Biology subjects

Desai, M.

Publications and source records attributed to Desai, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Cfap410a and Cby work together with tissue-specific requirements to build Drosophila ciliary transition zones

Cilia and flagella perform essential physiological functions in eukaryotes, and defects in these organelles cause several human diseases, including cancer and ciliopathies. The architecture of cilia is highly organized. The ciliary compartment is separated from the cytoplasm by the transition zone (TZ). The severity of ciliopathies linked to TZ assembly defects highlights the TZ's critical role. Although several core conserved complexes are involved in TZ assembly, variations in TZ composition are associated with structurally and functionally diverse cilia. Here, we identify Cfap410a as a novel component of the ciliary TZ in the two Drosophila ciliated tissues, male germ cells and sensory neurons. Cfap410a is one of the two Drosophila paralogs (Cfap410a and Cfap410b) of human CFAP410, whose mutations are associated with axial spondylo-metaphyseal dysplasia, retinitis pigmentosa and amyotrophic lateral sclerosis. We show here that Cfap410a is a proximity partner of Cby and that they act cooperatively in the hierarchy of the TZ assembly program by bridging the CEP290 and MKS transition zone modules. Simultaneous loss of Cfap410a and Cby halts ciliary growth by disrupting TZ formation in multiple types of Drosophila ciliated cells, each of which exhibiting varying dependence on these two proteins. Interestingly, the function of Cfap410a and Cfap410b are not functionally redundant, indicating that the two proteins have evolved towards specific functions. In summary, our results propose a novel role for CFAP410a at the TZ and provide an explanation for how deregulation of conserved TZ components could lead to tissue-specific ciliopathies.

cell biology↗

bioRxiv2026

Unlocking Sensitive Data with SPHERE in the Age of AI

Sensitive human data underpin discoveries across medicine, biology and the social sciences, yet privacy regulation often prevents sharing them with collaborators or artificial intelligence (AI) systems. We introduce SPHERE, a model-free method that makes sensitive datasets directly usable by AI and shareable for open science as a synthetic twin, while the original records never leave the local environment. Across 33 datasets spanning five scientific domains, SPHERE protects individual privacy against adversarial re-identification attacks while preserving the data's statistical structure: means, variances and correlations are reproduced exactly, effect size and P value in linear statistical analysis is numerically identical, nonlinear machine-learning utility is retained, and each twin is generated in seconds on a laptop. Frontier AI agents running on the twin reach the same scientific conclusions as on the original records. Analyses of the twin reproduce genome- and proteome-wide results at UK Biobank scale and recover the findings of landmark studies across three independent cohorts and consortia. The approach also extends to deep-learning embeddings across language, vision and time-series, with minimal utility loss. We make the Stanford Alzheimer's Disease Research Center cohort openly available for the first time, as a SPHERE twin spanning nine modalities that any registered researcher can analyze without an approval process. We release SPHERE with certification of each twin's privacy and fidelity, and an AI agent that autonomously executes research tasks on sensitive data without ever accessing it. Sensitive datasets that are currently closed to research could thus become routine inputs to open science and AI to enable key discoveries.

bioinformatics↗

bioRxiv2026

Centrosome maintains the integrity of and repairs mature olfactory cilia in adult Drosophila

Mechanisms of cilium assembly are well studied; however, how mature metazoan cilia maintain their structures and functions in vivo remains unknown. It is also unclear whether the centrosome-derived basal body (BB) directly contributes to ciliary homeostasis. We combined biochemistry, genetics, high-resolution subcellular imaging, and electrophysiology to investigate long-lived ciliated olfactory sensory neurons (OSNs) and their olfactory behaviour in adult Drosophila. Several centrosome assembly proteins are absent, but another subset persists through dynamic protein exchange at the BBs of mature olfactory cilia. At this ciliary base, pericentriolar material (PCM) components, e.g., {gamma}-Tubulin23C, centrosomin, and pericentrin-like protein form an interconnected network required for ciliary maintenance. Adult- and OSN-specific depletions of these proteins, particularly in combination, disrupt accumulation of the heterotrimeric kinesin-2 at the ciliary base and, subsequently, in the shaft, causing loss of ciliary tubulin, EB1, and odorant receptor co-receptor. These dysregulations cause profound loss of ciliary shaft and impair olfactory function/behaviour. The centrosomal kinases PLK1/POLO and Aurora A also work with this PCM network and are required for mature ciliary homeostasis. Remarkably, these defects in ciliary structure, function, and adult olfactory behaviour are reversible, suggesting that this centrosome-derived BB is a dynamic homeostatic epicentre that regulates trafficking and ciliary structural and compositional integrity in vivo. These findings uncover an active, centrosome-dependent, cell-autonomous mechanism for maintaining and repairing mature metazoan cilia in fully grown organs in adulthood and also provide a possible explanation for how deregulation of conserved ciliary base components could lead to progressive, late-onset cilia-related disorders.

