Biology subjects

Chatterjee, A.

Publications and source records attributed to Chatterjee, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Embodied timing turns a robotic tug-of-war into cooperative transport

Living systems move loads with agents that pull against one another. Kinesin and dynein pull one vesicle, ants haul a dead insect, and antagonist muscles move a joint. Whether the timing of the forces can, by itself, determine which side moves the load is not well understood. Here, combining experiments, theory, and simulations of a tug-of-war between two matched teams of spring-coupled robots, we show that the relative timing of the pull forces breaks the symmetry and decides the contest. Teams pulling in unison or in strict alternation tie. Between these, the lagging team wins, most strongly near a quarter cycle, because the springs unload while the leading team coasts and the lagging team still pulls. In the model and in robot simulations, braking rather than coasting between pulls, once strong enough, shifts the advantage to the leading team. Winning and losing leave distinct signatures in each robot's motor current. Using these local signals, we formulate an embodied decentralized phase-adaptation rule that enables transient leadership to switch between teams, allowing the collective to transport high-friction cargo and to navigate around obstacles towards a prescribed target without explicit communication.

biophysics↗

bioRxiv2026

A Community-Driven Single-Cell PBMC Reference Integrating Landmark Datasets Spanning Health and Disease

Blood provides an accessible window into human health, yet the absence of a peripheral blood mononuclear cells (PBMCs) reference with standardized immune cell annotations has constrained comparisons between single-cell RNA sequencing (scRNAseq) studies. Here, we present HARP (Human Cell Atlas Reference for PBMCs), an integrated atlas of ~9 million PBMCs from >2,600 donors across 15 studies spanning four continents, encompassing diverse populations, neonates to 97 years, across health and diverse immune-related diseases. We developed optimized integration workflows, including novel label-free metrics to assess integration quality, and generated community-driven consensus annotations for 192 immune cell subsets, identifying rare populations representing as few as 0.004% of PBMCs. HARP reveals coordinated cellular modules associated with age, sex, and disease, identifies female-biased interferon and inflammatory gene programs and their perturbation by COVID-19, and uncovers a novel sexual dimorphism in prostaglandin signaling. Finally, we introduce scTiger, a hierarchical label-transfer framework that accurately projects these 192 cell annotations onto ~18 million additional PBMCs, providing a robust and transferable reference for harmonizing future PBMC studies. HARP provides a high-resolution community-driven reference atlas for PBMC annotation and analysis, as a basis for emerging clinical applications of single-cell genomics.

immunology↗

bioRxiv2026

A Synthetic Microbial Therapy Rewires Antitumor Immunity Across Multiple Cancer Types

Microbial immunotherapies show promise against cancer, yet broad efficacy and mechanistic insight remain elusive. Here, we introduce SPIKE 1.0 (S1.0), a metabolically engineered bacterium that converts tryptophan into immunomodulatory hydroxyindoles via tryptophan monooxygenase to remodel the tumor microenvironment (TME). A single systemic dose of S1.0 elicited potent, durable antitumor responses across multiple murine models, including humanized mice, with minimal toxicity. S1.0 enhanced inflammatory signaling, activated innate and adaptive immunity, and promoted T cell persistence, memory, and resistance to exhaustion. It outperformed checkpoint inhibitors and synergized with chemotherapy. Multi-omics profiling revealed that S1.0 rewired amino acid metabolism in tumor-infiltrating immune cells and disrupted immunosuppressive networks. These results establish S1.0 as a scalable, cost-effective microbial immunotherapy with broad translational potential for solid tumors.

immunology↗

bioRxiv2026

Mating imperatives drive plasticity of the daily temporal niche via dopamine signaling.

