XIAP-mediated degradation of IFT88 disrupts HSC cilia to stimulate HSC activation and liver fibrosis.

Activation of hepatic stellate cells (HSCs) plays a critical role in liver fibrosis. However, the molecular basis for HSC activation remains poorly understood. Herein, we demonstrate that primary cilia are present on quiescent HSCs but exhibit a significant loss upon HSC activation which correlates with decreased levels of the ciliary protein intraflagellar transport 88 (IFT88). Ift88-knockout mice are more susceptible to chronic carbon tetrachloride-induced liver fibrosis. Mechanistic studies show that the X-linked inhibitor of apoptosis (XIAP) functions as an E3 ubiquitin ligase for IFT88. Transforming growth factor-ß (TGF-ß), a profibrotic factor, enhances XIAP-mediated ubiquitination of IFT88, promoting its proteasomal degradation. Blocking XIAP-mediated IFT88 degradation ablates TGF-ß-induced HSC activation and liver fibrosis. These findings reveal a previously unrecognized role for ciliary homeostasis in regulating HSC activation and identify the XIAP-IFT88 axis as a potential therapeutic target for liver fibrosis.

A new chromosome-scale duck genome shows a major histocompatibility complex with several expanded multigene families.

BACKGROUND: The duck (Anas platyrhynchos) is one of the principal natural hosts of influenza A virus (IAV), harbors almost all subtypes of IAVs and resists to many IAVs which cause extreme virulence in chicken and human. However, the response of duck's adaptive immune system to IAV infection is poorly characterized due to lack of a detailed gene map of the major histocompatibility complex (MHC). RESULTS: We herein reported a chromosome-scale Beijing duck assembly by integrating Nanopore, Bionano, and Hi-C data. This new reference genome SKLA1.0 covers 40 chromosomes, improves the contig N50 of the previous duck assembly with highest contiguity (ZJU1.0) of more than a 5.79-fold, surpasses the chicken and zebra finch references in sequence contiguity and contains a complete genomic map of the MHC. Our 3D MHC genomic map demonstrated that gene family arrangement in this region was primordial; however, families such as AnplMHCI, AnplMHCIIß, AnplDMB, NKRL (NK cell receptor-like genes) and BTN underwent gene expansion events making this area complex. These gene families are distributed in two TADs and genes sharing the same TAD may work in a co-regulated model. CONCLUSIONS: These observations supported the hypothesis that duck's adaptive immunity had been optimized with expanded and diversified key immune genes which might help duck to combat influenza virus. This work provided a high-quality Beijing duck genome for biological research and shed light on new strategies for AIV control.

Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety.

Proteolysis Targeting Chimeras (PROTACs) represent a significant advancement in therapeutic drug development by leveraging the ubiquitin-proteasome system to enable targeted protein degradation, particularly impacting oncology. This review delves into the various types of PROTACs, such as peptide-based, nucleic acid-based, and small molecule PROTACs, each addressing distinct challenges in protein degradation. It also discusses innovative strategies like bridged PROTACs and conditional switch-activated PROTACs, offering precise targeting of previously "undruggable" proteins. The potential of PROTACs extends beyond oncology, with ongoing research and technological advancements needed to maximize their therapeutic potential. Future progress in this field relies on interdisciplinary collaboration and the integration of advanced computational tools to open new treatment avenues across various diseases.

Menarche-a journey into womanhood: age at menarche and health-related outcomes in East Asians.

