Biology subjects

Jack, A.

Publications and source records attributed to Jack, A..

13 recordsLinked to original sources

bioRxiv2026

Neuronal FICD shapes motivated behavior through modulation of dopamine receptor dynamics

Motivated behaviors rely on dopaminergic signaling, which in turn depends on the correct folding and trafficking of receptors through the endoplasmic reticulum (ER). Within the ER, the AMPylase enzyme FICD acts as a molecular rheostat through its modification of the chaperone BiP, dynamically tuning the organelle's responsiveness to folding perturbations and cellular stress. While the biochemistry of FICD is well-established, its role in complex animal behavior remains poorly understood. Here, we identify FICD as a conserved contributor to the generation of motivated behavior. In Drosophila, pan-neuronal knockdown of dFic significantly reduces feeding, spontaneous locomotion, and reward-seeking behavior. These alterations occur without disrupting circadian architecture, motor capacity, or homeostatic hunger, indicating a specific loss of motivational drive. Depleting dFic within subsets of dopamine receptor-expressing (Dop1R1) neurons recapitulates these behavioral alterations. Transcriptomic profiling reveals that dFic depletion does not induce a canonical unfolded protein response, pointing to a specific post-transcriptional alteration rather than global ER stress. At the molecular level, dysregulated dFic alters the localization and abundance of Dop1R1. Finally, we demonstrate that this regulatory axis is evolutionarily conserved, as loss of FICD similarly diminishes motivated behaviors in C. elegans and mice. Together, these findings implicate FICD in the generation of motivated behavior and link dynamic control of ER proteostasis to dopamine-receptor maturation.

neuroscience↗

bioRxiv2026

Altered biological aging-related brain profile in adolescents with autism: A neuroimaging study based on DunedinPACNI

Individuals with Autism Spectrum Disorder (ASD) show increased rates of physical health conditions across major organ systems, some of which are commonly linked with aging, suggesting that body-wide biological profiles may be altered compared to neurotypical controls. Since brain structure associates with peripheral physiology and biomarkers of aging, it may inform understanding of broader biological differences and physical health risks in ASD. Here, we assessed this possibility using DunedinPACNI, a neuroimaging-based model that estimates the pace of longitudinal aging in peripheral organ systems from brain structural information, in 329 adolescents (8-18 years) from the Autism Centers of Excellence network, with replication in an independent age-matched sample of comparable size from the Autism Brain Imaging Data Exchange. Across both datasets and sensitivity analyses, autistic individuals showed significantly larger DunedinPACNI values than controls, consistent with brain structural features that align with patterns associated with a faster pace of biological aging in adults. Group differences were mainly driven by the volume of the 3rd ventricle, cortical thickness of the left entorhinal cortex, grey matter volume of the right entorhinal cortex and grey-to-white matter ratio in the left temporal pole. No association between DunedinPACNI and core autistic traits was found. Our results provide novel evidence for a possible altered brain-body profile in ASD, motivating future studies combining neuroimaging with peripheral biomarkers to better understand the neurobiology of physical health conditions in autism.

neuroscience↗

bioRxiv2026

Task-based functional connectivity in striato-motor-cortical system in autism: Associations with sex and executive function

Previously we found that female autistic youth (Aut-F) showed reduced brain response in dorsal striatum (putamen) when viewing human motion, alongside larger rare copy number variants that included genes expressed in early striatal development. Thus, striatal differences may characterize Aut-F, but broader systems-level and behavioral implications of these differences remain unexplored. We conducted secondary data analysis of the sex-balanced cohort (8-17y) in which we first discovered these patterns, in order to: 1) understand how functional connectivity between putamen and frontal targets might vary from the non-autistic population, and differ by sex; and 2) explore which brain connectivity and phenotypic features best predicted executive function. Using psychophysiological interaction analysis (N=184), we found that Aut-F youth (n=45) showed reduced functional connectivity between left anterior putamen (Pa) and dorsal premotor cortex/pre-supplementary motor area versus matched non-autistic female peers (NAut-F; n=45), suggesting reduced engagement of a typical Pa-frontal pathway for attentional regulation. Best subsets regression (N=200) indicated that left Pa-left dorsolateral prefrontal functional connectivity explained significant variance in executive functioning across all participants, controlling for neurotype. These results suggest that striatal differences in Aut-F may have adaptive consequences in part due to impacts on connectivity between Pa and frontal regions important for attentional control. Lay summaryWe previously found that female autistic people show differences in a part of the brain called the striatum. Some parts of the striatum connect to the frontal lobe of the brain, and may help people control their attention and behavior. We studied how the striatum "talked to" the frontal lobe in autistic girls. We found out that this communication is lower in autistic than non-autistic girls. We also found out that how much striatum "talks to" frontal lobe helps explain differences in how well both autistic and non-autistic youth of both sexes control their attention and behavior.

