Biology subjects

Song, W.

Publications and source records attributed to Song, W..

9 recordsLinked to original sources

bioRxiv2026

Microbial valerate is associated with CAR T dysbiosis and its supplementation enhances CAR T function in B-cell lymphoma

Anaerobe-depleting antibiotic exposure is associated with inferior progression-free survival after CD19 CAR T-cell therapy in large B-cell lymphoma, yet the cellular mechanisms linking gut dysbiosis to the CAR T-cell product and whether this imprint is reversible have remained undefined. In two independent CAR-T candidate cohorts, low stool valerate at the time of CAR-T eligibility identified a multi-metabolite-deficient dysbiotic gut microbiome state marked by depletion of fiber-fermenting commensals and loss of carbohydrate-fermentation, SCFA-biosynthesis, and amino-acid metabolism pathways. Reanalysis of single-cell RNA sequencing from 42 lymphoma patients stratified by piperacillin-tazobactam/imipenem/meropenem (PIM) exposure revealed that PIM-exposed CAR T-cell products were CD4-skewed, with significantly elevated AP-1/immediate-early gene (IEG) and cellular activation signatures that together predicted inferior progression-free survival. Ex vivo conditioning of CAR T-cells with valerate produced a chromatin and transcription factor program distinct from butyrate or propionate, characterized by KLF/SP/EGR family engagement, KLF4 promoter opening, and broad induction of AP-1/IEG and MHC class II transcripts, whereas butyrate drove broader chromatin remodeling with TBX21/EOMES/NF-{kappa}B gains and KLF2 promoter closure, and propionate induced an NFY-centered program with preferential commitment to low-mitochondrial-content states. Untargeted metabolomics confirmed valerate uptake and mitochondrial {beta}-oxidation in CAR T-cells, while dietary sodium valerate supplementation in meropenem-treated mice bearing A20 lymphoma significantly reduced tumor burden and extended survival compared with CAR T-cells alone. These findings identify stool valerate as a bedside-deployable biomarker of dysbiosis-imprinted CAR T-cell dysfunction and support ex vivo or dietary valerate supplementation as a clinically tractable strategy to improve CAR-T anti-tumor function in patients with disrupted gut microbiomes.

cancer biology↗

bioRxiv2018

Dynamic plant height QTL revealed in maize through remote sensing phenotyping using a high-throughput unmanned aerial vehicle (UAV)

Plant height is the key factor for plant architecture, biomass and yield in maize (Zea mays). In this study, plant height was investigated using unmanned aerial vehicle high-throughput phenotypic platforms (UAV-HTPPs) for maize diversity inbred lines at four important growth stages. Using an automated pipeline, we extracted accurate plant heights. We found that in temperate regions, from sowing to the jointing period, the growth rate for temperate maize was faster than tropical maize. However, from jointing to flowering stage, tropical maize maintained a vigorous growth state, and finally resulted in a taller plant than temperate lines. Genome-wide association study for temperate, tropical and both groups identified a total of 238 quantitative trait locus (QTLs) for the 16 plant height related traits over four growth periods. And, we found that plant height at different stages were controlled by different genes, for example, PIN1 controlled plant height at the early stage and PIN11 at the flowering stages. In this study, the plant height data collected by the UAV-HTTPs were credible and the genetic mapping power is high, indicating that the application of this UAV-HTTPs into the study of plant height will have great prospects.\n\nHighlightWe used UAV-based sensing platform to investigate plant height over 4 growth stages for different maize populations, and detected numbers of reliable QTLs using GWAS.

genetics↗

bioRxiv2018

State-Dependent Lipid Interactions with the A2a Receptor Revealed by MD Simulations Using In Vivo-Mimetic Membranes

