Use of statins and risks of ovarian, uterine, and cervical diseases: a cohort study in the UK Biobank.

PURPOSE: To examine the associations between use of statins and risks of various ovarian, uterine, and cervical diseases, including ovarian cancer, endometrial cancer, cervical cancer, ovarian cyst, polycystic ovarian syndrome, endometriosis, endometrial hyperplasia, endometrial polyp, and cervical polyp. METHODS: We conducted a cohort study among female participants in the UK Biobank. Information on the use of statins was collected through verbal interview. Outcome information was obtained by linking to national cancer registry data and hospital inpatient data. We used Cox proportional hazards regression to examine the associations. RESULTS: A total of 180,855 female participants (18,403 statin users and 162,452 non-users) were included. Use of statins was significantly associated with increased risks of cervical cancer (adjusted hazard ratio (HR), 1.55; 95% confidence interval (95% CI), 1.05-2.30) and polycystic ovarian syndrome (adjusted HR, 4.39; 95% CI, 1.68-11.49). However, we observed no significant association between use of statins and risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial hyperplasia, endometrial polyp, or cervical polyp. CONCLUSION: Our findings suggest that use of statins is associated with increased risks of cervical cancer and polycystic ovarian syndrome, but is not associated with increased or decreased risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial polyp, or cervical polyp.

Adverse drug reaction signal detection methods in spontaneous reporting system: A systematic review.

BACKGROUND: A series of signal detection methods have been developed to detect adverse drug reaction (ADR) signals in spontaneous reporting system. However, different signal detection methods yield quite different signal detection results, and we do not know which method has the best detection performance. How to choose the most suitable signal detection method is an urgent problem to be solved. In this study, we systematically reviewed the characteristics and application scopes of current signal detection methods, with the goal of providing references for the optimization selection of signal detection methods in spontaneous reporting system. METHODS: We searched six databases from inception to January 2023. The search strategy targeted literatures regarding signal detection methods in spontaneous reporting system. We used thematic analysis approach to summarize the advantages, disadvantages, and application scope of each signal detection method. RESULTS: A total of 93 literatures were included, including 27 reviews and 66 methodological studies. Moreover, 31 signal detection methods were identified in these literatures. Each signal detection method has its inherent advantages and disadvantages, resulting in different application scopes of these methods. CONCLUSION: Our systematic review finds that there are variabilities in the advantages, disadvantages, and application scopes of different signal detection methods. This finding indicates that the most suitable signal detection method varies across different drug safety scenarios. Moreover, when selecting signal detection method in a particular drug safety scenario, the following factors need to be considered: purpose of research, database size, drug characteristics, adverse event characteristics, and characteristics of the relations between drugs and adverse events.

Initial study and phylogenetic analysis of hard ticks (Acari: Ixodidae) in Nantong, China along the route of avian migration.

The growing concern about migratory birds potentially spreading ticks due to global warming has become a significant issue. The city of Nantong in this study is situated along the East Asia-Australasian Flyway (EAAF), with numerous wetlands serving as roosting sites for migratory birds. We conducted an investigation of hard ticks and determined the phylogenetic characteristics of tick species in this city. We utilized three different genes for our study: the mitochondrial cytochrome oxidase subunit 1 (COX1) gene, the second internal transcribed spacer (ITS2), and the mitochondrial small subunit rRNA (12 S rRNA) gene. The predominant tick species were Haemaphysalis flava (H. flava) and Haemaphysalis longicornis (H. longicornis). Additionally, specimens of Haemaphysalis campanulata (H. campanulata) and Rhipicephalus sanguineus (R. sanguineus) were collected. The H. flava specimens in this study showed a close genetic relationship with those from inland provinces of China, as well as South Korea and Japan. Furthermore, samples of H. longicornis exhibited a close genetic relationship with those from South Korea, Japan, Australia, and the USA, as well as specific provinces in China. Furthermore, R. sanguineus specimens captured in Nantong showed genetic similarities with specimens from Egypt, Nigeria, and Argentina.

Engineering the synthesis of unsaturated fatty acids by introducing desaturase improved the stress tolerance of yeast.

