Biology subjects

Mahmood, A.

Publications and source records attributed to Mahmood, A..

15 recordsLinked to original sources

bioRxiv2026

SARS-CoV-2 maturation driven by a mechano-active nucleocapsid-RNA condensate

The nucleocapsid (N) protein, the core component of the SARS-CoV-2 virus, binds to the 30-kb viral genomic RNA (vgRNA) to form ribonucleoprotein assemblies that are packaged into ~100 nm membrane-enclosed virions. In addition to viral assembly, the N protein performs other functions, including roles in viral mRNA transcription, replication, and immune regulation, making it a key target for developing diagnostics and vaccines. Recent studies show that N protein and RNA undergo phase separation to form a biomolecular condensate that constitutes the viral core. However, how this condensate becomes selectively enveloped by a membrane remains unclear. Here, using a minimal reconstituted system, we demonstrate that N protein-vgRNA condensates are spontaneously enveloped by lipid bilayer membranes, whereas condensates formed by N protein alone or with genomic RNA fragments fail to undergo envelopment and instead adhere to or weakly deform membranes. We show that RNA length tunes the material properties of N protein condensates, with vgRNA imparting enhanced elasticity. We propose a physical model for SARS-CoV-2 maturation in which adhesion between the membrane and the N protein-vgRNA condensate drives membrane bending, while condensate elasticity preserves core geometry. These results identify RNA-dependent material properties as an underlying physical principle for selective SARS-CoV-2 maturation.

biophysics↗

bioRxiv2026

Telomere Length as an Indicator of Lifestyle-Related Biological Aging in Hypertensive Adults: A Pilot Exploratory Study

BackgroundMultiple epidemiological studies have given a global perspective that hypertension leads to changes in telomere length (TL). This study aimed to investigate the association between leukocyte telomere length and lifestyle factors among individuals with hypertension, a family history of the disease and healthy controls. MethodsThis pilot exploratory cross-sectional study included 45 participants (n = 15 per group) divided into hypertensive, familial hypertensive, and control groups. Lifestyle behaviors were assessed using the FANTASTIC Lifestyle Checklist, evaluating domains such as physical activity, diet, sleep, and stress. Relative telomere length (T/S ratio) of leucocytes was measured from peripheral blood samples using quantitative real-time PCR (qPCR). Data were analyzed using SPSS software, with ANOVA, Kruskal-Wallis test, and multivariable linear regression applied for statistical analysis. ResultsRelative telomere length differed significantly among the study groups (p = 0.008), with hypertensive participants demonstrating the highest median telomere-to-single-copy gene (T/S) ratio (2.66), followed by familial hypertensive (1.25) and control participants (0.87). Total lifestyle scores also varied significantly across groups (p < 0.001), with hypertensive individuals exhibiting higher mean scores (77.07 {+/-} 5.59) than familial hypertensive (67.20 {+/-} 3.00) and control participants (67.07 {+/-} 5.97). A modest positive correlation was observed between total lifestyle score and relative telomere length (r = 0.329, p < 0.05), suggesting that healthier lifestyle behaviors in diagnosed hypertensive subjects following healthy lifestyles and regular medications were associated with longer telomeres. However, in multivariable linear regression analyses, lifestyle score, age, gender, hypertension status, and family history of hypertension were not independently associated with telomere length (all p > 0.05). ConclusionLifestyle scores were positively associated with telomeres, and significantly higher telomere ratios in hypertensive subjects suggest complex biological interactions that require further investigation through larger longitudinal studies in the target population.

