Biology subjects

Ali, S. A.

Publications and source records attributed to Ali, S. A..

15 recordsLinked to original sources

bioRxiv2026

Amino Acid Metabolic Signature Links Pediatric Environmental Enteric Dysfunction to Maternal-Fetal Growth Restriction Across Two Independent Cohorts

Environmental Enteric Dysfunction (EED) is a leading contributor to childhood stunting. Most EED literature derives from postnatal pediatric cohorts, leaving unclear how much of the metabolic signature reflects acquired intestinal pathology versus growth restriction originating earlier. We applied genome-scale metabolic modeling to explore whether metabolic features of pediatric EED overlap with those of maternal plasma proteomes associated with adverse early-life growth. Duodenal transcriptomics from the Study of Environmental Enteropathy and Malnutrition (SEEM; 52 children with EED, 24 controls) and maternal plasma proteomics from the Alliance for Maternal and Newborn Health Improvement (AMANHI; n = 2,485 pregnant women) were integrated with the Human1 model using Reaction Inclusion by Parsimony and Transcript Distribution (RIPTiDe), followed by flux sampling and Linear Discriminant Analysis, across five growth-related proxies (small-for-gestational-age, low birth weight, preterm birth, stunting, and wasting). Amino acid and nucleotide metabolism were prominent among the top discriminating reactions in EED and most proxies. Of the 50 reactions distinguishing EED from control, 24 (48%) were among the top reactions in at least one proxy, and 19 (38%) with low birth weight, the largest of any proxy. These exploratory findings suggest shared metabolic pathways across tissues and life stages and motivate longitudinal studies.

systems biology↗

bioRxiv2026

Safe Redosable Low-Immunogenic In Vivo CAR-T Therapy for B Cell Malignancies and Solid Tumors

In vivo CAR-T cell therapy eliminates manufacturing complexities associated with ex vivo autologous approaches, but safety concerns have limited adoption. We developed viroVbot, a next-generation in vivo CAR-T platform, by combining computational immunogenicity prediction (CIMMEXTM) with envelope engineering. Screening 22,562 glycoprotein sequences, we identified 641 vesiculovirus homologs, from which we selected Piry virus glycoprotein (PIRYV) as the optimal candidate. PIRYV exhibited lower MHC-epitope density, reduced human seroprevalence, with decreased T cell activation compared to VSV-G. To enhance targeting specificity, we engineered receptor-binding-deficient PIRYV (ePIRYVRBD) displaying CD3/CD7 nanobodies for T cell-selective transduction. To maximize safety, we engineered CAR-TRAP producer cells to eliminate unwanted B cell transduction and incorporated machine learning-optimized T cell-specific promoters that restrict CAR activation exclusively to lymphocytes. Additional modifications suppressed hepatocyte expression and prevented phagocytic uptake. In humanized xenograft models, viroVbot3 generated potent BCMA/CD19 specific CAR-T responses against multiple myeloma and Claudin18.2-targeting gastric cancer, demonstrating sequential redosing with alternative envelopes. Critically, viroVbot3 exhibited minimal off-target organ biodistribution with CAR expression restricted to T lymphocytes. These findings establish viroVbot as a low-immunogenic platform for scalable in vivo CAR-T manufacturing with capability for sequential redosing across hematologic and solid tumors.

bioengineering↗

bioRxiv2026

Omics-analyses of Fermented Onion pickle in Shaping Gut Microbiota and Immune Response in Women: A Community-Based Trial in Pakistan

