Biology subjects

Jiang, P.

Publications and source records attributed to Jiang, P..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Molecular stratification of human fetal vaginal epithelium by spatial transcriptome analysis

The human vaginal epithelium is a crucial component in numerous reproductive processes and serves as a vital protective barrier against pathogenic invasion. Despite its significance, a comprehensive exploration of its molecular profiles, including molecule expression and distribution across its multiple layers, remains elusive. In our study, we undertook a spatial transcriptomic analysis within the vaginal wall of human fetuses to fill this knowledge gap. We successfully categorized vaginal epithelium into four distinct zones based on their transcriptomic profiles and anatomical features. This approach unveiled unique transcriptomic signatures within these regions, allowing us to identify differentially expressed genes and uncover novel markers for distinct regions of the vaginal epithelium. Additionally, our findings have highlighted the varied expression of KRT genes across different zone of the vaginal epithelium, with a gradual shift in expression patterns observed from the basal layer to the surface/superficial layer. This suggests a potential differentiation trajectory of human vaginal epithelium, shedding light on the dynamic nature of this tissue. Furthermore, abundant biological processes were found to be enriched in the basal zone by the KEGG pathway analysis, indicating an active state of the basal zone cells. Subsequently, the expression of latent stem cell markers in the basal zone were identified. In summary, our research provides crucial understanding of human vaginal epithelial cells and the complex mechanisms of the vaginal mucosa, with potential applications in vaginal reconstruction and drug delivery, making this atlas a valuable tool for future research in womens health and reproductive medicine.

cell biology↗

bioRxiv2024

A Trisomy 21-linked Hematopoietic Gene Variant in Microglia Confers Resilience in Human iPSC Models of Alzheimers Disease

SUMMARYWhile challenging, identifying individuals displaying resilience to Alzheimers disease (AD) and understanding the underlying mechanism holds great promise for the development of new therapeutic interventions to effectively treat AD. Down syndrome (DS), or trisomy 21, is the most common genetic cause of AD. Interestingly, some people with DS, despite developing AD neuropathology, show resilience to cognitive decline. Furthermore, DS individuals are at an increased risk of myeloid leukemia due to somatic mutations in hematopoietic cells. Recent studies indicate that somatic mutations in hematopoietic cells may lead to resilience to neurodegeneration. Microglia, derived from hematopoietic lineages, play a central role in AD etiology. We therefore hypothesize that microglia carrying the somatic mutations associated with DS myeloid leukemia may impart resilience to AD. Using CRISPR-Cas9 gene editing, we introduce a trisomy 21-linked hotspot CSF2RB A455D mutation into human pluripotent stem cell (hPSC) lines derived from both DS and healthy individuals. Employing hPSC-based in vitro microglia culture and in vivo human microglia chimeric mouse brain models, we show that in response to pathological tau, the CSF2RB A455D mutation suppresses microglial type-1 interferon signaling, independent of trisomy 21 genetic background. This mutation reduces neuroinflammation and enhances phagocytic and autophagic functions, thereby ameliorating senescent and dystrophic phenotypes in human microglia. Moreover, the CSF2RB A455D mutation promotes the development of a unique microglia subcluster with tissue repair properties. Importantly, human microglia carrying CSF2RB A455D provide protection to neuronal function, such as neurogenesis and synaptic plasticity in chimeric mouse brains where human microglia largely repopulate the hippocampus. When co-transplanted into the same mouse brains, human microglia with CSF2RB A455D mutation phagocytize and replace human microglia carrying the wildtype CSF2RB gene following pathological tau treatment. Our findings suggest that hPSC-derived CSF2RB A455D microglia could be employed to develop effective microglial replacement therapy for AD and other age-related neurodegenerative diseases, even without the need to deplete endogenous diseased microglia prior to cell transplantation.

