Biology subjects

Yu, Z.

Publications and source records attributed to Yu, Z..

At least 217 records · Page 12Linked to original sources

bioRxiv2023

APOE-NOTCH Axis Governs Elastogenesis During Human Cardiac Valve Remodeling

BackgroundValve remodeling is a complex process involving extracellular matrix organization, development of trilaminar structures, and physical elongation of valve leaflets. However, the cellular and molecular mechanisms regulating valve remodeling and their roles in congenital valve disorders remain poorly understood. MethodsSemilunar valves and atrioventricular valves from healthy and age-matched human fetal hearts with pulmonary stenosis (PS) were collected. Single-Cell RNA-sequencing (scRNA-seq) was performed to determine the transcriptomic landscape of multiple valvular cell subtypes in valve remodeling and disease. Spatial localization of newly-identified cell subtypes was determined via immunofluorescence and RNA in situ hybridization. The molecular mechanisms mediating valve development was investigated utilizing primary human fetal heart valve interstitial cells (VICs) and endothelial cells (VECs). ResultsscRNA-seq analysis of healthy human fetal valves identified a novel APOE+ elastin-producing VIC subtype (Elastin-VICs) spatially located underneath VECs sensing the unidirectional flow. Knockdown of APOE in fetal VICs resulted in significant elastogenesis defects. In pulmonary valve with PS, we observed decreased expression of APOE and other genes regulating elastogenesis such as EMILIN1 and LOXL1, as well as elastin fragmentation. These findings suggested the crucial role of APOE in regulating elastogenesis during valve remodeling. Furthermore, cell-cell interaction analysis revealed that JAG1 from unidirectional VECs activates NOTCH signaling in Elastin-VICs through NOTCH3. In vitro Jag1 treatment in VICs increased elastogenesis, while similar observations were found in VICs co-cultured with VECs in the presence of unidirectional flow. Notably, we found that the JAG1-NOTCH3 signaling pair was drastically reduced in the PS valves. Lastly, we demonstrated that APOE is indispensable for JAG1-induced NOTCH activation in VICs, reinforcing the presence of a synergistic intrinsic and external regulatory network involving APOE and NOTCH signaling that is responsible for regulating elastogenesis during human valve remodeling. ConclusionscRNA-seq analysis of human fetal valves identified a novel Elastin-VIC subpopulation, and revealed mechanism of intrinsic APOE and external NOTCH signaling in regulating elastogenesis during cardiac valve remodeling. These mechanisms may contribute to deciphering the pathogenesis of elastin malformation in congenital valve diseases. Clinical Perspective What Is New?O_LIHigh-resolution single-cell transcriptome atlas generated from healthy human fetal heart valves and valves affected by pulmonary stenosis during the early phase of valve remodeling prior to birth. C_LIO_LIA unique subset of valve interstitial cells (VICs) that produce elastin (Elastin-VICs) was identified. C_LIO_LIElastin-VICs specifically located underneath the valve endothelial cells (VECs) sensing unidirectional flow, and played a crucial role in elastin maturation via the expression of APOE. C_LIO_LIElastin-VICs communicated with adjacent VECs via the JAG1-NOTCH signaling, facilitating elastin formation and valve remodeling. C_LI What Are the Clinical Implications?O_LIElastin-VICs from patient valvular tissues with Pulmonary Stenosis exhibit decreased APOE-NOTCH signaling and elastin fragmentation. C_LIO_LIDirect targeting of APOE and NOTCH signaling could be a novel approach to promote elastin fiber formation and valve remodeling in patients with valvular defects. C_LI

bioinformatics↗

bioRxiv2023

Rare SH2B3 coding variants identified in lupus patients impair B cell tolerance and predispose to autoimmunity

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3 - a negative regulator of cytokine and growth factor receptor signaling - harbors rare coding variants in over 5% of SLE patients. Here we show that unlike the variant found exclusively in healthy controls, most SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles. Generation of two mouse lines carrying variants orthologous to those found in patients revealed SH2B3 is important to limit the numbers of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk. SummaryZhang et al. reveal a role for hypomorphic SH2B3 in lupus risk. The study shows rare and damaging variants identified in lupus patients enable breach of B cell immune tolerance checkpoints and suggests involvement for dysregulated IL-4R signaling and BAFF-R expression.

