Helper T cells: A potential target for sex hormones to ameliorate rheumatoid arthritis? (Review).

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease whose etiology is not fully understood. Defective peripheral immune tolerance and subsequent mis­differentiation and aberrant infiltration of synovium by various immune cells, especially helper T (Th) cells, play an important role in the development of RA. There are significant sex differences in RA, but the results of studies on the effects of sex hormones on RA have been difficult to standardize and hormone replacement therapy has been limited by the potential for serious side effects. Existing research has amply demonstrated that cellular immune responses are largely determined by sex and that sex hormones play a key role in Th cell responses. Based on the aforementioned background and the plasticity of Th cells, it is reasonable to hypothesize that the action of sex hormones on Th cells will hopefully become a therapeutic target for RA. The present review discussed the role of various Th cell subsets in the pathogenesis of RA and also explored the role of sex hormones on the phenotype and function of these aberrantly regulated immune cells in RA as well as other pathologic effects on RA.

Endosomal pH, Redox Dual-Sensitive Prodrug Micelles Based on Hyaluronic Acid for Intracellular Camptothecin Delivery and Active Tumor Targeting in Cancer Therapy.

Background: CPT is a pentacyclic monoterpene alkaloid with a wide spectrum of antitumor activity. Its clinical application is restricted due to poor water solubility, instability, and high toxicity. We developed a new kind of multifunctional micelles to improve its solubility, reduce the side effecs, and obtain enhanced antitumor effects. Methods: We constructed HA-CPT nano-self-assembly prodrug micelles, which combined the advantages of pH-sensitivity, redox-sensitivity, and active targeting ability to CD44 receptor-overexpressing cancer cells. To synthesize dual sensitive HA-CPT conjugates, CPT was conjugated with HA by pH-sensitive histidine (His) and redox-sensitive 3,3'-dithiodipropionic acid (DTPA). In vitro, we studied the cellular uptake and antitumor effect for tumor cell lines. In vivo, we explored the bio-distribution and antitumor effects of the micelles in HCT 116 tumor bearing nude mice. Results: The dual-sensitive and active targeting HA-His-ss-CPT micelles was proved to be highly efficient in CPT delivery by the in vitro cellular uptake study. The HA-His-ss-CPT micelles escaped from endosomes of tumor cells within 4 h after cellular uptake due to the proton sponge effect of the conjugating His and then quickly released CPT in the cytosol by glutathione (GSH). In mice, HA-His-ss-CPT micelles displayed efficient tumor accumulation and conspicuous inhibition of tumor growth. Conclusions: The novel, dual-sensitive, active targeting nano-prodrug micelles exhibited high efficiency in drug delivery and cancer therapy. This "all in one" drug delivery system can be realized in an ingenious structure and avoid intricate synthesis. This construction strategy can illume the design of nanocarriers responding to endogenous stimuli in tumors.

Testicular fibrosis pathology, diagnosis, pathogenesis, and treatment: A perspective on related diseases.

Testicular fibrosis is a chronic and progressive condition characterized by the excessive deposition of extracellular matrix proteins. This process leads to fibrotic remodeling, damage to testicular tissue, and the irreversible loss of male reproductive function. However, there is currently a lack of comprehensive reviews systematically elucidating the pathology, diagnosis, pathogenesis, and treatment of testicular fibrosis from the perspectives of different related diseases. This review addresses these aspects of testicular fibrosis, with a particular emphasis on elucidating the underlying mechanisms of testicular cells. It provides insights that can be relevant for future research and clinical interventions.

Effects of a prior failed attempt on the outcomes of subsequent chronic total occlusion-percutaneous coronary intervention.