Molecular Biology↗

bioRxiv2026

Stimulus-Specific and Generalized Taste Aversion Behaviors and Their Relationship to Cortical Dynamics

Aversive taste behaviors, such as gaping, are commonly viewed as fixed, hard-wired responses important for ejecting potentially toxic tastes from the mouth. Yet, taste responses are highly susceptible to modulation by experience and context; for instance, conditioned taste aversion (CTA), a form of learning in which rats are made to respond aversively to a sweet taste after it has been paired with gastric malaise, can cause gaping to previously acceptable tastes. Here, we compare aversive responses to saccharin sodium (sacc CS) caused by repeated aversive experience (in the form of CTA training) to those caused by naturally aversive quinine HCl, and how these responses are aligned with gustatory cortical (GC) activity. Using simultaneous single-neuron ensemble recordings in GC and electromyography (EMG) recordings in the jaw-opener muscle in awake, freely-moving rats and a machine-learning based behavioral classifier, we not only identified two classes of gaping, but characterized how these classes reflect different mechanisms driving aversive behavioral outputs. The first gape class is taste-specific and emerges following GC ensemble dynamics associated with taste identity and palatability coding, leading to canonical gaping responses to naturally or learned-aversive stimuli. The second is rapid-onset (<200 ms following taste delivery), internal state-dependent gaping the animal exhibits to all tastes in a state of heightened vigilance. This generalized aversion is subsequently suppressed once palatability-related responses emerge in GC, such that only gapes to truly aversive tastes remain. Together, these findings demonstrate that gaping is not a unitary reflex but is instead driven by multiple aversion judgment systems active in different contexts.

neuroscience↗

bioRxiv2026

Histidine exchange sustains LAT1 activity and proliferation in glutamine-addicted breast cancers.

L-type amino acid transporter (LAT1) drives the uptake of essential amino acids (EAA) and activation of mTORC1 signaling in cancer cells. Current models propose that glutamine exchange is required for LAT1-dependent EAA transport; however, in many tumours, including MYC-driven cancers, glutamine is simultaneously consumed for bioenergetic and biosynthetic processes. How LAT1 activity is maintained under these conditions remains unclear. Here, we identify histidine as an efficient bidirectional LAT1 substrate that is preferentially utilised under glutamine-limitation in Gln-dependent tumour cells. Histidine uptake is modulated by glutamine availability, revealing an unexpected role for histidine in maintaining amino acid homeostasis. We demonstrate that histidine availability supports LAT1-mediated transport, promotes mTORC1/4E-BP1 signaling, and enhances protein synthesis and supports tumour cell proliferation. Under histidine limitation, MYC and ATF4 induce amino acid transporter expression, including LAT1, to preserve intracellular EAA levels. Importantly, histidine restriction sensitizes tumour cells to LAT1 inhibition, enhancing sensitivity to LAT1 inhibition and reducing tumour burden. Together, our findings establish histidine as a key regulator of LAT1 function and mTORC1 activity, suggesting a potential metabolic vulnerability in glutamine-dependent tumours.

cancer biology↗

bioRxiv2026

VesSynth: Tubes Are All You Need for Robust Cross-Scale Cross-Modal 3D Vessel Segmentation

The cerebral vasculature is central to brain function, with alterations linked to numerous cerebrovascular and neurological disorders. Yet, no single imaging modality can capture the entire cerebral vascular network in humans. Instead, an array of techniques are sensitized to different spatial scales, while trading off resolution for coverage. Magnetic Resonance Imaging (MRI) typically resolves only large pial vessels, while high-resolution microscopy allows micrometer-scale vessels to be mapped over limited spatial extents. These techniques must therefore be combined to obtain a complete mapping of the cerebral angioarchitecture, which underscores the need for automatic, cross-modal vessel segmentation. Here, we introduce VesSynth, a flexible vessel segmentation framework that achieves state-of-the-art accuracy across multiple modalities and spatial resolutions (MR, optical and X-ray imaging), despite being trained entirely on synthetic data. By enabling consistent vascular mapping across scales, this framework paves the way to comprehensive investigation of cerebrovascular organization and its role in health and disease.