cell biology↗

bioRxiv2026

A CK2α-G3BP1 signaling axis regulates local translation in developing neurons and is disrupted in OCNDS

Neurodevelopmental disorders are frequently caused by mutations in pleiotropic kinases, yet downstream effectors driving neuronal pathology remain undefined. Here, we identify the G3BP1-dependent stress granule pathway as the dominant effector of casein kinase 2 (CK2) in developing neurons, implying that its dysregulation underlies the neurodevelopmental deficits of Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS-associated CK2 mutations reduce phosphorylation of G3BP1 at serine 149, promoting aberrant phase separation and persistent granules that sequester neuronal mRNAs and suppress local protein synthesis across axonal and dendritic compartments. These phenotypes produce allele-specific deficits in neuronal morphogenesis, synaptic abundance, and network excitability, which are conserved in a knock-in mouse model and in patient-derived iPSC neurons. G3bp1 knockdown rescues translational and morphological phenotypes across all OCNDS alleles, demonstrating that restoring granule homeostasis reverses neuronal pathology. Together, these findings establish OCNDS as a disorder of compartment-specific translational dysregulation driven by impaired CK2-G3BP1 control of RNA granule homeostasis. SummaryOCNDS mutations disrupt CK2-G3BP1 signaling, causing persistent granules and defective neuronal translation and development.

neuroscience↗

bioRxiv2026

Patient-Specific Heart Rate Modulates Developmental Electrophysiology in Transcriptomic-Guided In Silico Models of Pediatric Human Atrial Cardiomyocytes

Cardiac electrophysiology adapts throughout pediatric development, driven by factors including age-associated ion channel expression changes and decreasing heart rate. Our prior transcriptomic-guided simulations of human atrial cardiomyocytes predicted developmental-associated changes in electrophysiology biomarkers at a fixed pacing rate, leaving the contribution of age- and patient-specific heart rate unresolved. In this study, we incorporated intrinsic heart rate into gene expression-guided computational models to predict the interaction between developmental maturation and pacing rate to shape atrial electrophysiology. Virtual patient-specific populations of atrial cardiomyocytes were generated from the right atrial cardiomyocyte gene expression data from 117 patients, spanning neonates to young adults. We simulated each population at pacing rates corresponding to each patients intrinsic ECG-based heart rate and at fixed rates corresponding to the patient cohort minimum, median, and maximum. Action potential and calcium transient biomarkers were quantified, and partial least squares regression assessed key biomarker dependencies. For intrinsic-rate pacing conditions, action potential duration at 50% and 90% repolarization increased with age, whereas early repolarization shortened; maximum upstroke velocity increased, resting membrane potential became more negative, and alternans prevalence decreased. Developmental differences persisted during fixed-rate pacing conditions, indicating that differences were not explained solely by the faster heart rates of younger patients. Notably, intrinsic-rate simulations exhibited stronger age associations for upstroke velocity and alternans than fixed-rate simulations. Sensitivity analyses indicated that electrophysiological phenotypes arose from interactions among ionic conductances, calcium handling, age, and heart rate. Collectively, we find that pediatric atrial electrophysiology reflects both intrinsic developmental remodeling and rate-dependent modulation.

biophysics↗

bioRxiv2026

Human auditory cortex preferentially tracks speech over music without explicit attention

