Causal relationship between resting-state networks and depression: a bidirectional two-sample mendelian randomization study.

BACKGROUND: Cerebral resting-state networks were suggested to be strongly associated with depressive disorders. However, the causal relationship between cerebral networks and depressive disorders remains controversial. In this study, we aimed to investigate the effect of resting-state networks on depressive disorders using a bidirectional Mendelian randomization (MR) design. METHODS: Updated summary-level genome-wide association study (GWAS) data correlated with resting-state networks were obtained from a meta-analysis of European-descent GWAS from the Complex Trait Genetics Lab. Depression-related GWAS data were obtained from the FinnGen study involving participants with European ancestry. Resting-state functional magnetic resonance imaging and multiband diffusion imaging of the brain were performed to measure functional and structural connectivity in seven well-known networks. Inverse-variance weighting was used as the primary estimate, whereas the MR-Pleiotropy RESidual Sum and Outliers (PRESSO), MR-Egger, and weighted median were used to detect heterogeneity, sensitivity, and pleiotropy. RESULTS: In total, 20,928 functional and 20,573 structural connectivity data as well as depression-related GWAS data from 48,847 patients and 225,483 controls were analyzed. Evidence for a causal effect of the structural limbic network on depressive disorders was found in the inverse variance-weighted limbic network (odds ratio, [Formula: see text]; 95% confidence interval, [Formula: see text]; [Formula: see text]), whereas the causal effect of depressive disorders on SC LN was not found(OR=1.0025; CI,1.0005-1.0046; P=0.012). No significant associations between functional connectivity of the resting-state networks and depressive disorders were found in this MR study. CONCLUSIONS: These results suggest that genetically determined structural connectivity of the limbic network has a causal effect on depressive disorders and may play a critical role in its neuropathology.

Discovery of novel oridonin sulfamide derivatives as potent NLRP3 inhibitors by a visible-light photocatalysis-enabled peripheral editing.

The progress of organicsyntheticmethod can promote late-stage lead compound modification and novel active compound discovery. Molecular editing technology in the field of organic synthesis, including peripheral and skeletal editing, facilitates rapid access to molecular diversity of a lead compound. Peripheral editing of CH bond activation is gradually used in lead optimization to afford novel active scaffolds and chemical space exploitation. To develop oridonin derivatives with high anti-inflammatory potency, novel oridonin sulfamides had been designed and synthesized by a scaffoldhopping strategy based on a visible-light photocatalysis peripheral editing. All novel compounds revealed measurable inhibition of IL-1ß and low cytotoxicity in THP-1 cells. The docking study indicated that the best active compound ZM640 was accommodated in thebinding site of NLRP3 with two hydrogen bond interaction. These preliminary results confirm that α, ß-unsaturated carbonyl of oridonin is not essential for NLRP3 inhibitory effect. This new oridonin scaffold has its potential to be further developed as a promising class of NLRP3 inhibitors.

Synthesis and antibacterial evaluation of novel psoralen derivatives against methicillin-resistant Staphylococcus aureus (MRSA).

Today, the bacterial infections caused by multidrug-resistant pathogens seriously threaten human health. Thereby, there is an urgent need to discover antibacterial drugs with novel mechanism. Here, novel psoralen derivatives had been designed and synthesized by a scaffold hopping strategy. Among these targeted twenty-five compounds, compound ZM631 showed the best antibacterial activity against methicillin-resistant S. aureus (MRSA) with the low MIC of 1 µg/mL which is 2-fold more active than that of the positive drug gepotidacin. Molecular docking study revealed that compound ZM631 fitted well in the active pockets of bacterial S. aureus DNA gyrase and formed a key hydrogen bond binding with the residue ASP-1083. These findings demonstrated that the psoralen scaffold could serve as an antibacterial lead compound for further drug development against multidrug-resistant bacterial infections.

Prediction of preeclampsia from retinal fundus images via deep learning in singleton pregnancies: a prospective cohort study.

