Biology subjects

Bakhtiari, M.

Publications and source records attributed to Bakhtiari, M..

16 recordsLinked to original sources

bioRxiv2026

No Evidence of tACS-Primed Enhancement of Alpha Neurofeedback

Neurofeedback shows promise as a clinical intervention, but its effectiveness is hindered by variability of response across individuals. One factor influencing neurofeedback success may be endogenous brain states, particularly the baseline power within target frequency bands. Transcranial alternating current stimulation (tACS) provides a potential mechanism to modulate these baseline frequency bands. This study explored whether tACS could effectively enhance participants' ability to gain neurofeedback control by increasing lateralised posterior alpha activity prior to engagement in a covert spatial attention-based neurofeedback task. Participants completed three counterbalanced sessions: 1) alpha tACS and active neurofeedback, 2) alpha tACS and sham neurofeedback, 3) gamma (40Hz) tACS and active neurofeedback. Neurofeedback performance was assessed via lateralised posterior alpha power shifts and Posner task reaction times. We identified no difference in reaction times or lateralised alpha power shifts across conditions. While participants reliably demonstrated lateralised posterior alpha patterns, consistent with the covert spatial attention neurofeedback protocol, no advantage of active neurofeedback over sham was observed. The lack of significant effects underscores the need for further rigorous tACS studies to identify the parameters essential for successful neural entrainment, and to evaluate its potential in enhancing neurofeedback efficacy.

neuroscience↗

bioRxiv2026

Integrated coding-noncoding genome annotation expands single-cell transcriptomic discovery and identifies clinically relevant noncoding RNAs in multiple myeloma

Although the human genome encodes a vast repertoire of noncoding RNAs that regulate gene expression, the noncoding genome remains underexplored due to technical challenges. Specifically, during transcriptomic sequencing data alignment, the overlap between noncoding and coding loci can create ambiguous read alignments that are subsequently discarded from downstream analysis. For this reason, most of the noncoding genome is excluded from standard genomic annotations used for sequencing alignment. To address this challenge and enable concurrent profiling of the coding and noncoding transcriptome, we systematically integrated standard coding (GENCODE) and noncoding (LncBook) genome annotations, preserving coding gene annotations and removing overlapping noncoding regions. The resulting integrated genome annotation expanded the number of annotated noncoding genes from 40,785 to 138,296 while preserving all coding genes and reducing ambiguous read assignment. To evaluate the utility of our integrated genome annotation for uncovering novel, biologically relevant noncoding RNAs (ncRNAs), we realigned CD138-positive bulk RNA-seq (N = 942) and CD138-negative single-cell RNA-seq (N = 478) data from the MMRF CoMMpass study, generating a comprehensive coding-noncoding atlas of the myeloma bone marrow microenvironment with noncoding genes representing 51% of highly variable genes and displaying significant cell type specificity. Tumor expression profiling based on this integrated profiling identified 15 clusters, including two enriched for amp(1q21) or t(4;14) and associated with shorter progression-free survival (PFS). Differential expression and systematic filtering yielded 19 candidate high-risk ncRNAs, including previously uncharacterized ENSG00000310209, which was associated with poor PFS (HR = 1.141, P = 0.0025), increased IRF4 activity, Wnt pathway activation, CCL5 signaling, and the accumulation of anergic-like CD8+ T cells. These findings establish integrated coding-noncoding analysis as a strategic approach for discovering functional ncRNAs from transcriptomic sequencing data.

cancer biology↗

bioRxiv2026

Single-cell RNA-seq reveals conserved and divergent cellular states across wound types and species

