Biology subjects

Yin, S.

Publications and source records attributed to Yin, S..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Decoding the temporal dynamics of affective scene processing

Natural images containing affective scenes are used extensively to investigate the neural mechanisms of visual emotion processing. Functional fMRI studies have shown that these images activate a large-scale distributed brain network that encompasses areas in visual, temporal, and frontal cortices. The underlying spatial and temporal dynamics among these network structures, however, remain to be characterized. We recorded simultaneous EEG-fMRI data while participants passively viewed affective images from the International Affective Picture System (IAPS). Applying multivariate pattern analysis to decode EEG data, and representational similarity analysis to fuse EEG data with simultaneously recorded fMRI data, we found that: (1) ~100 ms after picture onset, perceptual processing of complex visual scenes began in early visual cortex, proceeding to ventral visual cortex at ~160 ms, (2) between ~200 and ~300 ms (pleasant pictures: ~200 ms; unpleasant pictures: ~260 ms), affect-specific neural representations began to form, supported mainly by areas in occipital and temporal cortices, and (3) affect-specific neural representations, lasting up to ~2 s, were stable and exhibited temporally generalizable activity patterns. These results suggest that affective scene representations in the brain are formed in a valence-dependent manner and are sustained by recurrent neural interactions among distributed brain areas.

neuroscience↗

bioRxiv2022

Observing noncovalent interactions in experimental electron density for macromolecular systems: A novel perspective for protein-ligand interaction research

We report for the first time the use of experimental electron density (ED) in the Protein Data Bank for modeling non-covalent interactions (NCIs) for protein-ligand complexes. Our methodology is based on the reduced electron density gradient (RDG) theory describing intermolecular NCI by ED and its first derivative. We established a database called the Experimental NCI Database (ExptNCI; http://ncidatabase.stonewise.cn/#/nci) containing ED saddle points, indicating ~200,000 NCIs from over 12,000 protein-ligand complexes. We also demonstrated the use of the database for depicting amide-{pi} interactions in a protein-ligand binding system. In summary, the database provides details on experimentally observed NCIs for protein-ligand complexes and can support future studies, including studies on rarely documented NCIs and the development of artificial intelligent models for protein-ligand binding prediction.

biochemistry↗

bioRxiv2021

Effects of Chronic Intermittent Hypoxia and Chronic Sleep Fragmentation on Gut Microbiome, Serum Metabolome, Liver and Adipose Tissue Morphology

Chronic intermittent hypoxia (CIH) and chronic sleep fragmentation (CSF) are two cardinal pathological features of obstructive sleep apnea (OSA). Dietary obesity is a crucial risk intermediator for OSA and metabolic disorders. Gut microbiota affect hepatic and adipose tissue morphology under conditions of CIH or CSF through downstream metabolites. However, the exact relationship is unclear. Herein, chow and high-fat diet (HFD)-fed mice were subjected to CIH or CSF for 10 weeks each and compared to normoxia (NM) or normal sleep (NS) controls. 16S rRNA amplicon sequencing, untargeted liquid chromatography-tandem mass spectrometry, and histological assessment of liver and adipose tissues were used to investigate the correlations between the microbiome, metabolome, and lipid metabolism under CIH or CSF condition. Our results demonstrated that CIH and CSF regulate the abundance of intestinal microbes (such as Akkermansia mucinphila, Clostridium spp., Lactococcus spp., and Bifidobacterium spp.) and functional metabolites, such as tryptophan, free fatty acids, branched amino acids, and bile acids, which influence adipose tissue and hepatic lipid metabolism, and the level of lipid deposition in tissues and peripheral blood. In conclusion, CIH and CSF adversely affect fecal microbiota composition and function, and host metabolism; these findings provide new insight into the independent and synergistic effects of CIH, CSF, and HFD on lipid disorders.

microbiology↗

bioRxiv2021

Habitat loss exacerbates pathogen spread: An Agent-based model of avian influenza infection in migratory waterfowl