INTRODUCTION: Early prediction of preeclampsia (PE) is of universal importance in controlling the disease process. Our study aimed to assess the feasibility of using retinal fundus images to predict preeclampsia via deep learning in singleton pregnancies. METHODS: This prospective cohort study was conducted at Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine. Eligible participants included singleton pregnancies who presented for prenatal visits before 14 weeks of gestation from September 1, 2020, to February 1, 2022. Retinal fundus images were obtained using a nonmydriatic digital retinal camera during their initial prenatal visit upon admission before 20 weeks of gestation. In addition, we generated fundus scores, which indicated the predictive value of hypertension, using a hypertension detection model. To evaluate the predictive value of the retinal fundus image-based deep learning algorithm for preeclampsia, we conducted stratified analyses and measured the area under the curve (AUC), sensitivity, and specificity. We then conducted sensitivity analyses for validation. RESULTS: Our study analyzed a total of 1138 women, 92 pregnancies developed into hypertension disorders of pregnancy (HDP), including 26 cases of gestational hypertension and 66 cases of preeclampsia. The adjusted odds ratio (aOR) of the fundus scores was 2.582 (95% CI, 1.883-3.616; P  < 0.001). Otherwise, in the categories of prepregnancy BMI less than 28.0 and at least 28.0, the aORs were 3.073 (95%CI, 2.265-4.244; P  < 0.001) and 5.866 (95% CI, 3.292-11.531; P  < 0.001). In the categories of maternal age less than 35.0 and at least 35.0, the aORs were 2.845 (95% CI, 1.854-4.463; P  < 0.001) and 2.884 (95% CI, 1.794-4.942; P  < 0.001). The AUC of the fundus score combined with risk factors was 0.883 (sensitivity, 0.722; specificity, 0.934; 95% CI, 0.834-0.932) for predicting preeclampsia. CONCLUSION: Our study demonstrates that the use of deep learning algorithm-based retinal fundus images offers promising predictive value for the early detection of preeclampsia.

E2-Loaded Microcapsules and Bone Marrow-Derived Mesenchymal Stem Cells with Injectable Scaffolds for Endometrial Regeneration Application.

Bone marrow-derived mesenchymal stem cells (BMSCs) have been recognized as new candidates for the treatment of serious endometrial injuries. However, owing to the local microenvironment of damaged endometrium, transplantation of BMSCs yielded disappointing results. In this study, Pectin-Pluronic® F-127 hydrogel as scaffolds were fabricated to provide three-dimensional architecture for the attachment, growth, and migration of BMSCs. E2 was encapsulated into the W/O/W microspheres to construct pectin-based E2-loaded microcapsules (E2 MPs), which has the potential to serve as a long-term reliable source of E2 for endometrial regeneration. Then, the BMSCs/E2 MPs/scaffolds system was injected into the uterine cavity of mouse endometrial injury model for treatment. At 4 weeks after transplantation, the system increased proliferative abilities of uterine endometrial cells, facilitated microvasculature regeneration, and restored the ability of endometrium to receive an embryo, suggesting that the BMSCs/E2 MPs/scaffolds system is a promising treatment option for endometrial regeneration. Furthermore, the mechanism of E2 in promoting the repair of endometrial injury was also investigated. Exosomes are critical paracrine mediators that act as biochemical cues to direct stem cell differentiation. In this study, it was found that the expression of endometrial epithelial cell (EEC) markers was upregulated in BMSCs treated by exosomes secreted from endometrial stromal cells (ESCs-Exos). Exosomes derived from E2-stimulated ESCs further promoted the expression level of EECs markers in BMSCs, suggesting exosomes released from ESCs by E2 stimulation could enhance the differentiation efficiency of BMSCs. Therefore, exosomes derived from ESCs play paracrine roles in endometrial regeneration stimulated by E2 and provide optimal estrogenic response.

Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Promote Trophoblast Cell Proliferation and Migration by Targeting TFPI2 in Preeclampsia.

