Biology subjects

Su, Y.

Publications and source records attributed to Su, Y..

At least 145 records · Page 8Linked to original sources

bioRxiv2022

Microbial metabolite butyrate-prodrug polymeric micelles promote gut health and treat food allergies

The microbiome modulates host immunity and aids in maintenance of tolerance in the gut, where microbial and food-derived antigens are abundant. Modern lifestyle practices, including diet and antibiotic use, have depleted beneficial taxa, specifically butyrate-producing Clostridia. This depletion is associated with the rising incidence of food allergy, inflammatory bowel diseases, and other noncommunicable chronic diseases. Although butyrate is known to play important roles in regulating gut immunity and maintaining epithelial barrier function, its clinical translation is challenging due to its offensive odor and quick absorption in the upper gut. Here, we have developed two polymeric micelle systems, one with a neutral charge (NtL-ButM) and one with a negative charge (Neg-ButM) that release butyrate from their polymeric core in different regions of the gastrointestinal tract when administered intragastrically to mice. We show that these butyrate-containing micelles, used in combination, restore a barrier-protective response in mice treated with either dextran sodium sulfate or antibiotics. Moreover, butyrate micelle treatment protects peanut-allergic dysbiotic mice from an anaphylactic reaction to peanut challenge and rescues their antibiotic-induced dysbiosis by increasing the abundance of Clostridium Cluster XIVa. Butyrate micelle treatment also reduces the severity of colitis in a murine model. By restoring microbial and mucosal homeostasis, these butyrate-prodrug polymeric micelles may function as a new, antigen-agnostic approach for the treatment of allergic and inflammatory disease.

bioengineering↗

bioRxiv2022

Disrupting ACE2 Dimerization Mitigates the Infection by SARS-COV-2

The coronavirus disease 2019 (COVID-19) pandemic has caused over 6 million death and 460 million reported cases globally. More effective antiviral medications are needed to curb the continued spread of this disease. The infection by SARS-COV-2 virus is initiated via the interaction between the receptor binding domain (RBD) of the viral glycoprotein Spike (S protein) and the N-term peptidase domain (PD) of the angiotensin-converting enzyme 2 (ACE2) expressed on host cell membrane. ACE2 forms protein homodimer primarily through its ferredoxin-like fold domain (aka. Neck-domain). We investigated whether the dimerization of ACE2 receptor plays a role in SARS-COV-2 virus infection. We report here that the ACE2 receptor dimerization enhances the recognition of SARS-COV-2 S protein. A 43 amino acid peptide based on the N-term of Neck-domain could block the ACE2 dimerization and the interaction between RBD and ACE2, and mitigate the SARS-COV-2/host cell interaction. Our study illustrated a new route to develop potential therapeutics for the prevention and treatment of SARS-COV-2 viral infection.

molecular biology↗

bioRxiv2022

A deep hierarchy of predictions enables assignment of semantic roles in real-time speech comprehension

Understanding speech requires mapping fleeting and often ambiguous soundwaves to meaning. While humans are known to exploit their capacity to contextualize to facilitate this process, how internal knowledge is deployed on-line remains an open question. Here, we present a model that extracts multiple levels of information from continuous speech online. The model applies linguistic and nonlinguistic knowledge to speech processing, by periodically generating top-down predictions and incorporating bottom-up incoming evidence in a nested temporal hierarchy. We show that a nonlinguistic context level provides semantic predictions informed by sensory inputs, which are crucial for disambiguating among multiple meanings of the same word. The explicit knowledge hierarchy of the model enables a more holistic account of the neurophysiological responses to speech compared to using lexical predictions generated by a neural-network language model (GPT-2). We also show that hierarchical predictions reduce peripheral processing via minimizing uncertainty and prediction error. With this proof-of-concept model we demonstrate that the deployment of hierarchical predictions is a possible strategy for the brain to dynamically utilize structured knowledge and make sense of the speech input.

neuroscience↗

bioRxiv2022

Incorporating the image formation process into deep learning improves network performance in deconvolution applications

