Biology subjects

Hashemi Gheinani, A.

Publications and source records attributed to Hashemi Gheinani, A..

8 recordsLinked to original sources

bioRxiv2026

Integrated transcriptomic and proteomic analyses identify novel biomarkers of bladder outlet obstruction

Bladder outlet obstruction leads to pathological remodeling and emergence of lower urinary tract symptoms. Although relief of obstruction is associated with symptomatic improvement, it is not universally successful, reflecting persistent alterations in the bladder. Reliable surrogate biomarkers of obstruction are lacking, particularly early in the disease course before irreversible damage to the bladder may have occurred. In this study, re-analysis of publicly available transcriptomic datasets from diverse rodent models of obstruction identified tissue transcripts including Cthrc1, Grem1, Ltbp2 and Msn that were induced in response to injury. Candidate markers were validated experimentally in an independent model of neurogenic obstruction demonstrating time-dependent changes. Candidate markers were also attenuated with either surgical removal of obstruction or treatment with anticholinergic medication or inosine. Integrated analysis of tissue transcriptomics data and tissue and urine proteomics data from a model of neurogenic obstruction revealed significant concordance between markers observed in tissue and urine. Urinary proteomics analysis identified a statistically significant increase in MSN in patients with neurogenic bladder compared to unaffected controls. These findings identify tissue and urine biomarkers of both non-neurogenic and neurogenic obstruction that may reflect early changes in obstructive uropathy that could be monitored in a non-invasive manner.

bioinformatics↗

bioRxiv2025

Functional architecture of cardiac TF regulatory landscapes in control of mammalian heart development

Congenital heart disease (CHD), the most common human birth defect, often results from disruptions in gene regulatory networks (GRNs) that control cardiac lineage specification and cell type identity during heart development. A conserved core set of cardiac transcription factors (TFs) orchestrates these processes through combinatorial interactions that are cell type-specific and tightly regulated across space and time. However, the genomic enhancer architecture that integrates upstream effectors to establish precise cardiac TF dosage and downstream transcriptional output remains largely unresolved. Here, we assessed the functional necessity of five developmental heart enhancer modules previously linked to the regulation of Gata4 and Hand2, core cardiac TFs exhibiting overlapping roles in myocardial and endocardial development. While individual enhancer deletions in mouse embryonic hearts revealed a surprising degree of transcriptional resilience, a subset of Gata4 enhancers proved indispensable for embryonic progression in a genetically compromised background. To achieve higher precision in cardiac cell type-specific enhancer prediction, we applied single-nucleus multiome profiling, enabling the delineation of cardiac cistromes underlying heart morphogenesis. By integrating this resource with deep learning applications, site-directed transgenesis, and chromatin conformation modeling, we mapped the cardiac enhancer repertoire and regulatory signatures that orchestrate Hand2 dynamics across distinct cardiac compartments and lineages. Genome editing further revealed an essential role for the Hand2-upstream regulatory interval (H2-URI) in transcriptional control of endocardial lineage effectors and, consequently, trabecular network formation and cardiac cushion patterning. Together our findings highlight substantial resilience in the cis-regulatory architectures governing cardiac TF dynamics and demonstrate that combinatorial integration of upstream lineage identities across modular enhancer landscapes establishes the cardiac cell type-specific programs driving heart morphogenesis. These results advance the reconstruction of cardiac GRNs and enhance the functional interpretation of CHD-associated variants.

developmental biology↗

bioRxiv2024

A lymphoid tissue chemokine checkpoint prevents loss of CD8+ T cell functionality

The generation of effector CD8+ T cells (TEFF) requires activation of naive CD8+ T cells (TN) by dendritic cells (DCs) within lymphoid tissue. To date, it remains elusive how the duration of TN-DC interactions and integration of activation signals are controlled in vivo. Here, we report that lymphoid stroma-secreted ligands for CCR7 constrained interaction duration by gradually inducing CD8+ T cell release from DCs. At late time points of interactions, CCR7 ligands repositioned the F-actin-promoting factor DOCK2 away from the DC interface to enable CD8+ T cell detachment, proliferation onset and acquisition of cytotoxicity. Lack of CCR7 signaling, as during ex vivo activation or in chronically inflamed lymphoid tissue, caused sustained T cell-DC interactions, and generated dysfunctional TEFF with high expression of inhibitory receptors, impaired antimicrobial activity, and poor recall responses. In sum, our findings uncover that lymphoid stromal chemokines act as built-in "disruptors" of T cell-DC interactions for long-term preservation of TEFF functionality.