Animals confine their daily activity to distinct diurnal, crepuscular, or nocturnal windows. It remains unclear how hundreds of sympatric species sharing the same temporal niche manage to coexist. To address this, we monitored the daily activity of the twilight-active, species-rich Drosophila genus under naturalistic conditions. Here, we show that intense sociosexual interactions rapidly drive a species-specific reformatting of their canonical crepuscular niche. The dominant sensory modality used for sexual communication predicts niche shift direction: reliance on chemosensation for courtship redirects behavioral activity into the night, while visual reliance shifts it into the day. This temporal plasticity bypasses the circadian clock, instead operating via a conserved dopaminergic pathway that simultaneously inhibits sleep and sustains sexual motivation. Our results reveal how mating imperatives enable conditional colonization of otherwise restricted temporal windows. Ultimately, by driving the divergence of previously overlapping niches, sociosexually induced temporal plasticity provides a powerful mechanism for sympatric coexistence in crowded environments.

neuroscience↗

bioRxiv2026

Clinical Trial and Ontology-Derived Positive and Negative Benchmark Datasets for Drug Repurposing Across Rare Diseases

Evaluating the potential applications of a medicine is a fundamental challenge in drug development. There is a lack of standardized, decision-oriented benchmarks that test whether computational models can generalize therapeutic hypotheses across diseases in ways that reflect real-world pharmaceutical investment decision making. To address this gap, we introduce two complementary resources: the Indication Expansion Investment Decision Network (IxIDN) and the Orphanet Rare Disease Ontology Negative-network (ORDON). IxIDN is a clinical-trial-derived positive benchmark constructed by projecting drug-disease associations from pharmaceutical clinical trials into a disease-disease network; each edge connects disease pairs that have entered clinical trials for the same drug, thereby capturing cases when concrete indication-expansion decisions have been made. The current release contains 574 rare diseases and 5,336 edges. In contrast, ORDON serves as a stringent, biology-aware negative benchmark derived from the authoritative Orphanet Rare Disease Ontology. It identifies maximally distant disease pairs according to curated hierarchical structure and genetics-linked inheritance patterns, providing 793 rare diseases and 5,000 edges that represent high-separation negative candidates across therapeutic areas. Together, IxIDN and ORDON enable rigorous cross-evidence generalization from clinical trials to disease ontology, testing for Disease- Disease Association Learning (DDAL), a core task for mechanism-centered drug repurposing and indication expansion. All data are publicly available with detailed metadata, enabling reproducible evaluation of models on transparent, decision-relevant benchmarks.

Systems Biology↗

bioRxiv2026

Cellular Complexity and Systemic Immune Profiles across Ancestral Diversity in Thailand and Mainland Southeast Asia

Mainland Southeast Asia (MSEA) remains under-represented in global immunogenomic references despite its extensive genetic heterogeneity. We present the first single-cell immune atlas of an MSEA population, utilizing Thai individuals from the Asian Immune Diversity Atlas (AIDA) as a representative cohort. We demonstrate that the Thai population is highly genetically diverse, reflecting its history as a geographic nexus for Asian admixture. By integrating single-cell transcriptomics with high-resolution genotyping, we show that genetic ancestry significantly shapes innate immune profiles, specifically CD14+ monocytes, highlighting potential evolutionary adaptations to regional pathogens. We identify specific sex-by-ancestry interactions that may drive the baseline activation of pro-inflammatory pathways in females, providing a long-sought cellular rationale for the high prevalence of autoimmune disorders observed in Southeast Asian populations. Ultimately, our study reveals that population-specific genetic architecture dictates immune heterogeneity often missed by self-reported ethnicity or country of origin, providing a critical immunogenomic reference for precision medicine in MSEA regions.

systems biology↗

bioRxiv2026

A chemically reactive and Raman-active non-canonical amino acid reveals photocycle complexity in a blue-light receptor

Photosensory protein function spans multiple time and length scales, demanding integrative approaches. We introduce 4-diacetylenyl-phenylalanine (DAF), a dual-purpose non-canonical amino acid (ncAA) that enables both chemical control and spectroscopic readout of photoreceptor dynamics. Genetically encoded in E. coli, DAF combines a reactive diyne for bioorthogonal ligations (thiols, azides, tetrazines) with a strong, solvatochromic Raman signal in the cell-silent region. Applied to the light-oxygen-voltage (LOV) transcription factor EL222, DAF enables multifaceted interrogation of its photocycle. We engineer a covalently cross-linked variant that suppresses light-driven conformational changes and DNA binding, and generate a donor-acceptor construct for Forster resonance energy transfer (FRET) tracking of photoinduced structural dynamics. Time-resolved stimulated Raman spectroscopy following flavin mononucleotide (FMN) excitation reveals additional processes -from vibrational energy transfer to local unfolding-spanning femtoseconds to milliseconds. DAF thus constitutes a versatile tool to resolve protein dynamics with high spatiotemporal resolution.

