Biology subjects

Jaiswal, A. K.

Publications and source records attributed to Jaiswal, A. K..

7 recordsLinked to original sources

bioRxiv2026

On the Robustness of Biomolecular Systems to Perturbations in Translational Resources

The reliable operation of biomolecular circuits depends on the availability of shared cellular resources such as ribosomes, whose levels can vary substantially across growth conditions and cellular contexts. Although resource competition among co-expressed genes is well recognized, the relationship between resource variation and the robustness of circuit dynamics has not been characterized quantitatively. This paper integrates a resource-aware gene expression model, contraction theory-based analytical bounds, and experimental validation to study the effect of translational resource variation on constitutive gene expression and its mitigation through feedback. We show that the constitutive circuit exhibits sensitivity to resource perturbations, and that redesigning it with negative autoregulatory feedback enhances the contraction rate and reduces the steady-state deviation bound, though at lower expression levels. Experiments in E. coli using both plasmid copy number variation and a ribosome sequestration module are consistent with these predictions, confirming that the feedback circuit maintains relatively stable expression under conditions where the constitutive circuit shows large changes. These findings offer a systematic approach for analyzing and improving the robustness of biomolecular circuits operating under variable resource conditions.

systems biology↗

bioRxiv2025

Earth-Observation and Environmental Vision Transformers Reveal Genome-Environment Associations in Macroalgae

Macroalgae thrive in extreme environments, yet the genomic basis of their tolerance remains poorly resolved. We describe nine Arabian Gulf macroalgae and integrate them with 117 published genomes (126 total; 70 Rhodophyta, 43 Ochrophyta, 13 Chlorophyta) to test genome-environment associations. Google Earth Engine (GEE) for broad-scale oceanography and 10-meter resolution AlphaEarth Foundations (AEF) embeddings for fine-scale habitat heterogeneity. We identified 157 significant (FDR q < 0.05) correlations with global GEE variables--including a strong negative temperature association with DUF3570--while AEF embeddings uncovered over 1,000 lineage-specific signals within Rhodophyta and identified climate-driven Pfam modules. The von Willebrand factor type-A domain emerged as uniquely robust across all frameworks and enriched in Arabian Gulf species. In the Arabian Gulf, enrichment of this domain is consistent with selection for adhesion mechanisms capable of withstanding chronic hydrodynamic stress compounded by high temperature and salinity. These results demonstrate that converging remote sensing with deep learning identifies conserved and lineage-specific genomic signatures of ecological differentiation across diverse macroalgal lineages.

genomics↗

bioRxiv2025

A small molecule inhibitor of RNA-binding protein IGF2BP3 shows anti-leukemic activity

The RNA-binding protein IGF2BP3 is an oncofetal protein overexpressed in B-acute lymphoblastic leukemia and is critical for leukemogenesis in experimental models. With cancer-specific expression, functional dispensability for normal development, and an unleveraged pro-oncogenic function in mRNA homeostasis, IGF2BP3 represents an excellent target. With no small molecule inhibitors of IGF2BP3 in clinical use, we undertook an effort to identify new IGF2BP3 inhibitors using biochemical methods. A biochemical screen, followed by a cell-based counter screen, led to the identification of compounds with protein-RNA interaction inhibition and leukemic cell growth-inhibitory activity. One of these compounds, designated I3IN-002, shows consistent cell growth-inhibitory activity, altered cell cycle and increased apoptosis in multiple leukemia cell lines, and is the most potent inhibitor of IGF2BP3 reported to date. I3IN-002 was tolerated in mice when administered intraperitoneally and showed potent anti-leukemic activity in a syngeneic transplantation model of MLL-Af4 leukemia. I3IN-002 inhibits the function of IGF2BP3, disrupting in situ binding of IGF2BP3 to target mRNAs, and altering IGF2BP3-dependent gene expression regulation. Furthermore, cell-free and cellular thermal shift assays as well as drug affinity responsive target stability assays support on target activity of I3IN-002 for IGF2BP3. Thus, the identification of I3IN-002 paves the way for the discovery of potent and selective small molecule inhibitors of IGF2BP3.

cancer biology↗

bioRxiv2024

Metabolic regulation of RNA methylation by the m6A-reader IGF2BP3

The interplay of RNA modifications - deposited by "writers", removed by "erasers" and identified by RNA binding proteins known as "readers" - forms the basis of the epitranscriptomic gene regulation hypothesis. Recent studies have identified the oncofetal RNA-binding protein IGF2BP3 as a "reader" of the N6-methyladenosine (m6A) modification and crucial for regulating gene expression. Yet, how its function as a reader overlaps with its critical oncogenic function in leukemia remains an open question. Here, we report the novel finding that the reader IGF2BP3 reprograms cellular metabolism, resulting in an altered ability of the "writers" to modify the epitranscriptome. In leukemia cells, IGF2BP3 supports increased glycolytic flux and one-carbon metabolism, leading to increased production of S-adenosyl methionine (SAM), a key substrate for methylation reactions within the cell. IGF2BP3 directly regulates the translation of MAT2B, the regulatory subunit of the methionine-adenosyltransferase complex, which is the final enzyme in a pathway leading to SAM production. This, in turn, results in increased m6A modifications on RNA, resulting in positive feedback regulation. This novel mechanism illustrates how metabolism mutually acts with epitranscriptomic modifications, underscoring the pervasive impact of IGF2BP3 in gene regulatory mechanisms governing a broad range of cancer-specific processes.