immunology↗

bioRxiv2024

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. Using next-generation sequencing (NGS) transcriptome data from bladder biopsies of patients with BPS, benign prostatic obstruction with DO and controls, our statistical approach successfully identified 13 candidate genes capable of discerning BPS from control and DO patients. This set was subsequently validated using Quantitative Polymerase Chain Reaction (QPCR) in a larger patient cohort. To confirm our findings, we applied both supervised and unsupervised ML approaches to the QPCR dataset. Notably, a three-mRNA signature TPPP3, FAT1, and NCALD, emerged as a robust classifier, effectively distinguishing patients with non- ulcerative BPS from controls and patients with DO. This signature was universally selected by both supervised and unsupervised approaches. The ML-based framework used to define BPS classifiers not only establishes a solid foundation for comprehending the specific gene expression changes in the bladder of the patients with BPS but also serves as a valuable resource and methodology for advancing signature identification in other fields. The proposed ML pipeline demonstrates its efficacy in handling challenges associated with limited sample sizes, offering a promising avenue for applications in similar domains.

bioinformatics↗

bioRxiv2023

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. Here, we applied multi-omics analysis to explore molecular alterations in the bladder and their sensitivity to inosine following SCI. Canonical pathways regulated by SCI included those associated with protein synthesis, neuroplasticity, wound healing, and neurotransmitter degradation. Upstream regulator analysis identified MYC as a key regulator, whereas causal network analysis predicted multiple regulators of DNA damage response signaling following injury, including PARP-1. Staining for both DNA damage ({gamma}H2AX) and PARP activity (poly-ADP-ribose) markers in the bladder was increased following SCI, and attenuated in inosine-treated tissues. Proteomics analysis suggested that SCI induced changes in protein synthesis-, neuroplasticity-, and oxidative stress-associated pathways, a subset of which were shown in transcriptomics data to be inosine-sensitive. These findings provide novel insights into the molecular landscape of the bladder following SCI, and highlight a potential role for PARP inhibition to treat neurogenic bladder dysfunction. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/571015v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@7c3e79org.highwire.dtl.DTLVardef@e998f5org.highwire.dtl.DTLVardef@38fd4aorg.highwire.dtl.DTLVardef@17d3aba_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIEmployed a multi-omics approach, integrating both transcriptomic and proteomic analyses, to investigate the molecular response in a rat model of spinal cord injury (SCI) and the therapeutic effect of inosine. C_LIO_LIDiscovered multiple regulators of the DNA damage response, including PARP-1, using causal network analysis. C_LIO_LIObserved decreased markers of DNA damage and PARP activity in inosine-treated tissues, indicating the therapeutic potential of inosine in neurogenic dysfunction. C_LIO_LIIdentified significant alterations in molecular pathways associated with protein synthesis, neuroplasticity, wound healing, and neurotransmitter degradation after SCI, and their modulation by inosine, highlighting its neuroprotective effects beyond DNA damage repair. C_LI