We present Richardson-Lucy Network (RLN), a fast and lightweight deep learning method for 3D fluorescence microscopy deconvolution. RLN combines the traditional Richardson-Lucy iteration with a fully convolutional network structure, improving network interpretability and robustness. Containing only [~]16 thousand parameters, RLN enables 4- to 50-fold faster processing than purely data-driven networks with many more parameters. By visual and quantitative analysis, we show that RLN provides better deconvolution, better generalizability, and fewer artifacts than other networks, especially along the axial dimension. RLN outperforms Richardson-Lucy deconvolution on volumes contaminated with severe out of focus fluorescence or noise and provides 4- to 6-fold faster reconstructions of large, cleared tissue datasets than classic multi-view pipelines. We demonstrate RLNs performance on cells, tissues, and embryos imaged with widefield-, light sheet-, and structured illumination microscopy.

biophysics↗

bioRxiv2021

Human KIR+CD8+ T cells target pathogenic T cells in Celiac disease and are active in autoimmune diseases and COVID-19

Previous reports show that Ly49+CD8+ T cells can suppress autoimmunity in mouse models of autoimmune diseases. Here we find a markedly increased frequency of CD8+ T cells expressing inhibitory Killer cell Immunoglobulin like Receptors (KIR), the human equivalent of the Ly49 family, in the blood and inflamed tissues of various autoimmune diseases. Moreover, KIR+CD8+ T cells can efficiently eliminate pathogenic gliadin-specific CD4+ T cells from Celiac disease (CeD) patients leukocytes in vitro. Furthermore, we observe elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 and influenza-infected patients, and this correlates with disease severity and vasculitis in COVID-19. Expanded KIR+CD8+ T cells from these different diseases display shared phenotypes and similar T cell receptor sequences. These results characterize a regulatory CD8+ T cell subset in humans, broadly active in both autoimmune and infectious diseases, which we hypothesize functions to control self-reactive or otherwise pathogenic T cells. One-Sentence SummaryHere we identified KIR+CD8+ T cells as a regulatory CD8+ T cell subset in humans that suppresses self-reactive or otherwise pathogenic CD4+ T cells.

immunology↗

bioRxiv2021

Population genomic analysis of the speckled dace species complex (Rhinichthys osculus) identifies three species-level lineages in California

The speckled dace (Rhinichthys osculus) is small cyprinid fish that is widespread in the Western USA. Currently treated as a single species, speckled dace consists of multiple evolutionary lineages that can be recognized as species and subspecies throughout its range. Recognition of taxonomic distinctiveness of speckled dace populations is important for developing conservation strategies. In this study, we collected samples of speckled dace from 38 locations in the American West, with a focus on California. We used RAD sequencing to extract thousands of SNPs across the genome from samples to identify genetic differences among seven California populations informally recognized as speckled dace subspecies: Amargosa, Owens, Long Valley, Lahontan, Klamath, Sacramento, and Santa Ana speckled dace. We performed principal component analysis, admixture analysis, estimated pairwise Fst, and constructed a phylogeny to explore taxonomic relationships among these groups and test if these subspecies warrant formal recognition. Our analyses show that the seven subspecies fit into three major lineages equivalent to species: western (Sacramento-Klamath), Santa Ana, and Lahontan speckled dace. Death Valley speckled dace were determined to be two lineages (Amargosa and Long Valley) within Lahontan speckled dace. Western and Lahontan speckled dace lineages had branches that can be designated as subspecies. These designations fit well with the geologic history of the region which has promoted long isolation of populations. This study highlights the importance of genetic analysis for conservation and management of freshwater fishes.

genomics↗

bioRxiv2021

Zinc finger protein Zfp335 controls early T cell development and survival through beta-selection-dependent and -independent mechanisms