STUDY QUESTION: Are there associations of age at menarche (AAM) with health-related outcomes in East Asians? SUMMARY ANSWER: AAM is associated with osteoporosis, Type 2 diabetes (T2D), glaucoma, and uterine fibroids, as demonstrated through observational studies, polygenic risk scores, genetic correlations, and Mendelian randomization (MR), with additional findings indicating a causal effect of BMI and T2D on earlier AAM. WHAT IS KNOWN ALREADY: Puberty timing is linked to adult disease risk, but research predominantly focuses on European populations, with limited studies in other groups. STUDY DESIGN, SIZE, DURATION: We performed an AAM genome-wide association study (GWAS) with 57 890 Han Taiwanese females and examined the association between AAM and 154 disease outcomes using the Taiwanese database. Additionally, we examined genetic correlations between AAM and 113 diseases and 67 phenotypes using Japanese GWAS summary statistics. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed AAM GWAS and gene-based GWAS studies to obtain summary statistics and identify potential AAM-related genes. We applied phenotype, polygenic risk scores, and genetic correlation analyses of AAM to explore health-related outcomes, using multivariate regression and linkage disequilibrium score regression analyses. We also explored potential bidirectional causal relationships between AAM and related outcomes through univariable and multivariable MR analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Fifteen lead single-nucleotide polymorphisms and 24 distinct genes were associated with AAM in Taiwan. AAM was genetically associated with later menarche and menopause, greater height, increased osteoporosis risk, but lower BMI, and reduced risks of T2D, glaucoma, and uterine fibroids in East Asians. Bidirectional MR analyses indicated that higher BMI/T2D causally leads to earlier AAM. LIMITATIONS, REASONS FOR CAUTION: Our findings were specific to Han Taiwanese individuals, with genetic correlation analyses conducted in East Asians. Further research in other ethnic groups is necessary. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides insights into the genetic architecture of AAM and its health-related outcomes in East Asians, highlighting causal links between BMI/T2D and earlier AAM, which may suggest potential prevention strategies for early puberty. STUDY FUNDING/COMPETING INTEREST(S): The work was supported by China Medical University, Taiwan (CMU110-S-17, CMU110-S-24, CMU110-MF-49, CMU111-SR-158, CMU111-MF-105, CMU111-MF-21, CMU111-S-35, CMU112-SR-30, and CMU112-MF-101), the China Medical University Hospital, Taiwan (DMR-111-062, DMR-111-153, DMR-112-042, DMR-113-038, and DMR-113-103), and the Ministry of Science and Technology, Taiwan (MOST 111-2314-B-039-063-MY3, MOST 111-2314-B-039-064-MY3, MOST 111-2410-H-039-002-MY3, and NSTC 112-2813-C-039-036-B). The funders had no influence on the data collection, analyses, or conclusions of the study. No conflict of interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Establish and validate the reliability of predictive models in bone mineral density by deep learning as examination tool for women.

While FRAX with BMD could be more precise in estimating the fracture risk, DL-based models were validated to slightly reduce the number of under- and over-treated patients when no BMD measurements were available. The validated models could be used to screen for patients at a high risk of fracture and osteoporosis. PURPOSE: Fracture risk assessment tool (FRAX) is useful in classifying the fracture risk level, and precise prediction can be achieved by estimating both clinical risk factors and bone mineral density (BMD) using dual X-ray absorptiometry (DXA). However, DXA is not frequently feasible because of its cost and accessibility. This study aimed to establish the reliability of deep learning (DL)-based alternative tools for screening patients at a high risk of fracture and osteoporosis. METHODS: Participants were enrolled from the National Bone Health Screening Project of Taiwan in this cross-sectional study. First, DL-based models were built to predict the lowest T-score value in either the lumbar spine, total hip, or femoral neck and their respective BMD values. The Bland-Altman analysis was used to compare the agreement between the models and DXA. Second, the predictive model to classify patients with a high fracture risk was built according to the estimated BMD from the first step and the FRAX score without BMD. The performance of the model was compared with the classification based on FRAX with BMD. RESULTS: Approximately 10,827 women (mean age, 65.4 ± 9.4 years) were enrolled. In the prediction of the lumbar spine BMD, total hip BMD, femoral neck BMD, and lowest T-score, the root-mean-square error (RMSE) was 0.099, 0.089, 0.076, and 0.68, respectively. The Bland-Altman analysis revealed a nonsignificant difference between the predictive models and DXA. The FRAX score with femoral neck BMD for major osteoporotic fracture risk was 9.7% ± 6.7%, whereas the risk for hip fracture was 3.3% ± 4.6%. Comparison between the classification of FRAX with and without BMD revealed the accuracy rate, positive predictive value (PPV), and negative predictive value (NPV) of 78.8%, 64.6%, and 89.9%, respectively. The area under the receiver operating characteristic curve (AUROC), accuracy rate, PPV, and NPV of the classification model were 0.913 (95% confidence interval: 0.904-0.922), 83.5%, 71.2%, and 92.2%, respectively. CONCLUSION: While FRAX with BMD could be more precise in estimating the fracture risk, DL-based models were validated to slightly reduce the number of under- and over-treated patients when no BMD measurements were available. The validated models could be used to screen for patients at a high risk of fracture and osteoporosis.