BACKGROUND: Yeast is often used to build cell factories to produce various chemicals or nutrient substances, which means the yeast has to encounter stressful environments. Previous research reported that unsaturated fatty acids were closely related to yeast stress resistance. Engineering unsaturated fatty acids may be a viable strategy for enhancing the stress resistance of cells. RESULTS: In this study, two desaturase genes, OLE1 and FAD2 from Z. rouxii, were overexpressed in S. cerevisiae to determine how unsaturated fatty acids affect cellular stress tolerance of cells. After cloning and plasmid recombination, the recombinant S. cerevisiae cells were constructed. Analysis of membrane fatty acid contents revealed that the recombinant S. cerevisiae with overexpression of OLE1 and FAD2 genes contained higher levels of fatty acids C16:1 (2.77 times), C18:1 (1.51 times) and C18:2 (4.15 times) than the wild-type S. cerevisiae pY15TEF1. In addition, recombinant S. cerevisiae cells were more resistant to multiple stresses, and exhibited improved membrane functionality, including membrane fluidity and integrity. CONCLUSION: These findings demonstrated that strengthening the expression of desaturases was beneficial to stress tolerance. Overall, this study may provide a suitable means to build a cell factory of industrial yeast cells with high tolerance during biological manufacturing. © 2023 Society of Chemical Industry.

Escherichia coli inhibits endometriosis by inducing M1 polarity of peritoneal macrophages and the IL-1 signaling pathway.

The development of endometriosis is closely linked to macrophages, and the type M1 macrophage has been hypothesized to play an inhibitory role in its progression. Escherichia coli induces macrophage polarization toward M1 in numerous diseases and differs in the reproductive tract of patients with and without endometriosis; however, its specific role in endometriosis development remains unknown. Therefore, in this study, E. coli was selected as a stimulator to induce macrophages, and its effects on the growth of endometriosis lesions in vitro and in vivo were investigated using C57BL/6N female mice and endometrial cells. It was revealed that E. coli inhibited the migration and proliferation of co-cultured endometrial cells by IL-1 in vitro and prevented the growth of lesions and induced macrophage polarization toward M1 in vivo. However, this change was counteracted by C-C motif chemokine receptor 2 inhibitors, suggesting that it was associated with bone marrow-derived macrophages. Overall, the presence of E. coli in the abdominal cavity may be a protective factor for endometriosis.

Endometrial stromal cell autophagy-dependent ferroptosis caused by iron overload in ovarian endometriosis is inhibited by the ATF4-xCT pathway.

Ferroptosis is an iron-dependent programmed cell death process characterized by the accumulation of lethal oxidative damage. Localized iron overload is a unique clinical phenomenon in ovarian endometriosis (EM). However, the role and mechanism of ferroptosis in the course of ovarian EM remain unclear. Traditionally, autophagy promotes cell survival. However, a growing body of research suggests that autophagy promotes ferroptosis under certain conditions. This study aimed to clarify the status of ferroptosis in ovarian EM and explore the mechanism(s) by which iron overload causes ferroptosis and ectopic endometrial resistance to ferroptosis in human. The results showed increased levels of iron and reactive oxygen species in ectopic endometrial stromal cells (ESCs). Some ferroptosis and autophagy proteins in the ectopic tissues differed from those in the eutopic endometrium. In vitro, iron overload caused decreased cellular activity, increased lipid peroxidation levels, and mitochondrial morphological changes, whereas ferroptosis inhibitors alleviated these phenomena, illustrating activated ferroptosis. Iron overload increased autophagy, and ferroptosis caused by iron overload was inhibited by autophagy inhibitors, indicating that ferroptosis caused by iron overload was autophagy-dependent. We also confirmed the effect of iron overload and autophagy on lesion growth in vivo by constructing a mouse EM model; the results were consistent with those of the in vitro experiments of human tissue and endometrial stomal cells. However, ectopic lesions in patients can resist ferroptosis caused by iron overload, which can promote cystine/glutamate transporter hyperexpression by highly expressing activating transcription factor 4 (ATF4). In summary, local iron overload in ovarian EM can activate autophagy-related ferroptosis in ESCs, and ectopic lesions grow in a high-iron environment via ATF4-xCT while resisting ferroptosis. The effects of iron overload on other cells in the EM environment require further study. This study deepens our understanding of the role of ferroptosis in ovarian EM.

Infection of epithelioma papulosum cyprini (EPC) cells with spring viremia of carp virus (SVCV) induces autophagy and apoptosis through endoplasmic reticulum stress.