Preeclampsia is a pregnancy disorder characterized by systemic organ damage and high blood pressure. It has been reported that microRNA-195 (miR-195) is associated with preeclampsia. In this study, we discovered the target of miR-195 in regulating human extravillous cytotrophoblast-derived transformed cell proliferation and migration. We analyzed the clinicopathological factors of preeclampsia and normal pregnancies. The messenger ribonucleic acid (mRNA) levels of miR-195 and tissue factor pathway inhibitor 2 (TFPI2) were measured in placental tissues derived from normal and preeclampsia patients by real-time polymerase chain reaction (PCR). Human umbilical cord mesenchymal stem cell (hUC-MSC)-derived extracellular vesicles were verified by western blot. HTR8-S/Vneo cell proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and cell migration rate was assessed by the transwell assay. Relative luciferase activities were measured in TFPI2 wild-type (WT) and mutant cells. miR-195 expression was negatively correlated with TFPI2 mRNA levels in preeclampsia patients. Extracellular vesicles derived from hUC-MSCs enhanced HTR8-S/Vneo cell proliferation and migration. In addition, miR-195 isolated from hUC-MSCs enhanced HTR8-S/Vneo cell proliferation and migration by targeting TFPI2. Our findings demonstrate that the upregulation of miR-195 in extracellular vesicles derived from hUC-MSCs promotes HTR8-S/Vneo cell proliferation and migration by targeting TFPI2.

Quercetin prevents the ferroptosis of OPCs by inhibiting the Id2/transferrin pathway.

Spinal cord injury (SCI) is a destructive neurological disorder that causes impaired mobility, sensory, and autonomic dysfunctions. The loss of oligodendrocyte progenitor cells (OPCs), which can differentiate into mature oligodendrocytes and re-myelinate damaged axons, is related to poorer recovery for SCI patients. However, inhibiting OPCs loss has always been a difficult problem to overcome. In this study, we demonstrated the anti-ferroptosis effects of quercetin as a mechanism in erastin-induced OPC ferroptosis. Quercetin ameliorated erastin-induced ferroptosis in OPCs, as indicated by decreased iron concentration, reactive oxygen species (ROS) production, and increased content of glutathione (GSH) as well as more normal mitochondria morphology. Compared with erastin-induced OPCs, the myelin basic protein (MBP)-positive myelin and NF200-positive axonal was remarkably increased in quercetin-treated OPCs. Furthermore, quercetin ameliorated the erastin-induced ferroptosis as well as the myelin and axon loss of OPCs by downregulating transferrin. Transfected OPCs with transferrin overexpression plasmids significantly abrogated the protective role of quercetin in OPC ferroptosis. Using ChIP-qPCR, a direct interaction of transferrin with its upstream gene Id2 was found. The overexpression of Id2 reversed the effect of quercetin on OPC ferroptosis. In vivo study found that quercetin greatly decreased the area of injury, and enhanced the BBB score after SCI. Furthermore, in the SCI model, quercetin significantly downregulated Id2 and transferrin expression, while significantly up-regulated GPX4 and PTGS2 expression. In conclusion, quercetin prevents the ferroptosis of OPCs by inhibiting the Id2/transferrin pathway. These findings highlight quercetin as an anti-ferroptosis agent for the treatment or prevention of spinal cord injury.

Morphology analysis of the C2 pediculoisthmic component and feasibility of safe C2 pedicle screw placement: comparison of multiplanar reconstruction versus traditional radiographic methods.

