Biology subjects

Rehman, A.

Publications and source records attributed to Rehman, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Microbial valerate is associated with CAR T dysbiosis and its supplementation enhances CAR T function in B-cell lymphoma

Anaerobe-depleting antibiotic exposure is associated with inferior progression-free survival after CD19 CAR T-cell therapy in large B-cell lymphoma, yet the cellular mechanisms linking gut dysbiosis to the CAR T-cell product and whether this imprint is reversible have remained undefined. In two independent CAR-T candidate cohorts, low stool valerate at the time of CAR-T eligibility identified a multi-metabolite-deficient dysbiotic gut microbiome state marked by depletion of fiber-fermenting commensals and loss of carbohydrate-fermentation, SCFA-biosynthesis, and amino-acid metabolism pathways. Reanalysis of single-cell RNA sequencing from 42 lymphoma patients stratified by piperacillin-tazobactam/imipenem/meropenem (PIM) exposure revealed that PIM-exposed CAR T-cell products were CD4-skewed, with significantly elevated AP-1/immediate-early gene (IEG) and cellular activation signatures that together predicted inferior progression-free survival. Ex vivo conditioning of CAR T-cells with valerate produced a chromatin and transcription factor program distinct from butyrate or propionate, characterized by KLF/SP/EGR family engagement, KLF4 promoter opening, and broad induction of AP-1/IEG and MHC class II transcripts, whereas butyrate drove broader chromatin remodeling with TBX21/EOMES/NF-{kappa}B gains and KLF2 promoter closure, and propionate induced an NFY-centered program with preferential commitment to low-mitochondrial-content states. Untargeted metabolomics confirmed valerate uptake and mitochondrial {beta}-oxidation in CAR T-cells, while dietary sodium valerate supplementation in meropenem-treated mice bearing A20 lymphoma significantly reduced tumor burden and extended survival compared with CAR T-cells alone. These findings identify stool valerate as a bedside-deployable biomarker of dysbiosis-imprinted CAR T-cell dysfunction and support ex vivo or dietary valerate supplementation as a clinically tractable strategy to improve CAR-T anti-tumor function in patients with disrupted gut microbiomes.

cancer biology↗

bioRxiv2026

Colon-delivered multivitamin supplementation enhances working memory-related fMRI responses in older adults: a randomized, placebo-controlled trial

BackgroundVitamins are important modulators of intestinal health and may affect the gut-brain axis through microbial metabolites such as short-chain fatty acids (SCFAs). However, the neurocognitive effects of colon-delivered vitamins in older adults remain unexplored - a critical gap given the gut-brain axiss emerging role in cognitive aging. ObjectiveWe investigated the effect of a colon-delivered multivitamin (CDMV) supplement on intestinal health and neurocognitive outcomes in older adults at risk of cognitive decline. MethodsWithin the double-blind randomized placebo-controlled trial COMBI (ClinicalTrials.govID: NCT05675007), we included 75 older adults (60-75 years) at risk of cognitive decline based on lifestyle-related factors. Participants consumed a colon-delivered capsule with vitamins B2, B3, B6, B9, C and D3, or a placebo, daily for six weeks. Pre- and post-intervention, we employed neuroimaging, feces- and blood collection. Primary outcomes were fecal SCFA concentrations, working memory (WM)-related fMRI responses, and WM performance measured with the n-back task. ResultsAfter adjusting for baseline values, we found no significant between-group differences in total fecal SCFA levels (p=0.30) and WM performance (p=0.50). Post-intervention WM-related fMRI responses in the hippocampus (p=0.01; p{superscript 2}=0.09) and dorsolateral prefrontal cortex (dlPFC) (p=0.06; p{superscript 2}=0.04), driven by the right dlPFC (p=0.02), were higher in the CDMV group compared to placebo. Independent of intervention group, post-pre increases in fecal SCFA levels were significantly correlated to increases in dlPFC fMRI responses ({rho}=0.31; p=0.02) and WM performance ({rho}=0.43; p=0.001). ConclusionsOur findings suggest that CDMV supplementation increases WM-related responses of the dlPFC and hippocampus in older adults, but this effect was not accompanied by changes in fecal SCFA levels or WM performance. The positive correlation of within-subject changes in fecal SCFAs with changes in WM dlPFC responses and performance across intervention groups provides human evidence for gut-brain communication in cognitive aging beyond cross-sectional associations.

