Polysaccharide NAP-3 Synergistically Enhances the Efficiency of Metformin in Type 2 Diabetes via Bile Acid/GLP-1 Axis through Gut Microbiota Remodeling.

The polysaccharides of edible mushrooms are excellent phytochemicals for adjuvant treatment of metabolic diseases, but the potential mechanisms of synergistic effects are unclear. In this work, we discovered that NAP-3 enhanced the efficiency of metformin in lipid and glucose metabolism in type 2 diabetic (T2D) mice in a gut microbiome-dependent way. NAP-3 remodeled the intestinal microbial, resulting in the decreased activity of bile salt hydrolases and upregulation of CYP27A1 and CYP7B1 functions in the alternative pathway of bile acid synthesis, which leads to accumulation of the conjugated bile acids in ileum, specifically TßMCA and TUDCA. The accumulated conjugated bile acids either blocked or stimulated the nuclear receptors Farnesoid-X-receptor and TGR5, inducing the release of GLP-1 and ultimately enhanced glucose metabolism in mice. Collectively, our research indicated that edible mushroom polysaccharide NAP-3 may serve as a promising adjunctive oral therapeutic agent for T2D.

Clinical significance of peripheral blood immune cells in patients with gastric cancer after surgery.

BACKGROUND: Gastric cancer is one of the most common malignant tumors worldwide, and surgical resection is one of the main ways to treat gastric cancer. However, the immune status of postoperative patients is crucial for prognosis and survival, and immune cells play an important role in this process. Therefore, it is helpful to understand the immune status of postoperative patients by evaluating the levels of peripheral blood immune cells, especially total T cells (CD3+), helper T cells (CD3+CD4+), and suppressor T cells (CD3+CD8+), and its relationship to survival. AIM: To analyzed the immune cells in peripheral blood of patients with gastric cancer after surgery, detect the levels of total T cells, helper T cells and suppressor T cells. METHODS: A total of 58 patients with gastric cancer who received surgical treatment were included in the retrospective study. Flow cytometry was used to detect the level of peripheral blood immune cells and analyze the correlation between total T cells, helper T cells and inhibitory T cells. To explore the relationship between these immune markers and patient survival. RESULTS: The results showed that the levels of total T cells, helper T cells, and suppressor T cells changed in patients after gastric cancer surgery. There was a significant positive correlation between total T cells, helper T cells and suppressor T cells (r = 0.35, P < 0.01; r = 0.56, P < 0.01). However, there was a negative correlation between helper T cells and suppressor T cells (r = -0.63, P < 0.01). Follow-up showed that the survival rate of patients in the high-level total T cell group was significantly higher than that in the low-level group (28.87 ± 24.98 months vs 18.42 ± 16.21 months). The survival curve shows that the curve of patients in the high-level group is shifted to the upper right, and that of the low-level group is shifted downward. There was no significant difference between the levels of helper T cells and suppressor T cells and patient survival time. CONCLUSION: By detecting peripheral blood immune cells with flow cytometry, we can initially evaluate the immune status of patients after gastric cancer surgery and initially explore its relationship with patient survival.

Development and characterization of tilapia skin collagen-inulin oleogel as the potential fat substitute in beef patty formulations.

The effects of inulin addition, olive oil content, and ultrasonic treatment on the rheological, texture, and structural properties of collagen-based oleogels were investigated in this study. Furthermore, the fat substitution ability of the oleogel in low-fat beef patties was evaluated. Initially, a uniform and dense network cross-linked structure was found when the ratio of collagen to inulin complex was 1:5. The oleogel sample exhibited good stability and oil binding ability with an additional amount of 50 % olive oil. Ultrasonic treatment improved the stability of the oleogel structure in all samples. Additionally, the addition of inulin reduced cooking loss in beef patties. Beef patties prepared at a 50 % fat substitution level showed physical properties that were the least different from those of pure adipose tissue (control group), which could significantly reduce the content of saturated fatty acids and improve the storage stability of beef patties. This study provided guidance for the application of collagen-inulin oleogel in food processing.