BACKGROUND: Preoperatively evaluating the feasibility of safe C2 pedicle screw placement is the key to avoiding iatrogenic vertebral artery injury. However, it has not been verified whether the conventional CT measurements of C2 pediculoisthmic component (PIC) are reliable and accurate, and the results may lack validity. The purpose of this study is to analyze the evaluative performance of conventional CT measurements and to create an accurate predictor of morphometrics of C2 PIC. METHODS: A total of 304 C2 PICs were measured in 152 consecutive patients who underwent CT examination of the cervical spine between April 2020 and December 2020. We obtained the morphometric parameters of C2 PIC by measuring minimum PIC diameter (MPD) in CT multiplanar reconstruction versus conventional measurements of transverse PIC width (TPW), oblique PIC width (OPW) and definition of high-riding vertebral artery (HRVA). The outer diameter measured less than 4 mm in MPD was regarded as the standard of precluding safe C2 pedicle screw insertion. The evaluative performance of the conventional CT measurements was assessed, and the correlation between conventional CT measurements and measurements in CT multiplanar reconstruction was calculated. RESULTS: The parameters in OPW and MPD were measured significantly larger than those in TPW, and the preclusion of C2 pedicle screw placement evaluated from TPW and HRVA was significantly higher than that evaluated from OPW and MPD. The sensitivity of TPW was 93.09%, and the specificity was 79.31%. The sensitivity and specificity of OPW were 97.82% and 82.76%. The sensitivity of HRVA was 88.36%, and the specificity was 96.55%. Strong agreement with the highest correlation coefficient (0.879) and determination coefficient (0.7720) suggested that the outer diameter of OPW could be useful for the precise prediction of MPD. CONCLUSIONS: CT MPR allows accurate measurement of the narrowest section of the C2 PIC. The outer diameter of OPW could be simply measured and be useful for precise prediction of MPD, which makes C2 pedicle screw placement more safely than the conventional measurement of TPW and HRVA.

Discovery of Novel 3,11-Bispeptide Ester Arenobufagin Derivatives with Potential in Vivo Antitumor Activity and Reduced Cardiotoxicity.

Arenobufagin, one of the bufadienolides isolated from traditional Chinese medicine Chan'su, exhibits potent antitumor activity. However, serious toxicity and small therapeutic window limits its drug development. In the present study, to our knowledge, novel 3,11-bispeptide ester arenobufagin derivatives have been firstly designed and synthesized on the base of our previous discovery of active 3-monopeptide ester derivative. The in vitro antiproliferative activity evaluation revealed that the moiety at C3 and C11 hydroxy had an important influence on cytotoxic activity and selectivity. Compound ZM350 notably inhibited tumor growth by 58.8 % at a dose 10 mg/kg in an A549 nude mice xenograft model. Therefore, compound ZM350 also presented a concentration-dependent apoptosis induction and low inhibitory effect against both hERG potassium channel and Cav1.2 calcium channel. Our study suggests that novel 3,11-bispeptide ester derivatives will be a potential benefit to further antitumor agent development of arenobufagin.

CT-based machine learning radiomics predicts CCR5 expression level and survival in ovarian cancer.

OBJECTIVE: We aimed to evaluate the prognostic value of C-C motif chemokine receptor type 5 (CCR5) expression level for patients with ovarian cancer and to establish a radiomics model that can predict CCR5 expression level using The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA) database. METHODS: A total of 343 cases of ovarian cancer from the TCGA were used for the gene-based prognostic analysis. Fifty seven cases had preoperative computed tomography (CT) images stored in TCIA with genomic data in TCGA were used for radiomics feature extraction and model construction. 89 cases with both TCGA and TCIA clinical data were used for radiomics model evaluation. After feature extraction, a radiomics signature was constructed using the least absolute shrinkage and selection operator (LASSO) regression analysis. A prognostic scoring system incorporating radiomics signature based on CCR5 expression level and clinicopathologic risk factors was proposed for survival prediction. RESULTS: CCR5 was identified as a differentially expressed prognosis-related gene in tumor and normal sample, which were involved in the regulation of immune response and tumor invasion and metastasis. Four optimal radiomics features were selected to predict overall survival. The performance of the radiomics model for predicting the CCR5 expression level with 10-fold cross- validation achieved Area Under Curve (AUCs) of 0.770 and of 0.726, respectively, in the training and validation sets. A predictive nomogram was generated based on the total risk score of each patient, the AUCs of the time-dependent receiver operating characteristic (ROC) curve of the model was 0.8, 0.673 and 0.792 for 1-year, 3-year and 5-year, respectively. Along with clinical features, important imaging biomarkers could improve the overall survival accuracy of the prediction model. CONCLUSION: The expression levels of CCR5 can affect the prognosis of patients with ovarian cancer. CT-based radiomics could serve as a new tool for prognosis prediction.

