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Ali, M. K.

Publications and source records attributed to Ali, M. K..

11 recordsLinked to original sources
bioRxiv2026

A Temporal Reliability and Sustainability Score Framework for Ranking Heart Rate Variability Metrics During Pharmacological Autonomic Blockade in Rats

Background: While Heart Rate Variability (HRV) is a cornerstone of non-invasive autonomic assessment, the sensitivity and sustainability of specific HRV parameters remain debated. This study introduces a "sustainability score" to systematically validate which metrics best reflect autonomic nervous system (ANS) modulation following pharmacological blockade. Methods: Ten male Sprague-Dawley rats were implanted with ECG electrodes. After recovery, rats underwent randomized atropine (1 mg/kg, intraperitoneal) and propranolol (10 mg/kg, intraperitoneal) sessions separated by at least 3 days. Baseline ECG was recorded for 30 min before each session, followed by 90-min post-drug ECG recording. HRV parameters were analyzed in sequential 15-min and 30-min segments. Reliability was assessed using average p-values across post-drug segments and a sustainability score, defined as the number of segments significantly different from baseline. Results: After atropine, HF Power showed the strongest rapid parasympathetic-related response in 15-min segments, with the lowest average p-value (0.1476) and highest sustainability score (4), followed by RSA (p=0.16148; score=4). HFn was less reliable in 15-min segments (p=0.23147; score=2) but became the most reliable parasympathetic-related metric in 30-min segments (p=0.0001; score=3). After propranolol, SI was the most reliable sympathetic-related metric in both 15-min (p=0.18225; score=2) and 30-min segments (p=0.0393; score=2), while SD2/SD1 showed the strongest 30-min sympathovagal-balance response (p=0.0200; score=3). Conclusion: HF Power is recommended for rapid parasympathetic-related assessment in short windows, HFn for longer-window parasympathetic assessment, SI for sympathetic-assessment, and SD2/SD1 for 30-min sympathovagal-balance analysis. Sustainability scoring provides a structured framework for selecting ECG-derived autonomic markers.

pharmacology and toxicology↗
bioRxiv2026

HRV-GUI: A MATLAB Graphical User Interface for Heart Rate Variability Analysis and Validation Using Human, Rodent, and Clinical Diabetic Gastroparesis Data

Background and Objective: Heart rate variability (HRV) analysis provides a non-invasive method for quantifying autonomic modulation from electrocardiographic recordings. However, practical HRV analysis often depends on fragmented workflows, limited signal-quality review, and software tools optimized for either human or preclinical recordings, but not both. This study developed and evaluated HRV-GUI, a MATLAB-based graphical interface for electrocardiogram (ECG)-derived HRV analysis in translational biomedical research. Methods: The HRV-GUI integrates electrocardiographic and RR interval loading, human and rat analysis modes, preprocessing, segment selection, automated R-peak detection, manual peak correction, RR interval generation, multi-domain HRV computation, diagnostic visualization, result export, and session saving/loading. The software was evaluated using deterministic synthetic RR interval datasets, baseline recordings from healthy human controls and healthy rats, and a clinical use-case comparison between healthy controls and patients with diabetic gastroparesis. Results: The HRV-GUI produced expected outputs in synthetic RR validation tests, including constant RR sequences, alternating RR sequences, outlier-containing RR sequences, and low-frequency- or high-frequency-dominant sinusoidal RR modulation. The software generated physiologically plausible HRV profiles in both human and rat recordings. In the clinical use-case analysis, patients with diabetic gastroparesis showed higher heart rate and sympathetic index, together with lower respiratory sinus arrhythmia, absolute low- and high-frequency spectral power, standard deviation of normal-to-normal intervals (SDNN), root mean square of successive differences (RMSSD), percentage of successive RR intervals differing by more than 50 ms (pNN50), Poincare short-term variability (SD1), and Poincare long-term variability (SD2) compared with healthy controls. Conclusions: HRV-GUI provides an integrated biomedical software workflow for ECG-derived HRV analysis. The validation results support its use for controlled RR testing, human and rodent ECG recordings, and clinical autonomic assessment in diabetic gastroparesis.

