Profiling the role of m6A effectors in the regulation of pluripotent reprogramming.

The N6-methyladenosine (m6A) RNA modification plays essential roles in multiple biological processes, including stem cell fate determination. To explore the role of the m6A modification in pluripotent reprogramming, we used RNA-seq to map m6A effectors in human iPSCs, fibroblasts, and H9 ESCs, as well as in mouse ESCs and fibroblasts. By integrating the human and mouse RNA-seq data, we found that 19 m6A effectors were significantly upregulated in reprogramming. Notably, IGF2BPs, particularly IGF2BP1, were among the most upregulated genes in pluripotent cells, while YTHDF3 had high levels of expression in fibroblasts. Using quantitative PCR and Western blot, we validated the pluripotency-associated elevation of IGF2BPs. Knockdown of IGF2BP1 induced the downregulation of stemness genes and exit from pluripotency. Proteome analysis of cells collected at both the beginning and terminal states of the reprogramming process revealed that the IGF2BP1 protein was positively correlated with stemness markers SOX2 and OCT4. The eCLIP-seq target analysis showed that IGF2BP1 interacted with the coding sequence (CDS) and 3'UTR regions of the SOX2 transcripts, in agreement with the location of m6A modifications. This study identifies IGF2BP1 as a vital pluripotency-associated m6A effector, providing new insight into the interplay between m6A epigenetic modifications and pluripotent reprogramming.

N6-Methyladenosine-Modified KREMEN2 Promotes Tumorigenesis and Malignant Progression of High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) remains the most lethal female cancer by far. Herein, clinical HGSOC samples had higher N6-methyladenosine (m6A) modification than normal ovarian tissue, and its dysregulation had been reported to drive aberrant transcription and translation programs. However, Kringle-containing transmembrane protein 2 (KREMEN2) and its m6A modification have not been fully elucidated in HGSOC. In this study, the data from the high-throughput messenger RNA (mRNA) sequencing of clinical samples were processed using the weighted correlation network analysis and functional enrichment analysis. Results revealed that KREMEN2 was a driver gene in the tumorigenesis of HGSOC and a potential target of m6A demethylase fat-mass and obesity-associated protein (FTO). KREMEN2 and FTO levels were upregulated and downregulated, respectively, and correlation analysis showed a significant negative correlation in HGSOC samples. Importantly, upregulated KREMEN2 was remarkably associated with lymph node metastasis, distant metastasis, peritoneal metastasis, and high International Federation of Gynecology and Obstetrics stage (Ⅲ/Ⅳ), independent of the age of patients. KREMEN2 promoted the growth of HGSOC in vitro and in vivo, which was dependent on FTO. The methylated RNA immunoprecipitation qPCR and RNA immunoprecipitation assays were performed to verify the m6A level and sites of KREMEN2. FTO overexpression significantly decreased m6A modification in the 3' and 5' untranslated regions of KREMEN2 mRNA and downregulated its expression. In addition, we found that FTO-mediated m6A modification of KREMEN2 mRNA was recognized and stabilized by the m6A reader IGF2BP1 rather than by IGF2BP2 or IGF2BP3. This study highlights the m6A modification of KREMEN2 and extends the importance of RNA epigenetics in HGSOC.

Bridging-BPs: a novel approach to predict potential drug-target interactions based on a bridging heterogeneous graph and BPs2vec.

Predicting drug-target interactions (DTIs) is a convenient strategy for drug discovery. Although various computational methods have been put forward in recent years, DTIs prediction is still a challenging task. In this paper, based on indirect prior information (we term them as mediators), we proposed a new model, called Bridging-BPs (bridging paths), for DTIs prediction. Specifically, we regarded linkage process between mediators and DTs (drugs and proteins) as 'bridging' and source (drug)-mediators-destination (protein) as bridging paths. By integrating various bridging paths, we constructed a bridging heterogeneous graph for DTIs. After that, an improved graph-embedding algorithm-BPs2vec-was designed to capture deep topological features underlying the bridging graph, thereby obtaining the low-dimensional node vector representations. Then, the vector representations were fed into a Random Forest classifier to train and score the probability, outputting the final classification results for potential DTIs. Under 5-fold cross validation, our method obtained AUPR of 88.97% and AUC of 88.63%, suggesting that Bridging-BPs could effectively mine the link relationships hidden in indirect prior information and it significantly improved the accuracy and robustness of DTIs prediction without direct prior information. Finally, we confirmed the practical prediction ability of Bridging-BPs by case studies.

