Biology subjects

Reilly, J.

Publications and source records attributed to Reilly, J..

11 recordsLinked to original sources

bioRxiv2026

Neural tracking of surprisal and semantic distance in naturalistic movie viewing

Understanding speech requires listeners to integrate incoming input with prior linguistic and thematic knowledge to access meaning, a task greatly aided by prediction. Surprisal and related phenomena (e.g., next word prediction) tend to be associated with broad activation of language regions during listening. A major challenge for interpreting the neural correlates of surprisal is that lexical expectancies are constrained both by syntactic and semantic information. In contrast, semantic distance yields more of a pure metric of relatedness between one language constituent (e.g., word, phrase, n-gram) and another within a high-dimensional semantic space. We contrasted surprisal and semantic distance in running discourse during naturalistic audiovisual language comprehension. We analyzed fMRI scans from 20 English-speaking adults who viewed the full-length film 500 Days of Summer. Our focus was on brain sensitivity to either surprisal or semantic distance as language unfolded word-by-word. To this end, we implemented a series of hierarchical voxelwise encoding models. After accounting for low-level auditory and visual features, the addition of either surprisal or semantic distance improved prediction in bilateral superior temporal gyrus (STG), left inferior frontal gyrus, and right cerebellum. Critically, both semantic distance and surprisal explained unique variation in bilateral temporal cortex after accounting for the other. These results support the notion that the brain tracks both broad probabilistic prediction as well as semantic integration. More generally, these findings extend previous work on auditory-only speech by demonstrating that surprisal and semantic distance predict meaningful neural variation even within a rich audiovisual context.

neuroscience↗

bioRxiv2026

Comprehensive Mapping of Immune Nanobody Repertoires with NanoMAP

Nanobodies have recently emerged as alternatives to classical antibodies in therapeutic and diagnostic contexts from parasites to bacteria to viruses, promising improved stability and simpler manufacturing. To improve nanobody discovery efficiency, we developed an integrated experimental and computational pipeline for detailed characterization of the target binding properties of complete alpaca immune repertoires using our custom Nanobody Meta-clustering Analysis Platform (NanoMAP). We tested our pipeline on three distinct pools of targets, immunizing two alpacas with each pool and generating cDNA and phage display libraries from their immune repertoires. We then panned the phage libraries on each target. To produce more detailed binding information, we performed panning variations using subunits, natural variants, intact pathogens, and binding site competitors. Deep sequencing reads from nanobody libraries before and after each panning were pooled and analyzed with NanoMAP to identify nanobody clonal families and assess their levels of enrichment from the library in each panning, reflecting their affinities. NanoMAP outperformed standard clustering methods, producing clonal families that are coherent in sequence and function and detecting rare but high affinity families. By aggregating sequencing data within clonal families, NanoMAP produced reliable and rich data on nanobody repertoire binding phenotypes for each antigen, enhancing nanobody discovery capabilities.

immunology↗

bioRxiv2025

Phosphorylation Deficient Inducible cAMP Early Repressor (ICER) Modulates Tumorigenesis and Survival in a Transgenic Zebrafish (Danio rerio) Model of Melanoma

Melanoma, the most lethal form of skin cancer, is commonly associated by mutations in the BRAF gene, particularly BRAFV600E, which drives tumor proliferation via ERK1/2 signaling cascade. While BRAF inhibitors initially demonstrate efficacy, therapeutic resistance remains a significant challenge. Emerging evidence implicates the cAMP signaling pathway, particularly the cAMP response element-binding protein (CREB) and its repressor, Inducible cAMP Early Repressor (ICER), in melanoma progression and drug resistance. ICER, a transcriptional repressor regulated via Ras/MAPK-mediated phosphorylation and ubiquitination, is degraded in melanoma, undermining its tumor-suppressive role. In a brafV600E; p53(loss of function) transgenic zebrafish (Danio rerio) model, we investigated the role of a ubiquitin-resistant ICER mutant (S35-41A-ICER) in tumor progression. Transgenic fish expressing S35-41A-ICER exhibited extended survival and reduced tumor invasiveness compared to wild-type ICER. RNA sequencing revealed dysregulation of CREB/CREM targets and compensatory pathways, including Rap1 and PI3K/AKT signaling, as well as candidate gene targets of ICER regulation, including the Protein Kinase A catalytic subunit prkacaa. Our findings suggest that a ubiquitin resistant ICER mitigates melanoma progression and represses oncogenic pathways in a brafV600E melanoma context. Summary StatementThis study shows that ubiquitin-resistant ICER mutant suppresses melanoma progression, prolongs survival in brafV600E zebrafish, revealing its potential as a tumor suppressor and therapeutic target in melanoma resistance.

