Biology subjects

Vyas, S.

Publications and source records attributed to Vyas, S..

13 recordsLinked to original sources

bioRxiv2026

Understanding Strategic Motor Learning as a Process of Hypothesis Testing

Multiple learning processes contribute to successful goal-directed actions under changing physiological states, biomechanical constraints, and environmental contexts. Among these, explicit strategies enable us to discover new movement patterns when existing ones no longer achieve the desired outcome. Yet, how strategies are discovered during motor learning remains unknown. To address this, we developed a novel behavioral paradigm that isolates strategy discovery in response to a range of visuomotor perturbations. This approach revealed that strategy discovery unfolds through an initial period of systematic exploration across multiple candidate strategies, followed by an 'aha' moment in which behavior converges on a stable solution. To account for these dynamics, we developed a computational model based on hypothesis testing in which learners generate and evaluate visuomotor rules to counteract the perturbation. This hypothesis testing model outperformed a range of alternative accounts, including gradual error reduction, win-stay lose-shift learning, and sudden one-shot insight. Together, these findings identify hypothesis testing as a computational mechanism by which humans discover new strategies during motor learning.

neuroscience↗

bioRxiv2026

Pan-neutralization of parainfluenza viruses by a hemagglutinin-neuraminidase antibody

Human parainfluenza viruses (HPIVs) can cause severe respiratory illnesses, such as croup, bronchiolitis, and pneumonia, particularly in children, the elderly and immunocompromised individuals. No vaccines or specific therapeutics are available for use in humans. Here, we report the discovery of a human monoclonal antibody designated PVA269 that broadly and potently neutralizes all four HPIV subtypes, PIV5, and Sendai virus by targeting the hemagglutinin-neuraminidase (HN) glycoprotein. We show that PVA269 inhibits neuraminidase activity and hemagglutination of erythrocytes through insertion of a long heavy chain complementary-determining region 3 in the enzyme active site. We reveal that the antibody markedly remodels its interactions to accommodate distinct viral features across HPIV subtypes, such as HPIV2 N-linked glycans. These results define the molecular basis for the unique PVA269 pan-neutralizing activity of human and animal viruses spanning two genera. PVA269 provides potent prophylactic activity against HPIV3 replication in the upper and lower airways of the clinically predictive cotton rat model, thus supporting translation of its protective efficacy to humans. These data establish PVA269 as a best-in-class monoclonal antibody and a promising clinical candidate to prevent HPIV infection, transmission, and disease in vulnerable populations.

immunology↗

bioRxiv2026

Toll-like receptor 9 contributes in microglial activation and lysosomal dysfunction to promote Alzheimer disease

Toll like receptor 9 (TLR9) is an endosomal-lysosomal innate immune receptor which recognizes microbial and host-derived double-stranded DNA (dsDNA) to induce cellular immunity. TLR9 pathway has been implicated in Alzheimers disease (AD) pathology via its ability to modulate peripheral immune cells but its exact role in the central nervous system (CNS) remains unclear. Here we show that extranuclear dsDNA accumulating in human AD brain and in a mouse model of AD, together with microglia around amyloid-{beta} (A{beta}) plaques stimulates TLR9 in vitro. Loss of TLR9 inhibits the transition of homeostatic microglia to reactive microglia, a cell type associated with a chronic pro-inflammatory state, promoting their reprogramming into an anti-inflammatory state, thereby restoring lysosomal integrity required for A{beta} peptides degradation. Predisposition to lysosome permeabilization could be mimicked with repeated TLR9 stimulation using CpG-A ODNs in a human microglial cell line and was rescued with TLR9 inhibition. Furthermore, lack of TLR9 protects mice developing AD from cognitive defects and neuronal loss. A{beta} pathology is also reduced specifically in male mice. Altogether, our results have identified a critical role of TLR9 in AD, where it modulates microglial activation and lysosome function to interfere with the progression of AD. These findings suggest that targeting TLR9 signaling and lysosomal function may be a relevant strategic approach to reduce AD pathology.

immunology↗

bioRxiv2025

An estrogen-independent and IL-1-dependent pathway controls vulvovaginal candidiasis through combined IL-17/IL-22 signaling

