Biology subjects

Saha, S.

Publications and source records attributed to Saha, S..

At least 19 recordsLinked to original sources

bioRxiv2026

iGEX: an interactive Gene EXpression exploration platform for the analysis of transcriptomic and proteomic datasets

High-throughput transcriptomic and proteomic studies have generated a rapidly expanding collection of publicly available datasets. However, extracting biological insight from these resources often requires researchers to repeatedly download, reformat, integrate and analyse individual files using specialised tools. This process is time-consuming and often requires coding expertise. Here, we present iGEX, an interactive exploration platform that can incorporate publicly available and user-generated transcriptomic and proteomic datasets into a single visual workspace to simplify the analysis of multiple transcripts and/or proteins across numerous datasets. iGEX enables researchers to select gene/protein targets and experiments and compare expression patterns across biological conditions and experiments. User-generated data can be examined alongside numerous public resources such as EMBL-EBI Expression Atlas, Bgee, and PaxDb to determine whether any observed patterns are evident across experiments, species or experimental contexts. Users can visualise and move directly between data tables, principal component analysis, expression and correlation heatmaps, hierarchical clustering and volcano plots, all of which are editable and downloadable.

bioinformatics↗

bioRxiv2026

Mitochondrial dysfunction plays a key role in premature musculoskeletal aging in hypochondroplasia mouse model

Hypochondroplasia (HCH) is a mild form of chondrodysplasia, caused by variants in fibroblast growth factor receptor 3 (FGFR3). Today, the biological mechanism underlying musculoskeletal aging in HCH remains largely unknown. In this study, we show that Hch mice exhibit phenotypic traits of bone fragility and accelerated age-dependent articular cartilage and subchondral bone changes. Hch mice also presented decreased muscle strength and reduction in muscle fibers size. Furthermore, proteomics analyses of the cortical bone revealed that Hch mice follow a different aging trajectory than control. FGFR3 mutation leads to a premature boost of the mitochondrial processes forcing the mutant to reach a physiological state much earlier than the control. Together, these findings demonstrate that aging in Hch mice is accompanied by bone fragility and osteoarthritis-like changes. Proteomics analyses highlighted the key role for mitochondria in the cortical bone of Hch mice, providing insight into the mechanisms underlying premature aging in HCH.

genetics↗

bioRxiv2026

Parathyroid Hormone Receptor 1 Signaling Encodes Multifaceted Metabolic Programs in AgRP Neurons

Organisms continuously adapt food intake and nutrient utilization to fluctuating energy demands, requiring the brain to accurately integrate signals coming from diverse metabolic organs and local signals into distinct physiological responses. How hypothalamic neurons discriminate these signals to independently regulate feeding behavior and peripheral metabolism remains poorly understood. In recent years, a coordinated regulation between bone physiology and the central control of energy metabolism has emerged, opening questions about potential common hormonal networks and signaling pathways between the bone and the brain. Here, we identify parathyroid hormone receptor 1 (PTH1R) signaling, a master regulator of calcium ion biochemistry and bone formation, in Agouti-related peptide (AgRP) neurons as an unexpected neuroendocrine mechanism for the control of feeding behaviourand nutrient partitioning. the two cognate endocrine and paracrine ligands, PTH and PTH-related peptide (PTHrP), selectively activat segregated intracellular kinases activation and lipophagic processes in AgRP neuron, ultimately producing convergent physiological outputs. Together, our findings identify the parathyroid hormonal system acts as a fine-tuning mechanism in specialized neuronal circuits allowing for hypothalamic adaptive responses to energy demands and systemic metabolic signals. Keywords: Parathyroid hormone-related peptide (PTHrP), hypothalamus, arcuate nucleus, agouti-related peptide neurons, energy metabolism, fasting, autophagy, free fatty acids

neuroscience↗

bioRxiv2026

Root exudates enhance the ecological fitness of a non-native PGPR and reshape rhizosphere microbiome assembly

