Clinical phenotypes of adult-onset Behçet's syndrome: a comprehensive cross-sectional study in China.

Behçet's syndrome (BS) is a variant vasculitis that can involve multiple organs with inflammatory manifestations. This study aimed to provide a more comprehensive analysis of the clinical phenotypes and characteristics of BS patients. We enrolled 2792 BS patients referred from China nationwide to Huadong Hospital Affiliated to Fudan University from October 2012 to December 2022. Detailed assessments of demographic information, clinical manifestations, laboratory results, gastroscopy, and medical imaging were conducted. Cluster analysis was performed based on 13 variables to determine the clinical phenotypes, and each phenotype was characterized according to the features of BS patients. A total of 1834 BS patients were included, while 958 invalid patients were excluded. The median age at onset was 31 years (IQR, 24-40 years), and the median disease duration was 10 years (IQR, 5-15 years). Eight clusters were identified, including mucocutaneous (n = 655, 35.7%), gastrointestinal (n = 363, 19.8%), articular (n = 184, 10%), ocular (n = 223, 12.2%), cardiovascular (n = 119, 6.5%), neurological (n = 118, 6.4%), vascular (n = 114, 6.2%), and hematological phenotype (n = 58, 3.2%). Ocular (RR = 1.672 (95% CI, 1.327-2.106); P < 0.001), gastrointestinal (RR = = 1.194 (95% CI, 1.031-1.383); P = 0.018), cardiovascular (RR = = 2.582 (95% CI, 1.842-3.620); P < 0.001), and vascular (RR = = 2.288 (95% CI, 1.600-3.272); P < 0.001) involvement were more prevalent in male BS patients, while the hematological (RR = 0.528 (95% CI, 0.360-0.776); P = 0.001) involvement was more common among female patients. BS presents significant heterogeneity and gender differences. The eight phenotypes of BS patients we propose hold the potential to assist clinicians in devising more personalized treatment and follow-up strategies. Key Points • This cluster analysis divided adult-onset BS into eight clinical phenotypes. • BS demonstrates a high level of clinical heterogeneity and gender differences. • Hematologic phenotypes of BS present distinctive clinical characteristics.

SEC: A core hub during cell fate alteration.

Pol II pause release is a rate-limiting step in gene transcription, influencing various cell fate alterations. Numerous proteins orchestrate Pol II pause release, thereby playing pivotal roles in the intricate process of cellular fate modulation. Super elongation complex (SEC), a large assembly comprising diverse protein components, has garnered attention due to its emerging significance in orchestrating physiological and pathological cellular identity changes by regulating the transcription of crucial genes. Consequently, SEC emerges as a noteworthy functional complex capable of modulating cell fate alterations. Therefore, a comprehensive review is warranted to systematically summarize the core roles of SEC in different types of cell fate alterations. This review focuses on elucidating the current understanding of the structural and functional basis of SEC. Additionally, we discuss the intricate regulatory mechanisms governing SEC in various models of cell fate alteration, encompassing both physiological and pathological contexts. Furthermore, leveraging the existing knowledge of SEC, we propose some insightful directions for future research, aiming to enhance our mechanistic and functional comprehension of SEC within the diverse landscape of cell fate alterations.

Optimal obesity- and lipid-related indices for predicting type 2 diabetes in middle-aged and elderly Chinese.

To investigate the screening and predicting functions of obesity- and lipid-related indices for type 2 diabetes (T2D) in middle-aged and elderly Chinese, as well as the ideal predicted cut-off value. This study's data comes from the 2011 China Health and Retirement Longitudinal Study (CHARLS). A cross-sectional study design was used to investigate the relationship of T2D and 13 obesity- and lipid-related indices, including body mass index (BMI), waist circumference (WC), waist-height ratio (WHtR), visceral adiposity index (VAI), a body shape index (ABSI), body roundness index (BRI), lipid accumulation product (LAP), conicity index (CI), Chinese visceral adiposity index (CVAI), triglyceride- glucose index (TyG index) and its correlation index (TyG-BMI, TyG-WC, TyG-WHtR). The unadjusted and adjusted correlations between 13 indices and T2D were assessed using binary logistic regression analysis. The receiver operating characteristic curve (ROC) was used to determine the usefulness of anthropometric indices for screening for T2D and determining their cut­off value, sensitivity, specificity, and area under the curve (AUC). The study comprised 9488 people aged 45 years or above in total, of whom 4354 (45.89%) were males and 5134 (54.11%) were females. Among them were 716 male cases of T2D (16.44%) and 870 female cases of T2D (16.95%). A total of 13 obesity- and lipid-related indices were independently associated with T2D risk after adjusted for confounding factors (P < 0.05). According to ROC analysis, the TyG index was the best predictor of T2D among males (AUC = 0.780, 95% CI 0.761, 0.799) and females (AUC = 0.782, 95% CI 0.764, 0.799). The AUC values of the 13 indicators were higher than 0.5, indicating that they have predictive values for T2D in middle-aged and elderly Chinese. The 13 obesity- and lipid-related indices can predict the risk of T2D in middle­aged and elderly Chinese. Among 13 indicators, the TyG index is the best predictor of T2D in both males and females. TyG-WC, TyG-BMI, TyG-WHtR, LAP, and CVAI all outperformed BMI, WC, and WHtR in predicting T2D.

