Biology subjects

Chiu, H.

Publications and source records attributed to Chiu, H..

14 recordsLinked to original sources

bioRxiv2026

Anatomy of the Visual Word Form Area in Dyslexia

The Visual Word Form Area (VWFA), located in ventral occipitotemporal cortex, plays a critical role in skilled reading. Researchers have theorized that the VWFA develops in its specific anatomical location due to the convergence of major white matter tracts and proximity to functionally similar regions. This suggests that precise anatomical positioning may be crucial for optimal VWFA function. Previous research has identified several functional differences in this region between typical and struggling readers (i.e. dyslexia): struggling readers show weaker text-selective responses and often exhibit a smaller or even absent VWFA. However, it remains unexplored whether the precise anatomical location of this region also differs between typical and struggling readers. We tested whether VWFA anatomy differs between children with and without dyslexia (N=87). Participants completed a functional localizer, which we used to manually define the VWFA in each individual's native anatomy. We examined whether: (1) VWFA anatomical location relates to reading ability, (2) children with dyslexia show greater variability in VWFA location compared to typical readers, and (3) VWFA location with respect to white matter tracts relates to reading ability. Results reveal that, despite being smaller in children with dyslexia, there is no relationship between VWFA location and reading ability. Specifically, individual VWFA location relative to anatomy, relative to other's VWFAs, and relative to white matter tracts, is not related to reading ability. These findings suggest that while the VWFA's general anatomy may be facilitated by development, its precise location remains stable and unrelated to reading proficiency.

neuroscience↗

bioRxiv2026

Neonatal brain-age models in full- and preterm infants

Prematurity affects brain development and increases risk for neurodevelopmental impairments. Yet reliable biomarkers for at-risk infants remain limited. The goals of this study are (1a) to construct a white matter neonatal brain-age model including full-term and preterm neonates from a large publicly-available data set, (1b) to evaluate the accuracy of this model for characterizing the preterm brain from the same data set; (2) to determine if a similar model can predict brain-age based on clinical MRI scans from high-risk neonates born preterm; and (3) to evaluate whether this predictive model provides information about the infants health beyond conventional clinical and demographic measures. We developed brain-age prediction models using diffusion magnetic resonance imaging-derived white matter features from two datasets: (1) the developing Human Connectome Project (dHCP; 368 healthy infants) and (2) a clinical sample collected at the Lucile Packard Childrens Hospital (LPCH; 162 high-risk preterm infants). White matter features demonstrated strong predictive performance in the dHCP dataset (within 3.9 days) and the LPCH clinical dataset (within 6.6 days). However, brain-age metrics (i.e., brain-age gap) showed no significant associations with health complications measured by a composite score of common prematurity complications. While tractometry-derived brain-age models accurately characterize brain maturation in the neonatal brain, their sensitivity to clinical complications in preterm infants appears limited. Global white matter maturation measures derived from clinical grade data may be insufficiently sensitive to capture the cumulative burden of prematurity-related morbidities, suggesting need for multimodal or longitudinal biomarkers. HIGHLIGHTSBrain-age models of neonatal dMRI data predict age within days. Brain-age models of preterm infants predict post-menstrual age within a week. Brain-age models are accurate with research and clinical dMRI data in preterm infants. Brain-age gap was not sensitive to health status in a clinical preterm sample. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/701337v1_ufig1.gif" ALT="Figure 1000"> View larger version (15K): org.highwire.dtl.DTLVardef@16f5c5dorg.highwire.dtl.DTLVardef@1918e0org.highwire.dtl.DTLVardef@1b0246eorg.highwire.dtl.DTLVardef@127f132_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Cell type-specific contributions to a persistent aggressive internal state in female Drosophila

