Investigation of the impact of bromodomain inhibition on cytoskeleton stability and contraction.

Background: Injury to contractile organs such as the heart, vasculature, urinary bladder and gut can stimulate a pathological response that results in loss of normal contractility. PDGF and TGFβ are among the most well studied initiators of the injury response and have been shown to induce aberrant contraction in mechanically active cells of hollow organs including smooth muscle cells (SMC) and fibroblasts. However, the mechanisms driving contractile alterations downstream of PDGF and TGFβ in SMC and fibroblasts are incompletely understood, limiting therapeutic interventions.

Machine Learning-Based Classification of Transcriptome Signatures of Non-Ulcerative Bladder Pain Syndrome.

Lower urinary tract dysfunction (LUTD) presents a global health challenge with symptoms impacting a substantial percentage of the population. The absence of reliable biomarkers complicates the accurate classification of LUTD subtypes with shared symptoms such as non-ulcerative Bladder Pain Syndrome (BPS) and overactive bladder caused by bladder outlet obstruction with Detrusor Overactivity (DO). This study introduces a machine learning (ML)-based approach for the identification of mRNA signatures specific to non-ulcerative BPS.

Machine Learning-based Classification of transcriptome Signatures of non-ulcerative Bladder Pain Syndrome.

Lower urinary tract dysfunction (LUTD) presents a global health challenge with symptoms impacting a substantial percentage of the population. The absence of reliable biomarkers complicates the accurate classification of LUTD subtypes with shared symptoms such as non-ulcerative Bladder Pain Syndrome (BPS) and overactive bladder caused by bladder outlet obstruction with Detrusor Overactivity (DO). This study introduces a machine learning (ML)-based approach for the identification of mRNA signatures specific to non-ulcerative BPS.

Machine Learning Made Easy (MLme): a comprehensive toolkit for machine learning-driven data analysis.

Background: Machine learning (ML) has emerged as a vital asset for researchers to analyze and extract valuable information from complex datasets. However, developing an effective and robust ML pipeline can present a real challenge, demanding considerable time and effort, thereby impeding research progress. Existing tools in this landscape require a profound understanding of ML principles and programming skills.

Integrated omics analysis unveils a DNA damage response to neurogenic injury.

Spinal cord injury (SCI) evokes profound bladder dysfunction. Current treatments are limited by a lack of molecular data to inform novel therapeutic avenues. Previously, we showed systemic inosine treatment improved bladder function following SCI in rats.

Investigation of the impact of bromodomain inhibition on cytoskeleton stability and contraction.

Injury to contractile organs such as the heart, vasculature, urinary bladder and gut can stimulate a pathological response that results in loss of normal contractility. PDGF and TGFβ are among the most well studied initiators of the injury response and have been shown to induce aberrant contraction in mechanically active cells of hollow organs including smooth muscle cells (SMC) and fibroblasts. However the mechanisms driving contractile alterations downstream of PDGF and TGFβ in SMC and fibroblasts are incompletely understood, limiting therapeutic interventions.

SpheroScan: a user-friendly deep learning tool for spheroid image analysis.

Background: In recent years, 3-dimensional (3D) spheroid models have become increasingly popular in scientific research as they provide a more physiologically relevant microenvironment that mimics in vivo conditions. The use of 3D spheroid assays has proven to be advantageous as it offers a better understanding of the cellular behavior, drug efficacy, and toxicity as compared to traditional 2-dimensional cell culture methods. However, the use of 3D spheroid assays is impeded by the absence of automated and user-friendly tools for spheroid image analysis, which adversely affects the reproducibility and throughput of these assays.

Bioinformatics in urology - molecular characterization of pathophysiology and response to treatment.