The Dual Role of NRF2 in Colorectal Cancer: Targeting NRF2 as a Potential Therapeutic Approach.

Colorectal cancer (CRC), as the third most common bisexual cancer worldwide, requires urgent research on its underlying mechanisms and intervention methods. NRF2 is an important transcription factor involved in the regulation of redox homeostasis, protein degradation, DNA repair, and other cancer processes, playing an important role in cancer. In recent years, the complex role of NRF2 in CRC has been continuously revealed: on the one hand, it exhibits a chemopreventive effect on cancer by protecting normal cells from oxidative stress, and on the other hand, it also exhibits a protective effect on malignant cells. Therefore, this article explores the dual role of NRF2 and its related signaling pathways in CRC, including their chemical protective properties and promoting effects in the occurrence, development, metastasis, and chemotherapy resistance of CRC. In addition, this article focuses on exploring the regulation of NRF2 in CRC ferroptosis, as well as NRF2 drug modulators (activators and inhibitors) targeting CRC, including natural products, compounds, and traditional Chinese medicine formulations.

Exploring the role of KIR3DL2 on NK cells in hepatocellular carcinoma and its potential prognostic implications.

Hepatocellular carcinoma (HCC) is a globally prevalent malignancy with a high recurrence rate, significantly impacting prognosis and survival. This study aims to identify prognostic molecular markers using single-cell sequencing of tumors and adjacent tissues in primary and recurrent HCC patients. We analyzed single-cell sequencing data from tumor and adjacent normal tissues of primary and recurrent HCC cases to compare immune cell quantity and gene expression profiles. Recurrent HCC patients exhibited a significant reduction in infiltrating NK cells expressing KIR3DL2. Pseudotemporal and cell communication analyses revealed these KIR3DL2high NK cells were in a quiescent state, suggesting NK cell exhaustion and poor prognosis. KIR3DL2 expression in peripheral blood NK cells correlated with that in tissues, highlighting its potential as a prognostic marker for HCC.

A scoring-based clinical grading model for xanthelasma palpebrarum: predicting treatment frequency and prognosis.

Xanthelasma palpebrarum is one of the most common cutaneous xanthomas in humans. Currently, there are various methods available for treating xanthelasma palpebrarum, but the high treatment frequency and recurrence rate remain significant challenges for patients. Therefore, it is necessary to establish a reasonable and effective clinical grading system to guide the diagnosis and treatment of xanthelasma palpebrarum. We developed a clinical scoring system related to local injection of pingyangmycin for the treatment of xanthelasma palpebrarum, which can be used to predict early prognosis and treatment outcomes in patients. We collected and retrospectively studied 246 outpatient cases of xanthelasma palpebrarum treated with local injection of pingyangmycin in the Department of Plastic Surgery at Shanghai East Hospital from February 2020 to August 2022. Potential independent risk factors for adverse outcomes (recurrence or non-recurrence) were considered in univariate and multivariate logistic regression models. Predictive factors were determined based on the multivariate logistic regression model and Cox model, and a scoring grading system was established. External validation was conducted on an independent cohort of 110 patients. Based on logistic regression analysis, the number, area, and color of lesions were identified as significant predictive indicators (P < 0.05), with respective AUCs of 0.710, 0.799, and 0.755. The Cox model established hazard ratios for four new severity indicators of xanthelasma palpebrarum: hyperlipidemia, number of lesions, lesion area, and lesion grayscale value. Based on these findings, a new clinical grading model was developed, which was validated to be effective in the external cohort. The new scoring-based clinical predictive model can effectively predict the number of pingyangmycin injection treatments and prognosis in patients with xanthelasma palpebrarum. It holds promise for broader application in clinical practice.

Establishment of a reverse genetics system for virulent systemic feline calicivirus using circular polymerase extension reaction.