neuroscience↗

bioRxiv2025

Enteropathogenic Escherichia coli manipulates the host exocyst complex to enhance pedestal formation

Enteropathogenic Escherichia coli (EPEC), a major cause of diarrheal disease, produces plasma membrane pedestals that promote colonization of host cells. Critical for pedestal formation is EPECs type III secretion system, which injects [~] 20 effector proteins into human cells. One of these effectors is Tir, which inserts into the host plasma membrane and stimulates the assembly of actin filaments essential for pedestal generation. To date, actin polymerization is the only host process known to contribute to pedestal formation. Here we report that EPEC co-opts the membrane trafficking pathway of polarized exocytosis, which acts together with actin polymerization to allow the efficient production of pedestals. Polarized exocytosis is mediated by the exocyst -- a human octameric complex that uses intracellular vesicles to expand the plasma membrane. We found that EPEC stimulated exocytosis at sites of pedestal formation in a manner dependent on the exocyst. The bacterial effector EspH recruited the exocyst and promoted exocytosis. Genetic inactivation of espH or RNA interference (RNAi)-induced depletion of exocyst components reduced both the frequency and size of pedestals. Additional RNAi experiments indicated that the exocyst is dispensable for actin filament assembly in pedestals. Co-depletion of components of the exocyst and the Arp2/3 complex showed that exocytosis and actin polymerization make additive contributions to pedestal formation. Collectively, these results indicate that exocyst-mediated expansion of the plasma membrane acts together with actin polymerization to optimize the generation of pedestals. IMPORTANCEEnteropathogenic E. coli (EPEC) induces the formation of host cell plasma membrane protrusions called "pedestals" that mediate tight adherence to intestinal epithelial cells. Substantial evidence indicates that the generation of pedestals requires bacterial-induced polymerization of the host cell actin cytoskeleton. However, it remains unknown if EPEC manipulates other human processes to augment the efficiency of pedestal generation. The significance of this research is to demonstrate that EPEC co-opts a second host process called polarized exocytosis to increase the frequency of pedestals and the size of these structures. EPEC induces exocytosis by using its effector protein EspH to recruit the human exocyst complex, which mediates the insertion of membrane at sites of bacterial attachment. Our results demonstrate EPECs ability to coordinate host membrane trafficking with cytoskeletal changes to enhance infection. Remarkably, EPEC shares this strategy with the intracellular bacterial pathogens Listeria monocytogenes and Shigella flexneri.

microbiology↗

bioRxiv2025

Novel Gain of Function Mouse Model of KCNT1-Related Epilepsy

KCNT1-related epilepsy is an autosomal dominant neurodevelopmental disorder with at least 64 known human variants, each with unique electrophysiological and epileptic characteristics. A multi-disciplinary collaboration generated a novel mouse model (C57BL/6-Kcnt1em1Bryd) carrying the G269S variant, corresponding to human G288S, located within the coding region of the channel pore. Network excitability of cultured cortical neurons from Kcnt1+/G269S exhibited sustained hyperexcitability and hypersynchronous bursting while Kcnt1G269S/G269S neurons showed early excessive bursting followed by network collapse, suggesting excitotoxicity. Kcnt1+/G269S displayed poor motor coordination, erratic breathing, and increased apneas. Critically, Kcnt1+/G269S were more susceptible to thermal-induced seizures in early life. In summary, these data: (i) provide a novel mouse model of KCNT1-related epilepsy, (ii) provide strong in vitro evidence of neuronal hyperexcitability, (iii) illustrate early-life seizures as a functional outcome measure, and (iv) lay the groundwork for future analysis of neural activity in vivo and modeling circuit level dynamics in vitro and in silico. Significance StatementGain-of-function mutations in the sodium-gated potassium channel KCNT1 have been linked to pediatric epilepsy of varying severity. The human KCNT1 variant G288S (G269S in mice) is linked to Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE), Epilepsy of Infancy with Migrating Focal Seizures (EIMFS), and other severe developmental epileptic encephalopathies. There are currently no therapeutics to prevent the progression of KCNT1-related epilepsy, therefore, the scientific community requires a novel mouse model that is well characterized, in vitro and in vivo, to screen and assess targeted therapeutics. Herein, we engineered a novel mouse to assess developmental and adult phenotypes resulting from the G288S/G269S variant, in vitro and in vivo, to advance translation toward therapeutic testing for individuals with KCNT1-related epilepsy.