Objectives: Patients undergoing a prior failed attempt of chronic total occlusion-percutaneous coronary intervention (CTO-PCI) represent a challenging subgroup across all patients undergoing CTO-PCI. There are limited data on the effects of a prior failed attempt on the outcomes of subsequent CTO-PCI. We aimed to compare the procedural results and 24-month outcomes of prior-failed-attempt CTO-PCI with those of initial-attempt CTO-PCI. Methods: Patients who underwent attempted CTO-PCI between January 2017 and December 2019 were prospectively enrolled. We analyzed the procedural results and 24-month major adverse cardiac events (MACE) between patients who underwent prior-failed-attempt and initial-attempt CTO-PCI. MACE was defined as a composite of cardiac death, target vessel-related myocardial infarction, and ischemia-driven target vessel revascularization (TVR) during follow-up. Results: In total, 484 patients who underwent CTO-PCI (prior-failed-attempt, n = 49; initial-attempt, n = 435) were enrolled during the study period. After propensity score matching (1:3), 147 patients were included in the initial-attempt group. The proportion of the Japanese-CTO (J-CTO) score ≥2 was higher in the patients who underwent prior failed attempt than in those who underwent initial attempt (77.5% vs. 38.8%, p < 0.001). The retrograde approach was more often adopted in the prior-failed-attempt group than in the initial-attempt group (32.7% vs. 3.4%, [P< 0.001). Successful CTO revascularization rates were significantly lower in the prior-failed attempt-group than in the initial attempt group (53.1% vs. 83.3%, P < 0.001). The multivariate analysis revealed that J-CTO score ≥2 [odds ratio (OR), 0.359; 95% confidence interval (CI), 0.159-0.812; P = 0.014], intravascular ultrasound procedure (OR, 4.640; 95% CI, 1.380-15.603; P = 0.013), and prior failed attempt (OR, 0.285; 95% CI, 0.125-0.648; P = 0.003) were the independent predictors for successful CTO revascularization. There were no significant differences in major procedural complications (2.0% vs. 0.7%, p = 0.438) and MACE rates (4.1% vs. 8.8%, p = 0.438) between the groups, mainly due to the TVR rate (4.1% vs. 8.2%, P = 0.522). Conclusions: Compared with initial-attempt CTO-PCI, prior-failed-attempt CTO-PCI deserves more attention, since it is associated with a lower successful CTO revascularization rate. Prior failed attempt, J-CTO score ≥2, and IVUS procedure are the determining factors for predicting successful CTO revascularization. There are no significantly different unfavorable outcomes between patients who undergo prior-failed-attempt and initial-attempt CTO-PCI.

From SNVs to Genes: Identifying the Genetic Links Between Sleep and Psychiatric Disorders.

STUDY OBJECTIVES: Sleep disorders and psychiatric disorders frequently coexist and interact, yet the shared genetic basis linking these two domains remains poorly understood. METHODS: We investigated the genetic correlation and overlap between seven sleep/circadian traits and three psychiatric disorders at the level of genome-wide association studies (GWAS), utilizing LDSC, HDL and GPA. To identify potential polygenic single nucleotide variations (SNVs) within each trait pair, we used PLACO, while gene-level analyses were performed using MAGMA and POPS. Furthermore, the functions and biological mechanisms, enriched phenotypes, tissues, cellular features, and pathways were thoroughly investigated using FUMA, deTS, and enrichment analyses at the biological pathway level. RESULTS: Our study revealed extensive genetic associations and overlap in all 21 trait pairs. We identified 18,494 SNVs and 543 independent genomic risk loci, with 113 confirmed as causative through colocalization analysis. These loci collectively spanned 196 unique chromosomal regions. We pinpointed 43 distinct pleiotropic genes exhibiting significant enrichment in behavioral/physiological phenotypes, nervous system phenotypes, and brain tissue. Aberrations in synaptic structure and function, neurogenesis and development, as well as immune responses, particularly involving the MAPK pathway, emerged as potential underpinnings of the biology of sleep/circadian traits and psychiatric disorders. CONCLUSIONS: We identified shared loci and specific sets of genes between sleep/circadian traits and psychiatric disorders, shedding light on the genetic etiology. These discoveries hold promise as potential targets for novel drug interventions, providing valuable insights for the development of therapeutic strategies for these disorders.

Targeted delivery of rosuvastatin enhances treatment of hyperhomocysteinemia-induced atherosclerosis using macrophage membrane-coated nanoparticles.

