healthy donors. USCs were transfected with FGF2 (USCs-FGF2). Sixty-five SD male rats were divided into five groups (G). A control group of normal rats (G1, n = 10), and four other test groups of type 2 diabetic erectile dysfunction rats: PBS as a negative control (G2, n = 10), USCs (G3, n = 15), lentivirus-FGF2 (G4, n = 15), and USCs-FGF2 (G5, n = 15). Diabetes was induced in the rats via a high fat diet for 28 days and a subsequent intraperitoneal injection of streptozotocin (35 mg/kg). Erectile dysfunction was screened with apomorphine (100 μg/kg). Cell injections in the test groups (G2-G5) occurred directly into the corpora cavernosa. The implanted cells were tracked at 7 days (n = 5 animals/G) and 28 days (n = 10 animals/G) post injection. Mean arterial pressure (MAP), intracavernosal pressure (ICP), expression of endothelial markers (CD31, VEGF and eNOS), smooth muscle markers (desmin and smoothelin), histological changes and erectile function were assessed for each group. RESULTS: USCs expressed mesenchymal stem cell markers, and secreted a number of proangiogenic growth factors. USCs expressed endothelial cell markers (CD31 and vWF) after transfection with FGF2. Implanted USCs or USCs-FGF2 displayed a significantly raised ICP and ICP/MAP ratio (p

The aim of this study was to determine whether adipose derived stem cells (ADSCs) expressing vascular endothelial growth factor (VEGF) gene can improve endothelial function, recover the impaired VEGF signaling pathway and enhance smooth muscle contents in a rat diabetic erectile dysfunction (DED) model. DED rats were induced via intraperitoneal injection of streptozotocin (40 mg/kg), and then screened by apomorphine (100 µg/kg). Five groups were used (n = 12/group)-Group 1 (G1): intracavernous injection of lentivirus-VEGF; G2: ADSCs injection; G3: VEGF-expressing ADSCs injection; G4: Phosphate buffered saline injection; G1-G4 were DED rats; G5: normal rats. The mean arterial pressure (MAP) and intracavernosal pressure (ICP) were measured at days 7 and 28 after the injections. The components of the VEGF system, endothelial, smooth muscle, pericytes markers in cavernoursal tissue were assessed. On day 28 after injection, the group with intracavernosum injection of ADSCs expressing VEGF displayed more efficiently and significantly raised ICP and ICP/MAP (p

BACKGROUND: Insulin resistance (IR) triggers endothelial dysfunction, which contributes to erectile dysfunction (ED) and cardiovascular disease. AIM: To evaluate whether IR was related to ED in young adult patients. METHODS: A total of 283 consecutive men complaining of ED at least six months were enrolled, with a full medical history, physical examination, and laboratory tests collected. Quantitative Insulin Sensitivity Check Index (QUICKI) was used to determine IR. The severity of ED was assessed by IIEF-5 questionnaire. Endothelial function was assessed by ultrasonographic examination of brachial artery flow mediated dilation (FMD). RESULTS: IR was detected in 52% patients. Subjects with IR had significant higher total cholesterol, triglycerides, low density lipoprotein-cholesterol (LDL-c), glycated haemoglobin (HBA1c), high sensitivity C-reactive protein (hs-CRP) and body mass index (BMI), but showed significant lower IIEF-5 score, FMD%, high density lipoprotein -cholesterol (HDL-c), testosterone, sex hormone binding globulin (SHBG) levels than patients without IR. Multiple regression analysis showed QUICKI and testosterone were independent predictors of IIEF-5 score. Furthermore, the incidence of IR was correlated with the severity of ED. CONCLUSIONS: Compared with other CVFs, IR was found as the most prevalent in our subjects. Besides, IR was independently associated with ED and its severity, suggesting an adverse effect of insulin resistance on erectile function.