T cell development in the thymus undergoes the process of differentiation, selective proliferation and survival from CD4-CD8- double negative (DN) stage to CD4+CD8+ double positive (DP) stage prior to the formation of CD4+ helper and CD8+ cytolytic T cells ready for circulation. Each developmental stage is tightly regulated by sequentially-operating molecular networks, of which only limited numbers of transcription regulators have been deciphered. Here we identified Zfp335 transcription factor as a new player in the regulatory network controlling thymocyte development. We demonstrate that Zfp335 intrinsically controls DN to DP transition, as T cell-specific deficiency in Zfp335 leads to a substantial accumulation of DN3 along with reduction of DP, CD4+ and CD8+ thymocytes. This developmental blockade at DN stage results from the impaired intracellular TCR{beta} expression as well as increased susceptibility to apoptosis in thymocytes. Transcriptomic and ChIP-seq analyses revealed a direct regulation of transcription factors Bcl6 and Rorc by Zfp335. Importantly, enhanced expression of TCR{beta} and Bcl6/Ror{gamma}T restores the developmental defect during DN3 to DN4 transition and improves thymocytes survival, respectively. These findings identify a critical role of Zfp335 in controlling T cell development by maintaining intracellular TCR{beta} expression-mediated {beta}- selection and independently activating cell survival signaling.

immunology↗

bioRxiv2021

A live attenuated influenza virus-vectored intranasal COVID-19 vaccine provides rapid, prolonged, and broad protection against SARS-CoV-2 infection

Remarkable progress has been made in developing intramuscular vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, they are limited with respect to eliciting local immunity in the respiratory tract, which is the primary infection site for SARS-CoV-2. To overcome the limitations of intramuscular vaccines, we constructed a nasal vaccine candidate based on an influenza vector by inserting a gene encoding the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2, named CA4-dNS1-nCoV-RBD (dNS1-RBD). A preclinical study showed that in hamsters challenged 1 day and 7 days after single-dose vaccination or 6 months after booster vaccination, dNS1-RBD largely mitigated lung pathology, with no loss of body weight, caused by either the prototype-like strain or beta variant of SARS-CoV-2. Lasted data showed that the animals could be well protected against beta variant challenge 9 months after vaccination. Notably, the weight loss and lung pathological changes of hamsters could still be significantly reduced when the hamster was vaccinated 24 h after challenge. Moreover, such cellular immunity is relatively unimpaired for the most concerning SARS-CoV-2 variants. The protective immune mechanism of dNS1-RBD could be attributed to the innate immune response in the nasal epithelium, local RBD-specific T cell response in the lung, and RBD-specific IgA and IgG response. Thus, this study demonstrates that the intranasally delivered dNS1-RBD vaccine candidate may offer an important addition to fight against the ongoing COVID-19 pandemic, compensating limitations of current intramuscular vaccines, particularly at the start of an outbreak.

pathology↗

bioRxiv2021

Sub-Cluster Identification through Semi-SupervisedOptimization of Rare-cell Silhouettes (SCISSORS) in Single-Cell Sequencing

Single-cell RNA-sequencing (scRNA-seq) has enabled the molecular profiling of thousands to millions of cells simultaneously in biologically heterogenous samples. Currently, common practice in scRNA-seq is to determine cell type labels through unsupervised clustering and the examination of cluster-specific genes. However, even small differences in analysis and parameter choice can greatly alter clustering solutions and thus impose great influence on which cell types are identified. Existing methods largely focus on determining the optimal number of robust clusters, which is not favorable for identifying cells of extremely low abundance due to their subtle contributions towards overall patterns of gene expression. Here we present a carefully designed framework, SCISSORS, which accurately profiles subclusters within major cluster(s) for the identification of rare cell types in scRNA-seq data. SCISSORS employs silhouette scoring for the estimation of heterogeneity of clusters and reveals rare cells in heterogenous clusters by implementing a multi-step, semi-supervised reclustering process. Additionally, SCISSORS provides a method for the identification of marker genes of rare cells, which may be used for further study. SCISSORS is wrapped around the popular Seurat R package and can be easily integrated into existing Seurat pipelines. SCISSORS, including source code and vignettes for two example datasets, is freely available at https://github.com/jrleary/SCISSORS.