C2 pedicle screw placement on 3D-printed models for the performance assessment of CTA-based screw preclusion.

BACKGROUND: 3-D printing technology has a large spectrum of applications in upper cervical spinal surgery, but none have evaluated the radiological analysis of the feasibility of C2 pedicle screw placement. Thus, this study aimed to perform 3.5-mm-diameter C2 pedicle screw placement on models for performance assessment of CTA-based preoperative screw preclusion. METHODS: We enrolled 152 patients who underwent CTA of the cervical spine between April 2020 and December 2020. Transverse pediculoisthmic width (TPW), oblique pediculoisthmic width (OPW), minimum pediculoisthmic diameter (MPD), internal height, and isthmus height were measured preoperatively. Subsequently, 1:1 3D-printed bone models were created, and a 3.5-mm-diameter C2 pedicle screw was placed on the models. All 3D-printed models underwent postoperative CT multiplanar reconstruction to evaluate the screw trajectory for the performance assessment of CTA-based preoperative screw preclusion. RESULTS: The ROC curves of the MPD, TPW, OPW, Internal height and Isthmus height showed that the optimal cutoff values for each of the five groups were measured values of 4.78, 4.44, 4.37, 4.22 and 5.59 mm, respectively. The AUC, sensitivity, and specificity of MPD were 0.992, 95.1% and 100%, respectively. The MPD had higher metrics than the TPW (AUC, 0.949; sensitivity, 87.9%), internal height (AUC, 0.885; sensitivity, 80.8%; specificity, 84.6%), and isthmus height (AUC, 0.941; sensitivity, 87.2%). We found no evidence of a difference between MPD and OPW in terms of the AUC and sensitivity (0.93 and 95.5%, respectively). CONCLUSIONS: C2 pedicle screw placement on 3D-printed models is useful for performance assessment of CTA-based preoperative screw preclusion. MPD measurement with CTA multiplanar reconstruction showed the best performance for judging acceptable or unacceptable screws. However, the definition of HRVA could be modified by a 4.2 mm-internal height or by measuring only the isthmus height for judging the preclusion of C2 pedicle screw placement.

Atroposelective Access to 1,3-Oxazepine-Containing Bridged Biaryls via Carbene-Catalyzed Desymmetrization of Imines.

We disclose herein an atroposelective synthesis of novel bridged biaryls containing medium-sized rings via N-heterocyclic carbene organocatalysis. The reaction starts with addition of the carbene catalyst to the aminophenol-derived aldimine substrate. Subsequent oxidation and intramolecular desymmetrization lead to the formation of 1,3-oxazepine-containing bridged biaryls in good yields and excellent enantioselectivities. These novel bridged biaryl products can be readily transformed into chiral phosphite ligands. Preliminary density function theory calculations suggest that the origin of enantioselectivity arises from the more favorable frontier molecular orbital interactions in the transition state leading to the major product.

Prevalence of syphilis among people living with HIV and its implication for enhanced coinfection monitoring and management in China: A meta-analysis.

