Biology subjects

Hur, J.

Publications and source records attributed to Hur, J..

29 records · Page 2Linked to original sources

bioRxiv2021

Role of Gasdermins in the Biogenesis of Apoptotic Cell-Derived Exosomes

The gasdermins, GSDMA, GSDMB, GSDMC, GSDMD, DFNA5, and DFNB59, are a family of pore-forming proteins that has recently been suggested to play a central role in the pyroptosis and the release of inflammatory cytokines. Here, we describe the novel roles of gasdermins in the biogenesis of apoptotic cell-derived exosomes. In apoptotic cells, GADMA, GSDMC, GSDMD, and DFNA5 increased the release of ApoExos, and both their full-length and cleaved forms were localized in the exosomal membrane. GSDMB and DFNB59, on the other hand, negatively affected the release of ApoExos. The caspase-mediated cleavage of gasdermins, especially DFNA5, is suggested to enable cytosolic Ca2+ to flow through endosomal pores and thus increase the biogenesis of ApoExos. In addition, the DFNA5-meidiated biogenesis of ApoExos depended on the ESCRT-III complex and endosomal recruitment of Ca2+-dependent proteins: annexins A2 and A7, the PEF domain family proteins sorcin and grancalcin, and the Bro1 domain protein HD-PTP. Therefore, we propose that the biogenesis of ApoExos begins when gasdermin-mediated endosomal pores increase cytosolic Ca2+, continues through the recruitment of annexin-sorcin/grancalcin-HD-PTP, and is completed when the ESCRT-III complex synthesizes intraluminal vesicles in the multivesicular bodies of dying cells. Finally, we found that Dfna5-bearing tumors released ApoExos to induce inflammatory responses in the in vivo 4T1 orthotropic model of breast cancer. The data presented in this study indicate that the switch from apoptosis to pyroptosis could drive the transfer of mass signals to nearby or distant living cells and tissues by way of extracellular vesicles, and that gasdermins play critical roles in that process.

cell biology↗

bioRxiv2021

Anxiety-related frontocortical activity is associated with dampened stressor reactivity in the real world

Negative affect is a fundamental dimension of human emotion. When extreme, it contributes to a variety of adverse outcomes--from physical and mental illness to divorce and premature death. Mechanistic work in animals and neuroimaging research in humans and monkeys has begun to reveal the broad contours of the neural circuits governing negative affect, but the relevance of these discoveries to everyday distress remains incompletely understood. Here we used a combination of approaches-- including neuroimaging assays of threat anticipation and emotional face perception and >10,000 momentary assessments of emotional experience--to demonstrate that individuals showing greater activation in a cingulo-opercular circuit during an anxiety-eliciting laboratory paradigm experience lower levels of stressor-dependent distress in their daily lives (n=202-208). Extended amygdala activation was not significantly related to momentary negative affect. These observations provide a framework for understanding the neurobiology of negative affect in the laboratory and in the real world. STATEMENT OF RELEVANCEAnxiety, sadness, and other negative emotions are hallmarks of the human condition. When extreme, they contribute to a variety of adverse outcomes--from physical and mental illness to divorce and premature death--pointing to the need to develop a better understanding of the underlying brain circuitry. Recent work has begun to reveal the neural systems governing negative affect, but the relevance of these tantalizing laboratory discoveries to the real world has remained unclear. Here we used a combination of brain imaging and smartphone-based survey techniques to show that individuals marked by greater activation in a cingulo-opercular circuit during an anxiety-promoting laboratory paradigm tend to experience diminished distress in response to everyday stressors. These observations provide new insights into the brain systems most relevant to moment-by-moment fluctuations in negative mood, underscoring the importance of more recently evolved cortical association areas.

neuroscience↗

bioRxiv2021

Daily caffeinated soda intake is associated with impaired working memory and higher impulsivity in children