Obesity and lipid indices as predictors of depressive symptoms in middle-aged and elderly Chinese: insights from a nationwide cohort study.

BACKGROUND: Depressive symptoms are one of the most common psychiatric disorders, with a high lifetime prevalence rate among middle-aged and elderly Chinese. Obesity may be one of the risk factors for depressive symptoms, but there is currently no consensus on this view. Therefore, we investigate the relationship and predictive ability of 13 obesity- and lipid-related indices with depressive symptoms among middle-aged and elderly Chinese. METHODS: The data were obtained from The China Health and Retirement Longitudinal Study (CHARLS). Our analysis includes individuals who did not have depressive symptoms at the baseline of the CHARLS Wave 2011 study and were successfully follow-up in 2013 and 2015. Finally, 3790 participants were included in the short-term (from 2011 to 2013), and 3660 participants were included in the long-term (from 2011 to 2015). The average age of participants in short-term and long-term was 58.47 years and 57.88 years. The anthropometric indicators used in this analysis included non-invasive [e.g. waist circumference (WC), body mass index (BMI), and a body mass index (ABSI)], and invasive anthropometric indicators [e.g. lipid accumulation product (LAP), triglyceride glucose index (TyG index), and its-related indices (e.g. TyG-BMI, and TyG-WC)]. Receiver operating characteristic (ROC) analysis was used to examine the predictive ability of various indicators for depressive symptoms. The association of depressive symptoms with various indicators was calculated using binary logistic regression. RESULTS: The overall incidence of depressive symptoms was 20.79% in the short-term and 27.43% in the long-term. In males, WC [AUC = 0.452], LAP [AUC = 0.450], and TyG-WC [AUC = 0.451] were weak predictors of depressive symptoms during the short-term (P < 0.05). In females, BMI [AUC = 0.468], LAP [AUC = 0.468], and TyG index [AUC = 0.466] were weak predictors of depressive symptoms during the long-term (P < 0.05). However, ABSI cannot predict depressive symptoms in males and females during both periods (P > 0.05). CONCLUSION: The research indicates that in the middle-aged and elderly Chinese, most obesity- and lipid-related indices have statistical significance in predicting depressive symptoms, but the accuracy of these indicators in prediction is relatively low and may not be practical predictors.

Engineered Bacteriophage-Based In Situ Vaccine Remodels a Tumor Microenvironment and Elicits Potent Antitumor Immunity.

In situ vaccines (ISVs) utilize the localized delivery of chemotherapeutic agents or radiotherapy to stimulate the release of endogenous antigens from tumors, thereby eliciting systemic and persistent immune activation. Recently, a bioinspired ISV strategy has attracted tremendous attention due to its features such as an immune adjuvant effect and genetic plasticity. M13 bacteriophages are natural nanomaterials with intrinsic immunogenicity, genetic flexibility, and cost-effectiveness for large-scale production, demonstrating the potential for application in cancer vaccines. In this study, we propose an ISV based on the engineered M13 bacteriophage targeting CD40 (M13CD40) for dendritic cell (DC)-targeted immune stimulation, named H-GM-M13CD40. We induce immunogenic cell death and release tumor antigens through local delivery of (S)-10-hydroxycamptothecin (HCPT), followed by intratumoral injection of granulocyte-macrophage colony stimulating factor (GM-CSF) and M13CD40 to enhance DC recruitment and activation. We demonstrate that this ISV strategy can result in significant accumulation and activation of DCs at the tumor site, reversing the immunosuppressive tumor microenvironment. In addition, H-GM-M13CD40 can synergize with the PD-1 blockade and induce abscopal effects in cold tumor models. Overall, our study verifies the immunogenicity of the engineered M13CD40 bacteriophage and provides a proof of concept that the engineered M13CD40 phage can function as an adjuvant for ISVs.

