Biology subjects

Han, S.

Publications and source records attributed to Han, S..

At least 217 records · Page 12Linked to original sources

bioRxiv2021

Defining the transcriptional signature of esophageal-to-skin lineage conversion

The ability of epithelial cells to rewire their cell fate program beyond their physiological repertoire has become a new paradigm in stem cell biology. This plasticity leaves behind the concept of strict stem cell hierarchies, opening up new exciting questions about its limits and underlying regulation. Here we developed a heterotypic 3D culture system to study the mechanisms modulating changes in the identity of adult esophageal epithelial cells. We demonstrate that, when exposed to the foreign stroma of adult skin, esophageal cells transition towards hair follicle identity and architecture. Heterotypic transplantation experiments recapitulated this cell fate conversion process in vivo. Single-cell RNA sequencing and histological analysis, capturing the temporality of this process, reveal that most esophageal cells switching towards skin identity remain in an intermediate state marked by a transient regenerative profile and a particularly strong hypoxic signature. Inhibition of HIF1a establishes the central role of this pathway in regulating epithelial cell plasticity, driving cells away from their transition state in favor of cell fate conversion.

cell biology↗

bioRxiv2021

A biomechanical switch regulates the transition towards homeostasis in esophageal epithelium

Epithelial cells are highly dynamic and can rapidly adapt their behavior in response to tissue perturbations and increasing tissue demands. However, the processes that finely control these responses and, particularly, the mechanisms that ensure the correct switch to and from normal tissue homeostasis are largely unknown. Here we explore changes in cell behavior happening at the interface between postnatal development and homeostasis in the epithelium of the mouse esophagus, as a physiological model exemplifying a rapid but controlled tissue growth transition. Single cell RNA sequencing and histological analysis of the mouse esophagus reveal significant mechanical changes in the epithelium upon tissue maturation. Organ stretching experiments further indicate that tissue strain caused by the differential growth of the mouse esophagus relative to the entire body promotes the emergence of a defined committed population in the progenitor compartment as homeostasis is established. Our results point to a simple mechanism whereby the mechanical changes experienced at the whole tissue level are integrated with those "sensed" at the cellular level to control epithelial cell behavior and tissue maintenance.

cell biology↗

bioRxiv2021

Neural mechanisms underlying regulation of empathy and altruism by beliefs of others' pain

Perceived cues signaling others pain induce empathy that in turn motivates altruistic behavior toward those who appear suffering. This perception-emotion-behavior reactivity is the core of human altruism but does not always occur in real life situations. Here, by integrating behavioral and multimodal neuroimaging measures, we investigate neural mechanisms underlying the functional role of beliefs of others pain in modulating empathy and altruism. We show evidence that decreasing (or enhancing) beliefs of others pain reduces (or increases) subjective estimation of others painful emotional states and monetary donations to those who show pain expressions. Moreover, decreasing beliefs of others pain attenuates neural responses to perceived cues signaling others pain within 200 ms after stimulus onset and modulate neural responses to others pain in the frontal cortices and temporoparietal junction. Our findings highlight beliefs of others pain as a fundamental cognitive basis of human empathy and altruism and unravel the intermediate neural architecture.

evolutionary biology↗

bioRxiv2020

Platycodin D prevents both lysosome- and TMPRSS2-driven SARS-CoV-2 infection in vitro by hindering membrane fusion

An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to the global public health. Herbal medicines and their derived natural products have drawn much attention to treat COVID-19, but there has been no natural product showing inhibitory activity against SARS-CoV-2 infection with detailed mechanism. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection-routes via lysosome- and transmembrane protease, serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host-entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by a pharmacological inhibition or gene-silencing of NPC1, which is mutated in Niemann-Pick type C (NPC) patients displaying disrupted membrane cholesterol. Finally, readily available local foods or herbal medicines containing PG root show the similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that a brief disruption of membrane cholesterol can be a novel therapeutic approach against SARS-CoV-2 infection.

pharmacology and toxicology↗

bioRxiv2020

Oligomerization of the Human Adenosine A2A Receptor Is Driven by the Intrinsically Disordered C-Terminus

