Biology subjects

Stephen, J.

Publications and source records attributed to Stephen, J..

6 recordsLinked to original sources

bioRxiv2025

Dynamic Inter-Modality Source Coupling Reveals Sex Differences in Children based on Brain Structural-Functional Network Connectivity: A Multimodal MRI Study of the ABCD Dataset

BackgroundSex differences in brain development are well-documented, yet the dynamic coupling between structure and function remains underexplored. We introduce dynamic inter-modality source coupling (dIMSC), extending our previous work to link structural MRI source-based morphometry (SBM) with dynamic functional network connectivity (dFNC). MethodsWe used data from the Adolescent Brain Cognitive Development (ABCD) study (ages 9-11) and combined SBM-derived gray matter sources with sliding-window dFNC. dIMSC was computed as the time-resolved cross-correlation between these modalities to quantify structure-function coupling strength. We evaluated sex differences in these profiles and their interaction with cognitive performance. ResultsSignificant sex-specific patterns emerged: males exhibited stronger positive coupling in sensorimotor regions (postcentral gyrus), while females showed stronger coupling in higher-order associative regions (inferior parietal lobule). These configurations were functionally distinct: higher positive coupling occupancy predicted better crystallized cognition (vocabulary) in females, whereas it predicted better fluid cognition (working memory) in males. ConclusionTogether, these findings suggest that males and females utilize distinct structural-functional configurations to support cognitive processing, males relying on a sensorimotor-anchored organization and females on an associative-anchored one. The dIMSC method advances our earlier work by enabling time-resolved analysis of brain coupling, providing a powerful framework for investigating sex-specific neurodevelopmental mechanisms.

neuroscience↗

bioRxiv2024

Abnormal multisensory facilitation patterns relate to disorganized thinking severity and cognitive decline in schizophrenia

Past research has demonstrated that patients with schizophrenia (SP) have visual processing and multisensory integration deficits. Additional studies report that sensory abnormalities are related to positive symptoms. To further understand how multisensory abnormalities relate to positive symptoms, we administered a multisensory integration task requiring the evaluation of perceived distance from auditory, visual, and multisensory stimuli with varying synchrony as well as clinical and neurocognitive assessments. Overall, patients had greater facilitation than healthy controls and the near synchronous condition had the most facilitation in comparison to other conditions. To further examine how multisensory facilitation relates to symptom severity, we performed a Ward cluster analysis that grouped participants by their multisensory facilitation profile. In contrast to what was expected, none of the Ward clusters were populated by a single group. Patients in cluster 3 had a significantly greater disorganization factor score than those in cluster 1. Our in-depth comparison between Ward clusters and neuropsychological tests reveal patients with greater multisensory facilitation experience the most cognitive deficits. Overall, our results demonstrate that multisensory integration is related to behavioral and cognitive deficits in complex ways. Further research is needed to understand the relationship between multisensory integration and schizophrenia symptomology. HighlightsO_LIPatients with schizophrenia have greater multisensory facilitation in perceived synchronous conditions C_LIO_LIMultisensory facilitation patterns are heterogenous across patients with Schizophrenia. C_LIO_LIDifferent multisensory patterns relate to cognitive decline and disorganized thinking in Schizophrenia. C_LI

neuroscience↗

bioRxiv2024

A Demographic-Conditioned Variational Autoencoder for fMRI Distribution Sampling and Removal of Confounds

ObjectivefMRI and derived measures such as functional connectivity (FC) have been used to predict brain age, general fluid intelligence, psychiatric disease status, and preclinical neurodegenerative disease. However, it is not always clear that all demographic confounds, such as age, sex, and race, have been removed from fMRI data. Additionally, many fMRI datasets are restricted to authorized researchers, making dissemination of these valuable data sources challenging. MethodsWe create a variational autoencoder (VAE)-based model, DemoVAE, to decorrelate fMRI features from demographics and generate high-quality synthetic fMRI data based on user-supplied demographics. We train and validate our model using two large, widely used datasets, the Philadelphia Neurodevel-opmental Cohort (PNC) and Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP). ResultsWe find that DemoVAE recapitulates group differences in fMRI data while capturing the full breadth of individual variations. Significantly, we also find that most clinical and computerized battery fields that are correlated with fMRI data are not correlated with DemoVAE latents. An exception are several fields related to schizophrenia medication and symptom severity. ConclusionOur model generates fMRI data that captures the full distribution of FC better than traditional VAE or GAN models. We also find that most prediction using fMRI data is dependent on correlation with, and prediction of, demographics. SignificanceOur DemoVAE model allows for generation of high quality synthetic data conditioned on subject demographics as well as the removal of the confounding effects of demographics. We identify that FC-based prediction tasks are highly influenced by demographic confounds.

