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Biology subjects

Yu, Y.

Publications and source records attributed to Yu, Y..

At least 325 records · Page 18Linked to original sources

Myosin VIII and XI isoforms interact with Agrobacterium VirE2 protein and help direct transport from the plasma membrane to the perinuclear region during plant transformation

Virulent Agrobacterium strains transfer single-strand T-DNA (T-strands) and virulence effector proteins into plant cells. VirE2, one of these virulence effectors, enters the plant cell and is thought to bind T-strands, protecting them from nuclease degradation and helping guide them to the nucleus. How VirE2 is trafficked inside the plant cell is not fully understood. Using bimolecular fluorescence complementation, in vitro pull-down, yeast two-hybrid, and in vivo co-immunoprecipitation assays, we found that VirE2 binds directly to the cargo binding domains of several myosin VIII family members, and to myosin XI-K. We observed reduced susceptibility of several Arabidopsis actin mutants and a myosin VIII-1/2/a/b quadruple mutant to Agrobacterium-mediated transformation. Expression of cargo binding domains of myosin VIII-1, VIII-2, VIII-A, or VIII-B in transgenic plants inhibits Arabidopsis root transformation. However, none of the myosin VIII proteins contribute to the intracellular trafficking of VirE2. Expression of myosin VIII-2, -A, -B, but not VIII-1, cDNAs in the myosin VIII-1/2/a/b mutant partially restored transformation. Furthermore, functional fluorescently-tagged VirE2, synthesized in plant cells, relocalized from the cellular periphery into the cytoplasm after delivery of T-strands from Agrobacterium. Surprisingly, mutation of myosin XI-k and expression of the myosin XI-K cargo binding domain had no effect on transformation, although it blocked VirE2 movement along actin filaments. We hypothesize that myosin VIII proteins facilitate VirE2 tethering to the plasma membrane and are required for efficient localization of VirE2 to membrane sites from which they bind incoming T-strands. Myosin XI-K is important for VirE2 movement through the cytoplasm towards the nucleus.

plant biology↗

Spatiotemporal cell landscape of human embryonic tooth development

Understanding the cellular composition and trajectory of human tooth development is valuable for dentistry and stem cell engineering research. Previous single-cell studies have focused on mature human tooth and developing mice tooth, but cell landscape on human embryonic dental development is still lacking. We collected tooth germ tissues from aborted fetus (17-24 week) for single cell RNA sequence and spatial transcriptome. We classified all cells into seven subclusters of epithelium, seven clusters of mesenchyme and other cell types like Schwann cell precursor and pericyte. For epithelium, the Stratum intermedium branch and the ameloblast branch diverged from a same set of KRT15+-HOPX+-ALCAM+ epithelial stem cell lineage, but the spatial distribution of two branches were not clearly distinct. This trajectory received spatially adjacent regulation signals from mesenchyme and pericyte, including JAG1 and APP. The differentiation of pulp cell and pre-odontoblast showed four waves of temporally distinct gene expression, which involved regulation networks of LHX9, DLX5 and SP7 and were regulated by upstream ligands like BMP family. Taken together, we provided a reference landscape for the research on human early tooth development, covering different spatial structures and developmental periods.

cell biology↗

Normative Modeling of Brain Morphometry Across the Lifespan using CentileBrain: Algorithm Benchmarking and Model Optimization

We present an empirically benchmarked framework for sex-specific normative modeling of brain morphometry that can inform about the biological and behavioral significance of deviations from typical age-related neuroanatomical changes and support future study designs. This framework was developed using regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The Multivariate Factorial Polynomial Regression (MFPR) emerged as the preferred algorithm optimized using nonlinear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins, and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3,000 study participants. The model and scripts described here are freely available through CentileBrain (https://centilebrain.org/).

bioinformatics↗

Protein Representation Learning via Knowledge Enhanced Primary Structure Modeling

