Immune and oxidative stress disorder in ovulation-dysfunction women revealed by single-cell transcriptome.

Introduction: Ovulation dysfunction is now a widespread cause of infertility around the world. Although the impact of immune cells in human reproduction has been widely investigated, systematic understanding of the changes of the immune atlas under female ovulation remain less understood. Methods: Here, we generated single cell transcriptomic profiles of 80,689 PBMCs in three representative statuses of ovulation dysfunction, i.e., polycystic ovary syndrome (PCOS), primary ovarian insufficiency (POI) and menopause (MENO), and identified totally 7 major cell types and 25 subsets of cells. Results: Our study revealed distinct cluster distributions of immune cells among individuals of ovulation disorders and health. In patients with ovulation dysfunction, we observed a significant reduction in populations of naïve CD8 T cells and effector memory CD4 T cells, whereas circulating NK cells and regulatory NK cells increased. Discussion: Our results highlight the significant contribution of cDC-mediated signaling pathways to the overall inflammatory response within ovulation disorders. Furthermore, our data demonstrated a significant upregulation of oxidative stress in patients with ovulation disorder. Overall, our study gave a deeper insight into the mechanism of PCOS, POI, and menopause, which may contribute to the better diagnosis and treatments of these ovulatory disorder.

Aspartate Aminotransferase/Platelet Ratio Index Upon Admission Predicts 24-Week Mortality in Patients With HIV-Associated Talaromyces marneffei.

Background: A high aspartate aminotransferase/platelet ratio index (APRI) predicts mortality in patients with severe infection. This study aims to assess the potential of APRI as a predictor for mortality in patients with HIV-associated Talaromyces marneffei (HTM). Methods: Associations between APRI and CD4 count, white blood cell count, C-reactive protein (CRP) level, procalcitonin (PCT) level, and cytokines were assessed in 119 patients. Univariate and multivariate Cox regression models were used to predict APRI on 24-week mortality. Results: APRI was positively associated with CRP (r = 0.190, P = .039), PCT (r = 0.220, P = .018), interleukin 6 (r = 0.723, P < .001), interleukin 10 (r = 0.416, P = .006), and tumor necrosis factor α (r = 0.575, P < .001) and negatively associated with CD4 count (r = -0.234, P = .011). In total, 20.2% (24/119) of patients died within the 24-week follow-up. The 24-week survival rate was 88.0% for patients with APRI <5.6% and 61.1% for those with APRI ≥5.6 (log-rank P < .001). After adjustment for sex, age, body mass index, and CD4 count, as well as serum levels of hemoglobin, APRI ≥5.6 (adjusted hazard ratio [95% CI]; 3.0 [1.2-7.1], P = .015), PCT ≥1.7 ng/mL (3.7 [1.5-9.6], P = .006), and non-amphotericin B deoxycholate treatment (2.8 [1.2-6.6], P = .018) were independent risk factors for 24-week mortality. Conclusions: For patients with HTM, APRI is associated with severity and is an independent risk factor for 24-week mortality.

A Versatile PDA(DOX) Nanoplatform for Chemo-Photothermal Synergistic Therapy against Breast Cancer and Attenuated Doxorubicin-Induced Cardiotoxicity.

Photothermal therapy (PTT) is a highly clinical application promising cancer treatment strategy with safe, convenient surgical procedures and excellent therapeutic efficacy on superficial tumors. However, a single PTT is difficult to eliminate tumor cells completely, and tumor recurrence and metastasis are prone to occur in the later stage. Chemo-photothermal synergistic therapy can conquer the shortcomings by further killing residual tumor cells after PTT through systemic chemotherapy. Nevertheless, chemotherapy drugs' extreme toxicity is also a problematic issue to be solved, such as anthracycline-induced cardiotoxicity. Herein, we selected polydopamine nanoparticles (PDA) as the carrier of the chemotherapeutic drug doxorubicin (DOX) to construct a versatile PDA(DOX) nanoplatform for chemo-photothermal synergistic therapy against breast cancer and simultaneously attenuated DOX-induced cardiotoxicity (DIC). The excellent photothermal properties of PDA were used to achieve the thermal ablation of tumors. DOX carried out chemotherapy to kill residual and occult distant tumors. Furthermore, the PDA(DOX) nanoparticles significantly alleviate DIC, which benefits from PDA's excellent antioxidant enzyme activity. The experimental data of the chemotherapy groups showed that the results of the PDA(DOX) group were much better than the DOX group. This study not only effectively inhibits cancer but tactfully attenuates DIC, bringing a new perspective into synergistic therapy against breast cancer.