neuroscience↗

bioRxiv2024

Gustatory-neuron-supplied R-spondin-2 is required for taste bud replenishment

Taste buds undergo continuous cell turnover throughout life, and taste cell replenishment relies strictly on innervation, a phenomenon first described almost 150 years ago. Recently, we provided evidence that R-spondin 2 (Rspo2) may be the long-sought gustatory neuron-supplied factor that regulates taste stem cell activity, via its interaction with taste stem/progenitor cell-expressed receptor Rnf43/Znrf3. Yet, whether gustatory-neuron-supplied Rspo2 is strictly required for taste tissue maintenance has not been resolved. Here, we set out to determine the necessity of gustatory-neuron-supplied Rspo2 in taste tissue homeostasis using genetic approaches. We used a mouse line that harbors the neomycin-resistance gene (NeoR) in one of the intron regions of the Rspo2 gene, which results in reduced expression of Rspo2. The number of taste buds is significantly reduced in these mice, compared to wild-type mice, in both anterior and posterior tongue. This phenotypic change was completely reversed by removing NeoR from the Rspo2 gene, thus making it normal. We also combined adeno-associated virus (AAV)-based delivery of Cre recombinase with a mouse line amenable to Cre-based ablation of the Rspo2 exons encoding the receptor-binding domains. Such deletion of Rspo2 in the nodose-petrosal-jugular ganglion complex led to nearly complete loss of taste buds in the circumvallate papilla. Thus, we demonstrate that Rspo2 is the long-sought gustatory-neuron-supplied factor that acts on taste stem cells to maintain taste tissue homeostasis. SignificanceWe have known for 150 years that innervation is required to induce and maintain cell replacement in taste buds. Until recently, the identity of the inducing factor produced by neurons was unknown. We have shown that R-spondin alone is sufficient to substitute for neuronal input to induce taste bud regeneration. Using a genetic loss-of-function approach, we now demonstrate that gustatory-neuron-expressed Rspo2 is required to maintain taste tissue homeostasis. Altogether, our work reveals that Rspo2 is the long-sought neuron-supplied factor that regulates the activity of taste stem/progenitor cells.

neuroscience↗

bioRxiv2024

From Understudied to Understood: Multi-Omics Analysis with MiniENCODE Exemplified by Zebrafish

Building multi-omics resources for understudied organisms requires assay selection, public-data curation, gene identifier handling, portal deployment, and visualization, yet these tasks are rarely packaged into a reusable framework. To fill this gap, we developed the mini Omics Data Portal (miniODP), which combines species pages, gene-centric modules, genome browsing, and sequence search with configuration files, species onboarding workflows, and demonstration data for self-deployment. Alongside the software, we propose miniENCODE core assays: a reduced RNA-seq, ATAC-seq, and H3K27ac profiling set for regulatory analysis. Current miniODP includes seven species, covering 3,568 bulk runs, 3.61 million cells, and 1,865 genome-browser tracks. Matched core-assay datasets support regulatory outputs. As a zebrafish benchmark, using datasets from three core assays and 17 samples, we identified 52,350 enhancer-like signatures (ELSs) and constructed ELS-to-gene linkages and gene regulatory networks (GRNs). Genes near H3K27ac-supported ELSs were expressed at higher levels than those near ATAC-only distal peaks. Literature curation of top TFs from zebrafish and cattle GRNs found 19 direct, 15 indirect, and six unsupported cases among 40 candidates. Datasets lacking matched core assays still provide browsing, visualization, and search functions. miniODP serves as a reusable framework for constructing and extending multi-omics resources for understudied organisms. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/573815v3_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1542265org.highwire.dtl.DTLVardef@9e5424org.highwire.dtl.DTLVardef@a630d5org.highwire.dtl.DTLVardef@d0163c_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2023

Multi-Omics Analysis Of Antiviral Interactions Of Elizabethkingia anophelis And Zika Virus

