Biology subjects

Song, I.

Publications and source records attributed to Song, I..

11 recordsLinked to original sources

bioRxiv2025

Prediction of zoonotic virus-host transmissibility using comparative airway organoids

AbstractThe emergence of new pandemic zoonotic diseases is accelerating. However, current approaches to control after outbreaks often allow the epidemic or pandemic spread of new zoonotic diseases, exemplified by the case of COVID-19. Prediction of zoonotic transmissibility will help minimize the outbreaks and socioeconomic damage. Here, we established highly efficient comparative airway organoids with minimal components from a panel of mammalian species for long-term culture and passaging and validated their utility to predict the transmissibility of zoonotic pathogens. Airway organoids from each species recapitulated the airway histology and contained the major cell types in the airway. They recapitulated the known susceptibility of their host species and tissues to diverse viruses. Transcriptomic analyses revealed that organoids from susceptible species induced genes of anti-viral immune responses only in common upon exposure to the same virus, although each species organoids displayed differential gene expression profiles. Also, organoids of the same species displayed differential transcriptomic responses against different viruses but induced anti-viral immune genes only in common. Our work provides a roadmap for comprehensive species- and tissue-level organoid panels for quick and reproducible uncharacterized pathogen surveillance to predict and prevent the next pandemic.

developmental biology↗

bioRxiv2023

Partially hydrolyzed guar gum attenuates the symptoms of SARS-CoV-2 infection through gut microbiota modulation in an animal model.

The coronavirus disease 2019 (COVID-19) pandemic has caused worldwide health issues. Although several vaccines have been developed, it is still difficult to prevent and reduce the inflammation caused by the infection. Studies have shown that there are correlations between the gut environment and severity of symptoms caused by SARS-CoV-2 infection. Several gut metabolites produced by the gut microbiota such as SCFAs and the secondary bile acid UDCA are reported to improve the survival rate of the host after viral infection in an animal model through modulation of the host immune system. Therefore, in this study, we attempted to use the prebiotic dietary fiber PHGG to modulate the gut microbiome and intestinal metabolites for improvement of host survival rate after SARS-CoV-2 infection in a Syrian hamster model. We were able to show that PHGG significantly improved the host survival rate and body weight reduction. Analysis of the gut microbiome, serum, and intestinal metabolites revealed that PHGG significantly increased the concentrations of several intestinal SCFAs, fecal secondary bile acids, and serum secondary bile acids. Furthermore, several microbial species and metabolites identified in this study are consistent with reports in humans. Taken together, our data suggest that PHGG is a candidate prebiotic food for reducing the morbidity of COVID-19.

microbiology↗

bioRxiv2023

Heparan sulfates regulate axonal excitability and context generalization through Ca2+/calmodulin-dependent protein kinase II

Our previous studies demonstrated that enzymatic removal of highly sulfated heparan sulfates with heparinase 1 impaired axonal excitability and reduced expression of ankyrin G at the axon initial segments in the CA1 region of the hippocampus ex vivo, impaired context discrimination in vivo, and elevated Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity in vitro. Here, we show that in vivo delivery of heparinase 1 in the CA1 region of the hippocampus elevated autophosphorylation of CaMKII 24 hours after injection in mice. Patch-clamp recording in CA1 neurons revealed no significant heparinase effects on the amplitude or frequency of miniature excitatory and inhibitory postsynaptic currents, while the threshold for action potential generation was increased and fewer spikes were generated in response to current injection. Delivery of heparinase on the next day after contextual fear conditioning induced context overgeneralization 24 hours after injection. Co-administration of heparinase with the CaMKII inhibitor (autocamtide-2-related inhibitory peptide) rescued neuronal excitability and expression of ankyrin G at the axon initial segment. It also restored context discrimination, suggesting a key role of CaMKII in neuronal signaling downstream of heparan sulfate proteoglycans and highlighting a link between impaired CA1 pyramidal cell excitability and context generalization during recall of contextual memories.

neuroscience↗

bioRxiv2023

Considering dynamic nature of the brain: the clinical importance of connectivity variability in machine learning classification and prediction