Dynamic measurement of airway surface liquid volume with an ex vivo trachea-chip.

The volume and composition of airway surface liquid (ASL) is regulated by liquid secretion and absorption across airway epithelia, controlling the pH, solute concentration, and biophysical properties of ASL in health and disease. Here, we developed a method integrating explanted tracheal tissue with a micro-machined device (referred to as "ex vivo trachea-chip") to study the dynamic properties of ASL volume regulation. The ex vivo trachea-chip allows real-time measurement of ASL transport (Jv) with intact airway anatomic structures, environmental control, high-resolution, and enhanced experimental throughput. Applying this technology to freshly excised tissue we observed ASL absorption under basal conditions. The apical application of amiloride, an inhibitor of airway epithelial sodium channels (ENaC), reduced airway liquid absorption. Furthermore, the basolateral addition of NPPB, a Cl- channel inhibitor, reduced the basal rate of ASL absorption, implicating a role for basolateral Cl- channels in ASL volume regulation. When tissues were treated with apical amiloride and basolateral methacholine, a cholinergic agonist that stimulates secretion from airway submucosal glands, the net airway surface liquid production shifted from absorption to secretion. This ex vivo trachea-chip provides a new tool to investigate ASL transport dynamics in pulmonary disease states and may aid the development of new therapies targeting ASL regulation.

Sodium para-aminosalicylic acid attenuates combined manganese/iron-induced cortical synaptic damage in rats.

We established experimental models of manganese (Mn) and iron (Fe) exposure in vitro and in vivo, and addressed the effects of manganese and iron combined exposure on the synaptic function of pheochromocytoma derived cell line 12 (PC12) cells and rat cortex, respectively. We investigated the protective effect of sodium para-aminosalicylate (PAS-Na) on manganese and iron combined neurotoxicity, providing a scientific basis for the prevention and treatment of ferromanganese combined neurotoxicity. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to detect the expression levels of protein and mRNA related to synaptic damage. Y-maze novelty test and balance beam test were used to evaluate the motor and cognitive function of rats. Haematoxylin and eosin (H&E) and Nissl staining were performed to observe the cortical damage of rats. The results showed that the combined exposure of Mn and Fe in rats led to a synergistic effect, attenuating growth and development, and altering learning and memory as well as motor function. The combination of Mn and Fe also caused damage to the synaptic structure of PC12 cells, which is manifested as swelling of dendrites and axon terminals, and even lead to cell death. PAS-Na displayed some antagonistic effects against the Mn- and Fe-induced synaptic structural damage, growth, learning and memory impairment.

Cervical septum incision adversely impacts clinical outcomes in women with complete uterine septum and duplicated cervix.

STUDY OBJECTIVE: To investigate the reproductive outcomes of women with complete septate uterus and duplicated cervix who either did or did not receive cervical septum incision during hysteroscopic transcervical incision of the uterine septum. DESIGN: Retrospective study approved by the Hospital Ethics Committee. SETTING: Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China. PATIENTS: Women with complete septate uterus and duplicated cervix who underwent hysteroscopic transcervical incision of the uterine septum in Obstetrics and Gynecology Hospital of Fudan University between January 2008 and December 2020 (n=105). INTERVENTIONS: Hysteroscopic incision of the septum. MEASUREMENTS AND MAIN RESULTS: Included patients were grouped according to whether or not cervical septum incision was performed. Reproductive outcomes including gravidity, abortion rate, preterm birth rate, full-term birth rate, premature rupture of membranes (PROM), and cervical incompetence were assessed. In no incision group, the abortion rate (7.4%) was significantly lower than that of incision group (27.6%, p=0.01); the preterm birth rate (4.6%) was significantly lower than that of incision group (36.8%); and the full-term birth rate (95.5%) exceeded that of incision group (63.2%, p<0.01). Incidence of PROM and cervical incompetence during pregnancy was higher in incision group (15.8% and 10.5%, p<0.01 and p=0.03). CONCLUSION: Significantly improved reproductive outcomes were observed among patients with complete septate uterus and duplicated cervix whose cervical septum was preserved during the hysteroscopic transcervical incision of the uterine septum procedure.