bioengineering↗
bioRxiv2025

Engineered antimicrobial scaffolds protect bone marrow mesenchymal stem cell-Based Implants from bacterial infections

Bone marrow mesenchymal stem cell (BM-MSC)-based implants is a promising method for bone regeneration. Implant failures are often caused by their susceptibility to bacterial infections. The aim of this study is to develop and evaluate antimicrobial scaffolds designed to protect BM-MSC-based implants from bacterial colonization while promoting bone repair. Biocompatible polycaprolactone (PCL) scaffolds were fabricated with incorporated antimicrobial agents, including silver nanoparticles (AgNPs) and vancomycin, using electrospinning and surface coating techniques. The scaffolds were characterized for morphology, mechanical properties, and antimicrobial release profiles. The findings of in vitro studies revealed that the scaffolds effectively inhibited bacterial growth (>90% reduction in CFUs) and biofilm formation for Staphylococcus aureus and Escherichia coli, without affecting BM-MSC viability or osteogenic potential. In vivo implantation on a rat femoral defect model showed that antimicrobial scaffolds significantly reduced bacterial load and enhanced bone regeneration, with micro-CT showing 65% bone volume compared to 35% in controls. Histological analysis confirmed active osteogenesis and infection control. These findings showed the potential of antimicrobial scaffolds as a dual-functional platform for bone tissue engineering. Future research can explore scaffold optimization for different applications and examine their efficacy against multi-drug-resistant bacteria to broaden clinical relevance.

bioengineering↗
bioRxiv2023

Rat microbial biogeography and age-dependent lactic acid bacteria in healthy lungs

The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined a multi-tissue full lifespan microbial biogeography for healthy Fischer 344 rats. Microbial community profiling data was extracted and integrated with host transcriptomic data from the Sequencing Quality Control (SEQC) consortium. Unsupervised machine learning, Spearmans correlation, taxonomic diversity, and abundance analyses were performed to determine and characterize the rat microbial biogeography and the identification of four inter-tissue microbial heterogeneity patterns (P1-P4). The 11 body habitats harbor a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundances progressively declined in lungs from breastfeed newborn to adolescence/adult and was below detectable levels in elderly rats. LABs presence and levels in lungs were further evaluated by PCR in the two validation datasets. The lung, testes, thymus, kidney, adrenal, and muscle niches were found to have age-dependent alterations in microbial abundance. P1 is dominated by lung samples. P2 contains the largest sample size and is enriched for environmental species. Liver and muscle samples were mostly classified into P3. Archaea species were exclusively enriched in P4. The 357 pattern-specific microbial signatures were positively correlated with host genes in cell migration and proliferation (P1), DNA damage repair and synaptic transmissions (P2), as well as DNA transcription and cell cycle in P3. Our study established a link between metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures would be useful for microbiome therapeutic approaches to human health and good quality of life. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/541527v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1387224org.highwire.dtl.DTLVardef@cdb7dborg.highwire.dtl.DTLVardef@1e1c7ccorg.highwire.dtl.DTLVardef@440ca_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗
bioRxiv2022

PTPN1 deficiency modulates BMPR2 signaling and induces endothelial dysfunction in Pulmonary Arterial Hypertension