neuroscience↗

bioRxiv2025

Cell-specific RNA isoform remodeling in the aging mouse brain

Aging is associated with increases in risk of multiple chronic diseases and at the cellular level, with disruptions in RNA homeostasis. Single-cell transcriptomic studies have revealed RNA abundance heterogeneity across brain cell types but the more complex changes in RNA processing such as alternative splicing, isoform usage, transcription start and polyadenylation site selection remain uncharacterized. Here, we combine single-cell analysis with long-read nanopore sequencing to capture full-length RNA isoforms and uncover temporal changes in RNA transcription, processing, and alternative splicing in the aging mouse cortex and hippocampus. By profiling transcriptomes from young adult to very old mice, we identify non-linear, cell-type-specific isoform expression changes and isoform usage shifts, primarily driven by transcription start site selection. These aging-associated isoform changes alter the coding potential and poly(A) site position of genes. Our data also reveal a high proportion of senescence in immune cells, far exceeding that of other cell types. We also identify isoform markers that, when applied to a machine learning model, distinguish senescent from normal immune cells. This study provides a full-length RNA isoform-based atlas of the aging mouse brain, offering insights into RNA metabolism remodeling across brain cell types throughout the lifespan.

genomics↗

bioRxiv2025

Excess prenatal folic acid supplementation alters cortical gene expression networks and electrophysiology

Folate is crucial for various biological processes, with deficiencies during pregnancy being linked to increased risk for neural tube defects and neurodevelopmental disorders. As a proactive measure, folic acid fortification in foods has been mandated in many countries, in addition to dietary supplementation recommendations during pregnancy. However, the risks of excess prenatal folic acid supply have yet to be fully understood. To better appreciate in utero molecular changes in mouse brain exposed to 5-fold folic acid excess over normal supplementation, we investigated the transcriptome and methylome for alterations in gene networks. RNA-seq analysis of cerebral cortex collected at birth, revealed significant expression differences in 646 genes with major roles in protein translation. Whole genome bisulfite sequencing revealed 910 significantly differentially methylated regions with functions enriched in glutamatergic synapse and glutathione pathways. To explore the physiological consequences of excess prenatal folic acid exposure, we applied high-density microelectrode arrays to record network-level firing patterns of dissociated cortical neurons. Folic acid excess-derived cortical neurons exhibited significantly altered network activity, characterized by reduced burst amplitude and increased burst frequency, indicating compromised network synchronization. These functional deficits align with the observed molecular alterations in glutamatergic synapse pathways, underscoring the potential for excess prenatal folic acid exposure to disrupt developing metabolic and neurological pathways.

neuroscience↗

bioRxiv2025

DNA Methylation Dynamics of Dose-dependent Acute Exercise, Training Adaptation, and Detraining