A fermented-food intervention trial conducted in Pakistan suggested beneficial changes in the composition of the gut microbiota in healthy women. Using a subset (n=17) of the same participants, this study further investigates the impact of fermented food (onion pickle) on gene expression levels using RNA transcriptomics, with a focus on host-microbiome interactions. After consuming pickles (50g/day) for eight weeks, blood and stool samples of participants were collected at baseline and post-intervention to assess inflammatory markers, 16S rRNA gene sequencing, clinical parameters, and RNA sequencing. Among inflammatory biomarkers, lipocalin (LCN-2) levels significantly decreased (pre=86.5{+/-}80.1ng/mL, post=61.0{+/-}59.0 ng/mL, p=0.04, paired T-test). Additionally, the intervention downregulated pathways (p<0.05) involved host responses to microbial stimuli, including response to bacterial origin, chemotaxis, and response to lipopolysaccharide. In gut microbiota, observed -diversity significantly increased post-intervention (p=0.02). Linear discriminant analysis effect size (LEfSe) revealed differential expressions (LDA [≥] 2.0) of Olsenella and Coriobacteriales at week-8, where Olsenella sp. showed a significant negative correlation with LCN-2 (R=-0.36, p<0.05, Spearmans correlation). These findings suggest that fermented onion pickle consumption for eight weeks modestly alters gut microbial diversity and composition and is associated with reduced inflammatory markers and altered host immune-related gene expression, potentially improving intestinal health. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/711246v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@18679e0org.highwire.dtl.DTLVardef@1ab62eeorg.highwire.dtl.DTLVardef@ec318forg.highwire.dtl.DTLVardef@a9b94c_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Precision functional mapping reveals less inter-individual variability in the child vs. adult human brain

Human brain organization shares a common underlying structure, though recent studies have shown that features of this organization also differ significantly across individual adults. Understanding the developmental pathways that lead to individually unique brains is important for advancing models of cognitive development and neurodevelopmental disorders. Here we use highly personalized precision neuroimaging methods to map brain networks within 12 individual children, ages 8-12 years. We demonstrate fMRI functional connectivity maps that substantially exceed the reliability of traditional techniques, allowing us to measure individual differences after overcoming biases from measurement noise. Children share core functional network topography, with greatest inter-individual variability in association regions, consistent with adult findings. However, children show less between-subject variability than adults, suggesting increasing individual differentiation in brain networks with development. This pediatric precision neuroimaging dataset is publicly available to support future brain development research and provides a high-fidelity foundation for studying individual variation in atypical development.

neuroscience↗

bioRxiv2025

Treatment with the ribosome biogenesis inhibitor CX-5461 increases platelet count in humans and enhances murine megakaryopoiesis

Thrombocytopenia is a common and serious complication of anticancer therapies. Here, we identify a novel thrombopoietic activity of the first-in-class ribosome biogenesis inhibitor CX-5461. In a phase I trial, 56% (9/16) of patients exhibited up to a 34% increase in platelet count following a single dose of CX-5461. In mice, CX-5461 elicited a rapid, reversible, and sustained [~]1.7-fold increase in platelet numbers without altering platelet function, lifespan, or inflammatory cytokines. Bone marrow analysis revealed a specific expansion of megakaryocytes (MKs), increased Sca1 MKs, and selective enrichment of MK-biased multipotent progenitor 2, independent of thrombopoietin (TPO) or c-mpl signalling. CX-5461 also mitigated carboplatin-induced thrombocytopenia, accelerating platelet recovery. Single-cell RNA sequencing and RNA velocity analysis confirmed enhanced differentiation of MK progenitors. These findings demonstrate that inhibition of ribosome biogenesis promotes TPO-independent megakaryopoiesis and identifies a previously unrecognised therapeutic opportunity to support platelet recovery in cancer treatment and potentially other thrombocytopenic states.

cell biology↗

bioRxiv2025

E2F1 Suppresses EBV Lytic Reactivation through Cellular and Viral Transcriptional Networks