Bone morphogenic protein receptor 2 (BMPR2) expression and signaling are impaired in pulmonary arterial hypertension (PAH). How BMPR2 signaling is decreased in PAH is poorly understood. Protein tyrosine phosphatases (PTPs) play important roles in vascular remodeling in PAH. To identify whether PTPs modify BMPR2 signaling we used a siRNA-mediated high throughput screening of 22,124 murine genes in mouse myoblastoma reporter cells using ID1 expression as read-out for BMPR2 signaling. We further experimentally validated the top hit, PTPN1 (PTP1B), in human healthy pulmonary arterial endothelial cells (PAECs) either silenced by siRNA or exposed to hypoxia and confirmed its relevance to PAH by measuring PTPN1 levels in blood and PAECs collected from PAH patients. We identified PTPN1 as a novel regulator of BMPR2 signaling in PAECs, which is downregulated in the blood of PAH patients and documented that downregulation of PTPN1 is linked to endothelial dysfunction in PAECs. These findings point to a potential involvement for PTPN1 in PAH and will aid in our understanding of the molecular mechanisms involved in the disease.

cell biology↗
bioRxiv2022

Identifying transcriptomic downstream targets of genes commonly mutated in Hereditary Hemorrhagic Telangiectasia

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease that causes arteriovenous vascular malformations (AVMs) in different organs, including the lung. Three genes, ENG (endoglin), ACVRL1 (ALK1) and SMAD4, all members of the TGF-{beta}/BMPR2 signaling pathway, are responsible for over 85% of all HHT cases. However, how these loss-of-function gene mutations lead to AVMs formation and what common downstream signaling they target is unknown. Here, using a combination of siRNA-mediated gene silencing, whole transcriptomic RNA sequencing, bioinformatic analysis, transcriptomic-based drug discovery, endothelial cells functional assays and VEGF signaling analysis, and ex vivo precision cut lung slice (PCLS) cultures approach, we uncovered common downstream transcriptomic gene signatures of HHT-casing genes and identified promising drug for HHT. We found the commonly used BMPR2-signaling downstream target ID1 is not a common downstream target of all the three HHT genes knockdown in human pulmonary microvascular endothelial cells (PMVECs). We identified novel common downstream targets of all the three HHT-causing genes that were enriched for HHT-related biological process and signaling pathways. Among those downstream genes, LYVE1, GPNMB, and MC5R were strong downstream targets that could serve as a better common downstream target than ID1. Furthermore, using the common downstream upregulated genes (HHT disease signature) following HHT gene knockdown, we identified a small molecule drug, Brivanib, that reversed the HHT disease signature, and inhibited VEGF-induced ERK1/2 phosphorylation, proliferation, and angiogenesis in PMVECs and inhibited some of the upregulated HHT disease genes in PCLS. Our findings suggest that Brivanib could be an emerging new drug for HHT.

cell biology↗
bioRxiv2021

Selective Src-Family B Kinases Inhibition Promotes Pulmonary Artery Endothelial Cell Dysfunction.

Protein tyrosine kinase (PTK) inhibition is efficacious in treating conditions ranging from cancer to fibrosis but can be limited by endothelial cell dysfunction. In trials of protein tyrosine kinase inhibitors (TKIs) a broad range of vascular effects is observed, inducing clinically detrimental endothelial cell apoptosis, impaired barrier function, or improved pulmonary vascular resistance in pulmonary arterial hypertension (PAH). We hypothesize this range of effects is due to subsets of PTKs either impairing or promoting endothelial homeostasis by modulating Bone Morphogenetic Protein receptor 2 (BMPR2) signaling, a pathway essential for vascular development and dysfunctional in PAH. In a high-throughput siRNA screen we find SRC-Family B PTKs activate whereas SRC-Family A PTKs suppress BMPR2 signaling, measured by the transcription factor inhibitor of differentiation 1 (Id1). Induced loss of function of the strongest ID1 activating PTK LCK (a Src-B kinase) in human pulmonary artery endothelial cells suppresses BMPR2 signaling and induces multiple measures of endothelial dysfunction. However, loss of function of the strongest ID1 inhibitor PTK FYN (a Src- A kinase) does the opposite. Whole-genome transcriptional analysis identifies two multi-gene signatures inversely regulated by LCK and FYN we term "endothelial" and "inflammatory". To find TKIs mimicking selective Src-A and Src-B inhibition, we use Connectivity map to identify drugs connecting to the endothelial and inflammatory signatures. We find several TKIs: a pro-inflammatory (Regorafanib), a BMPR2 potentiating (Brivanib), and a BMPR2 suppressing (Quizartinib). Here we show a dichotomy in pathway regulation by Src- A and -B kinases that may have utility in transcriptionally based drug discovery.