neuroscience↗

bioRxiv2026

The impact of seizures on REM sleep and the cholinergic pedunculopontine nucleus in a mouse model of Dravet Syndrome

Sleep disruption is a common and burdensome feature in epilepsy, with rapid eye movement (REM) sleep particularly affected. While sleep disturbances in epilepsy patients are multifactorial, clinical evidence suggests that recent seizures acutely impair REM sleep architecture. To investigate this relationship, we used a haploinsufficient mouse model of Dravet Syndrome, which allows experimental control of seizure timing and burden. We found that hyperthermia-induced seizures profoundly decreased subsequent sleep, specifically impairing REM entry. In vivo fiber photometry revealed acute, seizure-induced activation of cholinergic neurons in the pedunculopontine nucleus (PPN), a brainstem structure critical for REM entry. We additionally found that repeated seizures triggered anatomical changes in the PPN, including reduced cholinergic neuron number and significant hypertrophy of remaining cholinergic neurons. These results suggest seizures are a driver of both acute and chronic disruption of PPN cholinergic networks, which in turn impair REM sleep in epilepsy. Our findings identify the PPN as a potential therapeutic target for interventions to address sleep-related sequelae of seizures.

neuroscience↗

bioRxiv2025

Altered aperiodic EEG spectral power during speech perception task is associated with verbal communication in youths with Autism Spectrum Disorder

Most children with Autism Spectrum Disorder (ASD) have co-occurring language impairment, but its neural mechanisms are not well known. Excitation (E) / inhibition (I) imbalance is considered as a key neurobiological mechanism of ASD, and several electroencephalography (EEG)-based E/I balance metrics have been proposed in the previous studies. The goal of the present research was to focus on these metrics abstracted from the speech perception task to investigate their relation to language/communication in autistic youths. We used a high-density 128-channel EEG to register neural responses during speech perception task in the sex- and age-matched groups of youths with ASD (N = 162) and typically developing (TD) controls (N = 144), aged 7-18 years old. The results revealed alterations in the E/I measures in the ASD group, pointing to a higher level of excitation or neural noise in the cortex as well as broadband reduction of spectral power during speech perception. A greater neural noise reflected in the reduction of aperiodic exponent and offset was associated with lower verbal communication skills in youths with ASD. The findings suggested that the higher noisiness in the cortical systems may be a relevant marker to monitor in relation to language/communication in ASD.

neuroscience↗

bioRxiv2025

The Bacterial Methylorubrum extorquens Product TS201 Induces Multiple Modes of Action to Reduce Insect Feeding Damage on Maize

Microbial technologies are increasingly adopted to improve sustainable agriculture amid escalating economic, regulatory, and ecological pressures, yet few, if any, are supported by mechanistic understanding that translates to real-world performance. Here, we report TS201, a U.S. EPA-registered bioinsecticide, composed of Methylorubrum extorquens, that enhances maize yield and resilience under pest pressure. Across seven years (2016-2022) of field trials at 22 U.S. locations, TS201 increased yield and reduced lodging. Large-scale evaluations at 81 sites in eight U.S. states (2023-2024) confirmed its agronomic benefit. Mechanistically, TS201 induced biosynthesis of methyl anthranilate, a volatile insect-repellent compound, and triggered pest avoidance of treated roots. These findings reveal a novel plant-microbe-insect interaction and establish a systems biology framework for harnessing microbial plant resilience to advance crop production.

