From Waterloo to the Great Wall: A retrospective, multicenter study on the clinical practice and cultural attitudes in the management of premature ejaculation, in China.

Premature ejaculation (PE), despite its wide prevalence, is largely underdiagnosed and undertreated. Being a multifactorial dysfunction with strong cultural characteristics, PE requires skillful attitudes in the psychosexological support, necessary to manage the patient's and the couple's expectations, as well as in the medical treatment. Dapoxetine is a short-acting selective serotonin reuptake inhibitor approved for use in lifelong and acquired PE in a number of countries. Opinions, not always generated by the evidence-based medicine, impacted the attitudes of Western andrologists, as a nocebo effect which produced a drug's Waterloo, characterized by low prescription rates much more built on the patients' and doctors' expectations than on costs, side effects, and efficacy. In the present study, we retrospectively reviewed real-life data from eight Andrology and Sexual Medicine Public Centers in China to assess the prevalence of PE among attending patients, its association with erectile dysfunction, its subtype, and the proposed treatments. In 2019, among 156,486 patients coming to the centers, 32,667 visits having PE as the chief complaint were performed (20.9%). Almost all patients received treatment prescriptions (32,641 patients, 99.92%); 23,273 patients came back for a follow-up visit in the subsequent 12 months (71.2% of those who initially received treatment). Dapoxetine, either alone or in combination with another therapy, was the most prevalent treatment, prescribed to 22,767 patients (69.7% of treated patients), followed by traditional Chinese medicine (TCM) (39.4%). At follow-up, 8174 patients were unsatisfied with treatment, and a new treatment was proposed (35.12%). Dapoxetine was the best treatment, with an overall 27.1% switching rate when used either alone or in combination: Although the switching rate for Dapoxetine alone was 44.2%, the association of the same drug with psychotherapy resulted in much lower rates (19.5%) and reached a minimum of 12% when also combined with TCM demonstrating how cultural aspects and medical attitudes may dramatically impact on the therapy of a multifaceted, complex, and culture-grounded sexual symptom such as PE. In conclusion, taking switching rates as surrogate markers of treatment failure, this real-life study-the largest in the field-shows that in a more patient-oriented (as in Chinese medical culture), and less symptom-oriented (as in Western medical attitudes), Dapoxetine is a successful treatment for PE patients, with higher reliability when used alone or as part of combined and integrated therapies.

Association between central obesity and semen quality: A cross-sectional study in 4513 Chinese sperm donation volunteers.

BACKGROUND: General obesity classified by body mass index has been linked to a reduction in semen quality; however, evidence on the adverse effect of central obesity on semen quality remains limited. OBJECTIVES: To investigate the association between central obesity and semen quality. MATERIALS AND METHODS: We conducted a cross-sectional study of 4513 sperm donation volunteers in Guangdong Provincial Human Sperm Bank during 2018-2021. Three central obesity indicators, including waist circumference, waist-to-hip ratio, and waist-to-height ratio, were measured using a multi-frequency bioelectrical impedance analysis for each subject. Semen analysis was conducted according to the World Health Organization laboratory manual for the examination and processing of human semen 5th edition. Linear regression models and unconditional logistic regression models were used to quantify the association between central obesity and semen parameters. RESULTS: With adjustment for age, race, education level, marital status, fertility status, occupation, year of semen collection, abstinence period, ambient temperature, and relative humidity, central obesity defined as waist circumference ≥90 cm, waist-to-hip ratio ≥0.9, or waist-to-height ratio ≥0.5 was significantly associated with a 0.27 (95% confidence interval: 0.15, 0.38) mL, 14.47 (3.60, 25.34) × 106 , 7.06 (0.46, 13.76) × 106 , and 6.80 (0.42, 13.18) × 106 reduction in semen volume, total sperm number, total motile sperm number, and total progressive motile sperm number, respectively, and a 53% (10%, 112%) increase in odds of below the World Health Organization 2010 reference value for semen volume. These associations did not significantly vary across age. Similar results were observed for central obesity defined using each of the three indicators, except that subjects with a waist circumference ≥90 cm had a slightly higher total motility (estimated change: 1.30%; 95% confidence interval: 0.27%, 2.34%) and progressive motility (estimated change: 1.27%; 95% confidence interval: 0.23%, 2.31%). DISCUSSION AND CONCLUSION: We found that central obesity was significantly associated with a reduction in semen volume, total sperm number, total motile sperm number, and total progressive motile sperm number. Future studies are warranted to confirm our results in other regions and populations.