G protein-coupled receptors (GPCRs) have long been shown to exist as oligomers with functional properties distinct from those of the monomeric counterparts, but the driving factors of GPCR oligomerization remain relatively unexplored. In this study, we focus on the human adenosine A2A receptor (A2AR), a model GPCR that forms oligomers both in vitro and in vivo. Combining experimental and computational approaches, we discover that the intrinsically disordered C-terminus of A2AR drives the homo-oligomerization of the receptor. The formation of A2AR oligomers declines progressively and systematically with the shortening of the C-terminus. Multiple interaction sites and types are responsible for A2AR oligomerization, including disulfide linkages, hydrogen bonds, electrostatic interactions, and hydrophobic interactions. These interactions are enhanced by depletion interactions along the C-terminus, forming a tunable network of bonds that allow A2AR oligomers to adopt multiple interfaces. This study uncovers the disordered C-terminus as a prominent driving factor for the oligomerization of a GPCR, offering important guidance for structure-function studies of A2AR and other GPCRs.

biophysics↗

bioRxiv2020

Cognitive and neural bases of collateral damage during intergroup conflict

Civilian casualties occur during military attacks. Such "collateral damage" is prohibited by international laws but increases with substantial consequences when intergroup conflict escalates. Here, we investigate cognitive and neural bases of decision-making processes resulting in civilian harm, using a task that simulates punishment decision-making during intergroup conflict. We test two groups of Chinese participants in a laboratory setting, and two ethnic groups (Jewish and Palestinian) in Israel. The results dissociate two psychological constructs, harm preference and harm avoidance, which respectively characterize punishment decision-making related to outgroup combatants and outgroup noncombatants during intergroup conflict. In particular, individuals show decreased avoidance of harming outgroup noncombatants when conflict escalates. Brain imaging (functional magnetic resonance imaging) reveals that decreased harm avoidance is predicted by inhibition of the left middle frontal activity during selection of punishment decisions. Our findings provide insight into the cognitive and neural bases of decision-making involving civilian harm during intergroup conflict.

neuroscience↗

bioRxiv2020

Unified neural pathways that gate affective pain and multisensory innate threat signals to the amygdala

Perception of aversive sensory stimuli such as pain and innate threat cues is essential for animal survival. The amygdala is critical for aversive sensory perception, and it has been suggested that multiple parallel pathways independently relay aversive cues from each sensory modality to the amygdala. However, a convergent pathway that relays multisensory aversive cues to the amygdala has not been identified. Here, we report that neurons expressing calcitonin gene-related peptide (CGRP) in the parvocellular subparafasicular thalamic nucleus (SPFp) are necessary and sufficient for affective-motivational pain perception by forming a spino-thalamo-amygdaloid pain pathway. In addition, we find that this thalamic CGRP pain pathway, together with well-known parabrachio-amygdaloid CGRP pain pathway, is critical for the perception of multisensory innate threat cues. The discovery of unified pathways that collectively gate aversive sensory stimuli from all sensory modalities may provide critical circuit-based insights for developing therapeutic interventions for affective pain- and innate fear-related disorders.

neuroscience↗

bioRxiv2020

Neural basis of opioid-induced respiratory depression and its rescue

Opioid-induced respiratory depression (OIRD) causes death following an opioid overdose, yet the neurobiological mechanisms of this process are not well understood. Here, we show that neurons within the lateral parabrachial nucleus that express the -opioid receptor (PBLOprm1 neurons) are involved in OIRD pathogenesis. PBLOprm1 neuronal activity is tightly correlated with respiratory rate, and this correlation is abolished following morphine injection. Chemogenetic inactivation of PBLOprm1 neurons mimics OIRD in mice, whereas their chemogenetic activation following morphine injection rescues respiratory rhythms to baseline levels. We identified several excitatory G-protein coupled receptors expressed by PBLOprm1 neurons and show that agonists for these receptors restore breathing rates in mice experiencing OIRD. Thus, PBLOprm1 neurons are critical for OIRD pathogenesis, providing a promising therapeutic target for treating OIRD in patients.