Rosuvastatin (RVS) is an excellent drug with anti-inflammatory and lipid-lowering properties in the academic and medical fields. However, this drug faces a series of challenges when used to treat atherosclerosis caused by hyperhomocysteinemia (HHcy), including high oral dosage, poor targeting, and long-term toxic side effects. In this study, we applied nanotechnology to construct a biomimetic nano-delivery system, macrophage membrane (Møm)-coated RVS-loaded Prussian blue (PB) nanoparticles (MPR NPs), for improving the bioavailability and targeting capacity of RVS, specifically to the plaque lesions associated with HHcy-induced atherosclerosis. In vitro assays demonstrated that MPR NPs effectively inhibited the Toll-like receptor 4 (TLR4)/hypoxia-inducible factor-1α (HIF-1α)/nucleotide-binding and oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) signaling pathways, reducing pyroptosis and inflammatory response in macrophages. Additionally, MPR NPs reversed the abnormal distribution of adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1)/ATP binding cassette transporter G1 (ABCA1)/ATP binding cassette transporter G1 (ABCG1) caused by HIF-1α, promoting cholesterol efflux and reducing lipid deposition. In vivo studies using apolipoprotein E knockout (ApoE -/-) mice confirmed the strong efficacy of MPR NPs in treating atherosclerosis with favorable biosecurity, and the mechanism behind this efficacy is believed to involve the regulation of serum metabolism and the remodeling of gut microbes. These findings suggest that the synthesis of MPR NPs provides a promising nanosystem for the targeted therapy of HHcy-induced atherosclerosis.

Ultrasound-Based Radiomics for Predicting the WHO/ISUP Grading of Clear-Cell Renal Cell Carcinoma.

OBJECTIVE: To explore the performance of ultrasound image-based radiomics in predicting World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading of clear-cell renal cell carcinoma (ccRCC). METHODS: A retrospective study was conducted via histopathological examination on participants with ccRCC from January 2021 to August 2023. Participants were randomly allocated to a training set and a validation set in a 3:1 ratio. The maximum cross-sectional image of the lesion on the preoperative ultrasound image was obtained, with the region of interest (ROI) delineated manually. Radiomic features were computed from the ROIs and subsequently normalized using Z-scores. Wilcoxon test and least absolute shrinkage and selection operator (LASSO) regression were applied for feature reduction and model development. The performance of the model was estimated by indicators including area under the curve (AUC), sensitivity and specificity. RESULTS: A total of 336 participants (median age, 57 y; 106 women) with ccRCC were finally included, of whom 243 had low-grade tumors (grade 1-2) and 93 had high-grade tumors (grade 3-4). A total of 1163 radiomic features were extracted from the ROIs for model construction and 117 informative radiomics features selected by Wilcoxon test were submitted to LASSO. Our ultrasound-based radiomics model included 51 features and achieved AUCs of 0.90 and 0.79 for the training and validation sets, respectively. Within the training set, the sensitivity and specificity measured 0.75 and 0.92, respectively, whereas in the validation set, the sensitivity and specificity measured 0.65 and 0.84, respectively. In the subgroup analysis, for the training and validation sets Philips AUCs were 0.91 and 0.75, Toshiba AUCs were 0.82 and 0.90, and General Electric AUCs were 0.95 and 0.82, respectively. CONCLUSION: Ultrasound-based radiomics can effectively predict the WHO/ISUP grading of ccRCC.

Brain lncRNA-mRNA co-expression regulatory networks and alcohol use disorder.

Prolonged alcohol consumption can disturb the expression of both coding and noncoding genes in the brain. These dysregulated genes may co-express in modules and interact within networks, consequently influencing the susceptibility to developing alcohol use disorder (AUD). In the present study, we performed an RNA-seq analysis of the expression of both long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) in 192 postmortem tissue samples collected from eight brain regions (amygdala, caudate nucleus, cerebellum, hippocampus, nucleus accumbens, prefrontal cortex, putamen, and ventral tegmental area) of 12 AUD and 12 control subjects of European ancestry. Applying the limma-voom method, we detected a total of 57 lncRNAs and 51 mRNAs exhibiting significant differential expression (Padj < 0.05 and fold-change ≥2) across at least one of the eight brain regions investigated. Machine learning analysis further confirmed the potential of these top genes in predicting AUD. Through Weighted Gene Co-expression Network Analysis (WGCNA), we identified distinct lncRNA-mRNA co-expression modules associated with AUD in each of the eight brain regions. Additionally, lncRNA-mRNA co-expression networks were constructed for each brain region using Cytoscape to reveal gene regulatory interactions implicated in AUD. Hub genes within these networks were found to be enriched in several key KEGG pathways, including Axon Guidance, MAPK Signaling, p53 Signaling, Adherens Junction, and Neurodegeneration. Our results underscore the significance of networks involving AUD-associated lncRNAs and mRNAs in modulating neuroplasticity in response to alcohol exposure. Further elucidating these molecular mechanisms holds promise for the development of targeted therapeutic interventions for AUD.