biochemistry↗

bioRxiv2026

Elevated Expression of MALAT1 Contributes to the Survival of Drug-Tolerant Persister Cells Following Targeted Therapy in Lung Adenocarcinoma

Lung adenocarcinomas frequently harbour actionable oncogenic mutations that are vulnerable to treatment with targeted therapies. While responses to targeted therapies are often initially dramatic, relapse is almost inevitable and prevents durable responses in advanced-stage patients. Relapse is, in part, caused by drug tolerant persister cells (DTPs) which are able to survive treatment by entering a reversible, dormant state. Although long non-coding RNAs (lncRNAs) regulate processes thought to allow DTPs to survive and become stably resistant, the potential roles of lncRNAs in DTPs are largely unknown. In this study, we sought to investigate the expression of lncRNAs in in vitro DTP models of lung adenocarcinoma. We found that the lncRNAs Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) were enriched in DTPs and that knocking down MALAT1 enhanced the effect of targeted therapies in both EGFR- and KRAS-mutant DTP models. To better understand pathways that MALAT1 might regulate in DTPs, bulk RNA-sequencing was performed and several pathways that may contribute to the actions of MALAT1 in DTPs were identified. Overall, our work describes a role for the lncRNA MALAT1 in DTPs in NSCLC and suggests that MALAT1 may be a novel target for the prevention of drug tolerance and subsequent resistance to targeted therapy in NSCLC.

cancer biology↗

bioRxiv2026

Glutamine-dependent downregulation of FLT3-ITD is a mechanism of FLT3 inhibitor resistance in FLT3-ITD AML in hypoxia

FLT3 inhibitors have improved outcomes in acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD), but responses are not durable. Notably, FLT3 inhibitors clear blasts from the blood, but not the bone marrow, a hypoxic niche. We investigated effects of hypoxia and the key nutrient glutamine on FLT3 inhibitor response. FLT3-ITD AML cell lines and patient blasts were cultured with FLT3 inhibitors under normoxia (21%) or hypoxia (<1% O2) with or without glutamine or the glutaminase inhibitor telaglenastat (CB-839). Cytotoxicity was measured in WST-1 assays and drug combination effects by Chou-Talalay analysis. Protein expression was measured by immunoblotting, turnover and proteasomal degradation by cycloheximide chase with and without MG-132, and mRNA expression by RT-qPCR. Effect of the ubiquitin ligase c-CBL was tested by siRNA knockdown. FLT3 inhibitor IC50s were 3-5-fold higher in hypoxia than normoxia, associated with FLT3-ITD and p-STAT5 downregulation and accelerated FLT3-ITD proteasomal degradation (half-life, 1.0 vs. 2.5 hours). c-CBL expression increased in hypoxia, and c-CBL knockdown restored FLT3-ITD expression and FLT3 inhibitor sensitivity. Glutamine deprivation or telaglenastat treatment abrogated c-CBL upregulation in hypoxia and preserved FLT3-ITD and p-STAT5 expression and FLT3 inhibitor sensitivity. Telaglenastat synergized with FLT3 inhibitors in hypoxia, supporting clinical testing. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/722336v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1746bf8org.highwire.dtl.DTLVardef@5c9cdeorg.highwire.dtl.DTLVardef@3ee12aorg.highwire.dtl.DTLVardef@30c90c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Unique nasal cell states induced by common pediatric respiratory viruses