One-pot tandem reduction and site-selective halogenation of nitroarenes.

Halogenated aryl amines are a widely used chemical feedstock in the pharmaceutical and agrochemical industries. Achieving a single regioselective product from the para-selective halogenation of the aryl ring is significantly challenging because of the presence of several C-H bonds with similar reactivities. In this study, single para-halogenated aniline derivatives were prepared by the cascade para-selective halogenation (Cl, Br) and reduction of nitrobenzene derivatives using a mixture of SnCl2/SnCl4 salts. The mechanistic study confirmed that the noncovalent interactions between the chalcogen bond and Sn salt were pivotal for achieving regioselectivity. This synthetic method was applied for the development of potent and highly selective positron emission tomography molecular probes for serotonin transporters.

Exposure and health risk assessment of volatile organic compounds among drivers and passengers in long-distance buses.

Exposure to volatile organic compounds (VOCs) such as benzene, toluene, ethylbenzene, xylene, and formaldehyde from long-distance buses has been reported to adversely affect human health. This study investigates the concentrations of these five VOCs and evaluates their health risks to drivers and passengers on board. Ten trips from Taipei to Taichung were performed during the warm and cold seasons of 2021-2022. Two locations inside the bus were established to collect air samples by a 6-liter canister for drivers and passengers. Exposure concentrations of benzene, toluene, ethylbenzene, and xylene were analyzed via gas chromatography with a flame ionization detector and the formaldehyde concentration was monitored using a formaldehyde meter. Subsequently, a Monte Carlo simulation was conducted to evaluate the carcinogenic and non-carcinogenic risks of the five VOCs. Formaldehyde emerged as the highest detected compound (9.06 ± 3.77 µg/m3), followed by toluene (median: 6.11 µg/m3; range: 3.86-14.69 µg/m3). In particular, formaldehyde was identified to have the significantly higher concentration during non-rush hours (10.67 ± 3.21 µg/m3) than that during rush hours (7.45 ± 3.41 µg/m3) and during the warm season (10.71 ± 2.97 µg/m3) compared with that during the cold season (7.41 ± 4.26 µg/m3). Regarding non-carcinogenic risks to drivers and passengers, the chronic hazard indices for these five VOCs were under 1 to indicate an acceptable risk. In terms of carcinogenic risk, the median risks of benzene and formaldehyde for drivers were 2.88 × 10-6 (95% confidence interval [CI]: 2.11 × 10-6 - 5.13 × 10-6) and 1.91 × 10-6 (95% CI: 4.54 × 10-7 - 3.44 × 10-6), respectively. In contrast, the median carcinogenic risks of benzene and formaldehyde for passengers were less than 1 × 10-6 to present an acceptable risk. This study suggests that benzene and formaldehyde may present carcinogenic risks for drivers. Moreover, the non-carcinogenic risk for drivers and passengers is deemed acceptable. We recommended that the ventilation frequency be increased to mitigate exposure to VOCs in long-distance buses.

Chronic kidney disease and cognitive performance: NHANES 2011-2014.

PURPOSE: Previous studies suggest an association between chronic kidney disease (CKD) and cognitive impairment. The purpose of this study was to explore the association between the diverse stages of CKD and the cognitive performance of elderly American adults. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 were used. Multivariate adjusted logistic regression, subgroup analysis, and the restricted cubic spline model were used to assess the associations of CKD stage and estimated glomerular filtration rate (eGFR) with cognitive performance. The measures used to evaluate cognitive function included the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test, the Animal Fluency test, and the Digit Symbol Substitution test (DSST). RESULTS: This study included 2234 participants aged ≥ 60 years. According to the fully adjusted model, stages 3-5 CKD were significantly associated with the CERAD test score (OR = 0.70, 95% CI [0.51, 0.97], p = 0.033), the Animal Fluency test score (OR = 0.64, 95% CI [0.48, 0.85], p = 0.005), and the DSST score (OR = 0.60, 95% CI [0.41, 0.88], p = 0.013). In addition, the incidence of poor cognitive function increased with decreasing eGFR, especially for individuals with low and moderate eGFRs. Both the DSST score (p nonlinearity < 0.0001) and the Animal Fluency test score (p nonlinearity = 0.0001) had nonlinear dose-response relationships with the eGFR. However, a linear relationship was shown between the eGFR and CERAD test score (p nonlinearity = 0.073). CONCLUSIONS: CKD, especially stages3-5 CKD, was significantly associated with poor cognitive performance in terms of executive function, learning, processing speed, concentration, and working memory ability. All adults with CKD should be screened for cognitive impairment.