immunology↗

bioRxiv2023

The Impact of Chronic Phthalate Exposure on Rodent Anxiety and Cognition

There is a growing importance for environmental contributions to psychiatric disorders and understanding the impact of the exposome (i.e., pollutants and toxins). Increased biomonitoring and epidemiological studies, for example, suggest that daily phthalate chemical exposure contribute to neurological and behavioral abnormalities, however these mechanisms remain poorly understood. The current study therefore aimed to examine the effects of chronic phthalate exposure on rodent anxiety behaviors, cognition, and the impact on hypothalamic-pituitary{-} adrenal (HPA)-axis function. Adult male mice (C57BL6/J) were administered mono-2-ethylhexyl phthalate (MEHP) via drinking water (1 mg/ml), and anxiety-like behavior, cognition combined with HPA- axis and inflammatory assays were assessed after 3 weeks of MEHP exposure. MEHP-treated mice exhibited enhanced generalized anxiety-like behaviors, as demonstrated by reduced time spent in the open-arm of the elevated plus maze (EPM) and center exploration in the open field (OF). Tests of spatial, cognition and memory function were unchanged. Following MEHP administration, circulating levels of corticosterone and pro{-} inflammatory cytokines were significantly increased, while at the tissue level, MEHP-dependent reductions in glucocorticoid metabolism genes 11{beta}-hydroxysteroid dehydrogenase (11{beta}-HSD) 1 and 2. These data suggest that chronic MEHP exposure leads to enhanced generalized-anxiety behaviors independent of rodent measures of cognition and memory, which maybe driven by MEHP-dependent effects on HPA-axis and peripheral glucocorticoid metabolism function.

pharmacology and toxicology↗

bioRxiv2023

Origin and early divergence of tandem duplicated sorbitol transporter genes in Rosaceae

Sorbitol is a critical photosynthate and storage substance in the Rosaceae family. Sorbitol transporters (SOTs) play a vital role in facilitating sorbitol allocation from source to sink organs and sugar accumulation in sink organs. Despite observing gene duplications in the SOT gene family, the origin and evolutionary process of these duplications are unclear, due to the complicated interplay of whole genome duplications and tandem duplications. Here, we investigated the synteny relationships of all detected Polyol/Monosaccharide Transporter (PLT) genes in 61 angiosperm genomes and SOT genes in major representative Rosaceae genomes. Combining phylogenetic analysis, we elucidated the lineage-specific expansion and syntenic conservation of PLTs and SOTs across different plant lineages. We found that Rosaceae SOTs, as PLT family members, originated from a pair of PLT tandem duplicating genes belonging to Class III-A. Additionally, lineage-specific and synergistic duplications in Amygdaloideae had contributed to the expansion of SOTs in Rosaceae plants. Overall, our findings provide insights into the genomic origins, duplication, and divergence of SOT gene family members, which are fundamental for further functional characterizations of each member.

genomics↗

bioRxiv2023

The anti-cancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3' processing machinery

JTE-607 is a small molecule compound with anti-inflammation and anti-cancer activities. Upon entering the cell, it is hydrolyzed to Compound 2, which directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-mRNA 3' processing. Although CPSF73 is universally required for mRNA 3' end formation, we have unexpectedly found that Compound 2- mediated inhibition of pre-mRNA 3' processing is sequence-specific and that the sequences flanking the cleavage site (CS) are a major determinant for drug sensitivity. By using massively parallel in vitro assays, we have measured the Compound 2 sensitivities of over 260,000 sequence variants and identified key sequence features that determine drug sensitivity. A machine learning model trained on these data can predict the impact of JTE-607 on poly(A) site (PAS) selection and transcription termination genome-wide. We propose a biochemical model in which CPSF73 and other mRNA 3' processing factors bind to RNA of the CS region in a sequence-specific manner and the affinity of such interaction determines the Compound 2 sensitivity of a PAS. As the Compound 2-resistant CS sequences, characterized by U/A-rich motifs, are prevalent in PASs from yeast to human, the CS region sequence may have more fundamental functions beyond determining drug resistance. Together, our study not only characterized the mechanism of action of a compound with clinical implications, but also revealed a previously unknown and evolutionarily conserved sequence-specificity of the mRNA 3' processing machinery.