Our brains constantly filter incoming sounds to understand our environment. While extensively studied in adults, how this ability develops across childhood remains unclear. We recorded intracranial brain activity from 54 participants aged 4-21 while they watched movie clips containing simultaneous speech and music. We used deep neural networks to separate the mixed audio into isolated speech and music streams, then built encoding models to determine which stream best predicted neural responses in the auditory cortex. Although participants heard only the original mixture with no instruction to attend to either stream, higher-order auditory regions including the superior temporal gyrus (STG), superior temporal sulcus (STS) and middle temporal gyrus (MTG), responded preferentially to speech. This speech-bias strengthened with age in STG, suggesting that this region progressively sharpens its representation of socially relevant sound across development. These findings indicate that speech prioritization in the developing brain emerges automatically, without directed attention.

neuroscience↗

bioRxiv2025

Effects of ΔmotY mutations on motility behavior of Pseudomonas aeruginosa chimeric periplasmic stator variants

Pseudomonas aeruginosa utilizes dual flagellar stator systems for motility; and dual stator bacteria possess auxiliary flagellar rotor ring components in their periplasm. In P. aeruginosa MotAB and MotCD comprise the dual stator system and MotY is the auxiliary periplasmic ring component. We investigated motility of strains and their isogenic {Delta}motY derivatives which expressed chimeric MotB/MotD periplasmic domains and characterized differences in motility behaviors. We found in general motility is severely impaired in strains carrying motY deletions and which express C-terminal periplasmic regions of MotD, compared with strains expressing MotB C-terminal counterparts. Motility in soft agar is slightly increased in strains expressing N-terminal MotB transmembrane domains and MotD C-terminal periplasmic plug, PGB, and extensions, but motility is severely impaired in {Delta}motY strains. Addition of the extended 24-residue C-terminus of MotB to the C-terminus of MotD does not significantly affect either motility or compensate for the deleterious effect of {Delta}motY mutation, but does significantly increase motility in motY+ backgrounds. The soft agar motility results for organisms with wild type MotAB stators was not different from those with MotAB stators carrying 24 residue MotB C-terminal deletions; however, motility of these mutants was significantly lower in {Delta}motY mutants compared to {Delta}motY mutants expressing wild type MotAB stators. We discuss contributions of stator functional domains to motility and the effects of {Delta}motY deletion. Lastly, we speculate on possible mechanistic roles for the two stator plug types based on thermodynamic considerations related to differences in composition of the hydrophobic surfaces of the two amphipathic helices. IMPORTANCEPseudomonas aeruginosa uses two torque-generating stators, MotAB and MotCD, to drive flagellar rotation. Dual stator bacteria have additional rotor components; in P. aeruginosa, this component has been identified as MotY. This study investigates the interaction between the C-terminal plug and periplasmic regions of the MotB and MotD components of the MotAB and MotCD stator complexes with MotY. Motility assays of periplasmic chimeric strains expressing variants with MotB and MotD C-terminal plug and peptidoglycan binding domains reveal an enhanced sensitivity of MotD C-terminus to MotY deletions. These data suggest that critical interactions, either direct or indirect, must take place between the basal body MotY ring complex and MotD periplasmic regions for proper function of the MotCD stator in flagellar motility.

microbiology↗

bioRxiv2025

Enabling wider access to human molecular neuroscience research in pain: A simple preservation method for human dorsal root ganglion neurons in Hibernate A media

The use of human dorsal root ganglion (DRG) from organ donors opens the door for research into the molecular biology and physiology of human nociceptors; however, there are barriers to working with this tissue including logistical difficulties and limited access. We present an approach using Hibernate media to temporarily store either whole DRGs or dissociated DRG neurons prior to culturing and functional testing. Dissociation of DRGs following temporary storage (4-16hrs) in Hibernate media resulted in similar neuronal and immune cell yield as acutely dissociated DRGs. Neurons derived from DRGs stored in Hibernate media prior to dissociation exhibited similar electrophysiological properties and capsaicin responses as acutely dissociated DRG neurons. Similarly, neurons from acutely dissociated DRGs stored in Hibernate media (>24hrs) and shipped to geographically distant laboratories produced neuronal cultures displaying comparable electrophysiological properties as acutely cultured neurons. This approach overcomes insurmountable logistical burdens and increases access to freshly recovered human DRGs.

neuroscience↗

bioRxiv2025

Chamber-Specific Transcriptomic Insight into Cardiac Development using Guinea Pig and Human Heart Tissue