Persistent internal states are important for maintaining survival-promoting behaviors, such as aggression. In female Drosophila melanogaster, we have previously shown that individually activating either aIPg or pC1d cell types can induce aggression. Here we investigate further the individual roles of these cholinergic, sexually dimorphic cell types, and the reciprocal connections between them, in generating a persistent aggressive internal state. We find that a brief 30-second optogenetic stimulation of aIPg neurons was sufficient to promote an aggressive internal state lasting at least 10 minutes, whereas similar stimulation of pC1d neurons did not. While we previously showed that stimulation of pC1e alone does not evoke aggression, persistent behavior could be promoted through simultaneous stimulation of pC1d and pC1e, suggesting an unexpected synergy of these cell types in establishing a persistent aggressive state. Neither aIPg nor pC1d show persistent neuronal activity themselves, implying that the persistent internal state is maintained by other mechanisms. Moreover, inactivation of pC1d did not significantly reduce aIPg-evoked persistent aggression arguing that the aggressive state did not depend on pC1d-aIPg recurrent connectivity. Our results suggest the need for alternative models to explain persistent female aggression.

neuroscience↗

bioRxiv2022

HOPX governs a molecular and physiological switch between cardiomyocyte progenitor and maturation gene programs

This study establishes the homeodomain only protein, HOPX, as a determinant controlling the molecular switch between cardiomyocyte progenitor and maturation gene programs. Time-course single-cell gene expression with genome-wide footprinting reveal that HOPX interacts with and controls core cardiac networks by regulating the activity of mutually exclusive developmental gene programs. Upstream hypertrophy and proliferation pathways compete to regulate HOPX transcription. Mitogenic signals override hypertrophic growth signals to suppress HOPX and maintain cardiomyocyte progenitor gene programs. Physiological studies show HOPX directly governs genetic control of cardiomyocyte cell stress responses, electro-mechanical coupling, proliferation, and contractility. We use human genome-wide association studies (GWAS) to show that genetic variation in the HOPX-regulome is significantly associated with complex traits affecting cardiac structure and function. Collectively, this study provides a mechanistic link situating HOPX between competing upstream pathways where HOPX acts as a molecular switch controlling gene regulatory programs underpinning metabolic, signaling, and functional maturation of cardiomyocytes.

developmental biology↗

bioRxiv2021

The Ribb-osome: Ribbon boosts ribosomal protein gene expression to coordinate organ form and function

Cell growth is well defined for the late (post-embryonic) stages of development, but evidence for early (embryonic) cell growth during post-mitotic morphogenesis is quite limited. Here, we identify early cell growth as a key characteristic of tubulogenesis in the Drosophila embryonic salivary gland (SG). A BTB/POZ domain nuclear factor, Ribbon (Rib), mediates this early cell growth. Rib binds the transcription start site of nearly every SG-expressed ribosomal protein gene (RPG) and is required for full expression of all RPGs tested. Rib binding to RPG promoters in vitro is weak and not sequence-specific, suggesting that specificity is achieved through co-factor interactions. Consistent with this hypothesis, we demonstrate Ribs ability to physically interact with each of the three known contributors to RPG transcription. Surprisingly, Rib-dependent early cell growth in another tubular organ--the embryonic trachea--is not mediated by direct RPG transcription. These findings support a model of early cell growth sustained by transcriptional regulatory networks customized for organ form and function.

developmental biology↗

bioRxiv2021

Two microRNA regulatory circuits set start and end times for dendritic arborization of a nociceptive neuron

Choreographic dendritic arborization takes place within a defined time frame, but the timing mechanism is currently not known. Here, we report that the precisely timed lin-4-lin-14 regulatory circuit triggers an initial dendritic growth activity whereas the precisely timed lin-28-let-7-lin-41 regulatory circuit signals a subsequent developmental decline in dendritic growth ability, hence restricting dendritic arborization within a set time frame. Loss-of-function mutations in the lin-4 microRNA gene cause limited dendritic outgrowth whereas loss-of-function mutations in its direct target, the lin-14 transcription factor gene, cause precocious and excessive outgrowth. In contrast, loss-of-function mutations in the let-7 microRNA gene prevent a developmental decline in dendritic growth ability whereas loss-of-function mutations in its upstream regulator, the lin-28 RNA-binding protein gene, and its direct target, the lin-41 tripartite motif protein gene, cause further decline. lin-4 and let-7 regulatory circuits are expressed in the right place at the right time to set start and end times for PVD dendritic arborization. Replacing the endogenous lin-4 promoter at the lin-4 locus with a late-onset let-7 promoter delays PVD dendrite arborization whereas replacing the endogenous let-7 promoter at the let-7 locus with an early-onset lin-4 promoter causes precocious decline in dendritic growth ability in PVD neurons. Our results indicate that the lin-4-lin-14 and the lin-28-let-7-lin-41 regulatory circuits control the timing of dendrite arborization through antagonistic regulation of the DMA-1 receptor level on dendrites. The LIN-14 transcription factor directly represses the dma-1 gene expression through a transcriptional means whereas the LIN-41 tripartite motif protein indirectly activates the dma-1 gene expression through a post-transcriptional means.