cancer biology↗

bioRxiv2020

Post-transcriptional gene regulation by the RNA binding protein IGF2BP3 is critical for MLL-AF4 mediated leukemogenesis

Despite recent advances in therapeutic approaches, patients with MLL-rearranged leukemia still have poor outcomes and a high risk of relapse. Here, we found that MLL-AF4, the most common MLL fusion protein in patients, transcriptionally induces IGF2BP3 and that IGF2BP3 strongly amplifies MLL-Af4 mediated leukemogenesis. Deletion of Igf2bp3 significantly increases the survival of mice with MLL-Af4 driven leukemia and greatly attenuates disease, with a minimal impact on baseline hematopoiesis. At the cellular level, MLL-Af4 leukemia-initiating cells require Igf2bp3 for their function in leukemogenesis. eCLIP and transcriptome analysis of MLL-Af4 transformed stem and progenitor cells and MLL-Af4 bulk leukemia cells reveals a complex IGF2BP3-regulated post-transcriptional operon governing leukemia cell survival and proliferation. Regulated mRNA targets include important leukemogenic genes such as those in the Hoxa locus and numerous genes within the Ras signaling pathway. Together, our findings show that IGF2BP3 is an essential positive regulator of MLL-AF4 mediated leukemogenesis and represents an attractive therapeutic target in this disease.

cancer biology↗

bioRxiv2020

Hemispheric asymmetry of entrained auditory steady state responses arise from the structural connectome

Structure-function relationships are fundamental to studies of neural systems, yet the mechanistic underpinnings of how structural networks shape hemispheric lateralization remain elusive. For instance, the asymmetric neuroanatomic embedding of primary auditory cortices was shown when connectivity with all other brain areas were considered. Concomitantly, functional lateralization e.g., left hemispheric dominance of speech processing and right hemispheric dominance of music perception, is widely acknowledged. The present article provides a parsimonious mechanistic explanation based on computational modelling and empirical recordings to demonstrate emergence of hemispheric lateralization of brain function. For validation of the model, empirical EEG recordings of auditory steady state responses (ASSR) were undertaken, and empirical findings suggest right hemispheric dominance at the level of cortical sources in binaural and monaural hearing conditions. Subsequently, we demonstrate the entrainment and phase of oscillations in connected brain regions based on a neurodynamic model constrained by empirically derived structural connectivity matrix from diffusion data. For relevance, we have taken into consideration time-delays in neural communication stemming from fibre distances and neuronal coupling arising from fibre densities. Based on relevant network parameters, we could demonstrate the emergence of right hemispheric dominance of ASSR in binaural and monaural hearing conditions when auditory cortical areas were chosen as triggers of entrained phase oscillators. Furthermore, we discovered emergence of left-lateralized functional response when bilateral Brocas area replaced auditory areas as triggers. Hence, a single unified mechanism based on entrainment of phase oscillators in a large-scale brain network could explain both emergence of right and left hemispheric laterality. Significance statementThe origin of hemispheric specialization of sensory processing is a fundamental question in neuroscience. For instance, speech and language are predominantly processed in the left hemispheric regions, while the right hemisphere is specialized for processing rhythmic, tonal, and melodic stimuli. Identification of the network mechanisms that give rise to such functional lateralization from structural constraints remains elusive. In the present study, we simulate neural activity observed during human EEG recordings of auditory steady-state responses from a biophysically realistic large-scale model constrained by underlying structural connectivity. Subsequently, we demonstrate how hemispheric lateralization of brain responses to sensory stimuli emerge from the time-delayed interactions among whole-brain neuronal ensembles.

neuroscience↗

bioRxiv2019

Comparison of beamformer implementations for MEG source localization

Beamformers are applied for estimating spatiotemporal characteristics of neuronal sources underlying measured MEG/EEG signals. Several MEG analysis toolboxes include an implementation of a linearly constrained minimum-variance (LCMV) beamformer. However, differences in implementations and in their results complicate the selection and application of beamformers and may hinder their wider adoption in research and clinical use. Additionally, combinations of different MEG sensor types (such as magnetometers and planar gradiometers) and application of preprocessing methods for interference suppression, such as signal space separation (SSS), can affect the results in different ways for different implementations. So far, a systematic evaluation of the different implementations has not been performed. Here, we compared the localization performance of the LCMV beamformer pipelines in four widely used open-source toolboxes (FieldTrip, SPM12, Brainstorm, and MNE-Python) using datasets both with and without SSS interference suppression.\n\nWe analyzed MEG data that were i) simulated, ii) recorded from a static and moving phantom, and iii) recorded from a healthy volunteer receiving auditory, visual, and somatosensory stimulation. We also investigated the effects of SSS and the combination of the magnetometer and gradiometer signals. We quantified how localization error and point-spread volume vary with SNR in all four toolboxes.\n\nWhen applied carefully to MEG data with a typical SNR (3-15 dB), all four toolboxes localized the sources reliably; however, they differed in their sensitivity to preprocessing parameters. As expected, localizations were highly unreliable at very low SNR, but we found high localization error also at very high SNRs. We also found that the SNR improvement offered by SSS led to more accurate localization.

neuroscience↗