cancer biology↗

bioRxiv2025

Hyper-ovulation in an ovarian-specific transgenic mouse model.

Ovulation is a fundamental prerequisite for achieving successful reproduction. In vertebrates, ovulation is controlled by the cyclical action of hormones, particularly the gonadotropins such as follicle stimulating hormone (FSH) and luteinizing hormone (LH). A critical component of the intracellular activity of these two hormones is relayed by the second messenger cAMP. Although it is well established that a family of transcription factors facilitate cAMP mediated gene expression, it remains unknown how these factors directly affect ovulation. In particular, the Inducible cAMP Early Repressor (ICER) has been implicated in the transcriptional repression of FSH inducible genes during folliculogenesis. Here we show, using an ovarian-specific transgenic mouse model that ICER potentiates ovulation. We observed a twofold rate increase in ovulation for transgenic mice when compared to the wild type in response to exogenous gonadotropin treatment. Furthermore, mature cycling transgenic mice display a significantly enhanced ovulation rate compared to the wild-type. The observed changes in ovulation in the transgenic females are accompanied by altered gonadotropins production and gene expression. Most significantly, the expression of inhibin alpha subunit (INHA) was found to be about 5-fold higher in the transgenic mice. These observations may aid in unraveling some of the molecular mechanisms underlying ovulation and be relevant to the development of novel reproductive technologies. Summary SentenceGeneration of an FSH inducible ovarian specific FLAG-ICER-II(C) Tg Mice results in hyper-ovulation upon gonadotropin stimulation.

developmental biology↗

bioRxiv2023

Bidirectional Generative Adversarial Representation Learning for Natural Stimulus Synthesis

Thousands of species use vocal signals to communicate with one another. Vocalisations carry rich information, yet characterising and analysing these complex, high-dimensional signals is difficult and prone to human bias. Moreover, animal vocalisations are ethologically relevant stimuli whose representation by auditory neurons is an important subject of research in sensory neuroscience. A method that can efficiently generate naturalistic vocalisation waveforms would offer an unlimited supply of stimuli with which to probe neuronal computations. While unsupervised learning methods allow for the projection of vocalisations into low-dimensional latent spaces learned from the waveforms themselves, and generative modelling allows for the synthesis of novel vocalisations for use in downstream tasks, there is currently no method that would combine these tasks to produce naturalistic vocalisation waveforms for stimulus playback. In this paper, we demonstrate BiWaveGAN: a bidirectional Generative Adversarial Network (GAN) capable of learning a latent representation of ultrasonic vocalisations (USVs) from mice. We show that BiWaveGAN can be used to generate, and interpolate between, realistic vocalisation waveforms. We then use these synthesised stimuli along with natural USVs to probe the sensory input space of mouse auditory cortical neurons. We show that stimuli generated from our method evoke neuronal responses as effectively as real vocalisations, and produce receptive fields with the same predictive power. BiWaveGAN is not restricted to mouse USVs but can be used to synthesise naturalistic vocalisations of any animal species and interpolate between vocalisations of the same or different species, which could be useful for probing categorical boundaries in representations of ethologically relevant auditory signals.