Feline caliciviruses can cause oral and upper respiratory tract infections in cats. However, a virulent and systemic feline calicivirus (VS-FCV) variant implicated in multisystem lesions and death in cats has emerged recently. To date, the mechanism underlying virulence variations in VS-FCV remains unclear. The aim of the present study was to provide a tool for exploring genetic variation in VS-FCV, by constructing an infectious clone of VS-FCV SH/2014. First, a full-length cDNA molecular clone of VS-FCV SH/2014 strain, which contains an Xba I recognition site generated by mutating one base (A→T) as a genetic marker, was constructed using the circular polymerase extension reaction (CPER) method. Second, the full-length cDNA clone was introduced into Crandell-Rees feline kidney cells using liposomes to rescue recombinant VS-FCV SH/2014 (rVS-FCV SH/2014). Third, the rescued viruses were identified by real-time PCR, immunofluorescence assay, western blotting, and electron microscopy. The full-length cDNA molecular clone of the VS-FCV SH/2014 strain was successfully constructed and that rVS-FCV SH/2014 could be rescued efficiently. rVS-FCV SH/2014 had the expected genetic markers and morphology and growth characteristics similar to those of the parental virus. The reverse genetics system provides a research platform for future studies on VS-FCV genetic variation and pathogenesis.

Effect of Combined Application of Wood Vinegar Solution and Biochar on Saline Soil Properties and Cotton Stress Tolerance.

Biomass pyrolysis by-products, such as biochar (BC) and wood vinegar (WV), are widely used as soil conditioners and efficiency enhancers in agriculture. A pot experiment was conducted to examine the effects of WV, both alone and in combination with BC, on soil properties in mildly saline soil and on cotton stress tolerance. The results demonstrated that BC and WV application, either individually or together, increased soil nutrient content. The combined application was more effective than the individual applications, resulting in a 5.18-20.12% increase in organic matter, a 2.65-15.04% increase in hydrolysable nitrogen, a 2.23-58.05% increase in effective phosphorus, and a 2.71-29.38% increase in quick-acting potassium. Additionally, the combined application of WV and BC led to greater improvements in cotton plant height, net photosynthetic rate (Pn), leaf nitrate reductase (NR), superoxide dismutase (SOD), and catalase (CAT) activities compared to the application of BC or WV alone. The enhancements in this study varied across different parameters. Plant height showed an increase of 14.32-21.90%. Net photosynthetic rate improved by 13.56-17.60%. Leaf nitrate reductase increased by 5.47-37.79%. Superoxide dismutase and catalase showed improvements of 5.82-64.95% and 10.36-71.40%, respectively (p < 0.05). Moreover, the combined treatment outperformed the individual applications of WV and BC, resulting in a significant decrease in MDA levels by 2.47-51.72% over the experimental period. This combined treatment ultimately enhanced cotton stress tolerance. Using the entropy weight method to analyze the results, it was concluded that the combined application of WV and BC could enhance soil properties in mildly saline soils, increase cotton resistance, and hold significant potential for widespread application.

Lipopolysaccharide Triggers Luminal Acidification to Promote Defense Against Bacterial Infection in Vaginal Epithelium.

The vaginal epithelium plays pivotal roles in host defense against pathogen invasion, contributing to the maintenance of an acidic microenvironment within the vaginal lumen through the activity of acid-base transport proteins. However, the precise defense mechanisms of the vaginal epithelium after a bacterial infection remain incompletely understood. This study showed that bacterial lipopolysaccharide (LPS) potentiated net proton efflux by up-regulating the expression of Na+-H+ exchanger 1 (NHE1) without affecting other acid-base transport proteins in vaginal epithelial cells. Pharmacologic inhibition or genetic knockdown of Toll-like receptor-4 and the extracellular signal-regulated protein kinase signaling pathway effectively counteracted the up-regulation of NHE1 and the enhanced proton efflux triggered by LPS in vaginal epithelial cells. In vivo studies revealed that LPS administration led to luminal acidification through the up-regulation of NHE1 expression in the rat vagina. Moreover, inhibition of NHE exhibited an impaired defense against acute bacterial infection in the rat vagina. These findings collectively indicate the active involvement of vaginal epithelial cells in facilitating luminal acidification during acute bacterial infection, offering potential insights into the treatment of bacterial vaginosis.