Latent EBV infection is causally associated with various B-cell malignancies, while periodic lytic-cycle replication is essential for sustaining viral progeny. Lytic cycle induction represents a promising therapeutic strategy for EBV-associated neoplasms. Therefore, uncovering the mechanisms that regulate EBV lytic-cycle reactivation is pivotal for understanding viral pathogenesis and advancing novel therapies. Our genome-wide transcriptomic analysis reveals that E2F1 expression is transcriptionally activated during EBV latent infection in B-lymphocytes but significantly suppressed during lytic cycle reactivation. While ectopic E2F1 expression suppresses lytic replication, E2F1 depletion markedly accelerates this process. Mechanistically, we establish that E2F1 and the lytic transactivator BZLF1 form a negative transcriptional feedback loop, tightly controlling viral lytic replication. Furthermore, E2F1 positively regulates c-Myc expression and together they repress the leaky BZLF1 expression during latency. Importantly, c-Myc does not influence E2F1 expression, nor does BZLF1 modulate c-Myc transcription, underlining a distinct regulatory hierarchy. In sum, our findings reveal that EBV tightly controls the latent-to-lytic switch through precise regulation of E2F1 expression, positioning E2F1 as a pivotal regulator of both cellular and viral gene expression. SynopsisEBV coordinates the latent-to-lytic switch by sensing E2F1 abundance, which acts as a crucial transcriptional regulator of both cellular and viral gene expressions. O_LIDuring EBV latent infection, E2F1 promotes c-Myc transcription, and together they suppress EBV lytic cycle transactivator BZLF1 expression. C_LIO_LIE2F1 and BZLF1 form a negative feedback loop in order to control each others transcriptions. C_LIO_LIBZLF1-driven controlled E2F1 expression successively inhibits c-Myc level, thereby stimulating EBV lytic cycle reactivation. C_LIO_LIBZLF1 does not regulate c-Myc, nor does c-Myc reciprocally regulate E2F1, emphasizing a unidirectional regulatory hierarchy. C_LI

cancer biology↗

bioRxiv2025

Interaction of Gut-Microbial Amyloids with Endogenous Amyloids can Drives Microglial Hyperactivity and Neuroinflammation in Alzheimers Disease

Gut bacteria have emerged as silent drivers in the pathology of Alzheimers disease (AD). They also make amyloids with structure analogue to pathological amyloids and have potential to cross-seed and propagate in a prion-like manner. AD is characterised by the accumulation of mature extracellular Amyloid-{beta} (A{beta}) plaques which are surrounded by inflammatory microglia. We report that exposure to interspecies microbial amyloids of FapC (fimbriae) and CsgA (curli) from opportunistic gut pathogens Pseudomonas aeruginosa and Escherichia coli hyperactivates microglia against A{beta} fibrils. Microbial amyloids and A{beta} fibrils converge in phagocytic compartments through subsequent internalization, not observed with A{beta} fibrils alone. This convergence promotes pro-inflammatory microglia with a defective proteome similar to those observed in AD brains. The resulting clusters develop a pro-inflammatory, indigestible interactome that is eventually regurgitated, inducing progressive degeneration in bystander neurons and ultimately leading to cognitive decline. Collectively, these findings provide compelling evidence that microbial amyloids can trigger progressive AD pathology through microglia-driven neuroinflammation.

cell biology↗

bioRxiv2024

Circulating miR-126-3p is a mechanistic biomarker for knee osteoarthritis

As a chronic joint disease, osteoarthritis (OA) is a major contributor to pain and disability worldwide, and yet there are currently no validated soluble biomarkers or disease-modifying treatments. Since microRNAs are promising mechanistic biomarkers that can be therapeutically targeted, we aimed to prioritize reproducible circulating microRNAs in knee OA. We performed secondary analysis on two microRNA-sequencing datasets and found circulating miR-126-3p to be elevated in radiographic knee OA compared to non-OA individuals. This finding was validated in an independent cohort (N=145), where miR-126-3p showed an area under the receiver operating characteristic curve of 0.91 for distinguishing knee OA. Measuring miR-126-3p in six primary human knee OA tissues, subchondral bone, fat pad and synovium exhibited the highest levels, and cartilage the lowest. Following systemic miR-126-3p mimic treatment in a surgical mouse model of knee OA, we found reduced disease severity. Following miR-126-3p mimic treatment in human knee OA tissue explants, we found direct inhibition of genes associated with angiogenesis and indirect inhibition of genes associated with osteogenesis, adipogenesis, and synovitis. These findings suggest miR-126-3p becomes elevated during knee OA and mitigates disease processes to attenuate severity.

molecular biology↗

bioRxiv2024

Enhanced feature matching in single-cell proteomics characterizes response to IFN-gamma and reveals co-existence of different cell states