AO_SCPLOWBSTRACTC_SCPLOWProtein representation learning has primarily benefited from the remarkable development of language models (LMs). Accordingly, pre-trained protein models also suffer from a problem in LMs: a lack of factual knowledge. The recent solution models the relationships between protein and associated knowledge terms as the knowledge encoding objective. However, it fails to explore the relationships at a more granular level, i.e., the token level. To mitigate this, we propose Knowledge-exploited Auto-encoder for Protein (KeAP), which performs tokenlevel knowledge graph exploration for protein representation learning. In practice, non-masked amino acids iteratively query the associated knowledge tokens to extract and integrate helpful information for restoring masked amino acids via attention. We show that KeAP can consistently outperform the previous counterpart on 9 representative downstream applications, sometimes surpassing it by large margins. These results suggest that KeAP provides an alternative yet effective way to perform knowledge enhanced protein representation learning. Code and models are available at https://github.com/RL4M/KeAP.

bioinformatics↗

EVIDENCE FOR ANGIOTENSIN II AS A NATURALLY EXISTING SUPPRESSOR FOR THE NATRIURETIC PEPTIDE SYSTEM

BackgroundNatriuretic peptide system (NPS) and renin angiotensin aldosterone system (RAAS) function oppositely at multiple levels. While it has long been suspected that angiotensin II (ANGII) may directly suppress NPS activity, no clear evidence to date support this notion. ObjectivesThis study was designed to systematically investigate ANGII-NPS interaction in humans, in vivo, and in vitro for translational insights. MethodsCirculating atrial, b-type, and c-type natriuretic peptides (ANP, BNP, CNP), cyclic guanosine monophosphate (cGMP), and ANGII were simultaneously investigated in 128 human subjects. Prompted hypothesis was validated in rat model to determine influence of ANGII on ANP actions. Multiple engineered HEK293 cells and surface plasmon resonance (SPR) technology were leveraged for mechanistic exploration. ResultsIn humans, ANGII showed inverse relationship with ANP, BNP, and cGMP. In regression models predicting cGMP, adding ANGII levels and interaction term between ANGII and natriuretic peptide increased predicting accuracy of base models constructed with either ANP or BNP, but not CNP. Importantly, stratified correlation analysis further revealed positive association between cGMP with ANP or BNP only in subjects with low, but not high, ANGII levels. In rats, co-infusion of ANGII even at physiological dose attenuated blood pressure reduction and cGMP generation triggered by ANP infusion. In vitro, we showed that the suppression effect of ANGII on ANP-stimulated cGMP requires the presence of ANGII type-1 (AT1) receptor and mechanistically involves protein kinase C (PKC), which can be substantially rescued by either valsartan (AT1 blocker) or Go6983 (PKC inhibitor). Using SPR, we showed ANGII has low affinity for particulate guanylyl cyclase A (GC-A) receptor binding compared to ANP or BNP. ConclusionsOur study reveals ANGII as a natural suppressor for cGMP-generating action of GC-A via AT1/PKC dependent manner and highlights importance of dual-targeting RAAS and NPS in maximizing beneficial properties of natriuretic peptides in cardiovascular disease. STRUCTURED GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/525806v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@6febe8org.highwire.dtl.DTLVardef@1e8e21corg.highwire.dtl.DTLVardef@54a98eorg.highwire.dtl.DTLVardef@47ade7_HPS_FORMAT_FIGEXP M_FIG C_FIG CLINICAL PERSPECTIVESAccumulating evidence continues to support the NPS as a promising therapeutic target via the function of the GC-A receptor and production of the second messenger cGMP for heart failure, hypertension, and other cardiovascular diseases. Improving our mechanistic understanding on GC-A/cGMP pathway regulation may further advance the development of novel NPS enhancing therapies. Here we report evidence from multiple avenues supporting a fundamental, yet previously underappreciated mechanism involving a negative action of ANGII in suppressing GC-A receptor-mediated cGMP production via an AT1 receptor-dependent manner. This study also provides a solid rationale for the superiority of combinatory neurohormonal therapies such as sacubitril/valsartan in treating cardiovascular disease, and further highlights a promising therapeutic avenue of dual targeting both the NPS and RAAS to maximize protection.

molecular biology↗

Single-cell transcriptomic landscape deciphers novel olfactory neuroblastoma subtypes and intratumoral heterogeneity