Exercise and diet are direct physical contributors to human health, wellness, resilience, and performance1-5. Endurance and resistance training are known to improve healthspan through various biological processes such as mitochondrial function6-8, telomere maintenance9, and inflammaging10. Although several training prescriptions have been defined with specific merits 1,10-20, the long-term effects of these in terms of their molecular alterations have not yet been well explored. In this study, we focus on two combined endurance and resistance training programs: (1) traditional moderate-intensity continuous endurance and resistance exercise (TRAD) and (2) a variation of high-intensity interval training (HIIT) we refer to as high intensity tactical training (HITT), to assess the dynamics of DNA methylation (DNAm) in blood and muscle derived from males (N=23) and females (N=31), over a 12-week period of training followed by a 4-week period of detraining, sampled at pre-exercise and acute time points, totaling 528 samples. Due to its rapid responsiveness to stimuli and its stability, DNAm has been known to facilitate regulatory cascades that significantly affect various physiological processes and pathways. We find that several thousand differentially methylated regions (DMRs) associated with acute exercise in blood, many of which are shared across males and females. This trend is reversed when comparing the baseline (pre-exercise) time points or post-exercise timepoints at the untrained state with those at the post-conditioned state. Here, muscle shows majority of DNAm changes, with most of those being unique. We also find several hundred "memory" DMRs in muscle that maintain the gain or loss of methylation after four weeks of inactivity. Comparing phenotypic measurements, we find specific DMRs that correlate significantly with mitochondrial function and myofiber switching. Using machine learning, we select a subset of DMRs that are most characteristic of training modalities, sex and timepoint. Most of the DMRs are enriched in pathways associated with immune function, cell differentiation, and exercise adaptation. These findings reveal mechanisms by which exercise- and training-induced epigenetic changes alter immune surveillance, mitochondrial function, and inflammatory response, and underscore the relevance of epigenetic plasticity to health monitoring and wellness.

genomics↗

bioRxiv2025

Human Milk Oligosaccharides Modulate Inflammatory Responses and Lipid Metabolism in a Human Intestinal Organoid Model

Human milk oligosaccharides (HMOs) are a major component of human breast milk and have significant protective effects on infant gut health. HMOs are also present in the amniotic fluid surrounding the developing fetus in the womb. Beginning at 10 weeks of gestational age, HMOs enter the fetal gut through the swallowing of amniotic fluid. The effects of this earliest exposure to HMOs on the gut epithelium, which pre-term infants partially miss, remains unknown. In this study, we investigate the effect of a blend of HMOs, including 2-fucosyllactose (2FL), 3-sialyllactose (3SL), and difucosyllactose (DFL), on intestinal epithelial cells, examining their role in steady-state conditions and during inflammation. By utilizing advanced intestinal epithelial organoid models derived from fetal and pediatric donors, we reveal developmental-stage-specific responses to this HMO blend, as well as its potential to mitigate inflammatory damage. These findings offer important insights into the role of HMOs in early-life nutrition and gut health, lending compelling evidence to support their inclusion in infant nutrition strategies.

cell biology↗

bioRxiv2025

Interactive effect of Moringa oleifera mediated green nanoparticles and arbuscular mycorrhizal fungi on growth, root system architecture, and nutrient uptake in maize (Zea mays L.)

The synergistic interaction between green nanoparticles (NPs) and mycorrhizal fungi promotes plant growth by improving nutrient absorption, optimizing root function, and stress resistance. In this study, we explored the impact of arbuscular mycorrhizal fungus (AMF) Funnaliformis mosseae and Moringa oleifera mediated green NPs viz; iron oxide (FeO), zinc oxide (ZnO), and Zn doped FeO (Zn/Fe) NPs, both individually and in combination, on maize growth, root system architecture, organic acids production, mycorrhizal colonization, and nutrients uptake. Prior to NP synthesis, metabolomic analysis of Moringa oleifera leaves was conducted to characterize its bioactive compounds. The structural properties of green synthesized NPs confirmed by characterization using scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, UV-Vis spectrophotometry, and X-ray diffraction (XRD). The results showed that all individual and combined treatments of AMF and green NPs significantly enhanced maize growth compared to the control. Among the single NP treatments, Zn/Fe NPs exhibited superior performance over FeO and ZnO. However, when combined with AMF, ZnO and Zn/Fe NPs induced the highest growth responses than FeO NPs. The ZnO NPs proved most compatibility with AMF for improving colonization in maize roots, whereas FeO and Zn/Fe NPs reduced colonization efficiency. Furthermore, combination of AMF and ZnO NPs (AMF+ ZnO) noted as most prominent treatment for improvement of maize growth compared to other all treatments, highlighting the potential of AMF+ ZnO NPs for sustainable agricultural applications.

plant biology↗

bioRxiv2024

Structural serology of polyclonal antibody responses to mRNA-1273 and NVX-CoV2373 COVID-19 vaccines