Alterations of small non-coding RNA in the spermatozoa of mice with paternal experimental autoimmune epididymo-orchitis are associated with metabolic dysfunction in offspring.

BACKGROUND: Infection and inflammation of the genital tract are major potentially treatable factors contributing to male infertility. The profile of small non-coding RNA (sncRNAs) in spermatozoa can be altered by environmental exposures and inflammatory conditions. OBJECTIVES: Experimental autoimmune epididymo-orchitis (EAEO) is a well-established model of autoimmune-induced chronic testicular and epididymal inflammation. This model investigates the effect of chronic inflammation on sperm sncRNA profiles and offspring phenotypes. MATERIALS AND METHODS: Regarding the EAEO model, mice were immunized with testis homogenates thrice. Subsequently, flow cytometry and histological analyses were conducted on EAEO mice. Next-generation sequencing was used to profile small RNA of spermatozoa from the caput, corpus, and cauda epididymis. We performed a comprehensive integrative analysis of sperm sncRNAs and chronic epididymitis and identified their molecular signatures. The metabolic functions of the first-generation (F1) offspring were evaluated using a glucose tolerance test (GTT). RESULTS: Body weight and metabolic function were significantly altered in F1 offspring from EAEO sperm donors. The analysis of cauda sperm sncRNA profiles revealed that the proportions of miRNAs and tsRNAs increased and decreased, respectively, after autoimmunization. Three differentially expressed miRNAs and seven differentially expressed tsRNAs were significantly correlated with F1 metabolic dysfunction. The expression patterns of miRNAs and tsRNAs in mice partially overlapped with those observed in the spermatozoa from human patients with chronic epididymitis. DISCUSSION AND CONCLUSIONS: We revealed that autoimmune epididymo-orchitis alters sncRNA profiles in mouse spermatozoa. Offspring from mice with autoimmune orchitis develop metabolic disorders. A comprehensive analysis of human and mouse inflammation data revealed an association between alterations in the miRNA and tsRNA profiles of epididymal spermatozoa and offspring phenotypes.

Adrenomedullin has a pivotal role in trophoblast differentiation: A promising nanotechnology-based therapeutic target for early-onset preeclampsia.

Early-onset preeclampsia (EOPE) is a severe pregnancy complication associated with defective trophoblast differentiation and functions at implantation, but manifestation of its phenotypes is in late pregnancy. There is no reliable method for early prediction and treatment of EOPE. Adrenomedullin (ADM) is an abundant placental peptide in early pregnancy. Integrated single-cell sequencing and spatial transcriptomics confirm a high ADM expression in the human villous cytotrophoblast and syncytiotrophoblast. The levels of ADM in chorionic villi and serum were lower in first-trimester pregnant women who later developed EOPE than those with normotensive pregnancy. ADM stimulates differentiation of trophoblast stem cells and trophoblast organoids in vitro. In pregnant mice, placenta-specific ADM suppression led to EOPE-like phenotypes. The EOPE-like phenotypes in a mouse PE model were reduced by a placenta-specific nanoparticle-based forced expression of ADM. Our study reveals the roles of trophoblastic ADM in placental development, EOPE pathogenesis, and its potential clinical uses.

Heat wave exposure and semen quality in sperm donation volunteers: A retrospective longitudinal study in south China.