Aquablation versus HoLEP in patients with benign prostatic hyperplasia: a comparative prospective non-randomized study.

PURPOSE: The question of best surgical treatment for lower urinary tract symptoms (LUTS) due to benign prostate hyperplasia (BPH) remains controversial. We compared the outcomes of aquablation and holmium laser enucleation of the prostate ("HoLEP") in a prospective cohort. METHODS: Patients with BPH underwent aquablation or HoLEP according to their preference between June 2020 and April 2022. Prostate volume ("PV"), laboratory results, postvoid residual volume, uroflowmetry, IPSS, ICIQ-SF, MSHQ-EjD, EES and IIEF were evaluated preoperatively and at three, six and 12 months postoperatively. We also analyzed perioperative characteristics and complications via the Clavien Dindo ("CD") classification. RESULTS: We included 40 patients, 16 of whom underwent aquablation and 24 HoLEP. Mean age was 67 years (SD 7.4). Baseline characteristics were balanced across groups, except the HoLEP patients' larger PV. IPSS fell from 20.3 (SD 7.1) at baseline to 6.3 (SD 4.2) at 12 months (p < 0.001) without differences between aquablation and HoLEP. HoLEP was associated with shorter operation time (59.5 (SD 18.6) vs. 87.2 (SD 14.8) minutes, p < 0.001) and led to better PV reduction over all timepoints. At three months, aquablation's results were better regarding ejaculatory (p = 0.02, MSHQ-EjD) and continence function (p < 0.001, ICIQ-SF). Beyond three months, erectile, ejaculatory, continence function and LUTS reduction did not differ significantly between aquablation and HoLEP. CD ≥ grade 3b complications were noted in six patients in aquablation group while only one in HoLEP group (p = < 0.01). CONCLUSIONS: While aquablation revealed temporary benefits regarding ejaculation and continence at three months, HoLEP was superior concerning operation time, the safety profile and volumetric results.

Symptom flares in women with chronic pelvic pain: Questionnaire study within a cohort study (translational research in pelvic pain (TRiPP)).

OBJECTIVE: To quantify the variation, triggers and impact on quality of life of symptom flares in women with chronic pelvic pain (CPP). DESIGN: Cross-sectional questionnaire within the Translational Research in Pelvic Pain clinical cohort study. SETTING: Women with CPP, with subgroups of women with endometriosis (EAP), interstitial cystitis/bladder pain syndrome (BPS), comorbid endometriosis and interstitial cystitis/bladder pain syndrome (EABP), and those with pelvic pain without endometriosis or interstitial cystitis/bladder pain syndrome (PP). POPULATION OR SAMPLE: A total of 100 participants. METHODS: Descriptive and comparative analysis from flares questionnaire. MAIN OUTCOME MEASURES: The prevalence, characteristics and triggers of short, medium and long symptom flares in CPP. RESULTS: We received 100 responses of 104 questionnaires sent. Seventy-six per cent of women with CPP have ever experienced symptom flares of at least one length (short, medium and/or long). Flares are associated with painful and non-painful symptoms. There is large variation for the frequency, duration, symptoms and triggers for flares. Over 60% of participants reported flares as stopping them from doing things they would usually do, >80% reported thinking about symptoms of flares and >80% reported flares being bothersome. CONCLUSIONS: Flares are prevalent and clinically very important in CPP. More research is needed to elucidate the mechanisms and characteristics underlying flares. Clinical practice should include an enquiry into flares with the aim of finding strategies to lessen their burden.

Coping With Interstitial Cystitis/Bladder Pain Syndrome.

