Biology subjects

Yao, H.

Publications and source records attributed to Yao, H..

100 records · Page 6Linked to original sources

bioRxiv2019

Orbitofrontal control of visual cortex gain promotes visual associative learning

The orbitofrontal cortex (OFC) encodes expected outcomes and plays a critical role in flexible, outcome-guided behavior. The OFC projects to primary visual cortex (V1), yet the function of this top-down projection is unclear. We find that optogenetic activation of OFC projection to V1 reduces the amplitude of V1 visual responses via the recruitment of local somatostatin-expressing (SST) interneurons. Using mice performing a Go/No-Go visual task, we show that the OFC projection to V1 mediates the outcome-expectancy modulation of V1 responses to the reward-irrelevant No-Go stimulus. Furthermore, V1-projecting OFC neurons reduce firing during expectation of reward. In addition, chronic optogenetic inactivation of OFC projection to V1 impairs, whereas chronic activation of SST interneurons in V1 improves the learning of Go/No-Go visual task, without affecting the immediate performance. Thus, OFC top-down projection to V1 is crucial to drive visual associative learning by modulating the response gain of V1 neurons to non-relevant stimulus.

neuroscience↗

bioRxiv2019

The chromosomal-level genome assembly and comprehensive transcriptomes of Chinese razor clam (Sinonovacula constricta) with deep-burrowing life style and broad-range salinity adaptation

BackgroundThe Chinese razor clam, Sinonovacula constricta, is one of the commercially important marine bivalves with deep-burrowing lifestyle and remarkable adaptability of broad-range salinity. Despite its economic impact and representative of the less-understood deep-burrowing bivalve lifestyle, there are few genomic resources for exploring its unique biology and adaptive evolution. Herein, we reported a high-quality chromosomal-level reference genome of S. constricta, the first genome of the family Solenidae, along with a large amount of short-read/full-length transcriptomic data of whole-ontogeny developmental stages, all major adult tissues, and gill tissues under salinity challenge.\n\nFindingsA total of 101.79 Gb and 129.73 Gb sequencing data were obtained with the PacBio and Illumina platforms, which represented approximately 186.63X genome coverage. In addition, a total of 160.90 Gb and 24.55 Gb clean data were also obtained with the Illumina and PacBio platforms for transcriptomic investigation. A de novo genome assembly of 1,340.13 Mb was generated, with a contig N50 of 689.18 kb. Hi-C scaffolding resulted in 19 chromosomes with a scaffold N50 of 57.99 Mb. The repeat sequences account for 50.71% of the assembled genome. A total of 26,273 protein-coding genes were predicted and 99.5% of them were annotated. Phylogenetic analysis revealed that S. constricta diverged from the lineage of Pteriomorphia at approximately 494 million years ago. Notably, cytoskeletal protein tubulin and motor protein dynein gene families are rapidly expanded in the S. constricta genome and are highly expressed in the mantle and gill, implicating potential genomic bases for the well-developed ciliary system in the S. constricta.\n\nConclusionsThe high-quality genome assembly and comprehensive transcriptomes generated in this work not only provides highly valuable genomic resources for future studies of S. constricta, but also lays a solid foundation for further investigation into the adaptive mechanisms of benthic burrowing mollusks.

genomics↗

bioRxiv2019

Manganese/iron-supported sulfate-dependent anaerobic oxidation of methane by archaea in lake sediments

Anaerobic oxidation of methane (AOM) by methanotrophic archaea is an important sink of this greenhouse gas in marine sediments. However, evidence for AOM in freshwater habitats is rare, and little is known about the pathways, electron acceptors and microbes involved. Here, we show that AOM occurs in anoxic sediments of a lake in southern Switzerland (Lake Cadagno). Combined AOM-rate and 16S rRNA gene-sequencing data suggest that Candidatus Methanoperedens archaea are responsible for the observed methane oxidation. Members of the Methanoperedenaceae family were previously reported to conduct nitrate- or iron/manganese-dependent AOM. However, we demonstrate for the first time that the methanotrophic archaea do not necessarily rely upon these oxidants as terminal electron acceptors directly, but mainly perform canonical sulfate-dependent AOM, which under sulfate-starved conditions can be supported by metal (Mn, Fe) oxides through oxidation of reduced sulfur species to sulfate. The correspondence of high abundances of Desulfobulbaceae and Candidatus Methanoperedens at the same sediment depth confirm the interdependence of anaerobic methane-oxidizing archaea and sulfate-reducing bacteria. The relatively high abundance and widespread distribution of Candidatus Methanoperedens in lake sediments highlight their potentially important role in mitigating methane emissions from terrestrial freshwater environments to the atmosphere, analogous to ANME-1, -2 and -3 in marine settings.