Spring viremia of carp virus (SVCV) is a lethal freshwater pathogen of cyprinid fish that has caused significant economic losses to aquaculture. To reduce the economic losses caused by SVCV, its pathogenic mechanism needs to be studied more thoroughly. Here, we report for the first time that SVCV infection of Epithelioma papulosum cyprini (EPC) cells can induce cellular autophagy and apoptosis through endoplasmic reticulum stress. The presence of autophagic vesicles in infected EPC cells was shown by transmission electron microscopy. Quantitative fluorescence PCR and Western blot results showed that p62 mRNA expression was decreased, and the expression of Beclin1 and LC3 mRNA was increased. The p62 protein was decreased, and the Beclin1 protein and LC3 were increased in the endoplasmic reticulum stress activation state. To further clarify the mode of death of SVCV-infected EPC cells, we examined caspase3, caspase9, BCL-2, and Bax mRNA, which showed that they were all increased. Apoptosis of SVCV-infected cells increased upon activation of endoplasmic reticulum stress. Our results suggest that endoplasmic reticulum stress can regulate SVCV infection-induced autophagy and apoptosis. The results of this study provide theoretical data for the pathogenesis of SVCV and lay the foundation for future drug development and vaccine construction.

Application of elastography to diagnose adenomyosis and evaluate the degree of dysmenorrhea: a prospective observational study.

BACKGROUND: To determine whether there is a correlation between stiffness measured by strain elastography and the severity of dysmenorrhea and to determine the value of elastography in evaluating severe dysmenorrhea in patients with adenomyosis. METHODS: The correlation between tissue stiffness and dysmenorrhea was analyzed by performing elastography on premenopausal women diagnosed with adenomyosis. Expression levels of transforming growth factor-ß (TGF-ß), α-smooth muscle actin (α-SMA), and protein gene product 9.5 (PGP9.5) were detected by immunohistochemistry; the correlation of TGF-ß and α-SMA levels with the tissue stiffness and the degree of fibrosis was further analyzed. Also, the relationship of the PGP9.5 expression level with the tissue stiffness and degree of dysmenorrhea was determined. RESULTS: The degree of dysmenorrhea was significantly positively correlated with lesion stiffness in patients with adenomyosis but not with the uterine or lesion volume. The cutoff for the strain ratio was > 1.36 between the adenomyosis and control groups, with an area under the curve (AUC) of 0.987. For severe dysmenorrhea, the cutoff for the strain ratio was > 1.65 in patients with adenomyosis, with an AUC of 0.849. TGF-ß, α-SMA, and PGP9.5 expression levels were higher in adenomyotic lesions than in the endometrium of the adenomyosis and control groups. Both TGF-ß and α-SMA levels were positively correlated with the tissue stiffness and degree of fibrosis. Additionally, the expression level of PGP9.5 showed a positive correlation with the tissue stiffness and degree of dysmenorrhea. CONCLUSIONS: Elastography can be used to evaluate the degree of dysmenorrhea; the greater the tissue stiffness, the greater the degree of dysmenorrhea. In addition, elastography performed well in the diagnosis of adenomyosis and the evaluation of severe dysmenorrhea in patients with adenomyosis.

Hierarchical dynamic regulation of Saccharomyces cerevisiae for enhanced lutein biosynthesis.

Lutein, as a carotenoid with strong antioxidant capacity and an important component of macular pigment in the retina, has wide applications in pharmaceutical, food, feed, and cosmetics industries. Besides extraction from plant and algae, microbial fermentation using engineered cell factories to produce lutein has emerged as a promising route. However, intra-pathway competition between the lycopene cyclases and the conflict between cell growth and production are two major challenges. In our previous study, de novo synthesis of lutein had been achieved in Saccharomyces cerevisiae by dividing the pathway into two stages (δ-carotene formation and conversion) using temperature as the input signal to realize sequential cyclation of lycopene. However, lutein production was limited to microgram level, which is still too low to meet industrial demand. In this study, a dual-signal hierarchical dynamic regulation system was developed and applied to divide lutein biosynthesis into three stages in response to glucose concentration and culture temperature. By placing the genes involved in δ-carotene formation under the glucose-responsive ADH2 promoter and genes involved in the conversion of δ-carotene to lutein under temperature-responsive GAL promoters, the growth-production conflict and intra-pathway competition were simultaneously resolved. Meanwhile, the rate-limiting lycopene ε-cyclation and carotene hydroxylation reactions were improved by screening for lycopene ε-cyclase with higher activity and fine tuning of the P450 enzymes and their redox partners. Finally, a lutein titer of 19.92 mg/L (4.53 mg/g DCW) was obtained in shake-flask cultures using the engineered yeast strain YLutein-3S-6, which is the highest lutein titer ever reported in heterologous production systems.

