Construction of a human cell landscape at single-cell level.

Single-cell analysis is a valuable tool for dissecting cellular heterogeneity in complex systems1. However, a comprehensive single-cell atlas has not been achieved for humans. Here we use single-cell mRNA sequencing to determine the cell-type composition of all major human organs and construct a scheme for the human cell landscape (HCL). We have uncovered a single-cell hierarchy for many tissues that have not been well characterized. We established a 'single-cell HCL analysis' pipeline that helps to define human cell identity. Finally, we performed a single-cell comparative analysis of landscapes from human and mouse to identify conserved genetic networks. We found that stem and progenitor cells exhibit strong transcriptomic stochasticity, whereas differentiated cells are more distinct. Our results provide a useful resource for the study of human biology.

Rusty pipe syndrome: a case report and review of the literature.

BACKGROUND: Painless bloody nipple discharge is often classified as pathological due to its association with malignant lesions. However, it can also be a completely harmless condition. Rusty pipe syndrome is a rare cause of benign, self-limiting bloody nipple discharge during late pregnancy and early lactation. Given that rusty pipe syndrome is not described in conventional textbooks, we thought it would be appropriate to bring this benign disease to the notice of readers. CASE PRESENTATION: A 31-year-old G1P1 female delivered an infant with a birth weight of 3000 g via cesarean section at 39 weeks of gestation. The baby was admitted to the pediatric intensive care unit for a suspected oblique inguinal hernia. The mother had bilateral painless bloody nipple discharge when she started to express milk. A physical examination uncovered no signs of inflammation, engorgement, palpable mass, tenderness, cracks or ulcers. A breast ultrasound and cytological analysis revealed no signs of a neoplasm. Without any medical intervention, the color of the rusty milk changed from dark brown to light brown during hospitalization and finally resolved six days postpartum. CONCLUSION: Rusty pipe syndrome is a self-limiting benign condition that should be considered in the differential diagnosis of bloody nipple discharge. Awareness of this rare disease by medical professionals would be extremely beneficial for avoiding unneeded examinations and discontinuity of exclusive breastfeeding.

Treatment of chronic hepatitis C viral infection with sofosbuvir and daclatasvir in kidney transplant recipients.

OBJECTIVES: To assess the efficacy and the risk of sofosbuvir-daclatasvir treatment among kidney transplant recipients (KTRs) with chronic hepatitis C virus (HCV) infection. METHODS: A real-life retrospective cohort analysis was performed on KTRs treated with sofosbuvir-daclatasvir at our center between January 2016 and March 2018. We collected data from 19 KTRs (13 males; age 48.3 ± 9.6 years; HCV genotype I, n = 16; chronic active hepatitis B coinfection, n = 8). Virological and clinical data were assessed. RESULTS: Overall, 100% of the patients had achieved a sustained virological response 12 weeks after treatment (SVR12). Their liver function improved notably, with a significant decline in the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (ALT 34.8 ± 18.6 IU/L pre-treatment and 15.0 ± 6.8 IU/L post-treatment, P = 0.0003; AST: 35.05 ± 18.1 IU/L pre-treatment and 19.1 ± 7.0 post-treatment, P = 0.001). A significant amelioration was observed in patients with proteinuria (n = 12) (0.95 [0.35-3.31] g/g at baseline to 0.39 [0.27-1.02] g/g post-therapy, P = 0.048). The serum creatinine, eGFR, and tacrolimus levels were stable during therapy. CONCLUSION: The preliminary data demonstrated that sofosbuvir-daclatasvir was highly effective in treating HCV infection in KTRs with acceptable tolerance.

Effects of dysregulated glucose metabolism on the occurrence and ART outcome of endometriosis.

BACKGROUND: Endometriosis is associated with systemic metabolic indicators, including body mass index (BMI), glucose metabolism and lipid metabolism, while the association between metabolic indexes and the occurrence and assisted reproductive technology (ART) outcome of endometriosis is unclear. We aimed to evaluate the characteristics of systemic metabolic indexes of endometriosis patients with infertility and their effects on pregnancy outcome after ART treatment. METHODS: A retrospective cohort study involve 412 endometriosis patients and 1551 controls was conducted. Primary outcome was metabolic indexes, and secondary measures consisted of the influence of metabolic indexes on the number of retrieved oocytes and ART outcomes. RESULTS: Endometriosis patients had higher insulin (INS) [6.90(5.10-9.50) vs 6.50(4.80-8.90) µU/mL, P = 0.005]. A prediction model for endometriosis combining the number of previous pregnancies, CA125, fasting blood glucose (Glu) and INS, had a sensitivity of 73.9%, specificity of 67.8% and area under curve (AUC) of 0.77. There were no significant differences in ART outcomes and complications during pregnancy. The serum levels of Glu before pregnancy were associated with GDM both in endometriosis group (aOR 12.95, 95% CI 1.69-99.42, P = 0.014) and in control group (aOR 4.15, 95% CI 1.50-11.53, P = 0.006). CONCLUSIONS: We found serum Glu is related to the number of retrieved oocytes in control group, serum INS is related to the number of retrieved oocytes in endometriosis group, while serum Glu and INS before pregnancy are related to the occurrence of GDM in two groups. A prediction model based on metabolic indexes was established, representing a promising non-invasive method to predict endometriosis patients with known pregnancy history.

