Biology subjects

Bhandarkar, S.

Publications and source records attributed to Bhandarkar, S..

3 recordsLinked to original sources

bioRxiv2026

Spatial distribution of blood-brain barrier membrane proteins is controlled by sorting motifs and physiological signals in vivo

The blood-brain barrier (BBB), formed by brain endothelial cells (BECs), creates a safe and homeostatic environment for proper brain function. Together with pericytes and astrocytes, the BBB controls substance influx and efflux into and out of the brain. While BECs are extraordinarily thin, their luminal and abluminal plasma membranes face markedly different environments: the blood and brain parenchyma, respectively. How BBB membrane proteins are spatially distributed between these membranes and the factors regulating their localization are not clear. Here, we establish a method for measuring polarized protein sorting at the BBB in vivo. We characterize the distribution of transporters and receptors on the luminal and abluminal plasma membranes and identify protein-intrinsic motifs that control polarized sorting. Finally, we observe a change in membrane protein distribution that aligns with circadian rhythms, revealing an under-appreciated dimension of BBB dynamics. This method can be broadly used for evaluating membrane protein landscape changes during development and disease and for choosing optimal molecular targets for BBB-crossing therapeutics.

cell biology↗

bioRxiv2024

Structured flexibility in recurrent neural networks via neuromodulation

The goal of theoretical neuroscience is to develop models that help us better understand biological intelligence. Such models range broadly in complexity and biological detail. For example, task-optimized recurrent neural networks (RNNs) have generated hypotheses about how the brain may perform various computations, but these models typically assume a fixed weight matrix representing the synaptic connectivity between neurons. From decades of neuroscience research, we know that synaptic weights are constantly changing, controlled in part by chemicals such as neuromodulators. In this work we explore the computational implications of synaptic gain scaling, a form of neuromodulation, using task-optimized low-rank RNNs. In our neuromodulated RNN (NM-RNN) model, a neuromodulatory subnetwork outputs a low-dimensional neuromodulatory signal that dynamically scales the low-rank recurrent weights of an output-generating RNN. In empirical experiments, we find that the structured flexibility in the NM-RNN allows it to both train and generalize with a higher degree of accuracy than low-rank RNNs on a set of canonical tasks. Additionally, via theoretical analyses we show how neuromodulatory gain scaling endows networks with gating mechanisms commonly found in artificial RNNs. We end by analyzing the low-rank dynamics of trai ned NM-RNNs, to show how task computations are distributed.

neuroscience↗

bioRxiv2024

Quantitative profiling of human translation initiation reveals regulatory elements that potently affect endogenous and therapeutically modified mRNAs

mRNA therapeutics offer a potentially universal strategy for the efficient development and delivery of therapeutic proteins. Current mRNA vaccines include chemically modified nucleotides to reduce cellular immunogenicity. Here, we develop an efficient, high-throughput method to measure human translation initiation on therapeutically modified as well as endogenous RNAs. Using systems-level biochemistry, we quantify ribosome recruitment to tens of thousands of human 5' untranslated regions and identify sequences that mediate 250-fold effects. We observe widespread effects of coding sequences on translation initiation and identify small regulatory elements of 3-6 nucleotides that are sufficient to potently affect translational output. Incorporation of N1-methylpseudouridine (m1{Psi}) selectively enhances translation by specific 5' UTRs that we demonstrate surpass those of current mRNA vaccines. Our approach is broadly applicable to dissect mechanisms of human translation initiation and engineer more potent therapeutic mRNAs. HighlightsO_LIMeasurement of >30,000 human 5' UTRs reveals a 250-fold range of translation output C_LIO_LISystematic mutagenesis demonstrates the causality of short (3-6nt) regulatory elements C_LIO_LIN1-methylpseudouridine alters translation initiation in a sequence-specific manner C_LIO_LIOptimal modified 5' UTRs outperform those in the current class of mRNA vaccines C_LI

systems biology↗