Background: People living with HIV (PLWH) are at an increased risk of syphilis infection. The objectives of this study were to assess the overall prevalence of syphilis among PLWH in China and identify factors associated with syphilis infection among PLWH. Methods: We searched Medline, Embase, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), Wan-fang Data, and Chinese Biomedical Literature Database (CBM) to identify studies that reported the prevalence of syphilis among PLWH in China and were published in English or Chinese from January 1, 1990, to May 31, 2022. The reference lists of retrieved articles and relevant reviews were also checked to identify additional studies. A random-effect model was fitted to calculate the pooled syphilis prevalence among PLWH. Subgroup analyses, meta-regression analyses and sensitivity analyses were conducted to determine the potential source of heterogeneity. Results: Of the 1,599 articles screened, 29 studies involving 34,740 participants were eligible for inclusion in this meta-analysis. The overall prevalence of syphilis among PLWH in China was 19.9% [95% confidence interval (CI): 15.4-24.8%, I 2 = 98.9%]. Subgroup analysis showed that the pooled prevalence of syphilis among men who have sex with men (MSM) with HIV (21.9%, 95% CI: 17.2-26.9%) was much higher than that among heterosexuals (10.3%, 95% CI: 5.2-16.8%); there was regional diversity in the prevalence of syphilis, the highest in northern China (31.7%, 95% CI: 17.9-47.4%), followed by central-southern China (26.7%, 95% CI: 11.4-45.7%), and the lowest in northwestern China (15.0%, 95% CI: 6.9-25.4%); the syphilis prevalence among PLWH decreased as CD4 + T cell count increased (19.6% in CD4 + T cell < 200 vs. 8.7% in ≥ 500) and was higher among non-antiretroviral therapy (non-ART) HIV-infected patients (21.0%, 95% CI: 9.9-35.0%) than that among ART ones (16.1%, 95% CI: 3.9-34.3%). Conclusions: Our study showed a significantly high prevalence of syphilis among PLWH in China, particularly among MSM with HIV. Developing national guidelines for the integrated screening, monitoring, and management of HIV and syphilis as well as syphilis diagnosis and treatment training programs for physicians at designated HIV treatment hospitals is urgent and crucial to combat HIV and syphilis coinfection in China.

Application of a fluorine strategy in the lead optimization of betulinic acid to the discovery of potent CD73 inhibitors.

The ecto-5'-nucleotidase (CD73) is an important enzyme in the adenosine pathway and catalyzes the extracellular hydrolysis of adenosine monophosphate (AMP) yielding adenosine which is involved in the inflammation and immunosuppression. Inhibitors of CD73 have potential as novel immunotherapy agents for the treatment of cancer and infection. In this study, we discovered a series of fluorinated betulinic acid derivatives as potent CD73 inhibitors by a fluorine scanning strategy. Among these, three compounds ZM522, ZM553 and ZM557 exhibited inhibitory activity with IC50 values of 0.56 uM, 0.74 uM and 0.47 uM, respectively. In addition, these compounds showed a 7-fold, 5-fold and 8-fold increase in activity compared to the positive control drug α, ß-methylene adenosine diphosphate (APCP) against the human CD73 enzyme. Two of these (ZM522 and ZM553) also exhibited effective interferon gamma (INF-γ) elevation and indicated the regulation of rescued T cell activation. Therefore, our study provides both a lead optimization strategy and potential compounds for further development of small molecule CD73 inhibitors.

Influence of Intellectual-cultural Orientation as Family Culture on Chinese College Students' Subjective Well-being: A Moderation Model.

The well-known mediation-moderation model of subjective well-being has been criticized because it oversimplified the concept of culture. This study aimed to explore whether the family culture, as supplement of social culture, has significant impacts on subjective well-being. The intellectual-cultural orientation subscale (ICO) of family environment scale-CV (FES-CV), Eysenck personality questionnaire for adult (EPQA), and index of well-being (IWB) were used to test 340 college students from China. Results showed that the extraversion and neuroticism of personality traits have great influences on subjective well-being, and intellectual-cultural orientation as family culture, to represent characteristic of family culture, serves as a moderating variable for the 2 components of subjective well-being. And all these findings revealed that the trait of family culture should be considered as a supplement of the social culture and a critical complementary moderating influenced factor for subjective well-being. Together with personality traits, it can explain the variance of subjective well-being to some extent. The family cultural has an important influence on college students' personality and subjective well-being. It is important to provide a high quality family cultural environment for college students.