BACKGROUND: Previous studies have suggested an association between non-optimum ambient temperature and decreased semen quality. However, the effect of exposure to heat waves on semen quality remains unclear. METHODS: Volunteers who intended to donate sperm in Guangdong provincial human sperm bank enrolled. Heat waves were defined by temperature threshold and duration, with a total of 9 definitions were employed, specifying daily mean temperature exceeding the 85th, 90th, or 95th percentile for at least 2, 3, or 4 consecutive days. Residential exposure to heat waves during 0-90 days before ejaculation was evaluated using a validated gridded dataset on ambient temperature. Association and potential windows of susceptibility were evaluated and identified using linear mixed models and distributed lag non-linear models. RESULTS: A total of 2183 sperm donation volunteers underwent 8632 semen analyses from 2018 to 2019. Exposure to heat wave defined as daily mean temperature exceeding the 95th percentile for at least 4 consecutive days (P95-D4) was significantly associated with a 0.11 (95% confidence interval [CI]: 0.03, 0.18) ml, 3.36 (1.35, 5.38) × 106/ml, 16.93 (7.95, 25.91) × 106, and 2.11% (1.4%, 2.83%) reduction in semen volume, sperm concentration, total sperm number, and normal forms, respectively; whereas exposure to heat wave defined as P90-D4 was significantly associated with a 1.98% (1.47%, 2.48%) and 2.08% (1.57%, 2.58%) reduction in total motility and progressive motility, respectively. Sperm count and morphology were susceptible to heat wave exposure during the early stage of spermatogenesis, while sperm motility was susceptible to exposure during the late stage. CONCLUSION: Heat wave exposure was significantly associated with a reduction in semen quality. The windows of susceptibility during 0-90 days before ejaculation varied across sperm count, motility, and morphology. Our findings suggest that reducing heat wave exposure before ejaculation may benefit sperm donation volunteers and those attempting to conceive.

Myd88 Signaling Is Involved in the Inflammatory Response in LPS-Induced Mouse Epididymitis and Bone-Marrow-Derived Dendritic Cells.

Epididymitis is an epididymal inflammation that may lead to male infertility. Dendritic cells (DCs) and myeloid differentiation primary response gene 88 (Myd88) were associated with epididymitis in rodents. However, the functions of Myd88 on epididymal DCs remain unclear. This study investigated the role of Myd88 in DCs for epididymitis. The Myd88 signaling pathway, phenotypes of DC subsets, and cytokines were investigated in lipopolysaccharide (LPS)-induced epididymitis in mice. CRISPR-Cas9 was used to knockout Myd88 in bone-marrow-derived dendritic cells (BMDCs) and immortalized mouse epididymal (DC2) cell line. In the vivo experiments, levels of the proinflammatory cytokines IL-1α, IL-6, IL-17A, TNF-α, IL-1ß, MCP-1, and GM-CSF, mRNA for MyD88 related genes, and the percentages of monocyte-derived DCs (Mo-DCs) were significantly elevated in mice with epididymitis. In the vitro experiments, LPS significantly promoted the apoptosis of BMDCs. In addition, the concentration of inflammatory cytokines in BMDCs and DC2s were increased in the LPS group, while decreasing after the knockout of Myd88. These findings indicate that Myd88 on DCs is involved in the inflammation of epididymitis in mice, which may be a potential target for better strategies regarding the treatment of immunological male infertility.

Application of a JEG-3 organoid model to study HLA-G function in the trophoblast.

The human placenta is a unique temporary organ with a mysterious immune tolerance. The formation of trophoblast organoids has advanced the study of placental development. HLA-G is uniquely expressed in the extravillous trophoblast (EVT) and has been linked to placental disorders. With older experimental methodologies, the role of HLA-G in trophoblast function beyond immunomodulation is still contested, as is its role during trophoblast differentiation. Organoid models incorporating CRISPR/Cas9 technology were used to examine the role of HLA-G in trophoblast function and differentiation. JEG-3 trophoblast organoids (JEG-3-ORGs) were established that highly expressed trophoblast representative markers and had the capacity to differentiate into EVT. CRISPR/Cas9 based on HLA-G knockout (KO) significantly altered the trophoblast immunomodulatory effect on the cytotoxicity of natural killer cells, as well as the trophoblast regulatory effect on HUVEC angiogenesis, but had no effect on the proliferation and invasion of JEG-3 cells and the formation of TB-ORGs. RNA-sequencing analysis further demonstrated that JEG-3 KO cells followed similar biological pathways as their wild-type counterparts during the formation of TB-ORGs. In addition, neither HLA-G KO nor the exogenous addition of HLA-G protein during EVT differentiation from JEG-3-ORGs altered the temporal expression of the known EVT marker genes. Based on the JEG-3 KO (disruption of exons 2 and 3) cell line and the TB-ORGs model, it was determined that HLA-G has a negligible effect on trophoblast invasion and differentiation. Despite this, JEG-3-ORG remains a valuable model for studying trophoblast differentiation.