Immunization effect of recombinant Lactobacillus casei displaying Aeromonas veronii Aha1 with an LTB adjuvant in carp.

Aeromonas veronii is an important aquatic zoonotic, which elicits a range of diseases, such as haemorrhagic septicemia. To develop an effective oral vaccine against Aeromonas veronii infection in carp, the Aeromonas veronii adhesion (Aha1) gene was used as a target molecule to attach to intestinal epithelial cells. Two anchored recombinant. Lactic acid bacteria strains (LC-pPG-Aha1 1038 bp and LC-pPG-Aha1-LTB 1383 bp) were constructed by fusing them with the E. coli intolerant enterotoxin B subunit (LTB) gene and using Lactobacillus casei as antigen delivery vector to evaluate immune effects of these in carp. Western blotting and immunofluorescence were used to confirm that protein expression was successful. Additionally, levels of specific IgM in serum and the activities of ACP, AKP, SOD, LYS, C3, C4, and lectin enzymes-were assessed. Cytokines IL-10, IL-1ß, TNF-α, IgZ1, and IgZ2 were measured in the liver, spleen, kidney, intestines, and gills tissue by qRT-PCR, which showed an increasing trend compared with the control group (P < 0.05). A colonization assay showed that the two L. casei recombinants colonized the middle and hind intestines of immunized fish. When immunized carp were experimentally challenged with Aeromonas veronii the relative percentage protection of LC-pPG-Aha1 was 53.57%, and LC-pPG-Aha1-LTB was 60.71%. In conclusion, these results demonstrate that Aha1 is a promising candidate antigen when it is displayed on lactic acid bacteria (Lc-pPG-Aha1 and Lc-pPG-Aha1-LTB) seems promising for a mucosal therapeutic approach. We plan to investigate the molecular mechanism of the L. casei recombinant in regulating the intestinal tissue of carp in future studies.

Drug-associated kidney injury in children: a disproportionality analysis of the FDA Adverse Event Reporting System.

Drug-associated kidney injury is related to longer hospitalization and increased risk of chronic kidney disease and mortality. However, there is currently a lack of large population studies on drug-associated kidney injury in children. This study aimed to study perform data mining to generate hypotheses on drugs, which may deserve to be assessed as per their potential risk of increasing kidney injury in children. We extracted and analyzed reports on drugs associated with kidney injury in children in the FDA Adverse Event Reporting System (FAERS). We conducted a disproportionality analysis using proportional reporting ratio (PRR) to evaluate the association between drugs and kidney injury in children. Meanwhile, comparisons were performed with drug labels to identify drugs that, despite not having kidney injury currently mentioned in their labels, may potentially be associated with risks of kidney injury in children. A total of 6347 children had drug-associated kidney injury in the FAERS database. The top five drugs with the highest PRR were gentamicin (PRR = 12.28, N = 157 cases, Chi-Squared = 1602.77), piperacillin-tazobactam (PRR = 9.77, N = 129 cases, Chi-Squared = 1003.24), amlodipine (PRR = 8.98, N = 271 cases, Chi-Squared = 1861.46), vancomycin (PRR = 8.91, N = 295 cases, Chi-Squared = 1998.64), and ceftriaxone (PRR = 8.00, N = 251 cases, Chi-Squared = 1494.02). According to drug labels, 9 drugs (9/30) were classified as potential nephrotoxins. CONCLUSIONS: Approximately one-third of drugs associated with kidney injury in children do not list kidney injury as a side effect in their drug labels. Future studies are therefore warranted to evaluate whether these drugs are associated with such a risk. WHAT IS KNOWN: • Nephrotoxic drugs are an increasingly common cause of acute kidney injury in hospitalized children. • Currently, no study has systematically combed drugs associated with kidney injury in children. WHAT IS NEW: • Approximately a third of drugs showing signals for potential kidney injury in children in data mining do not mention this side effect in their drug labels. • This study provides data on drugs needing further study to determine whether they might increase the risk of kidney injury in children.

Clinical efficacy and safety of trimonthly administration of goserelin acetate 10.8 mg in premenopausal Chinese females with symptomatic adenomyosis: a prospective cohort study.

