Biology subjects

Yu, T.

Publications and source records attributed to Yu, T..

At least 109 records · Page 6Linked to original sources

bioRxiv2021

Profiling tumor immune microenvironment of non-small cell lung cancer using multiplex immunofluorescence

PurposeWe attempt to profile the tumor immune microenvironment (TIME) of non-small cell lung cancer (NSCLC) by multiplex immunofluorescence (MIF). Experimental DesignMIF test was performed on 681 NSCLC cases in our center between 2009 and 2011. The number, density, proportion and correlation of 26 types of immune cells in tumor nest and tumor stroma were evaluated. An unsupervised consensus clustering approach was utilized to identify robust clusters of patients. Immune-related risk score (IRRS) was constructed for prognosis prediction for disease-free survival (DFS). ResultsThe landscape of TIME was illustrated, revealing some close interactions particularly between intrastromal neutrophils and intratumoral regulatory T cells (Treg) (r2 = 0.439, P < 0.001), intrastromal CD4+CD38+ T cells and intrastromal CD20-positive B cells (r2 = 0.539, P < 0.001), and intratumoral CD8-positive T cells and intratumoral M2 macrophages expressing PD-L1 (r2 = 0.339, P < 0.001). Three immune subtypes correlated with distinct immune characteristics and clinical outcomes were identified. The immune-activated subtype had the longest DFS and demonstrated the highest infiltration of CD4-positive T cells and CD20-positive B cells. The immune-defected subtype had the highest levels of cancer stem cells and macrophages. The immune-exempted subtype had the highest levels of neutrophils and Treg. The IRRS based on six robust prognostic biomarkers showed potential ability for risk stratification (high vs. median vs. low) and prediction of five-year DFS rates (43.1% vs. 37.9% vs. 23.2%, P<0.001). ConclusionsOur study profiled the intricate and intrinsic structure of TIME in NSCLC, which showed potency in subtyping and prognostication. Translational RelevanceSignificant unmet need exists in understanding the tumor immune microenvironment (TIME) of non-small cell lung cancer (NSCLC) and its correlation with prognosis. In this retrospective cohort study (n = 681), we profiled the immune landscape of NSCLC in situ and identified a novel stratification of TIME by three immune subtypes: immune-activated, immune-exempted, and immune-defected using multiplex immunofluorescence for testing 26 kinds of immune cells. Each of the immune subtypes was correlated with distinct composition, spatial distribution, and functional orientation of immune cells, and accordingly indicating significantly different disease-free survival (DFS). Close interactions were observed for several kinds of immune cells, including neutrophils and regulatory T cells, CD4+CD38+ T cells and CD20-positive B cells, and CD8-positive T cells and M2 macrophages. We also developed the immune-related risk score (IRRS) with different immune characteristics based on six robust immune biomarkers in TIME and evaluated its role in risk stratification and prognosis prediction of DFS. This study might bring potential clinical implementations for the design of novel immunotherapies and the optimization of combined strategies.

cancer biology↗

bioRxiv2021

The testis-specific transcription factor TCFL5 responds to A MYBto elaborate the male meiotic program in placental mammals

In male mice, the transcription factor (TF) A-MYB initiates reprogramming of gene expression after spermatogonia enter meiosis. We report that A-MYB activates Tcfl5, a testis-specific TF first produced in pachytene spermatocytes. Subsequently, A-MYB and TCFL5 reciprocally reinforce their own transcription to establish an extensive circuit that regulates meiosis. TCFL5 promotes transcription of genes required for mRNA turnover, pachytene piRNA production, meiotic exit, and spermiogenesis. This transcriptional architecture is conserved in rhesus macaque, suggesting TCFL5 plays a central role in meiosis and spermiogenesis in placental mammals. Tcfl5em1/em1 mutants are sterile, and spermatogenesis arrests at the mid- or late-pachytene stage of meiosis.

genetics↗

bioRxiv2021

Cell-to-cell and type-to-type heterogeneity of signaling networks: Insights from the crowd