Habitat availability determines the distribution of migratory waterfowl along their flyway, which further influences the transmission and spatial spread of avian influenza viruses (AIVs). The extensive habitat loss in the East Asian-Australasian Flyway (EAAF) may have potentially altered the virus transmission and spread, but those consequences are rarely studied. We constructed 6 fall migration networks that differed in their level of habitat loss, wherein an increase in habitat loss resulted in smaller networks with fewer sites. The networks were integrated with an agent-based model and a susceptible-infected-recovered model to simulate waterfowl migration and AIV transmission. We found that extensive habitat loss in the EAAF can 1) relocate the outbreaks northwards responding to the distribution changes of wintering waterfowl geese, 2) increase the outbreak risk in remaining sites due to larger bird congregations, and 3) facilitate AIV transmission among wintering geese. Our modelling output suggested that there was a certain system resilience of migration network to confront the site removal. In addition, the outputs were in line with the predictions from the concept of "migratory escape", affecting the pattern of infection prevalence in the waterfowl population. Our modelling shed light on the potential consequences of habitat loss in transmitting and spreading AIV at the flyway scale, and suggested the driving mechanisms behind these effects, advocating the importance of nature conservation in changing spatial and temporal patterns of AIV outbreak. Author summaryWhat are the possible consequences of extensive habitat loss on the transmission and spread of avian influenza viruses (AIVs)? We used a logistic regression model to select the suitable habitats of Greater white-fronted goose in the East Asian-Australasian Flyway and treated these habitats as sites to construct 6 fall migration networks that differed in their level of habitat loss (i.e., site removal). We then simulate geese migration in these networks, and explore the impacts of habitat loss on habitat connectivity and AIV transmission. We found the extensive habitat loss can cause relocation of the outbreaks and increase the outbreak risk and AIV transmission. Our modelling outputs suggested a certain network resilience to confront the site loss, and a "migratory escape" to change the spatial and temporal pattern of infection prevalence in the population. Overall, our study showed that land use changes and habitat loss can affect disease distribution and prevalence, suggested the importance of habitat conservation in changing the spatial and temporal pattern of AIVs transmission and spread.

ecology↗

bioRxiv2021

Phenotyping the tumor-immune microenvironment (TiME) in vivo by cellular-level optical imaging reveals unique combination phenotypes with variable inflammation and endothelial anergy

Immunotherapies have shown unprecedented clinical benefits in several malignancies1-3. However, clinical responses remain variable and unpredictable, indicating the need to develop predictive platforms that can improve patient stratification4. Phenotyping of tumors into hot, altered, or cold5 based on assessment of only T-cell infiltration in static tumor biopsies provides suboptimal prediction of immunotherapy response6,7. In vivo dynamic mechanisms within the tumor microenvironment such as tumor angiogenesis and leukocyte trafficking5,8,9 also play a central role in modulating anti-tumor immunity and therefore immunotherapy response. Here, we report novel tumor immune microenvironment (TiME) phenotyping in vivo in patients with non-invasive spatially-resolved cellular-level imaging based on endogenous contrast. Investigating skin cancers as a model, with reflectance confocal microscopy (RCM) imaging10, we determined four major phenotypes with variable prevalence of vasculature (Vasc) and inflammation (Inf) features: VaschiInfhi, VaschiInflo, VascloInfhi and Vascmed/hiInflo. The VaschiInfhi phenotype correlates with high immune activation, exhaustion, and vascular signatures while VaschiInflo with endothelial anergy and immune exclusion. Automated quantification of TiME features demonstrates moderate-high accuracy and correlation with corresponding gene expression. Prospectively analyzed response to topical immunotherapy show highest response in VascloInfhi, and reveals the added value of vascular features in predicting treatment response. Our novel in vivo cellular-level imaging and phenotyping approach can potentially advance our fundamental understanding of TiME, develop robust predictors for immunotherapy outcomes and identify novel targetable pathways in future.

cancer biology↗

bioRxiv2021

Amelioration of hemophilia B through CRISPR/Cas9 induced homology-independent targeted integration

Site-specific integration of exogenous gene through genome editing is a promising strategy for gene therapy. However, homology-directed repair (HDR) only occurring in proliferating cells is inefficient especially in vivo. To investigate the efficacy of Cas9-induced homology-independent targeted integration (HITI) strategy for gene therapy, a rat hemophilia B model was generated and employed. Through HITI, a DNA sequence encoding the last exon of rat Albumin (rAlb) gene fused with a high-specific-activity Factor IX variant (R338L) using T2A, was inserted into the last intron of rAlb via recombinant adeno-associated viral (rAAV). The knock-in efficiency reached up to 3.66% determined by ddPCR. The clotting time was reduced to normal level 4 weeks after treatment, and the circulating FIX level was gradually increased up to 52% of normal during 9 months even after partial hepatectomy, demonstrating the amelioration of hemophilia. Through PEM-seq, no significant off-targeting effect was detected. Moreover, this study provides a promising therapeutic approach for hereditary diseases.