The brain connectivity of resting-state fMRI (rs-fMRI) represents an intrinsic state of brain architecture, and it has been used as a useful neural marker for detecting psychiatric conditions as well as for predicting psychosocial characteristics. However, most studies using brain connectivity have focused more on the strength of functional connectivity over time (static-FC) but less attention to temporal characteristics of connectivity changes (FC-variability). The primary goal of the current study was to investigate the effectiveness of using the FC-variability in classifying an individuals pathological characteristics from others and predicting psychosocial characteristics. In addition, the current study aimed to prove that benefits of the FC-variability are reliable across various analysis procedures. To this end, three open public large resting-state fMRI datasets including individuals with Autism Spectrum Disorder (ABIDE; N = 1249), Schizophrenia disorder (COBRE; N = 145), and typical development (NKI; N = 672) were utilized for the machine learning (ML) classification and prediction based on their static-FC and the FC-variability metrics. To confirm the robustness of FC-variability utility, we benchmarked the ML classification and prediction with various brain parcellations and sliding window parameters. As a result, we found that the ML performances were significantly improved when the ML included FC-variability features in classifying pathological populations from controls (e.g., individuals with autism spectrum disorder vs. typical development) and predicting psychiatric severity (e.g., score of autism diagnostic observation schedule), regardless of parcellation selection and sliding window size. Additionally, the ML performance deterioration was significantly prevented with FC-variability features when excessive features were inputted into the ML models, yielding more reliable results. In conclusion, the current finding proved the usefulness of the FC-variability and its reliability.

neuroscience↗

bioRxiv2022

Association of intrinsic functional connectivity between the locus coeruleus and salience network with attentional ability

The LC is a brainstem region associated with broad physiological and neural arousal as part of the release of norepinephrine, but it has increasingly been associated with multiple specific cognitive processes. These include sustained attention, deficits in which are associated with a variety of neuropsychological disorders. Neural models of attention deficits to date have focused on interrupted dynamics between the salience network (SAL) with the fronto-parietal network (FPN), which has been associated with task-switching and processing of external stimuli, respectively. Conflicting findings based on these regions suggest the possibility of upstream signaling leading to attention dysfunction, and recent research suggest the LC may play this role. In this study, resting-state functional connectivity (FC) and behavioral performance on an attention task was examined within 584 individuals. Analysis revealed significant clusters connected to the LC activity in the bilateral insula, anterior cingulate cortex (ACC), and bilateral ventral striatum, all regions associated with the SAL. Given previous findings that attention deficits may be caused by dysfunctions in network switching by the SAL, our findings here further suggest that dysfunction in LC signaling to the SAL may interfere with attention.

neuroscience↗

bioRxiv2021

OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy

Mitochondrial stress triggers a response in the cells mitochondria and nucleus, but how these stress responses are coordinated in vivo is poorly understood. Here, we characterize a family with myopathy caused by a dominant p.G58R mutation in the mitochondrial protein CHCHD10. To understand the disease etiology, we developed a novel knock-in mouse model and found that mutant CHCHD10 aggregates in affected tissues, applying a toxic protein stress to the inner mitochondrial membrane. Unexpectedly, survival of CHCHD10 knock-in mice depended on a protective stress response mediated by OMA1. The OMA1 stress response acted both locally within mitochondria, inhibiting mitochondrial fusion, and signaled outside the mitochondria, activating the integrated stress response. We additionally identified an isoform switch in the terminal complex of the electron transport chain as a novel component of this response. Our results demonstrate that OMA1 is essential for neonatal survival conditionally in the setting of inner mitochondrial membrane stress, coordinating local and global stress responses to reshape the mitochondrial network and proteome. Graphical Abtract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/473493v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1ab5990org.highwire.dtl.DTLVardef@85080dorg.highwire.dtl.DTLVardef@1d3a036org.highwire.dtl.DTLVardef@bb4679_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2021

Age-related intrinsic functional connectivity changes of locus coeruleus from childhood to older adults

The locus coeruleus is critical for selective information processing by modulating brains connectivity configuration. Increasingly studies have suggested that LC controls sensory inputs at the sensory gating stage. Furthermore, accumulating evidence has examined that young children and older adults are more prone to distraction and filter out irrelevant information less efficiently, possibly due to the impaired LC connectivity. However, the LC connectivity pattern across the life span is not fully examined yet, hampering our ability to understand the relationship between LC development and the distractibility. In this study, we examined the intrinsic network connectivity of the LC using resting-state fMRI from the enhanced NKI dataset with wide-range age samples. Based on LC-seed functional connectivity maps, we examined the age-related variation in the LC connectivity with a quadratic model. The analyses revealed two connectivity patterns explicitly. The sensory-related brain regions showed a positive quadratic age effect (u-shape), and the frontal regions for the cognitive control showed a negative quadratic age effect (inverted u-shape). Our results imply that such age-related distractibility is possibly due to the impaired sensory gating by the LC and the insufficient top-down controls by the frontal regions. We discuss the underlying neural mechanisms and limitations of our study.

neuroscience↗

bioRxiv2021

Molecular mechanism underlying substrate recognition of the peptide macrocyclase PsnB