Factors associated with spontaneous miscarriage risk in IUI treatment: A retrospectively cohort of 31,933 cycles.

To determine the factors associated with intrauterine insemination (IUI) miscarriages and reduce the IUI miscarriage rate, a retrospective study was performed by reviewing 31,933 IUI cycles from 2006 to 2018. The overall there were 14.50% clinical pregnancies, and 16.74% miscarriages. Logistic regression revealed the following three predictive variables: females aged ≥ 35 years (odds ratio [OR] = 2.131; p < 0.001), spontaneous miscarriage history (OR = 1.513; p = 0.005), and ovarian stimulation schemes such as clomiphene citrate (CC) (OR = 1.459; p = 0.003). The natural cycle led to a lower miscarriage rate for patients without spontaneous miscarriage history both for those over 35 years old (OR = 0.402; p = 0.034) and for those under 35 years old (OR = 0.806; p = 0.017). Gonadotropin (Gn) showed the lowest miscarriage rate for patients without abortion history, though no significant differences were found. Patients under 35 with a history of miscarriage were protected from miscarriage by using CC and Gn together (OR = 0.516; p = 0.032). No significant differences were found between various ovarian protocols when patients with abortion history were aged ≥ 35 years (p = 0.606). CC + Gn showed the lowest miscarriage rate. In conclusion, the natural cycle could be suggested for infertility couples to minimize abortion risk. When ovarian induction is required, CC + Gn had the lowest miscarriage rate for women with a history of spontaneous miscarriage while Gn is more successful for individuals without such a history.

Early differentiation and gene expression characteristics of trophoblast lineages†.

With the development of the embryo, the totipotent blastomere undergoes the first lineage decision to the inner cell mass (ICM) and the trophectoderm (TE). The ICM forms the fetus while the TE forms the placenta, which is one of the unique organs in mammals serving as the interface between maternal and fetal bloodstreams. Proper trophoblast lineage differentiation is crucial for correct placental and fetal development, including the TE progenitor self-renewal and its differentiation toward mononuclear cytotrophoblast, which later either develops into invasive extravillous trophoblast, remodeling the uterine vascular, or fuses into multinuclear syncytiotrophoblast, secreting pregnancy-sustaining hormone. Aberrant differentiation and gene expression of trophoblast lineage is associated with severe pregnancy disorders and fetal growth restriction. This review focuses on the early differentiation and key regulatory factors of trophoblast lineage, which have been poorly elucidated. Meanwhile, the recent development of trophoblast stem cells, trophectoderm stem cells, and blastoids derived from pluripotent stem cells bring the accessible model to investigate the profound mystery of embryo implantation and placentation and were also summarized.

Profiling of Homocysteine Metabolic Pathway Related Metabolites in Plasma of Diabetic Mellitus Based on LC-QTOF-MS.

Background: Homocysteine (Hcy) has been found to be closely related to the occurrence of diabetes mellitus (DM) and is considered as one of the risk factors of DM. However, Hcy alone is not enough as a factor to predict DM, and our study analyzed and determined the relationship between the main metabolites involved in the Hcy metabolic pathway and DM. Methods: A total of 48 clinical samples were collected, including 18 health control samples and 30 DM samples. All standards and samples were detected by LC-QTOF-MS. Multivariate statistical analysis and k-means cluster analysis were performed to screen and confirm the metabolites significantly correlated with DM. Results: A total of 13 metabolites of the Hcy metabolic pathway were detected in the samples. The content of Hcy, cysteine, taurine, pyridoxamine, methionine, and choline were significantly increased in the DM group (p < 0.05). Hcy, choline, cystathionine, methionine, and taurine contributed significantly to the probabilistic principal component analysis (PPCA) model. The odds ratios (OR) of Hcy, cysteine, taurine, methionine, and choline were all greater than one. K-means cluster analysis showed that the Hcy, taurine, methionine, and choline were significantly correlated with the distribution of glucose values (divided into four levels: 10.5−11.7 mmol/L, 7.7−9.7 mmol/L, 6.0−6.9 mmol/L, and 5.0−5.9 mmol/L, respectively). Conclusion: Hcy, taurine, methionine, and choline can be used as risk factors for diabetes diagnosis and are expected to be used for the assessment of diabetes severity.

Clinical Features, Phenotypic Markers and Outcomes of Diffuse Large B-Cell Lymphoma between HIV-Infected and HIV-Uninfected Chinese Patients.

