Biology subjects

Biswas, M.

Publications and source records attributed to Biswas, M..

13 recordsLinked to original sources

bioRxiv2025

Emergent Effect of Mixed Crowders on Protein Dimerization

In vivo protein-protein association is modulated by non-specific interactions with the cellular matrix, known as crowding. Replicating the heterogeneity and complexity of cellular conditions in experiments and simulations to quantify the crowding influences remains a formidable challenge. As an alternative, homogeneous mixtures of polymers or proteins as crowders are employed, although they provide limited insight to the actual effect. In this work, we present a coarse-grained model of GB1 dimerization in lysozyme crowders by adjusting the GB1-lysozyme effective potential parameters obtained through high-resolution Martini simulation. Employing these parameters it is shown that GB1 dimerization is destabilized in presence of lysozyme, as observed in experiments. The model is further extended to incorporate binary crowder mixtures for crowder species of various sizes and interaction potentials. It is found that depending on mixing conditions and crowder volume fraction, dimerization can either be stabilized or destabilized. In particular, in presence of crowders of different sizes, the smaller one plays the dominant role. Finally, we observe that the overall change of stability due to crowding emerges from a delicate balance between enthalpy and entropy that cannot be predicted by considering the property of single crowder species. These results provide invaluable insights for interpreting experimental observations under cell-like conditions.

biophysics↗

bioRxiv2025

Interpersonal Synchrony and Implicit Identification

The transformative effects of interpersonal synchrony on reshaping the relationship between the self and the group by fostering self-other blurring are well-documented. However, these findings largely rely on self-reported measures, leaving aspects of the self inaccessible to explicit measures unexplored. We combined the Implicit Association Task (IAT) with conventional explicit evaluations of self-other blurring to examine how experiences of synchronous movement may also swiftly shape implicit measures indicative of self-other blurring. In three online experiments participants experienced synchronous movement as opposed to no movement (Experiment 1) or unpredictable movement (Experiment 2) or asynchronous movement (Experiment 3) with virtually presented agents. Our data indicate that synchronous movement led to higher levels of self-other blurring on the Inclusion of Other in Self (IOS) scale and implicit self-concept evaluations on the IAT. Participants demonstrated a preference for associating self-related words with images of the synchronous group, while associating other-related words with images from the no-movement, unpredictable, and asynchronous movement groups. This suggests that experiencing synchronous movement with a group influences implicit semantic self-associations. These findings suggest that interpersonal synchrony may alter self-concept at both an embodied and semantic level, extending beyond conscious affiliation. Our combined methodology offers a deeper insight into the impact of synchronous experiences on self-constructs and social relationships.

animal behavior and cognition↗

bioRxiv2024

Neural mechanisms of attention, not expectation, govern spatial selection by probabilistic cueing

Spatial probabilistic "Posner" cueing is widely employed in studies of endogenous spatial attention. Such cueing guides attention by providing prior knowledge about the likely spatial location of task-relevant events. Yet, it has been compellingly argued that such spatial priors also elicit expectation effects, rendering Posner cueing unsuitable for measuring attentional effects in isolation. We address this debate by combining signal detection theory models of behavior with concurrent electrophysiological recordings, and directly compare Posner cueing effects with those of attention and expectation cueing. Participants performed two tasks: a dual cueing task, with orthogonal relevance (attention) and probability (expectation) cues, as well as a Posner cueing task. Relevance and probability cueing independently modulated distinct behavioral parameters - perceptual sensitivity and decisional criterion, respectively - whereas Posner cueing modulated both sensitivity and criterion. However, only sensitivity modulations by Posner cueing were correlated with those of relevance cueing. Criterion modulations by Posner cueing were uncorrelated with those of probability cueing. Both Posner and relevance cueing, but not probability cueing, modulated various neural markers of spatial attention, including steady-state visually evoked potential (SSVEP) amplitude and alpha-band (8-12 Hz) oscillation power. Representational similarity analysis and cue-label prediction with deep convolutional neural networks revealed dissociable underpinnings of relevance and probability cueing, and identified Posner cueings neural representations with those of relevance cueing. Our results address a long-standing debate in the attention literature and clearly demonstrate that spatial selection by probabilistic cueing is governed by neural mechanisms of attention, not expectation. Significance StatementHow does our brain select relevant information for accomplishing task goals? "Posner cueing" is a popular choice for studying brain mechanisms of goal-driven attention in the lab. Posner cues guide attention by providing advance information about the likely location of task-relevant events. Yet, Posner cueing has been criticized because it engages brain mechanisms not only of attention but of event expectation, as well. We address this critique by employing state-of-the-art neural decoding approaches, including deep convolutional neural networks, and show that behavioral and neural underpinnings of Posner cueing closely match those of attention, not expectation. The results address a long-standing debate in the attention literature and validate Posner cueing as a reliable method for measuring attentions effects in the brain.