Root exudates play critical roles in rhizosphere microbiome assembly. Nevertheless, the molecular mechanisms by which plant growth-promoting rhizobacteria (PGPR) perceive these signals, adapt to the rhizosphere, and influence native microbial communities remain poorly understood. Here, using maize (Zea mays cv. Early Golden Bantam) and the rhizobacterium Priestia aryabhattai AB211, we took a multi-omics approach combining metabolomics, bacterial transcriptomics and proteomics, and rhizosphere metagenomics to elucidate the mechanism underlying this process. Maize root exudates were enriched in diverse carbon and nitrogen metabolites that promoted bacterial growth and induced extensive molecular reprogramming of pathways involved in nutrient acquisition, chemotaxis, motility, stress adaptation, and plant growth promotion, thereby enhancing rhizosphere competence. In field-conditioned soil, AB211 persisted as a core member of the maize rhizosphere microbiome, promoted early seedling growth, and reshaped microbial community composition and function. Root exudates-primed (RE-primed) AB211 further enhanced the enrichment of microbial functions associated with nutrient cycling, quorum sensing, plant growth promotion, and rhizosphere fitness, highlighting the role of root exudates in modulating the rhizosphere-adaptative potential of beneficial bacteria. These findings establish a mechanistic framework linking root exudates composition with PGPR adaptation and microbiome assembly, providing a foundation for engineering ecologically adapted microbial inoculants to improve crop productivity and sustainable agriculture.

microbiology↗

bioRxiv2026

Reactivation of neural signatures of food during REM-like sleep in the high-level visual cortex of monkeys

Can we tell what animals are dreaming about from their brain activity? This fascinating question has been explored extensively using the rodent hippocampus, where place cells are sequentially reactivated during sleep, consistent with replay of paths explored while awake. However, dreams involve vivid visual experiences, and whether analogous replays occur in the visual cortex has not been explored, that too in primates. To address this gap, we performed wireless neural recordings from the high-level visual (IT) and motor regions (PMv, PFC) in two monkeys while they viewed food images on a screen while awake, and afterwards while they slept in their natural setting. Decoders trained on sleep/wake neural activity in each region were able to accurately predict the ongoing sleep/wake state, as well as upcoming transitions between states. Interestingly, decoders trained to categorize neural responses to food (but not faces/objects) showed increased probability during REM-like sleep compared to NREM or awake states. Thus, behaviorally relevant visual stimuli seen while awake are reactivated during REM-like sleep. In other words, these monkeys saw food, faces and objects while awake, and dreamt selectively about food while sleeping.

neuroscience↗

bioRxiv2026

Bone regulates locomotion by sustaining motoneuronal mitochondrial function

Body-brain communication is crucial for optimal neuronal performance across the lifespan, yet whether peripheral organs regulate spinal cord motoneuron (MN) function through circulating molecules remains unknown. The expression of hormone receptors by spinal MNs raises the possibility that circulating cues allow the spinal cord to sense the body's energetic state and sustain motor activity. Here, we show that the bone-derived hormones osteocalcin (OCN) signals on spinal MNs via its receptor GPR158. GPR158 is selectively enriched in spinal cholinergic MNs, and its loss, globally or specifically in spinal MNs, or the one of OCN, impairs locomotor function and reduces choline acetyltransferase (ChAT) levels. Mechanistically, OCN signaling through GPR158 fine-tunes autophagy, mitophagy and mitochondrial activity in spinal MNs. Restoring any of these processes, by pharmacologically inducing mitophagy or chemogenetically activating mitochondria, is sufficient to rescue the locomotor deficits of Gpr158-deficient mice. Finally, OCN restoration in aged mice reverses age-related locomotor decline through a mechanism that requires MN autophagy and mitophagy. This study reveals that through OCN, the skeleton influences motor functions by fine-tuning motoneuronal mitochondria, and suggests that age-related motor decline is, at least in part, reversible.