Four-years change of BMI and waist circumference are associated with metabolic syndrome in middle-aged and elderly Chinese.

The purpose of the study was to determine whether changes in body mass index (BMI) and waist circumference (WC) in middle-aged and elderly Chinese are associated with metabolic syndrome. In this cohort investigation, 3697 middle-aged and elderly people aged 45 or over were recruited from the China Health and Retirement Longitudinal Study (CHARLS). The National Cholesterol Education Program Adult Treatment Panel III (2005) defined metabolic syndrome (MetS). With Cox regression analysis, we calculated hazard ratio (HR) and 95% confidence intervals (CIs) for MetS based on BMI-WC change categories. To assess the prevalence of MetS, the changes in BMI and WC levels were classified into four quartiles based on their relative and absolute changes. In subjects whose BMI and WC decreased (HR = 0.338; 95% CIs 0.264, 0.433) as well as those whose BMI increased and their WC decreased (HR = 0.375; 95% CIs 0.228, 0.499), metabolic syndrome risk was significantly lower compared with those with increases in both BMI and WC. Regarding the absolute changes in BMI, the lowest percentile of BMI was significantly lower in both males (HR = 0.302; 95% CIs 0.204, 0.448) and females (HR = 0.486; 95% CIs 0.354, 0.667) for the risk of metabolic syndrome. Similar results were observed in the absolute changes in WC, with the lowest quantile of WC having a significant impact on MetS risk in males (HR = 0.170; 95% CIs 0.107, 0.270) and females (HR = 0.303; 95% CIs 0.217, 0.424). The risk of metabolic syndrome was significantly associated with changes in BMI and WC in middle-aged and elderly Chinese. A reduced BMI and WC are associated with lower metabolic syndrome risks in middle-aged and elderly people.

Improving the Quality of Wheat Flour Bread by a Thermophilic Xylanase with Ultra Activity and Stability Reconstructed by Ancestral Sequence and Computational-Aided Analysis.

Xylanase is an essential component used to hydrolyze the xylan in wheat flour to enhance the quality of bread. Presently, cold-activated xylanase is popularly utilized to aid in the development of dough. In this study, ancestral sequence reconstruction and molecular docking of xylanase and wheat xylan were used to enhance the activity and stability of a thermophilic xylanase. The results indicated that the ancestral enzyme TmxN3 exhibited significantly improved activity and thermal stability. The Vmax increased by 2.7 times, and the catalytic efficiency (Kcat/Km) increased by 1.7 times in comparison to TmxB. After being incubated at 100 °C for 120 min, it still retained 87.3% of its activity, and the half-life in 100 °C was 330 min, while the wild type xylanase was only 55 min. This resulted in an improved shelf life of bread, while adding TmxN3 considerably enhanced its quality with excellent volume and reduced hardness, chewiness, and gumminess. The results showed that the hardness was reduced by 55.2%, the chewiness was reduced by 40.11%, and the gumminess was reduced by 53.52%. To facilitate its industrial application, we further optimized the production conditions in a 5L bioreactor, and the xylanase activity reached 1.52 × 106 U/mL culture.

Synthesis of Calix[4]arene-Based Porous Organic Cages and Their Gas Adsorption.

Two crystalline large-sized porous organic cages (POCs) based on conical calix[4]arene (C4A) were designed and synthesized. The four-jaw C4A unit tends to follow the face-directed self-assembly law with the planar triangular building blocks such as tris(4-aminophenyl)amine (TAPA) or 1,3,5-tris(4-aminophenyl)benzene (TAPB) to generate a predictable cage with a stoichiometry of [6+8]. The formation of the large cages is confirmed through their relative molecular mass measured using MALDI-TOF/TOF spectra. The protonated molecular ion peaks of C4A-TAPA and C4A-TAPB were observed at m/z 5109.0 (calculated for C336H240O24N32: m/z 5109.7) and m/z 5594.2 (calculated for C384H264O24N24: m/z 5598.4). C4A-POCs exhibit I-type N2 adsorption-desorption isotherms with the BET surface areas of 1444.9 m2 ⋅ g-1 and 1014.6 m2 ⋅ g-1. The CO2 uptakes at 273 K are 62.1 cm3 ⋅ g-1 and 52.4 cm3 ⋅ g-1 at a pressure of 100 KPa. The saturated iodine vapor static uptakes at 348 K are 3.9 g ⋅ g-1 and 3.5 g ⋅ g-1. The adsorption capacity of C4A-TAPA for SO2 reaches to 124.4 cm3 ⋅ g-1 at 298 K and 1.3 bar. Additionally, the adsorption capacities of C4A-TAPA for C2H2, C2H4, and C2H6 were evaluated.