Current COVID-19 vaccines are largely limited in their ability to induce broad, durable immunity against emerging viral variants. Design and development of improved vaccines utilizing existing platforms requires an in-depth understanding of the antigenic and immunogenic properties of available vaccines. Here we examined the antigenicity of two of the original COVID-19 vaccines, mRNA-1273 and NVX-CoV2373, by electron microscopy-based polyclonal epitope mapping (EMPEM) of serum from immunized non-human primates (NHPs) and clinical trial donors. Both vaccines induce diverse polyclonal antibody (pAb) responses to the N-terminal domain (NTD) in addition to the receptor-binding domain (RBD) of the Spike protein, with the NTD supersite being an immunodominant epitope. High-resolution cryo-EMPEM studies revealed extensive pAb responses to and around the supersite with unique angles of approach and engagement. NTD supersite pAbs were also the most susceptible to variant mutations compared to other specificities, indicating that ongoing Spike ectodomain-based vaccine design strategies should consider immuno-masking this site to prevent induction of these strain-specific responses.

immunology↗

bioRxiv2024

Advancing White Blood Cell Detection: A Multi-Domain Dataset for Morphological Analysis and Addressing Sparse Annotation Challenges

Leukemia is 10th most frequently diagnosed cancer and one of the leading causes of cancer-related deaths worldwide. Realistic analysis of Leukemia requires White Blook Cells (WBC) localization, classification, and morphological assessment. Despite deep learning advances in medical imaging, leukemia analysis lacks a large, diverse multi-task dataset, while existing small datasets lack domain diversity, limiting real-world applicability. To overcome dataset challenges, we present a large-scale WBC dataset named Large Leukemia Dataset (LLD) and novel methods for detecting WBC with their attributes. Our contribution here is threefold. First, we present a large-scale Leukemia dataset collected through Peripheral Blood Films (PBF) from several patients, through multiple microscopes, multi-cameras, and multi-magnification. To enhance diagnosis explainability and medical expert acceptance, each leukemia cell is annotated at 100x with 7 morphological attributes, ranging from Cell Size to Nuclear Shape. Secondly, we propose a multi-task model that not only detects WBCs but also predicts their attributes, providing an interpretable and clinically meaningful solution. Third, we propose a method for WBC detection with attribute analysis using sparse annotations. This approach reduces the annotation burden on hematologists, requiring them to mark only a small area within the field of view. Our method enables the model to leverage the entire field of view rather than just the annotated regions, enhancing learning efficiency and diagnostic accuracy. From diagnosis explainability to overcoming domain-shift challenges, presented datasets could be used for many challenging aspects of microscopic image analysis. The datasets, code, and demo are available at: https://im.itu.edu.pk/sparse-leukemiaattri/.

pathology↗

bioRxiv2024

Single-dose avian influenza A(H5N1) Clade 2.3.4.4b hemagglutinin-Matrix-M nanoparticle vaccine induces neutralizing responses in nonhuman primates

With the recent rise in cases of highly pathogenic avian influenza (HPAI) A(H5N1) clade 2.3.4.4b infection in humans and animals, there is an associated increase in the risk of human-to-human transmission. In this study, we characterize recombinant A(H5N1) A/American Wigeon/South Carolina/22/000345-001/2021 (A/AW/SC/2021) clade 2.3.4.4b vaccine. Purified recombinant A/AW/SC/2021 HA trimers upon formulation with Matrix-M adjuvant, saponin-cholesterol-phospholipid icosahedral particles, non-covalently anchored to the vertices of the Matrix-M forming A(H5N1) HA-Matrix-M nanoparticles (H5-MNPs). In naive mice, two intranasal (IN) or intramuscular (IM) doses of A/AW/SC/2021 H5-MNP vaccine induced robust antibody- and cell-mediated immune responses, including neutralizing antibodies against A(H5N1). In non-human primates (NHPs) primed with seasonal influenza vaccine, a single IM or IN dose of the A/AW/SC/2021 H5-MNP vaccine induced geometric mean serum A(H5N1) clade 2.3.4.4b pseudovirus neutralizing titers of 1:1160 and 1:54, respectively; above the generally accepted seroconverting neutralizing titer of 1:40. Immunization with H5-MNP vaccine induced antibody responses against conserved epitopes in the A(H5N1) HA stem, vestigial esterase subdomain, and receptor binding site. This novel A(H5N1) H5-MNP IN and IM vaccine was immunogenic in rodents and NHPs as a potential A(H5N1) pandemic single-dose vaccine.