neuroscience↗

bioRxiv2026

High-level visual and motor regions are doubly dissociated in controlled tasks but only at specific times during natural behaviors

Our knowledge of the neural basis of sensory and motor information processing comes largely from recording brain activity in controlled settings. This approach, while insightful, blinds us from understanding natural behaviors, which involve far richer visual inputs and far larger range of movements. The prevailing belief is that, during natural behaviors, movement information would modulate visual cortex, and visual inputs would modulate motor cortex. Alternatively, this mixing might only reflect correlations between sensory inputs and movements present during natural behavior. To resolve this issue, we performed wireless recordings from high-level visual (IT) and motor regions (PMv/PFC) in freely moving monkeys while they performed a natural task and a fixation task. In each task, we extracted visual and movement features and asked to what degree these features explained neural activity. In the fixation task, we found a striking double dissociation whereby visual (but not movement) features predicted neural activity in IT, whereas motor (but not visual) features predicted neural activity in PMv & PFC. This dissociation was far weaker in the natural task but present particularly at key events when the visual and motor features were less correlated. Thus, high-level sensory and motor regions in the brain are doubly dissociated under controlled conditions, and remain so at specific times during natural behavior.

neuroscience↗

bioRxiv2026

ORMDL3-mediated SPT regulation Coordinates Myelin Sphingolipid and Protein Synthesis in Oligodendrocytes

Myelin is an essential and highly specialized membrane in the central and peripheral nervous systems that enwraps axons to accelerate electrical transmission and support neuronal health. The generation of this multilamellar structure requires a tightly coordinated synthesis of specific proteins and lipids. Among these are sphingolipids (SLs), which are major components of myelin. SL production is initiated by the serine palmitoyltransferase (SPT) enzyme complex, the rate-limiting enzyme in the de novo SL biosynthesis pathway. ORMDL proteins (ORMDL1-3) are the regulatory subunits of SPT, which, by sensing ceramide levels, tune SL flux. Although ORMDL3 has been linked to asthma and peripheral myelination, its role in CNS myelination and the CNS myelin-making oligodendrocytes (OLGs) remains unclear. We therefore assessed the function of ORMDL3 in OLs by generating a Cnp-Cre-driven, oligodendrocyte-specific Ormdl3 conditional knockout (cKO) mouse model. Loss of Ormdl3 selectively increased myelin SLs, particularly long-chain sulfatides, without altering ceramide or galactosylceramide abundance. These changes are most prominent around postnatal day 35, a developmental period of active myelin turnover. Ultrastructural analysis of optic nerves shows a thicker myelin sheath and increased axon caliber in cKO mice. Unexpectedly, deletion of Ormdl3 also increases levels of major myelin proteins (MBP, MOG, and PLP) and is accompanied by dynamic, region- and sex-dependent regulation of enzymes involved in sulfatide biosynthesis, without altering OLGs number or maturation. Together, for the first time, these findings identify Ormdl3 as a key regulator of SL homeostasis during developmental myelination and suggest that it helps synchronize lipid synthesis with myelin protein expression.

biochemistry↗

bioRxiv2026

Hyaluronan Surface Architecture Dictates Colorectal Cancer Progression and Extracellular Vesicle Communication

Hyaluronan (HA) is a principal component of the tumor glycocalyx in colorectal cancer (CRC). However, how the disease progression is linked to HA abundance and its nanoscale organization remains unclear. Single-molecule measurements of surface glycans on cell membranes and extracellular vesicles (EVs) have not yet been correlated. In this work, using single-molecule force spectroscopy, we mapped HA density and chain length on CRC cells and their EVs across Dukes' stages. HA density increased with stage in both compartments, but their organization diverged. Cell-surface HA became progressively fragmented, whereas EVs remained enriched in short HA chains at every stage. EVs, therefore, appear to select HA during formation rather than inherit it from the parent cell. This divergence had mechanical consequences. Both cells and EVs softened with stage, and removing HA reversed this softening. In addition, coarse-grained membrane simulations revealed that both HA chain length and surface density regulate membrane wrapping, with chain length primarily influencing wrapping kinetics and surface density affecting the final wrapping extent. These findings provide a physical basis for the differences we observed in EV uptake. Reprogramming stage D cells with exogenous high-molecular-weight HA reversed this signature, lowering EV surface HA density, stiffening the vesicles, slowing migration, and suppressing EV uptake by recipient cells. These findings establish HA surface architecture as a stage-encoded and experimentally reversible determinant of CRC progression.