molecular biology↗

bioRxiv2023

NanoMOFs with Encapsulated Photosensitizer: Accumulation in Chlamydia trachomatis Inclusions and Antimicrobial Effects

Metal-organic framework nanoparticles (nanoMOFs) are a promising class of hybrid nanomaterials for biomedical applications. Some of them, including biodegradable porous iron carboxylates are proposed for encapsulation and delivery of antibiotics. Due to the high drug loading capacity and fast internalization kinetics nanoMOFs are more beneficial for the treatment of intracellular bacterial infections compared to free antibacterial drugs, which poorly accumulate inside the cells because of the inability to cross membrane barriers or have low intracellular retention. However, nanoparticle internalization does not ensure their accumulation in the cell compartment that shelters a pathogen. This study shows the availability of MIL-100(Fe) MOF nanoparticles to co-localize with Chlamydia trachomatis, an obligate intracellular bacterium, in the infected RAW264.7 macrophages. Furthermore, nanoMOFs loaded with photosensitizer methylene blue (MB) exhibit complete photodynamic inactivation of Chlamydia trachomatis growth. Simultaneous infection and treatment of RAW264.7 cells with empty nanoMOFs resulted in a 3-fold decrease in bacterial load that indicates an intrinsic anti-chlamydial effect of this iron-containing nanomaterial. Thus, our findings suggest the use of iron-based nanoMOFs as a promising drug delivery platform, which contributes to antibacterial effect, for the treatment of chlamydial infections.

biophysics↗

bioRxiv2023

Rice Gene Index (RGI): a comprehensive pan-genome database for comparative and functional genomics of Asian rice

To integrate the genomic information of the rice pan-genome, we performed comparative analyses and established a user-friendly Rice Gene Index (RGI, https://riceome.hzau.edu.cn) platform with 16 platinum standard reference genomes and supplementary transcriptome data. To logically organize and scientifically the index of 744,233 genes among rice accessions, we detected 112,658 Ortholog Gene Indices, and provide GeneCard pages to query genomic, transcriptomic, and homology information for each gene. The RGI allows users to search for relationships and comprehensive information of genes in keyword-based, sequence-based, and relationship-based ways. Furthermore, users can visualize these relationships at local and global scales corresponding to Microcollinearity and Macrocollinearity modules.

genomics↗

bioRxiv2023

Single-cell transcriptomic analyses reveal the cellular and genetic basis of aquatic locomotion in scyphozoan jellyfish

The authors have withdrawn their manuscript because the authors need to re-organize the data and writing. More experimental evidence from whole-mount ISH assay and RNAi assays will be added to support the viewpoints. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

ecology↗

bioRxiv2023

CRISPR-based editing of the ω- and γ-gliadin gene clusters reduces wheat immunoreactivity without affecting grain protein quality

Wheat immunotoxicity is associated with abnormal reaction to gluten-derived peptides. Attempts to reduce immunotoxicity using breeding and biotechnology often affect dough quality. Here, the multiplexed CRISPR-Cas9 editing of cultivar Fielder was used to modify the {omega} -and {gamma}-gliadin gene clusters abundant in immunoreactive peptides identified in the genomes assembled using the long-read sequencing technologies. The whole genome sequencing of an edited line showed editing or deletion of nearly all {omega}-gliadin and half of the {gamma}-gliadin gene copies and lack of editing in the /{beta}-gliadin genes. The detected 62% and 52% reduction in {omega}- and {gamma}-gliadin content, respectively, had no negative impact on grain protein quality. A 47-fold immunoreactivity reduction compared to wild-type was detected using antibodies against immunotoxic peptides. Our results indicate that genome profiling to identify gliadin gene copies abundant in immunoreactive peptides and their targeted editing could be an effective mean for reducing immunotoxicity of wheat cultivars while minimizing the impact of editing on protein quality.