Vulvovaginal candidiasis (VVC) affects >75% of women, with considerable morbidity and high medical cost burden. While Type 17 cytokines (IL-17, IL-22) are critical for oral and dermal immunity to C. albicans, their role in VVC has been less clear. Th17 gene signatures are potently upregulated in VVC, yet impairment of individual Th17 components (IL-17A, IL-17R subunits, IL-22) does not worsen disease. Rather, estrogen activity is tightly linked to VVC, leading to a paradigm that hormonal pathways rather than immune defense, dominate susceptibility. Here, we reveal a previously unappreciated role for IL-1/Type 17 in VVC that operates independently of estrogenic hormones. In contrast to mice lacking IL-17A, IL-17RA, IL-22, or IL-22R individually, mice lacking IL-17RA and IL-22RA1 together (Il17raIl22ra1-/-) exhibited high fungal loads and exacerbated tissue damage and inflammation. In human vulvar epithelial cells, IL-17 and IL-22 drive synergistic signaling. IL-1R signaling but surprisingly not IL-23 wa upstream of this response. Il17raIl22ra1-/- mice expressed high IL-1{beta} yet did not control disease, indicating that IL-1 is upstream but not downstream of Type 17 responses. Unexpectedly, Type 17-dependent control occurred in the absence of exogenous estrogen administration and persisted even when estrus was prevented by progesterone treatment. Collectively, these data indicate that susceptibility to VVC is driven not only by estrogen sensitization but through combinatorial loss of IL-17 and IL-22. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/671995v2_ufig1.gif" ALT="Figure 1000"> View larger version (52K): org.highwire.dtl.DTLVardef@19946e9org.highwire.dtl.DTLVardef@1feac71org.highwire.dtl.DTLVardef@eb433aorg.highwire.dtl.DTLVardef@18ab622_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Methylphenidate modulates motor cortical dynamics and behavior

Methylphenidate (MPH, brand: Ritalin) is a common stimulant used both medically and non-medically. Though typically prescribed for its cognitive effects, MPH also affects movement. While it is known that MPH noncompetitively blocks the reuptake of catecholamines through inhibition of dopamine and norepinephrine transporters, a critical step in exploring how it affects behavior is to understand how MPH directly affects neural activity. This would establish an electrophysiological mechanism of action for MPH. Since we now have biologically-grounded network-level hypotheses regarding how populations of motor cortical neurons plan and execute movements, there is a unique opportunity to make testable predictions regarding how systemic MPH administration - a pharmacological perturbation - might affect neural activity in motor cortex. To that end, we administered clinically-relevant doses of MPH to Rhesus monkeys as they performed an instructed-delay reaching task. Concomitantly, we measured neural activity from dorsal premotor and primary motor cortex. Consistent with our predictions, we found dose-dependent and significant effects on reaction time, trial-by-trial variability, and movement speed. We confirmed our hypotheses that changes in reaction time and variability were accompanied by previously established population-level changes in motor cortical preparatory activity and the condition-independent signal that precedes movements. We expected changes in speed to be a result of changes in the amplitude of motor cortical dynamics and/or a translation of those dynamics in activity space. Instead, our data are consistent with a mechanism whereby the neuromodulatory effect of MPH is to increase the gain and/or the signal-to-noise of motor cortical dynamics during reaching. Continued work in this domain to better understand the brain-wide electrophysiological mechanism of action of MPH and other psychoactive drugs could facilitate more targeted treatments for a host of cognitive-motor disorders.

neuroscience↗

bioRxiv2023

Large-scale brain-wide neural recording in nonhuman primates

High-density, integrated silicon electrodes have begun to transform systems neuroscience, by enabling large-scale neural population recordings with single cell resolution. Existing technologies, however, have provided limited functionality in nonhuman primate species such as macaques, which offer close models of human cognition and behavior. Here, we report the design, fabrication, and performance of Neuropixels 1.0-NHP, a high channel count linear electrode array designed to enable large-scale simultaneous recording in superficial and deep structures within the macaque or other large animal brain. These devices were fabricated in two versions: 4416 electrodes along a 45 mm shank, and 2496 along a 25 mm shank. For both versions, users can programmatically select 384 channels, enabling simultaneous multi-area recording with a single probe. We demonstrate recording from over 3000 single neurons within a session, and simultaneous recordings from over 1000 neurons using multiple probes. This technology represents a significant increase in recording access and scalability relative to existing technologies, and enables new classes of experiments involving fine-grained electrophysiological characterization of brain areas, functional connectivity between cells, and simultaneous brain-wide recording at scale.