Recent technological developments allow us to measure the status of dozens of proteins in individual cells. This opens the way to understand the heterogeneity of complex multi-signaling networks across cells and cell-types, with important implications to understand and treat diseases such as cancer. These technologies are however limited to proteins for which antibodies are available and are fairly costly, making predictions of new markers and of existing markers under new conditions a valuable alternative. To assess our capacity to make such predictions and boost further methodological development, we organised the Single Cell Signaling in Breast Cancer DREAM challenge. We used a mass cytometry data set, covering 36 markers in over 4,000 conditions totalling 80 million single cells across 67 breast cancer cell lines. Through four increasingly difficult subchallenges, the participants predicted missing markers, new conditions, and the time course response of single cells to stimuli in the presence and absence of kinase inhibitors. The challenge results show that despite the stochastic nature of signal transduction in single cells, the signaling events are tightly controlled and machine learning methods can accurately predict new experimental data. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=58 SRC="FIGDIR/small/436603v2_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@a95337org.highwire.dtl.DTLVardef@966d5aorg.highwire.dtl.DTLVardef@1e55b18org.highwire.dtl.DTLVardef@bfb5d7_HPS_FORMAT_FIGEXP M_FIG C_FIG Key pointsO_LIOver 80 million single-cell multiplexed measurements across 67 cell lines, 54 conditions and 10 time points to benchmark predictive models of single cell signaling C_LIO_LI73 approaches from 27 teams for predicting response to kinase inhibitors on single cell level, and dynamic response from unperturbed basal omics data C_LIO_LIPredictions of single marker models correlate with measurements with a correlation coefficient of 0.76 C_LIO_LITop models of whole signaling response models perform almost as well as a biological replicate C_LIO_LICell-line specific variation in dynamics can be predicted from basal omics C_LI

bioinformatics↗

bioRxiv2021

ACE: Explaining cluster from an adversarial perspective

A common workflow in single-cell RNA-seq analysis is to project the data to a latent space, cluster the cells in that space, and identify sets of marker genes that explain the differences among the discovered clusters. A primary drawback to this three-step procedure is that each step is carried out independently, thereby neglecting the effects of the nonlinear embedding and inter-gene dependencies on the selection of marker genes. Here we propose an integrated deep learning framework, Adversarial Clustering Explanation (ACE), that bundles all three steps into a single work-flow. The method thus moves away from the notion of "marker genes" to instead identify a panel of explanatory genes. This panel may include genes that are not only enriched but also depleted relative to other cell types, as well as genes that exhibit differences between closely related cell types. Empirically, we demonstrate that ACE is able to identify gene panels that are both highly discriminative and nonredundant, and we demonstrate the applicability of ACE to an image recognition task. 1

bioinformatics↗

bioRxiv2021

Neural mechanisms underlying regulation of empathy and altruism by beliefs of others' pain

Perceived cues signaling others pain induce empathy that in turn motivates altruistic behavior toward those who appear suffering. This perception-emotion-behavior reactivity is the core of human altruism but does not always occur in real life situations. Here, by integrating behavioral and multimodal neuroimaging measures, we investigate neural mechanisms underlying the functional role of beliefs of others pain in modulating empathy and altruism. We show evidence that decreasing (or enhancing) beliefs of others pain reduces (or increases) subjective estimation of others painful emotional states and monetary donations to those who show pain expressions. Moreover, decreasing beliefs of others pain attenuates neural responses to perceived cues signaling others pain within 200 ms after stimulus onset and modulate neural responses to others pain in the frontal cortices and temporoparietal junction. Our findings highlight beliefs of others pain as a fundamental cognitive basis of human empathy and altruism and unravel the intermediate neural architecture.

evolutionary biology↗

bioRxiv2021

20-HETE-promoted cerebral blow flow autoregulation is associated with enhanced α-smooth muscle actin positive cerebrovascular pericyte contractility

We previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response and autoregulation of cerebral blood flow (CBF) in rats. The present study demonstrated that CYP4A was coexpressed with alpha-smooth muscle actin (-SMA) in vascular smooth muscle cells (VSMCs) and most pericytes along parenchymal arteries (PAs) isolated from SD rats. Cell contractile capabilities of cerebral VSMCs and pericytes were reduced with a 20-HETE synthesis inhibitor, N-Hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016) but restored with 20-HETE analog 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (WIT003). Similarly, intact myogenic responses of the middle cerebral artery and PA of SD rats decreased with HET0016 and rescued by WIT003. Lastly, HET0016 impaired well autoregulated CBF in the surface and deep cortex of SD rats. These results demonstrate that 20-HETE has a direct effect on cerebral mural cell contractility that may play an essential role in CBF autoregulation.

pharmacology and toxicology↗

bioRxiv2020

Photostimulation of lymphatic clearance of red blood cells from the mouse brain after intraventricular hemorrhage