Follicular helper T lymphocytes in the endometria of patients with reproductive failure: Association with pregnancy outcomes and inflammatory status of the endometria.

PROBLEM: The phenotypes and functions of B and CD4+ T-helper cell subsets during chronic inflammation of the endometria remain largely unexplored. This study aimed to investigate the characteristics and functions of follicular helper T (Tfh) cells to understand the pathological mechanisms of chronic endometritis (CE). METHOD OF STUDY: Eighty patients who underwent hysteroscopic and histopathological examinations for CE were divided into three groups-those with positive results for hysteroscopy and CD138 staining (DP), negative results for hysteroscopy but positive CD138 staining (SP), and negative results for hysteroscopy and CD138 staining (DN). The phenotypes of B cells and CD4+ T-cell subsets were analyzed using flow cytometry. RESULTS: CD38+ and CD138+ cells were mainly expressed in the non-leukocyte population of the endometria, and the endometrial CD19+ CD138+ B cells were fewer than the CD3+ CD138+ T cells. The percentage of Tfh cells increased with chronic inflammation in the endometria. Additionally, the elevated percentage of Tfh cells correlated with the number of miscarriages. CONCLUSIONS: CD4+ T cells, particularly Tfh cells, may be critical in chronic endometrial inflammation and affect its microenvironment, thereby regulating endometrial receptivity, compared to B cells.

Integrated MicroRNA and Secretome Analysis of Human Endometrial Organoids Reveal the miR-3194-5p/Aquaporin/S100A9 Module in Regulating Trophoblast Functions.

Successful placentation requires delicate communication between the endometrium and trophoblasts. The invasion and integration of trophoblasts into the endometrium during early pregnancy are crucial to placentation. Dysregulation of these functions is associated with various pregnancy complications, such as miscarriage and preeclampsia. The endometrial microenvironment has an important influence on trophoblast cell functions. The precise effect of the endometrial gland secretome on trophoblast functions remains uncertain. We hypothesized that the hormonal environment regulates the miRNA profile and secretome of the human endometrial gland, which subsequently modulates trophoblast functions during early pregnancy. Human endometrial tissues were obtained from endometrial biopsies with written consent. Endometrial organoids were established in matrix gel under defined culture conditions. They were treated with hormones mimicking the environment of the proliferative phase (Estrogen, E2), secretory phase (E2+Progesterone, P4), and early pregnancy (E2+P4+Human Chorionic Gonadotropin, hCG). miRNA-seq was performed on the treated organoids. Organoid secretions were also collected for mass spectrometric analysis. The viability and invasion/migration of the trophoblasts after treatment with the organoid secretome were determined by cytotoxicity assay and transwell assay, respectively. Endometrial organoids with the ability to respond to sex steroid hormones were successfully developed from human endometrial glands. By establishing the first secretome profiles and miRNA atlas of these endometrial organoids to the hormonal changes followed by trophoblast functional assays, we demonstrated that sex steroid hormones modulate aquaporin (AQP)1/9 and S100A9 secretions through miR-3194 activation in endometrial epithelial cells, which in turn enhanced trophoblast migration and invasion during early pregnancy. By using a human endometrial organoid model, we demonstrated for the first time that the hormonal regulation of the endometrial gland secretome is crucial to regulating the functions of human trophoblasts during early pregnancy. The study provides the basis for understanding the regulation of early placental development in humans.