Generalized dark hollow sine-Gaussian beam and its propagation properties.

A model of the generalized dark hollow sine-Gaussian beam (GDHsGB) is proposed to uniformly describe both conventional dark hollow beams (DHBs) and anomalous dark hollow beams (ADHBs) with circular or elliptic geometrical patterns. Using the Collins formula, we derive the analytical expression for GDHsGBs propagating in ABCD paraxial optical systems. We analyze the evolution of the intensity pattern and beam width of circular ADHBs, as well as the ellipticity of elliptic ADHBs, providing mathematical expressions for these physical quantities. The results reveal various evolution forms based on beam parameters, with elliptic ADHBs exhibiting more intricate propagation behavior compared to circular ADHBs. By controlling parameters, the intensity pattern of elliptic ADHBs undergoes a transformation into a petal-like distribution in the near field, later reverting to its original elliptic configuration but rotated 90° from its initial orientation on the source plane in the far field.

Negative regulation of CcPAL2 gene expression by the repressor transcription factor CcMYB4-12 modulates lignin and capsaicin biosynthesis in Capsicum chinense fruits.

Peppers globally renowned for their distinctive spicy flavor, have attracted significant research attention, particularly in understanding spiciness regulation. While the activator MYB's role in spiciness regulation is well-established, the involvement of repressor MYB factors remains unexplored. This study identified the MYB4 transcription factor through RNA-seq and genome-wide analysis as being associated with spiciness. Consequently, CcMYB4-2 and CcMYB4-12 were cloned from Hainan Huangdenglong peppers, both exhibiting nuclear subcellular localization. qRT-PCR analysis revealed that CcMYB4-2/4-12 had high expression levels during the accumulation period of capsaicin, but there were differences in their peak expression levels, which may be related to the formation of pepper spiciness. Heterologous expression in Arabidopsis thaliana resulted in significantly elevated CcMYB4-2/4-12 expression levels and reduced lignin content. In CcMYB4-2 silenced plants, PAL expression remained unchanged, while PAL expression significantly increased in CcMYB4-12 silenced plants, leading to elevated lignin content and reduced capsaicin content. Yeast one-hybrid (Y1H) and dual luciferase reporter assays (DLR) demonstrated that CcMYB4-2/4-12 inhibited the transcription of CcPAL2 by binding to its promoter. Notably, CcMYB4-12 exhibited more pronounced inhibition. Therefore, it is hypothesized that CcMYB4-12 plays a pivotal role in regulating lignin and capsaicin biosynthesis. This study elucidates the molecular mechanism of MYB4 binding to the PAL promoter, providing a foundational understanding for analyzing phenylpropanoid metabolism and its diverse branches. KEY MESSAGE: Through functional verification analysis of the repressor CcMYB4, transcriptional regulation experiments revealed that CcMYB4 can bind to the CcPAL2 promoter, negatively regulating the capsaicin biosynthesis in Capsicum chinense fruits.

Radiomics nomogram based on CT radiomics features and clinical factors for prediction of Ki-67 expression and prognosis in clear cell renal cell carcinoma: a two-center study.

