Multimodal AI/ML for discovering novel biomarkers and predicting disease using multi-omics profiles of patients with cardiovascular diseases.

Cardiovascular diseases (CVDs) are complex, multifactorial conditions that require personalized assessment and treatment. Advancements in multi-omics technologies, namely RNA sequencing and whole-genome sequencing, have provided translational researchers with a comprehensive view of the human genome. The efficient synthesis and analysis of this data through integrated approach that characterizes genetic variants alongside expression patterns linked to emerging phenotypes, can reveal novel biomarkers and enable the segmentation of patient populations based on personalized risk factors.

Comprehensive network modeling approaches unravel dynamic enhancer-promoter interactions across neural differentiation.

Background: Increasing evidence suggests that a substantial proportion of disease-associated mutations occur in enhancers, regions of non-coding DNA essential to gene regulation. Understanding the structures and mechanisms of the regulatory programs this variation affects can shed light on the apparatuses of human diseases.

Results: We collect epigenetic and gene expression datasets from seven early time points during neural differentiation.

Sexual Dimorphism of Spinal Neural Circuits Controlling the Mouse External Urethral Sphincter With and Without Spinal Cord Injury.

Spinal cord injury (SCI) disrupts coordination between the bladder and the external urinary sphincter (EUS), leading to transient or permanent voiding impairment, which is more severe in males. Male versus female differences in spinal circuits related to the EUS as well as post-SCI rewiring are essential for understanding of sex-/gender-specific impairments and possible recovery mechanisms. To quantitatively assess differences between EUS circuits in males versus females and in spinal intact (SI) versus SCI animals, we retrogradely traced and counted EUS-related neurons.

: Interactive and user-friendly multimodal AI/ML application for biomarker discovery and predictive medicine.

Artificial intelligence (AI) and machine learning (ML) have advanced in several areas and fields of life; however, its progress in the field of multi-omics is not matching the levels others have attained. Challenges include but are not limited to the handling and analysis of high volumes of complex multi-omics data, and the expertise needed to implement and execute AI/ML approaches. In this article, we present IntelliGenes, an interactive, customizable, cross-platform, and user-friendly AI/ML application for multi-omics data exploration to discover novel biomarkers and predict rare, common, and complex diseases.

Comprehensive network modeling approaches unravel dynamic enhancer-promoter interactions across neural differentiation.

Background: Increasing evidence suggests that a substantial proportion of disease-associated mutations occur in enhancers, regions of non-coding DNA essential to gene regulation. Understanding the structures and mechanisms of regulatory programs this variation affects can shed light on the apparatuses of human diseases.

Results: We collected epigenetic and gene expression datasets from seven early time points during neural differentiation.

GWAS advancements to investigate disease associations and biological mechanisms.

Genome-wide association studies (GWAS) have been instrumental in elucidating the genetic architecture of various traits and diseases. Despite the success of GWAS, inherent limitations such as identifying rare and ultra-rare variants, the potential for spurious associations, and in pinpointing causative agents can undermine diagnostic capabilities. This review provides an overview of GWAS and highlights recent advances in genetics that employ a range of methodologies, including Whole Genome Sequencing (WGS), Mendelian Randomization (MR), the Pangenome's high-quality T2T-CHM13 panel, and the Human BioMolecular Atlas Program (HuBMAP), as potential enablers of current and future GWAS research.

Discovering biomarkers associated and predicting cardiovascular disease with high accuracy using a novel nexus of machine learning techniques for precision medicine.

Personalized interventions are deemed vital given the intricate characteristics, advancement, inherent genetic composition, and diversity of cardiovascular diseases (CVDs). The appropriate utilization of artificial intelligence (AI) and machine learning (ML) methodologies can yield novel understandings of CVDs, enabling improved personalized treatments through predictive analysis and deep phenotyping. In this study, we proposed and employed a novel approach combining traditional statistics and a nexus of cutting-edge AI/ML techniques to identify significant biomarkers for our predictive engine by analyzing the complete transcriptome of CVD patients.