Association between exposure to ambient air pollution and semen quality: A systematic review and meta-analysis.

BACKGROUND: Accumulating evidence has linked exposure to ambient air pollution to a reduction in semen quality; however, the exposure-response associations are yet to be synthesized. OBJECTIVE: To summarize the exposure-response associations between air pollution and semen quality. METHODS: We systematically searched PubMed, Embase, and Web of Science for relevant studies published before April 20, 2022. Studies investigating the exposure-response association of PM2.5, PM10, SO2, NO2, CO, and O3 with semen quality written in English were included. Semen quality parameters included semen volume, sperm concentration, total sperm number, total motility, progressive motility, and normal forms. Random-effects and fixed-effects models were performed to synthesize associations in the meta-analysis. RESULTS: The search returned 850 studies, 11 of which were eligible for meta-analysis. Each 10 µg/m3 increase of exposure to PM10 and SO2 was respectively associated with a 2.18 % (95 % confidence interval [CI]: 0.10 %-4.21 %) and 8.61 % (1.00 %-15.63 %) reduction in sperm concentration, and a 2.76 % (0.10 %-5.35 %) and 9.52 % (5.82 %-13.93 %) reduction in total sperm number. Each 10 µg/m3 increase of exposure to PM2.5 and PM10 was respectively associated with a 1.06 % (95 % CI: 0.31 %-1.82 %) and 0.75 % (0.43 %-1.08 %) reduction in total motility, and a 0.55 % (0.09 %-1.01 %) and 0.31 % (0.06 %-0.56 %) reduction in progressive motility. No association was observed for PM2.5 or PM10 with semen volume; PM2.5, NO2, CO, or O3 with sperm concentration or total sperm number; and gaseous air pollutants with total or progressive motility. The association between air pollution and normal forms was not summarized due to insufficient number of studies. No significant publication bias was detected. CONCLUSIONS: Exposure to ambient PM2.5, PM10, and SO2 was inversely associated with sperm concentration, total sperm number, total motility, and/or progressive motility. Our findings add to the evidence that air pollution may lead to adverse effects on male reproductive system and suggest that reducing exposure to air pollution may help maintain better semen quality.

Association between ambient temperature and semen quality among sperm donation volunteers in South China.

BACKGROUND: Potential adverse effects of non-optimum temperatures on human semen quality have drawn much concern worldwide; however, the exposure-response relationship remains less understood. OBJECTIVES: To quantitatively assess the association between exposure to ambient temperature and semen quality in South China, and to identify potential critical exposure windows. METHODS: We conducted a longitudinal study to investigate 11,050 volunteers who lived in Guangdong province, China and intended to donate sperm in the Guangdong provincial human sperm bank during 2016-2021. Exposure to ambient temperature during 0-90 days before semen collection was assessed by extracting daily temperatures from a validated grid dataset at each subject's residential address. Linear mixed models and linear regression models were used to perform exposure-response analyses. RESULTS: During the study period, the 11,050 subjects underwent 44,564 semen analyses. Each 5 °C increase of lag 0-90 day exposure to ambient temperature was approximately linearly associated with a 3.11 (95 % confidence interval [CI]: 2.08, 4.14) × 106/ml, 9.31 (4.83, 13.80) × 106, 1.27 % (0.91 %, 1.62 %), 8.20 (5.33, 11.08) × 106, 1.37 % (1.01 %, 1.74 %), 8.29 (5.52, 11.06) × 106, 0.67 % (0.28 %, 1.05 %), and 4.50 (2.20, 6.80) × 106 reduction in sperm concentration, total sperm number, total motility, total motile sperm number, progressive motility, total progressive sperm number, normal forms, and total normal form sperm number, respectively (all p < 0.001), which was not significantly modified by age (all p for effect modification > 0.05). We identified a critical exposure period of 10-14 days before semen collection for sperm motility, and 70-90 days before semen collection for sperm count and morphology. CONCLUSIONS: Our study provides consistent evidence that higher ambient temperature was significantly associated with a reduction in semen quality in South China. The findings highlight the needs to reduce high temperature exposures during 3 months before ejaculation to maintain better semen quality.