Chronic wounds, such as diabetic foot ulcers, fail to progress through the normal healing process and impose a significant burden on healthcare systems. While previous single-cell studies have characterized specific wound conditions, a unified understanding of the shared and distinct cellular landscapes across diverse wound microenvironments has been lacking. Therefore, we integrated over 500,541 cells from patients and mice across multiple wound conditions, including acute wound, diabetic foot ulcer, and venous ulcer as well as their healing outcome. Fibroblast-focused analysis identified a bifurcation in differentiation trajectories and identified STAT3 as a potential regulator of a reparative program in chronic wound. Furthermore, we discovered immune dysfunctions in non-healed chronic wounds, contrasting the quiescent memory-like T cells and TIMP1+ macrophages in healed chronic wounds with the exhausted T cells and foamy SPP1+ macrophage enriched in non-healed chronic wounds. Finally, we translated these results into a clinically applicable three-gene signature (CHI3L1, TIMP1, and SPP1) that accurately predicts chronic wound healing. To support wound biology community, we developed WoundSCAtlas, an interactive web resource for exploring diverse wound pathologies. In conclusion, this work provides a comprehensive and cross-species landscape of chronic wound healing, identifying conversed wound outcome-associated molecular programs, predictive biomarker, and interactive data resource.

bioinformatics↗

bioRxiv2026

Single-cell profiling of innate and adaptive immune dysregulation in Long COVID

The COVID-19 pandemic has infected more than 778 million people worldwide. Roughly 7% of these patients progress to Long COVID (LC), suffering from persistent symptoms and cognitive impairment well past the acute stage. As the mechanisms of LC remain elusive, we utilized single-cell profiling (SCP) on 156,478 peripheral blood mononuclear cells (PBMCs) from 20 LC patients and 18 recovered controls (RC) to characterize the disease-associated immune dysregulation. Comparative analysis of LC and RC profiles revealed cellular heterogeneity along with differential abundances across B, T, and myeloid cell compartments. The focused analysis on the B-cell compartment showed that naive B cells in the LC exhibit elevated IL4R expression and BCR signaling, indicative of sustained antigen exposure and aberrant chronic activation. Concurrently, monocytes adopted heightened interferon signaling and enhanced migratory states, culminating into impaired myeloid differentiation. Furthermore, the T-cell compartment exhibited a functional dichotomy, maintaining sustained quiescence in the central memory compartment while displaying chronic exhaustion within effector memory populations. This dysregulation of effector immunity extended to the NK compartment, where terminally differentiated cells exhibited increased cytotoxicity yet compromised regulatory function, potentially contributing to poor viral clearance. Cellular communication analysis further supports this NK cell dysfunction that is likely driven by galectin and prostaglandin signaling involving monocytes and B cells. We stratified LC patients into mild and severe groups based on symptom and cognitive severity, identifying a distinct immune signature where severe disease is linked to chronic AP-1-mediated inflammation in NK cells and CD14+ monocytes. In contrast, patients with mild symptoms retain functionally competent NK cells with significantly lower exhaustion and apoptosis scores. Collectively, these insights into persistent immune remodeling provide a crucial framework for future biomarker discovery and the development of targeted therapeutic strategies. Abstract (Short)COVID-19 has affected >778 million worldwide, with [~]7% developing Long COVID (LC), characterized by persistent symptoms and cognitive impairment. The mechanisms of LC remain elusive; we utilized single-cell profiling on 156,478 peripheral blood mononuclear cells from LC and recovered controls. Comparative analysis revealed cellular heterogeneity and differential abundance across multiple immune compartments. B-cells exhibited hallmarks of sustained antigen exposure and aberrant activation. Concurrently, monocytes adopted heightened interferon signaling, enhanced migratory states, and impaired differentiation. T-cells exhibited chronic exhaustion within the effector memory populations. Dysregulated effector immunity extended to NK, with increased expression of cytotoxic genes yet compromised regulatory function, potentially contributing to viral clearance. LC patients with severe symptoms showed enhanced AP-1-mediated inflammation in NK cells and CD14+ monocytes, whereas mild cases had fitter NK cells with significantly lower exhaustion and apoptosis. Collectively, these insights provide a framework for biomarker discovery and the development of targeted LC therapeutic strategies.

genomics↗

bioRxiv2026

Spatial multi-omics of multiple myeloma uncovers niche-dependent pro-myeloma and immunosuppressive signaling in the bone marrow and extramedullary lesions