Background and ObjectivesUse of psychotropic substances in childhood has been associated with both impulsivity and other manifestations of poor executive function as well as escalation over time to use of progressively stronger substances. However, how this relationship may start in earlier childhood has not been well explored. Here, we investigated the neurobehavioral correlates of daily caffeinated soda consumption in preadolescent children and examined whether caffeinated soda intake is associated with a higher risk of subsequent alcohol initiation. MethodsUsing Adolescent Brain Cognitive Development study data, we first investigated cross-sectional relationships between frequent caffeinated soda intake and well-known risk factors of substance misuse: impaired working memory, high impulsivity, and aberrant reward processing. We then examined whether caffeinated soda intake at baseline predicts more alcohol sipping at 12 months follow-up using a machine learning algorithm. ResultsDaily consumption of caffeinated soda was cross-sectionally associated with neurobehavioral risk factors for substance misuse such as higher impulsivity scores and lower working memory performance. Furthermore, caffeinated soda intake predicted greater alcohol sipping after 12 months even after controlling for rates of baseline alcohol sipping; children who drink caffeinated soda daily are twice as likely to start sipping alcohol after one year compared to those who do not drink caffeinated soda at all. ConclusionsThese findings suggest that previous linkages between caffeine and substance use in adolescence also extend to younger initiation, and may stem from core neurocognitive features thought conducive to substance initiation.

neuroscience↗

bioRxiv2020

Anxiety and the neurobiology of uncertain threat anticipation

When extreme, anxiety--a state of distress and arousal prototypically evoked by uncertain danger--can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for functional MRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically co-localized in fronto-cortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with fronto-cortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the extended amygdala showing the reverse pattern. Although there is widespread agreement that the bed nucleus of the stria terminalis and dorsal amygdala--the two major subdivisions of the extended amygdala--play a critical role in orchestrating adaptive responses to potential danger, their precise contributions to human anxiety have remained contentious. Follow-up analyses demonstrated that these regions show statistically indistinguishable responses to temporally uncertain and certain threat anticipation. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for accelerating the development of more effective intervention strategies for pathological anxiety. SIGNIFICANCE STATEMENTAnxiety--an emotion prototypically associated with the anticipation of uncertain harm--has profound significance for public health, yet the underlying neurobiology remains unclear. Leveraging a novel neuroimaging paradigm in a relatively large sample, we identify a core circuit responsive to both uncertain and certain threat anticipation, and show that this circuitry can be fractionated into subdivisions with a bias for one kind of threat or the other. The extended-amygdala occupies center-stage in neuropsychiatric models of anxiety, but its functional architecture has remained contentious. Here we demonstrate that its major subdivisions show statistically indistinguishable responses to temporally uncertain and certain threat. Collectively, these observations indicate the need to revise how we think about the neurobiology of anxiety and fear. RESOURCE SHARINGRaw data are available at the National Institute of Mental Healths Data Archive. Key statistical maps are or will be publicly available at NeuroVault.org.

neuroscience↗

bioRxiv2019

Identification of conserved gene regulatory networks that integrate environmental sensing and growth in the root cambium

Cambium drives lateral growth of stems and roots, contributing to diverse plant growth forms. Root crop is one outstanding example of the cambium-driven growth. To understand its molecular basis, we used radish to generate a compendium of root tissue- and stage-specific transcriptomes from two contrasting inbred lines in root growth. Expression patterns of key cambium regulators and hormone signaling components were validated. Clustering and GO enrichment analyses of radish datasets followed by comparative analysis against the newly established Arabidopsis early cambium data revealed evolutionary conserved stress-response transcription factors that might intimately control the cambium. Indeed, in vivo network made of selected stress-response and cambium regulators indicated ERF-1 as a potential key checkpoint of cambial activities, explaining how the cambium-driven growth is altered in response to environmental changes. Together, this study provides rich information about dynamic gene expression changes along the cambium-driven root growth with future engineering schemes for crop yields.

developmental biology↗

bioRxiv2019

High-phytate/low-calcium diet is a risk factor for crystal nephropathies, renal phosphate wasting, and bone loss