plant biology↗

bioRxiv2025

Transcription Factor (TF) validation using Dam-IT simultaneously captures genome-wide TF-DNA binding, direct gene regulation, and chromatin accessibility in plant cells

Transcription Factors (TFs) govern vast networks of gene regulation. However, TF-DNA binding and TF-gene regulation datasets are typically measured separately due to experimental constraints, making it challenging to disentangle true biological relationships from batch effects. To fill this gap, we developed DamID-seq Incorporating Transcriptomics (Dam-IT), which simultaneously captures TF-DNA binding, direct TF-gene regulation, and chromatin accessibility in the same batch of cells. Dam-IT uses a transient cell-based TF-target validation system that is scalable and flexible to many experimental designs. As proof of concept, we used Dam-IT to reveal that bZIP1 directly regulates genes by binding to DNA regions of relatively low chromatin accessibility, supporting a "Hit-and-Run" mechanism of transcription.

systems biology↗

bioRxiv2025

Structural Determinants of Signal Speed: A Multimodal Investigation of Face Processing in Autism Spectrum Disorder

It has not previously been possible to investigate the fundamental relationship between axonal structure - which dictates action potential transmission - and human neuronal function in vivo. Here, we introduce a novel metric of axonal signal speed, estimated axonal latency (EAL), derived from the relationship between axonal diameter, myelination, and length measured via MRI. We validate EAL along two pathways of the face processing network by relating it to N170 latency, an electrophysiological marker of face processing speed measured via EEG. Our results show that EAL along these pathways predicts N170 latency specifically during face processing. Moreover, we demonstrate that individuals with and without autism rely upon different pathways, potentially providing a structural account for autism-related face processing differences. By establishing this relationship between EEG-based electrical function and MRI-based axonal microstructure, we provide a non-invasive, spatially detailed estimate of neuronal processing speed that can inform our understanding of brain function, development, and disorder. TeaserEstimated axonal latency is a non-invasive, spatially detailed measure of neuronal speed to inform brain function and disorder.

neuroscience↗

bioRxiv2024

Viro3D: a comprehensive database of virus protein structure predictions

Viruses are intracellular parasites of organisms from all domains of life. They infect and cause disease in humans, animals and plants but also play crucial roles in the ecology of microbial communities. Tolerance to genetic change, high-mutation rates, adaptations to hosts and immune escape has driven high divergence of viral genes, hampering their functional annotation and phylogenetic inference. The protein structure is more conserved than sequence and can be used for searches of distant homologs and evolutionary analysis of divergent proteins. Structures of viral proteins are traditionally underrepresented in public databases, but recent advances in protein structure prediction allows us to address this issue. Combining two state-of-the-art approaches, AlphaFold2-ColabFold and ESMFold, we predicted models for 85,000 proteins from 4,400 human and animal viruses, expanding the structural coverage for viral proteins by 30 times compared to experimental structures. We also performed structural and network analyses of the models to demonstrate their utility for functional annotation and inference of distant phylogenetic relationships. Taking this approach, we examined the deep evolutionary history of viral class-I fusion glycoproteins, gaining insights on the origins of coronavirus spike protein. To enable further discoveries, we have created Viro3D (https://viro3d.cvr.gla.ac.uk/), a virus species-centred protein structure database. It allows users to search, browse and download protein models from a virus of interest and explore similar structures present in other virus species. This resource will facilitate fundamental molecular virology, investigation of virus evolution, and may enable structure-informed design of therapies and vaccines.

microbiology↗

bioRxiv2024

Protection of the Telomeric Junction by the Shelterin Complex

Shelterin serves critical roles in suppressing superfluous DNA damage repair pathways on telomeres. The junction between double-stranded telomeric tracts (dsTEL) and single-stranded telomeric overhang (ssTEL) is the most accessible region of the telomeric DNA. The shelterin complex contains dsTEL and ssTEL binding proteins and can protect this junction by bridging between the ssTEL and dsTEL tracts. To test this possibility, we monitored shelterin binding to telomeric DNA substrates with varying ssTEL and dsTEL lengths and quantified its impact on telomere accessibility using single-molecule fluorescence microscopy methods in vitro. We identified the first dsTEL repeat nearest to the junction as the preferred binding site for creating the shelterin bridge. Shelterin requires at least two ssTEL repeats while the POT1 subunit of shelterin that binds to ssTEL requires longer ssTEL tracts for stable binding to telomeres and effective protection of the junction region. The ability of POT1 to protect the junction is significantly enhanced by the 5-phosphate at the junction. Collectively, our results show that shelterin enhances the binding stability of POT1 to ssTEL and provides more effective protection compared to POT1 alone by bridging single- and double-stranded telomeric tracts. Table of Content Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/608453v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@a58e79org.highwire.dtl.DTLVardef@12cb172org.highwire.dtl.DTLVardef@135bf40org.highwire.dtl.DTLVardef@19f3fe4_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2022