bioengineering↗

bioRxiv2025

The Ingestive Response Reflects Neural Dynamics in Gustatory Cortex

Upon delivery of a taste onto the tongue, gustatory neural activity determines whether the stimulus is ingested or rejected. While some work in rodents has been devoted to investigating the neural activity leading to the rejection decision and its associated orofacial movements, little is known about what behaviors lead to ingestion of palatable tastes (and what neural activity is associated with that decision), largely because identifying ingestion-related behaviors is a difficult challenge--and probably undoable with video analysis given that the behaviors are largely intraoral. To address this gap in our understanding, we analyzed simultaneously-collected electromyographic (EMG) activity of the jaw opener muscle and the firing of gustatory cortical (GC) ensembles. We developed a machine-learning classifier to identify individual orofacial movements from EMG signals, demonstrating that it outperforms previously developed methods and using the technique to reveal three novel subtypes of ingestion-related tongue/mouth movements. Investigating the dynamics of these behaviors, we found that the frequency of occurrence of each type subtype shifts significantly at the time of the consumption decision, and is both tightly coupled with and reliably follows the transition in GC population activity into the state reflecting the tastants emotional/hedonic value. However, rather than the onset of single "ingestion" movement (as occurs for rejection decisions in the form of gapes), we show that the transition to ingestion is instead characterized by a collective change in the frequencies all ingestion-related behaviors. These findings demonstrate a direct link between neural dynamics in GC and the orchestration of the physical movements that define ingestive behavior, highlighting GCs general role in taste perception, decision making, and the control of motor actions.

neuroscience↗

bioRxiv2025

Perceptual processing of tastes is performed by the amygdala-cortical loop

Gustatory cortical (GC) and basolateral amygdalar (BLA) taste responses consist of an inter-regionally coherent 3-part state sequence. This coherence suggests that reciprocal BLA-GC connectivity is important for taste processing, but it remains unknown: 1) whether BLA-GC coherence actually reflects a reciprocal "conversation" (as opposed to one region simply driving the other); and 2) whether such a "conversation" has anything to do with the taste processing observed within GC response dynamics. Here, we address these questions using network and single-neuron analysis of simultaneously-recorded GC and BLA taste responses in awake rats. We find asymmetric, reciprocal {micro}-frequency influences that reflect taste processing dynamics: BLA[->]GC influence dominates between 300 and 1000msec (the epoch in which BLA codes palatability); afterward, when GC responses become palatability-related and GC has been shown to release a behavior-relevant signal, the direction of influence reverses, becoming GC[->]BLA. Follow-up analyses demonstrate that this "turn-taking" exists alongside effectively synchronous amygdala-cortical coupling--the two regions functioning as a unified structure. Finally, to assess the implications of these interactions for single-neuron responses, we tested the response properties of GC neurons categorized by their inferred connectivity with BLA: GC neurons influenced by BLA produce stronger taste-specific and palatability-related responses than other GC neurons, and the strongest taste encoding is specifically found in GC neurons that both influence and receive influence from BLA--those most deeply embedded in the reciprocal circuit. These results, consistent with findings in multiple systems, support the novel conclusion that taste processing and decision-making is a function of the amygdala-cortical loop. New & NoteworthyConventionally, taste circuitry is considered feedforward, travelling up from the brainstem, with each additional node containing more sophisticated information. We challenge this convention by demonstrating that amygdala and cortex instead influence each other bidirectionally, yet in a direction-specific and asymmetric manner. These influences appear to drive different parts of the taste response, with distinct patterns for decision-making and behavioral output; furthermore, involvement in cortex-amygdala functional connectivity determines the strength of encoding in cortical single neurons.

neuroscience↗

bioRxiv2024

In Vitro/In Vivo Assessment of Aripiprazole-Loaded Thiolated Arabinoxylan based Nanoparticles: An Innovative Approach for Targeted Schizophrenia Therapy