neuroscience↗

bioRxiv2021

Village in a dish: a model system for population-scale hiPSC studies

The mechanisms by which DNA alleles contribute to disease risk, drug response, and other human phenotypes are highly context-specific, varying across cell types and under different conditions. Human induced pluripotent stem cells (hiPSCs) are uniquely suited to study these context-dependent effects, but to do so requires cell lines from hundreds or potentially thousands of individuals. Village cultures, where multiple hiPSC lines are cultured and differentiated together in a single dish, provide an elegant solution for scaling hiPSC experiments to the necessary sample sizes required for population-scale studies. Here, we show the utility of village models, demonstrating how cells can be assigned back to a donor line using single cell sequencing, and addressing whether line-specific signaling alters the transcriptional profiles of companion lines in a village culture. We generated single cell RNA sequence data from hiPSC lines cultured independently (uni-culture) and in villages at three independent sites. We show that the transcriptional profiles of hiPSC lines are highly consistent between uni- and village cultures for both fresh (0.46 < R < 0.88) and cryopreserved samples (0.46 < R < 0.62). Using a mixed linear model framework, we estimate that the proportion of transcriptional variation across cells is predominantly due to donor effects, with minimal evidence of variation due to culturing in a village system. We demonstrate that the genetic, epigenetic or hiPSC line-specific effects on gene expression are consistent whether the lines are uni- or village-cultured (0.82 < R < 0.94). Finally, we identify the consistency in the landscape of cell states between uni- and village-culture systems. Collectively, we demonstrate that village methods can be effectively used to detect hiPSC line-specific effects including sensitive dynamics of cell states.

genomics↗

bioRxiv2021

The kpc-1 (furin) 3'UTR promotes dendritic transport and local translation of mRNAs to regulate dendrite branching and self-avoidance of a nociceptive neuron

A recently reported Schizophrenia-associated genetic variant in the 3UTR of the human furin gene, a homolog of C. elegans kpc-1, highlights an important role of the furin 3UTR in neuronal development(1). We isolate three kpc-1 mutants that display abnormal dendrite arborization in PVD neurons and defective male mating behaviors. We show that the kpc-1 3UTR participates in dendrite branching and self-avoidance. The kpc-1 3UTR facilitates mRNA localization to branching points and contact points between sibling dendrites and promotes local protein synthesis. We identify a secondary structural motif in the kpc-1 3UTR required for dendrite self-avoidance. Animals with dma-1 receptor over-expression exhibit similar dendrite branching and self-avoidance defects that are suppressed with kpc-1 over-expression. Our results support a model in which KPC-1 proteins are synthesized at branching points and contact points to locally down-regulate DMA-1 receptors to promote dendrite branching and self-avoidance of a mechanosensory neuron important for male courtship.

neuroscience↗

bioRxiv2019

Pharmacological inhibition of acid sensing ion channel 1a protects the heart from ischemia-reperfusion injury