The application of bioinformatics has revolutionized the practice of medicine in the past 20 years. From early studies that uncovered subtypes of cancer to broad efforts spearheaded by the Cancer Genome Atlas initiative, the use of bioinformatics strategies to analyse high-dimensional data has provided unprecedented insights into the molecular basis of disease. In addition to the identification of disease subtypes - which enables risk stratification - informatics analysis has facilitated the identification of novel risk factors and drivers of disease, biomarkers of progression and treatment response, as well as possibilities for drug repurposing or repositioning; moreover, bioinformatics has guided research towards precision and personalized medicine.

Machine Learning Made Easy (MLme): A Comprehensive Toolkit for Machine Learning-Driven Data Analysis.

Background: Machine learning (ML) has emerged as a vital asset for researchers to analyze and extract valuable information from complex datasets. However, developing an effective and robust ML pipeline can present a real challenge, demanding considerable time and effort, thereby impeding research progress. Existing tools in this landscape require a profound understanding of ML principles and programming skills.

SpheroScan: A User-Friendly Deep Learning Tool for Spheroid Image Analysis.

Background: In recent years, three-dimensional (3D) spheroid models have become increasingly popular in scientific research as they provide a more physiologically relevant microenvironment that mimics in vivo conditions. The use of 3D spheroid assays has proven to be advantageous as it offers a better understanding of the cellular behavior, drug efficacy, and toxicity as compared to traditional two-dimensional cell culture methods. However, the use of 3D spheroid assays is impeded by the absence of automated and user-friendly tools for spheroid image analysis, which adversely affects the reproducibility and throughput of these assays.

Neuropilin 2 Is a Novel Regulator of Distal Colon Contractility.

Appropriate coordination of smooth muscle contraction and relaxation is essential for normal colonic motility. The impact of perturbed motility ranges from moderate, in conditions such as colitis, to potentially fatal in the case of pseudo-obstruction. The mechanisms underlying aberrant motility and the extent to which they can be targeted pharmacologically are incompletely understood.

A Comprehensive Transcriptomic Analysis of Arsenic-Induced Bladder Carcinogenesis.

Arsenic (sodium arsenite: NaAsO2) is a potent carcinogen and a known risk factor for the onset of bladder carcinogenesis. The molecular mechanisms that govern arsenic-induced bladder carcinogenesis remain unclear. We used a physiological concentration of NaAsO2 (250 nM: 33 µg/L) for the malignant transformation of normal bladder epithelial cells (TRT-HU1), exposed for over 12 months.

Interaction of TLK1 and AKTIP as a Potential Regulator of AKT Activation in Castration-Resistant Prostate Cancer Progression.

Prostate cancer (PCa) progression is characterized by the emergence of resistance to androgen deprivation therapy (ADT). AKT/PKB has been directly implicated in PCa progression, often due to the loss of PTEN and activation of PI3K>PDK1>AKT signaling. However, the regulatory network of AKT remains incompletely defined.

Wnt Site Signaling Inhibitor Secreted Frizzled-Related Protein 3 Protects Mitral Valve Endothelium From Myocardial Infarction-Induced Endothelial-to-Mesenchymal Transition.

Background The onset and mechanisms of endothelial-to-mesenchymal transition (EndMT) in mitral valve (MV) leaflets following myocardial infarction (MI) are unknown, yet these events are closely linked to stiffening of leaflets and development of ischemic mitral regurgitation. We investigated whether circulating molecules present in plasma within days after MI incite EndMT in MV leaflets. Methods and Results We examined the onset of EndMT in MV leaflets from 9 sheep with inferior MI, 8 with sham surgery, and 6 naïve controls.

Integrated mRNA-miRNA transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis.

Background: Interstitial cystitis, or bladder pain syndrome (IC/BPS), is a chronic bladder disorder characterized by lower abdominal pain associated with the urinary bladder and accompanied by urinary frequency and urgency in the absence of identifiable causes. IC/PBS can be separated into the classic Hunner's ulcerative type and the more prevalent non-ulcerative disease. Our aim was to unravel the biological processes and dysregulated cell signaling pathways leading to the bladder remodeling in non-ulcerative bladder pain syndrome (BPS) by studying the gene expression changes in the patients' biopsies.