biophysics↗

bioRxiv2026

Contributions of the gut microbiota and intestinal gluconeogenesis to metabolic adaptations in a mouse model of anorexia nervosa.

Anorexia nervosa is a metabolic-psychiatric disorder characterized by severe food restriction, often accompanied by hyperactivity, associated with high mortality and the lack of specific pharmacological treatment. Despite a marked energy deficit, patients paradoxically maintain euglycemia, suggesting adaptations in energy homeostasis. This study aims to characterize the interactions between food restriction, the gut microbiota and peripheral organs in a mouse model mimicking anorexia nervosa. Our results show that food-restricted mice exhibit improved glucose tolerance and increased expression of the gluconeogenic genes G6pc and Pck1 in the intestine, suggesting an adaptation in endogenous glucose production. Gut microbiota analysis reveals a marked shift in composition in food-restricted mice, with an increase in the Lachnospiraceae and Marinifilaceae families and a decrease in Lactobacillaceae. These changes are associated with metabolic parameters such as glycemia, body weight, and GLP-1 levels. Transfer of microbiota from food-restricted mice into control mice improves glucose tolerance and increases the gluconeogenic gene expression. Furthermore, the improvement in glucose tolerance is abolished in mice lacking intestinal gluconeogenesis, suggesting that intestinal gluconeogenesis is required for the effects of the FR microbiota on glucose homeostasis. Overall, these findings highlight a complex metabolic adaptation in a mouse model of anorexia nervosa, involving interactions between the gut microbiota, intestinal gluconeogenesis and maintenance of energy homeostasis.

physiology↗

bioRxiv2026

TBC-2, a Rab GTPase activating protein, regulates the localization of the HLH-30/TFEB and PQM-1 transcription factors in the C. elegans intestine

Insulin/IGF signaling (IIS) inhibits the nuclear localization of the DAF-16/FOXO transcription factor to regulate longevity and stress resistance in C. elegans. In the intestine, IIS promotes DAF-16 localization to endosomes and loss of TBC-2, a RAB-5 GAP, results in increased endomembrane localization of DAF-16 at the expense of nuclear localization, decreased DAF-16 target gene expression, longevity and stress resistance. Here we found that TBC-2 differentially regulates the localization of the IIS-regulated transcription factors PQM-1 and HLH-30/TFEB. Our results suggest a broader role for TBC-2 in negatively regulating IIS and that TBC-2 likely functions at an upstream point in the IIS pathway.

cell biology↗

bioRxiv2026

Graphene Device for High-Temperature Crystallography Visualizes How Enzymatic Reactivity is Rooted in Ensemble Probability

Life exists at temperatures ranging from -20 to 122 {degrees}C. However, the majority of high-resolution structural data in the Protein Data Bank (PDB) were obtained at cryogenic temperatures, where biological function is halted due to the lack of thermal fluctuations. To overcome this fundamental problem and directly link structure to biological function, we have created a graphene-based device that significantly extends the temperature range for high-resolution macromolecular X-ray diffraction data collection. Using the new device, we obtained models of the transition state ensembles for a psychrophilic, a mesophilic, and a thermophilic homolog of the enzyme orotidine 5-monophosphate decarboxylase from -173 to 65 {degrees}C. The data reveal how the active site ensemble structure at the transition state of each homolog changes with temperature, directly visualizing how the measured catalytic rates are rooted in the ensemble probabilities of reactive distances. The multi-temperature transition state ensembles further illuminate why cryogenic data, although useful, are inaccurate for describing biological processes.