This study was conducted with the primary objective of improving the bioavailability of aripiprazole (APZ) through the development of nanoparticles using thiolated arabinoxylan (TAX) sourced from corn husk. TAX was synthesized via thiolation, employing thiourea as a thiol donor and hydrochloric acid as a catalyst. Characterization of TAX revealed a surface free thiol group content of 37.461 mmol/g, accompanied by an angle of repose measuring 0.393{+/-}0.035. Bulk density, tapped density, Hausner ratio, and Carr index fell within prescribed limits. Subsequently, APZ-loaded thiolated arabinoxylan based nanoparticles were fabricated using the ionotropic gelation method, with barium chloride serving as a cross-linker. Encapsulation efficiency was highest for formulation F4, at 97.1%{+/-}2.36. In vitro drug release demonstrated sustained release profiles at both pH 1.2 and pH 6.8, with F4 exhibiting the most favourable release kinetics. In vitro, characterization indicated that the optimized thiolated arabinoxylan based nanoparticle formulation had an average particle size of 211.1 nm with a Polydispersity Index (PDI) of 0.092 and a zeta potential of 0.621 mV. SEM imaging showed uniform, slightly spherical particles with minimal pores. DSC and TGA confirmed the conversion of APZ to amorphous states within the nanoparticles, enhancing solubility. Ex-vivo permeation studies exhibited favourable drug permeation. An In-vivo pharmacodynamics studies in a ketamine-induced schizophrenia rat model indicated the effectiveness of APZ loaded thiolated arabinoxylan based nanoparticles in behavioural tests, with no significant cataplectic effects observed. Acute oral toxicity assessments demonstrated the safety, with no mortality, no significant alterations in food and water consumption, or any histopathological abnormalities. In conclusion, these developed APZ-loaded thiolated arabinoxylan based nanoparticles hold promise for the effective treatment of schizophrenia without inducing toxic effects, showcasing their potential for clinical applications.

biochemistry↗

bioRxiv2024

Both the transcriptional activator, Bcd, and transcriptional repressor, Cic, form small mobile oligomeric clusters in early fly embryo nuclei

Transcription factors play an essential role in pattern formation during early embryo development, generating a strikingly fast and precise transcriptional response that results in sharp gene expression boundaries. To characterize the steps leading up to transcription, we performed a side-by-side comparison of the nuclear dynamics of two morphogens, a transcriptional activator, Bicoid (Bcd), and a transcriptional repressor, Capicua (Cic), both involved in body patterning along the anterior-posterior axis of the early Drosophila embryo. We used a combination of fluorescence recovery after photobleaching, fluorescence correlation spectroscopy, and single particle tracking to access a wide range of dynamical timescales. Despite their opposite effects on gene transcription, we find that Bcd and Cic have very similar nuclear dynamics, characterized by the co-existence of a freely diffusing monomer population with a number of oligomeric clusters, which range from low stoichiometry and high mobility clusters to larger, DNA-bound hubs. Our observations are consistent with the inclusion of both Bcd and Cic into transcriptional hubs or condensates, while putting constraints on the mechanism by which these form. These results fit in with the recent proposal that many transcription factors might share a common search strategy for target genes regulatory regions that makes use of their large unstructured regions, and may eventually help explain how the transcriptional response they elicit can be at the same time so fast and so precise. SIGNIFICANCEBy conducting a comparative study of the nuclear dynamics of Bicoid (a transcriptional activator) and Capicua (a transcriptional repressor) in the Drosophila embryo, we have uncovered a striking similarity in their behaviours. Despite their divergent roles in transcription, both proteins have a propensity to form oligomeric species ranging from highly mobile, low stoichiometry clusters to larger, DNA-bound hubs. Such findings impose new constraints on the existing models of gene regulation by transcription factors, particularly in aspects related to target search and oligomeric binding to gene regulatory regions needed to explain the rapid and precise transcriptional response observed in developmental processes.

biophysics↗

bioRxiv2022

A study on packed cell volume for deducing hemoglobin: Cholistani camels in perspective