BackgroundThe microbial communities residing in the mosquito midgut play a key role in determining the outcome of mosquito pathogen infection. Elizabethkingia anophelis, originally isolated from the midgut of Anopheles gambiae, has drawn much attention due to its close association with Aedes and Anopheles mosquitoes, primary vectors of dengue virus and malaria parasites, respectively. E. anophelis possesses a broad-spectrum antiviral phenotype, yet a gap in knowledge regarding the mechanistic basis of its interaction with viruses exists. Methodology/Principal findingsTo further understand the antiviral interactions between E. anophelis and Zika virus (ZIKV), we utilized a non-targeted multi-omics approach, analyzing lipids, proteins, and metabolites of cell monolayers co-infected with ZIKV and E. anophelis. We further assessed the gene expression of ZIKV when cultured in the presence of E. anophelis. ZIKV cultured in the presence of E. anophelis resulted in an attenuated replicative fitness and unproductive virus infection. Further, in this treatment, we observed lower levels of the nonstructural protein 5 (NS5) and RNA-directed RNA polymerase (RdRp) protein. Lastly, a significant decrease in arginine levels, an essential requirement for viral replication and progression of viral infection was observed. Conclusions/SignificanceThis study provides insights into the molecular basis of E. anophelis antiviral phenotype. These findings improve our knowledge of how microbes and viruses interact to impact viral replication. In the future, our findings can be utilized to unravel the mechanism behind the antiviral phenotype of E. anophelis, and this can help develop novel paradigms for viral therapeutics. AUTHOR SUMMARYZika is a re-emerging disease and is endemic in many regions of sub-Saharan Africa, Asia and Latin America. It remains a major public health threat and lacks FDA-approved therapeutics or vaccines, hence the urgent need for the identification of alternative approaches that limit the transmission of the pathogens by its primary vector, Aedes spp. The microbial communities residing in the mosquito midgut play a key role in determining the outcome of mosquito pathogen infection. Flavobacteria dominates the mosquito midgut including Elizabethkingia, which is a gram-negative bacillus prevalent in Aedes and Anopheles species of mosquitoes. E. anophelis, a poorly studied midgut microbe, has a broad-spectrum antiviral phenotype, yet the mechanism of its antiviral action is unknown. In this study, we have identified several pathways as well as Zika virus proteins perturbed when the Zika virus is cultivated in the presence of E. anophelis. Our findings do not only provide insights into microbial, virus interaction but could be harnessed to develop novel antiviral tools.

microbiology↗

bioRxiv2023

Disrupted sleep-wake regulation in the MCI-Park mouse model of Parkinson's Disease

Disrupted sleep has a profound adverse impact on lives of Parkinsons disease (PD) patients and their caregivers. Sleep disturbances are exceedingly common in PD, with substantial heterogeneity in type, timing, and severity. Among the most common sleep-related symptoms reported by PD patients are insomnia, excessive daytime sleepiness, and sleep fragmentation, characterized by interruptions and decreased continuity of sleep. Alterations in brain wave activity, as measured on the electroencephalogram (EEG), also occur in PD, with changes in the pattern and relative contributions of different frequency bands of the EEG spectrum to overall EEG activity in different vigilance states consistently observed. The mechanisms underlying these PD-associated sleep-wake abnormalities are poorly understood, and they are ineffectively treated by conventional PD therapies. To help fill this gap in knowledge, a new progressive model of PD - the MCI-Park mouse - was studied. Near the transition to the parkinsonian state, these mice exhibited significantly altered sleep-wake regulation, including increased wakefulness, decreased non-rapid eye movement (NREM) sleep, increased sleep fragmentation, reduced rapid eye movement (REM) sleep, and altered EEG activity patterns. These sleep-wake abnormalities mirror those identified in PD patients. Thus, this model may help elucidate the circuit mechanisms underlying sleep disruption in PD and identify targets for novel therapeutic approaches.

neuroscience↗

bioRxiv2023

Identification of potential distribution area for the sweet cherry (Prunus avium) by the MaxEnt model

The potential distribution of species offers important information for species management, especially for fruit trees with economic value. The sweet cherry is a tree species with higher economic value among deciduous fruit trees in north China. Herein, its potential distributions were modeled under current conditions. The performances of this model were excellent with AUCs of >0.9 for model training and testing. The key factors identified were the thermal factors (min temperature of coldest month (bio06) from -14.5 to 4.5{degrees}C, the mean temperature of warmest quarter (bio10) from 21.0 to 28.0{degrees}C), followed by water factor (the annual precipitation (bio12) from 500 to 1200 mm). Its suitable region in China mainly is located on 6 geographical regions including southwest China (eastern Sichuan, northeast and main urban areas of Chongqing, mid-western Guizhou and mid-northern Yunnan), northwest China (mid-southern Shaanxi, southern Ningxia mid-southern and eastern Gansu), northeast China (Coastal region of Liaoning), central China (most of Henan, mid-northern Hubei and central Hunan), north China (Beijing, Tianjing, mid-southern Shanxi), east China (Shanghai, Jiangsu, Shandong, central Zhejiang, central and northern Anhui and eastern Jiangxi) and south China (western Guangxi). Relative to their actual distributions, Hubei, Hunan and Anhui etc have been identified to have some potentially suitable areas for these sweet cherries. Among them, these 9 provinces or cities (Shaanxi, Beijing, Tianjing, Shanxi, Hebei, Henan, Shanghai, Jiangsu and Shandong) are main regions for its current development and utilization, followed by Sichuan, Guizhou,Yunnan, Gansu, Liaoning, Hubei, Zhejiang and Guangxi etc. The results can be adopted to identify the suitable areas for its introduction and cultivation to avoid the losses of human labor, material and financial resources due to improper decision, and to provide a scientific basis for its current introduction, cultivation and management.