Fe-TiO2-x/TiO2 S-scheme homojunction for efficient photocatalytic CO2 reduction.

CO2-to-high value-added chemicals via a photocatalytic route is of interest but strangled by the low efficiency. Herein, a novel Fe-TiO2-x/TiO2 S-scheme homojunction was designed and constructed by using a facile surface modification approach whereby oxygen vacancy (OV) and Fe introducing on the TiO2 nanorod surface. The as-synthesized Fe-TiO2-x/TiO2 S-scheme homojunction exhibits positive properties on promoting photocatalytic CO2 reduction: i) the nanorod structure provides numerous active sites and a radical charge transfer path; ii) the doped Fe and OV not only synergistically enhance light utilization but also promote CO2 adsorption; iii) the Fe-TiO2-x/TiO2 S-scheme homojunction benefits photoexcited charge separation and retains stronger redox capacity. Thanks to those good characters, the Fe-TiO2-x/TiO2 homojunction exhibits superior CO2 reduction performances with optimized CO/CH4 generation rates of 122/22 µmol g-1h-1 which exceed those of pure TiO2 by more than 9.4/7.3 folds and most currently reported catalytic systems. This manuscript develops a facile and universal approach to synthesize well-defined homojunction and may inspire the construction of other more high-efficiency photocatalysts toward CO2 reduction and beyond.

A LATS2 and ALKBH5 positive feedback loop supports their oncogenic roles.

N(6)-methyladenosine (m6A) critically regulates RNA dynamics in various biological processes. The m6A demethylase ALKBH5 promotes tumorigenesis of glioblastoma, while the intricate web that orchestrates its regulation remains enigmatic. Here, we discover that cell density affects ALKBH5 subcellular localization and m6A dynamics. Mechanistically, ALKBH5 is phosphorylated by the large tumor suppressor kinase 2 (LATS2), preventing its nuclear export and enhancing protein stability. Furthermore, phosphorylated ALKBH5 reciprocally erases m6A from LATS2 mRNA, thereby stabilizing this transcript. Unexpectedly, LATS2 depletion suppresses glioblastoma stem cell self-renewal independent of yes-associated protein activation. Additionally, deficiency in either LATS2 or ALKBH5 phosphorylation impedes tumor progression in mouse xenograft models. Moreover, high levels of LATS2 expression and ALKBH5 phosphorylation are associated with tumor malignancy in patients with gliomas. Collectively, our study unveils an oncogenic positive feedback loop between LATS2 and ALKBH5, revealing a non-canonical branch of the Hippo pathway for RNA processing and suggesting potential anti-cancer interventions.

Advanced application of carbohydrate-based micro/nanoparticles for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a kind of synovitis and progressive joint destruction disease. Dysregulated immune cell activation, inflammatory cytokine overproduction, and subsequent reactive oxidative species (ROS) production contribute to the RA process. Carbohydrates, including cellulose, chitosan, alginate and dextran, are among the most abundant and important biomolecules in nature and are widely used in biomedicine. Carbohydrate-based micro/nanoparticles(M/NPs) as functional excipients have the ability to improve the bioavailability, solubility and stability of numerous drugs used in RA therapy. For on-demand therapy, smart reactive M/NPs have been developed to respond to a variety of chemical and physical stimuli, including light, temperature, enzymes, pH and ROS, alternating their physical and macroscopic properties, resulting in innovative new drug delivery systems. In particular, advanced products with targeted dextran or hyaluronic acid are exploiting multiple beneficial properties at the same time. In addition to those that respond, there are promising new derivatives in development with microenvironment and chronotherapy effects. In this review, we provide an overview of these recent developments and an outlook on how this class of agents will further shape the landscape of drug delivery for RA treatment.

NOX4 promotes tumor progression through the MAPK-MEK1/2-ERK1/2 axis in colorectal cancer.