genetics↗

bioRxiv2023

In situ structures of secretins from bacterial type II secretion system reveal their membrane interactions and translocation process

The GspD secretin is the outer membrane channel of the bacterial type II secretion system (T2SS) which secrets diverse effector proteins or toxins that cause severe diseases such as diarrhea and cholera. GspD needs to translocate from the inner to the outer membrane to exert its function, and this process is an essential step for T2SS to assemble. Here, we investigate two types of secretins discovered so far in Escherichia coli, GspD and GspD{beta}, respectively. By electron cryotomography subtomogram averaging, we determine in situ structures of all the key intermediate states of GspD and GspD{beta} in the translocation process, with resolution ranging from 9 [A] to 19 [A]. In our results, GspD and GspD{beta} present entirely different membrane interaction patterns and ways of going across the peptidoglycan layer. We propose two distinct models for the membrane translocation of GspD and GspD{beta}, providing a comprehensive perspective on the inner to outer membrane biogenesis of T2SS secretins.

microbiology↗

bioRxiv2022

FOXC2 marks and maintains the primitive spermatogonial stem cells subpopulation in the adult testis

In adult mammals, spermatogenesis embodies the complex developmental process from spermatogonial stem cells (SSCs) to spermatozoa. At the top of this developmental hierarchy lie a series of SSC subpopulations. Their individual identities as well as the relationships with each other, however, remain largely elusive. Using single-cell analysis and lineage tracing, we discovered both in mice and humans the quiescent adult SSC subpopulation marked specifically by forkhead box protein C2 (FOXC2). All spermatogenic progenies can be derived from FOXC2+ SSCs and the ablation of FOXC2+ SSCs led to the depletion of the undifferentiated spermatogonia pool. During germline regeneration, FOXC2+ SSCs were activated and able to completely restore the process. Germ cell specific Foxc2 knockout resulted in an accelerated exhaustion of SSCs and eventually led to male infertility. Furthermore, FOXC2 prompts the expressions of negative regulators of cell cycle thereby ensures the SSCs reside in quiescence. Thus, this work proposes that the quiescent FOXC2+ SSCs are essential for maintaining the homeostasis and regeneration of spermatogenesis in adult mammals.

developmental biology↗

bioRxiv2022

rcCAE: a convolutional autoencoder based method for detecting tumor clones and copy number alterations from single-cell DNA sequencing data

Intra-tumor heterogeneity (ITH) is one of the major confounding factors that result in cancer relapse, and deciphering ITH is essential for personalized therapy. Single-cell DNA sequencing (scDNA-seq) now enables profiling of single-cell copy number alterations (CNAs) and thus aids in high-resolution inference of ITH. Here, we introduce an integrated framework called rcCAE, to accurately infer cell subpopulations and single-cell CNAs from scDNA-seq data. A convolutional autoencoder (CAE) is employed in rcCAE to learn latent representation of the cells as well as distill copy number information from noisy read counts data. This unsupervised representation learning via the CAE model makes it convenient to accurately cluster cells over the low-dimensional latent space, and detect single-cell CNAs from enhanced read counts data. Extensive performance evaluations on simulated datasets show rcCAE outperforms existing CNA calling methods, and is highly effective in inferring clonal architecture. Furthermore, evaluations of rcCAE on two real datasets demonstrate it is able to provide more refined clonal structure, of which some details are lost in clonal inference based on integer copy numbers.

bioinformatics↗

bioRxiv2022

Unraveling the viral dark matter of the rumen microbiome with a new global virome database

Like in the human gut and other environments, viruses are probably also diverse and modulate the microbiome (both population and function) in the rumen of ruminants, but it remains largely unknown. Here we mined 975 published rumen metagenomes for viral sequences, created the first rumen virome database (RVD), and perform ecogenomic meta-analyses of these data. This identified 397,180 species-level viral operational taxonomic units (vOTUs) and allowed for a 10-fold increase in classification rate of rumen viral sequences compared with other databases. Most of the classified vOTUs belong to the order Caudovirales, but distinct from those in the human gut. Rumen viruses likely have ecosystem impacts as they were predicted to infect dominant fiber degraders and methane producers, and they carry diverse auxiliary metabolic genes and antibiotic resistance genes. Together, the RVD database and these findings provide a baseline framework for future research on how viruses may impact the rumen ecosystem.

