Biology subjects

Kshirsagar, A.

Publications and source records attributed to Kshirsagar, A..

6 recordsLinked to original sources

bioRxiv2025

The Earlier You Know, the Smoother You Act

Intercepting a moving object with our hands requires that the moving object and the hand come into contact at some point along the objects trajectory. Hand movement must, therefore, be planned in advance so that the hand reaches a chosen spatial location along this trajectory at the correct moment in time. To enable such anticipatory behavior, the objects trajectory must be predicted based on sensory information collected before movement planning is concluded. Early completion of planning would allow for a smooth and economical movement; however, it also requires sufficiently accurate information about the objects movement to be available earlier. We investigate interception in the context of a complex, naturalistic motor task, toss juggling, to understand the extent to which proprioceptive and tactile information influence anticipatory movements of the catching hand. In our study, we compared solo juggling, where the efferent, tactile and proprioceptive information from the throwing hand is available during catch planning, with dyadic juggling, a functionally "deafferented" condition where no such information is available because the ball has been thrown by another person. Our results indicate that when internal and tactile information from the toss is absent, anticipatory behavior is greatly reduced. Experienced jugglers seem to rely more strongly on internal information than vision, allowing earlier planning and lower target uncertainty. In the dyadic condition, when internal information is absent, trajectory planning is delayed, leading to greater target uncertainty.

neuroscience↗

bioRxiv2025

Paracrine Bone-Derived Senescent Secretome Induces Spatially Patterned ECM and Biomechanical Vulnerability in Human Brain Organoids

Aging is increasingly recognized as a systemic process, yet the mechanisms by which senescent cells signal from peripheral tissues accelerate brain aging remain poorly defined. Here, we used chronic exposure of human cerebral organoids to the secretome of senescent osteocytes to investigate how peripheral aging signals reshape brain tissue architecture. We combined spatially resolved optical fiber-based interferometry nanoindentation with transcriptomic and immunofluorescence profiling, demonstrating that bone-derived senescence-associated secretory phenotype (SASP) factors induce a biphasic mechanical response, early global tissue softening, followed by the emergence of discrete hyper-stiff microdomains. This spatially heterogeneous biomechanical remodeling was accompanied by upregulation of extracellular matrix (ECM), inflammatory, and senescence pathways, and suppression of neurodevelopmental and synaptic gene networks. Our results reveal that chronic paracrine SASP exposure from senescent osteocytes drives localized ECM reorganization and mechanical vulnerability in human brain tissue, providing mechanistic insight into how peripheral cellular senescence may contribute to regional brain fragility during aging.

bioengineering↗

bioRxiv2025

Neural Progenitors as a Novel Pathogenic Mechanism in Microcephaly

Despite their significance, the genetic and molecular bases of neurodevelopmental disorders remain poorly understood. In this study, using human brain organoids and mouse models, we show that loss of NDE1, a gene closely associated with microcephaly, disrupts progenitor identity, prolongs mitosis, and alters regional patterning in the forebrain. NDE1 knockout leads to a caudal identity shift of neural progenitor cells in the organoids and mouse brains, coinciding with aberrant ERK signaling. Notably, downstream activation of the ERK pathway restored rostral PAX6 expression in human brain organoids. Parallel analyses of Nde1 knockout mice confirmed disrupted regional patterning of the forebrain. Together, our data establish NDE1 as a critical regulator of early human brain regionalization and elucidate molecular mechanisms underlying the structural abnormalities observed in NDE1-associated microcephaly.

developmental biology↗

bioRxiv2025

Point-Of-Need One-Pot Multiplexed RT-LAMP Test For Detecting Three Common Respiratory Viruses In Saliva