Placenta exosomal miRNA-30d-5p facilitates decidual macrophage polarization by targeting HDAC9.

Pregnancy involves a wide range of adaptations in the maternal body. Maternal immune tolerance toward the foreign fetus is critical for a successful pregnancy. Decidual macrophages are the primary antigen-presenting and phagocytic cells responsible for antigen presentation and apoptotic cell removal. Their phenotype changes dynamically during pregnancy. Placenta-derived exosomes are small vesicles carrying active biological molecules such as microRNAs, proteins, and lipids. The placenta-derived exosomes have been implicated in endothelial cell activation, smooth muscle cell migration, and T-cell apoptosis, but it is unknown whether placenta-derived exosomes would affect the development and functions of decidual macrophages. In this study, we reported that placenta-derived exosomes stimulated macrophage polarization into alternatively activated (M2) macrophages. Mechanistically, miRNA-30d-5p from the placenta-derived exosomes induced macrophage polarization to the M2 phenotype by targeting histone deacetylase 9. Furthermore, the conditioned medium of placenta-derived exosome-treated macrophages promoted trophoblast migration and invasion. By contrast, the conditioned medium impaired the ability of endothelial cell tube formation and migration. Placenta-derived exosome-treated macrophages had no impact on T-cell proliferation. Together, we demonstrated that placenta-derived exosomes polarize macrophages to acquire a decidua-like macrophage phenotype to modulate trophoblast and endothelial cell functions.

Transcriptomic analysis of mid-secretory endometrium reveals essential immune factors associated with pregnancy after single euploid blastocyst transfer.

PURPOSE: Implantation is a limiting factor for treatment success in assisted reproduction. Both embryonic and endometrial factors contribute to implantation. Embryonic factors have often been ignored in previous studies about the role of endometrium in implantation. In this study, we sought to identify the endometrial genes associated with negative pregnancy outcomes following the transfer of a single euploid blastocyst. METHODS: Computational analyses of the transcriptomes of mid-secretory endometria from nine pregnant and seven non-pregnant patients in a cycle preceding the transfer of a single euploid blastocyst in a vitrified-warmed cycle were performed. RESULTS: Principal component analysis of two reported endometrial receptivity gene sets showed close clustering of the pregnant and non-pregnant samples. Differential gene expression analysis and co-expression module analysis identified 131 genes associated with the pregnancy status. The endometrial signatures identified highlight the importance of immune and metabolic regulation in pregnancy outcome. Network analysis identified 20 hub genes that could predict pregnancy outcomes with 88.9% sensitivity and 85.7% specificity. Single-cell gene expression analysis highlighted the regulation of endometrial natural killer (NK) cells, T cells, and macrophages during embryo implantation. Immune cell abundance analysis supported the dysregulation of cytotoxic immune cells in the endometria of non-pregnant women. CONCLUSIONS: We reported the first endometrial gene signature associated with pregnancy after elimination of embryo aneuploidy and highlighted the importance of the endometrial immune microenvironment and metabolic status in pregnancy outcomes.

Role of small RNAs harbored by sperm in embryonic development and offspring phenotype.

BACKGROUND: RNA harbored by mammalian sperm is increasingly considered to be an additional source of paternal hereditary information, beyond DNA. Recent studies have demonstrated the role of sperm small noncoding RNAs (sncRNAs) in modulating early embryonic development and offspring phenotype. The biogenesis of the sperm sRNA payload of mammalian sperm has been explored in many studies. AIMS: To summarize the possible mechanisms underpinning sperm sncRNAs regulating embryonic development and offspring phenotypes. MATERIALS AND METHODS: PubMed database (papers published from 2002 to 2022) was searched for studies reporting the impact of sperm sncRNAs on early embryonic development and offspring phenotype. RESULTS: The sncRNAs categories and source (such as tRNA-derived small RNAs, ribosomal RNA-derived small RNAs, microRNAs, and PIWI-interacting RNAs), and RNA modification upon different types of environmental exposure or by paternally-acquired factors were summarized. The potential mechanisms whereby the modifications of sperm sncRNAs modulate embryonic development and offspring phenotype under normal and pathological conditions (such as obesity, altered glucose metabolism, and psychological stress) were discussed. DISCUSSION AND CONCLUSION: Sperm sncRNAs modulate embryo development and offspring phenotype, and the resulting modifications may be transgenerationally inherited.