ecology↗

bioRxiv2023

Dysregulated neuroimmune interactions and sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids

Human immunodeficiency virus type-1 (HIV-1) associated neurocognitive disorder (HAND) affects up to half of HIV-1 positive patients with long term neurological consequences, including dementia. There are no effective therapeutics for HAND because the pathophysiology of HIV-1 induced glial and neuronal functional deficits in humans remains enigmatic. To bridge this knowledge gap, we established a model simulating HIV-1 infection in the central nervous system using human induced pluripotent stem cell (iPSC) derived microglia combined with sliced neocortical organoids. Upon incubation with two replication-competent macrophage-tropic HIV-1 strains (JRFL and YU2), we observed that microglia not only became productively infected but also exhibited inflammatory activation. RNA sequencing revealed a significant and sustained activation of type I interferon signaling pathways. Incorporating microglia into sliced neocortical organoids extended the effects of aberrant type I interferon signaling in a human neural context. Collectively, our results illuminate the role of persistent type I interferon signaling in HIV-1 infected microglial in a human neural model, suggesting its potential significance in the pathogenesis of HAND. Highlights of the workO_LIHIV-1 productively infects iPSC-derived microglia and triggers inflammatory activation. C_LIO_LIHIV-1 infection of microglia results in sustained type I interferon signaling. C_LIO_LIMicroglia infected by HIV-1 incorporate into sliced neocortical organoids with persistent type I interferon signaling and disease risk gene expression. C_LI

neuroscience↗

bioRxiv2023

Modulating Mesenchymal Stromal Cell Microenvironment Alters Exosome RNA Content and Ligament Healing Capacity

Although mesenchymal stromal cell (MSC) based therapies hold promise in regenerative medicine, their applications in clinical settings remain challenging due to issues such as immunocompatibility and cell stability. MSC-derived exosomes, small vesicles carrying various bioactive molecules, are a promising cell-free therapy to promote tissue regeneration. However, it remains unknown mainly regarding the ability to customize the content of MSC-derived exosomes, how alterations in the MSC microenvironment influence exosome content, and the effects of such modifications on healing efficiency and mechanical properties in tissue regeneration. In this study, we used an in vitro system of human MSC-derived exosomes and an in vivo rat ligament injury model to address these questions. We found a context-dependent correlation between exosomal and parent cell RNA content. Under native conditions, the correlation was moderate but heightened with microenvironmental changes. In vivo rat ligament injury model showed that MSC-derived exosomes increased ligament max load and stiffness. We also found that changes in the MSCs microenvironment significantly influence the mechanical properties driven by exosome treatment. Additionally, a link was identified between altered exosomal microRNA levels and expression changes in microRNA targets in ligaments. These findings elucidate the nuanced interplay between MSCs, their exosomes, and tissue regeneration. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/563485v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@2b45bborg.highwire.dtl.DTLVardef@ef2222org.highwire.dtl.DTLVardef@1a9f1f1org.highwire.dtl.DTLVardef@4b1ca2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Requirement of microtubules for secretion of a micronemal protein CpTSP4 in the invasive stage of the apicomplexan Cryptosporidium parvum