bioengineering↗

bioRxiv2020

Discovery of a new Neisseria gonorrhoeae Type IV pilus assembly factor, TfpC

Neisseria gonorrhoeae rely on Type IV pili (T4p) to promote colonization of their human host and to cause the sexually transmitted infection, gonorrhea. This organelle cycles through a process of extension and retraction back into the bacterial cell. Through a genetic screen, we identified the NGO0783 locus of N. gonorrhoeae strain FA1090 as containing a gene encoding a protein required to stabilize the Type IV pilus in its extended, non-retracted conformation. We have named the gene tfpC and the protein TfpC. Deletion of tfpC produces a nonpiliated colony morphology and immuno-transmission electron microscopy confirms that the pili are lost in the {Delta}tfpC mutant, although there is some pilin detected near the bacterial cell surface. A copy of the tfpC gene expressed from a lac promoter restores pilus expression and related phenotypes. A {Delta}tfpC mutant shows reduced levels of pilin protein, but complementation with a tfpC gene restored pilin to normal levels. Bioinformatic searches show there are orthologues in numerous bacteria species but not all Type IV pilin expressing bacteria contain orthologous genes. Co-evolution and NMR analysis indicates that TfpC contains an N-terminal transmembrane helix, a substantial extended/unstructured region and a highly charge C-terminal coiled-coil domain. ImportanceMost bacterial species express one or more extracellular organelles called pili/fimbriae that are required for many properties of each bacterial cell. The Neisseria gonorrhoeae Type IV pilus is a major virulence and colonization factor for the sexually transmitted infection, gonorrhea. We have discovered a new protein of Neisseria gonorrhoeae called TfpC that is required to maintain the Type IV pili on the bacterial cell surface. There are similar proteins found in the other members of the Neisseria genus and many other bacterial species important for human health.

microbiology↗

bioRxiv2020

mTOR S-nitrosylation inhibits autophagy and lysosomal proteolysis

Mammalian Target of Rapamycin (mTOR) is a master regulator of autophagy and lysosomes, and its downstream kinase-dependent pathways have been extensively characterized. Here, we report an unexpected kinase-independent regulation of autophagy and lysosomes by S-nitrosylation at Cys423 position of mTOR that resulted in suppression of VPS34 and PIKfyve-dependent phosphoinositide synthesis. Physiologically, S-nitrosylation of mTOR reduced basal lysosomal proteolysis via nitric oxide synthase (NOS)-mediated synthesis of NO from lysosomal arginine precursor, a marker of cellular nutrition status. Significantly, we found increased lysosomal NOS-mTOR complexes in APP-PS1 Alzheimers disease (AD) murine model, and increased mTOR S-nitrosylation in AD patient-derived fibroblasts. Lastly, we demonstrated that pharmacological inhibition of NOS or overexpression of mTORCys423Ala mutant reversed lysosomal and autophagic dysfunction in AD patient-derived fibroblasts, suggesting novel therapeutic strategies for autophagosome-lysosomal activation.

cell biology↗

bioRxiv2020

Decoding Multivoxel Representations of Affective Scenes in Retinotopic Visual Cortex

The perception of opportunities and threats in complex scenes represents one of the main functions of the human visual system. In the laboratory, its neurophysiological basis is often studied by having observers view pictures varying in affective content. This body of work has consistently shown that viewing emotionally engaging, compared to neutral, pictures (1) heightens blood flow in limbic structures and frontoparietal cortex, as well as in anterior ventral and dorsal visual cortex, and (2) prompts an increase in the late positive event-related potential (LPP), a scalp-recorded and time-sensitive index of engagement within the network of aforementioned neural structures. The role of retinotopic visual cortex in this process has, however, been contentious, with competing theoretical notions predicting the presence versus absence of emotion-specific signals in retinotopic visual areas. The present study used multimodal neuroimaging and machine learning to address this question by examining the large-scale neural representations of affective pictures. Recording EEG and fMRI simultaneously while observers viewed pleasant, unpleasant, and neutral affective pictures, and applying multivariate pattern analysis to single-trial BOLD activities in retinotopic visual cortex, we identified three robust findings: First, unpleasant-versus-neutral decoding accuracy, as well as pleasant-versus-neutral decoding accuracy, were well above chance level in all retinotopic visual areas, including primary visual cortex. Second, the decoding accuracy in ventral visual cortex, but not in early visual cortex or dorsal visual cortex, was significantly correlated with LPP amplitude. Third, effective connectivity from amygdala to ventral visual cortex predicted unpleasant-versus-neutral decoding accuracy, and effective connectivity from ventral frontal cortex to ventral visual cortex predicted pleasant-versus-neutral decoding accuracy. These results suggest that affective pictures evoked valence-specific multivoxel neural representations in retinotopic visual cortex and that these multivoxel representations were influenced by reentry signals from limbic and frontal brain regions.