The effect of cardiovascular disease on the perioperative period of radical surgery in elderly rectal cancer.

AIM: To investigate the impact of preoperative cardiovascular disease on the perioperative period of rectal cancer patients over 75 years old. METHODS: The clinicopathological data of 625 elderly patients aged ≥ 75 years who underwent radical rectal cancer surgery in the Cancer Hospital of the Chinese Academy of Medical Sciences and affiliated Heji Hospital of Changzhi Medical College from January 2011 to December 2022 were retrospectively collected and analyzed. According to preoperative comorbidities, all patients were divided into cardiovascular disease group (n = 361) and non-cardiovascular disease group (n = 264). One hundred and ninety-two pairs were selected from each group through Propensity score-matched to further analysis. Perioperative indexes and postoperative complications were compared between the two groups. RESULTS: There were no significant differences in clinicopathological data between the two groups (P > 0.05). The proportion of elderly patients with cardiovascular disease who went to ICU after radical surgery was significantly higher than those without cardiovascular disease (19.3% vs. 10.4%, P = 0.015). There was no significant difference between the two groups in the time to first flatus (3.0 vs. 3.5 days, P = 0.332) and postoperative hospital stay (11.3 vs. 10.5 days, P = 0.297). One patient in the cardiovascular disease group died due to pulmonary embolism. A total of 100 patients (26.0%) developed postoperative complications, and the incidence of overall complications (30.7% vs. 21.4%, P = 0.036) and grade 3-5 complications (12.5% vs. 6.3%, P = 0.036) in the cardiovascular disease group was significantly higher than that in the non-cardiovascular disease group. In terms of gastrointestinal disorders, the incidence of anastomotic leakage (6.8% vs. 2.1%, P = 0.026) in elderly patients with cardiovascular diseases was significantly higher than that in patients without cardiovascular disease. In addition, the incidence of cardiac disorders (8.3% vs. 2.6%, P = 0.014) in elderly patients with cardiovascular disease was significantly higher. CONCLUSION: Elderly rectal cancer patients over 75 years old with cardiovascular disease are more likely to develop severe complications after radical surgery, especially anastomotic leakage and cardiac disorders.

Novel long noncoding lncARF mediated hyperhomocysteinemia-induced atherosclerosis via autophagy inhibition in foam cells.

INTRODUCTION: Homocysteine (Hcy) is well recognized to be an independent risk factor for atherosclerosis. Long non-coding RNAs (lncRNAs) are emerging regulators of pathophysiological processes including atherosclerosis, while the underlying mechanisms of its involvement in Hcy induced-atherosclerosis remain largely unknown. OBJECTIVES: The primary aim of this study is to assess the role of lncARF (autophagy-related factor induced by Hcy) in Hcy induced-atherosclerosis and related mechanism. METHODS: RNA sequencing of foam cells treated with Hcy revealed a novel specific long noncoding RNA called lncARF. Locked nucleic acid gapmeRs-mediated lncARF knockdown was used to explore the role of lncARF both in vivo and in vitro. Mass spectrometry, RNA pull-down and RNA immunoprecipitation (RIP) assays were employed to uncover a mechanistic role of lncARF. Mass array assay and chromatin immunoprecipitation (ChIP) were used to detect the transcriptional activation of lncARF mediated by transcription factor. Clinically, receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic value of lncARF in atherosclerotic patients with hyperhomocysteinemia (HHcy). RESULTS: We observed that the expression of lncARF was substantially upregulated in atherosclerotic plaques, and knockdown of lncARF decreased the formation of atherosclerotic lesions by promoting autophagy in foam cells. Mechanistically, lncARF physically binds to RRAGD and inhibits its ubiquitination, further activating the PI3K/Akt and MAPK signaling pathways. Moreover, in vitro experiments showed that transcription factor FosB inhibited the binding of DNMT1 at the lncARF promoter, leading to transcriptional activation through DNA hypomethylation. Clinically, lncARF expression was positively correlated with serum Hcy levels, and it could distinguish atherosclerotic patients with HHcy with a high area under the ROC curve, sensitivity and specificity. CONCLUSIONS: Our study highlights the mechanisms of lncARF in protecting against the development of atherosclerosis involving the epigenetic modifications and RRAGD/PI3K/Akt and RRAGD/MAPK signaling pathways, which may provide novel diagnostic biomarkers to improve atherosclerosis treatment.