The proton-gated acid-sensing ion channel 1a (ASIC1a) is implicated in the injury response to cerebral ischemia but little is known about its role in cardiac ischemia. We provide genetic evidence that ASIC1a is involved in myocardial ischemia-reperfusion injury (IRI) and show that pharmacological inhibition of ASIC1a yields robust cardioprotection in rodent and human models of cardiac ischemia, resulting in improved post-IRI cardiac viability and function. Consistent with a key role for ASIC1a in cardiac ischemia, we show that polymorphisms in the ASIC1 genetic locus are strongly associated with myocardial infarction. Collectively, our data provide compelling evidence that ASIC1a is a key target for cardioprotective drugs to reduce the burden of disease associated with myocardial ischemia.

physiology↗

bioRxiv2019

NEURONS THAT FUNCTION WITHIN AN INTEGRATOR TO PROMOTE A PERSISTENT BEHAVIORAL STATE IN DROSOPHILA

Innate behaviors involve both reflexive motor programs and internal states. In Drosophila, optogenetic activation of male-specific P1 interneurons triggers courtship song, as well as a persistent behavioral state that prolongs courtship and enhances aggressiveness. Here we identify pCd neurons as persistently activated by repeated P1 stimulation. pCd neurons are required for P1-evoked persistent courtship and aggression, as well as for normal social behavior. Activation of pCd neurons alone is inefficacious, but enhances and prolongs courtship or aggression promoted by female cues. Transient female exposure induced persistent increases in male aggressiveness, an effect suppressed by transiently silencing pCd neurons. Transient silencing of pCd also disrupted P1-induced persistent physiological activity, implying a requisite role in persistence. Finally, P1 activation of pCd neurons enhanced their responsiveness to cVA, an aggression-promoting pheromone. Thus, pCd neurons function within a circuit that integrates P1 input, to promote a persistent internal state that enhances multiple social behaviors.

neuroscience↗

bioRxiv2018

A functional study of all 40 C. elegans insulin-like peptides

The human genome encodes ten insulin-like genes, whereas the C. elegans genome remarkably encodes forty insulin-like genes. The roles of insulin/insulin-like peptide ligands (INS) in C. elegans are not well understood. The functional redundancy of the forty INS genes makes it challenging to address their functions by using knock out strategies. Here, we individually overexpressed each of the forty ins genes pan-neuronally, and monitored multiple phenotypes including: L1 arrest life span, neuroblast divisions under L1 arrest, dauer formation and fat accumulation, as readouts to characterize the functions of each INS in vivo. Of the 40 INS peptides, we found functions for 35 INS peptides and functionally categorized each as agonists, antagonists or of pleiotropic function. In particular, we found that 9 of 16 agonistic INS peptides shortened L1 arrest life span and promoted neuroblast divisions during L1 arrest. Our study revealed that a subset of {beta}-class INS peptides that contain a distinct F peptide sequence are agonists. Our work is the first to categorize the structures of INS peptides and relate these structures to the functions of all forty INS peptides in vivo. Our findings will promote the study of insulin function on development, metabolism, and aging-related diseases.\n\nAuthor SummaryInsulin and insulin-like growth factors are found in all animals and regulate many physiological and developmental processes. The human genome has 10 insulin-like peptides including the well characterized insulin hormone. The nematode C. elegans has 40 insulin-like (INS) peptide genes. All 40 INS peptides have been knocked out but no single INS gene knock out resembles the loss of the C. elegans insulin receptor suggesting that the other INS peptides can compensate when one INS is lost. We have used a genetic approach to overexpress each of the 40 INS peptides in C. elegans and have identified in vivo function for 35 of the 40 INS peptides. Like the human insulin and IGF-1, C. elegans INS peptides are derived from a precursor protein and we have shown that INS peptides with an associated peptide called the F peptide are strong activators of the C. elegans insulin-like receptor. We also identified several INS peptides that inhibit the insulin-like receptor and these inhibitory INS peptides may have therapeutic potential.

genetics↗

bioRxiv2017

Cardiac directed differentiation using small molecule Wnt modulation at single-cell resolution