Intraventricular hemorrhage (IVH) is the most fatal form of brain injury, yet a therapy directed at ameliorating intraventricular clot is very limited. There is accumulating evidence that an augmentation of the meningeal lymphatic (MLVs) functions might be a promising therapeutic target for IVH. In particular, the photostimulation (PS) of MLVs could be promising for non-invasive therapy of IVH via PS of clearance of red blood cells (RBCs) from the brain via MLVs. Indeed, we uncover that PS has therapeutic effects on IVH in mice reducing the mortality, improving the emotional status, accelerating the RBCs evacuation from the ventricles and increasing the ICP recovery. Our findings strongly suggest that the PS-mediated stimulation of drainage and clearing functions of MLVs can be a novel bedside, readily applicable and commercially viable technologies for treatment of IVH. These pilot results open new horizons in a non-invasive therapy of IVH via PS stimulation of regenerative lymphatic mechanisms.

neuroscience↗

bioRxiv2020

A C. elegans neuron both promotes and suppresses motor behavior to fine tune motor output

How neural circuits drive behavior is a central question in neuroscience. Proper execution of motor behavior requires the precise coordination of many neurons. Within a motor circuit, individual neurons tend to play discrete roles by promoting or suppressing motor output. How exactly neurons function in specific roles to fine tune motor output is not well understood. In C. elegans, the interneuron RIM plays important yet complex roles in locomotion behavior. Here, we show that RIM both promotes and suppresses distinct features of locomotion behavior to fine tune motor output. This dual function is achieved via the excitation and inhibition of the same motor circuit by electrical and chemical neurotransmission, respectively. Additionally, this bi-directional regulation contributes to motor adaptation in animals placed in novel environments. Our findings reveal that individual neurons within a neural circuit may act in opposing ways to regulate circuit dynamics to fine tune behavioral output.

neuroscience↗

bioRxiv2020

Maternal transmission of a paramutant phenotype requires intact DNMT2 functions in the male germline

INTRODUCTION Abstract INTRODUCTION Results DISCUSSION METHODS AND MATERIALS SUPPLEMENTARY MATERIALS Funding Author contributions Competing interests Data and materials availability Supplemental Figures REFERENCES DNA methylation, as a major epigenetic modification in the genome of higher eukaryotes, is catalyzed by DNA methyltransferase enzymes (DNMTs) by addition of a methyl group to the 5th carbon position of cytosine, resulting 5-methylcytosine (5mC) (1, 2). DNMT1 is the most abundant DNA methyltransferase in mammalian cells, and mainly methylate hemi-methylated CpG dinucleotides as a maintenance methyltransferase, although DNMT1 has also been ...

genetics↗

bioRxiv2020

Tractography dissection variability: what happens when 42 groups dissect 14 white matter bundles on the same dataset?

White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process.

neuroscience↗

bioRxiv2020

BATHYARCHAEOTA OCCURRENCE IN SHALLOW MARINE METHANE-RICH SEDIMENTS (SACO DO MAMANGUA, RIO DE JANEIRO, BRAZIL)

Methane gas (CH4) reservoirs have previously been reported in tropical marine sediments of Saco do Mamangua ria (Rio de Janeiro, Brazil). It is known that a methane microbiome can be established in methane seeps sites; however, they are still poorly characterised. In this study, we aimed to investigate the spatial and vertical distribution of the bacterial and archaeal composition and the community structure in the sediments of Saco do Mamangua ria. For this purpose, we collected sediment samples through 100 cm long gravity corer at three different sites and performed community analysis based on 16S rRNA gene sequencing, quantification of the methyl coenzyme M reductase-encoding gene (mcrA) and geochemical analysis, including CH4 stable isotope. Our results revealed a biogenic trend for CH4 isotopic signature and a high proportion of archaeal sequences assigned as Bathyarchaeota, with a spatial distribution throughout the inner areas of the channel and the deepest strata. OTUs classified within Bathyarchaeota and Chloroflexi (Dehalococcoidia) showed positive correlation with methane concentrations, sediment depth and oxidation-reduction potential. Due to their prevalence in the microbial community, we also performed phylogenetic analysis to understand the closeness of our Bathyarchaeota OTUs with Bathyarchaeota subgroups, and the results demonstrated a close relationship particularly with Bathy-8 and Bathy-13, which possess genes for acetogenesis and methanogenesis. Although direct relations between microbial populations and the biogenic methane emissions in Saco do Mamangua cannot be assured, our results emphasize the importance of further investigations about the potential role of Bathyarchaeota in the carbon cycling in methane-rich tropical shallow ecosystems.