AIMS: Compensatory coping, or maladaptive alterations in behavior with the intention of preventing or managing symptoms, is increasingly being explored as a key factor in how people respond to bladder conditions. Preliminary investigations have identified relations between coping behaviors and psychological distress in urologic conditions, including interstitial cystitis/bladder pain syndrome (IC/BPS). However, previous explorations of coping have not accounted for heterogeneity in coping behaviors or addressed the likelihood that some coping behaviors may be more adaptive than others. This study sought to examine how two specific types of coping behaviors, primary control coping and disengaged coping, are related to distress and symptoms in IC/BPS, and to explore the potential role of pain phenotype in this relationship. MATERIALS AND METHODS: A secondary data analysis was conducted with a large community data set (N = 677 women with IC/BPS) and employed descriptive and inferential statistics to characterize coping patterns and explore novel predictors of distress. RESULTS: Results indicated that almost all participants engaged in at least one compensatory coping behavior within the last week. Both types of coping behaviors correlated with psychological symptoms, and when controlling for relevant clinical variables (i.e., age and severity of urinary symptoms), disengaged coping behaviors were significantly associated with psychological distress. Further, the addition of pain phenotype to multiple regression models resulted in a more effective predictive model when considering the relation between coping behaviors and depression. CONCLUSIONS: By investigating more deeply the relationship between coping and distress, understanding of potential risk factors and mechanisms is increased, offering valuable insights for intervention strategies for IC/BPS patients.

Early in life stressful events induce chronic visceral pain and changes in bladder function in adult female mice through a mechanism involving TRPV1 and alpha 1A adrenoceptors.

BACKGROUND: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain disorder with multiple phenotypes, one of which is associated with an overactive adrenergic system. OBJECTIVE: We investigated if the maternal deprivation model (MDM) in female and male mice mimics IC/BPS phenotype and if the overstimulation of alpha 1A adrenoceptor (A1AAR) and the crosstalk with transient receptor potential vanilloid-1 (TRPV1) are involved in the generation of pain and bladder functional changes. DESIGN, SETTING, AND PARTICIPANTS: C57BL/6 female and male mice were submitted to MDM. TRPV1 knockout (KO) mice were used to study TRPV1 involvement. Silodosin administration to MDM mice was used to study A1AAR involvement. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was chronic visceral pain measured by Von Frey filaments analysis (effect size: 3 for wild type, 3.9 for TRPV1 KO). Bladder changes were secondary outcome measurements. Unpaired T test, Mann-Whitney test, one-way analysis of variance followed by Newman-Keuls multiple comparisons test, and Kruskal-Wallis followed by Dunn's multiple comparisons test were used where appropriate. RESULTS AND LIMITATIONS: MDM induces pain behavior in female and not in male mice. Bladder afferents seem sensitize as MDM also increase the number of small volume spots voided, the bladder reflex activity, and urothelial damage. These changes were similarly absent after A1AAR blockade with silodosin or by TRPV1 gene KO. The main limitation is the number/type of pain tests used. CONCLUSIONS: MDM induced in female mice is able to mimic IC/BPS phenotype, through mechanisms involving A1AAR and TRPV1. Therefore, the modulation of both receptors may represent a therapeutic approach to treat IC/BPS patients.

Can personality disorder be accurately assessed in older age? A differential item functioning analysis of ICD-11 inventories.

OBJECTIVES: The contested categorical personality disorder (PD) criteria are not well suited to inform PD diagnoses in older adults. Yet, the classification of PDs is undergoing a critical transition phase with a paradigm shift to a dimensional approach for diagnosing PDs. No special attention was given to the expression of PDs in older age when the dimensional ICD-11 model was developed. Given that PDs are highly prevalent in older adults, there is an urgent need to examine if ICD-11 related instruments are able to adequately assess for PDs in older adults. METHODS: The age-neutrality of ICD-11 measures was examined in a sample of 208 Dutch community-dwelling adults (N = 208, M age = 54.96, SD = 21.65), matched on sex into 104 younger (age range 18-64) and 104 older (age range 65-93) adults. An instrument is considered not to be age-neutral if a collective large level of differential item functioning (DIF) exists in a group of items of an instrument (i.e., 25% or more with DIF). We therefore set out to detect possible DIF in the following ICD-11 self-report measures: the Standardized Assessment of Severity of Personality Disorder (SASPD), the Personality Inventory for ICD-11 (PiCD), and the Borderline Pattern Scale (BPS). RESULTS: DIF analyses using a non-parametric odds ratio approach demonstrated that SASPD, PiCD, and BPS were age-neutral with less than 25% of items showing DIF. Yet, impact of DIF at scale level, examined by way of differential test functioning (DTF), indicated a DTF effect on the SASPD total score. CONCLUSIONS: These results of age-neutrality of the PiCD and BPS are promising for measuring ICD-11 traits and the borderline pattern. Yet, the age-neutral measurement of PD severity requires further research. With a rapidly aging population, its accurate assessment across the entire adult life span, including older age, is a prerequisite for an adequate detection of PDs.