molecular biology↗
bioRxiv2019

Association and impact of hypertension defined using the 2017 AHA/ACC guidelines on the risk of atrial fibrillation in the Atherosclerosis Risk in Communities Study

Hypertension is an established risk factor for the development of atrial fibrillation (AF). We evaluated the association and population impact of hypertension, defined using the new 2017 guidelines, on risk of AF. In this analysis, we included 9,207 participants in the Atherosclerosis Risk in Communities study without history of cardiovascular disease or diabetes. Participants underwent blood pressure measurements at baseline and their antihypertensive medication use was assessed. AF was ascertained from study electrocardiograms, hospital records and death certificates. Cox proportional models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of AF among individuals with hypertension based on the JNC7 and 2017 ACC/AHA guidelines. Poisson models were used to obtain risk ratios and calculate population-attributable fractions (PAFs). We identified 1,573 cases of incident AF during 22.1 years of mean follow-up. Prevalence of hypertension was 29% and 43% under the JNC7 and 2017 ACC/AHA definitions, respectively. HRs (95%CI) of AF in hypertensives versus non-hypertensives were 1.54 (1.39, 1.72) and 1.45 (1.31, 1.61) after multivariable adjustment under the old and new guidelines, respectively. The corresponding PAF (95%CI) using the old and new guidelines were 12% (9%, 14%) and 14% (10%, 18%), respectively. Overall, our analysis shows that even though the prevalence of hypertension using the new criteria is 50% higher than with the old criteria, this does not translate into meaningful increases in AF attributable to hypertension. These results suggest that prevention or treatment of hypertension based on the new (versus old) guidelines may have limited impact on AF incidence.

epidemiology↗
bioRxiv2017

Diabetes mellitus is associated with increased prevalence of latent tuberculosis infection: Results from the National Health and Nutrition Examination Survey

AimsWe aimed to determine the association between prediabetes and diabetes with latent TB using National Health and Nutrition Examination Survey data.\n\nMethodsWe performed a cross-sectional analysis of 2011-2012 National Health and Nutrition Examination Survey data. Participants [≥]20 years were eligible. Diabetes was defined by glycated hemoglobin (HbA1c) as no diabetes ([≤]5.6% [38 mmol/mol]), prediabetes (5.7-6.4% [3946mmol/mol]), and diabetes ([≥]6.5% [48 mmol/mol]) combined with self-reported diabetes. Latent TB infection was defined by the QuantiFERON(R)-TB Gold In Tube (QFT-GIT) test. Adjusted odds ratios (aOR) of latent TB infection by diabetes status were calculated using logistic regression and accounted for the stratified probability sample.\n\nResultsDiabetes and QFT-GIT measurements were available for 4,958 (89.2%) included participants. Prevalence of diabetes was 11.4% (95%CI 9.8-13.0%) and 22.1% (95%CI 20.523.8%) had prediabetes. Prevalence of latent TB infection was 5.9% (95%CI 4.9-7.0%). After adjusting for age, sex, smoking status, history of active TB, and foreign born status, the odds of latent TB infection were greater among adults with diabetes (aOR 1.90, 95%CI 1.15-3.14) compared to those without diabetes. The odds of latent TB in adults with prediabetes (aOR 1.15, 95%CI 0.90-1.47) was similar to those without diabetes.\n\nConclusionsDiabetes is associated with latent TB infection among adults in the United States, even after adjusting for confounding factors. Given diabetes increases the risk of active TB, patients with co-prevalent diabetes and latent TB may be targeted for latent TB treatment.

epidemiology↗