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Srikanth, V.

Publications and source records attributed to Srikanth, V..

3 recordsLinked to original sources

Hydrodynamic dispersion drives viral-cellular contact for gene delivery in porous media

Reactive biological processes often hinge on rare collisions between particles that occupy vastly different physical regimes, yet the transport physics that govern these encounters remain poorly understood. Biological cell-virus encounters offer a uniquely quantifiable instance of this general problem: collisions between particles whose transport is governed by entirely different physical mechanisms, yet whose interactions determine system-level function. In stagnant liquids, nanoscale viral vectors explore space only through slow Brownian diffusion, while microscale cells rapidly sediment, producing species separation that suppresses the virus-cell interaction interface. Here we show that liquid absorption into a dry, macroporous sponge enhances viral-cellular interactions by shifting the system into an advection-dispersion regime that circumvents this sedimentation-diffusion limit. By integrating experimental results with a multiscale simulation model, we demonstrate that the tortuous sponge porosity converts capillary-driven flow into convective mixing, driving orders-of-magnitude increases in viral-cellular collision rates. Coupling these dispersive transport dynamics with a probabilistic capture model reveals that hydrodynamic dispersion accounts for the multifold enhancement in viral-cellular transduction efficiency observed in porous sponges. These results provide a quantitative framework for emergent collision dynamics in complex porous media and establish a generalizable strategy to optimize active transport in spatiotemporally heterogeneous biological systems.

bioengineering↗

Participant followup rate can bias structural imaging measures in longitudinal studies

Longitudinal MRI analysis is essential to accurately describe neuroanatomical changes over time. Loss of participants to followup (dropout) in longitudinal studies is inevitable and can lead to great difficulty in interpretation of statistical results if dropout is correlated with a study outcome or exposure. Beyond this, technical aspects of longitudinal MRI analysis require specialised processing pipelines to improve reliability while avoiding bias towards individual timepoints. In this article we test whether there is an additional problem that must be considered in longitudinal imaging studies, namely whether dropout has an impact on the function of FreeSurfer, a popular software pipeline used to estimate important structural brain metrics. We find that the number of acquisitions available per individual can impact the estimation of cortical thickness and brain volume using the FreeSurfer longitudinal pipeline, and can induce group differences in brain metrics. The effect on trajectories of brain metrics is smaller than the effect on brain metrics. HighlightsO_LILongitudinal MRI analysis is essential to accurately track neuroanatomical changes over time C_LIO_LILongitudinal MRI analysis requires specialised processing pipelines to reduce bias towards single timepoints C_LIO_LIParticipant drop out or loss can bias neuroanatomical measures derived from longitudinal pipelines C_LIO_LIWe find that group differences in the number of acquisitions available to analyse can cause group differences in estimated cortical thickness and brain volume C_LIO_LIThis bias appears to be due to the number of scans used to create individualised templates in the Freesurfer longitudinal pipeline C_LIO_LIThe effect on estimates of brain metric trajectories appears smaller than the effect on the estimates of brain metrics C_LI

neuroscience↗

The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1

SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that depletes cellular dNTPs in non-cycling cells to promote genome stability and to inhibit retroviral and herpes viral replication. In addition to being substrates, cellular nucleotides also allosterically regulate SAMHD1 activity. Recently, it was shown that high expression levels of SAMHD1 are also correlated with significantly worse patient responses to nucleotide analogue drugs important for treating a variety of cancers, including Acute Myeloid Leukemia (AML). In this study, we used biochemical, structural, and cellular methods to examine the interactions of various cancer drugs with SAMHD1. We found that both the catalytic and the allosteric sites of SAMHD1 are sensitive to sugar modifications of the nucleotide analogs, with the allosteric site being significantly more restrictive. We crystallized cladribine-TP, clofarabine-TP, fludarabine-TP, vidarabine-TP, cytarabine-TP, and gemcitabine-TP in the catalytic pocket of SAMHD1. We find that all of these drugs are substrates of SAMHD1 and that the efficacy of most of these drugs is affected by SAMHD1 activity. Of the nucleotide analogues tested, only cladribine-TP with a deoxyribose sugar efficiently induced the catalytically active SAMHD1 tetramer. Together, these results establish a detailed framework for understanding the substrate specificity and allosteric activation of SAMHD1 with regards to nucleotide analogues, which can be used to improve current cancer and antiviral therapies.\n\nSignificanceNucleoside analogue drugs are widely used to treat a variety of cancers and viral infections. With an essential role in regulating the nucleotide pool in the cell by degrading cellular nucleotides, SAMHD1 has the potential to decrease the cellular concentration of frequently prescribed nucleotide analogues and thereby decrease their clinical efficacy in cancer therapy. To improve future nucleotide analogue treatments, it is important to understand SAMHD1 interactions with these drugs. Our work thoroughly examines the extent to which nucleotide analogues interact with the catalytic and allosteric sites of SAMHD1. This work contributes to the assessment of SAMHD1 as a potential therapeutic target for cancer therapy and the future design of SAMHD1 modulators that might improve the efficacy of existing therapies.

biochemistry↗