neuroscience↗

bioRxiv2024

Insight into the Thermo-responsive Phase Behavior of P1 Domain of α-synuclein using Atomistic Simulations

Biomolecular condensate formation driven by intrinsically disordered proteins (IDPs) is regulated by interaction between various domains of the protein. Such condensates are implicated in various neurodegenerative diseases. The presynaptic intrinsically disordered protein, -Syn is involved in the pathogenesis of Parkinsons disease. The central non-amyloid {beta}-component (NAC) domain in the protein is considered to be a major driver of pathogenic aggregation, although recent studies have suggested that the P1 domain from the flanking N-terminal region, can act as a master controller for -Syn function and aggregation. To gain molecular insight into the phase behavior of the P1 domain itself, we investigate how assemblies of P1 (residues 36-42) chains phase separate with varying temperatures using all-atom molecular dynamics simulations. The simulations reveal that P1 is able to phase separate above a lower critical solution temperature. Formation of the condensed phase is driven by exclusion of water molecules by the hydrophobic chains. P1 chain density in the condensate is determined by weak multi-chain interactions between the residues. Moreover, Tyrosine (Y39) is involved in the formation of strongest contacts between residue pairs in the dense phase. These results provide a detailed picture of condensate formation by a key segment of the -Syn molecule, which may help deciphering the phase behavior of the full-length protein.

biophysics↗

bioRxiv2024

Shared Rhythm to Shared Vision: Synchronous Marching increases Conformity on Perceptual Decision making

Previous research on synchronous movement rituals have found that it increased prosocial propensity toward the synchronised group and reliance on the group opinions. However, whether basic cognitive processes such as perceptual decision-making are affected by synchronous movement remains unexplored. In this novel virtual reality experiment, we examined whether marching synchronously with a group can induce greater informational conformity on an unrelated perceptual task (forced choice random dot motion). We found higher degree of conformity following synchronised marching during low stimulus information. This finding indicates that synchronised movement induces minimal group membership expressed via increased self-other blurring and conformity. Thus, participation in movement-based rituals has the capacity to change our perception of the world to align more closely with the synchronised group.

animal behavior and cognition↗

bioRxiv2024

DIFFERENTIAL REGULATION OF GENES IN ENTORHINAL CORTEX AND HIPPOCAMPUS IN LATE ONSET AD

Amyloidogenic processing of APP mediated by increased BACE1 activity resulting in A{beta} production and accumulation of hyperphosphorylated tau cause neuronal degeneration in AD. Pathological changes occur early in the EC and the hippocampus, much before neurodegeneration sets in. Here, using 500 and 303 differentially expressed genes from the EC and hippocampus respectively, we observed impairment of several cellular functions owing to either disrupted transcription or post-translational regulation, through functional enrichment, PPI network, miRNA and convergent functional genomic analysis. In EC, functional enrichment analysis highlighted several processes of which the Oncostatin-M-mediated pathway is related in the disease pathogenesis by increasing BACE1 transcription through STAT3 activation. Hub genes, BRD4 and PIN1, involved in A{beta} and tau pathology are downregulated probably through the concerted action of hsa-miR-3613-3p and hsa-miR-4674, upregulated miRNAs in AD. In the hippocampus, upregulated FXR1 and downregulated RTN3 being involved in post-transcriptional processing of BACE1, result in increased A{beta} production. For the disruption observed in the autophagy-lysosomal pathway, neurotransmitter synthesis and A{beta} clearance, YWHAH, a downregulated hub gene is instrumental. Regulation of YWHAH expression is probably mediated at the post-transcriptional level through hsa-miR-455-3p and hsa-miR-4674, known to be heavily upregulated in AD. In both the regions, similar pattern of disrupted cellular pathways emerge, although the key players, differ. Whereas dysfunctional proteasomal degradation is mediated by SKP1-CUL1 in EC, it is CUL3 mediated in hippocampus. Thus, similar disease pathology develops through dysregulation of pathways that are evidently different in EC and hippocampus implying failure of therapeutics based on single target.