microbiology↗

bioRxiv2020

Genome-wide association study of TP53 R249S mutation in hepatocellular carcinoma with aflatoxin B1 exposure and hepatitis B virus infection in Guangxi

Background/AimsDietary aflatoxin B1 (AFB1) exposure, which induces DNA damage and codon 249 mutation of the TP53 gene, is one of the major risk factors for hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) infection and AFB1 exert synergistic effects to promote carcinogenesis and TP53 R249S mutation in HCC. MethodsA genome-wide association study (GWAS) was conducted on 485 cases of HCC with chronic HBV infection, followed by a two-stage replication study on 270 cases with chronic HBV infection. Susceptibility variants for the TP53 R249S mutation in HCC were identified based on both GWAS and replication analysis. The associations of identified variants with expression levels of their located genes were validated in 20 paired independent samples. ResultsOur results showed that TP53 R249S was significantly associated with ADAMTS18 rs9930984 (adjusted P = 4.84x10-6), WDR49 rs75218075 (adjusted P = 7.36 x 10-5) and SLC8A3 rs8022091 (adjusted P = 0.042). Additionally, ADAMTS18 mRNA expression was significantly higher in HCC tissue, compared with paired non-tumor tissue (P = 0.041) and patients carrying the TT genotype at rs9930984 showed lower ADAMTS18 expression in non-tumor tissue, compared with those carrying the GT genotype (P = 0.0028). ConclusionsTP53 expression is significantly associated with R249S mutation in HCC. Our collective results suggest that rs9930984, rs75218075 and rs8022091 are associated with susceptibility to the R249S mutation in cases of HCC exposed to AFB1 and HBV infection.

genetics↗

bioRxiv2020

DreamAI: algorithm for the imputation of proteomics data

Deep proteomics profiling using labeled LC-MS/MS experiments has been proven to be powerful to study complex diseases. However, due to the dynamic nature of the discovery mass spectrometry, the generated data contain a substantial fraction of missing values. This poses great challenges for data analyses, as many tools, especially those for high dimensional data, cannot deal with missing values directly. To address this problem, the NCI-CPTAC Proteogenomics DREAM Challenge was carried out to develop effective imputation algorithms for labeled LC-MS/MS proteomics data through crowd learning. The final resulting algorithm, DreamAI, is based on an ensemble of six different imputation methods. The imputation accuracy of DreamAI, as measured by Pearson correlation, is about 15%-50% greater than existing tools among less abundant proteins, which are more vulnerable to be missed in proteomics data sets. This new tool notably enhances data analysis capabilities in proteomics research.

bioinformatics↗

bioRxiv2020

Regional Differences in the Ghrelin-Growth Hormone Secretagogue Receptor Signalling System in Human Heart Disease

The hormone ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR) are expressed in myocardium. GHSR binding activates signalling pathways coupled to cardiomyocyte survival and contractility. These properties have made the ghrelin-GHSR axis a candidate for a biomarker of cardiac function. The dynamics of ghrelin-GHSR are altered significantly in late stages of heart failure and cardiomyopathy, when left ventricular (LV) function is failing. We examined the relationship of GHSR with ghrelin in cardiac tissue from patients with valvular disease with no detectable changes in LV function. Biopsy samples from the LV and left atrium (LA) were obtained from 25 patients with valvular disease (of whom 13 also had coronary artery disease) and preserved LV ejection fraction, and compared control samples obtained via autopsy. Using quantitative confocal fluorescence microscopy, levels of GHSR were determined using a fluorescent peptide analog of ghrelin, Cy5-ghrelin(1-19); ghrelin, the heart failure marker natriuretic peptide type-b (BNP), and contractility marker sarcoplasmic reticulum ATPase pump (SERCA2a) were measured by immunofluorescence. A positive correlation between GHSR and ghrelin was apparent in only diseased tissue. Ghrelin and BNP significantly correlated in the LV and strongly co-localized to the same intracellular compartment in both diseased and control tissue. GHSR, ghrelin and BNP all strongly and significantly correlated with SERCA2a in the LV of diseased tissue only. Our results suggest that the dynamics of the myocardial ghrelin/GHSR axis is altered in cardiovascular disease in the absence of measurable changes in heart function, and may accompany a regional shift in endocrine programming.

molecular biology↗

bioRxiv2020

Crowdsourcing assessment of maternal blood multi-omics for predicting gestational age and preterm birth