Inhibition of autophagy via 3-methyladenine alleviates the progression of preeclampsia.

Autophagy is a cellular mechanism for self-renewal that involves the breakdown of cytoplasmic proteins or organelles within lysosomes. Although preeclampsia (PE) exhibits several characteristics that could imply disrupted autophagy, there is limited evidence supporting the notion that impaired placental autophagy directly causes PE, as indicated by differential expression profiling of whole placental tissue. In this study, we aim to explore the significance of autophagy in maintaining pregnancy and its association with PE. First, the RNA-seq results show that 218 genes are differentially expressed in placentas from preeclamptic pregnancies. Notably, KEGG pathway analysis reveals significant enrichment of genes related to autophagy-related signaling pathways, including the PI3K-Akt signaling pathway, the AMPK signaling pathway, and the mTOR signaling pathway. Additionally, our findings indicate an increase in autophagy in placentas from pregnancies complicated by preeclampsia as well as in trophoblasts subjected to hypoxic conditions. Next, we examine the impact of 3-methyladenine (3-MA), a targeted inhibitor of autophagy, on the progression of PE. The administration of 3-MA profoundly alleviates the severity of PE-like symptoms in rats subjected to reduced uterine perfusion pressure (RUPP). The findings from our study suggest that inhibiting autophagy may serve as a promising approach for adjuvant chemotherapy for PE.

Coronary Microvascular Function Assessment using the Coronary Angiography-Derived Index of Microcirculatory Resistance in Patients with ST-segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

Background: Studies reporting the status of coronary microvascular function in the infarct-related artery (IRA) after primary percutaneous coronary intervention (PCI) remain limited. This study utilized the coronary angiography-derived index of microcirculatory resistance (caIMR) to assess coronary microvascular function in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. Methods: We used the FlashAngio system to measure the caIMR after primary PCI in 157 patients with STEMI. The primary endpoint was the occurrence of a major adverse cardiovascular event (MACE), defined as a composite endpoint encompassing cardiac mortality, target vessel revascularization, and rehospitalization due to congestive heart failure (CHF), myocardial infarction (MI), or angina. Results: Approximately 30% of patients diagnosed with STEMI and who experienced successful primary PCI during the study period had a caIMR in the IRA of > 40. The caIMR in the IRA was significantly higher than in the reference vessel (32.9 ± 15.8 vs. 27.4 ± 11.1, p < 0.001). The caIMR in the reference vessel of the caIMR > 40 group was greater than in the caIMR ≤ 40 group (30.9 ± 11.3 vs. 25.9 ± 10.7, p = 0.009). Moreover, the caIMR > 40 group had higher incidence rates of MACEs at 3 months (25.5% vs. 8.3%, p = 0.009) and 1 year (29.8% vs. 13.9%, p = 0.04), than in the caIMR ≤ 40 group, which were mainly driven by a higher rate of rehospitalization due to CHF, MI, or angina. A caIMR in the IRA of > 40 was an independent predictor of a MACE at 3 months (hazard ratio (HR): 3.459, 95% confidence interval (CI): 1.363-8.779, p = 0.009) and 1 year (HR: 2.384, 95% CI: 1.100-5.166, p = 0.03) in patients with STEMI after primary PCI. Conclusions: Patients with STEMI after primary PCI often have coronary microvascular dysfunction, which is indicated by an increased caIMR in the IRA. An elevated caIMR of > 40 in the IRA was associated with an increased risk of adverse outcomes in STEMI patients undergoing primary PCI.