neuroscience↗

bioRxiv2020

Genome sequencing sheds light on the contribution of structural variants to Brassica oleracea diversification

Brassica oleracea includes several morphologically diverse, economically important vegetable crops. Here we present high-quality chromosome-scale genome assemblies for two B. oleracea morphotypes, cauliflower and cabbage. Direct comparison of these two assemblies identifies ~120 K high-confidence structural variants (SVs). Population analysis of 271 B. oleracea accessions using these SVs clearly separates different morphotypes, suggesting the association of SVs with B. oleracea intraspecific divergence. Genes affected by SVs selected between cauliflower and cabbage are enriched with functions related to response to stress and stimulus and meristem and flower development. Furthermore, genes affected by selected SVs and involved in the switch from vegetative to generative growth that defines curd initiation, inflorescence meristem proliferation for curd formation, maintenance and enlargement, are identified, providing insights into the regulatory network of curd development. This study reveals the important roles of SVs in diversification of different morphotypes of B. oleracea, and the newly assembled genomes and the SVs provide rich resources for future research and breeding.

plant biology↗

bioRxiv2020

A small-molecule oral agonist of the human glucagon-like peptide-1 receptor

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited by the requirement for injection. Here we describe the first effective, orally bioavailable small molecule GLP-1R agonists. A sensitized high-throughput screen identified a series of small molecule GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nM potency. These small molecule agonists increased insulin levels in primates but not rodents, which is explained by a cryo-EM structure that revealed a binding pocket requiring primate-specific tryptophan 33. Importantly, oral administration of agonist PF-06882961 to healthy humans produced dose-dependent declines in serum glucose (NCT03309241). This opens the door to a new era of oral small molecule therapies that target the well-validated GLP-1R pathway for metabolic health. One Sentence SummaryPF-06882961 is an orally administered small molecule that activates the GLP-1 receptor to lower blood glucose in humans.

pharmacology and toxicology↗

bioRxiv2020

Widespread methylation quantitative trait loci and their role in schizophrenia risk

DNA methylation (DNAm) regulates gene expression and may represent gene-environment interactions. Using whole genome bisulfite sequencing, we surveyed DNAm in a large sample (n=344) of human brain tissues. We identify widespread genetic influence on local methylation levels throughout the genome, with 76% of SNPs and 38% of CpGs being part of methylation quantitative trait loci (meQTLs). These associations can further be clustered into regions that are differentially methylated by a given SNP, highlighting putative functional regions that explain much of the heritability associated with risk loci. Furthermore, some CpH sites associated with genetic variation. We have established a comprehensive, single base resolution view of association between genetic variation and genomic methylation, and implicate schizophrenia GWAS-associated variants as influencing the epigenetic plasticity of the brain. One-sentence summaryMost genetic variants associated with DNA methylation levels, and implicated schizophrenia GWAS variants in the human brain.

genomics↗

bioRxiv2020

Proneural genes define ground state rules to regulate neurogenic patterning and cortical folding

Transition from smooth, lissencephalic brains to highly-folded, gyrencephalic structures is associated with neuronal expansion and breaks in neurogenic symmetry. Here we show that Neurog2 and Ascl1 proneural genes regulate cortical progenitor cell differentiation through cross-repressive interactions to sustain neurogenic continuity in a lissencephalic rodent brain. Using in vivo lineage tracing, we found that Neurog2 and Ascl1 expression defines a lineage continuum of four progenitor pools, with double+ progenitors displaying several unique features (least lineage-restricted, complex gene regulatory network, G2 pausing). Strikingly, selective killing of double+ progenitors using split-Cre;Rosa-DTA transgenics breaks neurogenic symmetry by locally disrupting Notch signaling, leading to cortical folding. Finally, consistent with NEUROG2 and ASCL1 driving discontinuous neurogenesis and folding in gyrencephalic species, their transcripts are modular in folded macaque cortices and pseudo-folded human cerebral organoids. Neurog2/Ascl1 double+ progenitors are thus Notch-ligand expressing niche cells that control neurogenic periodicity to determine cortical gyrification. HIGHLIGHTSO_LINeurog2 and Ascl1 expression defines four distinct transitional progenitor states C_LIO_LIDouble+ NPCs are transcriptionally complex and mark a lineage branch point C_LIO_LIDouble+ NPCs control neurogenic patterning and cortical folding via Notch signaling C_LIO_LINeurog2 and Ascl1 expression is modular in folded and not lissencephalic cortices C_LI eTOC BLURBEmergence of a gyrencephalic cortex is associated with a break in neurogenic continuity across the cortical germinal zone. Han et al. identify a pool of unbiased neural progenitors at a lineage bifurcation point that co-express Neurog2 and Ascl1 and produce Notch ligands to control neurogenic periodicity and cortical folding.