Multiple myeloma (MM) is a plasma cell malignancy shaped by dynamic interactions between MM cells and non-malignant cells in the immune microenvironment. To spatially profile the influence of cellular context on MM and immune cell expression, we developed a multimodal framework integrating 10x Genomics Visium HD, 10x Genomics Xenium, and clinically annotated single-cell RNA (scRNA-seq) sequencing datasets. Visium HD enabled unbiased, whole transcriptome, spatial discovery at 16 {micro}m resolution, Xenium provided orthogonal validation at single-cell resolution, and scRNA-seq extended findings by mapping spatial labels and leveraging the greater sequencing depth. We developed a custom framework for cell type annotation within Visium HD spatial bins. Our approach enabled identification of plasma cell-dense niches enriched for non-canonical Wnt signaling, associated with gene expression supporting cell adhesion mediated drug resistance, inferior progression-free survival, and extramedullary lesions. Immune cells within these neighborhoods exhibited suppressed transcriptional states, including increased inhibitory receptor expression such as LAG3. Utilizing the niche-driven transcriptional states in MM and immune cells, we were able to develop a 15-gene signature independently predictive of progression free survival (HR = 2.00, p < 0.0001). Collectively, this study demonstrates the potential of integrated spatial and single-cell transcriptomics to define niche-specific programs supporting MM progression.

cancer biology↗

bioRxiv2025

Blood-based Epigenetic Instability Linked to Human Aging and Disease

The abundance, dynamics, and context-dependent heterogeneity of DNA methylation--where a pattern considered abnormal in one cell type may be normal in another--poses challenges in identifying methylation abnormalities linked to disease risk. Through genome-wide analyses, we identified CpG sites with remarkably consistent methylation profiles in healthy whole blood, predominantly existing in an unmethylated state. We examined alterations at these epigenetically stable loci in diverse cohorts, including those with cardiovascular disease and hematological cancers. Our findings reveal methylation pattern disruption in myeloid and lymphoid malignancies, correlating with clonal burden fluctuations during leukemia treatment. In non-cancer cohorts, we observed that normally stable CpG sites exhibited progressive instability with advancing age, which was also associated with the onset of cardiovascular disease and decreased survival rates. This study links DNA methylation instability with the expansion of risk-prone blood cells and highlights its role as a biomarker for both cancer and cardiovascular disease.

genetics↗

bioRxiv2024

Medulloblastoma Spatial Transcriptomics Reveals Tumor Microenvironment Heterogeneity with High-Density Progenitor Cell Regions Correlating with High-Risk Disease

The tumor microenvironment (TME) of medulloblastoma (MB) influences progression and therapy response, presenting a promising target for therapeutic advances. Prior single-cell analyses have characterized the cellular components of the TME but lack spatial context. To address this, we performed spatial transcriptomic sequencing on sixteen pediatric MB samples obtained at diagnosis, including two matched diagnosis-relapse pairs. Our analyses revealed inter- and intra-tumoral heterogeneity within the TME, comprised of tumor-associated astrocytes (TAAs), macrophages (TAMs), stromal components, and distinct subpopulations of MB cells at different stages of neuronal differentiation and cell cycle progression. We identified dense regions of quiescent progenitor-like MB cells enriched in patients with high-risk (HR) features and an increase in TAAs, TAMs, and dysregulated vascular endothelium following relapse. Our study presents novel insights into the spatial architecture and cellular landscape of the medulloblastoma TME, highlighting spatial patterns linked to HR features and relapse, which may serve as potential therapeutic targets.

cancer biology↗

bioRxiv2024

A single-cell atlas characterizes dysregulation of the bone marrow immune microenvironment associated with outcomes in multiple myeloma

Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We established a harmonized consortium to generate an Immune Atlas of MM aimed at informing disease etiology, risk stratification, and potential therapeutic strategies. We generated a transcriptome profile of 1,149,344 single cells from the bone marrow of 263 newly diagnosed patients enrolled in the CoMMpass study and characterized immune and hematopoietic cell populations. Associating cell abundances and gene expression with disease progression revealed the presence of a proinflammatory immune senescence-associated secretory phenotype in rapidly progressing patients. Furthermore, signaling analyses suggested active intercellular communication involving APRIL-BCMA, potentially promoting tumor growth and survival. Finally, we demonstrate that integrating immune cell levels with genetic information can significantly improve patient stratification.

genomics↗

bioRxiv2023

Integrated single-nuclei and spatial transcriptomic analysis reveals propagation of early acute vein harvest and distension injury signaling pathways following arterial implantation

BackgroundVein graft failure (VGF) following cardiovascular bypass surgery results in significant patient morbidity and cost to the healthcare system. Vein graft injury can occur during autogenous vein harvest and preparation, as well as after implantation into the arterial system, leading to the development of intimal hyperplasia, vein graft stenosis, and, ultimately, bypass graft failure. While previous studies have identified maladaptive pathways that occur shortly after implantation, the specific signaling pathways that occur during vein graft preparation are not well defined and may result in a cumulative impact on VGF. We, therefore, aimed to elucidate the response of the vein conduit wall during harvest and following implantation, probing the key maladaptive pathways driving graft failure with the overarching goal of identifying therapeutic targets for biologic intervention to minimize these natural responses to surgical vein graft injury. MethodsEmploying a novel approach to investigating vascular pathologies, we harnessed both single-nuclei RNA-sequencing (snRNA-seq) and spatial transcriptomics (ST) analyses to profile the genomic effects of vein grafts after harvest and distension, then compared these findings to vein grafts obtained 24 hours after carotid-cartoid vein bypass implantation in a canine model (n=4). ResultsSpatial transcriptomic analysis of canine cephalic vein after initial conduit harvest and distention revealed significant enrichment of pathways (P < 0.05) involved in the activation of endothelial cells (ECs), fibroblasts (FBs), and vascular smooth muscle cells (VSMCs), namely pathways responsible for cellular proliferation and migration and platelet activation across the intimal and medial layers, cytokine signaling within the adventitial layer, and extracellular matrix (ECM) remodeling throughout the vein wall. Subsequent snRNA-seq analysis supported these findings and further unveiled distinct EC and FB subpopulations with significant upregulation (P < 0.00001) of markers related to endothelial injury response and cellular activation of ECs, FBs, and VSMCs. Similarly, in vein grafts obtained 24 hours after arterial bypass, there was an increase in myeloid cell, protomyofibroblast, injury-response EC, and mesenchymal-transitioning EC subpopulations with a concomitant decrease in homeostatic ECs and fibroblasts. Among these markers were genes previously implicated in vein graft injury, including VCAN (versican), FBN1 (fibrillin-1), and VEGFC (vascular endothelial growth factor C), in addition to novel genes of interest such as GLIS3 (GLIS family zinc finger 3) and EPHA3 (ephrin-A3). These genes were further noted to be driving the expression of genes implicated in vascular remodeling and graft failure, such as IL-6, TGFBR1, SMAD4, and ADAMTS9. By integrating the ST and snRNA-seq datasets, we highlighted the spatial architecture of the vein graft following distension, wherein activated and mesenchymal-transitioning ECs, myeloid cells, and FBs were notably enriched in the intima and media of distended veins. Lastly, intercellular communication network analysis unveiled the critical roles of activated ECs, mesenchymal transitioning ECs, protomyofibroblasts, and VSMCs in upregulating signaling pathways associated with cellular proliferation (MDK, PDGF, VEGF), transdifferentiation (Notch), migration (ephrin, semaphorin), ECM remodeling (collagen, laminin, fibronectin), and inflammation (thrombospondin), following distension. ConclusionsVein conduit harvest and distension elicit a prompt genomic response facilitated by distinct cellular subpopulations heterogeneously distributed throughout the vein wall. This response was found to be further exacerbated following vein graft implantation, resulting in a cascade of maladaptive gene regulatory networks. Together, these results suggest that distension initiates the upregulation of pathological pathways that may ultimately contribute to bypass graft failure and presents potential early targets warranting investigation for targeted therapies. This work highlights the first applications of single-nuclei and spatial transcriptomic analyses to investigate venous pathologies, underscoring the utility of these methodologies and providing a foundation for future investigations.