biophysics↗

bioRxiv2026

Transforming clinical apheresis waste into a renewable source of patient-derived CD34+ hematopoietic stem cell biobank for beta-hemoglobinopathy research and therapeutic discovery

Background aimsThe development of next-generation therapies for sickle cell disease (SCD) and beta thalassemia (beta thal), including fetal globin-inducing small molecules and gene therapy approaches, depends on patient-derived CD34+ hematopoietic stem and progenitor cells (HSPCs) for discovery and preclinical validation, but commercial vendors stock only healthy donor material and disease-specific banks hold limited inventories. Recent US Food and Drug Administration and National Institutes of Health guidance favoring human cell-based methods over animal testing underscores the value of authentic patient cells. Methods: Over 14 months we recovered, purified, and biobanked CD34+ HSPCs from clinical apheresis product waste and mobilized peripheral blood (PB) otherwise discarded after clinical procedures, using immunomagnetic selection adapted for hemoglobinopathy specimens; a microfluidic technology was evaluated separately. We quantified yield and purity for bead-selected material and cell number and viability for the microfluidic pilot; engraftment was tested in NBSGW mice. Results: Immunomagnetic selection recovered a median of 4.71 x 106 CD34+ cells from just 1 to 2 mL of apheresis product waste, comparable to the 6.0 x 106 cells from a 10 to 40 fold larger volume of PB waste, with similar purity across sources and diagnoses. Because apheresis product waste is far more concentrated, it reaches equivalent yields without the density-gradient steps required for PB waste, approximately halving processing time. Recovered cells engrafted NBSGW mice, confirming preserved repopulating capacity. The microfluidic pilot (two patients, 11 specimens) recovered 2.17 x 106 CD34+ cells per specimen at greater than 90% viability and purity. Conclusions: A center with existing apheresis infrastructure can reproducibly recover, bank, and distribute research-grade patient CD34+ HSPCs, addressing a recognized gap in the hemoglobinopathy pipeline. HighlightsO_LIClinical apheresis waste is used to generate a single-center biobank of high-quality, research-grade CD34+ HSPCs from patients with sickle cell disease and beta-thalassemia. C_LIO_LIConcentrated apheresis waste matches large-volume PB waste in CD34+ yield and purity. C_LIO_LIMicrofluidic enrichment recovers CD34+ cells at >90% viability and purity across 2 patients. C_LIO_LIRecovered CD34+ HSPCs engraft mice and form erythroid cells, preserving function. C_LI

pharmacology and toxicology↗

bioRxiv2026

Microfluidic T-Chip enables one-step clinical-scale T-cell purification from blood products for CAR T-cell manufacturing

Treatment with chimeric antigen receptor (CAR) T cells has emerged as a promising immune therapy for relapsed and refractory hematologic malignancies. The CAR T cells are manufactured in a series of steps that involve isolating T cells from the patients leukapheresis product, genetically modifying them to express the CAR against the target antigen, and reinfusing them into the patient. Efficient T-cell enrichment from leukapheresis products is critical to the success of these therapies. Current methods for T-cell sorting on a clinical scale involve several washing steps to remove red blood cells and platelets, followed by T-cell selection and activation. These multi-step processes result in cell loss during processing and involve several handling steps. Here, we utilize fluidically assembled micromagnetic lenses to develop a high-throughput, continuous-flow microfluidic T-cell sorter, designated as the T-Chip, for sorting magnetic bead-labeled CD3+ T cells in a single step. Our approach allows direct sorting of T cells in expansion media from leukopaks without any washing steps, effectively removing 99.999% of RBCs and platelets from the leukapheresis product. A single 1-inch x 3-inch T-Chip can process leukapheresis product at a throughput of 60 mL/hr and 2.56 {+/-} 0.12 billion cells/hr. Using this optimized workflow, we demonstrate clinical-scale enrichment of highly pure CD3+ T cells (97.7 {+/-} 1.3%) with high viability (97.0 {+/-} 1.1%) and recovery (87.3 {+/-} 14.8%) in a functionally closed manner. Downstream processing of T cells isolated using the T-Chip yielded potent anti-mesothelin CAR T cells with demonstrated anti-tumor efficacy. Overall, by exploiting precisely engineered magnetic forces and laminar flow, the microfluidic T-Chip overcomes bottlenecks caused by low throughput and enables single-step large-scale T-cell purification for the rapid development of CAR T cells.