Exposure to bisphenol compounds accelerates the conjugative transfer of antibiotic resistance plasmid.

Antimicrobial resistance poses the most formidable challenge to public health, with plasmid-mediated horizontal gene transfer playing a pivotal role in its global spread. Bisphenol compounds (BPs), a group of environmental contaminants with endocrine-disrupting properties, are extensively used in various plastic products and can be transmitted to food. However, the impact of BPs on the plasmid-mediated horizontal transfer of antibiotic resistance genes (ARGs) has not yet been elucidated. Herein, we demonstrate that BPs could promote the conjugative transfer frequency of RP4-7 and clinically multidrug-resistant plasmids. Furthermore, the promoting effect of BPs on the plasmid transfer was also confirmed in a murine model. Microbial diversity analysis of transconjugants indicated an increase in α diversity in the BPAF-treated group, along with the declined richness of some beneficial bacteria and elevated richness of Faecalibaculum rodentium, which might serve as an intermediate repository for resistance plasmids. The underlying mechanisms driving the enhanced conjugative transfer upon BPAF treatment include exacerbated oxidative stress, disrupted membrane homeostasis, augmented energy metabolism, and the increased expression of conjugation-related genes. Collectively, our findings highlight the potential risk associated with the exacerbated dissemination of AMR both in vitro and in vivo caused by BPs exposure.

Enhancing the efficient degradation of BPS using the BPNS-CdS composite catalyst under visible light.

Black phosphorus nanosheets (BPNS), a novel two-dimensional nanomaterial, find extensive applications in the field of photocatalysis. With the prohibition of bisphenol A (BPA), the utilization of bisphenol S (BPS), which is more resistant to degradation than BPA, has been steadily increasing. In this study, few-layer BPNS was prepared using an improved liquid-phase exfoliation method, showcasing its commendable specific surface area and notable adsorption capacity. Subsequently, a new type of nanocomposite material, BPNS-Cadmium sulfide (CdS), was hydrothermal synthesized involving BPNS and CdS. We conducted comparative assessments of BPNS, CdS, and their composite materials to identify the most efficient catalysts. Ultimately, we found that the composite material BPNS-CdS exhibited the highest capability for degrading BPS in an alkaline environment, achieving an impressive degradation rate of 86.9%. Notably, the degradation rate remained higher in an acidic environment compared to a neutral one. Through Electron Spin Resoance (ESR) experiments, it is revealed that BPNS-CdS, when exposed to visible light, generates •O2-, •OH, and h+ as confirmed. Additionally, we tested and validated the carrier separation and migration abilities of BPNS-CdS while also calculating the band gap for each material. Building upon these results, a possible photocatalysis mechanism experiment was proposed. Finally, the degradation products were analyzed using High-Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS) and put forth a plausible pathway for the BPS degradation, and it was found that 4-Phenolsulfonic acid, Ethyl protocatechuate and Isophthalic acid are the main intermediates of BPS. This study contributes to a deeper understanding of the synergy between non-metallic catalysts like BPNS and metal catalysts like CdS. It also offers new insights into the degradation mechanisms and pathways for BPS.

Urinary concentrations of bisphenol A and its alternatives: Potential predictors of and associations with antral follicle count among women from an infertility clinic in Northern China.