cell biology↗

bioRxiv2023

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

BackgroundMachine 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. Furthermore, users are required to engage in the comprehensive configuration of their ML pipeline to obtain optimal performance. ResultsTo address these challenges, we have developed a novel tool called Machine Learning Made Easy (MLme) that streamlines the use of ML in research, specifically focusing on classification problems at present. By integrating four essential functionalities, namely Data Exploration, AutoML, CustomML, and Visualization, MLme fulfills the diverse requirements of researchers while eliminating the need for extensive coding efforts. To demonstrate the applicability of MLme, we conducted rigorous testing on six distinct datasets, each presenting unique characteristics and challenges. Our results consistently showed promising performance across different datasets, reaffirming the versatility and effectiveness of the tool. Additionally, by utilizing MLmes feature selection functionality, we successfully identified significant markers for CD8+ naive (BACH2), CD16+ (CD16), and CD14+ (VCAN) cell populations. ConclusionMLme serves as a valuable resource for leveraging machine learning (ML) to facilitate insightful data analysis and enhance research outcomes, while alleviating concerns related to complex coding scripts. The source code and a detailed tutorial for MLme are available at https://github.com/FunctionalUrology/MLme. Key PointsO_LIMLme is a novel tool that simplifies machine learning (ML) for researchers by integrating Data Exploration, AutoML, CustomML, and Visualization functionalities. C_LIO_LIMLme improves efficiency and productivity by streamlining the ML workflow and eliminating the need for extensive coding efforts. C_LIO_LIRigorous testing on diverse datasets demonstrates MLmes promising performance in classification problems. C_LIO_LIMLme provides intuitive interfaces for data exploration, automated ML, customizable ML pipelines, and result visualization. C_LIO_LIFuture developments aim to expand MLmes capabilities to include support for unsupervised learning, regression, hyperparameter tuning, and integration of user-defined algorithms. C_LI

bioinformatics↗

bioRxiv2023

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

BackgroundIn 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. ResultsTo address these issues, we have developed a fully automated, web-based tool called SpheroScan, which uses the deep learning framework called Mask Regions with Convolutional Neural Networks (R-CNN) for image detection and segmentation. To develop a deep learning model that could be applied to spheroid images from a range of experimental conditions, we trained the model using spheroid images captured using IncuCyte Live-Cell Analysis System and a conventional microscope. Performance evaluation of the trained model using validation and test datasets shows promising results. ConclusionSpheroScan allows for easy analysis of large numbers of images and provides interactive visualization features for a more in-depth understanding of the data. Our tool represents a significant advancement in the analysis of spheroid images and will facilitate the widespread adoption of 3D spheroid models in scientific research. The source code and a detailed tutorial for SpheroScan are available at https://github.com/FunctionalUrology/SpheroScan. Key PointsO_LIA deep learning model was trained to detect and segment spheroids in images from microscopes and Incucytes. C_LIO_LIThe model performed well on both types of images with the total loss decreasing significantly during the training process. C_LIO_LIA web tool called SpheroScan was developed to facilitate the analysis of spheroid images, which includes prediction and visualization modules. C_LIO_LISpheroScan is efficient and scalable, making it possible to handle large datasets with ease. C_LIO_LISpheroScan is user-friendly and accessible to researchers, making it a valuable resource for the analysis of spheroid image data. C_LI

bioinformatics↗

bioRxiv2022

MLcps: Machine Learning Cumulative Performance Score for classification problems

MotivationA performance metric is a tool to measure the correctness of a trained Machine Learning (ML) model. Numerous performance metrics have been developed for classification problems making it overwhelming to select the appropriate one since each of them represents a particular aspect of the model. Furthermore, selection of a performance metric becomes harder for problems with imbalanced and/or small datasets. Therefore, in clinical studies where datasets are frequently imbalanced and, in situations when the prevalence of a disease is low or the collection of patient samples is difficult, deciding on a suitable metric for performance evaluation of an ML model becomes quite challenging. The most common approach to address this problem is measuring multiple metrics and compare them to identify the best-performing ML model. However, comparison of multiple metrics is laborious and prone to user preference bias. Furthermore, evaluation metrics are also required by ML model optimization techniques such as hyperparameter tuning, where we train many models, each with different parameters, and compare their performances to identify the best-performing parameters. In such situations, it becomes almost impossible to assess different models by comparing multiple metrics. ResultsHere, we propose a new metric called Machine Learning Cumulative Performance Score (MLcps) as a Python package for classification problems. MLcps combines multiple pre-computed performance metrics into one metric that conserves the essence of all pre-computed metrics for a particular model. We tested MLcps on 4 different publicly available biological datasets and the results reveal that it provides a comprehensive picture of overall model robustness. AvailabilityMLcps is available at https://pypi.org/project/MLcps/ and cases of use are available at https://mybinder.org/v2/gh/FunctionalUrology/MLcps.git/main. Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