G protein-coupled receptors (GPCRs) are the largest family of integral membrane proteins and a major class of drug targets. Membranes are known to have modulatory effects on GPCRs via specific lipid interactions. However, the mechanisms of such modulations in cell membranes and how they influence GPCR functions remain unclear. Here we report coarse-grained MD simulations on the Adenosine A2a receptor embedded in an in vivo mimetic membrane model comprised of 10 different lipid species. Three conformational states of the receptor, i.e. the inactive state, the active state, and the active state with a mini-GS protein bound were simulated to study the impact of protein-lipid interactions on the receptor activation. The simulations revealed three specific lipids (GM3, cholesterol and PIP2) that form stable and preferential interactions with the receptor, differentiating these from bulk lipids such as PS, PE and PC. In total, nine specific lipid-binding sites were revealed. The strength of lipid interaction with these sites depends on the conformational state of the receptor, suggesting that these lipids may regulate the conformational dynamics of the receptor. In particular, we revealed a dual role of PIP2 in promoting A2aR activation, which involves stabilization of both the characteristic outward tilt of helix TM6 within receptor and also the association of A2aR and mini-Gs when the activated complex forms. Structural comparisons suggested that PIP2 may facilitate G activation. Our results reveal likely allosteric effects of bound lipids in regulating the functional behaviour of GPCRs, providing a springboard for design of allosteric modulators of these biomedically important receptors.

biophysics↗

bioRxiv2018

Genome analysis of the unicellular eukaryote Euplotes vannus provides insights into mating type determination and tolerance to environmental stresses

As a model organism in studies of cell and environmental biology, the free-living and cosmopolitan ciliated protist Euplotes vannus has more than ten mating types (sexes) and shows strong resistance to environmental stresses. However, the molecular basis of its sex determination mechanism and how the cell responds to stress remain largely unknown. Here we report a combined analysis of de novo assembled high-quality macronucleus (MAC; i.e. somatic) genome and partial micronucleus (MIC; i.e. germline) genome of Euplotes vannus. Furthermore, MAC genomic and transcriptomic data from several mating types of E. vannus were investigated and gene expression levels were profiled under different environmental stresses, including nutrient scarcity, extreme temperature, salinity and the presence of free ammonia. We found that E. vannus, which possesses gene-sized nanochromosomes in its MAC, shares a similar pattern on frameshifting and stop codon usage as Euplotes octocarinatus and may be undergoing incipient sympatric speciation with Euplotes crassus. Somatic pheromone loci of E. vannus are generated from programmed DNA rearrangements of multiple germline macronuclear destined sequences (MDS) and the mating types of E. vannus are distinguished by the different combinations of pheromone loci instead of possessing mating type-specific genes. Lastly, we linked the resilience to environmental temperature change to the evolved loss of temperature stress-sensitive regulatory regions of HSP70 gene in E. vannus. Together, the genome resources generated in this study, which are available online at Euplotes vannus DB (http://evan.ciliate.org), provide new evidence for sex determination mechanism in eukaryotes and common pheromone-mediated cell-cell signaling and cross-mating.

genomics↗

bioRxiv2018

Identification and characterization of cherry (Cerasus pseudocerasus G. Don) genes in response to parthenocarpy induced by GA3 through transcriptome analysis

Fruit set after successful pollination is a key process in the production of sweet cherries, but low fruit rate is the main problem for crop production in sweet cherries. Gibberellin treatment can directly induce parthenogenesis without pollination; therefore, gibberellin treatment is a very important method to improve the fruit setting rate of sweet cherries. Exogenous gibberellin can satisfy the hormone requirement during fruit growth and development. Some related studies have mainly focused on physiological aspects, such as breeding, branching, fertilization, etc., and the molecular mechanism is not clear. In this study, we analyzed the transcriptome of Meizao sweet cherry fruit treated with gibberellin during the anthesis and hard-core period to determine the genes associated with parthenocarpic fruit set. A total of 765 and 186 differentially expressed genes (DEGs) were found at anthesis and the hard-core stage after gibberellin 3 (GA3) treatment, respectively. The differentially expressed genes between the control and GA3 treatment showed that the GA3 response mainly included parthenocarpic fruit set and cell division. Exogenous gibberellin stimulated sweet cherry parthenocarpy and enlargement, which were verified by qRT-PCR results of related genes and the parthenocarpic fruit set and fruit size. Based on our research and previous studies on Arabidopsis thaliana, we identified the key genes associated with parthenocarpic fruit set and cell division. Briefly, we found patterns in the sweet cherry fruit setting-related DEGs, especially those associated with hormone balance, cytoskeleton formation and cell wall modification. Overall, the result provides a possible molecular mechanism regulating parthenocarpic fruit set, which is important for basic research and industrial development of sweet cherries.\n\nHighlightcherry genes in response to parthenocarpy and promote to fruit setting induced by GA3.