OBJECTIVES: To develop and validate a radiomics nomogram combining radiomics features and clinical factors for preoperative evaluation of Ki-67 expression status and prognostic prediction in clear cell renal cell carcinoma (ccRCC). METHODS: Two medical centers of 185 ccRCC patients were included, and each of them formed a training group (n = 130) and a validation group (n = 55). The independent predictor of Ki-67 expression status was identified by univariate and multivariate regression, and radiomics features were extracted from the preoperative CT images. The maximum relevance minimum redundancy (mRMR) and the least absolute shrinkage and selection operator algorithm (LASSO) were used to identify the radiomics features that were most relevant for high Ki-67 expression. Subsequently, clinical model, radiomics signature (RS), and radiomics nomogram were established. The performance for prediction of Ki-67 expression status was validated using area under curve (AUC), calibration curve, Delong test, decision curve analysis (DCA). Prognostic prediction was assessed by survival curve and concordance index (C-index). RESULTS: Tumour size was the only independent predictor of Ki-67 expression status. Five radiomics features were finally identified to construct the RS (AUC: training group, 0.821; validation group, 0.799). The radiomics nomogram achieved a higher AUC (training group, 0.841; validation group, 0.814) and clinical net benefit. Besides, the radiomics nomogram provided a highest C-index (training group, 0.841; validation group, 0.820) in predicting prognosis for ccRCC patients. CONCLUSIONS: The radiomics nomogram can accurately predict the Ki-67 expression status and exhibit a great capacity for prognostic prediction in patients with ccRCC and may provide value for tailoring personalized treatment strategies and facilitating comprehensive clinical monitoring for ccRCC patients.

Multiple pulp stones emerge across all teeth during mixed dentition: A case report.

BACKGROUND: This paper reports a rare presentation of multiple pulp stones (PSs) emerging in all teeth during mixed dentition. It offers valuable insights into the clinical diagnosis, treatment, and prognosis of multiple PSs, shedding light on their occurrence during the mixed dentition period. CASE SUMMARY: A 10-year-old girl presented with repeated pain in the mandibular right posterior teeth. Intraoral examination revealed carious lesions, abnormal tooth shapes, and anomalies in tooth number. Radiographic examinations showed multiple PSs with diverse shapes, sizes, and quantities in all teeth, alongside anomalies in tooth shape and number. Root canal therapy was initiated, but the patient initially lacked timely follow-up. Upon return for treatment completion, an extracted tooth revealed irregular calculus within the pulp cavity. CONCLUSION: This case underscores the importance of considering multiple PSs in mixed dentition, necessitating comprehensive evaluation and management strategies.

The combined detection of carcinoembryonic antigen, carcinogenic antigen 125, and carcinogenic antigen 19-9 in colorectal cancer patients.

BACKGROUND: Hepatic metastases are common and difficult to treat after colorectal cancer (CRC) surgery. The predictive value of carcinoembryonic antigen (CEA), cancer antigen (CA) 125 and CA19-9 combined tests for liver metastasis is unclear. AIM: To evaluate predictive value of combined tests for CEA, CA125, and CA19-9 levels in patients with liver metastases of CRC. METHODS: The retrospective study included patients with CRC alone (50 cases) and patients with CRC combined with liver metastases (50 cases) who were hospitalized between January 2021 and January 2023. Serum CEA, CA125 and CA19-9 levels were compared between the two groups, and binary logistic regression was used to analyze the predictive value of the combination of these tumor markers in liver metastasis. In addition, we performed receiver operating characteristic (ROC) curve analysis to assess its diagnostic accuracy. RESULTS: The results showed that the serum CEA, CA125 and CA19-9 levels in the CRC with liver metastasis group were significantly higher than those in the CRC alone group. Specifically, the average serum CEA level in the CRC with liver metastasis group was 162.03 ± 810.01 ng/mL, while that in the CRC alone group was 5.71 ± 9.76 ng/mL; the average serum CA125 levels were 43.47 ± 83.52 U/mL respectively. and 13.5 ± 19.68 U/mL; the average serum CA19-9 levels were 184.46 ± 473.13 U/mL and 26.55 ± 43.96 U/mL respectively. In addition, binary logistic regression analysis showed that CA125 was significant in predicting CRC liver metastasis (P < 0.05). ROC curve analysis results showed that the areas under the ROC curves of CEA, CA125 and CA19-9 were 0.607, 0.692 and 0.586. CONCLUSION: These results suggest that combined detection of these tumor markers may help early detection and intervention of CRC liver metastasis, thereby improving patient prognosis.

Continuous-wave degenerate cavity laser for optical imaging in scattering media.