Dynein Light Intermediate Chains Exhibit Different Arginine Methylation Patterns.

BACKGROUND: The motor protein dynein is integral to retrograde transport along microtubules and interacts with numerous cargoes through the recruitment of cargo-specific adaptor proteins. This interaction is mediated by dynein light intermediate chain subunits LIC1 (DYNC1LI1) and LIC2 (DYNC1LI2), which govern the adaptor binding and are present in distinct dynein complexes with overlapping and unique functions. METHODS: Using bioinformatics, we analyzed the C-terminal domains (CTDs) of LIC1 and LIC2, revealing similar structural features but diverse post-translational modifications (PTMs). The methylation status of LIC2 and the proteins involved in this modification were examined through immunoprecipitation and immunoblotting analyses. The specific methylation sites on LIC2 were identified through a site-directed mutagenesis analysis, contributing to a deeper understanding of the regulatory mechanisms of the dynein complex. RESULTS: We found that LIC2 is specifically methylated at the arginine 397 residue, a reaction that is catalyzed by protein arginine methyltransferase 1 (PRMT1). CONCLUSIONS: The distinct PTMs of the LIC subunits offer a versatile mechanism for dynein to transport diverse cargoes efficiently. Understanding how these PTMs influence the functions of LIC2, and how they differ from LIC1, is crucial for elucidating the role of dynein-related transport pathways in a range of diseases. The discovery of the arginine 397 methylation site on LIC2 enhances our insight into the regulatory PTMs of dynein functions.

New Diterpenes and Diterpene Glycosides with Antibacterial Activity from Soft Coral Lemnalia bournei.

Five new biflorane-type diterpenoids, biofloranates E-I (1-5), and two new bicyclic diterpene glycosides, lemnaboursides H-I (6-7), along with the known lemnabourside, were isolated from the South China Sea soft coral Lemnalia bournei. Their chemical structures and stereochemistry were determined based on extensive spectroscopic methods, including time-dependent density functional theory (TDDFT) ECD calculations, as well as a comparison of them with the reported values. The antibacterial activities of the isolated compounds were evaluated against five pathogenic bacteria, and all of these diterpenes and diterpene glycosides showed antibacterial activities against Staphylococcus aureus and Bacillus subtilis, with MICs ranging from 4 to 64 µg/mL. In addition, these compounds did not exhibit noticeable cytotoxicities on A549, Hela, and HepG2 cancer cell lines, at 20 µM.

Discovery of Novel Spike Inhibitors against SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current coronavirus disease pandemic. With the rapid evolution of variant strains, finding effective spike protein inhibitors is a logical and critical priority. Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV-2 viral entry, and thus related therapeutic approaches associated with the spike protein-ACE2 interaction show a high degree of feasibility for inhibiting viral infection. Our computer-aided drug design (CADD) method meticulously analyzed more than 260,000 compound records from the United States National Cancer Institute (NCI) database, to identify potential spike inhibitors. The spike protein receptor-binding domain (RBD) was chosen as the target protein for our virtual screening process. In cell-based validation, SARS-CoV-2 pseudovirus carrying a reporter gene was utilized to screen for effective compounds. Ultimately, compounds C2, C8, and C10 demonstrated significant antiviral activity against SARS-CoV-2, with estimated EC50 values of 8.8 µM, 6.7 µM, and 7.6 µM, respectively. Using the above compounds as templates, ten derivatives were generated and robust bioassay results revealed that C8.2 (EC50 = 5.9 µM) exhibited the strongest antiviral efficacy. Compounds C8.2 also displayed inhibitory activity against the Omicron variant, with an EC50 of 9.3 µM. Thus, the CADD method successfully discovered lead compounds binding to the spike protein RBD that are capable of inhibiting viral infection.

Effect of mixed fermentation of Lactiplantibacillus plantarum and Lactiplantibacillus pentosus on phytochemical and flavor characteristics of Wallace melon juice.