Respiratory viral infections pose a significant global public health challenge, partly due to the difficulty in rapidly and accurately distinguishing between viruses with similar symptoms at the point of care, hindering timely and appropriate treatment and limiting effective infection control and prevention efforts. Here, we developed a multiplexed, non- invasive saliva-based, reverse transcription loop-mediated isothermal amplification (RT- LAMP) test that enables the simultaneous detection of three of the most common respiratory infections, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Influenza (Flu), and respiratory syncytial virus (RSV), in a single reaction via specific probes and monitored in real-time by a machine-learning-enabled compact analyzer. Our results demonstrate that the multiplexed assay can effectively detect three target RNAs with high accuracy. Further, testing with spiked saliva samples showed strong agreement with reverse transcription polymerase chain reaction (RT-PCR) assay, with area under the curve (AUC) values of 0.82, 0.93, and 0.96 for RSV, Influenza, and SARS-CoV-2, respectively. By enabling the rapid detection of respiratory infections from easily collected saliva samples at the point of care, the device presented here offers a practical and efficient tool for improving outcomes and helping prevent the spread of contagious diseases. SignificanceThis research presents an innovative approach to respiratory infection diagnostics by combining a one-pot isothermal molecular test with machine learning-based analysis to simultaneously detect SARS-CoV-2, Influenza, and RSV in saliva samples. The battery- powered portable analyzer features novel machine-learning-assisted fluorescence detection for multiplexed reporter quantification, eliminating the need for traditional filter- based optical components and enabling adaptation to new targets without hardware changes. The test demonstrates high accuracy in detecting single and co-infections in spiked saliva samples, providing a rapid, cost-effective point-of-need solution. This tool can expand testing access, improve patient outcomes, and support more effective disease control, particularly in resource-limited or decentralized healthcare settings.

bioengineering↗

bioRxiv2025

Multi-Region Brain Organoid: Fusion Organoid with Cerebral, Endothelial and Mid-Hindbrain Components

Brain organoid technology has revolutionized our ability to model human neurodevelopment in vitro. However, current techniques remain limited by their reliance on simplified endothelial cell populations rather than a complete endothelial system. We engineered Multi-Region Brain Organoids (MRBOs) that integrate cerebral, mid/hindbrain, and complex endothelial organoids into one structure. Different from the earlier approaches based on isolated HUVECs, our endothelial organoids contain diverse vascular cell types, including vascular progenitors, mature endothelial cells, pericytes, proliferating angiogenic cells and stromal cells. Our strategy employs a sequential modulation of key developmental pathways to generate individual organoids, followed by optimized fusion conditions that maintain regional identities while supporting cellular integration. Single-nucleus RNA sequencing shows that MRBOs develop discrete neural populations specific to each brain region alongside specialized endothelial populations that establish paracrine signalling networks. Integration analysis with human fetal brain data shows that MRBOs contribute to 80% of cellular clusters found in human fetal brain tissue (Carnegie stages 12-16), whereas CellChat analysis identifies 13 previously uncharacterized endothelial-neural signalling interactions. Notably, we uncover endothelial-derived factors that support the persistence of intermediate progenitor populations during hindbrain development, but not during the cerebral one thereby revealing a new role for complex endothelial populations in regional brain patterning. This platform enables matching multiple developmental regions, fully incorporating the endothelial nature at the same time providing opportunities for studying neurodevelopmental disorders in which neural-endothelial interactions are disrupted. Our engineered MRBO system establishes a foundation for investigating complex neurodevelopmental processes, providing an enabling context closer to physiological relevance.

bioengineering↗

bioRxiv2022

LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways

Lissencephaly-1 (LIS1) is associated with neurodevelopmental diseases and is known to regulate the activity of the molecular motor cytoplasmic dynein. Here we show that LIS1 is essential for the viability of mouse embryonic stem cells (mESCs), and it regulates the physical properties of these cells. LIS1 dosage substantially affects gene expression, and we uncovered an unexpected interaction of LIS1 with RNA and RNA-binding proteins, most prominently the Argonaute complex. We demonstrate that LIS1 overexpression partially rescued the expression of extracellular matrix (ECM) and mechanosensitive genes conferring stiffness to Argonaute null mESCs. Collectively, our data transforms the current perspective on the roles of LIS1 in post- transcriptional regulation underlying development and mechanosensitive processes.

cell biology↗