Respiratory viral infections in early childhood are major drivers of acute morbidity and long-term airway disease, yet how distinct viruses remodel the pediatric nasal mucosa at cellular resolution remains unresolved. Here, we generated a single-cell RNA sequencing atlas of 335,174 nasal epithelial and immune cells from 132 children under five years of age with SARS-CoV-2, rhinovirus, or respiratory syncytial virus (RSV) infection, alongside uninfected controls. Mapping viral transcripts to individual cells revealed virus-specific infected epithelial states: an NF-kB-responsive ciliated subset in SARS-CoV-2 and a previously undescribed KRT17+ squamous-like subset in RSV. We delineated divergent mucosal response programs, including a robust interferon (IFN) response in SARS-CoV-2, an IL-13-responsive secretory program in rhinovirus, and heightened inflammatory and cytotoxic immune activation in RSV. In RSV, specific immune subsets and elevated IFN-response signatures were associated with disease severity, whereas rhinovirus-induced wheeze was marked by expansion of a CST1+ goblet cell subset. Integration of asthma genome-wide association data with our atlas revealed a KRT13+ hillock-like squamous epithelial subset enriched for expression of childhood-onset asthma risk loci. Finally, we demonstrate that this resource enables high-resolution annotation of independent pediatric cohorts in Kolkata, India and rural Bangladesh. Together, this atlas establishes a comprehensive view of antiviral immunity in the pediatric nasal mucosa and defines virus-specific mucosal immune programs relevant to disease severity and asthma risk in early life.

immunology↗

bioRxiv2026

Minimum inoculum of resistance assay for evaluating for anti-toxoplasmosis compounds that target phenyl alanine tRNA synthetase

Toxoplasma gondii is a globally important intracellular parasite, and treatment regimens are limited by the failure of drugs to target latent tissue cysts. Developing new candidates for treatment also needs to address the potential for resistance to arise. Here, we developed a Minimum Inoculum for Resistance (MIR) assay as a quantitative metric for evaluating inhibitors of T. gondii. The MIR assay, adapted from assays used in malaria drug discovery, measures the frequency for pre-existing resistance alleles by exposing different sized parasite populations to drug pressure. We profiled a series of bicyclic pyrrolidone analogs that inhibit phenylalanine tRNA synthetase (PheRS). We demonstrate that these inhibitors require higher inocula to lead to parasite resistance (up to > 108 parasites) in comparison with an inhibitor of DNA synthesis, and that MIR values vary across inhibitors with closely related chemical structures. Clonal analysis of resistant parasites emerging from MIR assays revealed both new and previously identified resistance conferring mutations in TgPheRS, and structural modeling revealed their potential impact the enzyme active site. The MIR assay provides a functional benchmark to compare new and existing inhibitors, allowing for rational prioritization of lead compounds with a high genetic barrier to resistance.

microbiology↗

bioRxiv2026

Structural determinants of broadly neutralizing human antibodies binding to morphological dengue virus variants.

Dengue virus (DENV) is a global health threat, with four antigenically distinct serotypes impeding vaccine and therapeutic development. We describe here, structural features of patient-derived, heavy chain-driven E-dimer-recognizing (HEDR) antibodies that achieve potent, pan-serotype activity by binding a conserved quaternary epitope on DENVs envelope (E) glycoprotein dimer. Single-particle cryo-EM structures of three HEDR broadly neutralizing antibodies (bnAbs) complexed to DENV delineate epitope engagement via E-glycoproteins fusion loop region and conserved glycans. We also identify capsule-shaped DENV, with helical cryo-EM reconstructions of Fab-bound tubular DENV from different strains revealing that the E-glycoprotein arrangement is determined by virus strain, not bnAb identity. Our findings elucidate key binding features of HEDR bnAbs and signify the need for intervention strategies capable of neutralizing diverse DENV morphologies.

biophysics↗

bioRxiv2026

A Benchmarking Framework for Comparative Evaluation of Low-Complexity Region Detection Tools in the Human Proteome

Low-complexity regions (LCRs) are compositionally biased segments of proteins that play critical roles in molecular recognition, structural flexibility, and phase separation. Yet, their accurate detection remains challenging due to methodological variability among computational tools. In this study, we conducted a comprehensive benchmarking of eight widely used LCR detection methods (with different parameter settings) across the Homo sapiens proteome. A modular computational framework was developed to systematically compare LCR characteristics, including residue-centric analyses such as length distributions and coverage percentages. Protein-centric analyses consisted of compositional bias, amino acid composition, and Shannon entropy. Consensus analyses revealed that regions detected by multiple tools were typically longer, more repetitive, and compositionally purer, suggesting stronger structural or functional relevance. Jaccard similarity matrices demonstrated distinct clustering patterns among algorithms based on shared detection principles. Additionally, entropy and purity analyses highlighted fundamental differences in sequence complexity captured by each tool. Together, these results provide a unified, reproducible framework for evaluating LCR detection performance and offer practical guidelines for reliably annotating low-complexity regions in proteome-scale studies.