In human medical practice, a hematological rule of three has been validated for healthy human populations. One such formula is estimating hemoglobin (Hb) levels as 1/3rd of Packed Cell Volume (PCV). However, no such hematological formulae have been devised and validated for veterinary medical practice. The present study was devised with an aim to evaluate the relationship between hemoglobin (Hb) concentration and Packed Cell Volume (PCV) in camels (n=215) being reared under pastoralism, and to devise a simple pen-side hematological formula for estimation of Hb from PCV. The PCV was determined through microhematocrit method whereas Hb estimation by cyanmethaemoglobin method (HbD). The Hb was also calculated as 1/3rd of PCV and was dubbed as calculated Hb (HbC). Overall HbD and HbC were significantly (P[≥]0.05) different. Similar results were attained for all study groups i.e. males (n=94) and females (n=121), and young (n=85) and adult (n=130) camels. The corrected Hb (CHb) was deduced through regression prediction equation attained from linear regression model. Scatter-plots were drawn, linear regression was carried out, and Bland Altman chart was built for agreement of both methods of Hb estimation. A non-significant (P[≥]0.05) difference was noticed between HbD and CHb. Bland Altman chart revealed good agreement between HbD and CHb and there was no proportional bias on the distribution of data around the mean difference line (Mean= 0.1436, 95% CI= 3.00, -2.72). We accordingly recommend a simplified pen-side hematological formula for deducing Hb concentration from PCV viz. Hb concentration (g/dL)=0.18(PCV)+5.4 for all age and gender groups of camels instead of its calculation as one-third of PCV.

physiology↗

bioRxiv2022

Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration

Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand1,2. Here, we show that interaction between glial cells - astrocytes and mature myelin-forming oligodendrocytes - is a critical determinant of remyelination. Astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.

neuroscience↗

bioRxiv2022

Exosome secretion kinetics are controlled by temperature

When multivesicular endosomes (MVEs) fuse with the plasma membrane, exosomes are released into the extracellular space where they can affect other cells. Whether exosomes regulate cells nearby or further away depends on whether they remain attached to the secreting cell membrane. The regulation and kinetics of exosome secretion are not well characterized, but probes for directly imaging single MVE fusion events have allowed for visualization of the fusion and release process. In particular, the design of an exosome marker with a pH sensitive dye in the middle of the tetraspanin protein CD63 has facilitated studies of individual MVE fusion events. Using TIRF microscopy, single MVE fusion events were measured in A549 cells held at 23-37{degrees}C and events were identified using an automated detection algorithm. Stable docking precedes fusion almost all of the time and a decrease in temperature was accompanied by decrease in the rate of content loss and a decrease in the frequency of fusion events. The loss of CD63-pHluorin fluorescence was measured at fusion sites and fit with a single or double exponential decay, with approximately 50% of the events requiring two components and a plateau because the loss of fluorescence was typically incomplete. To interpret the kinetics, fusion events were simulated as a point source release of tethered/untethered exosomes coupled with the membrane diffusion of CD63. The experimentally observed decay required three components in the simulation: 1) free exosomes, 2) CD63 membrane diffusion from the endosomal membrane into the plasma membrane at a rate of 0.038 {micro}m2/s, as measured by FRAP, and 3) tethered exosomes. The final component of the decay arises from exosomes being secreted but tethered to the surface with one tether that has a lifetime of 8 seconds at 37{degrees}C and longer at lower temperatures. Simulating with fixed tethers or the absence of tethers fails to replicate the experimental data. This kinetic analysis increases our understanding of exosome secretion and how it is regulated by temperature. Our model suggests that exosome release from the fusion site is incomplete due to post-fusion, membrane attachment.

cell biology↗

bioRxiv2022

LiCl-induced sickness modulates spontaneous activity and response dynamics in rat gustatory cortex.