Phosphate overload contributes to mineral bone disorders associated with crystal nephropathies. Phytate, the major form of phosphorus in plant seeds, is known as an indigestible and negligible in humans. However, the mechanism and adverse effects of high-phytate intake on Ca2+ and phosphate absorption and homeostasis are unknown. Here we show that excessive intake of phytate with a low-Ca2+ diet fed to rats contributed to the development of crystal nephropathies, renal phosphate wasting, and bone loss through tubular dysfunction secondary to dysregulation of intestinal calcium and phosphate absorption. Moreover, Ca2+ supplementation alleviated the detrimental effects of excess dietary phytate on bone and kidney through excretion of undigested Ca2+-phytate, which prevented a vicious cycle of intestinal phosphate overload and renal phosphate wasting while improving intestinal Ca2+ bioavailability. Thus, we demonstrate that phytate is digestible without a high-Ca2+ diet and a risk factor for phosphate overloading and developing crystal nephropathies and bone disease.

physiology↗

bioRxiv2018

Seed Genome Hypomethylated Regions Are Enriched In Transcription Factor Genes

The precise mechanisms that control gene activity during seed development remain largely unknown. Previously, we showed that several genes essential for seed development, including those encoding storage proteins, fatty acid biosynthesis enzymes, and transcriptional regulators, such as ABI3 and FUS3, are located within hypomethylated regions of the soybean genome. These hypomethylated regions are similar to the DNA methylation valleys (DMVs), or canyons, found in mammalian cells. Here, we address the question of the extent to which DMVs are present within seed genomes, and what role they might play in seed development. We scanned soybean and Arabidopsis seed genomes from post-fertilization through dormancy and germination for regions that contain < 5% or < 0.4% bulk methylation in CG-, CHG-, and CHH-contexts over all developmental stages. We found that DMVs represent extensive portions of seed genomes, range in size from 5 to 76 kb, are scattered throughout all chromosomes, and are hypomethylated throughout the plant life cycle. Significantly, DMVs are enriched greatly in transcription factor genes, and other developmental genes, that play critical roles in seed formation. Many DMV genes are regulated with respect to seed stage, region, and tissue - and contain H3K4me3, H3K27me3, or bivalent marks that fluctuate during development. Our results indicate that DMVs are a unique regulatory feature of both plant and animal genomes, and that a large number of seed genes are regulated in the absence of methylation changes during development - probably by the action of specific transcription factors and epigenetic events at the chromatin level.\n\nSignificanceWe scanned soybean and Arabidopsis seed genomes for hypomethylated regions, or DNA Methylation Valleys (DMVs), present in mammalian cells. A significant fraction of seed genomes contain DMV regions that have < 5% bulk DNA methylation, or, in many cases, no detectable DNA methylation. Methylation levels of seed DMVs do not vary detectably during seed development with respect to time, region, and tissue, and are present prior to fertilization. Seed DMVs are enriched in transcription factor genes and other genes critical for seed development, and are also decorated with histone marks that fluctuate with developmental stage, resembling in significant ways their animal counterparts. We conclude that many genes playing important roles in seed formation are regulated in the absence of detectable DNA methylation events, and suggest that selective action of transcriptional activators and repressors, as well as chromatin epigenetic events play important roles in making a seed - particularly embryo formation.

plant biology↗

bioRxiv2018

Identification of Casiopeina II-gly secondary targets through a systems pharmacology approach

Casiopeinas are a group of copper-based compounds designed to be used as less toxic, more efficient chemotherapeutic agents. In this study, we analyzed the in vitro effects of Casiopeina Il-gly on the expression of canonical biological pathways. Using microarray data from HeLa cell lines treated with Casiopeina II-gly, we identified biological pathways that are perturbed after treatment. We present a novel approach integrating pathway analysis and network theory: The Pathway Crosstalk Network. We constructed a network with deregulated pathways, featuring links between those pathways that crosstalk with each other. We identified modules grouping deregulated pathways that are functionally related. Through this approach, we were able to identify three features of Casiopeina treatment: a) Perturbation of signaling pathways, related to induction of apoptosis; b) perturbation of metabolic pathways, and c) activation of immune responses. These findings can be useful to drive new experimental exploration on their role in adverse effects and efficacy of Casiopeinas.