OBJECTIVE: This prospective cohort study aimed to compare the clinical efficacy and safety of goserelin 10.8 mg administered trimonthly with goserelin 3.6 mg administered monthly in premenopausal females with symptomatic adenomyosis. METHODS: We recruited 139 premenopausal females with adenomyosis who complained of dysmenorrhea and/or menorrhagia. The first group (n = 70) received a single subcutaneous injection of goserelin 10.8 mg, and the second group (n = 69) received monthly subcutaneous goserelin 3.6 mg administered for 3 months. Follow-up was performed at the outpatient department after 12 weeks. RESULTS: Ultimately, 130 patients completed the study, including 68 and 62 patients in the goserelin 10.8 mg (n = 70) and 3.6 mg (n = 69) groups, respectively. We observed a significant decrease in the dysmenorrhea (NRS) score, uterine volume, and cancer antigen 125 (CA125) levels, and a significant increase in hemoglobin (HGB) levels in both treatment groups. There was no significant difference between the two groups. The sum of the adverse event scores was slightly higher in the goserelin 3.6 mg than in the 10.8 mg group. CONCLUSIONS: The clinical efficacy of trimonthly administration of goserelin 10.8 mg was equivalent to monthly 3.6 mg dosing and was non-inferior regarding safety and tolerability. Hence, it can be a more cost-effective and convenient alternative treatment option in premenopausal females with symptomatic adenomyosis. TRIAL REGISTRATION: ChiCTR2200059548.

Contribution of different class 2 integron elements to fitness costs in multi-drug resistant Escherichia coli and evaluation of their adaptability in "farm-to-table" environments.

Integrons play a pivotal role in the dissemination of antimicrobial resistance, because they can capture and express exogenous antimicrobial resistance genes. This study aimed to elucidate the structure and contribution of different elements of class 2 integrons to fitness costs in their host bacteria and evaluate their adaptability to the "farm-to-table" process. We mapped 27 typical class 2 integrons of Escherichia coli isolated from aquatic foods and pork products, each harboring an inactive truncated class 2 integrase gene and the gene cassette (GC) array dfrA1-sat2-aadA1 with strong Pc2A/Pc2B promoters. Notably, the fitness costs associated with class 2 integrons depended on the Pc promoter strength and quantity and content of GCs in the array. Additionally, the costs of integrases were activity-dependent, and a balance was identified between GC capture ability and integron stability, which could explain the inactive truncated integrase identified. Although typical class 2 integrons exhibited low-cost structures in E. coli, the bacteria incurred biological costs, including decreasing growth rates and biofilm formation, in farm-to-table environments, especially under low-nutrient conditions. Nevertheless, sub-inhibitory antibiotic concentrations led to the selection of class 2 integron-carrying bacteria. This study provides important insights into how integrons may travel from preharvest to consumer goods.

Macrophage-associated immune checkpoint CD47 blocking ameliorates endometriosis.

Peritoneal macrophages play a significant role in the progression of endometriosis (EM), but their functional differentiation is still unclear, and their phagocytic ability is weak. CD47-signal-regulated protein α (SIRPα) and PD-L1-PD-1 are considered immune checkpoints associated with macrophage phagocytosis. A specific blockade of these two pathways had been shown to increase the phagocytic clearance of cancer cells by macrophages in most cancers. We hypothesized that targeting CD47/PD-L1 in EM could improve the phagocytosis of macrophages, thereby delaying the progression of EM. From localization to quantification, from mRNA to protein, we comprehensively evaluated the expression of CD47 and PD-L1 in EM. We demonstrated that the CD47 expression in ectopic endometrium from patients with EM was significantly increased, but PD-L1 was not. We performed direct co-culture experiments of endometrial stromal cells with macrophages in vitro and in vivo to assess whether ectopic endometrial stromal cells escape macrophage phagocytosis through the CD47-SIRPα signaling pathway. The results showed that targeting CD47 increased the phagocytic capacity of macrophages. Interestingly, we also found that the reduction of CD47 expression promoted apoptosis of endometrial stromal cells. In conclusion, these data suggested that targeting CD47 can effectively target ectopic endometrial stromal cells through a dual mechanism of increased phagocytosis of macrophages and induced apoptosis of ectopic endometrial stromal cells. Thus, immunotherapy based on the CD47-SIRPα signaling pathway has some potential in treating EM, but further mechanistic studies are needed to explore more effective and specific antibodies.