neuroscience↗

bioRxiv2024

A POLR3B-variant reveals a Pol III transcriptome response dependent on La protein/SSB

RNA polymerase III (Pol III, POLR3) synthesizes tRNAs and other small non-coding RNAs. Human POLR3 pathogenic variants cause a range of developmental disorders, recapitulated in part by mouse models, yet some aspects of POLR3 deficiency have not been explored. We characterized a human POLR3B:c.1625A>G;p.(Asn542Ser) disease variant that was found to cause mis-splicing of POLR3B. Genome-edited POLR3B1625A>G HEK293 cells acquired the mis-splicing with decreases in multiple POLR3 subunits and TFIIIB, although display auto-upregulation of the Pol III termination-reinitiation subunit POLR3E. La protein was increased relative to its abundant pre-tRNA ligands which bind via their U(n)U-3-termini. Assays for cellular transcription revealed greater deficiencies for tRNA genes bearing terminators comprised of 4Ts than of [≥]5Ts. La-knockdown decreased Pol III ncRNA expression unlinked to RNA stability. Consistent with these effects, small-RNAseq showed that POLR3B1625A>Gand patient fibroblasts express more tRNA fragments (tRFs) derived from pre-tRNA 3-trailers (tRF-1) than from mature-tRFs, and higher levels of multiple miRNAs, relative to control cells. The data indicate that decreased levels of Pol III transcripts can lead to functional excess of La protein which reshapes small ncRNA profiles revealing new depth in the Pol III system. Finally, patient cell RNA analysis uncovered a strategy for tRF-1/tRF-3 as POLR3-deficiency biomarkers.

molecular biology↗

bioRxiv2018

Codon usage influences fitness through RNA toxicity

Many organisms are subject to selective pressure that gives rise to unequal usage of synonymous codons, known as codon bias. To experimentally dissect the mechanisms of selection on synonymous sites, we expressed several hundred synonymous variants of the GFP gene in Escherichia coli, and used quantitative growth and viability assays to estimate bacterial fitness. Unexpectedly, we found many synonymous variants whose expression was toxic to E. coli. Unlike previously studied effects of synonymous mutations, the effect that we discovered is independent of translation, but it depends on the production of toxic mRNA molecules. We identified RNA sequence determinants of toxicity, and evolved suppressor strains that can tolerate the expression of toxic GFP variants. Genome sequencing of these suppressor strains revealed a cluster of promoter mutations that prevented toxicity by reducing mRNA levels. We conclude that translation-independent RNA toxicity is a previously unrecognized obstacle in bacterial gene expression.\n\nSignificance statementSynonymous mutations in genes do not change protein sequence, but they may affect gene expression and cellular function. Here we describe an unexpected toxic effect of synonymous mutations in Escherichia coli, with potentially large implications for bacterial physiology and evolution. Unlike previously studied effects of synonymous mutations, the effect that we discovered is independent of translation, but it depends on the production of toxic mRNA molecules. We hypothesize that the mechanism we identified influences the evolution of endogenous genes in bacteria, by imposing selective constraints on synonymous mutations that arise in the genome. Of interest for biotechnology and synthetic biology, we identify bacterial strains and growth conditions that alleviate RNA toxicity, thus allowing efficient overexpression of heterologous proteins.

synthetic biology↗

bioRxiv2017

KCC1 Activation protects Mice from the Development of Experimental Cerebral Malaria.

Plasmodium falciparum malaria causes half a million deaths per year, with up to 9% of this mortality caused by cerebral malaria (CM). One of the major processes contributing to the development of CM is an excess of host inflammatory cytokines. Recently K+ signaling has emerged as an important mediator of the inflammatory response to infection; we therefore investigated whether mice carrying an ENU induced activation of the electroneutral K+ channel KCC1 had an altered response to Plasmodium berghei. Here we show that Kcc1M935K/M935K mice are protected from the development of experimental cerebral malaria, and that this protection is associated with an increased CD4+ T cells and TNF- response. This is the first description of a K+ channel affecting the development of experimental cerebral malaria.

microbiology↗