Background: The effect of HIV infection on the clinicopathological characteristics of diffuse large B-cell lymphoma (DLBCL) remains debatable. Methods: Fifty-three HIV-infected and ninety-three HIV-uninfected DLBCL patients were enrolled in the retrospective study by propensity score matching for sex, age, body mass index and international prognostic index (IPI) at a ratio of 1:2. The clinicopathological characteristics were compared between the two groups. Results: HIV-infected DLBCL patients had lower white blood cell counts [×109/L; 4.4 (3.4−5.6) vs. 6.1 (4.2−8.2), p < 0.001], platelet counts (×109/L; 184.7 ± 89.3 vs. 230.0 ± 113.9, p = 0.014) and serum albumin (g/L; 37.3 ± 6.9 vs. 41.3 ± 6.2, p < 0.001) but higher incidences of central nervous system (CNS) involvement (9.4% vs. 1.1%, p = 0.014), bone marrow involvement (24.5% vs. 11.5%, p = 0.044) and Epstein−Barr viremia (61.1% vs. 26.7%, p = 0.002) than HIV-uninfected patients. In terms of histopathology, HIV-infected patients had higher positivity of Epstein−Barr virus-encoded small RNA (EBER) (41.7% vs. 6.7%, p = 0.002), but lower CD20 (90.2% vs. 98.7%, p= 0.029) and CD79a (23.1% vs. 53.7%, p < 0.001) expression. The overall response rate (ORR) at the end of chemotherapy (70.2% vs. 87.8%, p= 0.012) and 1-year overall survival (OS) (61.7% vs. 84.2%, log-rank p = 0.006) in HIV-infected patients were significantly lower than those in HIV-uninfected patients. Multivariate analysis suggested IPI ≤2.0 [adjusted odds ratio (AOR) (95% confidence interval): 5.0 (1.2−21.2), p = 0.030] was associated with ORR, hypoalbuminemia [AOR: 3.3 (1.3−9.1), p = 0.018] and CNS involvement [AOR: 3.3 (1.0−10.5), p = 0.044] were associated with reduced 1-year OS in HIV-infected patients. Conclusion: HIV-infected DLBCL patients have unique blood profiles and phenotypic markers. Low ORR and 1-year OS were observed in HIV-infected DLBCL patients in our study, even in the HAART era.

Pathological changes and oxidative stress of the HPG axis in hypothyroid rat.

Hypothyroidism is a common endocrine disease caused by a deficiency of thyroid hormones, which could affect the hypothalamus-pituitary-gonadal (HPG) axis and cause additional severe fertility problems. However, the pathogenesis of abnormal reproductive capacity caused by hypothyroidism and whether there are differences between females and males need more study. Here, we constructed a prolonged neonatal hypothyroid rat model using 6-propyl-2-thiouracil (PTU). H&E staining and RNA-sequencing were performed to detect histopathological and transcriptome changes. Our results indicated that the numbers of ventromedial hypothalamus nuclei were increased, and the number of pituitary chromophobes was sharply increased, whereas the proportion of pituitary acidophils and pituitary basophils were obviously reduced. The differentially expressed genes of the HPG axis organs were identified, and different tissues shared similar steroid hormone and oxidative stress-related terms in gene ontology analysis. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis indicated oxidative stress, and apoptosis-related genes were more enriched in male hypothyroid pituitaries, whereas the serum levels of growth hormone, follicle-stimulating hormone, and luteinizing hormone that were detected by ELISA were also reduced more in male hypothyroid rats, suggesting that prolonged neonatal hypothyroidism may have a more significant impact on male pituitaries. Moreover, the multi-organ oxidative stress in hypothyroid rats was confirmed by the higher expression of oxidative stress-related genes, such as the Txnip. The increased level of oxidative stress may have contributed to the histopathological and transcriptome changes of HPG axis organs in the prolonged neonatal hypothyroidism rats, especially in male pituitaries.

Does central environmental inspection improves enterprise total factor productivity? The mediating effect of management efficiency and technological innovation.

The strong demand from the public to find new ways to both improve economy and protect nature has been evoked by "pollute first and control later", which is the previous Chinese mode of development. With the new round of central environmental inspection approaching, should the Chinese government continue to intensify its supervision? The policy effect of the first round of central environmental inspection in 2015 can be a good reference. Based on the data from 1498 listed companies during the period between 2014 and 2018, the Levinsohn-Petrin (LP) method was used to measure enterprises' total factor productivity. Also, a propensity score matching-difference in difference (PSM-DID) method was established to explore the impact of central environmental inspection on enterprises' total factor productivity and its impact mechanism. The results indicate that first, central environmental inspection improved the total factor productivity of enterprises by promoting management efficiency and technological innovation. Second, the mediating effect of management efficiency accounts for approximately 16.6% of the total effect, while the mediating effect of technological innovation accounts for only 7.7% of the total effect.