developmental biology↗

bioRxiv2020

Renal proximal tubule cell state and metabolism are coupled by nuclear receptors

Kidney disease development is poorly understood due to the complex cellular interactions of more than 25 different cell types, each with specialized functions. Here, we used single cell RNA-sequencing to resolve cell type-specific and cell fraction changes in kidney disease. Whole kidney RNA-sequencing results were strongly influenced by cell fraction changes, but minimally informative to detect cell type-specific gene expression changes. Cell type-specific differential expression analysis identified proximal tubule cells (PT cells) as the key vulnerable cell type in diseased kidneys. Through unbiased cell trajectory analyses, we show that PT cell differentiation state is altered in disease state. Lipid metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and reproducible association with PT cells state. The coupling of cell state and metabolism is established by nuclear receptors such as PPARA and ESRRA that not only control cellular metabolism but also the expression of PT cell-specific genes in mice and patient samples.

cell biology↗

bioRxiv2020

A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in non-human primates

To contain the coronavirus disease 2019 (COVID-19) pandemic, a safe and effective vaccine against the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is urgently needed in quantities sufficient to immunise large populations. In this study, we report the design, preclinical development, immunogenicity and anti-viral protective effect in rhesus macaques of the BNT162b2 vaccine candidate. BNT162b2 contains an LNP-formulated nucleoside-modified mRNA that encodes the spike glycoprotein captured in its prefusion conformation. After expression of the BNT162b2 coding sequence in cells, approximately 20% of the spike molecules are in the one-RBD up, two-RBD down state. Immunisation of mice with a single dose of BNT162b2 induced dose level-dependent increases in pseudovirus neutralisation titers. Prime-boost vaccination of rhesus macaques elicited authentic SARS-CoV-2 neutralising geometric mean titers 10.2 to 18.0 times that of a SARS-CoV-2 convalescent human serum panel. BNT162b2 generated strong TH1 type CD4+ and IFN{gamma}+ CD8+ T-cell responses in mice and rhesus macaques. The BNT162b2 vaccine candidate fully protected the lungs of immunised rhesus macaques from infectious SARS-CoV-2 challenge. BNT162b2 is currently being evaluated in a global, pivotal Phase 2/3 trial (NCT04368728).

immunology↗

bioRxiv2020

The soybean Rhg1 amino acid transporter protein becomes abundant along the SCN penetration path and impacts ROS generation

Rhg1 mediates soybean resistance to soybean cyst nematode. Glyma.18G022400, one of three resistance-conferring genes at the complex Rhg1 locus, encodes the putative amino acid transporter AATRhg1 whose mode of action is largely unknown. We discovered that AATRhg1 protein abundance increases 7- to 15-fold throughout root cells penetrated by SCN. These root cells develop increased abundance of vesicles and larger vesicle-like bodies. AATRhg1 was often associated with these vesicles. AATRhg1 abundance remained low in syncytia (plant reprogrammed feeding cells), unlike the Rhg1 -SNAP protein whose abundance was previously shown to increase in syncytia. In N. benthamiana, if soybean AATRhg1 was present, oxidative stress promoted formation of larger macrovesicles and they contained AATRhg1. AATRhg1 was found to interact with GmRBOHC2, a soybean ortholog of Arabidopsis RBOHD previously found to exhibit upregulated expression upon SCN infection. Reactive oxygen species (ROS) generation was more elevated when AATRhg1 and GmRBOHC2 abundance were co-expressed. These findings suggest that AATRhg1 contributes to SCN resistance along the penetration path as SCN invades the plant, and does so at least in part by interactions with GmRBOHC2 that increase ROS production. The study also shows that Rhg1 resistance functions via at least two spatially and temporally separate modes of action.