neuroscience↗

bioRxiv2022

Direct neural perturbations reveal a dynamical mechanism for robust computation

The rich repertoire of skilled mammalian behavior is the product of neural circuits that generate robust and flexible patterns of activity distributed across populations of neurons. Decades of associative studies have linked many behaviors to specific patterns of population activity, but association alone cannot reveal the dynamical mechanisms that shape those patterns. Are local neural circuits high-dimensional dynamical reservoirs able to generate arbitrary superpositions of patterns with appropriate excitation? Or might circuit dynamics be shaped in response to behavioral context so as to generate only the low-dimensional patterns needed for the task at hand? Here, we address these questions within primate motor cortex by delivering optogenetic and electrical microstimulation perturbations during reaching behavior. We develop a novel analytic approach that relates measured activity to theoretically tractable, dynamical models of excitatory and inhibitory neurons. This computational model captures the dynamical effects of these perturbations and demonstrates that motor cortical activity during reaching is shaped by a self-contained, low-dimensional dynamical system. The subspace containing task-relevant dynamics proves to be oriented so as to be robust to strong non-normal amplification within cortical circuits. This task dynamics space exhibits a privileged causal relationship with behavior, in that stimulation in motor cortex perturb reach kinematics only to the extent that it alters neural states within this subspace. Our results resolve long-standing questions about the dynamical structure of cortical activity associated with movement, and illuminate the dynamical perturbation experiments needed to understand how neural circuits throughout the brain generate complex behavior.

neuroscience↗

bioRxiv2021

CRISPR-Cas9 mediated knockout of SagD gene for overexpression of streptokinase in Streptococcus equisimilis

Streptokinase is an enzyme that can break down the blood clots in some cases of myocardial infarction (Heart attack), pulmonary embolism, and arterial thromboembolism. Demand for streptokinase is high globally than the production due to increased incidences of various heart conditions. The main source of streptokinase is from various strains of Streptococcus. Expression of streptokinase in native strain Streptococcus equisimilis is limited due to the SagD inhibitor gene for production of streptokinase that needs to be knocked out in order to increase it expression. However, FasX is a small RNA (sRNA) present in group A Streptococcus species which is responsible for post-transcriptional regulation of streptokinase (ska) gene by binding at the 5 end of ska mRNA. S. equisimilis is a {beta}-hemolysin producing streptococcus bacterium (group C) containing the orthologue of FasX and natively expresses a clinically important thrombolytic streptokinase. In order to improve the stability of mRNA and increasing the expression of streptokinase which is inhibited by SagD. We used CRISPR-Cas9 to successfully knock-out of SagD gene and observed a 13.58-fold relative quantification of streptokinase expression in the mutant strain as compared to wild type. We have also demonstrated the successful target gene knockout using CRISPR-Cas9 in S. equisimilis that engineered strain can be used further for overexpression of streptokinase for therapeutic applications. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=68 SRC="FIGDIR/small/465095v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@8e3ebeorg.highwire.dtl.DTLVardef@b92f4eorg.highwire.dtl.DTLVardef@1d0dd8borg.highwire.dtl.DTLVardef@180ee54_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2021

A global dataset for the projected impacts of climate change on four major crops

Reliable estimates of the impacts of climate change on crop production are critical for assessing the sustainability of food systems. Global, regional, and site-specific crop simulation studies have been conducted for nearly four decades, representing valuable sources of information for climate change impact assessments. However, the wealth of data produced by these studies has not been made publicly available. Here, we develop a global dataset by consolidating previously published meta-analyses and data collected through a new literature search covering recent crop simulations. The new global dataset builds on 8314 simulations from 203 studies published between 1984 and 2020. It contains projected yields of four major crops (maize, rice, soybean, and wheat) in 91 countries under major emission scenarios for the 21st century, with and without adaptation measures, along with geographical coordinates, current temperatures, local and global warming levels. This dataset provides a basis for a comprehensive understanding of the impacts of climate change on crop production and will facilitate the rapidly developing data-driven machine learning applications.

plant biology↗

bioRxiv2020

Skill-specific changes in cortical preparatory activity during motor learning

Animals have a remarkable capacity to learn new motor skills, but it remains an open question as to how learning changes neural population dynamics underlying movement1. Specifically, we asked whether changes in neural population dynamics relate purely to newly learned movements or if additional patterns are generated that facilitate learning without matching motor output. We trained rhesus monkeys to learn a curl force field2 task that elicited new arm-movement kinetics for some but not all reach directions3,4. We found that along certain neural dimensions, preparatory activity in motor cortex reassociated existing activity patterns with new movements. These systematic changes were observed only for learning-altered reaches. Surprisingly, we also found prominent shifts of preparatory activity along a nearly orthogonal neural dimension. These changes in preparatory activity were observed uniformly for all reaches including those unaltered by learning. This uniform shift during learning implies formation of new neural activity patterns, which was not observed in other short-term learning contexts5-8. During a washout period when the curl field was removed, movement kinetics gradually reverted, but the learning-induced uniform shift of preparatory activity persisted and a second, orthogonal uniform shift occurred. This persistent shift may retain a motor memory of the learned field9-11, consistent with faster relearning of the same curl field observed behaviorally and neurally. When multiple different curl fields were learned sequentially, we found distinct uniform shifts, each reflecting the identity of the field applied and potentially separating the associated motor memories12,13. The neural geometry of these shifts in preparatory activity could serve to organize skill-specific changes in movement production, facilitating the acquisition and retention of a broad motor repertoire.