Association Between Maternal Weight Gain in Different Periods of Pregnancy and the Risk of Venous Thromboembolism: A Retrospective Case-Control Study.

Background: Venous thromboembolism (VTE) remains an important cause of maternal deaths. Little is known about the associations of specific periods of gestational weight gain (GWG) with the category of VTE, pulmonary embolism (PE), or deep venous thrombosis (DVT) with or without PE. Methods: In a retrospective case-control study conducted in Shanghai First Maternity and Infant Hospital from January 1, 2017 to September 30, 2021, cases of VTE within pregnancy or the first 6 postnatal weeks were identified. Controls without VTE were randomly selected from women giving birth on the same day as the cases, with 10 controls matched to each case. Total GWG and rates of early, mid, and late GWG values were standardized into z-scores, stratified by pre-pregnant body mass index (BMI). The adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated through multivariate logistic regression models. Results: There were 196 cases (14.4 per 10,000) of VTE within pregnancy or the first 6 postnatal weeks were identified. Higher total weight gain was associated with increased risks of PE (aOR, 13.22; 95% CI, 2.03-85.99) and VTE (OR, 10.49; 95% CI, 1.82-60.45) among women with underweight. In addition, higher total weight gain was associated with increased risk of PE (aOR, 2.06; 95% CI, 1.14-3.72) among women with healthy weight. Similarly, rate of higher early weight gain was associated with significantly increased risk for PE (aOR, 2.15; 95% CI, 1.05-4.42) among women with healthy BMI. The lower rate of late weight gain was associated with increased risks of PE (aOR, 7.30; 95% CI, 1.14-46.55) and VTE (OR, 7.54; 95% CI, 1.20-47.57) among women with underweight. No significant associations between maternal rate of mid GWG and increased risk for any category of VTE, PE, or DVT with or without PE were present, regardless of maternal pre-pregnant BMI. Conclusion: The GWG associations with the category of VTE, PE, or DVT with or without PE differ at different periods of pregnancy. In order to effectively improve maternal and child outcomes, intensive weight management that continues through pregnancy may be indispensable.

Exosomal miR-195 in hUC-MSCs alleviates hypoxia-induced damage of trophoblast cells through tissue factor pathway inhibitor 2.

MicroRNA-195 (miR-195) was decreased in the patients with pre-eclampsia (PE), which was implicated to modulate PE. Moreover, tissue factor pathway inhibitor 2 (TFPI2), which was highly expressed in the placenta of PE patients, was negatively correlated with miR-195 levels. This study aimed to explore the role of miR-195 in the cell therapy for the treatment of PE and the underlying mechanisms. Human umbilical cord mesenchymal stem cells (hUC-MSCs) were transfected with miR-195 mimic or mimic negative control to extract exosomes. HTR8/SVneo was incubated under hypoxia condition to induce cell damage, and co-co-cultured with exosomes derived from hUC-MSCs to evaluate its effect. Hypoxia time-dependently caused a decrease on miR-195 level with an increase on TFPI2 expression in HTR8/SVneo. MiR-195 directly bind to TFPI2 and inhibited TFPI2 expression in hUC-MSCs. Moreover, hypoxia-induced cell damage in HTR8/SVneo was significantly attenuated by co-culture with hUC-MSC-derived exosomes. Exosomes extracted from miR-195-overexpressed hUC-MSCs, could further ameliorate hypoxia-induced cell damage, due to the excessive amount of miR-195 delivered by exosomes. Exosomal miR-195 in hUC-MSCs alleviated hypoxia-induced cell damage through TFPI2, which might provide a potential therapeutic approach for pre-eclampsia.

Influence of ambient air pollution on successful pregnancy with frozen embryo transfer: A machine learning prediction model.