The heart undergoes significant molecular and functional adaptations throughout postnatal development. However, to date, our understanding of these dynamic changes in the human heart is limited. Moreover, advances in pediatric cardiac research can be hindered by a lack of preclinical models that accurately reflect human heart maturation. Guinea pigs may serve as a useful model for human cardiac research, as the guinea pig and human myocardium have similar ion channel expression and cardiovascular drug responsiveness. Despite these similarities, gene expression patterns during postnatal heart development have not been comprehensively investigated. In this study, we first characterized transcriptional changes in neonatal, juvenile, and adult guinea pig hearts - identifying gene ontologies and pathways associated with cardiac maturation. Second, we compared the transcriptional profile of right atria and left ventricular tissue to highlight unique and shared chamber-specific patterns in guinea pigs over time. Finally, we conducted a cross-species comparison of the right atrial transcriptome between humans and guinea pigs to identify conserved maturation markers and gene expression patterns. Our findings provide a molecular framework for understanding age- and chamber-specific cardiac development, supporting the guinea pig as a promising preclinical model for studying human heart maturation. By identifying conserved gene programs and developmental markers across species, this study lays the groundwork for age-specific pharmacological strategies and computational models that can help to refine treatment decisions and outcomes for pediatric cardiology patients. New and NoteworthyExisting knowledge on postnatal heart development and cardiomyocyte maturation is limited. We investigated age-dependent transcriptional changes in neonatal, juvenile, and adult guinea pig hearts - and then conducted a cross-species comparison to identify age-specific patterns that are conserved in the guinea pig and human atria. Expanding our knowledge of chamber- and age-specific gene expression patterns can inform and guide the selection of cardiovascular therapies in the pediatric population, where developmental differences are understudied.

genomics↗

bioRxiv2024

Inclusion of Hsp70 co-chaperone and RNA binding activities facilitates optimal function of spliceosomal disassembly factor Cwf23 in intron-rich Schizosaccharomyces pombe

Cwc23 is an essential J-domain protein that collaborates with the disassembly factor Ntr1 to facilitate spliceosomal disassembly. Although Cwc23 orthologs have been identified in spliceosomal extracts of many eukaryotes, their functionality in intron-rich eukaryotes remains largely unexplored. Here, we investigate the functionality of Cwf23, an ortholog of Cwc23 in Schizosaccharomyces pombe. Our study reveals that while the interaction between Cwf23 and SpNtr1 is conserved, it is not essential in S. pombe. Additionally, the RNA recognition motif (RRM) in Cwf23 is crucial for its function, as mutations in the RRM affect both growth and pre-mRNA splicing. Unlike its budding yeast counterpart, the J-domain of Cwf23 is indispensable, as J-domain mutants cannot support cell viability. These findings suggest a new paradigm in which the presence of a functional RRM and the essential nature of the J-domain underscore the increased requirements for an RNA-binding Hsp70 co-chaperone machinery in spliceosomal remodelling in "intron-rich" eukaryotes.

molecular biology↗

bioRxiv2024

Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies

Targeted recruitment of E3 ubiquitin ligases to degrade traditionally undruggable proteins is a disruptive paradigm for developing new therapeutics. Two salient limitations are that <2% of the ~600 E3 ligases in the human genome have been exploited to produce proteolysis targeting chimeras (PROTACs), and the efficacy of the approach has not been demonstrated for a vital class of complex multi-subunit membrane proteins-- ion channels. NEDD4-1 and NEDD4-2 are physiological regulators of myriad ion channels, and belong to the 28-member HECT (homologous to E6AP C-terminus) family of E3 ligases with widespread roles in cell/developmental biology and diverse diseases including various cancers, immunological and neurological disorders, and chronic pain. The potential efficacy of HECT E3 ligases for targeted protein degradation is unexplored, constrained by a lack of appropriate binders, and uncertain due to their complex regulation by layered intra-molecular and posttranslational mechanisms. Here, we identified a nanobody that binds with high affinity and specificity to a unique site on the N-lobe of the NEDD4-2 HECT domain at a location physically separate from sites critical for catalysis-- the E2 binding site, the catalytic cysteine, and the ubiquitin exosite-- as revealed by a 3.1 [A] cryo-electron microscopy reconstruction. Recruiting endogenous NEDD4-2 to diverse ion channel proteins (KCNQ1, ENaC, and CaV2.2) using a divalent (DiVa) nanobody format strongly reduced their functional expression with minimal off-target effects as assessed by global proteomics, compared to simple NEDD4-2 overexpression. The results establish utility of a HECT E3 ligase for targeted protein downregulation, validate a class of complex multi-subunit membrane proteins as susceptible to this modality, and introduce endogenous E3 ligase recruitment with DiVa nanobodies as a general method to generate novel genetically-encoded ion channel inhibitors.