genomics↗

bioRxiv2023

A deep population reference panel of tandem repeat variation

Tandem repeats (TRs) represent one of the largest sources of genetic variation in humans and are implicated in a range of phenotypes. Here we present a deep characterization of TR variation based on high coverage whole genome sequencing from 3,550 diverse individuals from the 1000 Genomes Project and H3Africa cohorts. We develop a method, EnsembleTR, to integrate genotypes from four separate methods resulting in high-quality genotypes at more than 1.7 million TR loci. Our catalog reveals novel sequence features influencing TR heterozygosity, identifies population-specific trinucleotide expansions, and finds hundreds of novel eQTL signals. Finally, we generate a phased haplotype panel which can be used to impute most TRs from nearby single nucleotide polymorphisms (SNPs) with high accuracy. Overall, the TR genotypes and reference haplotype panel generated here will serve as valuable resources for future genome-wide and population-wide studies of TRs and their role in human phenotypes.

genomics↗

bioRxiv2022

Variable Number Tandem Repeats (VNTRs) as modifiers of breast cancer risk in carriers of BRCA1 185delAG

Despite substantial efforts in identifying both rare and common variants affecting disease risk, in the majority of diseases, a large proportion of unexplained genetic risk remains. We propose that variable number tandem repeats (VNTRs) may explain a proportion of the missing genetic risk. Herein, we tested whether VNTRs are causal modifiers of breast cancer risk in 347 female carriers of BRCA1 185delAG, an important group given their high risk of developing breast cancer. We performed targeted-capture to sequence VNTRs, called genotypes with adVNTR, and tested the association of VNTRs and breast cancer risk using Cox regression models. Of 303 VNTRs that passed quality control checks, 4 VNTRs were significantly associated with risk to develop breast cancer at false discovery rate [FDR] < 0.05 and an additional 4 VNTRs had FDR < 0.25. After determining the specific risk alleles, there was a significantly earlier age at development of breast cancer in carriers of the risk genotypes compared to those without the risk genotypes for seven of eight VNTRs. Results from this first systematic study of VNTRs demonstrate that VNTRs may explain a proportion of the unexplained genetic risk for disease and have larger effects than SNPs.

cancer biology↗

bioRxiv2020

Variable Number Tandem Repeats mediate the expression of proximal genes

Variable Number Tandem Repeats (VNTRs) account for a significant amount of human genetic variation. VNTRs have been implicated in both Mendelian and Complex disorders, but are largely ignored by whole genome analysis pipelines due to the complexity of genotyping and the computational expense. We describe adVNTR-NN, a method that uses shallow neural networks for fast read recruitment. On 55X whole genome data, adVNTR-NN genotyped each VNTR in less than 18 cpu-seconds, while maintaining 100% accuracy on 76% of VNTRs. We used adVNTR-NN to genotype 10,264 VNTRs in 652 individuals from the GTEx project and associated VNTR length with gene expression in 46 tissues. We identified 163 eVNTR loci that were significantly associated with gene expression. Of the 22 eVNTRs in blood where independent data was available, 21 (95%) were replicated in terms of significance and direction of association. 49% of the eVNTR loci showed a strong and likely causal impact on the expression of genes and 80% had maximum effect size at least 0.3. The impacted genes have important role in complex phenotypes including Alzheimers, obesity and familial cancers. Our results point to the importance of studying VNTRs for understanding the genetic basis of complex diseases.

genomics↗

bioRxiv2019

Genotypic Variation in Below- to Aboveground Systemic Induction of Glucosinolates Mediates Plant Fitness Consequences under Herbivore Attack