molecular biology↗

bioRxiv2018

Androgen Promotes Differentiation of PLZF+ Spermatogonia pool via Indirect Regulatory Pattern

Androgen signaling plays a pivotal role in spermatogenesis, but the molecular mechanisms underlying androgen action in this process are unclear. Specifically, it is unknown if the androgen receptor (AR) is expressed in germ cells. Thus its interesting to reveal how androgen induces differentiation of spermatogonial progenitor cells (SPCs) in the niche. Here we observed the AR is primarily expressed in pre-spermatogonia of mice 2 days post partum (dpp), absent before spermatogenesis onset, and then expressed in surrounding Sertoli cells. Then we examined a regulatory role of the AR in spermatogenesis using a SPCs-Sertoli cells co-culture system, and demonstrated that androgen negatively regulated Plzf (the gene for stemness maintenance of SPCs). Additionally, we identified Gata2 as a target of AR in Sertoli cells, and demonstrated that Wilms tumor 1 (WT1) and {beta}1-integrin as two putative intermediate molecules to transfer differentiation signals to SPCs, which was further verified using androgen pharmacological-deprivation mice model. These results demonstrate a regulatory pattern of androgen in SPCs niche in an indirect way via multiple steps of signal transduction.

developmental biology↗

bioRxiv2017

Prometheus: omics portals for interkingdom comparative genomic analyses

Functional analyses of genes are crucial for unveiling biological responses, for genetic engineering, and for developing new medicines. However, functional analyses have largely been restricted to model organisms, representing a major hurdle for functional studies and industrial applications. To resolve this, comparative genome analyses can be used to provide clues to gene functions as well as their evolutionary history. To this end, we present Prometheus (http://prometheus.kobic.re.kr),web-based omics portal that contains more than 17,215 sequences from prokaryotic and eukaryotic genomes. This portal supports interkingdom comparative analyses via a domain architecture-based gene identification system, Gene Search, and users can easily and rapidly identify single or entire gene sets in specific pathways. Bioinformatics tools for further analyses are provided in Prometheus or through BioExpress, a cloud-based bioinformatics analysis platform. Prometheus suggests a new paradigm for comparative analyses with large amounts of genomic information.

bioinformatics↗

bioRxiv2017

Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington’s disease

Huntingtons Disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins. We carried out systematic genetic interaction studies testing lysine and arginine methylases and demethylases in a Drosophila melanogaster HD model. We found that modulating methylation enzymes that typically affect histone positions H3K4, H3K36 or H3K79 had varying effects on HD pathology while modulating ones that typically affect constitutive heterochromatin marks at H3K9 and H4K20 generally had limited impact on HD pathology. In contrast, modulating enzymes acting on the facultative heterochromatin mark at H3K27 had specific effects on HD pathology, with reduction of the demethylase Utx rescuing HTT induced pathology while reducing PRC2 complex core methylase components led to more aggressive pathology. Further exploration of the mechanism underlying the methylation-specific interactions suggest that these lysine and arginine methylases and demethylases are likely exerting their influence through non-histone targets. These results highlight a novel therapeutic approach for HD in the form of Utx inhibition.

neuroscience↗

bioRxiv2017

The Evolutionary Genomic Dynamics of Peruvians Before, During, and After the Inca Empire

Native Americans from the Amazon, Andes, and coast regions of South America have a rich cultural heritage, but have been genetically understudied leading to gaps in our knowledge of their genomic architecture and demographic history. Here, we sequenced 150 high-coverage and genotyped 130 genomes from Native American and mestizo populations in Peru. A majority of our samples possess greater than 90% Native American ancestry and demographic modeling reveals, consistent with a rapid peopling model of the Americas, that most of Peru was peopled approximately 12,000 years ago. While the Native American populations possessed distinct ancestral divisions, the mestizo groups were admixtures of multiple Native American communities which occurred before and during the Inca Empire. The mestizo communities also show Spanish introgression only after Peruvian Independence. Thus, we present a detailed model of the evolutionary dynamics which impacted the genomes of modern day Peruvians.

genomics↗