Electrophotocatalytic Tellurosulfonylation of Alkynes for the Synthesis of ß-(Telluro)vinyl Sulfones.

Difunctionalization of alkynes has gained a lot of interest in current organic chemistry. Herein, we developed an electrophotocatalytic multicomponent cascade reaction of alkynes and indoles with sulfinic acid sodium salts using elemental tellurium as the tellurium source. Using synergistic anodic oxidation and visible-light irradiation, various ß-(telluro)vinyl sulfones have been prepared. This strategy features mild reaction conditions, excellent substrate scope, readily available starting materials, and great functional group tolerance.

Prenatal exposure to polycyclic aromatic hydrocarbons and phthalate acid esters and gestational diabetes mellitus: A prospective cohort study.

BACKGROUND: Polycyclic aromatic hydrocarbons and phthalate acid esters (PAHs & PAEs), known as endocrine disrupting chemicals (EDCs), widely exist in daily life and industrial production. Previous studies have suggested that PAHs & PAEs may modify the intrauterine homeostasis and have adverse effects on fetal development. However, epidemiological evidence on the associations between PAHs & PAEs and gestational diabetes mellitus (GDM) is still limited. OBJECTIVE: To investigate the effects of prenatal PAHs &PAEs exposure on the risk of GDM and hyperglycemia in pregnant women. METHODS: The study population was a total of 725 pregnant women from a prospective birth cohort study conducted from December 2019 to December 2021. Blood glucose levels were collected by the hospital information system. Urinary PAHs & PAEs concentrations were determined by gas chromatography tandem mass spectrometry. The Poisson regression in a generalized linear model (GLM), multiple linear regression, quantile-based g-computation method (qgcomp), and Bayesian kernel machine regression (BKMR) were applied to explore and verify the individual and overall effects of PAHs & PAEs on glucose homeostasis. Potential confounders were adjusted in all statistical models. RESULTS: A total of 179 (24.69%) women were diagnosed with GDM. The Poisson regression suggested that a ln-unit increment of 4-OHPHE (4-hydroxyphenanthrene) (adjusted Risk Ratio (aRR) = 1.13; 1.02-1.26) was associated with the increased GDM risk. Mixed-exposure models showed similar results. We additionally found that MBZP (mono-benzyl phthalate) (aRR = 1.19; 1.02-1.39) was positively related to GDM risk in qgcomp model. Although neither model demonstrated that 2-OHNAP (2-hydroxynaphthalene) and 9-OHFLU (9-hydroxyfluorene) increased the risk of GDM, 2-OHNAP and 9-OHFLU exposure significantly increased blood glucose levels. BKMR model further confirmed that overall effects of PAHs & PAEs were significantly associated with the gestational hyperglycemia and GDM risk. CONCLUSIONS: Our study presents that environmental exposure to PAHs & PAEs was positively associated with gestational glucose levels and the risks of developing GDM. In particular, 2-OHNAP, 9-OHFLU, 4-OHPHE and MBZP may serve as important surveillance markers to prevent the development of GDM.

Effect of Altitude Gradients on the Spatial Distribution Mechanism of Soil Bacteria in Temperate Deciduous Broad-Leaved Forests.

Soil bacteria are an important part of the forest ecosystem, and they play a crucial role in driving energy flow and material circulation. Currently, many uncertainties remain about how the composition and distribution patterns of bacterial communities change along altitude gradients, especially in forest ecosystems with strong altitude gradients in climate, vegetation, and soil properties. Based on dynamic site monitoring of the Baiyun Mountain Forest National Park (33°38'-33°42' N, 111°47'-111°51' E), this study used Illumina technology to sequence 120 soil samples at the site and explored the spatial distribution mechanisms and ecological processes of soil bacteria under different altitude gradients. Our results showed that the composition of soil bacterial communities varied significantly between different altitude gradients, affecting soil bacterial community building by influencing the balance between deterministic and stochastic processes; in addition, bacterial communities exhibited broader ecological niche widths and a greater degree of stochasticity under low-altitude conditions, implying that, at lower altitudes, community assembly is predominantly influenced by stochastic processes. Light was the dominant environmental factor that influenced variation in the entire bacterial community as well as other taxa across different altitude gradients. Moreover, changes in the altitude gradient could cause significant differences in the diversity and community composition of bacterial taxa. Our study revealed significant differences in bacterial community composition in the soil under different altitude gradients. The bacterial communities at low elevation gradients were mainly controlled by stochasticity processes, and bacterial community assembly was strongly influenced by deterministic processes at middle altitudes. Furthermore, light was an important environmental factor that affects differences. This study revealed that the change of altitude gradient had an important effect on the development of the soil bacterial community and provided a theoretical basis for the sustainable development and management of soil bacteria.