BACKGROUND: Metabolic reprogramming plays a key role in cancer progression and clinical outcomes; however, the patterns and primary regulators of metabolic reprogramming in colorectal cancer (CRC) are not well understood. AIM: To explore the role of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in promoting progression of CRC. METHODS: We evaluated the expression and function of dysregulated and survival-related metabolic genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Consensus clustering was used to cluster CRC based on dysregulated metabolic genes. A prediction model was constructed based on survival-related metabolic genes. Sphere formation, migration, invasion, proliferation, apoptosis and clone formation was used to evaluate the biological function of NOX4 in CRC. mRNA sequencing was utilized to explore the alterations of gene expression NOX4 over-expression tumor cells. In vivo subcutaneous and lung metastasis mouse tumor model was used to explore the effect of NOX4 on tumor growth. RESULTS: We comprehensively analyzed 3341 metabolic genes in CRC and identified three clusters based on dysregulated metabolic genes. Among these genes, NOX4 was highly expressed in tumor tissues and correlated with worse survival. In vitro, NOX4 overexpression induced clone formation, migration, invasion, and stemness in CRC cells. Furthermore, RNA-sequencing analysis revealed that NOX4 overexpression activated the mitogen-activated protein kinase-MEK1/2-ERK1/2 signaling pathway. Trametinib, a MEK1/2 inhibitor, abolished the NOX4-mediated tumor progression. In vivo, NOX4 overexpression promoted subcutaneous tumor growth and lung metastasis, whereas trametinib treatment can reversed the metastasis. CONCLUSION: Our study comprehensively analyzed metabolic gene expression and highlighted the importance of NOX4 in promoting CRC metastasis, suggesting that trametinib could be a potential therapeutic drugs of CRC clinical therapy targeting NOX4.

Quercetin of huoxuehuayu tongluo decoction and azithromycin combination therapy effectively improves rat tubal factor infertility by inhibiting inflammation.

Objectives: Tubal factor infertility (TFI) is common female infertility responsible for a large portion of female factor infertility. This study reveals the effect of the quercetin of Huoxuehuayu Tongluo Decoction with azithromycin on the pregnancy rate and inflammation of TFI female rats. Materials and Methods: Female Sprague Dawley rats were constructed into the TFI model and treated with quercetin, Huoxuehuayu Tongluo Decoction, and combination therapy (quercetin and azithromycin). Pregnancy rate and litter size were measured. Network pharmacology was applied to analyze the interaction between Huoxuehuayu Tongluo Decoction and TFI. The combination of quercetin and IL-6 was analyzed by molecular docking. HE staining and electron microscopy were used to observe the histopathology and ultrastructure of fallopian tube tissues. The TNF-α, IL-1ß, IL-6, IL-8, and MPO levels were detected by ELISA. The activation of JAK/STAT, MAPK, and NF-κB p65 pathways was detected by western blot or immunohistochemistry. Results: Quercetin was the main active component of Huoxuehuayu Tongluo Decoction, and could bind to IL-6 in TFI. Target genes were enriched in the IL-17 signaling pathway, JAK-STAT signaling pathway, inflammatory disease, etc. Under the quercetin and azithromycin combination therapy, both rat pregnancy rates and litter sizes increased significantly. quercetin and azithromycin alleviated the symptoms of hydrosalpinx and inflammatory damage in fallopian tube tissues. The phosphorylation of JAK/STAT and MAPK pathways and NF-κB p65 translocation to the nucleus were significantly inhibited by the quercetin and azithromycin therapy. Conclusion: Quercetin and azithromycin combination therapy inhibited inflammation and phosphorylation of JAK/STAT and MAPK pathways to improve TFI inflammation and pregnancy function.

Epigenetic control of adaptive or homeostatic splicing during interval-training activities.

Interval-training activities induce adaptive cellular changes without altering their fundamental identity, but the precise underlying molecular mechanisms are not fully understood. In this study, we demonstrate that interval-training depolarization (ITD) of pituitary cells triggers distinct adaptive or homeostatic splicing responses of alternative exons. This occurs while preserving the steady-state expression of the Prolactin and other hormone genes. The nature of these splicing responses depends on the exon's DNA methylation status, the methyl-C-binding protein MeCP2 and its associated CA-rich motif-binding hnRNP L. Interestingly, the steady expression of the Prolactin gene is also reliant on MeCP2, whose disruption leads to exacerbated multi-exon aberrant splicing and overexpression of the hormone gene transcripts upon ITD, similar to the observed hyperprolactinemia or activity-dependent aberrant splicing in Rett Syndrome. Therefore, epigenetic control is crucial for both adaptive and homeostatic splicing and particularly the steady expression of the Prolactin hormone gene during ITD. Disruption in this regulation may have significant implications for the development of progressive diseases.