Impact of Shelterin Complex on Telomere Accessibility

Shelterin plays critical roles in maintaining and protecting telomeres by regulating access of various physiological agents to telomeric DNA. We present single molecule measurements investigating the impact of the POT1 and a four-component shelterin complex on the accessibility of human telomeric DNA overhangs with physiologically relevant lengths (28-150 nt), which to our knowledge is the first direct approach to measure this effect on such telomeric constructs. To quantify telomere accessibility, we monitored transient binding events of a short peptide nucleic acid (PNA) probe that is complementary to telomeric overhangs using FRET-PAINT. Although POT1 has a mild G-quadruplex unfolding activity, it reduced accessibility of the PNA probe by [~]2.5 fold, indicating that POT1 effectively binds to and protects otherwise exposed telomeric sequences. In comparison, a four-component shelterin reduced the accessibility of telomeric overhangs by [~]5-fold. This enhanced protection suggests shelterin restructures the region between single and double stranded telomere, which is otherwise the most accessible part of the overhang, by a synergistic cooperation of shelterin components located on single and double stranded telomere.

biophysics↗

bioRxiv2020

The mechanism of motor inhibition by microtubule-associated proteins

Microtubule (MT)-associated proteins (MAPs) regulate intracellular transport by selectively recruiting or excluding kinesin and dynein motors from MTs. We used single-molecule and cryo-electron imaging to determine the mechanism of MAP-motor interactions in vitro. Unexpectedly, we found that the regulatory role of a MAP cannot be predicted based on whether it overlaps with the motor binding site or forms liquid condensates on the MT. Although the MT binding domain (MTBD) of MAP7 overlaps with the kinesin-1 binding site, tethering of kinesin-1 by the MAP7 projection domain supersedes this inhibition and results in biphasic regulation of kinesin-1 motility. Conversely, the MTBD of tau inhibits dynein motility without overlapping with the dynein binding site or by forming tau islands on the MT. Our results indicate that MAPs sort intracellular cargos moving in both directions, as neither dynein nor kinesin can walk on a MAP-coated MT without favorably interacting with that MAP. HIGHLIGHTSO_LIMAP7 binds to a novel site and can coexist with tau on the MT. C_LIO_LIKinesin-1 motility is biphasically regulated by MAP7 accumulation on the microtubule. C_LIO_LIMT decoration of MAPs inhibits motors even when they do not block the motor binding site. C_LIO_LIMotors need to interact with a MAP to walk on MAP-decorated MTs C_LI

biophysics↗

bioRxiv2020

SARS CoV-2 nucleocapsid protein forms condensates with viral genomic RNA

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes COVID-19, a pandemic that seriously threatens global health. SARS-CoV-2 propagates by packaging its RNA genome into membrane enclosures in host cells. The packaging of the viral genome into the nascent virion is mediated by the nucleocapsid (N) protein, but the underlying mechanism remains unclear. Here, we show that the N protein forms biomolecular condensates with viral genomic RNA both in vitro and in mammalian cells. Phase separation is driven, in part, by hydrophobic and electrostatic interactions. While the N protein forms spherical assemblies with unstructured RNA, it forms asymmetric condensates with viral RNA strands that contain secondary structure elements. Cross-linking mass spectrometry identified a region that forms interactions between N proteins in condensates, and truncation of this region disrupts phase separation. We also identified small molecules that alter the formation of N protein condensates. These results suggest that the N protein may utilize biomolecular condensation to package the SARS-CoV-2 RNA genome into a viral particle.

biophysics↗