bioengineering↗

bioRxiv2026

Rational Redesign of an Fc-Binding Peptide for Multivalent Antibody Assembly

Multivalent antibody assemblies offer opportunities to enhance avidity, organize immune complexes, and modulate higher-order protein interactions, but constructing such architectures from existing immunoglobulin G (IgG) molecules without redesigning the antibody scaffold remains challenging. Here, we report the rational redesign of a Protein A-derived Fc-binding peptide into ADP1, a stable dimeric Fc-binding peptide that directs Fc-mediated antibody assembly. ADP1 was designed from the parent Fc-binding peptide Z34C by preserving the Fc-recognition surface while redesigning the opposite helical surface to promote peptide-peptide association. Biophysical characterization showed that ADP1 retained nanomolar Fc-binding affinity while exhibiting markedly enhanced chemical and proteolytic stability compared with the parent peptide. Structural analyses of ADP1-Fc complexes revealed that ADP1 bridges neighboring Fc regions through a combined ADP1-Fc and ADP1-ADP1 interface, generating spiral higher-order Fc assemblies. This assembly principle was further extended to full-length IgG, where ADP1 promoted higher-order antibody association in a concentration-sensitive manner. In addition, covalent ADP1 functionalization enabled Fc-directed modification of full-length IgG while retaining Fab-mediated antigen recognition, demonstrating the utility of ADP1 as an antibody assembly and functionalization module. Finally, competitive addition of the parent Z34C peptide modulated ADP1-driven antibody assembly, suggesting a potential route for tuning Fc-mediated assembly propagation. Together, this work establishes a redesigned Fc-binding peptide platform for directing multivalent antibody assembly and functionalization without genetic reengineering of the IgG scaffold. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/737354v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@57cadeorg.highwire.dtl.DTLVardef@1c7d8e6org.highwire.dtl.DTLVardef@170fb85org.highwire.dtl.DTLVardef@90e6d6_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Seizure-related gene 6 (SEZ6) encodes a Cancer stem cell-specific proangiogenic molecule: A novel glioma therapeutic target

Cancer stem-like cells (CSCs) not only initiate tumors but also orchestrate angiogenesis through multiple mechanisms, thereby sustaining vascularization and promoting tumor growth. In glioblastoma (GBM; WHO grade IV glioma), the most aggressive adult brain tumor, glioma stem-like cells (GSCs; glioma CSCs) are the main drivers of tumor progression, drug resistance, and recurrence. An interrogated multi-omic secretome analysis identified Wnt-{beta}-catenin signaling-regulated, membrane-localized Seizure Related 6 Homolog (SEZ6) as a patient-derived GSC-specific proangiogenic molecule. Silencing of SEZ6 inhibited the ability of the GSC secretome to induce angiogenic network formation by brain- and lung-derived endothelial cells, but not GSC growth as neurospheres in vitro. SEZ6 silencing also suppressed patient-derived GSC-initiated glioma tumors, resulting in reduced tumor vasculature in an orthotopic mouse model. We also found that SEZ6 induces TGF{beta}-dependent IL-8 expression in endothelial cells to promote angiogenesis. Coimmunoprecipitation and molecular dynamics simulation experiments determined that the Sushi 3 domain of SEZ6 mediates the interaction with TGF{beta} RII to activate the TGF{beta} pathway. Pharmacological inhibition of BACE1 with an in-house-developed small molecule, or blockade of the SEZ6-TGF{beta} RII interaction using a rationally designed peptide, markedly attenuated SEZ6-driven TGF{beta} signaling, and suppressed angiogenesis. Thus, our findings identify SEZ6 as a novel CSC-specific therapeutic target for GBM.