Olfactory neuroblastoma (ONB) is an uncommon malignant tumor known to originate from the olfactory epithelial. The complex tumor ecosystem of this pathology remained unclear. Here, we explored the cellular components with ONB tumors based on scRNA profiles of 96,325 single-cells derived from 10 tumors and 1 olfactory mucosa sample. We discovered 11 major cell types, including 6 immune cell, 3 stromal cell subtypes and epithelial cluster in the tumor microenvironment (TME), and identified 5 common expression programs from malignant epithelial cells. We analyzed subclusters of TME and the interactions among different cell types in the TME. An innovative three-classification of ONB was established via scRNA analysis. Markers for categorizing tumor samples into new subtypes were elucidated. Different responses towards certain chemotherapy regimens could be inferred according to the molecular features of three tumor types. Relative abundance of immunosuppressive TAMs indicated the benefits of immunotherapies targeting myeloid cells.

cancer biology↗

Plant selection and ecological microhabitat drive domestications of shrub-associated microbiomes in a revegetated shrub ecosystem

Shrubs are used for revegetation of degraded dryland ecosystem worldwide and could recruit large numbers of microbes from the soil; however, the plant-associated microbiome assembly and the effect of plant introduction on the soil microbiomes are not fully understood. We detected shrub-associated microbes from five ecological microhabitats, including the leaves, litter, roots, rhizosphere, and root zone, across four xeric shrub plantations (Artemisia ordosica, Caragana korshinskii, Hedysarum mongolicum, and Salix psammophila). To detect the patterns of shrub-associated microbiome assembly, 16S and ITS2 rRNA gene sequencing was performed. PERMANOVA and differential abundance analysis demonstrated that changes in the bacterial and fungal communities were more dependent on the microhabitats rather than on the plant species, with distinct niche differentiation. Moreover, source tracking and nestedness analysis showed that shrub-associated bacteria were primarily derived from bulk soils and slightly pruned in different microhabitats; however, a similar pattern was not found for fungi. Furthermore, the surrounding zone of roots was a hotpot for microbial recruitments of revegetated shrubs. Null model analysis indicated that homogeneous selection of determinism dominated the bacterial communities, whereas dispersal limitation and undominated process of stochasticity drove the assembly of fungal communities. Our findings indicate that ecological microhabitat of revegetated shrublands was the main predictor of the bacterial and fungal compositional variances. This study will help advance our understanding of the mechanism underlying the plant-soil microbiome feedbacks during the initial plant-establishment period in a dryland ecosystem. Further, this work provides theoretical reference for establishment and sustainable management of shrublands in drylands.

microbiology↗

Evolutionary transcriptomics reveals longevity mostly driven by polygenic and indirect selection in mammals

The maximum lifespan varies more than 100-fold in mammals. This experiment of nature may uncover of the evolutionary forces and molecular features that define longevity. To understand the relationship between gene expression variation and maximum lifespan, we carried out a comparative transcriptomics analysis of liver, kidney, and brain tissues of 106 mammalian species. We found that expression is largely conserved and very limited genes exhibit common expression patterns with longevity in all the three organs analyzed. However, many pathways, e.g., "Insulin signaling pathway", and "FoxO signaling pathway", show accumulated correlations with maximum lifespan across mammals. Analyses of selection features further reveal that methionine restriction related genes whose expressions associated with longevity, are under strong selection in long-lived mammals, suggesting that a common approach could be utilized by natural selection and artificial intervention to control lifespan. These results suggest that natural lifespan regulation via gene expression is likely to be driven through polygenic model and indirect selection.