bioinformatics↗

bioRxiv2021

Extrinsic motivators drive children's cooperation to conserve forests

Forests are essential common-pool resources. It is increasingly critical to nurture a lifelong concern for forest health both locally and globally. Here, in two experiments, we demonstrate that school age children (6-18 yrs. old; N>1000;) of three nationalities (China, D. R. Congo and U.S.) do not have levels of intrinsic motivation to allow for successful cooperation in common-pool goods games requiring them to maintain a forest. We instead find that the size, timing, and certainty of receiving individual payoffs from cooperation significantly boost the odds of successful conservation efforts. We also provide evidence that the experience of playing this game increases longer term motivation to conserve forests. Results have implications for designing policy and curriculum to encourage collective action for forest conservation. One Sentence SummaryExtrinsic motivation boosts concern for forests among children and adolescents in the United States, China, and the Democratic Republic of the Congo.

scientific communication and education↗

bioRxiv2021

Cytonemes coordinate asymmetric signaling and organization in the Drosophila muscle progenitor niche

Asymmetric signaling and organization in the stem-cell niche determine stem-cell fates. Here, we investigate the basis of asymmetric signaling and stem-cell organization using the Drosophila wing-disc that creates an adult muscle progenitor (AMP) niche. We show that AMPs extend polarized cytonemes to contact the disc epithelial junctions and adhere themselves to the disc/niche. Niche-adhering cytonemes localize FGF-receptor to selectively adhere to the FGF-producing disc and receive FGFs in a contact-dependent manner. Activation of FGF signaling in AMPs, in turn, reinforces disc-specific cytoneme polarity/adhesion, which maintains their disc-proximal positions. Loss of cytoneme-mediated adhesion promotes AMPs to lose niche occupancy and FGF signaling, occupy a disc-distal position, and acquire morphological hallmarks of differentiation. Discrete AMP organization and diversification patterns are determined by localized expression and presentation patterns of two different FGFs in the wing-disc and their polarized target-specific distribution through niche-adhering cytonemes. Thus, cytonemes are essential for asymmetric signaling and niche-specific AMP organization.

developmental biology↗

bioRxiv2021

Natural killer-like B cells promote Th17 cell differentiation and exacerbate rheumatoid arthritis

B cells are important participants in the pathogenesis of rheumatoid arthritis (RA). Besides classical B cells, novel B cell subsets are continually to be identified in recent years. Natural killer-like B (NKB) cells, a newly recognized B cell subset, are proved to be actively involved in the anti-infection immunity. However, their role in RA and the potential mechanism remain elusive. Here, we showed that NKB cells were expanded dramatically in collagen-induced arthritis (CIA) mice, demonstrating dynamic changes during the disease progression. These cells promoted CD4+ effector T cell proliferation and Th17 cell differentiation in vitro, while adoptive transfer of these cells exacerbated the arthritis severity of CIA mice. RNA Sequencing revealed that NKB cells displayed distinct differential gene expression profile under RA circumstance, potential perpetuating the disease progression. Moreover, the frequencies of NKB cells were significantly increased in RA patients, positively correlated with the clinical and immunological features. After effective therapy, these cells could be recovered to normal levels. Taken together, our results preliminarily revealed the pathogenic role of NKB cells in RA by promoting Th17 proinflammatory responses. Targeting these cells might provide potential therapeutic strategies for this persistent disease.

immunology↗

bioRxiv2021

Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2

HAP2 is a transmembrane gamete fusogen found in multiple eukaryotic kingdoms and is structurally homologous to viral class II fusogens. Studies in Plasmodium have suggested that HAP2 is an attractive target for vaccines that block transmission of malaria. HAP2 has three extracellular domains, arranged in the order D2, D1, and D3. Here, we report monoclonal antibodies against the D3 fragment of Plasmodium berghei HAP2 and crystal structures of D3 in complex with Fab fragments of two of these antibodies, one of which blocks fertilization of Plasmodium berghei in vitro and transmission of malaria in mosquitos. We also show how this Fab binds the complete HAP2 ectodomain with electron microscopy. The two antibodies cross-react with HAP2 among multiple plasmodial species. Our characterization of the Plasmodium D3 structure, HAP2 ectodomain architecture, and mechanism of inhibition provide insights for the development of a vaccine to block malaria transmission.

immunology↗

bioRxiv2021

miR2105 regulates ABA biosynthesis via OsbZIP86-OsNCED3 module to contribute to drought tolerance in rice