neuroscience↗

bioRxiv2019

High-fidelity Musculoskeletal Modeling Reveals a Motor Planning Contribution to the Speed-Accuracy Tradeoff

The speed-accuracy tradeoff is a fundamental aspect of goal-directed motor behavior, empirically formalized by Fitts law, which relates movement duration to movement distance and target width. Here, we introduce a computational model of three-dimensional upper extremity movements that reproduces well-known features of reaching movements and is more biomechanically realistic than previous models. Critically, these features arise without the need of signal-dependent noise. We analyzed motor cortical neural activity from monkeys reaching to targets of different sizes. We found that the contribution of preparatory neural states to movement duration variability was greater for smaller targets than larger targets, and that movements to smaller targets exhibited less variability in preparatory neural states, but greater movement duration variability. Taken together, these results suggest that Fitts law emerges from greater task demands constraining the optimization landscape in a fashion that reduces the number of "good" control solutions (i.e., faster reaches). Thus, the speed-accuracy tradeoff could be a consequence of motor planning variability and optimal control theory, and not exclusively signal-dependent noise, as is currently held. Significance StatementA long-standing challenge in motor neuroscience is to understand the relationship between movement speed and accuracy, known as the speed-accuracy tradeoff. We introduce a computational model of reaching movements based on optimal control theory using a realistic model of musculoskeletal dynamics. The model synthesizes three-dimensional point-to-point reaching movements that reproduce kinematics features reported in motor control studies. Such high-fidelity modeling reveals that the speed-accuracy tradeoff as described by Fitts law emerges even without the presence of motor noise, which is commonly believed to underlie the speed-accuracy tradeoff. This suggests an alternative theory based on suboptimal control solutions. The crux of this theory is that some features of human movement are attributable to planning variability rather than execution noise.

neuroscience↗

bioRxiv2018

Reversible temporally-specific inhibition of muscle using a light-activated chloride channel

Achieving reversible, temporally specific inhibition of motor neurons has the potential to revolutionize treatment of disorders marked by muscle hyperactivity. Current treatment strategies are inadequate - surgical interventions are irreversible and pharmaceutical interventions have off-target effects. Optogenetic strategies for inhibiting muscle activity have theoretical promise; however, trafficking and expression problems have prevented translatable optogenetic suppression of muscle activity. Here, we exploit recent innovations in opsin engineering to demonstrate virally mediated, temporally specific optogenetic inhibition of motor neurons and muscle activity in vivo. We show that intra-muscular injection of adeno-associated virus serotype 6 can drive expression of the inhibitory channelrhodopsin mutant iC++ in both immunodeficient and wild-type mice. Illumination of the sciatic nerve in wild-type mice resulted in 64.8% inhibition of evoked twitch force. Optical excitation during tetanic stimulation in wild-type mice resulted in 59.1% inhibition at 10 Hz and 55.4% at 25 Hz. The extent of optogenetic inhibition was titratable, and ranged from 0% to 78.4% as illumination intensity was changed from 1 mW to 20 mW/mm2. These results could have therapeutic applicability to disorders such as spasticity, hypertonia and urinary incontinence, and provide a new tool to neuroscientists and muscle physiologists wishing to reversibly inhibit motor neuron activity in vivo.

neuroscience↗

bioRxiv2017

Unsupervised discovery of demixed, low-dimensional neural dynamics across multiple timescales through tensor components analysis

Perceptions, thoughts and actions unfold over millisecond timescales, while learned behaviors can require many days to mature. While recent experimental advances enable large-scale and long-term neural recordings with high temporal fidelity, it remains a formidable challenge to extract unbiased and interpretable descriptions of how rapid single-trial circuit dynamics change slowly over many trials to mediate learning. We demonstrate a simple tensor components analysis (TCA) can meet this challenge by extracting three interconnected low dimensional descriptions of neural data: neuron factors, reflecting cell assemblies; temporal factors, reflecting rapid circuit dynamics mediating perceptions, thoughts, and actions within each trial; and trial factors, describing both long-term learning and trial-to-trial changes in cognitive state. We demonstrate the broad applicability of TCA by revealing insights into diverse datasets derived from artificial neural networks, large-scale calcium imaging of rodent prefrontal cortex during maze navigation, and multielectrode recordings of macaque motor cortex during brain machine interface learning.

neuroscience↗