Graspetides, also known as omega-ester-containing peptides (OEPs), are a family of ribosomally synthesized and post-translationally modified peptides (RiPPs) bearing side-to-side macrolactone or macrolactam linkages. Here we present molecular details of the precursor recognition of the macrocyclase enzyme PsnB in the biosynthesis of plesiocin, a Group 2 graspetide. Biochemical analysis revealed that, in contrast to other RiPPs, the core region of the plesiocin precursor peptide noticeably enhanced the enzyme-precursor interaction via the conserved glutamates. We obtained four crystal structures of symmetric or asymmetric PsnB dimers including those with a bound core peptide and a nucleotide, and suggest that the highly conserved Arg213 at the enzyme active site specifically recognizes a ring-forming acidic residue and escorts it to ATP for phosphorylation. Collectively, this study provides insights into the mechanism underlying substrate recognition in the graspetide biosynthesis, and lays a foundation for engineering new variants.

biochemistry↗

bioRxiv2020

A synthetic synaptic organizer protein restores glutamatergic neuronal circuits

Neuronal synapses undergo structural and functional changes throughout life, essential for nervous system physiology. However, these changes may also perturb the excitatory/inhibitory neurotransmission balance and trigger neuropsychiatric and neurological disorders. Molecular tools to restore this balance are highly desirable. Here, we report the design and characterization of CPTX, a synthetic synaptic organizer combining structural elements from cerebellin-1 and neuronal pentraxin-1 to interact with presynaptic neurexins and postsynaptic AMPA-type ionotropic glutamate receptors. CPTX induced the formation of excitatory synapses in vitro and in vivo and restored synaptic functions, motor coordination, spatial and contextual memories, and locomotion in mouse models for cerebellar ataxia, Alzheimers disease and spinal cord injury, respectively. Thus, CPTX represents a prototype for novel structure-guided biologics that can efficiently repair or remodel neuronal circuits. One Sentence SummaryStructural biology information was used to design CPTX, a synthetic protein that induces functional excitatory synapses and restores normal behaviors in mouse models of neurological diseases.

neuroscience↗

bioRxiv2018

High diversity, turnover, and structural constraints characterize TCR α and β repertoire selection

Recognition modes of individual T-cell receptors (TCR) are well studied, but how TCR repertoires are selected during acute through persistent human virus infections is less clear. Here, we show that persistent EBV-specific clonotypes account for only 9% of unique clonotypes but are highly expanded in acute infectious mononucleosis, and have distinct antigen-specific public features that drive selection into convalescence. The other 91% of highly diverse unique clonotypes disappear and are replaced in convalescence by equally diverse \"de-novo\" clonotypes. These broad fluctuating repertoires lend plasticity to antigen recognition and potentially protect against T-cell clonal loss and viral escape.

immunology↗

bioRxiv2018

Endoplasmic Reticulum Retention Motif Fused to Recombinant Anti-cancer Monoclonal Antibody (mAb) CO17-1A Affects mAb Expression and Plant Stress Response

The endoplasmic reticulum (ER) is the main site of protein synthesis, folding, and secretion to other organelles. The capacity of the ER to process proteins is limited, and excessive accumulation of unfolded and misfolded proteins can induce ER stress, which is associated with plant diseases. Here, a transgenic Arabidopsis system was established to express anti-cancer monoclonal antibodies (mAbs) that recognize the tumor-associated antigen GA733-2. The ER retention Lys-Asp-Glu-Leu (KDEL) motif sequence was added to the C-terminus of the heavy chain to retain anti-colorectal cancer mAbs in the ER, consequently boosting mAb production. Agrobacterium-mediated floral dip transformation was used to generate T1 transformants, and homozygous T4 seeds obtained from transgenic Arabidopsis plants expressing anti-colorectal cancer mAbs were used to confirm the physiological effects of KDEL tagging. Germination rates were not significantly different between mAb CO and mAb COK. However, mAb COK primary root lengths were shorter than those of mAb CO plants and non-transgenic Arabidopsis plants in in vitro media. Most ER stress-related genes, with the exception of bZIP28 and IRE1a, were upregulated in mAb COK plants compared to mAb CO plants. Western blot and SDS-PAGE analyses showed that mAb COK plants exhibited up to five-times higher expression and mAb amounts than mAb CO plants. Enhanced expression in mAb COK plants was confirmed by immunohistochemical analyses. mAb COK was distributed across most of the area of leaf tissues, whereas mAb CO was mainly distributed in extracellular areas. Surface plasmon resonance analyses revealed that both mAb CO and mAb COK possessed equivalent or slightly better binding activities to antigen EpCAM compared to a commercially available parental antibody. These results suggest that the introduction of the KDEL motif is a promising strategy for obtaining enhanced amounts of recombinant therapeutic proteins, but the KDEL sequence may induce ER stress and slightly reduce plant biomass.

plant biology↗