biophysics↗

bioRxiv2024

Connecting Transcriptomics with Computational Modeling to Reveal Developmental Adaptations in the Human Pediatric Myocardium

BackgroundNearly 1% or 1.3 million babies are born with congenital heart disease (CHD) globally each year - many of whom will require palliative or corrective heart surgery within the first few years of life. A detailed understanding of cardiac maturation can help to expand our knowledge on cardiac diseases that develop during gestation, identify age-appropriate cardiovascular drug therapies, and inform clinical care decisions related to surgical repair, myocardial preservation, or postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is largely limited to animal models. MethodsRight atrial tissue samples were collected from n=117 neonatal, infant, and pediatric patients undergoing correct surgery due to (acyanotic) CHD. Patients were stratified into five age groups: neonate (0-30 days), infant (31-364 days), toddler to preschool (1-5 years), school age (6-11 years), and adolescent to young adults (12-32 years). We measured age-dependent adaptations in cardiac gene expression, and used computational modeling to simulate action potential and calcium transients. ResultsEnrichment of differentially expressed genes (DEG) was explored, revealing age-dependent changes in several key biological processes (cell cycle, cell division, mitosis), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited both linear trends and sudden shifts across developmental stages, with changes in calcium handling (INCX) and repolarization (IK1) most strongly associated with an age-dependent decrease in the action potential plateau potential and increase in triangulation, respectively. We also note a shift in repolarization reserve, with lower IKr expression in younger patients, a finding likely tied to the increased amplitude of IKs triggered by elevated sympathetic activation in pediatric patients. ConclusionThis study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology among patients with CHD, shedding light on molecular mechanisms underlying cardiac development and function across different developmental stages.

cell biology↗

bioRxiv2024

Effects of access condition on substance use disorder-like phenotypes in male and female rats self-administering MDPV or cocaine

Substance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of substance use vary across individuals. Yet, when rats are allowed to self-administer drugs such as cocaine under short-access conditions, their behavior tends to be well-regulated and homogeneous in nature; though individual differences can emerge when rats are provided long- or intermittent-access to cocaine. In contrast to cocaine, significant individual differences emerge when rats are allowed to self-administer 3,4-methylenedioxypyrovalerone (MDPV), even under short-access conditions, wherein [~]30% of rats rapidly transition to high levels of drug-taking. This study assessed the SUD-like phenotypes of male and female Sprague Dawley rats self-administering MDPV (0.032 mg/kg/infusion) or cocaine (0.32 mg/kg/infusion) by comparing level of drug intake, responding during periods of signaled drug unavailability, and sensitivity to footshock punishment to test the hypotheses that: (1) under short-access conditions, rats that self-administer MDPV will exhibit a more robust SUD-like phenotype than rats that self-administered cocaine; (2) female rats will have a more severe phenotype than male rats; and (3) compared to short-access, long- and intermittent-access to MDPV or cocaine self-administration will result in a more robust SUD-like phenotype. After short-access, rats that self-administered MDPV exhibited a more severe phenotype than rats that self-administered cocaine. Though long- and intermittent-access to cocaine and MDPV self-administration altered drug-taking patterns, manipulating access conditions did not systematically alter their SUD-like phenotype. Evidence from behavioral and quantitative autoradiography studies suggest that these differences are unlikely due to changes in expression levels of dopamine transporter, dopamine D2 or D3 receptors, or 5-HT1B, 5-HT 2A, or 5-HT2C receptors, though these possibilities cannot be ruled out. These results show that the phenotype exhibited by rats self-administering MDPV differs from that observed for rats self-administering cocaine, and suggests that individuals that use MDPV and/or related cathinones may be at greater risk for developing a SUD, and that short-access MDPV self-administration may provide a useful method to understand the factors that mediate the transition to problematic or disordered substance use in humans.

pharmacology and toxicology↗

bioRxiv2023

A comparison of EEG encoding models using audiovisual stimuli and their unimodal counterparts