microbiology↗

bioRxiv2019

Palmitoylation is critically required for cancer intrinsic PD-1 expression and functions

Programmed cell death protein 1 (PD-1) is a crucial anticancer target, but the relatively low response rate and acquired resistance to existing antibody drugs highlight an urgent need to develop alternative targeting strategies. Here we report the palmitoylation of PD-1, discovered the main DHHC enzyme for this modification, revealed the mechanism for its effect on PD-1 expression, and rationally developed a peptide for targeting PD-1 expression. Palmitoylation promoted the trafficking of PD-1 to recycling endosome, thus preventing its lysosome-dependent degradation. Palmitoylation was required for the activation of PD-1 downstream signaling, and targeting palmitoylation by pharmacological inhibitor or depleting the modification enzyme caused significant anti-tumor effects. A peptide was designed to competitively inhibit PD-1 palmitoylation and expression, opening a new route for developing PD-1 inhibitors as a strategy for cancer immunotherapy.\n\nSignificanceWe show for the first time that PD-1 is palmitoylated, identify DHHC9 as the predominant enzyme for its palmitoylation, and reveal the molecular mechanisms underlying its effects on PD-1 stability and functions. Importantly, we also designed a competitive inhibitor targeting PD-1 palmitoylation, and this first-in-class molecule may inspire the development of new checkpoint inhibitors.

cancer biology↗

bioRxiv2019

Direct Comparative Analysis of 10X Genomics Chromium and Smart-seq2

Single cell RNA sequencing (scRNA-seq) is widely used for profiling transcriptomes of individual cells. The droplet-based 10X Genomics Chromium (10X) approach and the plate-based Smart-seq2 full-length method are two frequently-used scRNA-seq platforms, yet there are only a few thorough and systematic comparisons of their advantages and limitations. Here, by directly comparing the scRNA-seq data by the two platforms from the same samples of CD45-cells, we systematically evaluated their features using a wide spectrum of analysis. Smart-seq2 detected more genes in a cell, especially low abundance transcripts as well as alternatively spliced transcripts, but captured higher proportion of mitochondrial genes. The composite of Smart-seq2 data also resembled bulk RNA-seq data better. For 10X-based data, we observed higher noise for mRNA in the low expression level. Despite the poly(A) enrichment, approximately 10-30% of all detected transcripts by both platforms were from non-coding genes, with lncRNA accounting for a higher proportion in 10X. 10X-based data displayed more severe dropout problem, especially for genes with lower expression levels. However, 10X-data can better detect rare cell types given its ability to cover a large number of cells. In addition, each platform detected different sets of differentially expressed genes between cell clusters, indicating the complementary nature of these technologies. Our comprehensive benchmark analysis offers the basis for selecting the optimal scRNA-seq strategy based on the objectives of each study.

bioinformatics↗

bioRxiv2019

Coupling multiplex pre-amplification and droplet digital PCR for longitudinal monitoring of ESR1 and PIK3CA mutations from plasma cell-free DNA