Adverse impact of phthalate and polycyclic aromatic hydrocarbon mixtures on birth outcomes: A metabolome Exposome-Wide association study.

It has been well-investigating that individual phthalates (PAEs) or polycyclic aromatic hydrocarbons (PAHs) affect public health. However, there is still a gap that the mixture of PAEs and PAHs impacts birth outcomes. Through innovative methods for mixtures in epidemiology, we used a metabolome Exposome-Wide Association Study (mExWAS) to evaluate and explain the association between exposure to PAEs and PAHs mixtures and birth outcomes. Exposure to a higher level of PAEs and PAHs mixture was associated with lower birth weight (maximum cumulative effect: 143.5 g) rather than gestational age. Mono(2-ethlyhexyl) phthalate (MEHP) (posterior inclusion probability, PIP = 0.51), 9-hydroxyphenanthrene (9-OHPHE) (PIP = 0.53), and 1-hydroxypyrene (1-OHPYR) (PIP = 0.28) were identified as the most important compounds in the mixture. In mExWAS, we successfully annotated four overlapping metabolites associated with both MEHP/9-OHPHE/1-OHPYR and birth weight, including arginine, stearamide, Arg-Gln, and valine. Moreover, several lipid-related metabolism pathways, including fatty acid biosynthesis and degradation, alpha-linolenic acid, and linoleic acid metabolism, were disturbed. In summary, these findings may provide new insights into the underlying mechanisms by which PAE and PAHs affect fetal growth.

Seminal plasma S100A8/A9 as a potential biomarker of genital tract inflammation.

ABSTRACT: Infections and inflammatory reactions in the male genital tract are the leading causes of male infertility with a prevalence of 6%-10%, primarily affecting testicular and epididymal function and ultimately compromising sperm quality. However, most infertile patients with genital infection/inflammation are asymptomatic and easily overlooked. Traditional indicators, including white blood cells, elastase, and other components in semen, can reflect inflammation of the genital tract, but there is still a lack of a uniform standard method of detection. Therefore, it is necessary to explore reliable markers in semen that reflect the inflammatory status of the genital tract. Using the experimental autoimmune orchitis (EAO) model to simulate noninfectious chronic orchitis, we successfully collected ejaculated seminal fluid from EAO rats using optimized electrical stimulation devices. Proteomic analysis was performed using isobaric tags for relative and absolute quantification (iTRAQ). Compared to the control group, 55 upregulated and 105 downregulated proteins were identified in seminal plasma samples from the EAO group. In a preliminary screening, the inflammation-related protein S100A8/A9 was upregulated. We further verified that S100A8/A9 was increased in seminal plasma and highly expressed in testicular macrophages of the EAO model. In patients with oligoasthenospermia and genital tract infections, we also found that S100A8/A9 levels were remarkably increased in seminal plasma and testicular macrophages. S100A8/A9 in semen may be a potential biomarker for chronic genital inflammation. Our study provides a new potential biomarker for early diagnosis and further understanding of male infertility caused by genital inflammation.

Cervical elastography in predicting spontaneous preterm birth in singleton pregnancy with a short cervix receiving progesterone treatment at 18 to 24 weeks' gestation.