BACKGROUND: Experimental studies have suggested exposure to bisphenol A (BPA) and its alternatives, such as bisphenol F (BPF) and bisphenol S (BPS), may exert adverse effects on ovarian reserve, but human evidence is limited. Moreover, the potential predictors of exposure to bisphenols among women seeking infertility treatment have not been reported. OBJECTIVE: To explore whether individual or mixture of BPA, BPF, and BPS were related to antral follicle count (AFC), and further identify the predictors of exposure to bisphenols among women seeking assisted reproductive treatment. METHODS: A total of 111 women from a reproductive center in Shenyang, China were enrolled in this study from September 2020 to February 2021. The concentrations of urinary BPA, BPF, and BPS were measured using ultra-high-performance liquid chromatography-triple quadruple mass spectrometry (UHPLC-MS/MS). AFC was measured by two infertility physicians through transvaginal ultrasonography on the 2-5 days of a natural cycle. Demographic characteristics, dietary habits, and lifestyles were obtained by questionnaires. The associations between individual and mixture of urinary bisphenols concentrations (BPA, BPF, and BPS) and AFC were assessed by the Poisson regression models and the quantile-based g-computation (QGC) model, respectively. The potential predictors of exposure to bisphenols were identified by the multivariate linear regression models. RESULTS: After adjusting for confounders, elevated urinary concentrations of BPA, BPF and BPS were associated with reduced AFC (ß = -0.016; 95%CI: -0.025, -0.006 in BPA; ß = -0.017; 95%CI: -0.029, -0.004 in BPF; ß = -0.128; 95%CI: -0.197, -0.060 in BPS). A quantile increase in the bisphenols mixture was negatively associated with AFC (ß = -0.101; 95%CI: -0.173, -0.030). Intake of fried food had higher urinary concentrations of BPF, BPS, and total bisphenols (∑BPs) than women who did not eat, and age was related to increased urinary BPF concentrations. CONCLUSION: Our findings indicated that exposure to individual BPA, BPF, BPS and bisphenol mixtures were associated with impaired ovarian reserve. Furthermore, the intake of fried food, as identified in this study, could serve as an important bisphenols exposure route for reproductive-aged women.

Insights into the accumulation and hepatobiliary transport of bisphenols (BPs) in liver and bile.

Bisphenols (BPs) are widely distributed in daily life as typical endocrine disruptors. In this study, we examined the distribution of bisphenol A (BPA) and BPA alternatives in liver (n = 149) and bile (n = 102) tissues from the patients with liver cancer, and calculated the hepatobiliary transport efficiency of BPs (TB-L). Seven BPs were detected in both liver (median: 0.859 ng/g; range: 0.0200-26.7 ng/g) and bile (median: 0.307 ng/mL; range: 0.0200-26.7 ng/mL), and BPA was the predominant in both liver (mean: 1.89 ng/g) and bile (mean: 1.65 ng/mL). The TB-L of BPs was reported for the first time and found to be negatively correlated with the molecular weight and Log Kow of BPs. Furthermore, BPA and ∑BPs in liver showed a significant negative correlation with age, and a significant difference was found in BPs in liver and bile in hepatocellular carcinoma patients with different genders (p < 0.05). For liver function indicators, levels of BPs showed significant positive correlation with γ-glutamyl transferase (GGT) and alanine aminotransferase (ALT), especially BPBP levels in bile. This suggests that BPs may have some correlation with hepatocellular carcinoma. This is the first report on distribution characteristics of BPs in the liver and bile of hepatocellular carcinoma patients, and is the first study to report the hepatobiliary transport efficiency of BPs. The results should contribute to the understanding of BPs accumulation in the liver and bile and further relationship with hepatocellular carcinoma.

How Intravesical Platelet-Rich Plasma Can Help Patients with Interstitial Cystitis/Bladder Pain Syndrome: A Comprehensive Scoping Review.