The zoonotic Cryptosporidium parvum is a global contributor to infantile diarrheal diseases and opportunistic infections in immunocompromised/weakened individuals. Like other apicomplexans, it possesses several specialized secretory organelles, including micronemes, rhoptry and dense granules. However, the understanding of cryptosporidial micronemal composition and secretory pathway remains limited. Here we report a new micronemal protein in C. parvum, namely thrombospondin repeat domain-containing protein-4 (CpTSP4), providing insights into these ambiguities. Immunostaining and enzyme-linked assays show that CpTSP4 is prestored in the micronemes of unexcysted sporozoites but secreted during sporozoite excystation, gliding and invasion. In excysted sporozoites, CpTSP4 is also distributed on the two central microtubules unique to Cryptosporidium. The secretion and microtubular distribution could be completely blocked by selective kinesin-5 inhibitors, SB-743921 and SB-715992, resulting in the accumulation of CpTSP4 in micronemes. These support the kinesin-dependent microtubular trafficking of CpTSP4 for secretion. We also localize {gamma}-tubulin, consistent with kinesin-dependent anterograde trafficking. Additionally, recombinant CpTSP4 displays nanomolar binding affinity to host cell surface, for which heparin acts as one of the host ligands. A novel heparin-binding motif is identified and biochemically validated for its contribution to the adhesive property of CpTSP4 by peptide competition assays and site-directed mutagenesis. These findings shed light on the mechanisms of intracellular trafficking and secretion of a cryptosporidial micronemal protein and the interaction of a TSP-family protein with host cells. Importance Cryptosporidium parvum is a globally distributed apicomplexan parasite infecting humans and/or animals. Like other apicomplexans, it possesses specialized secretory organelles in the zoites, in which micronemes discharge molecules to facilitate the movement and invasion of zoites. Although past and recent studies have identified several proteins in cryptosporidial micronemes, our understanding on the composition, secretory pathways and domain-ligand interactions of micronemal proteins remains limited. This study identifies a new micronemal protein, namely CpTSP4, that is discharged during excystation, gliding and invasion of C. parvum sporozoites. The CpTSP4 secretion depends on the intracellular trafficking on the two Cryptosporidium-unique microtubes that could be blocked by kinesin-5/Eg5 inhibitors. Additionally, a novel heparin-binding motif is identified and biochemically validated, which contributes to the nanomolar binding affinity of CpTSP4 to host cells. These findings indicate that kinesin-dependent microtubular trafficking is critical to CpTSP4 secretion and heparin/heparan sulfate is one of the ligands for this micronemal protein.

microbiology↗

bioRxiv2023

Impaired bone morphogenetic protein signaling pathways disrupt decidualization in endometriosis

It is hypothesized that impaired endometrial decidualization contributes to decreased fertility in individuals with endometriosis. To identify the molecular defects that underpin defective decidualization in endometriosis, we subjected endometrial stromal cells from individuals with or without endometriosis to time course in vitro decidualization with estradiol, progesterone, and 8-bromo-cyclic-AMP (EPC) for 2, 4, 6, or 8 days. Transcriptomic profiling identified differences in key pathways between the two groups, including defective bone morphogenetic protein (BMP)/SMAD4 signaling (ID2, ID3, FST), oxidate stress response (NFE2L2, ALOX15, SLC40A1), and retinoic acid signaling pathways (RARRES, RARB, ALDH1B1). Genome-wide binding analyses identified an altered genomic distribution of SMAD4 and H3K27Ac in the decidualized stromal cells from individuals without endometriosis relative to those with endometriosis, with target genes enriched in pathways related to signaling by transforming growth factor {beta} (TGF{beta}), neurotrophic tyrosine kinase receptors (NTRK), and nerve growth factor (NGF)-stimulated transcription. We found that direct SMAD1/5/4 target genes control FOXO, PI3K/AKT, and progesterone-mediated signaling in decidualizing cells and that BMP2 supplementation in endometriosis patient-derived assembloids elevated the expression of decidualization markers. In summary, transcriptomic and genome-wide binding analyses of patient-derived endometrial cells and assembloids identified that a functional BMP/SMAD1/5/4 signaling program is crucial for engaging decidualization.

molecular biology↗

bioRxiv2023

Systematic Profiling of Ale Yeast Protein Dynamics across Fermentation and Repitching