The Regulatory Roles of Chemerin-Chemokine-Like Receptor 1 Axis in Placental Development and Vascular Remodeling During Early Pregnancy.

Chemerin is an adipokine that regulates metabolism in pregnancy. An elevation of serum chemerin level is associated with pregnancy complications. Consistently, we demonstrated that the chemerin expression was increased in placenta of preeclamptic patients at deliveries. The G protein-coupled receptor chemokine-like receptor 1 (CMKLR1) mediates the actions of chemerin. The functions of the chemerin-CMKLR1 axis in maintaining pregnancy are still unknown. In this study, we demonstrated that CMKLR1 was expressed in the decidual natural killer (dNK) cells and chorionic villi of human. Chemerin suppressed the proliferation of the dNK cells in vitro. Specific antagonist of CMKLR1, α-Neta abolished the suppressive effect of spent medium from chemerin-treated dNK cells culture on extravillous trophoblast invasion. Activation of the chemerin-CMKLR1 axis promoted fusion and differentiation of human cytotrophoblast to syncytiotrophoblast in vitro. We generated Cmklr1 knockout mice and showed that the Cmklr1 deficiency negatively affected pregnancy outcome in terms of number of implantation sites, litter size and fetal weight at birth. Histologically, the Cmklr1 deficiency impaired formation of the syncytiotrophoblast layer II, induced enlargement of the maternal lacunae in the labyrinth, increased the diameter of the spiral arteries and increased trophoblast invasion in the decidua. The Cmklr1 deficient placenta also displayed an increased number of dNK cells and serum IL-15 level. In summary, the chemerin-CMKLR1 axis regulated placental development and spiral artery remodeling in early pregnancy.

Integrative Analysis of Small RNA and mRNA Expression Profiles Identifies Signatures Associated With Chronic Epididymitis.

Chronic epididymitis (CE) refers to a long-lasting inflammatory condition of the epididymis, which is considered the most common site of intrascrotal inflammation and an important aetiological factor of male infertility. Recent studies demonstrate that small RNAs secreted from epididymal epithelium modulate embryo development and offspring phenotypes via sperm transmission, and the resulting modifications may lead to transgenerational inheritance. However, to date, the genome-wide analysis of small RNA together with the transcriptomic expression profiles of human epididymis and CE is still lacking. In this study, we facilitated next-generation sequencing and bioinformatics to comprehensively analyze the small RNA and mRNA in an integrative way and identified signatures associated with CE. Both of the small RNA and mRNA expression data demonstrated relatively larger molecular differences among the segmental region of the epididymides, including caput, corpus, and cauda, than that of the inflammatory conditions. By comparing the inflamed caputs to the controls, a total of 1727 genes (1220 upregulated and 507 downregulated; 42 most significant genes, adjusted P <0.05) and 34 miRNAs (23 upregulated and 11 downregulated) were identified as differentially expressed. In silico functional enrichment analysis showed their roles in regulating different biological activities, including leukocyte chemotaxis, extracellular milieu reconstruction, ion channel and transporter-related processes, and nervous system development. Integrative analysis of miRNA and mRNA identified a regulatory network consisting of 22 miRNAs and 31 genes (miRNA-mRNA) which are strong candidates for CE. In addition, analysis about other species of small RNA, including (miRNA), piwi-interacting RNA (piRNA), tRNA-derived small RNA (tsRNA), Y RNA, and rsRNA identified the distinct expression pattern of tsRNA in CE. In summary, our study performed small RNA and miRNA profiling and integrative analysis in human CE. The findings will help to understand the role of miRNA-mRNA in the pathogenesis of CE and provide molecular candidates for the development of potential biomarkers for human CE.