INTRODUCTION AND HYPOTHESIS: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a condition characterized by chronic inflammation that affects the bladder. The study was aimed at evaluating the effectiveness of intravesical platelet-rich plasma (PRP) injections in patients with IC/BPS. METHODS: We conducted a comprehensive search strategy to involve studies that investigate the efficacy of intravesical PRP injections or instillations over different time intervals. Various outcome measures were assessed, including pain scores, functional outcomes, urodynamic parameters, and surface expressions on the urothelium. RESULTS: Our search strategy revealed 1,125 studies. After screening, ten articles met the inclusion criteria. Intravesical PRP significantly reduced the visual analog scale (VAS) compared with baseline scores. Several clinical trials reported significant improvements in the global response rate (GRA), O'Leary-Sant Symptom (OSS) questionnaire, Interstitial Cystitis Symptom Index (ICSI), and Interstitial Cystitis Problem Index (ICPI). Urodynamic parameters such as maximum flow rate (Qmax) and post-voiding residual (PVR) showed significant improvements in some studies. CONCLUSION: The study concluded that intravesical PRP injections could be a promising effective treatment option for IC/BPS patients by their significant ability to reduce pain. However, improvement of urodynamic and functional outcomes is still not clear. Further large comparative trials are still warranted to assess the efficacy of PRP instillation.

Identification of Bromophenols' glucuronidation and its induction on UDP- glucuronosyltransferases isoforms.

Bromophenols (BPs) are prominent environmental pollutants extensively utilized in aquaculture, pharmaceuticals, and chemical manufacturing. This study aims to identify UDP- glucuronosyltransferases (UGTs) isoforms involved in the metabolic elimination of BPs. Mono-glucuronides of BPs were detected in human liver microsomes (HLMs) incubated with the co-factor uridine-diphosphate glucuronic acid (UDPGA). The glucuronidation metabolism reactions catalyzed by HLMs followed Michaelis-Menten or substrate inhibition kinetics. Recombinant enzymes and inhibition experiments with chemical reagents were employed to phenotype the principal UGT isoforms participating in BP glucuronidation. UGT1A6 emerged as the major enzyme in the glucuronidation of 4-Bromophenol (4-BP), while UGT1A1, UGT1A6, and UGT1A8 were identified as the most essential isoforms for metabolizing 2,4-dibromophenol (2,4-DBP). UGT1A1, UGT1A8, and UGT2B4 were deemed the most critical isoforms in the catalysis of 2,4,6-tribromophenol (2,4,6-TBP) glucuronidation. Species differences were investigated using the liver microsomes of pig (PLM), rat (RLM), monkey (MyLM), and dog (DLM). Additionally, 2,4,6-TBP effects on the expression of UGT1A1 and UGT2B7 in HepG2 cells were evaluated. The results demonstrated potential induction of UGT1A1 and UGT2B7 upon exposure to 2,4,6-TBP at a concentration of 50 µM. Collectively, these findings contribute to elucidating the metabolic elimination and toxicity of BPs.

Efficacy and safety of intravesical dimethyl sulfoxide treatment for patients with refractory Hunner-type interstitial cystitis: Real-world data postofficial approval in Japan.

OBJECTIVES: To examine real-world data regarding intravesical dimethyl sulfoxide (DMSO) therapy after official approval as a treatment for Hunner-type interstitial cystitis (HIC) in Japan. METHODS: This single institution, retrospective observational study was conducted between 2021 and 2022 to evaluate the outcomes of 30 patients with refractory HIC who received intravesical DMSO therapy according to the approved standardized regimen: administration of DMSO every 2 weeks for a total of 12 weeks. Treatment outcomes were evaluated using a 7-graded global response assessment scale, O'Leary and Sant's symptom and problem indices (OSSI/OSPI), the overactive bladder symptom score (OABSS), an 11-point pain intensity numerical rating scale, quality of life (QOL) score, and frequency volume chart variables. Related complications were also documented. RESULTS: The response rates at 2, 4, 6, 8, 10, and 12 weeks were 36.7%, 43.3%, 53.3%, 60.0%, 70.0%, and 70.0%, respectively. Compared with baseline, OSSI/OSPI, pain intensity, urinary frequency, and the QOL score improved significantly from 4 weeks of treatment. The OABSS score and functional bladder capacity also showed a tendency toward moderate improvement, but the difference was not significant. The mean duration of symptom relapse after termination of treatment was 6.4 ± 3.9 months. No patients discontinued treatment due to adverse events, although acute bladder irritation during infusion was noted in 21 patients (70%), which disappeared within 3 days. CONCLUSIONS: This study verifies the safety, moderately durable efficacy, and tolerability of the standard intravesical treatment with DMSO for HIC in Japan.