systems biology↗

bioRxiv2018

Acute alcohol administration dampens threat-related activation in the central extended amygdala

Alcohol abuse is common, imposes a staggering burden on public health, and is challenging to treat, underscoring the need to develop a deeper understanding of the underlying neurobiology. When administered acutely, ethyl alcohol reduces threat reactivity in humans and other animals, and there is growing evidence that threat-dampening and related negative reinforcement mechanisms support the etiology and recurrence of alcohol and other kinds of substance misuse. Converging lines of evidence motivate the hypothesis that these effects are mediated by the central extended amygdala (EAc)--including the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST)--but the relevance of this circuitry to acute alcohol effects in humans remains poorly understood. Using a single-blind, randomized-groups design, multiband imaging data were acquired from 49 social drinkers while they performed an fMRI-optimized emotional-faces/places paradigm after consuming alcohol or placebo. Relative to placebo, alcohol significantly dampened reactivity to threat-related emotional faces in the BST. To rigorously assess potential regional differences in activation, data were extracted from anatomically defined Ce and BST regions-of-interest. Analyses revealed a similar pattern of dampening across the two regions. In short, alcohol acutely dampens reactivity to threat-related faces in humans and it does so similarly across the two major divisions of the EAc. These observations provide a framework for understanding the translational relevance of addiction models derived from work in rodents, inform on-going debates about the functional organization of the EAc, and set the stage for bi-directional translational models aimed at developing improved treatment strategies for alcohol abuse and other addictions.

neuroscience↗

bioRxiv2018

The Impact of Spatial Normalization for Functional Magnetic Resonance Imaging Data Analyses Revisited

Spatial normalization--the process of aligning anatomical or functional data acquired from different individuals to a common stereotaxic atlas--is routinely used in the vast majority of functional neuroimaging studies, with important consequences for scientific inference and reproducibility. Although several approaches exist, multi-step techniques that leverage the superior contrast and spatial resolution afforded by T1-weighted anatomical images to normalize echo planar imaging (EPI) functional data acquired from the same individuals (T1EPI) is now standard. Yet, recent work suggests that direct alignment of functional data to a T2*-weighted template without recourse to an anatomical image--an EPI only (EPIO) approach--enhances normalization precision. This counterintuitive claim is intriguing, suggesting that a change in standard practices may be warranted. Here, we re-visit these conclusions, extending prior work to encompass newly developed measures of normalization precision, accuracy, and real-world statistical performance for the standard EPIO and T1EPI pipelines implemented in SPM12, a recently developed variant of the EPIO pipeline, and a novel T1EPI pipeline incorporating best practice tools from multiple software packages. The multi-tool T1EPI pipeline was consistently the most precise, most accurate, and resulted in the largest t values at the group level, in some cases dramatically so. The three SPM-based pipelines exhibited more modest and variable differences in performance relative to each another, with the widely used T1EPI pipeline showing the second best overall precision and accuracy, and the recently developed EPIO pipeline generally showing the poorest overall performance. The results demonstrate that standard pipelines can be easily improved and we encourage researchers to invest the resources necessary to do so. The multi-tool pipeline presented here provides a framework for doing so. In addition, the novel performance metrics described here should prove useful for reporting and validating future methods for pre-processing functional neuroimaging data.

neuroscience↗

bioRxiv2016

Melittin-induced alterations in morphology and deformability of human red blood cells using quantitative phase imaging techniques

Here, the actions of melittin, the active molecule of apitoxin or bee venom, were investigated on human red blood cells (RBCs) using quantitative phase imaging techniques. High-resolution realtime 3-D refractive index (RI) measurements and dynamic 2-D phase images of individual melittin-bound RBCs enabled in-depth examination of melittin-induced biophysical alterations of the cells. From the measurements, morphological, biochemical, and mechanical alterations of the RBCs were analyzed quantitatively. Furthermore, leakage of haemoglobin (Hb) inside the RBCs at high melittin concentration was also investigated.

biophysics↗