evolutionary biology↗

Calponin 2 harnesses metabolic reprogramming to determine kidney fibrosis

In the fibrotic kidneys, the extent of a formed deleterious microenvironment is determined by cellular mechanical forces. This process requires metabolism for energy; however, how cellular mechanics and metabolism are connected remains unclear. Our proteomics revealed that actin filament binding and cell metabolism are the two most dysregulated events in the fibrotic kidneys. As a prominent actin stabilizer, Calponin 2 (CNN2) is predominantly expressed in fibroblasts and pericytes. CNN2 knockdown preserves kidney function and alleviates fibrosis. Global proteomics profiled that CNN2 knockdown enhanced the activities of the key rate-limiting enzymes and regulators of fatty acid oxidation (FAO) in diseased kidneys. Inhibiting carnitine palmitoyltransferase 1 in the FAO pathway results in lipid accumulation and extracellular matrix deposition in the fibrotic kidneys, which were restored after CNN2 knockdown. In patients, increased serum CNN2 levels are correlated with lipid content. Bioinformatics and chromatin immunoprecipitation showed that CNN2 interactor, estrogen receptor 2 (ESR2) binds peroxisome proliferator-activated receptor- (PPAR) to transcriptionally regulate FAO downstream target genes expression amid kidney fibrosis. In vitro, ESR2 knockdown repressed the mRNA levels of PPAR and the key genes in the FAO pathway. Conversely, activation of PPAR reduced CNN2-induced matrix inductions. Our results suggest that balancing cell mechanics and metabolism is crucial to develop therapeutic strategies to halt kidney fibrosis.

pathology↗

Human mutations in SLITRK3 implicated in GABAergic synapse development in mice

We report on biallelic homozygous and monoallelic de-novo variants in SLITRK3 in 3 unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental delay. SLITRK3 encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. By analyzing the development and phenotype of SLITRK3 KO (SLITRK3-/-) mice, we bring additional evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG, as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, our results exhibit impaired development of peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. Our study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function.

genetics↗

A cosmopolitan inversion drives seasonal adaptation in overwintering Drosophila

Drosophila melanogaster living in temperate regions evolve as they track seasonal fluctuations. Yet, we lack an understanding of the genetic architecture of seasonal adaptive tracking. By sequencing orchard populations collected across multiple years, we characterized the genomic signal of seasonal demography and identified that the cosmopolitan inversion In(2L)t drives seasonal adaptation. In(2L)t shows footprints of selection that are inconsistent with simple explanations of genetic drift, as well as signatures of partial selective sweeps. A meta-analysis of phenotypic studies shows that seasonal loci within In(2L)t are associated with behavior, life-history, physiology, and morphology traits. Our results identify candidate regions that underlie seasonal adaptive tracking and link them to phenotype. This work supports the general hypothesis that inversions are important drivers of rapid adaptation. One-Sentence SummaryA chromosomal inversion drives adaptive evolution between seasons in wild fruit flies.

evolutionary biology↗

Self-regulation of PIN1-driven auxin transport by cell surface-based auxin signaling in Arabidopsis

PIN-FORMED (PIN)-driven auxin transport contributes to establishing and maintaining a dynamic auxin concentration gradient alongside plant tissues, which drives the majority of developmental processes in plants. To maintain developmental plasticity in ever-changing environments, plants have evolved self-organizing feedback machinery between auxin signaling and its transport, which has been shown to play essential roles in many fundamental plant processes. However, the molecular mechanism behind this mutual regulation has not yet been clarified. Here, we identified a cell surface-triggered auxin signaling that regulates the PIN1-mediated auxin efflux and further developmental patterning in Arabidopsis. Auxin was able to stimulate PIN1 phosphorylation in plants through transmembrane kinases (TMKs), key components in auxin signaling, at the plasma membrane. TMK1 and TMK4 directly interacted with and phosphorylated PIN1 and functioned redundantly in the regulation of PIN1 polarity in plant cells. The phosphorylation sites in PIN1 proteins, targeted by both auxin and TMKs, were required for PIN1 trafficking and polarity, which further controlled auxin responses and downstream developmental patterning in Arabidopsis. Therefore, our findings provide a direct mechanism for the self-regulation between auxin signaling and transport that drives the auxin flows and proper development in plants.

plant biology↗

ABLs and TMKs are co-receptors for extracellular auxin

Extracellular perception of auxin, an essential phytohormone in plants, has been debated for decades. Auxin binding protein 1 (ABP1) physically interacts with quintessential transmembrane kinases (TMKs) and was proposed to act as an extracellular auxin receptor, but its role was disputed because abp1 knockout mutants lack obvious morphological phenotypes. Here we identified two new auxin-binding proteins, ABL1 and ABL2, that are localized to the apoplast and directly interact with the extracellular domain of TMKs in an auxin-dependent manner. Furthermore, functionally redundant ABL1 and ABL2 genetically interact with TMKs and exhibit functions that are overlapping with those of ABP1 as well as independent of ABP1. Importantly, the extracellular domain of TMK1 itself binds auxin and synergizes with either ABP1 or ABL1 in auxin binding. Thus, our findings discovered new auxin receptors ABL1 and ABL2 having functions overlapping with but distinct from ABP1 and acting together with TMKs as co-receptors for extracellular auxin.