Lasers play a significant role in optical communication, medical, and scientific research, owing to their high brightness and high coherence. However, the high spatial coherence will lead to specific challenges, such as speckle noise in imaging and wavefront distortion during propagation through scattering media. Here, a continuous-wave (cw) degenerate cavity laser (DCL) with low spatial coherence is demonstrated with efficient suppression of the thermal lensing effect from the gain crystal. Experimentally, a cw degenerate laser output with about 2000 transverse modes corresponding to a speckle contrast of about 0.0224 is achieved. This laser can be used for speckle reduction and is robust against atmospheric turbulence, which may find applications in the field of laser imaging technology and illumination.

Reduction in chemotherapy relative dose intensity decreases overall survival of neoadjuvant chemoradiotherapy in patients with locally advanced esophageal carcinoma.

BACKGROUND: Many patients undergo dose reduction or early termination of chemotherapy to reduce chemoradiotherapy-related toxicity, which may increase their risk of survival. However, this strategy may result in underdosing patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). This study aimed to analyze the relationship between the relative dose intensity (RDI) and survival outcomes in patients with LA-ESCC. METHODS: This retrospective study assessed patients with LA-ESCC (cT2N + M0, cT3-4NanyM0) receiving neoadjuvant chemoradiotherapy (NCRT) with curative-intent esophagectomy. The patients received 2 courses of paclitaxel plus carboplatin (TC) combination radiotherapy prior to undergoing surgery. During NCRT, RDI was computed, defined as the received dose as a percentage of the standard dose, and the incidence of dose delays was estimated (≥ 7 days in any course cycle). The best RDI cutoff value (0.7) was obtained using ROC curve. The Kaplan-Meier survival curves were compared using the log-rank test, the treatment effect was measured using hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: We included 132 patients in this study, divided into RDI < 0.7 and RDI ≥ 0.7 groups using cut-off value of 0.7. RDI grade was an independent prognostic factor for OS. Baseline demographic and clinical characteristics were well balanced between the groups. There was no evidence that patients with RDI < 0.7 experienced less toxicity or those with RDI ≥ 0.7 resulted in more toxicity. However, patients with RDI < 0.7 who were given reduced doses had a worse overall survival [HR 0.49, 95% CI 0.27-0.88, P = 0.015]. The risk of a lower RDI increased with a longer dose delay time (P < 0.001). CONCLUSION: The RDI below 0.7 for avoiding chemoradiotherapy toxicity administration led to a reduction in the dose intensity of treatment and decreased overall survival.

Prediction of non-muscle invasive bladder cancer recurrence using deep learning of pathology image.

We aimed to build a deep learning-based pathomics model to predict the early recurrence of non-muscle-infiltrating bladder cancer (NMIBC) in this work. A total of 147 patients from Xuzhou Central Hospital were enrolled as the training cohort, and 63 patients from Suqian Affiliated Hospital of Xuzhou Medical University were enrolled as the test cohort. Based on two consecutive phases of patch level prediction and WSI-level predictione, we built a pathomics model, with the initial model developed in the training cohort and subjected to transfer learning, and then the test cohort was validated for generalization. The features extracted from the visualization model were used for model interpretation. After migration learning, the area under the receiver operating characteristic curve for the deep learning-based pathomics model in the test cohort was 0.860 (95% CI 0.752-0.969), with good agreement between the migration training cohort and the test cohort in predicting recurrence, and the predicted values matched well with the observed values, with p values of 0.667766 and 0.140233 for the Hosmer-Lemeshow test, respectively. The good clinical application was observed using a decision curve analysis method. We developed a deep learning-based pathomics model showed promising performance in predicting recurrence within one year in NMIBC patients. Including 10 state prediction NMIBC recurrence group pathology features be visualized, which may be used to facilitate personalized management of NMIBC patients to avoid ineffective or unnecessary treatment for the benefit of patients.

Toripalimab plus chemotherapy and radiotherapy for treatment-naive advanced esophageal squamous cell carcinoma: a single-arm phase 2 trial.