bioinformatics↗

bioRxiv2022

KDM6A loss sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition

Acute myeloid leukemia (AML) is a heterogeneous, aggressive malignancy with dismal prognosis and with limited availability of targeted therapies. AML exhibits epigenetic deregulation and transcriptional plasticity that contributes to pathogenesis. KDM6 proteins are histone-3 lysine-27 demethylases that play major context dependent roles in AML evolution and therapy resistance. Here, we demonstrate that KDM6 demethylase function critically regulates DNA damage repair (DDR) gene expression programs in AML. Mechanistically, KDM6 family protein expression is regulated by genotoxic stress, with deficiency of KDM6A (UTX) and KDM6B (JMJD3) impairing DDR transcriptional activation and compromising repair potential. Acquired KDM6A loss-of-function mutations have been implicated in chemoresistance, although a significant percentage of relapsed AML have upregulated KDM6A. Based on these mechanistic findings, olaparib treatment significantly reduced engraftment of patient-derived xenografts. Thus KDM6A-mutant human primary AML samples have increased susceptibility to Poly-(ADP-ribose)-polymerase (PARP) inhibition in vivo. Crucially, a higher KDM6A expression is correlated with venetoclax tolerance. Loss of KDM6A increased mitochondrial activity, BCL2 expression, and sensitized AML cells to venetoclax. Additionally, KDM6A loss was accompanied with a downregulated BCL2A1, which is commonly associated with venetoclax resistance. Corroborating these results, dual targeting of PARP and BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing AML apoptosis, and primary AML cells carrying acquired KDM6A-domain mutations were even more sensitive to the combination. Together, our study illustrates a mechanistic rationale in support for a novel combination targeted therapy for human AML based on subtype heterogeneity, and establishes KDM6A as an important molecular regulator for determining therapeutic efficacy.

cancer biology↗

bioRxiv2021

In vitro reconstitution demonstrates the amyloid-beta mediated myelin membrane deformation

Amyloid-beta (A{beta}) aggregation mediated neuronal membrane deformation, although poorly understood, is implicated in Alzheimers Disease (AD). Particularly, whether A{beta} aggregation can induce neuronal demyelination remains unknown. Here we show that A{beta}-40 binds and induces extensive tubulation in the myelin membrane in vitro. The binding of A{beta}-40 depends predominantly on the lipid packing defect densities and electrostatic interactions and results in rigidification of the myelin membrane in the early time scales. Furthermore, elongation of A{beta}-40 into higher oligomeric and fibrillar species leads to eventual fluidization of the myelin membrane followed by extensive membrane tubulation observed in the late phase. Taken together, our results capture mechanistic insights into snapshots of temporal dynamics of A{beta}-40 - myelin membrane interaction and demonstrate how short timescale, local phenomena of binding, and fibril mediated load generation manifests into long timescale, global phenomena of myelin tubulation and demonstrates the ability of A{beta}-40 to demyelinate.

biophysics↗

bioRxiv2021

Modeling Protein Association from Homogeneous to Mixed Environments: A Reaction-Diffusion Dynamics Approach

Protein-protein association in vivo occur in a crowded and complex environment. Theoretical models based on hard-core repulsion predict stabilization of the product under crowded conditions. Soft interactions, on the contrary, can either stabilize or destabilize the product formation. Here we modeled protein association in presence of crowders of varying size, shape, interaction potential and used different mixing parameters for constituent crowders to study the influence on the association reaction. It was found that size a more dominant factor in crowder-induced stabilization than the shape. Furthermore, in a mixture of crowders having different sizes but identical interaction potential, the change of free energy is additive of the free energy changes produced by individual crowders. However, the free energy change is not additive if two crowders of same size interact via different interaction potentials. These findings provide a systematic understanding of crowding influences in heterogeneous medium.

biophysics↗

bioRxiv2019

Multicenter Analysis of Dosing Protocols for Sotalol Initiation

Sotalol is a Vaughan-Williams Class III antiarrhythmic medication that is commonly used in the management of both atrial and ventricular arrhythmias. Like others in this class, sotalol carries a risk of the potentially lethal arrhythmia torsade de pointes due to its effect of prolonging the QT interval on ECG. For this reason, many centers admit patients for telemetry monitoring during the initial 2-3 days of dosing. However, despite its widespread use, little information is available about the dosing protocols used during this initiation process. In this multicenter investigation, we examine the characteristics of various dose protocols in 213 patients who initiated sotalol over a 4-year period. Of these patients, over 90% were able to successfully complete the dosing regimen (i.e., were discharged on the medication). Significant bradycardia, excessive QT prolongation, and ineffectiveness were the main reasons for failed completion. We found that any dose adjustment was one of the strongest univariate predictors of successful initiation (OR 6.6, 95%CI 1.3 - 32.7, p = 0.021), while initial dose, indication, and resting heart rate or QT interval on baseline ECG did not predict successful initiation. Several predictors of any dose adjustment were identified, and included diabetes, hypertension, presence of pacemaker, heart failure diagnosis, and depressed LV ejection fraction. Using marginal structural models (i.e., inverse probability weighting based on probability of a dose adjustment), we verified that these factors also predicted successful initiation via preventing any dose adjustment, and suggests that consideration of these factors may result in higher likelihood of successful initiation in future investigations. In conclusion, we found that the majority of patients admitted for sotalol initiation are successfully discharged on the medication, often without a single adjustment in the dose. Our findings suggest that several factors predicting lack of dose adjustment could be used clinically to identify patients who could potentially undergo outpatient initiation, although prospective studies are needed to verify this approach.