neuroscience↗

bioRxiv2020

Endoplasmic reticulum visits highly active spines and prevents runaway potentiation of synapses

In hippocampal pyramidal cells, a small subset of dendritic spines contain endoplasmic reticulum (ER). In large spines, ER frequently forms a spine apparatus, while smaller spines contain just a single tubule of smooth ER. Here we show that the ER visits dendritic spines in a non-random manner, targeting spines during periods of high synaptic activity. When we blocked ER motility using a dominant negative approach against myosin V, spine synapses became stronger compared to controls. We were not able to further potentiate these maxed-out synapses, but LTD was readily induced by low-frequency stimulation. We conclude that the brief ER visits to active spines have the important function of preventing runaway potentiation of individual spine synapses, keeping most of them at an intermediate strength level from which both LTP and LTD are possible.

neuroscience↗

bioRxiv2020

DNA extraction and sequencing of the Mawangdui ancient cadaver protected by formalin

Mawangdui ancient Cadaver is the first wet corpse found in the world, which is famous for being immortal for over two thousands of years. After being unearthed, the female corpse was immersed in the formalin protective solution for more than 40 years. We used magnetic bead method and formalin fixed paraffing (FFPE) method to extract the DNA of the female corpse, respectively. PCR amplification, sanger sequencing, library building, high throughput sequencing (testing) and data processing were carried out on the DNA samples, and about 0.5% of the whole genome coverage sequencing data was obtained. Comparing the results of DNA trough two extraction and sequencing methods. We found that the FFPE and high throughput sequencing methods is better than others for DNA extraction of the ancient samples which were preserved in formalin, providing a guidance for dealing with formalin preserved ancient samples in the future.

molecular biology↗

bioRxiv2020

Shared and distinct patterns of atypical cortical morphometry in children with autism and anxiety

Autism spectrum disorder (ASD) and anxiety disorders (ANX) are common neurodevelopmental conditions with several overlapping symptoms. Notably, many children and adolescents with ASD also have an ANX diagnosis, suggesting shared pathological mechanisms. Here, we leveraged structural imaging and phenotypic data from 82 closely matched children (28 ASD, 28 ANX, 26 typically developing controls). Our neuroimaging paradigm assessed cortical thickness and studied inter-regional structural covariance networks. Both ASD and ANX presented with atypical structural network organization relative to controls. Specifically, ASD presented with increased thickness in temporal and parietal midline cortices, while ANX was associated with increased cortical thickness in the left inferior frontal and precentral gyri. Despite the overall difference in the spatial distributions these clusters, unconstrained spin permutation testing showed that statistical maps from the ANX-vs-controls and ASD-vs-controls analyses were significantly correlated. The two diagnostic groups also presented with common decreases in structural covariance patterns, collectively pointing to decreased structural coupling between lateral frontal, lateral temporal, and temporo-parietal regions. Dimensional analysis of trait anxiety and social responsiveness partially recapitulated diagnosis-based findings. Collectively, our findings provide evidence for both shared as well as distinct effects of ASD and ANX on on regional and inter-regional structural network organization.

neuroscience↗

bioRxiv2020

Fear conditioning prompts sparser representations of conditioned threat in primary visual cortex

Repeated exposure to threatening stimuli alters sensory responses. We investigated the underlying neural mechanism by recording simultaneous EEG-fMRI from human participants viewing oriented gratings during Pavlovian fear conditioning. In acquisition, one grating (the CS+) was paired with a noxious noise, the unconditioned stimulus (US). The other grating (CS-) was never paired with US. In habituation, which preceded acquisition, and in final extinction, the same two gratings were presented without the US. Using fMRI-BOLD multivoxel patterns in primary visual cortex during habituation as reference, we found that during acquisition, aversive learning selectively prompted systematic changes in multivoxel patterns evoked by the CS+. Specifically, CS+ evoked voxel patterns in V1 became sparser as aversive learning progressed, and the sparse pattern was preserved in extinction. Concomitant with the voxel pattern changes, occipital alpha oscillations were increasingly more desynchronized during CS+ (but not CS-) trials. Across acquisition trials, the rate of change in CS+-related alpha desynchronization was correlated with the rate of change in multivoxel pattern representations of the CS+. Furthermore, alpha oscillations co-varied with BOLD in the right temporal-parietal junction, but not with BOLD in the amygdala. Thus, fear conditioning prompts persistent sparsification of threat cue representations, likely mediated by attention-related mechanisms.

neuroscience↗

bioRxiv2019

An activity-guided map of electrophile-cysteine interactions in primary human immune cells

Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These compounds are thought to act by cysteine modification to alter the functions of immune-relevant proteins; however, our understanding of electrophile-sensitive cysteines in the human immune proteome remains limited. Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology. We further show that electrophilic compounds can impair T cell activation by distinct mechanisms involving direct functional perturbation and/or ligand-induced degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells, underscoring the potential of electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders.

immunology↗

bioRxiv2019

PacBio amplicon sequencing method to measure pilin antigenic variation frequencies of Neisseria gonorrhoeae

Gene diversification is a common mechanism pathogens use to alter surface structures to aid in immune avoidance. Neisseria gonorrhoeae uses a gene conversion-based diversification system to alter the primary sequence of the gene encoding the major subunit of the pilus, pilE. Antigenic variation occurs when one of the non-expressed 19 silent copies donates part of its DNA sequence to pilE. We have developed a method using Pacific Biosciences amplicon sequencing and custom software to determine pilin antigenic variation frequencies. The program analyzes 37 variable regions across the strain FA1090 1-81-S2 pilE gene and can be modified to determine sequence variation from other starting pilE sequences or other diversity generation systems. Using this method, we measured pilin antigenic variation frequencies for various derivatives of strain FA1090 and showed we can also analyze pilin antigenic variation frequencies during macrophage infection.

microbiology↗

bioRxiv2019

Self-assembled primary tumor clusters for precision cancer therapy

Several patient-derived tumor models emerged recently as robust preclinical models. However, their potential to guide clinical therapy remained unclear. We report a novel model for personalized drug testing called patient-derived tumor-like cell clusters (PTC) that enabled us to accomplish personalized drug tests within 10-20 days. Mechanistically, PTCs result from the migration and aggregation of CD8+/CD44+ primary epithelial cells in a mixture of fibroblasts and macrophages, and form spheroid cultures. Phenotypic and genotypic profiling of PTCs showed a high degree of similarity with the original patient tumors, indicating that PTC structurally and functionally recapitulated original tumors. Over 200 PTC models have been established from at least six cancer types and diverse sampling approaches. Given its seamless integration with current clinical sampling approaches, the PTC platform will revolutionize chemotherapy programs for cancer patients.

cancer biology↗

bioRxiv2018

Highly multiplexed in situ protein imaging with signal amplification by Immuno-SABER

Probing the molecular organization of tissues requires in situ analysis by microscopy. However current limitations in multiplexing, sensitivity, and throughput collectively constitute a major barrier for comprehensive single-cell profiling of proteins. Here, we report Immunostaining with Signal Amplification By Exchange Reaction (Immuno-SABER), a rapid, highly multiplexed signal amplification method that simultaneously tackles these key challenges. Immuno-SABER utilizes DNA-barcoded antibodies and provides a method for highly multiplexed signal amplification via modular orthogonal DNA concatemers generated by Primer Exchange Reaction. This approach offers the capability to preprogram and control the amplification level independently for multiple targets without in situ enzymatic reactions, and the intrinsic scalability to rapidly amplify and image a large number of protein targets. We validated our approach in diverse sample types including cultured cells, cryosections, FFPE sections, and whole mount tissues. We demonstrated independently tunable 5-180-fold amplification for multiple targets, covering the full signal range conventionally achieved by secondary antibodies to tyramide signal amplification, as well as simultaneous signal amplification for 10 different proteins using standard equipment and workflow. We further combined Immuno-SABER with Expansion Microscopy to enable rapid and highly multiplexed super-resolution tissue imaging. Overall, Immuno-SABER presents an effective and accessible platform for rapid, multiplexed imaging of proteins across scales with high sensitivity.

cell biology↗

bioRxiv2018

Strong diffusional coupling between spines and dendrites promotes long-term potentiation of Schaffer collateral synapses

Dendritic spines on CA1 pyramidal cells are highly variable in size and shape. For some spine synapses, long and narrow spine necks provide strong diffusional and electrical isolation from the main dendrite, and it has been speculated that synapses on well isolated spines could be more plastic than synapses on spines with low resistance necks. Here we test this hypothesis by first measuring the diffusional resistance of spine necks, then pairing two-photon glutamate uncaging with bursts of back-propagating action potentials. Paired stimulation induced significant (155%) long-term potentiation (LTP) of synapses on weakly isolated spines, but no net functional change of synapses on highly isolated spines. No correlation was found between spine head volume and functional plasticity of the synapses. We conclude that contrary to our expectations, diffusional isolation makes potentiation of synapses more difficult. Our results support the concept that delivery of plasticity-related proteins from the dendrite into the spine is a limiting factor for LTP.

neuroscience↗