Induced abscisic acid (ABA) biosynthesis plays an important role in plant tolerance to abiotic stresses, including drought, cold and salinity. However, regulation pathway of the ABA biosynthesis in response to stresses is unclear. Here, we identified a rice miRNA, osa-miR2105 (miR2105), which plays a crucial role in ABA biosynthesis under drought stress. Analysis of expression, transgenic rice and cleavage site showed that OsbZIP86 is a target gene of miR2105. Subcellular localization and luciferase activity assays showed that OsbZIP86 is a nuclear transcription factor. In vivo and in vitro analyses showed that OsbZIP86 directly binds to the promoter of OsNCED3, and interacts with OsSAPK10, resulting in enhanced-expression of OsNCED3. Transgenic rice plants with knock-down of miR2105 or overexpression of OsbZIP86 showed higher ABA content, more tolerance to drought, a lower rate of water loss, more stomatal closure than wild type rice ZH11 under drought stress. These rice plants showed no penalty with respect to agronomic traits under normal conditions. By contrast, transgenic rice plants with miR2105 overexpression, OsbZIP86 downregulation, or OsbZIP86 knockout displayed less tolerance to drought stress and other phenotypes. Collectively, our results show that a regulatory network of miR2105-OsSAPK10/OsbZIP86-OsNCED3 control ABA biosynthesis in response to drought stress. One-sentence summary miR2105-OsbZIP86-OsNCED3 module plays crucial role in mediating ABA biosynthesis to contribute to drought tolerance with no penalty with respect to agronomic traits under normal conditions.

molecular biology↗

bioRxiv2021

Construction of a solid Cox model for AML patients based on multiomics bioinformatic analysis

Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy. The bone marrow (BM) microenvironment in AML plays an important role in leukemogenesis, drug resistance and leukemia relapse. In this study, we aimed to identify reliable immune-related biomarkers for AML prognosis by multiomics analysis. We obtained expression profiles from The Cancer Genome Atlas (TCGA) database and constructed a LASSO-Cox regression model to predict the prognosis of AML using multiomics bioinformatic analysis data. This was followed by independent validation of the model in the GSE106291 (n=251), GSE12417 (n=163) and GSE37642 (n=137) datasets and mutated genes in clinical samples for predicting overall survival (OS). Molecular docking was performed to predict the most optimal ligands to these hub genes. The single-cell RNA sequence dataset GSE116256 was used to clarify the expression of the hub genes in different immune cell types. According to their significant differences in immune gene signatures and survival trends, we concluded that the immune infiltration-lacking subtype (IL type) is associated with better prognosis than the immune infiltration-rich subtype (IR type). Using the LASSO model, we built a classifier based on 5 hub genes to predict the prognosis of AML (risk score = -0.086xADAMTS3 + 0.180xCD52 + 0.472xCLCN5 - 0.356xHAL + 0.368xICAM3). In summary, we constructed a prognostic model of AML using integrated multiomics bioinformatic analysis that could serve as a therapeutic classifier.

cancer biology↗

bioRxiv2021

C. elegans enteric motor neurons fire synchronized action potentials underlying the defecation motor program

The C. elegans nervous system was thought to be strictly analog, constituted solely by graded neurons. We recently discovered neuronal action potentials in the sensory neuron AWA; however, the extent to which the C. elegans nervous system relies on analog or digital neural signaling and coding is unclear. Here we report that the enteric motor neurons AVL and DVB fire all-or-none calcium-mediated action potentials that play essential roles in the rhythmic defecation behavior in C. elegans. Both AVL and DVB synchronously fire giant action potentials to faithfully execute all-or-none expulsion following the intestinal pacemaker. AVL fires unusual compound action potentials with each positive calcium-mediated spike followed by a potassium-mediated negative spike. The depolarizing calcium spikes in AVL are mediated by a CaV2 calcium channel UNC-2, while the negative potassium spikes are mediated by a repolarization-activated potassium channel EXP-2. Whole-body behavior tracking and simultaneous neural imaging in free-moving animals suggest that action potentials initiated in AVL in the head propagate along its axon to the tail and activate DVB through the INX-1 gap junction. Synchronized action potential spikes between AVL and DVB, as well as the negative spike and long-lasting afterhyperpolarization in AVL, play an important function in executing expulsion behavior. This work provides the first evidence that in addition to sensory coding, C. elegans motor neurons also use digital coding scheme to perform specific functions including long-distance communication and temporal synchronization, suggesting further, unforeseen electrophysiological diversity remains to be discovered in the C. elegans nervous system.