pharmacology and toxicology↗

bioRxiv2019

Applications of Machine Learning in Decision Analysis for Dose Management for Dofetilide

Initiation of the antiarrhythmic medication dofetilide requires an FDA-mandated 3 days of telemetry monitoring due to heightened risk of toxicity within this time period. Although a recommended dose management algorithm for dofetilide exists, there is a range of real-world approaches to dosing the medication. In this multicenter investigation, we examined the decision process for dose adjustment of dofetilide during the observation period using machine-learning approaches, including supervised, unsupervised, and reinforcement learning applications. Logistic regression approaches identified any dose-adjustment as a strong negative predictor of successful loading (i.e., discharged on dofetilide) of the medication (OR 0.19, 95%CI 0.12 - 0.31, p < 0.001 for discharge on dofetilide), indicating that these adjustments are strong determinants of whether patients "tolerate" the medication. Using multiple supervised approaches, including regularized logistic regression, random forest, boosted gradient decision trees, and neural networks, we were unable to identify any model that predicted dose adjustments better than a naive approach. A reinforcement-learning algorithm, in contrast, predicted which patient characteristics and dosing decisions that resulted in the lowest risk of failure to be discharged on the medication. Future studies could apply this algorithm prospectively to examine improvement over standard approaches.

pharmacology and toxicology↗

bioRxiv2018

Active presynaptic ribosomes in mammalian brain nerve terminals, and increased transmitter release after protein synthesis inhibition

Presynaptic neuronal activity requires the localization of thousands of proteins that are typically synthesized in the soma and transported to nerve terminals. Local translation for some dendritic proteins occurs, but local translation in mammalian presynaptic nerve terminals is difficult to demonstrate. Here, we present evidence for local presynaptic protein synthesis in the mammalian brain at a glutamatergic nerve terminal. We show an essential ribosomal component, 5.8s rRNA, in terminals. We also show active translation in nerve terminals, in situ, in brain slices demonstrating ongoing presynaptic protein synthesis. After inhibiting translation for ~1 hour, the presynaptic terminal exhibits increased spontaneous release, and increased evoked release with an increase in vesicle recycling during stimulation trains. Postsynaptic response, shape and amplitude were not affected. We conclude that ongoing protein synthesis limits vesicle release at the nerve terminal which reduces the need for presynaptic vesicle replenishment, thus conserving energy required for maintaining synaptic transmission.

cell biology↗

bioRxiv2017

Mycobacterium tuberculosis LprE enhances bacterial persistence by inhibiting cathelicidin and autophagy in macrophages

Mycobacterium tuberculosis(Mtb) lipoproteins are known to facilitate bacterial survival by manipulating the host immune responses. Here, we have characterized a novel Mtb lipoprotein LprE(LprEMtb), and demonstrated its role in mycobacterial survival. LprEMtb acts by down-regulating the expression of cathelicidin, Cyp27B1, VDR and p38-MAPK via TLR-2 signaling pathway. Deletion of lprEMtb resulted in induction of cathelicidin and decreased survival in the host. Interestingly, LprEMtb was also found to inhibit autophagy mechanism to dampen host immune response. Episomal expression of LprEMtb in non-pathogenic Mycobacterium smegmatis(Msm) increased bacillary persistence by down-regulating the expression of cathelicidin and autophagy, while deletion of LprEMtb orthologue in Msm, had no effect on cathelicidin and autophagy expression. Moreover, LprEMtb blocked phago-lysosome fusion by suppressing the expression of EEA1, Rab7 and LAMP-1 endosomal markers by down-regulating IL-12 and IL-22 cytokines. Our results indicate that LprEMtb plays an important role in mycobacterial pathogenesis in the context of innate immunity.

physiology↗