Association between thyroid autoimmunity and the decline of ovarian reserve in euthyroid women.

RESEARCH QUESTION: Is thyroid autoimmunity (TAI) associated with the decline of ovarian reserve in euthyroid women? DESIGN: Case-control study. Data from 4302 euthyroid women with normal ovarian reserve (NOR) and low ovarian reserve (LOR), including biochemical premature ovarian insufficiency (POI) and overt POI, were retrospectively analysed. The prevalence and effect of TAI on ovarian reserve was evaluated between women with NOR and LOR. Status of ovarian insufficiency and TSH levels was further stratified for analysis. The correlation between anti-thyroid peroxidase antibody (TPOAb), anti-thyroglobulin antibody (TgAb) titres and ovarian reserve markers was also determined. RESULTS: The prevalence of positive TAI and TgAb was equally distributed between women with NOR and LOR (P = 0.080, P = 0.172); the prevalence of TPOAb positivity was higher in the LOR group (P = 0.005). After stratifying ovarian reserve and TSH, positive TAI, TPOAb and TGAb were significantly associated with overt POI when TSH was >2.5 µIU/ml (all P < 0.001); no association was observed with biochemical POI or overt POI when TSH was ≤2.5 µIU/ml. No correlation was found between TPOAb, TGAb titres and AMH (P = 0.218, P = 0.368, respectively), and bilateral AFC (P = 0.184, P = 0.315, respectively) in patients with LOR; only TPOAb titre was positively correlated with FSH (P = 0.039). CONCLUSIONS: Among the whole population of euthyroid women, TAI was not associated with low ovarian reserve but was significantly associated with overt POI in women with TSH>2.5 µIU/ml. Further basic studies on underlying mechanisms are needed.

Immediate outcome prognostic value of plasma factors in patients with acute ischemic stroke after intravenous thrombolytic treatment.

In the present study, we explored multiple plasma factors to predict the outcomes of patients with AIS after IVT. Fifty AIS patients who received IVT with alteplase were recruited and divided into two groups according to their NIHSS scores. Serum from all subjects was collected to quantitatively analyze the levels of different plasma factors, IL-6, MMP-9, ADAMTS13, TNC, GSN and TRX, using Luminex assays or ELISA measurements. Compared with the levels assessed at the onset of AIS, the levels of MMP-9 (P < 0.001), ADAMTS13 (P < 0.001), and TRX (P < 0.001) significantly decreased after IVT. The level of IL-6 was significantly increased in the NIHSS > 5 group at admission (P < 0.001) compared to the NIHSS ≤ 5 group. AIS patients with a poor prognosis had lower levels of ADAMTS13 at 72 h post-IVT compared with patients with a good prognosis (P = 0.021). IL-6 also was notably higher in the poor outcome group (P = 0.012). After adjusting for confounders, ADAMTS13 at 72 h post-IVT was an independent protective factor for prognosis in AIS patients with an adjusted OR of 0.07 (P = 0.049), whereas IL-6 was an independent predictor of risk for AIS patients with an adjusted OR of 1.152 (P = 0.028). IVT decreased MMP-9, ADAMTS13, and TRX levels in the plasma of AIS patients. Patients with a NIHSS score of less than 5 exhibited lower IL-6 levels, indicating that increased levels of IL-6 correlated with AIS severity after IVT. Therefore, IL-6 and ADAMTS13 might be useful plasma markers to predict the prognosis in AIS patients at 90-days after IVT.

A cohort study of the efficacy of the dienogest and the gonadotropin-releasing hormone agonist in women with adenomyosis and dysmenorrhea.

PURPOSE: To study the efficacy and safety of the dienogest and the gonadotropin-releasing hormone agonist (GnRH-a) in symptomatic females with uterine adenomyosis. METHODS: A total of 127 patients with adenomyosis with a chief complaint of dysmenorrhea were recruited. The first group received 2 mg of dienogest (DNG) daily, whereas the second group received goserelin acetate (GS) (3.6 mg/4 weeks) for 12 weeks. Outpatient follow-up was undertaken after 12 weeks. RESULTS: Among 127 women, 56/63 (88.9%) patients completed the treatment in the DNG group, whereas 62/64 (96.9%) patients completed the treatment in the GS group. A significant decrease in dysmenorrhea symptoms as measured by the visual analog scale (VAS) and Carcinoma antigen125 (CA125) after 12 weeks of treatment was observed in both groups (p < .001). The hemoglobin of anemic patients did not significantly improve after 12 weeks of treatment (p＝0.21) and the uterine volume slightly increased without statistical significance (p＝0.10) in the DNG group. Simultaneously, The hemoglobin of anemic patients significantly improved (p < .001) and the uterine volume significantly decreased (p < .001) in the GS group. CONCLUSIONS: Dienogest effectively alleviates the symptoms of dysmenorrhea in patients with adenomyosis, but it cannot improve the anemia or reduce the size of the uterus. GnRH-a is more effective in improving anemia and reducing the uterine volume in patients with adenomyosis. TRIAL REGISTRATION: ChiCTR1900024958.