IntelliGenes: a novel machine learning pipeline for biomarker discovery and predictive analysis using multi-genomic profiles.

Summary: In this article, we present IntelliGenes, a novel machine learning (ML) pipeline for the multi-genomics exploration to discover biomarkers significant in disease prediction with high accuracy. IntelliGenes is based on a novel approach, which consists of nexus of conventional statistical techniques and cutting-edge ML algorithms using multi-genomic, clinical, and demographic data. IntelliGenes introduces a new metric, i.

Role of opioid and β-adrenergic receptors in bladder underactivity induced by prolonged pudendal nerve stimulation in cats.

Aims: To determine the role of opioid and β-adrenergic receptors in bladder underactivity induced by prolonged pudendal nerve stimulation (PNS).

Methods: In α-chloralose anesthetized cats, 30-min PNS was applied repeatedly for 3-9 times to induce poststimulation or persistent bladder underactivity. Then, naloxone (opioid receptor antagonist, 1 mg/kg, IV) or propranolol (β-adrenergic receptor antagonist, 3 mg/kg, IV) was given to reverse the bladder underactivity.

Pudendal Nerve Block by Adaptively Stepwise Increasing the Intensity of High-Frequency (10 kHz) Biphasic Stimulation.

Objective: The purpose of this study is to determine whether adaptively stepwise increasing the intensity of a high-frequency (10 kHz) biphasic stimulation (HFBS) can produce nerve conduction block without generating a large initial response.

Materials And Methods: In anesthetized cats, three cuff electrodes were implanted on the left pudendal nerve for stimulation or block. The urethral pressure increase induced by pudendal nerve stimulation was used to measure the pudendal nerve block induced by HFBS.

Therapeutic effects of p38 mitogen-activated protein kinase inhibition on hyperexcitability of capsaicin sensitive bladder afferent neurons in mice with spinal cord injury.

Aims: Nerve growth factor (NGF) has been implicated as a key molecule of pathology-induced changes in C-fiber afferent nerve excitability, which contributes to the emergence of neurogenic detrusor overactivity due to spinal cord injury (SCI). It is also known that the second messenger signaling pathways activated by NGF utilize p38 Mitogen-Activated Protein Kinase (MAPK). We examined the roles of p38 MAPK on electrophysiological properties of capsaicin sensitive bladder afferent neurons with SCI mice.

Model Analysis of Post-Stimulation Block of a Myelinated Axon by Direct Current.

Objective: To determine the role of ion concentrations and ion pump activity in conduction block of myelinated axon induced by a long-duration direct current (DC).

Methods: A new axonal conduction model for myelinated axons based on the classical Frankenhaeuser-Huxley (FH) equations is developed that includes ion pump activity and allows the intracellular and extracellular Na and K concentrations to change with axonal activity.

Results: Action potential generation, propagation, and acute DC block occurring within a short period (milliseconds) that do not significantly change the ion concentrations or trigger ion pump activity are successfully simulated by the new model in a similar way as the classical FH model.

Investigating genes associated with heart failure, atrial fibrillation, and other cardiovascular diseases, and predicting disease using machine learning techniques for translational research and precision medicine.

Cardiovascular disease (CVD) is the leading cause of mortality and loss of disability adjusted life years (DALYs) globally. CVDs like Heart Failure (HF) and Atrial Fibrillation (AF) are associated with physical effects on the heart muscles. As a result of the complex nature, progression, inherent genetic makeup, and heterogeneity of CVDs, personalized treatments are believed to be critical.

Effect of high-frequency membrane potential alternation between depolarization and hyperpolarization on dorsal root ganglion neurons of rats.

The purpose of this study was to determine how sensory neurons respond to high-frequency membrane potential alternation between depolarization and hyperpolarization. Membrane currents were recorded from dissociated dorsal root ganglion (DRG) neurons of adult rats using the whole cell patch clamp technique in voltage clamp mode. Stepwise depolarization of the membrane was applied first to determine the threshold membrane potential for inducing an action potential (AP) current.