BACKGROUND: Melons (Cucumis melo L.) are among the most commonly consumed fruits but they are highly susceptible to mechanical damage and rot during storage and transportation. New processed products are needed to avoid postharvest fruit loss and to increase health benefits. Fermentation is an effective means of utilizing the nutrients and improving flavor. RESULTS: Fermented melon juice (MJ) was prepared using three potential probiotics Lactiplantibacillus plantarum CICC21824 (LP), Lactiplantibacillus plantarum GB3-2 (LG), and Lactiplantibacillus pentosus XZ-34 (LX). The nutrition, flavor characteristics, and digestive properties of different fermented MJs were compared. The results demonstrated that, in comparison with mono-fermentation, mixed fermentation by LG and LX could increase the level of organic acids and phenolic acids. Correspondingly, antioxidant capacity was improved significantly and positively correlated with p-coumaric acid and cinnamic acid content. The production of alcohols and acids was more strongly enhanced by mixed culture fermentation, whereas mono-fermentation reduced the content of esters, especially ethyl acetate and isopropyl acetate. Aldehydes and ketones increased significantly in fermented MJ, and damascenone and heptanal could be the characteristic aroma compounds. CONCLUSION: Mixed fermented MJ provides more beneficial phytochemicals, better flavor, and stronger antioxidant properties than mono-fermentation. © 2024 Society of Chemical Industry.

Primary cilium-mediated signaling cascade suppresses age-related biliary fibrosis.

The primary cilium is increasingly recognized as a crucial player in the physiology of biliary epithelial cells (BECs). However, the precise role of primary cilia in the development of age-related biliary fibrosis remains unclear. Herein, using cilium-deficient mice, we demonstrate that disruption of ciliary homeostasis in BECs in aged mice leads to significant bile duct proliferation, augmented biliary fibrosis, and heightened indicators of liver injury. Our RNA-sequencing data revealed a dysregulation in genes associated with various biological processes such as bile secretion, fatty acid metabolism, and inflammation. Loss of primary cilia also significantly enhanced signaling pathways driving the development of biliary fibrosis. Our findings collectively suggest that loss of primary cilia in the BECs of aged mice initiates a cascade of signaling events that contribute to biliary fibrosis, highlighting the primary cilium as a potential therapeutic target in the treatment of fibrosing cholangiopathies.

Evaluation of Internet-based pharmaceutical care effect on young and middle-aged patients with hypertension by the principal component analysis and the Markov cohort during COVID-19 pandemic.

BACKGROUND: Pharmaceutical care has the potential to improve hypertension control rates in young and middle-aged patients. Due the COVID-19 epidemic, standard intervention methods may not be applicable. We propose establishing an internet-based pharmaceutical care (IPC) route to improve blood pressure control in young and middle-aged patients with hypertension. An evaluation method based on Principal Component Analysis (PCA) and Orthogonal Partial Least-Discriminant Analysis (OPLS-DA) was established to evaluate the effect of the IPC method. METHODS: 1) Internet-based Pharmaceutical care (IPC) was provided by pharmacists mainly using Wechat software for one year after enrollment; 2) PCA and OPLS-DA were applied to analyze questionnaire reliability and data variability; 3) Markov cohort was used to evaluate the IPC effect. RESULTS: Ninety-seven young and middle-aged patients were enrolled. 96 patients received the IPC. 1) The blood pressure control rate increased to 71.88% after IPC in 96 patients. 2) After conducting PCA and OPLS-DA analysis, 10 questions in the questionnaire were significantly improved after the IPC. 3) Markov cohort results showed that patient survival after 28 cycles was 18.62 years and the quality-adjusted life year (QALY) was extended by 5.40 years. The cumulative cost-effectiveness ratio was ¥87.10 per QALY. CONCLUSIONS: The IPC method could significantly improve the blood pressure control rate of patients. The questionnaire analysis method based on PCA and OPLS-DA is an effective method to evaluate the effect of the IPC method. The Markov cohort showed that the IPC had an effect on blood pressure control rate changes. Patients had a strong willingness to pay for IPC.

Inhibitory mechanism of KIF3A gene on nasopharyngeal carcinoma stem cells.