neuroscience↗

bioRxiv2021

FEDERATED MORPHOMETRY FEATURE SELECTION FOR HIPPOCAMPAL MORPHOMETRY ASSOCIATED BETA-AMYLOID AND TAU PATHOLOGY

Amyloid-{beta} (A{beta}) plaques and tau protein tangles in the brain are now widely recognized as the defining hallmarks of Alzheimers disease (AD), followed by structural atrophy detectable on brain magnetic resonance imaging (MRI) scans. One of the particular neurodegenerative regions is the hippocampus to which the influence of A{beta}/tau on has been one of the research focuses in the AD pathophysiological progress. This work proposes a novel framework, Federated Morphometry Feature Selection (FMFS) model, to examine subtle aspects of hippocampal morphometry that are associated with A{beta}/tau burden in the brain, measured using positron emission tomography (PET). FMFS is comprised of hippocampal surface-based feature calculation, patch-based feature selection, federated group LASSO regression, federated screening rule-based stability selection, and region of interest (ROI) identification. FMFS was tested on two ADNI cohorts to understand hippocampal alterations that relate to A{beta}/tau depositions. Each cohort included pairs of MRI and PET for AD, mild cognitive impairment (MCI) and cognitively unimpaired (CU) subjects. Experimental results demonstrated that FMFS achieves an 89x speedup compared to other published state-of-the-art methods under five independent hypothetical institutions. In addition, the subiculum and cornu ammonis 1 (CA1 subfield) were identified as hippocampal subregions where atrophy is strongly associated with abnormal A{beta}/tau. As potential biomarkers for A{beta}/tau pathology, the features from the identified ROIs had greater power for predicting cognitive assessment and for survival analysis than five other imaging biomarkers. All the results indicate that FMFS is an efficient and effective tool to reveal associations between A{beta}/tau burden and hippocampal morphometry.

neuroscience↗

bioRxiv2021

Deep Learning-Based Brain Transcriptomic Signatures Associated with the Neuropathological and Clinical Severity of Alzheimer's Disease

Brain tissue gene expression from donors with and without Alzheimers disease (AD) have been used to help inform the molecular changes associated with the development and potential treatment of this disorder. Here, we use a deep learning method to analyze RNA-seq data from 1,114 brain donors from the AMP-AD consortium to characterize post-mortem brain transcriptome signatures associated with amyloid-{beta} plaque, tau neurofibrillary tangles, and clinical severity in multiple AD dementia populations. Starting from the cross-sectional data in the ROSMAP cohort (n = 634), a deep learning framework was built to obtain a trajectory that mirrors AD progression. A severity index (SI) was defined to quantitatively measure the progression based on the trajectory. Network analysis was then carried out to identify key gene (index gene) modules present in the model underlying the progression. Within this dataset, SIs were found to be very closely correlated with all AD neuropathology biomarkers (R [~] 0.5, p < 1e-11) and global cognitive function (R = -0.68, p < 2.2e-16). We then applied the model to additional transcriptomic datasets from different brain regions (MAYO, n = 266; MSBB, n = 214), and observed that the model remained significantly predictive (p < 1e-3) of neuropathology and clinical severity. The index genes that significantly contributed to the model were integrated with AD co-expression regulatory networks, resolving four discrete gene modules that are implicated in vascular and metabolic dysfunction in different cell types respectively. Our work demonstrates the generalizability of this signature to frontal and temporal cortex measurements and additional brain donors with AD, other age-related neurological disorders and controls; and revealed the transcriptomic network modules contribute to neuropathological and clinical disease severity. This study illustrates the promise of using deep learning methods to analyze heterogeneous omics data and discover potentially targetable molecular networks that can inform the development, treatment and prevention of neurodegenerative diseases like AD.

genomics↗