neuroscience↗

bioRxiv2022

Inferring a cell's capabilities from omics data with ImmCellFie

ImmCellFie is a user-friendly, web-based platform for comprehensive analysis of metabolic functions inferred from transcriptomic or proteomic data. It enables researchers to leverage the powerful mechanistic insight provided by complex genome-scale metabolic models with little to no bioinformatics training required. The platform has been integrated with a series of useful tools and richly annotated scientific visualizations for interactive exploration by the user. ImmCellFie pushes beyond simple statistical enrichment and incorporates complex biological mechanisms to quantify cell activity. Graphical abstract

bioinformatics↗

bioRxiv2022

Language and the cerebellum: structural connectivity to the eloquent brain

Neurobiological models of receptive language have focused on the left-hemisphere perisylvian cortex with the assumption that the cerebellum supports peri-linguistic cognitive processes such as verbal working memory. The goal of this study was to identify language-sensitive regions of the cerebellum then map the structural connectivity profile of these regions. Functional imaging data and diffusion-weighted imaging data from the Human Connectome Project (HCP) were analyzed. We found that (a) working memory, motor activity, and language comprehension activated partially overlapping but mostly unique subregions of the cerebellum; (b) the linguistic portion of the cerebello-thalamo-cortical circuit was more extensive than the linguistic portion of the cortico-ponto-cerebellar tract; (c) there was a frontal-lobe bias in the connectivity from the cerebellum to the cerebrum; (d) there was some degree of specificity; and (e) for some cerebellar tracts, individual differences in picture identification ability covaried with fractional anisotropy metrics. These findings yield insights into the structural connectivity of the cerebellum as relates to the uniquely human process of language comprehension.

neuroscience↗

bioRxiv2021

Rod-genesis driven by mafba in an nrl knockout zebrafish model with altered photoreceptor compositions and progressive retinal degeneration

The neural retina leucine zipper (NRL) is an essential gene for the fate determination and differentiation of rod photoreceptors in mammals. Mutations in NRL have been associated with autosomal recessive enhanced S-cone syndrome and autosomal dominant retinitis pigmentosa. However, the exact role of Nrl in regulating the development and maintenance of photoreceptors in zebrafish, a popular animal model used for retinal degeneration and regeneration studies, has not been fully determined. In this study, we generated an nrl knockout zebrafish model by CRISPR-Cas9 technology and observed a surprising phenotype characterized by the reduction but not total elimination of rods and the over-grown of green-cones. By tracing the developmental process of rods, we discovered two waves of rod genesis in zebrafish, emerging at the embryonic stage with an nrl-dependent pattern and the post-embryonic stage with an nrl-independent pattern, respectively. Through bulk and single-cell RNA sequencing, we constructed the gene expression profiles for the whole retinal tissues and each of the retinal cell types in WT and nrl knockout zebrafish. We detected the rod/green-cone intermediate photoreceptors in nrl knockout zebrafish, suggesting that there may be a kind of rod/green-cone bipotent precursors and its fate choice between rod and green-cone is controlled by nrl. Besides, we identified the mafba gene as a novel regulator for nrl-independent rods, based on the cell-type-specific expression pattern and the retinal phenotype of nrl/mafba double knockout zebrafish. Furthermore, the altered photoreceptor compositions and abnormal gene expression caused progressive retinal degeneration and subsequent regeneration in nrl knockout zebrafish. Our work revealed a novel function of mafba gene in rod development and established a more suitable model for the developmental processes and regulatory mechanisms of rod and green-cone photoreceptors in zebrafish. Author SummaryVision is mediated by two types of light-sensing cells named rod and cone photoreceptors in animal eyes. Abnormal generation, dysfunction or death of photoreceptor cells can all cause irreversible vision problems. NRL is the most important gene for the occurrence and function of rod cells in mice and humans. Surprisingly, we found that in zebrafish, a popular animal model used for mimicking human diseases and testing treatments, there are two types of rod cells and breaking the function of nrl gene only affects the generation of rod cells at the embryonic stage but not the juvenile and adult stages. The rod cells produced later are proved to be driven by the mafba gene, which has not been reported to play a role in rod cells. In addition to the reduction of rod cells, deletion of nrl also results in the occurrence of rod/green-cone hybrid cells and the increasing number of green-cones. The combination of changes at cellular and molecular levels finally lead to a disease condition named retinal degeneration. These findings add new knowledge to the research field and highlight the conserved and species-specific regulatory mechanisms of photoreceptor development and maintenance.