bioinformatics↗

bioRxiv2026

Operations Near the Edge of cognitive decline: Behavioral and Neural Correlates of cognitive load in Mild cognitive impairment

MotivationEarly detection of cognitive strain is essential for identifying Mild Cognitive Impairment (MCI) and its progression to more severe neurodegenerative diseases. This study investigates cognitive strain in MCI by examining both behavioral and neural correlates during a real-world task. MethodsTwenty-four older adults (M=69, 14 male, 10 female), including 11 with MCI and 13 healthy controls (MMSE >22/30), performed a spatial navigation task under varying memory load. We recorded brain activity using electroencephalography (EEG) and a mismatch negativity (MMN) paradigm to capture error-related potentials (ErrPs), which reflect cognitive load and processing errors. ResultsBoth groups showed a decline in working memory performance as cognitive load increased ({beta} = -41.39, SE = 10.73, t(90) = -3.86, p < .001). MCI participants, however, exhibited more efficient use of non-intrinsic (allocentric) reference frames under high cognitive load ({beta} = 2.47, SE = 0.95, t(82) = 2.61, p = .009). MCI individuals also displayed larger ErrPs in central brain regions, indicating greater neural resource allocation. Additionally, MCI participants showed a decrease in parietal-to-frontal theta dominance under high load ({beta} = -0.68, SE = 0.32, t(90) = -2.12, p = .037), and reduced fronto-parietal connectivity. DiscussionThese findings suggest that MCI participants experience greater cognitive strain, evidenced by increased neural resource allocation and strategy-shifting under load. This heightened strain may serve as an early marker of MCI progression, offering potential for early detection of pathological changes.

neuroscience↗

bioRxiv2025

A changing hierarchy of environmental time cues guide development of the migratory pest moth Loxostege sticticalis

Insects use environmental cycling cues to align developmental progression. In holometabolous insects, the progression from larva to adulthood entails decision points, i.e., larval diapause and adult eclosion, that engage circadian timing mechanisms. What environmental time cues dynamically interact to regulate these developmental checkpoints lying at the intersection of the orthogonal timing systems, remains elusive. We used the seasonally migratory insect Loxostege sticticalis to disentangle the influence of photoperiod regimes and temperature conditions at distinct checkpoints of larval growth and metamorphosis. We here employed sensory conflict paradigms to reveal that the relative dominance of these cues changes over ontogeny. Our results confirm that diapause is induced primarily by the photoperiod during early larval development, rather than by the diel thermoperiod. In contrast, the circadian clock-controlled adult eclosion, normally locked to the first hour of the daybreak, is jointly controlled by light and temperature cycles. An increase in the constant temperature advanced the peak timing of daily eclosion. On the other hand, the interval timing mechanism regulating the duration of the eclosion event is tuned specifically by the night temperatures. Together, photoperiod dominates early developmental decisions, but thermoperiod gains weight at later stages. This shifting hierarchy provides a mechanistic framework for understanding phenological plasticity. Since the timing of eclosion presents a window of increased vulnerability for this pest insect, our results could help to optimize the daily timing of pest management intervention under variable thermal and light conditions.