microbiology↗

bioRxiv2022

Organization, genomic targeting and assembly of three distinct SWI/SNF chromatin remodeling complexes in Arabidopsis

Switch defective/sucrose non-fermentable (SWI/SNF) complexes are evolutionarily conserved multi-subunit machines that play vital roles in chromatin architecture regulation for modulating gene expression via sliding or ejection of nucleosomes in eukaryotes. In plants, perturbations of SWI/SNF subunits often result in severe developmental disorders. However, the subunit composition, pathways of assembly, and genomic targeting of the plant SWI/SNF complexes remain undefined. Here, we reveal the organization, genomic targeting and assembly of three distinct Arabidopsis SWI/SNF complexes: BRAHMA-Associated SWI/SNF complexes (BAS), SPLAYED-Associated SWI/SNF complexes (SAS) and MINUSCULE-Associated SWI/SNF complexes (MAS). We show that BAS complexes are equivalent to human ncBAF, whereas SAS and MAS complexes evolve in multiple subunits unique to plants, suggesting a plant-specific functional evolution of SWI/SNF complexes. We further demonstrate overlapping and specific genomic targeting of the three plant SWI/SNF complexes on chromatin and reveal that SAS complexes are necessary for the correct genomic localization of the BAS complexes. Finally, we define the role of core module subunit in the assembly of the plant SWI/SNF complexes and highlight that ATPase module subunit is required for global complex stability and the interaction of core module subunits in SAS and BAS complexes in Arabidopsis. Together, our work highlights the divergence of SWI/SNF chromatin remodelers during the eukaryote evolution and provides a comprehensive landscape for understanding the plant SWI/SNF complexes organization, assembly, genomic targeting, and function. One-sentence summaryComprehensively define the organization, genomic targeting and assembly of three distinct SWI/SNF chromatin remodeling complexes in Arabidopsis

plant biology↗

bioRxiv2022

Novel mRNA vaccines encoding Monkeypox virus M1R and A35R protect mice from a lethal virus challenge

The outbreak of Monkeypox virus infection urgently need effective vaccines. However, the vaccines so far approved are all based on whole-virus, which raises safety concerns. MRNA vaccines has demonstrated its high efficacy and safety against SARS-Cov-2 infection. Here, we developed three mRNA vaccines encoding Monkeypox proteins M1R and A35R, including A35R-M1R fusions (VGPox1 and VGPox 2) and a combination of encapsulated full-length mRNAs for A35R and M1R (VGPox 3). All three vaccines induced anti-A35R total IgGs as early as day 7 following a single vaccination. However, only VGPox 1 and 2 produced anti-M1R total IgGs at early dates following vaccination while VGPox 3 did not show significant anti-M1R antibody till day 35. Similar results were also found in neutralizing antibodies and T cell immune response. However, all mRNA vaccine groups completely protected mice from a lethal dose virus challenge and effectively cleared virus in lungs. Collectively, our results indicate that the novel mRNA vaccines coding for a fusion protein of A35R and M1R had a better anti-virus immunity than co-expression of the two individual proteins. The mRNA vaccines are highly effective and can be an alternative to the current whole-virus vaccines to defend Monkeypox virus infection.

immunology↗

bioRxiv2022

Modeling multiphage-bacteria kinetics to predict phage therapy potency and longevity