[Management system and development strategy of quality Chinese medicine].

The development of quality Chinese medicine is an important way to improve the quality of Chinese medicine, and ensure the safety and effectiveness of Chinese medicine. This article systematically elaborates the definition, classification, standard and mana-gement certification strategy of quality Chinese medicine. We present the quality Chinese medicine which is higher quality than that of eligible Chinese medicine based on quality control standards. Quality Chinese medicine is strictly in accordance with management procedures, likely GAP and GMP et al, during the productive process, which quality indicators is higher than that of the current relevant national quality standards, such as Chinese Pharmacopoeia(ChP) et al; its limited indicators such as exogenous pollutants and endogenous toxic substances are lower than that of the current relevant national quality standards, likely ChP et al; meanwhile these Chinese herbal medicine, medicinal pieces, patent medicines, and health products and foods with Chinese medicine raw materials are been certificated by quality Chinese medicine. At the same time, this article systematically expounds the five major management systems of quality Chinese medicine, including technical training management for practitioners, productive process management, standard mana-gement, quality inspection and certification management, and product traceability management. And we put forward strategies to improve the supervision and management system, and promote the standardization and development of quality Chinese medicine by improving the technical management system of quality Chinese medicine, strengthening the quality management system and six sigma(6σ) management in the company. These strategies will provide a reliable basis and effective way to improve the quality of Chinese medicine.

Dimensionality reduction by UMAP reinforces sample heterogeneity analysis in bulk transcriptomic data.

Transcriptomic analysis plays a key role in biomedical research. Linear dimensionality reduction methods, especially principal-component analysis (PCA), are widely used in detecting sample-to-sample heterogeneity, while recently developed non-linear methods, such as t-distributed stochastic neighbor embedding (t-SNE) and uniform manifold approximation and projection (UMAP), can efficiently cluster heterogeneous samples in single-cell RNA sequencing analysis. Yet, the application of t-SNE and UMAP in bulk transcriptomic analysis and comparison with conventional methods have not been achieved. We compare four major dimensionality reduction methods (PCA, multidimensional scaling [MDS], t-SNE, and UMAP) in analyzing 71 large bulk transcriptomic datasets. UMAP is superior to PCA and MDS but shows some advantages over t-SNE in differentiating batch effects, identifying pre-defined biological groups, and revealing in-depth clusters in two-dimensional space. Importantly, UMAP generates sample clusters uncovering biological features and clinical meaning. We recommend deploying UMAP in visualizing and analyzing sizable bulk transcriptomic datasets to reinforce sample heterogeneity analysis.

T Lymphocytes and Testicular Immunity: A New Insight into Immune Regulation in Testes.

The immune privilege of the testes is necessary to prevent immune attacks to gamete-specific antigens and paternal major histocompatibility complex (MHC) antigens, allowing for normal spermatogenesis. However, infection and inflammation of the male genital tract can break the immune tolerance and represent a significant cause of male infertility. Different T cell subsets have been identified in mammalian testes, which may be involved in the maintenance of immune tolerance and pathogenic immune responses in testicular infection and inflammation. We reviewed the evidence in the published literature on different T subtypes (regulatory T cells, helper T cells, cytotoxic T cells, γδ T cells, and natural killer T cells) in human and animal testes that support their regulatory roles in infertility and the orchitis pathology. While many in vitro studies have indicated the regulation potential of functional T cell subsets and their possible interaction with Sertoli cells, Leydig cells, and spermatogenesis, both under physiological and pathological processes, there have been no in situ studies to date. Nevertheless, the normal distribution and function of T cell subsets are essential for the immune privilege of the testes and intact spermatogenesis, and T cell-mediated immune response drives testicular inflammation. The distinct function of different T cell subsets in testicular homeostasis and the orchitis pathology suggests a considerable potential of targeting specific T cell subsets for therapies targeting chronic orchitis and immune infertility.