To investigate the inhibitory mechanism of the KIF3A gene on nasopharyngeal carcinoma (NPC) tumor stem cells. Set up a blank control group (BCG), NPC group, and KIF3A silence (si-KIF3A) group. The BCG cells were nasopharyngeal normal epithelial cell line NP69, without any treatment, and were cultured routinely; The NPC group cells are human NPC cell line CNE2 cells, which are not subjected to any treatment and are cultured routinely; si-KIF3A group cells were cultured in the offspring of human NPC cell line CNE2 infected with Lentivirus knockdown KIF3A gene. CCK8 was used to detect the cell proliferation ability, Western blot and qPCR were used to detect protein and related mRNA expression, while cell migration and invasion were detected using Transwell. The KIF3A protein and mRNA in the NPC group were higher than those in the BCG (P<0.05), while those in the si-KIF3A group cells were lower compared to BCG cells (P<0.05). The cell proliferation, migration and invasion activity in the si-KIF3A group were reduced than those in BCG (P<0.05). Si-KIF3A group cells HIF-1, NF-κB was reduced than that of BCG (P<0.05). The expression level of HIF-1, NF-κB protein in si-KIF3A group cells was reduced compared to BCG cells (P<0.05). Knocking down the KIF3A gene can reduce the vitality of NPC stem cells, and inhibit the malignant phenotype of NPC stem cells, via inhibiting HIF-1 and NF-κB expression.

Additional single dose GnRH agonist during luteal phase support may improve live birth rate in GnRHa-HRT frozen-thawed embryo transfer cycle: a retrospective cohort study.

BACKGROUND: GnRH agonist (GnRHa) has been reported to have direct effects and functional roles in the endometrium and embryos. Several meta-analyses have shown that GnRHa administration in the luteal phase improved the live birth rate or pregnancy rate in both fresh and frozen embryo transfer (FET) cycles. The aim of this study was to investigate whether luteal GnRHa administration could also improve in vitro fertilization (IVF) outcomes in patients undergoing hormone replacement therapy (HRT) cycles with GnRHa suppression. METHODS: The retrospective cohort study included a total of 350 patients undergoing GnRHa-HRT FET cycles. The study group included 179 patients receiving an additional single dose of GnRHa in the luteal phase following embryo transfer. A total of 171 patients in the control group did not receive luteal GnRHa. The baseline and cycle characteristics and reproductive outcomes were compared between the two groups. RESULTS: Baseline and cycle characteristics were similar between the two groups, except lower AMH levels were found in the luteal GnRHa group than in the control group. The luteal GnRHa group had a significantly higher ongoing pregnancy rate and live birth rate than the control group. The multivariate analysis revealed that luteal GnRHa administration was positively associated with ongoing pregnancy (OR 2.04, 95% CI 1.20-3.47, P = 0.008) and live birth (OR 2.03, 95% CI 1.20-3.45, P = 0.009). When the subgroup of patients with recurrent implantation failure was analyzed, the multivariate analysis also showed that luteal GnRHa administration had beneficial effects on ongoing pregnancy (OR 4.55, 95% CI 1.69-12.30, P = 0.003) and live birth (OR 4.30, 95% CI 1.59-11.65, P = 0.004). CONCLUSIONS: Our data suggest that the addition of one luteal dose of GnRHa may improve the live birth rate in patients undergoing the GnRHa-HRT protocol.

Effects of Differentially Expressed mRNAs Screened Based on GEO Database on Inflammatory Infiltration of Nasal Mucosa in Mice with Allergic Rhinitis.

Objective: To identify messenger RNAs (mRNAs) with differential expression in allergic rhinitis (AR) based on an online database, Gene Expression Omnibus (GEO), to provide a new research direction for future diagnosis and treatment of AR. Methods: The GSE44037 dataset from the CEO database was selected to obtain differentially expressed mRNAs (DEmRNAs) in AR. The keywords involved in these DEmRNAs were enriched and analyzed, and ECM1 and CCL2 were selected for subsequent analysis. In addition, BALB/c mice were purchased and randomized to control (normal feeding), model (AR modeling), si-CCL2 (AR modeling + CCL2 suppression by lentivirus vector), nc-CCL2 (AR modeling + CCL2 empty vector), si-ECM1 (AR modeling + ECM1 suppression by lentivirus vector), and nc-ECM1 (AR modeling + ECM1 empty vector) groups. The frequencies of sneezing and nasal rubbing were recorded in each group. Besides, levels of CCL2, ECM1, interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and high sensitivity C-reactive protein (hs-CRP) were quantified, and the inflammatory infiltration of nasal mucosa (NM) was observed. Results: Twenty-six DEmRNAs were acquired from the GSE44037 dataset, among which only CCL2 and ECM1 were found to be associated with keywords such as "immune response" and "inflammatory response" through enrichment analysis. In animal experiments, CCL2 presented lower mRNA expression in model mice than in control mice, while ECM1 showed higher mRNA expression (P < .05). The frequencies of sneezing and nose rubbing and the levels of inflammatory factors were significantly increased in si-CCL2 mice compared with model mice, while were significantly decreased in si-ECM1 mice (P < .05). The NM inflammatory infiltration was serious in the si-CCL2 group and significantly improved in the si-ECM1 group. Conclusions: Low expression of CCL2 and high expression of ECM1 in AR are strongly linked to the pathological progression of AR, and these two genes are expected to be new research directions for AR diagnosis and treatment.