Interactive Structural Analysis of KH3-4 Didomains of IGF2BPs with Preferred RNA Motif Having m6A Through Dynamics Simulation Studies.

m6A modification is the most common internal modification of messenger RNA in eukaryotes, and the disorder of m6A can trigger cancer progression. The GGACU is considered the most frequent consensus sequence of target transcripts which have a GGAC m6A core motif. Newly identified m6A 'readers' insulin-like growth factor 2 mRNA-binding proteins modulate gene expression by binding to the m6A binding sites of target mRNAs, thereby affecting various cancer-related processes. The dynamic impact of the methylation at m6A within the GGAC motif on human IGF2BPs has not been investigated at the structural level. In this study, through in silico analysis, we mapped IGF2BPs binding sites for the GGm6AC RNA core motif of target mRNAs. Subsequent molecular dynamics simulation analysis at 400 ns revealed that only the KH4 domain of IGF2BP1, containing the 503GKGG506 motif and its periphery residues, was involved in the interaction with the GGm6AC backbone. Meanwhile, the methyl group of m6A is accommodated by a shallow hydrophobic cradle formed by hydrophobic residues. Interestingly, in IGF2BP2 and IGF2BP3 complexes, the RNA was observed to shift from the KH4 domain to the KH3 domain in the simulation at 400 ns, indicating a distinct dynamic behavior. This suggests a conformational stabilization upon binding, likely essential for the functional interactions involving the KH3-4 domains. These findings highlight the potential of targeting IGF2BPs' interactions with m6A modifications for the development of novel oncological therapies.

Translational control by ketamine and its implications for comorbid cognitive deficits in depressive disorders.

Ketamine has shown antidepressant effects in patients with major depressive disorder (MDD) resistant to first-line treatments and approved for use in this patient population. Ketamine induces several forms of synaptic plasticity, which are proposed to underlie its antidepressant effects. However, the molecular mechanism of action directly responsible for ketamine's antidepressant effects remains under active investigation. It was recently demonstrated that the effectors of the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway, namely, eukaryotic initiation factor 4E (eIF4E) binding proteins 1 and 2 (4E-BP1 and 4E-BP2), are central in mediating ketamine-induced synaptic plasticity and behavioural antidepressant-like effect. 4E-BPs are a family of messenger ribonucleic acid (mRNA) translation repressors inactivated by mTORC1. We observed that their expression in inhibitory interneurons mediates ketamine's effects in the forced swim and novelty suppressed feeding tests and the long-lasting inhibition of GABAergic neurotransmission in the hippocampus. In addition, another effector pathway that regulates translation elongation downstream of mTORC1, the eukaryotic elongation factor 2 kinase (eEF2K), has been implicated in ketamine's behavioural effects. We will discuss how ketamine's rapid antidepressant effect depends on the activation of neuronal mRNA translation through 4E-BP1/2 and eEF2K. Furthermore, given that these pathways also regulate cognitive functions, we will discuss the evidence of ketamine's effect on cognitive function in MDD. Overall, the data accrued from pre-clinical research have implicated the mRNA translation pathways in treating mood symptoms of MDD. However, it is yet unclear whether the pro-cognitive potential of subanesthetic ketamine in rodents also engages these pathways and whether such an effect is consistently observed in the treatment-resistant MDD population.

SMAD signaling pathway is disrupted by BPA via the AMH receptor in bovine granulosa cells†.