BACKGROUND: A short cervix in the second trimester is known to increase the risk of preterm birth, which can be reduced with the administration of vaginal progesterone. However, some studies have suggested that a significant number of cases still experience preterm birth despite progesterone treatment. OBJECTIVE: This study was aimed to investigate the potential value of transvaginal cervical elasticity measured by E-Cervix as a predictor for spontaneous preterm birth (sPTB) in singleton pregnancies receiving progesterone treatment for a short cervix (CL ≤ 2.5 cm) diagnosed at 18 to 24 weeks' gestation. STUDY DESIGN: This prospective study was conducted at a single center premature high-risk clinic from January 2020 to July 2022. Singleton pregnancies with a short cervix at 18 to 24 weeks' gestation were enrolled. Cervical elastography using E-Cervix was performed, and maternal and neonatal demographic characteristics, cervical length (CL), elasticity contrast index (ECI), cervical hardness ratio, mean internal os strain (IOS), and mean external os strain (EOS) were compared before and after progesterone treatment in sPTB and term birth groups. Multivariate logistic regression was used to analyze the association between elasticity parameters and spontaneous preterm birth. The screening performance of CL and optimal cervical elasticity parameters in predicting sPTB was evaluated using receiver-operating characteristic (ROC) curve analysis. RESULTS: A total of 228 singleton pregnant women were included in the study, among which 26 (11.4%) had sPTB. There were no significant differences in maternal characteristics and gestational age at enrollment between women with and without sPTB. At the start of progesterone treatment, there were no significant differences in cervical elasticity parameters between the two groups. After two weeks of progesterone treatment, women who had sPTB showed significantly higher levels of ECI, IOS, EOS (p = 0.0108, 0.0001, 0.016), and lower hardness ratio (p = 0.011) compared to those who had a full-term birth. Cervical length did not show significant differences between the two groups, regardless of whether progesterone treatment was administered before or after. Among the post-treatment cervical elasticity parameters, IOS and EOS were associated with a 3.38-fold and 2.29-fold increase in the risk of sPTB before 37 weeks (p = 0.032, 0.047, respectively). The AUROC of the combined model including CL, IOS, and EOS (0.761, 95% CI0.589-0.833) was significantly higher than the AUROC of CL alone (0.618, 95% CI 0.359-0.876). At a fixed false-positive of 13%, the addition of IOS and EOS in the CL model increased sensitivity from 34.6% to 57.6%, PPV from 25.7% to 36.5%, and NPV from 91.1% to 94.1%. CONCLUSION: When assessing the risk of sPTB in singleton pregnancies with a short cervix receiving progesterone therapy, relying solely on cervical length is insufficient. It is crucial to also evaluate cervical stiffness, particularly the strain of the internal and external os, using cervical elastography.

Challenges with the Synthesis of a Macrocyclic Thioether Peptide: From Milligram to Multigram Using Solid Phase Peptide Synthesis (SPPS).

We describe an optimization and scale-up of the 45-membered macrocyclic thioether peptide BMS-986189 utilizing solid-phase peptide synthesis (SPPS). Improvements to linear peptide isolation, macrocyclization, and peptide purification were demonstrated to increase the throughput and purification of material on scale and enabled the synthesis and purification of >60 g of target peptide. Taken together, not only these improvements resulted in a 28-fold yield increase from the original SPPS approach, but also the generality of this newly developed SPPS purification sequence has found application in the synthesis and purification of other macrocyclic thioether peptides.

The combination of deep learning and pseudo-MS image improves the applicability of metabolomics to congenital heart defect prenatal screening.

To investigate the metabolic alterations in maternal individuals with fetal congenital heart disease (FCHD), establish the FCHD diagnostic models, and assess the performance of these models, we recruited two batches of pregnant women. By metabolomics analysis using Ultra High-performance Liquid Chromatography-Mass/Mass (UPLC-MS/MS), a total of 36 significantly altered metabolites (VIP >1.0) were identified between FCHD and non-FCHD groups. Two logistic regression models and four support vector machine (SVM) models exhibited strong performance and clinical utility in the training set (area under the curve (AUC) = 1.00). The convolutional neural network (CNN) model also demonstrated commendable performance and clinical utility (AUC = 0.89 in the training set). Notably, in the validation set, the performance of the CNN model (AUC = 0.66, precision = 0.714) exhibited better robustness than the six models above (AUC≤0.50). In conclusion, the CNN model based on pseudo-MS images holds promise for real-world and clinical applications due to its better repeatability.