microbiology↗

bioRxiv2024

The host GTPase Dynamin 2 modulates apical junction structure to control cell-to-cell spread of Listeria monocytogenes

The food-borne pathogen Listeria monocytogenes uses actin-based motility to generate plasma membrane protrusions that mediate the spread of bacteria between host cells. In polarized epithelial cells, efficient protrusion formation by Listeria requires the secreted bacterial protein InlC, which binds to a carboxyl-terminal Src Homology 3 (SH3) domain in the human scaffolding protein Tuba. This interaction antagonizes Tuba, thereby diminishing cortical tension at the apical junctional complex and enhancing L. monocytogenes protrusion formation and spread. Tuba contains five SH3 domains apart from the domain that interacts with InlC. Here we show that the human GTPase Dynamin 2 associates with two SH3 domains in the amino terminus of Tuba and acts together with this scaffolding protein to control spread of L. monocytogenes. Genetic or pharmacological inhibition of Dynamin 2 or knockdown of Tuba each restored normal protrusion formation and spread to a bacterial strain deleted for the inlC gene ({Delta}inlC). Dynamin 2 localized to apical junctions in uninfected human cells and to protrusions in cells infected with Listeria. Localization of Dynamin 2 to junctions and protrusions depended on Tuba. Knockdown of Dynamin 2 or Tuba diminished junctional linearity, indicating a role for these proteins in controlling cortical tension. Collectively, our results show that Dynamin 2 cooperates with Tuba to promote intercellular tension that restricts spread of {Delta}inlC Listeria. By expressing InlC, wild-type L. monocytogenes overcomes this restriction.

microbiology↗

bioRxiv2023

Intestinal epithelial Atg16l1 influences pregnancy-induced fecal microbiota shifts in mice

Throughout gestation, the female body undergoes a series of transformations, including profound alterations in intestinal microbial communities. Changes gradually increase towards the end of pregnancy and comprise reduced -diversity of microbial communities and an increased propensity for energy harvest. Despite the importance of the intestinal microbiota for the pathophysiology of inflammatory bowel diseases, very little is known about the relationship between these microbiota shifts and pregnancy-associated complications of the disease. Here, we explored the longitudinal dynamics of gut microbiota composition and functional potential during pregnancy and after lactation in Atg16l1{Delta}IECmice carrying an intestinal epithelial deletion of the Croh[n]s disease risk gene Atg16l1. Using 16S rRNA amplicon and shotgun metagenomic sequencing, we demonstrated divergent temporal shifts in microbial composition between Atg16l1 wildtype and Atg16l1{Delta}IECpregnant mice in trimester 3, which was validated in an independent experiment. Observed differences included microbial genera implicated in IBD such as Lachnospiraceae, Roseburia, Ruminococcus, and Turicibacter. Changes partially recovered after lactation. In addition, functional inference of metagenomic data suggest a reduced potential to biosynthesize mucosal protective polyamines and reduced capacity to metabolize acidic polysaccharides (ketogluconate metabolism). On the host side, we found that the immunological response of Atg16l1{Delta}IEC mice is characterized by higher colonic mRNA levels of TNFA, and CXCL1 in trimester 3 and a lower weight of offspring at birth. Understanding pregnancy-dependent microbiome changes in the context of IBD may constitute the first step in the identification of fecal microbial biomarkers and microbiota-directed therapies that could help improving precision care for managing pregnancies in IBD patients.

microbiology↗

bioRxiv2023

Senescence-specific translation dysregulation desensitizes cells to stress by inhibiting activation of the integrated stress response