Current Knowledge and Novel Frontiers in Lower Urinary Tract Dysfunction after Spinal Cord Injury: Basic Research Perspectives.

This review article aims to summarize the recent advancement in basic research on lower urinary tract dysfunction (LUTD) following spinal cord injury (SCI) above the sacral level. We particularly focused on the neurophysiologic mechanisms controlling the lower urinary tract (LUT) function and the SCI-induced changes in micturition control in animal models of SCI. The LUT has two main functions, the storage and voiding of urine, that are regulated by a complex neural control system.

Vaginal Lubrication and Pressure Increase Induced by Pudendal Nerve Stimulation in Cats.

Background: Vaginal lubrication and contractions are among the top difficulties affecting sexual intercourse in women after spinal cord injury.

Aim: This study aimed at determining if pudendal nerve stimulation (PNS) can improve vaginal lubrication and induce increases in vaginal pressure.

Methods: In anesthetized cats, a small piece of cotton was inserted into the vagina for 10 minutes with or without PNS to measure vaginal wetness by the weight increase of the vaginal cotton.

Penile Erection Induced by Stimulation of Sacral S1/S2 Spinal Root in Cats.

Objective: This study aimed at determining whether stimulation of sacral spinal roots can induce penile erection in cats.

Materials And Methods: In anesthetized cats, a 20-gauge catheter was inserted into the corpus cavernosum to measure the penile pressure. Stimulus pulses (5-80 Hz, 0.

Intracellular sodium concentration and membrane potential oscillation in axonal conduction block induced by high-frequency biphasic stimulation.

A new axonal conduction model was used to analyze the interaction between intracellular sodium concentration and membrane potential oscillation in axonal conduction block induced by high-frequency (kHz) biphasic stimulation (HFBS).The model includes intracellular and extracellular sodium and potassium concentrations and ion pumps. First, the HFBS (1 kHz, 5.

Sacral neuromodulation of bladder underactivity induced by prolonged pudendal afferent firing in cats.

This study examined the effect of sacral neuromodulation on persistent bladder underactivity induced by prolonged pudendal nerve stimulation (PudNS). In 10 α-chloralose-anesthetized cats, repetitive application of 30-min PudNS induced bladder underactivity evident as an increase in bladder capacity during a cystometrogram (CMG). S1 or S2 dorsal root stimulation (15 or 30 Hz) at 1 or 1.

Temperature Effect on Nerve Conduction Block Induced by High-Frequency (kHz) Biphasic Stimulation.

Objectives: This study aims to determine temperature effect on nerve conduction block induced by high-frequency (kHz) biphasic stimulation (HFBS).

Materials And Methods: Frog sciatic nerve-muscle preparation was immersed in Ringer's solution at a temperature of 15 or 20 °C. To induce muscle contractions, a bipolar cuff electrode delivered low-frequency (0.

Superficial peroneal neuromodulation of nonobstructive urinary retention induced by prolonged pudendal afferent activity in cats.

The purpose of this study is to determine whether superficial peroneal nerve stimulation (SPNS) can improve nonobstructive urinary retention (NOUR) induced by prolonged pudendal nerve stimulation (PNS). In this exploratory acute study using eight cats under anesthesia, PNS and SPNS were applied by nerve cuff electrodes. Skin surface electrodes were also used for SPNS.

Defecation induced by stimulation of sacral S2 spinal root in cats.

The aim of this study was to determine whether stimulation of sacral spinal nerve roots can induce defecation in cats. In anesthetized cats, bipolar hook electrodes were placed on the S1-S3 dorsal and/or ventral roots. Stimulus pulses (1-50 Hz, 0.

High-frequency stimulation induces axonal conduction block without generating initial action potentials.

The purpose of this modeling study is to develop a novel method to block nerve conduction by high frequency biphasic stimulation (HFBS) without generating initial action potentials. An axonal conduction model including both ion concentrations and membrane ion pumps is used to analyze the axonal response to 1 kHz HFBS. The intensity of HFBS is increased in multiple steps while maintaining the intensity at a sub-threshold level to avoid generating an action potential.