genetics↗

bioRxiv2021

Exploring the kinetic selectivity of drugs targeting the β1-adrenoceptor

In this study, we report the {beta}1-adrenoceptor binding kinetics of several clinically relevant {beta}1/2-adrenoceptor ({beta}1/2AR) agonists and antagonists. We demonstrate that the physicochemical properties of a molecule directly affect its kinetic association rate (kon) and affinity for the target. In contrast to our findings at the {beta}2-adrenoceptor, a drugs immobilized artificial membrane partition coefficient (KIAM), reflecting both hydrophobic and electrostatic interactions of the drug with the charged surface of biological membranes, was no better predictor than simple hydrophobicity measurements such as log P or logD7.4, characterized by a distribution between water and a non-aqueous organic phase (e.g. n-octanol) at predicting association rate. Overall, this suggests that hydrophobic interactions rather than a combination of polar and hydrophobic interactions play a more prominent role in dictating the binding of these ligands to the {beta}1-adrenoceptor. Using a combination of kinetic data, detailed structural and physicochemical information we rationalize the above findings and speculate that the association of positively charged ligands at the {beta}1AR is curtailed somewhat by its predominantly neutral/positive charged extracellular surface. Consequently, hydrophobic interactions in the ligand binding pocket dominate the kinetics of ligand binding. In comparison at the {beta}2AR, a combination of hydrophobicity and negative charge attracts basic, positively charged ligands to the receptors surface promoting the kinetics of ligand binding. Additionally, we reveal the potential role kinetics plays in the on-target and off-target pharmacology of clinically used {beta}-blockers.

pharmacology and toxicology↗

bioRxiv2020

Implementing an algorithm for controlling for female MC phase for clinical neuroscience

BackgroundRecent research suggests that hormones and/or menstrual cycle (MC) phase at time of study may significantly affect clinical neuroscience outcomes of interest. Prior research puts forth sound methods for characterizing MC phase in women not using hormonal contraceptives (HC). However, an estimated 40% of premenopausal women in the United States use some form of HC. We developed an algorithm for characterizing hormone levels and MC phase among women both using and not using HC. We have employed this algorithm among female collegiate athletes post-mild traumatic brain injury (mTBI) as female athletes are understudied in the sports mTBI field, MC phase may have important effects on mTBI-related outcomes and controlling for MC phase has not been employed in this population. MethodsThirty female collegiate athletes were studied. Fifteen incurred a mTBI 3-10 days prior to assessment and sixteen were age, ethnicity, and menstrual cycle (MC) phase matched to the injured athletes. MC matching was conducted with retrospective and prospective self-report MC tracking, self-report of HC use, and serum progesterone testing. Results53% (16/30) of females were on HC and 47% (14/30) were not. Of the non-HC users, seven female pairs were in the follicular and one was in the luteal phase. Among the non-HC users, there was 50% agreement in MC phase identification between self-report and progesterone measures and a {kappa} = 0.138. Of the HC users, eight were in the inactive and six were in the active phase of their medication. Among the HC users, average progesterone levels indicated medication compliance (.58ng/mL). ConclusionsThis study provides important methodology and proof-of-concept that MC phase can be used as a control variable for time-sensitive prospective clinical neuroscience studies including those involving brain injury. When studying females, it is important to properly examine and control for the sex-specific factor of MC phase in order to have a full understanding of brain behavior relationships in translational research.

neuroscience↗

bioRxiv2017

Common variants of NRXN1, LRP1B and RORA are associated with increased ventricular volumes in psychosis - GWAS findings from the B-SNIP deep phenotyping study

Schizophrenia, Schizoaffective, and Bipolar Disorders share common illness traits, intermediate phenotypes and a partially overlapping polygenic basis. We performed GWAS on deep phenotyping data, including structural MRI and DTI, clinical, and behavioral scales from 1,115 cases and controls. Significant associations were observed with two cerebrospinal fluid volumes: the temporal horn of left lateral ventricle was associated with NRXN1, and the volume of the cavum septum pellucidum was associated with LRP1B and RORA. Both volumes were associated with illness. Suggestive associations were observed with local gyrification indices, fractional anisotropy and age at onset. The deep phenotyping approach allowed unexpected genetic sharing to be found between phenotypes, including temporal horn of left lateral ventricle and age at onset.

genetics↗