Differentiation into diverse cell lineages requires the orchestration of gene regulatory networks guiding diverse cell fate choices. Utilizing human pluripotent stem cells, we measured expression dynamics of 17,718 genes from 43,168 cells across five time points over a thirty day time-course of in vitro cardiac-directed differentiation. Unsupervised clustering and lineage prediction algorithms were used to map fate choices and transcriptional networks underlying cardiac differentiation. We leveraged this resource to identify strategies for controlling in vitro differentiation as it occurs in vivo. HOPX, a non-DNA binding homeodomain protein essential for heart development in vivo was identified as dys-regulated in in vitro derived cardiomyocytes. Utilizing genetic gain and loss of function approaches, we dissect the transcriptional complexity of the HOPX locus and identify the requirement of hypertrophic signaling for HOPX transcription in hPSC-derived cardiomyocytes. This work provides a single cell dissection of the transcriptional landscape of cardiac differentiation for broad applications of stem cells in cardiovascular biology.

developmental biology↗

bioRxiv2017

Determining cell fate specification and genetic contribution to cardiac disease risk in hiPSC-derived cardiomyocytes at single cell resolution

The majority of genetic loci underlying common disease risk act through changing genome regulation, and are routinely linked to expression quantitative trait loci, where gene expression is measured using bulk populations of mature cells. A crucial step that is missing is evidence of variation in the expression of these genes as cells progress from a pluripotent to mature state. This is especially important for cardiovascular disease, as the majority of cardiac cells have limited properties for renewal postneonatal. To investigate the dynamic changes in gene expression across the cardiac lineage, we generated RNA-sequencing data captured from 43,168 single cells progressing through in vitro cardiac-directed differentiation from pluripotency. We developed a novel and generalized unsupervised cell clustering approach and a machine learning method for prediction of cell transition. Using these methods, we were able to reconstruct the cell fate choices as cells transition from a pluripotent state to mature cardiomyocytes, uncovering intermediate cell populations that do not progress to maturity, and distinct cell trajectories that terminate in cardiomyocytes that differ in their contractile forces. Second, we identify new gene markers that denote lineage specification and demonstrate a substantial increase in their utility for cell identification over current pluripotent and cardiogenic markers. By integrating results from analysis of the single cell lineage RNA-sequence data with population-based GWAS of cardiovascular disease and cardiac tissue eQTLs, we show that the pathogenicity of disease-associated genes is highly dynamic as cells transition across their developmental lineage, and exhibit variation between cell fate trajectories. Through the integration of single cell RNA-sequence data with population-scale genetic data we have identified genes significantly altered at cell specification events providing insights into a context-dependent role in cardiovascular disease risk. This study provides a valuable data resource focused on in vitro cardiomyocyte differentiation to understand cardiac disease coupled with new analytical methods with broad applications to single-cell data.

genomics↗

bioRxiv2017

Single-Cell Transcriptome Sequencing Of 18,787 Human Induced Pluripotent Stem Cells Identifies Differentially Primed Subpopulations

Heterogeneity of cell states represented in pluripotent cultures have not been described at the transcriptional level. Since gene expression is highly heterogeneous between cells, single-cell RNA sequencing can be used to identify how individual pluripotent cells function. Here, we present results from the analysis of single-cell RNA sequencing data from 18,787 individual WTC CRISPRi human induced pluripotent stem cells. We developed an unsupervised clustering method, and through this identified four subpopulations distinguishable on the basis of their pluripotent state including: a core pluripotent population (48.3%), proliferative (47.8%), early-primed for differentiation (2.8%) and late-primed for differentiation (1.1%). For each subpopulation we were able to identify the genes and pathways that define differences in pluripotent cell states. Our method identified four transcriptionally distinct predictor gene sets comprised of 165 unique genes that denote the specific pluripotency states; and using these sets, we developed a multigenic machine learning prediction method to accurately classify single cells into each of the subpopulations. Compared against a set of established pluripotency markers, our method increases prediction accuracy by 10%, specificity by 20%, and explains a substantially larger proportion of deviance (up to 3-fold) from the prediction model. Finally, we developed an innovative method to predict cells transitioning between subpopulations, and support our conclusions with results from two orthogonal pseudotime trajectory methods.

genomics↗