Significant events that determine oocyte competence occur during follicular growth and oocyte maturation. The anti-Mullerian hormone, a positive predictor of fertility, has been shown to be affected by exposure to endocrine disrupting compounds, such as bisphenol A and S. However, the interaction between bisphenols and SMAD proteins, mediators of the anti-Mullerian hormone pathway, has not yet been elucidated. AMH receptor (AMHRII) and downstream SMAD expression was investigated in bovine granulosa cells treated with bisphenol A, bisphenol S, and then competitively with the anti-Mullerian hormone. Here, we show that 24-h bisphenol A exposure in granulosa cells significantly increased SMAD1, SMAD4, and SMAD5 mRNA expression. No significant changes were observed in AMHRII or SMADs protein expression after 24-h treatment. Following 12-h treatments with bisphenol A (alone or with the anti-Mullerian hormone), a significant increase in SMAD1 and SMAD4 mRNA expression was observed, while a significant decrease in SMAD1 and phosphorylated SMAD1 was detected at the protein level. To establish a functional link between bisphenols and the anti-Mullerian hormone signaling pathway, antisense oligonucleotides were utilized to suppress AMHRII expression with or without bisphenol exposure. Initially, transfection conditions were optimized and validated with a 70% knockdown achieved. Our findings show that bisphenol S exerts its effects independently of the anti-Mullerian hormone receptor, while bisphenol A may act directly through the anti-Mullerian hormone signaling pathway providing a potential mechanism by which bisphenols may exert their actions to disrupt follicular development and decrease oocyte competence.

Effects of perinatal exposure to bisphenol A or S in EAE model of multiple sclerosis.

Epidemiological studies support the idea that multiple sclerosis (MS) is a multifactorial disease, overlapping genetic, epigenetic, and environmental factors. A better definition of environmental risks is critical to understand both etiology and the sex-related differences of MS. Exposure to endocrine-disrupting compounds (EDCs) fully represents one of these risks. EDCs are natural or synthetic exogenous substances (or mixtures) that alter the functions of the endocrine system. Among synthetic EDCs, exposure to bisphenol A (BPA) has been implicated in the etiology of MS, but to date, controversial data has emerged. Furthermore, nothing is known about bisphenol S (BPS), one of the most widely used substitutes for BPA. As exposure to bisphenols will not disappear soon, it is necessary to clarify their role also in this pathological condition defining their role in disease onset and course in both sexes. In this study, we examined, in both sexes, the effects of perinatal exposure to BPA and BPS in one of the most widely used mouse models of MS, experimental autoimmune encephalomyelitis (EAE). Exposure to bisphenols seemed to be particularly deleterious in males. In fact, both BPA- and BPS-treated males showed anticipation of the disease onset and an increased motoneuron loss in the spinal cord. Overall, BPA-treated males also displayed an exacerbation of EAE course and an increase in inflammation markers in the spinal cord. Analyzing the consequences of bisphenol exposure on EAE will help to better understand the role of both xenoestrogens and endogenous estrogens on the sexually dimorphic characteristics of MS.

Early and recent exposure to adversity, TLR-4 stimulated inflammation, and diurnal cortisol in women with interstitial cystitis/bladder pain syndrome: A MAPP research network study.

Both early (ELA) and recent life adversity (RLA) have been linked with chronic pain conditions and persistent alterations of neuroendocrine and inflammatory responses. Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic urologic disorder characterized by bladder and/or pelvic pain, and excessive urinary frequency and/or urgency. IC/BPS has been associated with high levels of ELA as well as a distinct inflammatory signature. However, associations between ELA and RLA with inflammatory mechanisms in IC/BPS that might underlie the link between adversity and symptoms have not been examined. Here we investigated ELA and RLA in women with IC/BPS as potential risk factors for inflammatory processes and hypothalamic-pituitaryadrenal (HPA) abnormalities using data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Women with IC/BPS and healthy controls (n = 154 and 32, respectively) completed surveys, collected salivary cortisol at awakening and bedtime for 3 days, and gave a blood sample which was analyzed for 7 LPS-stimulated cytokines and chemokines (IL-6, TNFα, IL-1ß, MIP1α, MCP1, IL-8, and IL-10). Two cytokine/chemokine composites were identified using principal components analysis. Patients with greater exposure to RLA or cumulative ELA and RLA of at least moderate severity showed elevated levels of a composite of all cytokines, adjusting for age, body mass index, and study site. Furthermore, there was a trending relationship between ELA and the pro-inflammatory composite score. Nocturnal cortisol and cortisol slope were not associated with ELA, RLA, or inflammation. The present findings support the importance of adverse events in IC/BPS via a biological mechanism and suggest that ELA and RLA should be assessed as risk factors for inflammation as part of a clinical workup for IC/BPS.