Studying the genetic and molecular characteristics of brewing yeast strains is crucial for understanding their domestication history and adaptations accumulated over time in fermentation environments, and for guiding optimizations to the brewing process itself. Saccharomyces cerevisiae (brewing yeast) is amongst the most profiled organisms on the planet, yet the temporal molecular changes that underlie industrial fermentation and beer brewing remain understudied. Here, we characterized the genomic makeup of a Saccharomyces cerevisiae ale yeast widely used in the production of Hefeweizen beers, and applied shotgun mass spectrometry to systematically measure the proteomic changes throughout two fermentation cycles which were separated by 14 rounds of serial repitching. The resulting brewing yeast proteomics resource includes 64,740 protein abundance measurements. We found that this strain possesses typical genetic characteristics of Saccharomyces cerevisiae ale strains and displayed progressive shifts in molecular processes during fermentation based on protein abundance changes. We observed protein abundance differences between early fermentation batches compared to those separated by 14 rounds of serial repitching. The observed abundance differences occurred mainly in proteins involved in the metabolism of ergosterol and isobutyraldehyde. Our systematic profiling serves as a starting point for deeper characterization of how the yeast proteome changes during commercial fermentations and additionally serves as a resource to guide fermentation protocols, strain handling, and engineering practices in commercial brewing and fermentation environments. Finally, we created a web interface (https://brewing-yeast-proteomics.ccbb.utexas.edu/) to serve as a valuable resource for yeast geneticists, brewers, and biochemists to provide insights into the global trends underlying commercial beer production.

systems biology↗

bioRxiv2023

Combined topological data analysis and geometric deep learning reveal niches by the quantification of protein binding pockets

Protein pockets are essential for many proteins to carry out their functions. Locating and measuring protein pockets as well as studying the anatomy of pockets helps us further understand protein function. Most research studies focus on learning either local or global information from protein structures. However, there is a lack of studies that leverage the power of integrating both local and global representations of these structures. In this work, we combine topological data analysis (TDA) and geometric deep learning (GDL) to analyze the putative protein pockets of enzymes. TDA captures blueprints of the global topological invariant of protein pockets, whereas GDL decomposes the fingerprints to building blocks of these pockets. This integration of local and global views provides a comprehensive and complementary understanding of the protein structural motifs (niches for short) within protein pockets. We also analyze the distribution of the building blocks making up the pocket and profile the predictive power of coupling local and global representations for the task of discriminating between enzymes and non-enzymes. We demonstrate that our representation learning framework for macromolecules is particularly useful when the structure is known, and the scenarios heavily rely on local and global information.

bioinformatics↗

bioRxiv2023

Optimal transport for mapping senescent cells in spatial transcriptomics

Spatial transcriptomics (ST) provides a unique opportunity to study cellular organization and cell-cell interactions at the molecular level. However, due to the low resolution of the sequencing data additional information is required to utilize this technology, especially for cases where only a few cells are present for important cell types. To enable the use of ST to study senescence we developed scDOT, which combines ST and single cell RNA-Sequencing (scRNA-Seq) to improve the ability to reconstruct single cell resolved spatial maps. scDOT integrates optimal transport and expression deconvolution to learn non-linear couplings between cells and spots and to infer cell placements. Application of scDOT to existing and new lung ST data improves on prior methods and allows the identification of the spatial organization of senescent cells, the identification of their neighboring cells and the identification of novel genes involved in cell-cell interactions that may be driving senescence.

cell biology↗

bioRxiv2023

Syncytiotrophoblast 5'-tRNA fragments are placental endocrine signals contributing to sterile inflammation in preeclampsia

BackgroundThe relationship between placental pathology and the maternal syndrome of preeclampsia is incompletely characterised. Mismatch between placental nutrient supply and fetal demands induces stress in the syncytiotrophoblast, the layer of placenta in direct contact with maternal blood. Such stress alters the content and increases the release of extracellular vesicles (STB-EVs) into the maternal circulation. We have previously shown 5-tRNA fragments (5-tRFs) constitute the majority of small RNA in STB-EVs in healthy pregnancy. 5-tRFs are produced in response to stress. We hypothesised STB-EV 5-tRF release might change in preeclampsia. MethodsWe perfused placentas from eight women with early-onset preeclampsia and six controls, comparing small RNA expression in STB-EVs. We used membrane-affinity columns to isolate maternal plasma vesicles and investigate placental 5-tRFs in-vivo. We quantified 5-tRFs from circulating STB-EVs using a placental alkaline phosphatase immunoassay. 5-tRFs and scrambled RNA controls were added to monocyte, macrophage and endothelial cells in culture to investigate transcriptional responses. Results5-tRFs constitute the majority of small RNA in STB-EVs from both preeclampsia and normal pregnancies. >900 small RNA fragments are differentially expressed in preeclampsia STB-EVs. Preeclampsia-dysregulated 5-tRFs are detectable in maternal plasma, where we identified a placentally-derived load. 5-tRF-Glu-CTC, the most abundant preeclampsia-upregulated 5-tRF in perfusion STB-EVs, is also increased in preeclampsia STB-EVs from maternal plasma. 5-tRF-Glu-CTC induced inflammation in macrophages but not monocytes. The conditioned media from 5-tRF-Glu-CTC-activated macrophages reduced eNOS expression in endothelial cells. ConclusionsIncreased release of syncytiotrophoblast-derived vesicle-bound 5-tRF-Glu-CTC contributes to preeclampsia pathophysiology.