plant biology↗

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↗

Self-assembly of CIP4 drives actin-mediated asymmetric pit-closing in clathrin-mediated endocytosis

Clathrin-mediated endocytosis is pivotal to signal transduction pathways between the extracellular environment and the intracellular space. Evidence from live-cell imaging and super-resolution microscopy of mammalian cells suggests an asymmetric distribution of actin fibres near the clathrin-coated pit, which induces asymmetric pit-closing rather than radial constriction. However, detailed molecular mechanisms of this asymmetricity remain elusive. Herein, we used high-speed atomic force microscopy to demonstrate that CIP4, a multi-domain protein with a classic F-BAR domain and intrinsically disordered regions, is necessary for asymmetric pit-closing. Strong self-assembly of CIP4 via intrinsically disordered regions, together with stereospecific interactions with the curved membrane and actin-regulating proteins, generates a small actin-rich environment near the pit, which deforms the membrane and closes the pit. Our results provide mechanistic insights into how disordered and structured domain collaboration promotes spatio-temporal actin polymerisation near the plasma membrane.

cell biology↗

An HBV mRNA vaccine with favorable virological suppression and superior immunity

BRIEF ABSTRACTHere we report on the development and comprehensive evaluations of an mRNA vaccine for chronic hepatitis B (CHB) treatment. In two different HBV carrier mouse models generated by viral vector-mediated HBV transfection (pAAV-HBV1.2 and rAAV8-HBV1.3), this vaccine demonstrates sufficient and persistent virological suppression, and robust immunogenicity in terms of induction of strong innate immune activation, high-level virus-specific antibodies, memory B cells and T cells. mRNA platform therefore holds prospects for therapeutic vaccine development to combat CHB.

immunology↗

The Cousa objective: a long working distance air objective for multiphoton imaging in vivo

Multiphoton microscopy can resolve fluorescent structures and dynamics deep in scattering tissue, but applying this technique in vivo can be limited by short working distance water-immersion objectives. Here we present an ultra long working distance (20 mm) air objective called the Cousa objective. It is optimized for performance across multiphoton imaging wavelengths, offers a > 4 mm2 field-of-view with submicron lateral resolution, and is compatible with commonly used multiphoton imaging systems. We share the full optical prescription, and report performance including in vivo 2-photon and 3-photon imaging in a range of species and preparations.

neuroscience↗

Quartet metabolite reference materials for assessing inter-laboratory reliability and data integration of metabolomic profiling

Various laboratory-developed metabolomic methods lead to big challenges in inter-laboratory comparability and effective integration of diverse datasets. As part of the Quartet Project, we established a publicly available suite of four metabolite reference materials derived from B-lymphoblastoid cell lines from a family quartet of parents and monozygotic twin daughters. We generated comprehensive LC-MS based metabolomic data from the Quartet reference materials using targeted and untargeted strategies in different laboratories. High variabilities in the qualitative and quantitative metabolomic measurements were observed across laboratories. Moreover, the Quartet multi-sample-based quality metrics were developed for objectively assessing the reliability of metabolomic profiling in detecting intrinsic biological differences among difference groups of samples. Importantly, the ratio-based metabolomic profiling, by scaling the absolute values of a study sample relative to those of a universal reference sample, enables data integration in long-term measurements across difference laboratories or platforms. Thus, we constructed the ratio-based high-confidence reference datasets between two reference samples, providing "ground truth" for inter-laboratory proficiency test, which enables objective assessment of various metabolomic methods. Our study provided the community with rich resources and best practice for objective assessment of inter-laboratory measurements and data integration, ensuring reliable large-scale and longitudinal metabolomic profiling.

systems biology↗