Recent advances in construction and regulation of yeast cell factories.

The past decade has witnessed the rapid progress in development of synthetic biology, and advances in construction of yeast cell factories open vast opportunities for green and sustainable production of chemicals. Focusing on the progress in yeast engineering for production of plant natural products in the last 5 years, this review introduces different yeast chassis used for cell factory construction, including Saccharomyces cerevisiae, Yarrowia lipolytica and Komagataella phaffii, together with the emerging genome editing tools. The metabolic regulation strategies developed for yeast engineering are highlighted, such as subcellular pathway localization dynamic regulation, and transporter engineering. C1-based chemical bioproduction by engineered yeast is also covered. Finally, the existing challenges and future prospects in creating efficient yeast cell factories are summarized.

Metabolite profiles in the peritoneal cavity of endometriosis patients and mouse models.

RESEARCH QUESTION: Which metabolites are altered in the peritoneal cavity of women with endometriosis? Could the mouse endometriosis model simulate these alterations? DESIGN: Thirteen women with endometriosis and seven women with other benign gynaecological diseases, who underwent laparoscopic surgery, were included in this study. None had received hormonal therapy for 3 months before surgery. For the animal experiments, six and five mice were included in the endometriosis and control groups, respectively. Peritoneal fluid from the patients and peritoneal lavage fluid from the mice was collected and analysed. Non-targeted metabolomics via liquid chromatography with tandem mass spectrometry was used to identify the altered metabolites in the peritoneal fluid of endometriosis patients and mouse models. MetaboAnalyst 4.0 was used to visualize the data. RESULTS: Several metabolites in the peritoneal cavity were significantly altered in both humans and mice with endometriosis. Concentrations of lysophosphatidylcholine (LysopC) (P=0.017 in patients and P=0.041 in the mouse model) and derivatives of phosphoethanolamine (1-arachidonoyl-sn-glycero-3-phosphoethanolamine in patients, P=0.027; 1-oleoyl-sn-glycero-3-phosphoethanolamine in patients, P=0.0086; and phosphorylethanolamine in the mouse model, P=0.0027) were significantly up-regulated in both, whereas concentrations of acylcarnitines (l-palmitoylcarnitine, P=0.047; and stearoylcarnitine, P=0.029) and kynurenine (P=0.045) were significantly increased only in humans. The human and mouse samples shared three altered enriched metabolite sets. CONCLUSIONS: Women with endometriosis show an altered metabolic state in the abdominal cavity. The endometriosis mouse model shared half of the significantly altered metabolite sets found in the abdominal cavity of humans.

Mutations in MSH5 in primary ovarian insufficiency.

Primary ovarian insufficiency (POI) is a genetically heterogeneous disorder that occurs in familial or sporadic fashion. Through whole exome sequencing in a Chinese pedigree with POI, we identified a novel homozygous missense mutation (ENST00000375755: c.1459G > T, p.D487Y) in the MSH5 gene in two sisters with POI. The homologous mutation in mice resulted in atrophic ovaries without oocytes, and in vitro functional study revealed that mutant MSH5 impaired DNA homologous recombination repair. From sanger sequencing of MSH5 in 200 sporadic POI patients, we identified three heterozygous mutations (ENST00000375755: c.1057C > A, p.L353M; c.1459G > T, p.D487Y and c.2107 A > G, p.I703V). Considering the heterozygous p.D487Y carrier in the POI pedigree was fertile, the causality of the three heterozygous mutations in POI need more evidence. Our studies confirmed that perturbation of genes involved in DNA damage repair could lead to non-syndromic POI. The underlying mechanism-inability to repair DNA damage-will receive increasing attention with respect to POI.