Proteome analysis by data-independent acquisition (DIA) has become a powerful approach to obtain deep proteome coverage, and has gained recent traction for label-free analysis of single cells. However, optimal experimental design for DIA-based single-cell proteomics has not been fully explored, and performance metrics of subsequent data analysis tools remain to be evaluated. Therefore, we here present DIA-ME, a data analysis strategy that exploits the co-analysis of low-input samples with a so-called matching enhancer (ME) of higher input, to increase sensitivity, proteome coverage, and data completeness. We evaluate the matching specificity of DIA-ME by a two-proteome model, and demonstrate that false discovery and false transfer are maintained at low levels when using DIA-NN software, while preserving quantification accuracy. We apply DIA-ME to investigate the proteome response of U-2 OS cells to interferon gamma (IFN-{gamma}) in single cells, and recapitulate the time-resolved induction of IFN-{gamma} response proteins as observed in bulk material. Moreover, we observe co- and anti-correlating patterns of protein expression within the same cell, indicating mutually exclusive protein modules and the co-existence of different cell states. Collectively our data show that DIA-ME is a powerful, scalable, and easy-to- implement strategy for single-cell proteomics.

systems biology↗

bioRxiv2022

Comparative Study between In-silico and Clinical Works on the Control of Blood Glucose Level in People with Type 1 Diabetes using Improved Hovorka Equations

BackgroundHovorka model is one of the diabetic models which is widely used in the artificial pancreas device (APD) also known as closed loop system, meant for people with type 1 diabetes (T1D). Previous workers had modified some equations in the sub-sections of the Hovorka model, which is also known as improved Hovorka equations, in regulating the blood glucose level (BGL) within normoglycemic range (4.0 to 7.0 mmol/L). However, the improved Hovorka equations have not been tested yet in terms of its usability to regulate and control the BGL in safe range for two or more people with T1D. This study aims to simulate their BGL with meal disturbances for 24 hours using the improved Hovorka equations. MethodsData for people with T1D were obtained from Clinic 1, Clinical Training Centre (CTC), UiTM Medical Specialist Centre, Sungai Buloh, Selangor. Data collected include gender, age, body weight, mealtimes, meal amount, and duration. Three patients whose ages range from 11 to 14 years old were selected. All patients consumed three meals daily: breakfast, lunch, and dinner. The simulation (in-silico work) was done using MATLAB software, and the BGL profile from both in-silico and clinical works were compared and analysed. ResultsIt was revealed that the BGLs for all three people with T1D were far better in the in-silico work compared to the clinical work. The BGL for patient 1 was able to achieve normoglycaemia 73% of the time in the in-silico work. Meanwhile, patient 2 managed to stay in the normoglycemic range for 85% of the time in the in-silico work compared to clinical work, which was merely 31%. For Patient 3, the time duration spent in the normoglycemic range was only 16% in the in-silico work compared to none as in the clinical work. The p-values obtained in the study were less than 0.05, indicating that the in-silico work using the improved Hovorka equations was acceptable for predicting the BGL for people with T1D. ConclusionsIt can be concluded that the improved Hovorka equations are reliable in simulating the meal disturbances effect on BGL and increasing people in T1D times duration in the normoglycemic range compared to the clinical work.

systems biology↗

bioRxiv2022

Diverse transcriptomic response of cellular system following low-dose exposure of mesoporous nanoparticles