Communication in the real world is inherently multimodal. When having a conversation, typically sighted and hearing people use both auditory and visual cues to understand one another. For example, objects may make sounds as they move in space, or we may use the movement of a persons mouth to better understand what they are saying in a noisy environment. Still, many neuroscience experiments rely on unimodal stimuli (visual only or auditory only) to understand encoding of sensory features in the brain. The extent to which visual information may influence encoding of auditory information and vice versa in natural environments is thus unclear. Here, we addressed this question by recording scalp electroencephalography (EEG) in 11 subjects as they listened to and watched movie trailers in audiovisual (AV), visual (V) only, and audio (A) only conditions. We then fit linear encoding models that described the relationship between the brain responses and the acoustic, phonetic, and visual information in the stimuli. We also compared whether auditory and visual feature tuning was the same when stimuli were presented in the original AV format versus when visual or auditory information was removed. We found that auditory feature tuning was similar in the AV and A-only conditions, and similarly, tuning for visual information was similar when stimuli were presented with the audio present (AV) and when the audio was removed (V only). In a cross prediction analysis, we investigated whether models trained on AV data predicted responses to A or V only test data as well as using the unimodal conditions for training. Overall, prediction performance using AV training and V test sets was similar to using V training and V test sets, suggesting that the auditory information has a relatively smaller effect on EEG. In contrast, prediction performance using AV training and A only test set was slightly worse than using matching A only training and test sets. This suggests the visual information has a stronger influence on EEG, though this makes no qualitative difference in the derived feature tuning. In effect, our results show that researchers may benefit from the richness of multimodal datasets, which can then be used to answer more than one research question.

neuroscience↗

bioRxiv2023

A Multiscale Protein Abundance Structured Population Kinetic Model Systematically Explores the Design Space of Constitutive and Inducible CAR-T cells

Engineered chimeric antigen receptor (CAR)-T cells are designed to bind to antigens overexpressed on the surface of tumor cells and induce tumor cell lysis. However, healthy cells can express these antigens at lower abundances and can get lysed by CAR-T cells. A wide variety of CAR-T cells have been designed that increase tumor cell elimination while decreasing destruction of healthy cells. However, given the cost and labor-intensive nature of such efforts, a systematic exploration of potential hypotheses becomes limited. To this end, we develop a framework (PASCAR) by combining multiscale population dynamic models and multi-objective optimization approaches with data obtained from published cytometry and cytotoxicity assays to systematically explore design space of constitutive and tunable CAR-T cells. We demonstrate PASCAR can quantitatively describe in vitro and in vivo results for constitutive and inducible CAR-T cells and can successfully predict experiments outside the training data. Our exploration of the CAR design space reveals that CAR affinities in an intermediate range of dissociation constants (KD) in constitutive and tunable CAR-T cells can dramatically decrease healthy cell lysis but sustain a high rate of tumor cell killing. In addition, our modeling provides guidance towards optimal tuning of CAR expressions in synNotch CAR T cells. The proposed framework can be extended for other CAR immune cells.

systems biology↗

bioRxiv2022

Mrj an Hsp40 family chaperone regulates oligomerization of Orb2 and long-term memory

Orb2 the Drosophila homolog of Cytoplasmic polyadenylation element binding protein (CPEB) forms prion-like oligomers. These oligomers consist of Orb2A and Orb2B isoforms and their formation are dependent on the oligomerization of the Orb2A isoform. Drosophila with a mutation diminishing Orb2As prion-like oligomerization forms long-term memory but fails to maintain it over time. Since, this prion-like oligomerization of Orb2A plays a crucial role in the maintenance of memory, here we aim to find what regulates this oligomerization. In an immunoprecipitation-based screen, we identify interactors of Orb2A in the Hsp40 and Hsp70 families of proteins. Amongst these, we find an Hsp40 family protein Mrj as a regulator of the conversion of Orb2A to its prion-like form. Mrj interacts with Hsp70 proteins and acts as a chaperone by interfering with the aggregation of pathogenic Huntingtin. Unlike its mammalian homolog, we find Drosophila Mrj is neither an essential gene nor causes any gross neurodevelopmental defect. We observe a loss of Mrj results in a reduction in Orb2 oligomers. Further, the knockdown of Mrj in the mushroom body neurons results in a deficit in long-term memory. Our work implicates a chaperone Mrj in mechanisms of memory regulation through controlling the oligomerization of Orb2A and its association with the translating polysomes.