Three New Cembranoids from a Xisha Soft Coral Sarcophyton sp.

Chemical investigation of the Xisha soft coral Sarcophyton sp. has led to the isolation of eight cembrane-type diterpenoids, including three new compounds, namely sarcophynoids A-C (1-3), and five known analog compounds (4-8). Their structures were clarified based on spectroscopic analysis, and computer-assisted methods including TDDFT-ECD calculation and the quantum mechanical-nuclear magnetic resonance (QM-NMR) method. All the above compounds were tested for their antibacterial activities. Among them, compounds 4-7 and 8 exhibited antibacterial activities against S. aureus, B. subtilis, and P. aeruginosa, with MIC of 4-64 µg/mL.

High serum anti-Müllerian hormone concentrations have a negative impact on fertilization and embryo development rates.

RESEARCH QUESTION: What is the impact of high serum anti-Müllerian hormone (AMH) concentrations on fertilization and embryo development among infertile women undergoing treatment with assisted reproductive technology (ART)? DESIGN: Retrospective study of 1036 infertile women undergoing ART; women were divided into three groups according to serum AMH concentrations: AMH <1.1 ng/ml, 1.1-5.0 ng/ml and >5.0 ng/ml. The fertilization and embryo development rates of patients with different AMH concentrations and after stratification according to age were compared. RESULTS: Women with high AMH concentrations were younger and had higher testosterone concentrations (0.4 ± 0.13 versus 0.3 ± 0.12 versus 0.3 ± 0.08 µg/dl, P < 0.001) than women with low AMH concentrations. However, analysis of the embryo development rate showed negative outcomes for women with high AMH concentrations, including a poor fertilization rate (76.3 ± 17.36 versus 82.1 ± 19.15 versus 82.4 ± 25.38, P = 0.003), and poor day 3 embryo development rate (55.6 ± 23.88 versus 62.6 ± 26.52 versus 62.8 ± 32.65, P = 0.014). Multivariate linear regression analysis showed significantly negative correlations of the AMH concentrations with the fertilization rate (P < 0.001) and day 3 embryo development rate (P = 0.006). Subgroup analysis showed that age 30 years or younger had a significant negative correlation with AMH and the embryo development rate, including the fertilization rate (P < 0.001) and day 3 embryo development rate (P = 0.037). CONCLUSION: These results suggest that high serum AMH concentrations, contributing to a hyperandrogenic environment and leading to decreased oocyte developmental competence, may have a negative impact on fertilization and the early stage of embryo development in women undergoing treatment with ART.

Sinuscalide A: An Antiviral Norcembranoid with an 8/8-Fused Carbon Scaffold from the South China Sea Soft Coral Sinularia scabra.

Sinuscalide A (1), featuring an uncommon 8/8-fused carbon scaffold, three new norditerpenes, sinuscalides B-D (2-4), and sinuscatone A (5), with a 5/4/9 tricyclic carbon ring system, along with four known compounds were isolated from the South China Sea soft coral Sinularia scabra. The structures of the new compounds were established by extensive spectroscopic analysis, X-ray diffraction, and electronic circular dichroism (ECD). A plausible biosynthetic pathway for 1 was proposed. In a bioassay, compound 1 showed antiviral activity against human enterovirus EV71 (IC50 = 5.0 µM) and an inhibitory effect against RANKL-induced osteoclastogenesis (92.3% inhibition at 10 µM). Compound 5 exhibited mild inhibition against Streptococcus pneumoniae and Salmonella paratyph (MIC 16 µg/mL).