Gustatory Cortex (GC), a structure deeply involved in the making of consumption decisions, presumably performs this function by integrating information about taste, experiences, and internal states related to the animals health, such as illness. Here, we investigated this assertion, examining whether illness is represented in GC activity, and how this representation impacts taste responses and behavior. We recorded GC single-neuron activity and local field potentials (LFP) from healthy rats and (the same) rats made ill (via LiCl injection). We show (consistent with the extant literature) that the onset of illness-related behaviors arises contemporaneously with alterations in spontaneous 7-12Hz LFP power at [~]11 min following injection. This process was accompanied by reductions in single-neuron taste response magnitudes and discriminability, and with enhancements in palatability-relatedness - a result reflecting the collapse of responses toward a simple "good-bad" code arising in a specific subset of GC neurons. Overall, our data show that a state (illness) that profoundly reduces consumption changes basic properties of the sensory cortical response to tastes, in a manner that can easily explain illness impact on consumption. Significance StatementNeural responses in primary sensory cortex are often thought to faithfully represent physical stimuli, and while recent studies (including ours) have challenged this view by documenting enhancements and decrements in stimulus-induced firing related to animals internal states, there has been little work setting these changes in any sort of functional, mechanistic context. Here we show that a state (illness) that profoundly reduces consumption changes basic properties of the sensory cortical response to tastes, and then go beyond this to precisely characterize this response plasticity, connecting it to the specific perceptual changes that drive illness impact on consumption.

neuroscience↗

bioRxiv2021

PDFGRα+ Stromal Cells Promote Salivary Gland Proacinar Differentiation Through FGF2-dependent BMP7 Signaling.

3.0Stromal cells can direct epithelial differentiation during organ development; however, these pathways remain poorly defined. FGF signaling is essential for submandibular salivary gland development, and FGF2 can regulate proacinar cell differentiation in organoids through autocrine signaling in stromal cells. We performed scRNA Seq and identified stromal cell subsets expressing Fgf2 and Fgf10 that also express Pdgfr. When combined with epithelial cells in organoids, MACS-sorted PDGFR+ cells sufficiently promoted proacinar differentiation. Gene expression analysis revealed FGF2 activates the gene Bmp7 in the stroma. BMP7 could replace stromalsignaling and stimulate epithelial acinar differentiation but not branching. However, in the absence of FGF2, pathway analysis revealed that the stromal cells differentiated into myofibroblasts. Myofibroblast differentiation was induced when we treated organoids with TGF{beta}1, which also prevented proacinar differentiation. Conversely, FGF2 reversed TGF{beta}s effects. Dissecting pathways driving acinar differentiation will facilitate development of regenerative therapies. 2.0 Summary StatementEmbryonic salivary glands contain multiple stromal cell populations. FGF2 maintains the stromal Pdgfr+ population in-vitro. The PDGFR+ stromal cells drive early epithelial secretory cell differentiation using BMP7.

developmental biology↗

bioRxiv2020

Integrating large-scale neuroimaging research datasets: harmonisation of white matter hyperintensity measurements across Whitehall and UK Biobank datasets

Large scale neuroimaging datasets present the possibility of providing normative distributions for a wide variety of neuroimaging markers, which would vastly improve the clinical utility of these measures. However, a major challenge is our current poor ability to integrate measures across different large-scale datasets, due to inconsistencies in imaging and non-imaging measures across the different protocols and populations. Here we explore the harmonisation of white matter hyperintensity (WMH) measures across two major studies of healthy elderly populations, the Whitehall II imaging sub-study and the UK Biobank. We identify pre-processing strategies that maximise the consistency across datasets and utilise multivariate regression to characterise sample differences contributing to study-level differences in WMH variations. We also present a parser to harmonise WMH-relevant non-imaging variables across the two datasets. We show that we can provide highly calibrated WMH measures from these datasets with: (1) the inclusion of a number of specific standardised processing steps; and (2) appropriate modelling of sample differences through the alignment of demographic, cognitive and physiological variables. These results open up a wide range of applications for the study of WMHs and other neuroimaging markers across extensive databases of clinical data. HIGHLIGHTSO_LIWe harmonised measures of WMHs across two studies on healthy ageing C_LIO_LISpecific pre-processing strategies can increase comparability across studies C_LIO_LIModelling of biological differences is crucial to provide calibrated measures C_LI

neuroscience↗