molecular biology↗

bioRxiv2023

Natural constraints explain working memory capacity limitations in sensory-cognitive models

The limited capacity of the brain to retain information in working memory has been well-known and studied for decades, yet the root of this limitation remains unclear. Here we built sensory-cognitive neural network models of working memory that perform tasks using raw visual stimuli. Contrary to intuitions that working memory capacity limitation stems from memory or cognitive constraints, we found that pre-training the sensory region of our models with natural images imposes sufficient constraints on models to exhibit a wide range of human-like behaviors in visual working memory tasks designed to probe capacity. Examining the neural mechanisms in our model reveals that capacity limitation mainly arises in a bottom-up manner. Our models offer a principled and functionally grounded explanation for the working memory capacity limitation without parameter fitting to behavioral data or much hyperparameter tuning. This work highlights the importance of developing models with realistic sensory processing even when investigating memory and other high-level cognitive phenomena.

neuroscience↗

bioRxiv2023

Inflammation induces bitter taste oversensitization via epigenetic changes in Tas2r gene clusters

T2R bitter receptors, encoded by Tas2r genes, are not only critical for bitter taste signal transduction but also important for defense against bacteria and parasites. However, little is known about whether and how Tas2r gene expression are regulated. Here we show that, in an inflammation model mimicking bacterial infection, the expression of many Tas2rs are significantly up-regulated and mice displayed markedly increased neural and behavioral responses to bitter compounds. Using single-cell assays for transposase-accessible chromatin with sequencing (scATAC-seq), we found that the chromatin accessibility of Tas2rs was highly cell type specific and inflammation increased the accessibility of many Tas2rs. scATAC-seq also revealed substantial chromatin remodeling in immune response genes in taste tissue stem cells, suggesting potential long-term effects. Together, our results suggest an epigenetic mechanism connecting inflammation, Tas2r gene regulation, and altered bitter taste, which may explain heightened bitter taste that can occur with infections and cancer treatments.

neuroscience↗

bioRxiv2023

Predicting tumor immune microenvironment and checkpoint therapy response of head & neck cancer patients from blood immune single-cell transcriptomics

The immune state of tumor microenvironment is crucial for determining immunotherapy response but is not readily accessible. Here we investigate if we can infer the tumor immune state from the blood and further predict immunotherapy response. First, we analyze a dataset of head and neck squamous cell carcinoma (HNSCC) patients with matched scRNA-Seq of peripheral blood mononuclear cells (PBMCs) and tumor tissues. We find that the tumor immune cell fractions of different immune cell types and many of the genes they express can be inferred from the matched PBMC scRNA-Seq. Second, analyzing another HNSCC dataset with PBMC scRNA-Seq and immunotherapy response, we find that the inferred ratio between tumor memory B and regulatory T cell fractions is predictive of immunotherapy response and is superior to the well-established cytolytic and exhausted T-cell signatures. Overall, these results showcase the potential of scRNA-Seq liquid biopsies in cancer immunotherapy, calling for their larger-scale testing. SignificanceThis head and neck cancer study demonstrates the potential of using blood single-cell transcriptomics to (1) infer the tumor immune status and (2) predict immunotherapy response from the tumor immune status inferred from blood. These results showcase the potential of single-cell transcriptomics liquid biopsies for further advancing personalized cancer immunotherapy.

bioinformatics↗