ecology↗

bioRxiv2025

Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors

FLT3 inhibitor efficacy in AML with FLT3-ITD is short-lived, frequently due to new mutations, most commonly in NRAS. Sphingosine kinase 1 (SPHK1), which phosphorylates sphingosine to generate sphingosine-1-phosphate (S1P), is upregulated and localized to the plasma membrane in RAS-mutated cells. We studied S1P and FLT3 co-targeting to overcome FLT3 inhibitor resistance in NRAS-mutated FLT3-ITD AML cells. NRAS-mutated FLT3-ITD AML cell lines and patient blasts were treated with FLT3 inhibitors and/or S1P receptor (S1PR) modulators. FLT3 inhibitor sensitivity was assessed by immunoblotting, cytotoxicity and apoptosis assays. Co-treatment was also assessed in vivo in an orthotopic mouse model. Downstream RAS and SPHK1 effectors were measured by immunoblotting and qRT-PCR. The S1PR modulators fingolimod (FTY720) and mocravimod (KRP-203) resensitized FLT3-ITD-expressing MOLM-14 and MV4-11 human AML cells with G12D, G12S, Q61K or Q61H, but not G12C, and patient blasts with G13D or G13V NRAS mutations to FLT3 inhibitors. Moreover, FTY720 co-treatment resensitized G12D NRAS-mutated M14(R)701 cells to gilteritinib in vivo. Co-treatment inactivated ERK, transcriptionally downregulated SPHK1, and inactivated downstream AKT, p70S6K and BAD, with inactivation abrogated by constitutive SPHK1 expression. The clinically applicable S1PR modulators fingolimod and mocravimod resensitize NRAS-mutated FLT3-ITD AML cells to FLT3 inhibitors, supporting potential clinical efficacy of these combinations.

cancer biology↗

bioRxiv2025

An Engineered Living Material with pro-angiogenic activity inducible by near-infrared light

Impaired angiogenesis is a central barrier in the treatment of chronic and deep tissue wounds, preventing progression through the normal healing cascade. While the combination of near-infrared (NIR) photobiomodulation and pro-angiogenic growth factors has shown synergistic therapeutic benefit, the clinical translation of growth factor therapy is hindered by high cost, instability and the need for localized dosing to avoid aberrant vasculature. Peptidomimetics such as the VEGF-derived QK peptide offer a more stable and predictable alternative, but still require a means for localized, tunable presentation. Here, we establish an engineered living material based delivery system that responds to clinically relevant NIR light to produce and releases a QK-Fusion protein directly at the target site. The probiotic Escherichia coli Nissle 1917 was engineered with an 800 nm-responsive optogenetic circuit and encapsulated within an optimized alginate core-shell hydrogel that ensures biocontainment while allowing controlled outward diffusion of the secreted peptide. The released peptide remains non-cytotoxic and capable of binding extracellular matrix analogs and promoting the formation of organized, branched capillary-like networks in endothelial cultures. We thus establish a strategy for developing engineered living materials towards remote-controlled angiogenic stimulation.

bioengineering↗

bioRxiv2025

Shared Binding Site but Divergent Resistance Profiles Uncover Novel Resistance Mechanisms in Plasmodium HSP90 Inhibitors

Drug resistance is a widespread problem across therapeutic areas including malaria, but what accounts for resistance propensity remains poorly understood. Here, we reveal that two HSP90 inhibitors targeting the identical ATP-binding site exhibit dramatically different resistance profiles in P. falciparum. Geldanamycin readily selected 10 distinct resistance mutations conferring up to 22-fold resistance, while AUY-922 required 44 weeks to yield a single A41S mutation with only 2-fold resistance to AUY-922 but not to geldanamycin. Resistance mapping in parasites and yeast revealed geldanamycin resistance mutations distributed throughout the binding pocket whereas AUY-922 resistance mutations localized close to the ATP-binding site. Unexpectedly, the A41S mutation enhanced AUY-922 binding affinity without changing geldanamycin binding. In silico analysis suggested this enhancement occurs through additional hydrogen bonding, yet stronger binding correlated with resistance. In yeast, A41S had opposite effects, hypersensitizing cells to all HSP90 inhibitors tested. Additionally, conditional HSP90 knockdown increased geldanamycin sensitivity but left AUY-922 activity unaffected, indicating different target dependencies despite shared binding sites. Based on these data, we propose a multi-target hypothesis where AUY-922s lower resistance risk stems from engaging multiple HSP90 family members. Our findings reveal how enhanced drug-target binding can paradoxically correlate with resistance and demonstrate that resistance risk cannot be predicted from binding site identity alone, providing insights for developing more durable drugs across therapeutic areas.

microbiology↗