Numerous air pollutants have been reported to influence the outcomes of in vitro fertilization (IVF). However, whether air pollution affects implantation in frozen embryo transfer (FET) process is under debate. We aimed to find the association between ambient air pollution and implantation potential of FET and test the value of adding air pollution data to a random forest model (RFM) predicting intrauterine pregnancy. Using a retrospective study of a 4-year single-center design，we analyzed 3698 cycles of women living in Shanghai who underwent FET between 2015 and 2018. To estimate patients' individual exposure to air pollution, we computed averages of daily concentrations of six air pollutants including PM2.5, PM10, SO2, CO, NO2, and O3 measured at 9 monitoring stations in Shanghai for the exposure period (one month before FET). Moreover, A predictive model of 15 variables was established using RFM. Air pollutants levels of patients with or without intrauterine pregnancy were compared. Our results indicated that for exposure periods before FET, NO2 were negatively associated with intrauterine pregnancy (OR: 0.906, CI: 0.816-0.989). AUROC increased from 0.712 to 0.771 as air pollutants features were added. Overall, our findings demonstrate that exposure to NO2 before transfer has an adverse effect on clinical pregnancy. The performance to predict intrauterine pregnancy will improve with the use of air pollution data in RFM.

Ultrasound-Indicated Cervical Cerclage Efficacy Between 16 and 28 Weeks of Gestation in Twin Pregnancy: Retrospective Cohort Study.

Objective: The aim of this study is to determine if cervical cerclage administration reduces the preterm birth (PTB) rate at a gestational age (GA) of 16-28 weeks in women with twin pregnancy. Methods: This is a retrospective cohort study on asymptomatic twin pregnancy with an ultrasound-identified cervix length (CL) of ≦25 mm. The patients were divided into two groups: ultrasound-indicated cerclage (UIC) group and control (expectant management) group. The primary outcome was a PTB rate at <34 weeks. A logistic regression was also performed, and a subgroup analysis stratified by CL and GA at first short cervix diagnosis was planned. Results: In all 320 women, there were no differences in the overall <34-week PTB rates and neonatal outcomes between the UIC group and control group. After performing a multivariate logistic regression analysis, the subgroup analyses were planned. In patients with a CL of ≦15 mm, the <34-week PTB rate was significantly decreased in the UIC subgroup compared with the control subgroup (60.78% vs 78.26%; odds ratio (OR) = 0.43, confidence interval (CI) = 95% [0.22-0.86]; and p = 0.020). In patients with a first short cervix diagnosis GA of ≦24 weeks, the <34-week PTB rate was significantly decreased in the UIC subgroup when compared with the control subgroup (61.54% vs 84.75%; OR = 0.29; CI = 95% [0.13-0.63]; and p = 0.001). Furthermore, compared with the control groups, the UIC groups had higher mean birth weight, lower perinatal mortality, and lower NICU admission, and the differences were statistically significant. Conclusion: UIC could significantly reduce the <34-week PTB rate and improve perinatal outcomes in patients with a CL of ≦15mm or first short cervix diagnosis GA of ≦24 weeks with asymptomatic twin pregnancy during the second trimester.

Discovery and optimization of betulinic acid derivatives as novel potent CD73 inhibitors.

The vast research and clinical result have verified the success of cancer immunotherapy. However, there is also facing the enormous challenges such as lack of precise pre-clinical models, optimal combined therapy regimen and acquired resistance to immunotherapy. Adenosine is a potent immune-modulating molecule and overexpression of CD73 on tumor leads to the high concentration of adenosine. Blockade of the key adenosine-generating enzyme CD73 can be a promising strategy for cancer immunotherapy. Here, we report the discovery of betulinic acid as a novel CD73 inhibitor lead compound by a hit-based substructure search strategy. Subsequent optimization led to the discovery of betulinic acid carbamate derivative ZM514 with 5.2-fold increased potency compared to lead compound. Simultaneously, study has showed that compound ZM514 was not a cytotoxic agent while betulinic acid showed modest antiproliferative activity. The present result provides a valuable inhibitor against the promising immuno-oncology target for further development.