Mesoporous nanoparticles (NPs) are an interesting drug delivery system that has generated considerable attention in the biomedical sector. Despite recent attempts to conduct safety assessments using traditional methods based on phenotypic data, our understanding of the underlying molecular processes produced by mesoporous NPs is still in its infancy. In the present study, RNA sequencing was used to assess the biological perturbations and the pathways induced in response to early exposure of two different mesoporous NPs; mesoporous silica NPs (MSN) and mesoporous carbon NPs (MCN) in human liver hepatocellular carcinoma cells. In order to better understand the risks associated with NPs, it is required to consider the initial low-dose exposure effects that mimic the real exposure scenario. No overt toxicity was detected in the MTT assay when performed at 6 hours at low concentrations (MCN 25 g/ml and MSN 15 g/ml) of NPs; thus, we have selected this dose for RNA sequencing analysis. Our transcriptomics analysis showed significant differences in the expression of many genes after exposure to both NPs. Surprisingly, both NPs frequently deregulated 52.9 percent of upregulated and 42 percent of downregulated genes. Gene ontology categories, in particular, revealed comparable perturbations of biological reactions in the cellular system. HepG2 cells reacted to mesoporous NPs by allowing alterations in genes involved in cytoskeleton reorganisation (ATAT1, DMTN, PTK2 and PFN2). Exposure to mesoporous NPs increased transcripts expressing ubiquitin ligase (RNF187, ARIH2, VHL, and RAB40C), transferase (FBXO3 and WDSUB1), conjugating (UBE2J2), and also proteasomal subunits (PSMD2, PSMD13) enzymes, indicating that protein turnover rates are altered in response to environmental damage. In addition, DNA damage and DNA damage checkpoint genes were upregulated, indicating that NPs induced stress in the cells. These finding showed low dosage acute exposure have comparable responses between mesoporous NPs. These results may add further knowledge in conceptualization of Safer-by-Design strategy of NPs in biomedical field.

pharmacology and toxicology↗

bioRxiv2022

ZnO nanoparticles and SWCNT induced general stress response pathway in HepG2 cells at non-cytotoxic doses revealed by RNA sequencing

Nanoparticles (NPs) are important in a variety of sectors, including disease diagnostics, medicine, nutrition, and many other industries. The risk of human exposure demands an early evaluation of both the basic dynamics of NPs interaction with biological systems and their potential consequences. Deciphering these occurrences will provide critical information regarding the health hazards and safety advantages associated with next-generation nanoformulations in clinical practice. We examined the HepG2 cell line in a systematic manner to determine the cellular response to single-walled carbon nanotubes (SWCNTs) and zinc oxide (ZnO) NPs. With the use of high-throughput transcriptomic methods, we found that both NPs induce comparable dysregulation of the endocytic and proteasomal complex genes in liver hepatocellular carcinoma cells, at levels (> 80 percent cell viability) that do not cause over-toxicity at early incubation period (6 h). SWCNT and ZnO NPs were shown to enter cells through clathrin-mediated pathways, affecting cytoskeleton gene expression, DNA damage and repair, protein ubiquitination, and cell transcriptional machinery. Our findings indicate that early response strategies activate stress-related mechanisms. Finally, this method for studying nanomaterial-cell interactions demonstrates how changes in the transcriptome profile may predict downstream consequences even at doses that do not cause acute toxicity.

pharmacology and toxicology↗

bioRxiv2020

Control of Blood Glucose Level for Type 1 Diabetes Mellitus using Improved Hovorka Equations: Comparison between Clinical and In-Silico Works

BackgroundType 1 diabetes mellitus (T1DM) occurs due to inability of the body to produce sufficient amount of insulin to regulate blood glucose level (BGL) at normoglycemic range between 4.0 to 7.0 mmol/L. Thus, T1DM patients require to do self-monitoring blood glucose (SMBG) via finger pricks and depend on exogenous insulin injection to maintain their BGL which is very painful and exasperating. Ongoing works on artificial pancreas device nowadays focus primarily on a computer algorithm which is programmed into the controller device. This study aims to simulate so-called improved equations from the Hovorka model using actual patients data through in-silico works and compare its findings with the clinical works. MethodsThe study mainly focuses on computer simulation in MATLAB using improved Hovorka equations in order to control the BGL in T1DM. The improved equations can be found in three subsystems namely; glucose, insulin and insulin action subsystems. CHO intakes were varied during breakfast, lunch and dinner times for three consecutive days. Simulated data are compared with the actual patients data from the clinical works. ResultsResult revealed that when the patient took 36.0g CHO during breakfast and lunch, the insulin administered was 0.1U/min in order to maintain the blood glucose level (BGL) in the safe range after meal; while during dinner time, 0.083U/min to 0.1 U/min of insulins were administered in order to regulate 45.0g CHO taken during meal. The basal insulin was also injected at 0.066U/min upon waking up time in the early morning. The BGL was able to remain at normal range after each meal during in-silico works compared to clinical works. ConclusionsThis study proved that the improved Hovorka equations via in-silico works can be employed to model the effect of meal disruptions on T1DM patients, as it demonstrated better control as compared to the clinical works.