This single-arm phase 2 trial (ChiCTR2100046715) examined previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) who received four cycles of paclitaxel with carboplatin every 3 weeks. Toripalimab was infused intravenously every 3 weeks for 12 months, or until disease progression or intolerable toxicity. Radiotherapy that encompassed the primary lesions and metastases commenced in the third cycle. The median progression-free survival time was 9.8 months (95% confidence interval [CI]: 6.8-not estimable) in the intent-to-treat population, failing to meet the pre-specified primary endpoints. Secondary endpoints included an objective response rate of 45.5%, a disease control rate of 57.6%, and a median duration of response of 11.5 months (interquartile range, 6.4-15.0). The 1-year progression-free survival and overall survival rates were 41.9% (95% CI: 27.7-63.5) and 69.7% (95% CI: 55.7-87.3), respectively. Lymphopenia was the most frequent grade ≥3 adverse event (82%), and an esophageal fistula developed in three patients (9.1%). No treatment-related deaths occurred. In prespecified exploratory biomarker analysis, higher densities of CD8 + T cells, CD11c+ dendritic cells, and CD68+ macrophages correlated with improved tumor response and prognosis. Radiotherapy supplementation to first-line chemo-immunotherapy for treatment-naive advanced ESCC demonstrated some antitumor activity and manageable safety profiles, warranting further randomized controlled trials.

The genetic architecture of age at menarche and its causal effects on other traits.

Age at menarche (AAM) is a sign of puberty of females. It is a heritable trait associated with various adult diseases. However, the genetic mechanism that determines AAM and links it to disease risk is poorly understood. Aiming to uncover the genetic basis for AAM, we conducted a joint association study in up to 438,089 women from 3 genome-wide association studies of European and East Asian ancestries. A series of bioinformatical analyses and causal inference were then followed to explore in-depth annotations at the associated loci and infer the causal relationship between AAM and other complex traits/diseases. This largest meta-analysis identified a total of 21 novel AAM associated loci at the genome wide significance level (P < 5.0 × 10-8), 4 of which were European ancestry-specific loci. Functional annotations prioritized 33 candidate genes at newly identified loci. Significant genetic correlations were observed between AAM and 67 complex traits. Further causal inference demonstrated the effects of AAM on 13 traits, including forced vital capacity (FVC), high blood pressure, age at first live birth, etc, indicating that earlier AAM causes lower FVC, worse lung function, hypertension and earlier age at first (last) live birth. Enrichment analysis identified 5 enriched tissues, including the hypothalamus middle, hypothalamo hypophyseal system, neurosecretory systems, hypothalamus and retina. Our findings may provide useful insights that elucidate the mechanisms determining AAM and the genetic interplay between AAM and some traits of women.

Ligand Oxidation Activates a Ruthenium(II) Precatalyst for C-H Hydroxylation.

A new class of Ru-sulfonamidate precatalysts for sp3 C-H hydroxylation is described along with a versatile process for assembling unique heteroleptic Ru(II) complexes. The latter has enabled structure-performance studies to identify an optimal precatalyst, 2h, bearing one 4,4'-di-tert-butylbipyridine (dtbpy) and one pyridylsulfonamidate ligand. Single-crystal X-ray analysis confirmed the structure and stereochemistry of this adduct. Catalytic hydroxylation reactions are conveniently performed in an aqueous, biphasic solvent mixture with 1 mol % 2h and ceric ammonium nitrate as the terminal oxidant and deliver oxidized products in yields ranging from 37 to 90%. A comparative mechanistic investigation of 2h against a related homoleptic precatalyst, [Ru(dtbpy)2(MeCN)2](OTf)2, convincingly establishes that the former generates one or more surprisingly long-lived active species under the reaction conditions, thus accounting for the high turnover numbers. Structure-performance, kinetics, mass spectrometric, and electrochemical analyses reveal that ligand oxidation is a prerequisite for catalyst activation. Our findings sharply contrast a large body of prior art showing that ligand oxidation is detrimental to catalyst function. We expect these results to stimulate future innovations in C-H oxidation research.