neuroscience↗

bioRxiv2021

Generalizable EEG encoding models with naturalistic audiovisual stimuli

In natural conversations, listeners must attend to what others are saying while ignoring extraneous background sounds. Recent studies have used encoding models to predict electroencephalography (EEG) responses to speech in noise-free listening situations, sometimes referred to as "speech tracking" in EEG. Researchers have analyzed how speech tracking changes with different types of background noise. It is unclear, however, whether neural responses from noisy and naturalistic environments can be generalized to more controlled stimuli. If encoding models for noisy, naturalistic stimuli are generalizable to other tasks, this could aid in data collection from populations who may not tolerate listening to more controlled, less-engaging stimuli for long periods of time. We recorded non-invasive scalp EEG while participants listened to speech without noise and audiovisual speech stimuli containing overlapping speakers and background sounds. We fit multivariate temporal receptive field (mTRF) encoding models to predict EEG responses to pitch, the acoustic envelope, phonological features, and visual cues in both noise-free and noisy stimulus conditions. Our results suggested that neural responses to naturalistic stimuli were generalizable to more controlled data sets. EEG responses to speech in isolation were predicted accurately using phonological features alone, while responses to noisy speech were more accurate when including both phonological and acoustic features. These findings may inform basic science research on speech-in-noise processing. Ultimately, they may also provide insight into auditory processing in people who are hard of hearing, who use a combination of audio and visual cues to understand speech in the presence of noise. Significance StatementUnderstanding spoken language in natural environments requires listeners to parse acoustic and linguistic information in the presence of other distracting stimuli. However, most studies of auditory processing rely on highly controlled stimuli with no background noise, or with background noise inserted at specific times. Here, we compare models where EEG data are predicted based on a combination of acoustic, phonetic, and visual features in highly disparate stimuli - sentences from a speech corpus, and speech embedded within movie trailers. We show that modeling neural responses to highly noisy, audiovisual movies can uncover tuning for acoustic and phonetic information that generalizes to simpler stimuli typically used in sensory neuroscience experiments.

neuroscience↗

bioRxiv2020

Naturalistic affective behaviors decoded from spectro-spatial features of multi-day human intracranial recordings

Task-based studies have uncovered distributed neural networks that support emotions, but little is known about how these networks produce affective behaviors in non-laboratory, ecological settings. We obtained continuous intracranial electroencephalography (iEEG) recordings from the emotion network in 11 patients with epilepsy during multi-day hospitalizations. We coded naturalistic affective behaviors (spontaneous expressions of positive or negative affect) from 116 hours of time-locked video recordings obtained over multiple days from subjects hospital rooms and utilized data driven classifiers to determine whether we could decode naturalistic affective behaviors from the neural data. Results indicated that binary within-subject random forest models could decode positive and negative affective behaviors from affectless behaviors (behaviors lacking valence) with up to 93% accuracy. Across the emotion network, positive and negative affective behaviors were associated with increased high frequency activity and decreased lower frequency activity. The anterior insula, amygdala, hippocampus, and anterior cingulate cortex (ACC) made strong contributions to affective behaviors in general. In a subset of subjects, three-state decoders distinguished among the positive, negative, and affectless behaviors using the spectro-spatial features from the emotion network. This study demonstrates that multi-day, highly resolved iEEG recordings in cortical and deep brain structures can reveal the circuit-level physiology of affective behaviors. By measuring behavior in an ecologically valid setting, our findings provide novel insights into the spatially distributed dynamics of local neural populations underlying naturalistic affective behaviors. SignificancePrevious neuroimaging and neurophysiological studies have identified a distributed network that supports emotions, but much remains unknown about how this network produces affective behaviors in ecological settings. We used intracranial electroencephalography recordings from the emotion network to decode naturalistic affective behaviors--spontaneous expressions of positive and negative affect that occurred during multi-day hospital stays--from neural data in patients with epilepsy. Our results complement prior neuroscientific studies of emotion and offer novel insights into the spectral and spatial dynamics of the emotion network that characterize naturalistic affective behaviors. The present study suggests intracranial electroencephalography can uncover new details about emotion network physiology and help to expand current neuroanatomical frameworks of human emotions.

neuroscience↗