bioengineering↗

bioRxiv2020

Behavioral, Biochemical and Histopathological effects of Standardised Pomegranate extract with Vinpocetine, Propolis or Cocoa in a rat model of Parkinsons disease

Introduction Parkinsonism is a neurodegenerative disorder. Pomegranate (POM) has been previously shown to have a dopaminergic neuroprotective effect against Parkinsonism.Objective The aim of the current study is to compare the efficacy of POM, vinpocetine, Propolis, Cocoa or L-dopa using RT-induced Parkinsonism rat model.Methods Rats were divided into seven groups; one normal and five RT model groups. One of the RT (2.5 mg/kg sc) groups served as non-treated parkinsonism model whereas the others were treated with either L-dopa (10 mg/kg PO) or with POM (150 mg/kg PO) together with each of the following; vinpocetine (VIN) (20 mg/kg PO), Propolis (300 mg/kg PO), Cocoa (24 mg/kg PO). Motor and cognitive performances were examined using three tests (catalepsy, open-field, Y-maze). Striatal dopamine, norepinephrine, serotonin, acetylcholinesterase, GABA, Glutamate, GSK 3B, BDNF levels were assessed as well as MDA, SOD, TAC, IL-1β, TNF-α, iNOs and caspase-3. Also, histopathological examinations of different brain regions were determined.Results Treatment with L-dopa alone or with all POM combination groups alleviated the deficits in locomotor activities, cognition, monoamine levels, acetylcholinesterase activity, oxidative stress, and inflammatory markers as well as caspase-3 expression induced by RT.Conclusion Combinations of POM with each of VIN, Propolis or Cocoa have a promising disease-modifying antiparkinsonian therapy even without being given as an adjuvant to L-dopa.View Full Text

animal behavior and cognition↗

bioRxiv2018

Initial Sequencing and Characterization of Gastrointestinal and Oral Microbiota in Urban Pakistani Adults Reveals Abnormally High Levels of Potentially Starch Metabolizing Bacteria in the General Population

We describe the characterization of the gastrointestinal tract (gut) and oral microbiota (bacteria) in 32 urban Pakistani adults representing seven major geographies and six ethnicities in the country. Study participants were between ages 18 and 40, had body mass index between 18 and 25 Kg/m2, and were early-career students or professionals belonging to 25 major cities of the country. These individuals donated a total of 61 samples (32 gut and 29 oral) that were subjected to 16S ribosomal RNA (rRNA) gene sequencing. Microbiome composition of Pakistani individuals was compared against the uBiome database of selected individuals who self-reported to be in excellent health. Using the crude measure of percentage overlap or similarity between the gut microbiota profile of Pakistani and uBiome dataset as proxy for health, our sequencing indicated that the Pakistani gut microbiota was moderately healthy relative to the uBiome dataset and Pakistani women appeared healthier relative to men. The Pakistani gut microbiome seemed susceptible to obesity and weight gain, levels of probiotics was very high likely due to the popularity of milk-based and fermented foods in the Pakistani diet, and bacteria that metabolize starch and carbohydrates (typically seen in the gut microbiota of honey bee) were abnormally enriched in the gut of Pakistani men. Our investigations reveal serious issues with the dietary habits and lifestyle of Pakistani individuals of consuming food enriched in high carbohydrates and fats, overcooked in oil and spices, following a sedentary lifestyle, little or no daily intake of fresh fruits, over-consumption of antibiotics from a very early age, and health and hygiene standards that do not meet international standards. Our sequencing is the first step towards generating a country-wide understanding of the impact of the local diet and lifestyle on Pakistani gut microbiota and can help understand its overall association with health and wellness.

microbiology↗