Knockin mouse models demonstrate differential contributions of synaptotagmin-1 and -2 as receptors for botulinum neurotoxins.

Botulinum neurotoxins (BoNTs) are the most potent toxins known and are also utilized to treat a wide range of disorders including muscle spasm, overactive bladder, and pain. BoNTs' ability to target neurons determines their specificity, potency, and therapeutic efficacy. Homologous synaptic vesicle membrane proteins synaptotagmin-1 (Syt1) and synaptotagmin-2 (Syt2) have been identified as receptors for BoNT family members including BoNT/B, DC, and G, but their contributions at physiologically relevant toxin concentrations in vivo have yet to be validated and established.

Urinary Tract Infections in Children with Vesicoureteral Reflux Are Accompanied by Alterations in Urinary Microbiota and Metabolome Profiles.

Children with vesicoureteral reflux (VUR) are at an increased risk of recurrent urinary tract infections (UTIs) and renal scarring. Gut microbiota are associated with disease phenotypes, but there has been no study that associates urinary microbiota (uMB) and metabolic profiles with VUR pathology. To identify dominant uMB genera and metabolites associated with UTIs in VUR, urine samples collected under sterile conditions underwent 16S ribosomal RNA sequencing (n = 49) and metabolomic analysis by mass spectrometry (n = 96).

Molecular mechanisms of esophageal epithelial regeneration following repair of surgical defects with acellular silk fibroin grafts.

Constructive remodeling of focal esophageal defects with biodegradable acellular grafts relies on the ability of host progenitor cell populations to repopulate implant regions and facilitate growth of de novo functional tissue. Intrinsic molecular mechanisms governing esophageal repair processes following biomaterial-based, surgical reconstruction is largely unknown. In the present study, we utilized mass spectrometry-based quantitative proteomics and in silico pathway evaluations to identify signaling cascades which were significantly activated during neoepithelial formation in a Sprague Dawley rat model of onlay esophagoplasty with acellular silk fibroin scaffolds.

A Single Cell Dissociation Approach for Molecular Analysis of Urinary Bladder in the Mouse Following Spinal Cord Injury.

We describe the implementation of spinal cord injury in mice to elicit detrusor-sphincter dyssynergia, a functional bladder outlet obstruction, and subsequent bladder wall remodeling. To facilitate assessment of the cellular composition of the bladder wall in non-injured control and spinal cord injured mice, we developed an optimized dissociation protocol that supports high cell viability and enables the detection of discrete subpopulations by flow cytometry. Spinal cord injury is created by complete transection of the thoracic spinal cord.

Systems analysis of benign bladder disorders: insights from omics analysis.

The signaling pathways and effectors that drive the response of the bladder to nonmalignant insults or injury are incompletely defined. Interrogation of biological systems has been revolutionized by the ability to generate high-content data sets that capture information on a variety of biomolecules in cells and tissues, from DNA to RNA to proteins. In oncology, such an approach has led to the identification of cancer subtypes, improved prognostic capability, and has provided a basis for precision treatment of patients.

MCL1 and DEDD Promote Urothelial Carcinoma Progression.

Focal amplification of chromosome 1q23.3 in patients with advanced primary or relapsed urothelial carcinomas is associated with poor survival. We interrogated chromosome 1q23.

Concordant miRNA and mRNA expression profiles in humans and mice with bladder outlet obstruction.

Bladder outlet obstruction (BOO) leads to lower urinary tract symptoms (LUTS) and urodynamic changes of the bladder function. Previously we identified microRNA (miRNA) and mRNA expression profiles associated with different states of BOO-induced LUTD in human patients. Bladder wall remodeling resulting from obstruction is widely studied in animal models of experimentally-induced partial BOO (pBOO).