cancer biology↗

bioRxiv2026

Interplay between β-catenin transcriptional and cell-cell junction activity regulates homeostasis and collective dynamics in the intestinal epithelium

Wnt signaling is crucial for stem cell maintenance during development and homeostasis, and its dysregulation is implicated in cancers across multiple tissues. {beta}-catenin, the primary mediator of canonical Wnt signaling, is also a crucial adaptor protein at cell-cell junctions and is required for maintaining tissue integrity. How the interplay and potential competition between these discrete functions of {beta}-catenin influences tissue homeostasis and organization is not well understood. Here, we address this open question in the intestinal epithelium, which is highly dependent on Wnt signaling during homeostasis and regeneration. Ectopic activation of Wnt signaling in intestinal organoids by pharmacological or genetic perturbation leads to tissue fluidification and loss of epithelial integrity, while disrupting Wnt activity perturbs intracellular {beta}-catenin localization and dynamics at cell-cell junctions. Stabilization of cell-cell junctions increases {beta}-catenin accumulation at junctions at the expense of nuclear localization, while junctional perturbation leads to {beta}-catenin release from junctions into the cytoplasm, leading to dysregulation of Wnt signaling. Together, our findings indicate that in tissues with active Wnt signaling, the interplay between junction- and signaling-associated {beta}-catenin is crucial for stem cell regulation and tissue homeostasis.

cell biology↗

bioRxiv2026

Neurodevelopmental Inequality arising from Early Childhood Stunting: Evidences from Brain Connectivity

Early childhood stunting (ECS) affects millions of children globally and conjectured to result in suboptimal brain and cognitive development later in life. Charting out the trajectory of brain network development and most importantly how the compensation of function can be achieved gives windows of intervention to clinicians, educators and policy makers. In this study, advanced network neuroscience tools, graph theoretical methods applied on diffusion weighted MR-imaging (DWI) revealed the effects of ECS on white matter (WM) organization in a community-based birth cohort of 170 children (mean age = 9.18 years, SD = 0.28) from Vellore, India. Based on stunting status at ages two, five, and nine years, children were categorised into four groups: always stunted (AS; n=21), stunted until five with catch-up at nine (S5C9; n=31), stunted until two with catch-up at five (S2C5; n=28), and never stunted or typically developing (TD; n=90). The catch-up groups showed strikingly similar anthropometric measures compared to TD. However, all stunted groups (AS, S5C9, S2C5) showed significantly lower performance and verbal IQ scores compared to TD children. DWI data revealed AS children exhibited shorter tract lengths across select cortico-cortical connections, an increased number and strength of short- and medium-range connections, and a corresponding reduction in long-range connections and strength. Network analyses further revealed that AS and S5C9 groups displayed higher local clustering and local efficiency relative to TD, reflecting greater local segregation of brain networks. Hub-like modules was broadly conserved across groups, although both catch-up groups (S2C5 and S5C9) showed additional hubs, suggesting compensatory network reorganization via a more modular architecture. Together, these findings provide novel evidence that ECS is linked to altered structural reorganization of brain networks and reduced cognitive performance in later childhood. While persistent stunting (AS) is associated with the most pronounced alterations, partial catch-up (S2C5 and S5C9) is accompanied by compensatory adaptations, such as increased short-range connectivity and recruitment of additional hubs. These results underscore the critical importance of early nutritional interventions to support optimal brain network development.

neuroscience↗