Here we report on the development of a sensitive and cost-effective method to longitudinally track ESR1 and PIK3CA mutations from cfDNA in patients with metastatic breast cancer (MBC) using a streamlined and de-centralized workflow. Hotspot mutations in ESR1 have been shown to cause resistance to aromatase inhibitor-based and anti-estrogenic therapies, while PIK3CA mutations have high prevalence in MBC. As a result, their utility as circulating biomarkers to predict or monitor response in the clinical development of investigational compounds has been the focus of many studies. Six regions in ESR1 and PIK3CA genes containing 20 hotspot mutations were pre-amplified, followed by optimized singleplex ddPCR assays to detect allele frequencies of individual mutations. Without pre-amplification, the limit of detection (LOD) and limit of linearity (LOL) of individual ddPCR assays were at 0.05-0.1% and 0.25% level, respectively. With pre-amplification, the LOD and LOL were slightly elevated at 0.1-0.25% and 0.25-0.5% levels, respectively. High concordance was achieved to the BEAMing assay (Sysmex Inostics) for mutation positive assays (r=0.98, P<0.0001). In conclusion, coupling pre-amplification and ddPCR assays allowed us for the detection of up to 20 hot spot mutations in ESR1 and PIK3CA with high sensitivity and reproducibility.

genetics↗

bioRxiv2019

RUNX1 safeguards the identity of the fetal ovary through an interplay with FOXL2

Sex determination of the gonads begins with fate specification of gonadal supporting cells into either ovarian granulosa cells or testicular Sertoli cells. This process of fate specification hinges on a balance of transcriptional control. We discovered that expression of the transcription factor RUNX1 is enriched in the fetal ovary in rainbow trout, turtle, mouse, goat and human. In the mouse, RUNX1 marks the supporting cell lineage and becomes granulosa cell-specific as the gonads differentiate. RUNX1 plays complementary/redundant roles with FOXL2 to maintain fetal granulosa cell identity, and combined loss of RUNX1 and FOXL2 results in masculinization of the fetal ovaries. At the chromatin level, RUNX1 occupancy overlaps partially with FOXL2 occupancy in the fetal ovary, suggesting that RUNX1 and FOXL2 target a common set of genes. These findings identify RUNX1, with an ovary-biased pattern conserved across species, as a novel regulator in securing the identity of ovarian supporting cells and the ovary.

developmental biology↗

bioRxiv2019

Whole genome base-wise aggregation and functional prediction for human non-coding regulatory variants

Predicting the functional or pathogenic regulatory variants in the human non-coding genome facilitates the interpretation of disease causation. While numerous prediction methods are available, their performance is inconsistent or restricted to specific tasks, which raises the demand of developing comprehensive integration for those methods. Here, we compile whole genome base-wise aggregations, regBase, that incorporate largest prediction scores. Building on different assumptions of causality, we train three composite models to score functional, pathogenic and cancer driver non-coding regulatory variants respectively. We demonstrate the superior and stable performance of our models using independent benchmarks and show great success to fine-map causal regulatory variants. We believe that regBase database together with three composite models will be useful in different areas of human genetic studies, such as annotation-based casual variant fine-mapping, pathogenic variant discovery as well as cancer driver mutation identification. regBase is freely available at https://github.com/mulinlab/regBase.

genomics↗

bioRxiv2018

Convergent recruitment of life cycle regulators to direct sporophyte development in two eukaryotic supergroups

Three amino acid loop extension homeodomain transcription factors (TALE HD TFs) act as life cycle regulators in green algae and land plants. In mosses these regulators are required for the deployment of the sporophyte developmental program. We demonstrate that mutations in either of two TALE HD TF genes, OUROBOROS or SAMSARA, in the brown alga Ectocarpus result in conversion of the sporophyte generation into a gametophyte. The OUROBOROS and SAMSARA proteins heterodimerise in a similar manner to TALE HD TF life cycle regulators in the green lineage. These observations demonstrate that TALE-HD-TF-based life cycle regulation systems have an extremely ancient origin, and that these systems have been independently recruited to regulate sporophyte developmental programs in at least two different complex multicellular eukaryotic supergroups, Archaeplastida and Chromalveolata.

plant biology↗

bioRxiv2018

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

The sarcomatoid variant of urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARCs and 84 cases of conventional urothelial carcinomas (UCs), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs showed a distinct mutational landscape with enrichment of TP53, RB1, and PIK3CA mutations. They were related to the basal molecular subtype of conventional UCs and could be divided into epithelial/basal and more clinically aggressive mesenchymal subsets based on TP63 and its target genes expression levels. Other analyses revealed that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of cell cycle and EMT networks, and nearly half exhibited a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.

genomics↗