Plants defend themselves against herbivore attack by constitutively producing toxic secondary metabolites, as well as by inducing them during herbivore feeding. Induction of secondary metabolites can cross plant tissue boundaries, such as from root to shoot. However, whether the potential for plants to systemically induce secondary metabolites from roots to shoots shows genetic variability, and thus, potentially, is under selection conferring fitness benefits to the plants is an open question. To address this question, we induced 26 maternal plant families of the wild species Cardamine hirsuta belowground (BG) using the wound-mimicking phytohormone jasmonic acid (JA). We measured resistance against a generalist (Spodoptera littoralis) and a specialist (Pieris brassicae) herbivore species, as well as the production of glucosinolates (GSLs) in plants. We showed that BG induction increased AG resistance against the generalist but not against the specialist, and found substantial plant family-level variation for resistance and GSL induction. We further found that the systemic induction of several GSLs tempered the negative effects of herbivory on total seed set production. Using a widespread natural system, we thus confirm that BG to AG induction has a strong genetic component, and it can be under positive selection by increasing plant fitness. We suggest that natural variation in systemic induction is in part dictated by allocation trade-offs between constitutive and inducible GSL production, as well as natural variation in AG and BG herbivore attack in nature.

ecology↗

bioRxiv2018

Reconstructing and characterizing focal amplifications in cancer using AmpliconArchitect

Focal oncogene amplification and rearrangements drive tumor growth and evolution in multiple cancer types. We developed a tool, AmpliconArchitect (AA), which can robustly reconstruct the fine structure of focally amplified regions using whole genome sequencing. AA-reconstructed amplicons in pan-cancer data and in virus-driven cervical cancer samples revealed many novel insights about focal amplifications. Specifically, the findings lend support to extrachromosomally mediated mechanisms for copy number expansion, and oncoviral pathogenesis.

bioinformatics↗

bioRxiv2017

Targeted Genotyping of Variable Number Tandem Repeats with adVNTR

Whole Genome Sequencing is increasingly used to identify Mendelian variants in clinical pipelines. These pipelines focus on single nucleotide variants (SNVs) and also structural variants, while ignoring more complex repeat sequence variants. We consider the problem of genotyping Variable Number Tandem Repeats (VNTRs), composed of inexact tandem duplications of short (6-100bp) repeating units. VNTRs span 3% of the human genome, are frequently present in coding regions, and have been implicated in multiple Mendelian disorders. While existing tools recognize VNTR carrying sequence, genotyping VNTRs (determining repeat unit count and sequence variation) from whole genome sequenced reads remains challenging. We describe a method, adVNTR, that uses Hidden Markov Models to model each VNTR, count repeat units, and detect sequence variation. adVNTR models can be developed for short-read (Illumina) and single molecule (PacBio) whole genome and exome sequencing, and show good results on multiple simulated and real data sets. adVNTR is available at https://github.com/mehrdadbakhtiari/adVNTR

bioinformatics↗

bioRxiv2017

Fine-mapping the Favored Mutation in a Positive Selective Sweep

Methods to identify signatures of selective sweeps in population genomics data have been actively developed, but mostly do not identify the specific mutation favored by the selective sweep. We present a method, iSAFE, that uses a statistic derived solely from population genetics signals to pinpoint the favored mutation even when the signature of selection extends to 5Mbp. iSAFE was tested extensively on simulated data and in human populations from the 1000 Genomes Project, at 22 loci with previously characterized selective sweeps. For 14 of the 22 loci, iSAFE ranked the previously characterized candidate mutation among the 13 highest scoring (out of [~] 21, 000 variants). Three loci did not show a strong signal. For the remaining loci, iSAFE identified previously unreported mutations as being favored. In these regions, all of which involve pigmentation related genes, iSAFE identified identical selected mutations in multiple non-African populations suggesting an out-of-Africa onset of selection. The iSAFE software can be downloaded from https://github.com/alek0991/iSAFE.

evolutionary biology↗