Senescence is a state of indefinite cell cycle arrest associated with aging, cancer, and age-related diseases. Here, using label-based mass spectrometry, ribosome profiling and nanopore direct RNA sequencing, we explore the coordinated interaction of translational and transcriptional programs of human cellular senescence. We find that translational deregulation and a corresponding maladaptive integrated stress response (ISR) is a hallmark of senescence that desensitizes senescent cells to stress. We present evidence that senescent cells maintain high levels of eIF2 phosphorylation, typical of ISR activation, but translationally repress production of the stress response transcription factor 4 (ATF4) by ineffective bypass of the inhibitory upstream open reading frames. Surprisingly, ATF4 translation remains inhibited even after acute proteotoxic and amino acid starvation stressors, resulting in a highly diminished stress response. Furthermore, absent a response, stress augments the senescence secretory phenotype, thus intensifying a proinflammatory state that exacerbates disease. Our results reveal a novel mechanism that senescent cells exploit to evade an adaptive stress response and remain viable.

molecular biology↗

bioRxiv2021

The MAGOH paralogs - MAGOH, MAGOHB and their multiple isoforms

A central processing event in eukaryotic gene expression is splicing. Concurrent with splicing, the core-EJC proteins, eIF4A3 and RBM8A-MAGOH heterodimer are deposited 24 bases upstream of newly formed exon-exon junctions. One of the core-EJC proteins, MAGOH contains a paralog MAGOHB, and this paralog pair is conserved across vertebrates. Upon analysis of the splice variants of MAGOH-paralogs, we have found the presence of alternate protein isoforms which are also evolutionarily conserved. Further, comparison of the amino acid sequence of the principal and alternate protein isoforms has revealed absence of key amino acid residues in the alternate isoforms. The conservation of principal and alternate isoforms correlates to the importance of MAGOH and MAGOHB across vertebrates.

molecular biology↗

bioRxiv2021

TISON: a next-generation multi-scale modeling theatre for in silico systems oncology

Multi-scale models integrating biomolecular data from genetic, transcriptional, and translational levels, coupled with extracellular microenvironments can assist in decoding the complex mechanisms underlying system-level diseases such as cancer. To investigate the emergent properties and clinical translation of such cancer models, we present Theatre for in silico Systems Oncology (TISON, https://tison.lums.edu.pk), a next-generation web-based multi-scale modeling and simulation platform for in silico systems oncology. TISON provides a "zero-code" environment for multi-scale model development by seamlessly coupling scale-specific information from biomolecular networks, microenvironments, cell decision circuits, in silico cell lines, and organoid geometries. To compute the temporal evolution of multi-scale models, a simulation engine and data analysis features are also provided. Furthermore, TISON integrates patient-specific gene expression data to evaluate patient-centric models towards personalized therapeutics. Several literature-based case studies have been developed to exemplify and validate TISONs modeling and analysis capabilities. TISON provides a cutting-edge multi-scale modeling pipeline for scale-specific as well as integrative systems oncology that can assist in drug target discovery, repositioning, and development of personalized therapeutics.

systems biology↗

bioRxiv2020

Genome Wide Characterization, Identification And Expression Analysis Of Erf Gene Family In Cotton

ERF is a subfamily of AP2/EREBP superfamily, contained single AP2 domain. The overexpression of ERF genes steered to abiotic stress tolerance and pathogen resistance in transgenic plants. Here, a genome-wide analysis of ERF gene family within two diploid species (G. arboreum & G. raimondii) and two tetraploid species (G. barbadense, G. hirsutum) was performed. A total of 118, 120, 213, 220 genes contained sequence single AP2 domain were identified in G. arboreum, G. raimondii, G. barbadense and G. hirsutum respectively. The identified genes were unevenly distributed across 13/26 chromosomes of A and D genomes of cotton. Genome comparison revealed that segmental duplication may have played crucial roles in the expansion of the cotton ERF gene family, and tandem duplication also played a minor role. Analysis of RNA-Seq data indicated that cotton ERF gene expression levels varied across different tissues and in response to different abiotic stress. Overall, our results could provide valuable information for better understanding the evolution of cotton ERF genes and lays a foundation for future investigation in cotton.

bioinformatics↗