Antibiotic Resistance and Mechanisms of Pathogenic Bacteria in Tubo-Ovarian Abscess.

A tubo-ovarian abscess (TOA) is a common type of inflammatory lump in clinical practice. TOA is an important, life-threatening disease, and it has become more common in recent years, posing a major health risk to women. Broad-spectrum antimicrobial agents are necessary to cover the most likely pathogens because the pathogens that cause TOA are polymicrobial. However, the response rate of antibiotic treatment is about 70%, whereas one-third of patients have poor clinical consequences and they require drainage or surgery. Rising antimicrobial resistance serves as a significant reason for the unsatisfactory medical outcomes. It is important to study the antibiotic resistance mechanism of TOA pathogens in solving the problems of multi-drug resistant strains. This paper focuses on the most common pathogenic bacteria isolated from TOA specimens and discusses the emerging trends and epidemiology of resistant Escherichia coli, Bacteroides fragilis, and gram-positive anaerobic cocci. Besides that, new methods that aim to solve the antibiotic resistance of related pathogens are discussed, such as CRISPR, nanoparticles, bacteriophages, antimicrobial peptides, and pathogen-specific monoclonal antibodies. Through this review, we hope to reveal the current situation of antibiotic resistance of common TOA pathogens, relevant mechanisms, and possible antibacterial strategies, providing references for the clinical treatment of drug-resistant pathogens.

IL-27 signaling negatively regulates FcɛRI-mediated mast cell activation and allergic response.

IL-27 is a member of the IL-12 family, exerting both anti- and pro-inflammatory activity in a cell-dependent and disease context-specific manner. Antigen-mediated cross-linking of IgE on mast cells triggers a signaling cascade that results in mast cell degranulation and proinflammatory cytokine production, which are key effectors in allergic reactions. Here, we show that the activation of mast cells is negatively regulated by IL-27 signaling. We found that mice lacking IL-27Rα (WSX-1) displayed increased sensitivity to IgE-mediated skin allergic response and chronic airway inflammation. The bone marrow-derived mast cells (BMMCs) of IL-27Rα-deficient mouse showed greater high-affinity receptor Fc epsilon RI (FcεRI)-mediated activation with significantly enhanced degranulation and cytokine production. Mechanistically, the dysregulated signaling in IL-27Rα-/- mast cells is associated with increased activation of Grb2-PLC-γ1-SLP-76, PI3K/Akt/IκBα signaling and decreased phosphorylation level of SH2 domain-containing protein phosphatase1 (SHP1). Furthermore, IL-27 treatment could inhibit mast cell activation directly, and retrovirus-based IL-27 expression in lung attenuated the airway inflammation in mice. Collectively, our findings reveal that IL-27 signaling negatively regulates mast cell activation and its mediated allergic response.

A Founder Pathogenic Variant of PPIB Unique to Chinese Population Causes Osteogenesis Imperfecta IX.

Background: Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility. PPIB pathogenic variants cause a perinatal lethal form of OI type IX. A limited number of pathogenic variants have been reported so far worldwide. Methods: We identified a rare pedigree whose phenotype was highly consistent with OI-IX. Exome sequencing was performed to uncover the causal variants. The variant pathogenicity was classified following the ACMG/AMP guidelines. The founder effect and the age of the variant were assessed. Results: We identified a homozygous missense variant c.509G > A/p.G170D in PPIB in an affected fetus. This variant is a Chinese-specific allele and can now be classified as pathogenic. We estimated the allele frequency (AF) of this variant to be 0.0000427 in a Chinese cohort involving 128,781 individuals. All patients and carriers shared a common haplotype, indicative of a founder effect. The estimated age of variant was 65,160 years. We further identified pathogenic variants of PPIB in gnomAD and ClinVar databases, the conserved estimation of OI type IX incidence to be 1/1,000,000 in Chinese population. Conclusion: We reported a founder pathogenic variant in PPIB specific to the Chinese population. We further provided our initial estimation of OI-IX disease incidence in China.

Tamoxifen attenuates dialysate-induced peritoneal fibrosis by inhibiting GSK-3ß/ß-catenin axis activation.

Peritoneal fibrosis is a severe complication arising from long-term peritoneal dialysis (PD). Tamoxifen (Tamo) has been clinically proven effective in a series of fibrotic diseases, such as PD-associated encapsulating peritoneal sclerosis (EPS), but the mechanisms underlying Tamoxifen's protective effects are yet to be defined. In the present study, C57BL/6 mice received intraperitoneal injections of either saline, 4.25% high glucose (HG) PD fluid (PDF) or PDF plus Tamoxifen each day for 30 days. Tamoxifen attenuated thickening of the peritoneum, and reversed PDF-induced peritoneal expression of E-cadherin, Vimentin, matrix metalloproteinase 9 (MMP9), Snail, and ß-catenin. Mouse peritoneal mesothelial cells (mPMCs) were cultured in 4.25% glucose or 4.25% glucose plus Tamoxifen for 48 h. Tamoxifen inhibited epithelial-to-mesenchymal transition (EMT) as well as phosphorylation of glycogen synthase kinase-3ß (GSK-3ß), nuclear ß-catenin, and Snail induced by exposure to HG. TWS119 reversed the effects of Tamoxifen on ß-catenin and Snail expression. In conclusion, Tamoxifen significantly attenuated EMT during peritoneal epithelial fibrosis, in part by inhibiting GSK-3ß/ß-catenin activation.