plant biology↗

bioRxiv2020

Membrane Nanoparticles Derived from ACE2-rich Cells Block SARS-CoV-2 Infection

The ongoing COVID-19 epidemic worldwide necessitates the development of novel effective agents against SARS-CoV-2. ACE2 is the main receptor of SARS-CoV-2 S1 protein and mediates viral entry into host cells. Herein, the membrane nanoparticles prepared from ACE2-rich cells are discovered with potent capacity to block SARS-CoV-2 infection. The membrane of human embryonic kidney-239T cell highly expressing ACE2 is screened to prepare nanoparticles. The nanomaterial termed HEK-293T-hACE2 NPs contains 265.1 ng mg-1 of ACE2 on the surface and acts as a bait to trap SARS-CoV-2 S1 in a dose-dependent manner, resulting in reduced recruitment of the viral ligand to host cells. Interestingly, SARS-CoV-2 S1 can translocate to the cytoplasm and affect the cell metabolism, which is also inhibited by HEK-293T-hACE2 NPs. Further studies reveal that HEK-293T-hACE2 NPs can efficiently suppress SARS-CoV-2 S pseudovirions entry into human proximal tubular cells and block viral infection with a low half maximal inhibitory concentration. Additionally, this biocompatible membrane nanomaterial is sufficient to block the adherence of SARS-CoV-2 D614G-S1 mutant to sensitive cells. Our study demonstrates a easy-to-acheive memrbane nano-antagonist for curbing SARS-CoV-2, which enriches the existing antiviral arsenal and provides new possibilities to treat COVID-19. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/247338v1_ufig1.gif" ALT="Figure 1"> View larger version (81K): org.highwire.dtl.DTLVardef@4086baorg.highwire.dtl.DTLVardef@4d239eorg.highwire.dtl.DTLVardef@5d8b76org.highwire.dtl.DTLVardef@16f2581_HPS_FORMAT_FIGEXP M_FIG Graphical Table of Contents C_FIG

microbiology↗

bioRxiv2020

Liquid-liquid phase separation of tau driven by hydrophobic interaction facilitates fibrillization of tau

Amyloid aggregation of tau protein is implicated in neurodegenerative diseases, yet its facilitating factors are poorly understood. Recently, tau has been shown to undergo liquid liquid phase separation (LLPS) both in vivo and in vitro. LLPS was shown to facilitate tau amyloid aggregation in certain cases, while independent of aggregation in other cases. It is therefore important to understand the differentiating properties that resolve this apparent conflict. We report on a model system of hydrophobically driven LLPS induced by high salt concentration (LLPS-HS), and compare it to electrostatically driven LLPS represented by tau-RNA/heparin complex coacervation (LLPS-ED). We show that LLPS-HS promotes tau protein dehydration, undergoes maturation and directly leads to canonical tau fibrils, while LLPS-ED is reversible, remains hydrated and does not promote amyloid aggregation. We show that the nature of the interaction driving tau condensation is the differentiating factor between aggregation-prone and aggregation-independent LLPS.

biophysics↗

bioRxiv2020

Persistent bacterial coinfection of a COVID-19 patient caused by a genetically adapted Pseudomonas aeruginosa chronic colonizer

This study characterized a genetically adapted Pseudomonas aeruginosa small colony variant isolated from a COVID-19 patient who suffered persistent bacterial coinfection and eventually recovered from critical illness. Specification and modification of the isolates discovered at genomic and transcriptomic levels with aligned phenotypic observations indicated that these isolates formed excessive biofilm with elevated quorum sensing systems.

microbiology↗