Pseudomonas aeruginosa is a frequent cause of life-threatening opportunistic infections in the critically ill and immunocompromised. Its treatment is challenging due to the increasing prevalence of resistance to most conventional antibiotics. Although numerous alternative therapies are currently under investigation, bacteriophage (phage) cocktail therapy appears poised for long-term success. Here, we investigate potency and longevity of individual Pseudomonas phages in cocktail to determine viral co-factors that promote optimal treatment efficacy. We combined in vitro and in silico models to predict sixty-eight treatment permutations with three phages that adsorb symmetrically and asymmetrically when administered singly, double simultaneously, or double sequentially. We showed that simultaneously administering two asymmetrically binding phages with high cell lysis efficiencies improved cocktail potency. Use of a higher-potency cocktail, along with a reduction in the net probability of independent gene mutations was associated with prolonged bacterial suppression. Nevertheless, in vitro we almost always observed evolution of multiphage resistance. Simulations also predict that when combining phages with polar potencies, susceptible host cells are monopolized by the more efficiently replicating phage. Thus, further perpetuating the growth demise of the weaker phage in cocktail. Our mathematical model was used to explore and predict changes in phage and bacterial populations that were difficult to measure experimentally. This framework has many inferential and exploratory uses for clinical investigation such as identifying the most sensitive parameters for phage selection and exploring different treatment regimens. Collectively, our findings attempt to dissect the mechanisms of phage cocktails combating P. aeruginosa infections and highlight the viral co-factors necessary for treatment efficacy.

microbiology↗

bioRxiv2022

Remodeling of a tripartite substrate-binding motif in the HD domain provides the mechanism for activation of CRISPR-Cas10 DNases

Type III CRISPR systems are endowed with multiple immune activities, including target RNA cleavage, RNA-activated DNA cleavage and the cOA synthesis among which molecular mechanism remains elusive for the DNase. Here, DNase of LdCsm is investigated. Structural modeling revealed two HD loop segments. Cas10 mutants carrying either loop truncation or amino acid substitution in the HD domain are generated and characterized. We found each HD loop contains a substrate-binding site essential for its immunity. In fact, the substrate binding requires a tripartite motif composed of the two loop binding sites and the HD catalytic site. We demonstrate cognate target RNA (CTR) remodels the tripartite motif to activate the LdCsm DNase in two consecutive events: (a) it reduces the flexibility of LD-L1 and facilitates the simultaneous substrate binding at both loops, (b) the bound substrate is then propelled into the catalytic site via LD-L2 oscillation, driving the substrate into the catalytic site for DNA cleavage.

microbiology↗

bioRxiv2022

Effect of Nrf2 Loss on Senescence and Cognition of Tau-Based P301S Mice

Cellular senescence may contribute to chronic inflammation involved in the progression of age-related diseases such as Alzheimers Disease (AD), and its removal prevents cognitive impairment in a model of tauopathy. Nrf2, the major transcription factor for damage response pathways and regulators of inflammation, declines with age. Our previous work showed that silencing Nrf2 gives rise to premature senescence in cells and mice. Others have shown that Nrf2 ablation can exacerbate cognitive phenotypes of some AD models. In this study we aimed to understand the relationship between Nrf2 elimination, senescence, and cognitive impairment in AD, by generating a mouse model expressing a mutant human tau transgene in an Nrf2 knockout (Nrf2KO) background. We assessed senescent cell burden and cognitive decline of P301S mice in the presence and absence of Nrf2. Lastly, we administered 4.5 month-long treatments with two senotherapeutic drugs to analyze their potential to prevent senescent cell burden and cognitive decline: the senolytic drugs Dasatinib and Quercetin (DQ) and the senomorphic drug rapamycin. Nrf2 loss accelerated the onset of hind-limb paralysis in P301S mice. At 8.5 months of age, P301S mice did not exhibit memory deficits, while P301S mice without Nrf2 were significantly impaired. However, markers of senescence were not elevated by Nrf2 ablation in any of tissues that we examined. Neither drug treatment improved cognitive performance, nor did it reduce expression of senescence markers in brains of P301S mice. Contrarily, rapamycin treatment at the doses used delayed spatial learning and led to a modest decrease in spatial memory. Taken together, our data suggests that the emergence of senescence may be causally associated with onset of cognitive decline in the P301S model, indicate that Nrf2 protects brain function in a model of AD through mechanisms that may include, but do not require the inhibition of senescence, and suggest possible limitations for DQ and rapamycin as therapies for AD.

animal behavior and cognition↗