Effect of Sperm Cryopreservation on miRNA Expression and Early Embryonic Development.

Although sperm preservation is a common means of personal fertility preservation, its effects on embryonic development potential need further investigation. The purpose of this study was to identify key microRNA (miRNA) in cryopreserved sperm and determine the changes of these miRNAs and their target genes during embryonic development using cryopreserved sperm. Moreover, the embryonic development potential of cryopreserved sperm was estimated in assisted reproductive technology (ART), where key miRNAs and target genes were validated in sperm and subsequent embryos. Clinical data of embryonic development from cryopreserved sperm indicated a significant decrease in fertilization rate in both in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cases, as well as a reduction in blastocyst formation rate in ICSI cases. Meanwhile there was a significant increase in blocked embryo ratio of Day1, Day2, and Day3.5 embryos when frozen-thawed mouse sperm was used, compared with fresh mouse sperm, suggesting a potential negative effect of sperm cryopreservation on embryonic development. From frozen-thawed and fresh sperm in humans and mice, respectively, 21 and 95 differentially expressed miRNAs (DEmiRs) were detected. miR-148b-3p were downregulated in both human and mouse frozen-thawed sperm and were also decreased in embryos after fertilization using cryopreserved sperm. Target genes of miR-148b-3p, Pten, was identified in mouse embryos using quantitative real-time PCR (qRT-PCR) and Western blot (WB). In addition, common characters of cryopreservation of mouse oocytes compared with sperm were also detected; downregulation of miR-148b-3p was also confirmed in cryopreserved oocytes. In summary, our study suggested that cryopreservation of sperm could change the expression of miRNAs, especially the miR-148b-3p across humans and mice, and may further affect fertilization and embryo development by increasing the expression of Pten. Moreover, downregulation of miR-148b-3p induced by cryopreservation was conserved in mouse gametes.

Effects of microwave time on quality of grass carp fillets processed through microwave combined with hot-air drying.

In this study, the quality changes of grass carp fillets dried by microwave-hot-air combined drying under different microwave time were investigated. The salted fillets were dried at 385 W microwave with different time (0, 2, 4, 6, 8, and 10 min), followed by 65℃ hot air to the end. The quality of fillets was evaluated by drying time, color, hardness, rehydration ratio, and taste characteristics (ATP-related compounds, free amino acids, E-tongue taste profile, EUC, and TAV). Results showed that grass carp fillets dried by microwave-hot-air combined drying had better qualities compared with single hot-air drying. Besides, microwave time had obvious effects on the quality changes of grass carp fillets, and 6 min was considered as the optimal drying time.

Research on quality changes of grass carp (Ctenopharyngodon idellus) during short-term starvation.

This study was aimed at to investigate the quality changes of grass carp during short-term starvation. The pH, lactic acid, free amino acid, and adenosine triphosphate-related compounds of dorsal meat, belly meat and red meat in grass carp were measured during starvation for 6 days, and the quality of grass carp was evaluated by K value, equivalent umami concentration (EUC), taste activity value (TAV), and electronic tongue. The pH of three parts meat reached the maximum value on the fourth day, which was closely related to the lactic acid content. Concurrently, the contents of fresh sweet amino acids were higher on the fourth day in all parts. The K values in dorsal meat and belly meat were below 10% during starvation. Considering the overall results of electronic tongue, EUC, and TAV analysis, it is suggested that grass carp should be marketed and eaten with a starvation period of 2-4 days for best taste and quality.

City Centrality, Migrants and Green Inovation Efficiency: Evidence from 106 Cities in the Yangtze River Economic Belt of China.

Based on the panel data of 106 cities in the Yangtze River Economic Belt of China from 2007 to 2016, this paper explores the impact of city centrality on the green innovation efficiency and proves the mediation effect of migrants by using spatial econometric model. The results show that there are more and more innovation contacts between cities, and the innovation network is becoming more and more dense. The core cities of the downstream innovation network are mainly Yangzhou, Zhenjiang, Wuxi, Changzhou, Suzhou and Hangzhou; the core cities in the midstream are mainly Wuhan, Changsha and Yichun; the core cities in the upstream are Chengdu and Bazhong. There is an inverted U-shaped relationship between city centrality and green innovation efficiency. In addition, the influence curve of city centrality on the green innovation efficiency of surrounding cities is also inverted U-shaped. Cities with high city centrality attract a large number of migrants that come from cities with lower centrality to improve the green innovation efficiency, but the green innovation efficiency of cities with low city centrality will decline due to lack of talents.