Identification of pregnancies at risk of preterm birth (PTB), the leading cause of newborn deaths, remains challenging given the syndromic nature of the disease. We report a longitudinal multi-omics study coupled with a DREAM challenge to develop predictive models of PTB. We found that whole blood gene expression predicts ultrasound-based gestational ages in normal and complicated pregnancies (r=0.83), as well as the delivery date in normal pregnancies (r=0.86), with an accuracy comparable to ultrasound. However, unlike the latter, transcriptomic data collected at <37 weeks of gestation predicted the delivery date of one third of spontaneous (sPTB) cases within 2 weeks of the actual date. Based on samples collected before 33 weeks in asymptomatic women we found expression changes preceding preterm prelabor rupture of the membranes that were consistent across time points and cohorts, involving, among others, leukocyte-mediated immunity. Plasma proteomic random forests predicted sPTB with higher accuracy and earlier in pregnancy than whole blood transcriptomic models (e.g. AUROC=0.76 vs. AUROC=0.6 at 27-33 weeks of gestation).

bioinformatics↗

bioRxiv2020

Network-enabled efficient image restoration for 3D microscopy of turbid biological specimens

Though three-dimensional (3D) fluorescence microscopy has been an essential tool for modern life science research, the light scattering by biological specimens fundamentally prevents its more widespread applications in live imaging. We hereby report a deep-learning approach, termed ScatNet, that enables reversion of 3D fluorescence microscopy from high-resolution targets to low-quality, light-scattered measurements, thereby allowing restoration for a single blurred and light-scattered 3D image of deep tissue, with achieving improved resolution and signal-to-noise ratio. Our approach can computationally extend the imaging depth for current 3D fluorescence microscopes, without the addition of complicated optics. Combining ScatNet approach with cutting-edge light-sheet fluorescence microscopy, we demonstrate that the image restoration of cell nuclei in the deep layer of live Drosophila melanogaster embryos at single-cell resolution. Applying our approach to two-photon excitation microscopy, we could improve the signal and resolution of neurons in mouse brain beyond the photon ballistic region.

bioengineering↗

bioRxiv2020

Molecular basis of ubiquitination catalyzed by the bacterial transglutaminase MavC

The Legionella pneumophila effector MavC is a transglutaminase that carries out atypical ubiquitination of the ubiquitin (Ub) E2 conjugation enzyme UBE2N by catalyzing the formation of an isopeptide bond between Gln40 of Ub and Lys92 (or to a less extent, Lys94) of UBE2N, which results in inhibition of UBE2N signaling in the NF-{kappa}B pathway. In the absence of UBE2N, MavC deamidates Ub at Gln40 or catalyzes self-ubiquitination. However, the mechanisms underlying these enzymatic activities of MavC are not fully understood at molecular level. In this study, we obtained the structure of the MavC-UBE2N-Ub ternary complex that represents a snapshot of covalent cross-linking of UBE2N and Ub catalyzed by MavC. The structure reveals the unique way by which the cross-linked catalytic product UBE2N-Ub binds mainly to the Insertion and the Tail domains of MavC prior to its release. Based on our structural, biochemical and mutational analyses, we proposed the catalytic mechanism for both the deamidase and the transglutaminase activities of MavC. Finally, by comparing the structures of MavC and MvcA, the homologous protein that reverses MavC-induced UBE2N ubiquitination, we identified several key regions of the two proteins responsible for their opposite enzymatic activity. Our results provide insights into the mechanisms for substrate recognition and ubiquitination mediated by MavC as well as explanations for the opposite activity of MavC and MvcA.

microbiology↗

bioRxiv2020

A single-cell analysis of the molecular lineage of chordate embryogenesis

In multicellular organisms, a single zygote develops along divergent lineages to produce distinct cell types. What governs these processes is central to the understanding of cell fate specification and stem cell engineering. Here we used the protochordate model Ciona savignyi to determine gene expression profiles of every cell of single embryos from fertilization through the onset of gastrulation and provided a comprehensive map of chordate early embryonic lineage specification. We identified 47 cell types across 8 developmental stages up to the 110-cell stage in wild type embryos and 8 fate transformations at the 64-cell stage upon FGF-MAPK inhibition. The identities of all cell types were evidenced by in situ expression pattern of marker genes and expected number of cells based on the invariant lineage. We found that, for the majority of asymmetrical cell divisions, the bipotent mother cell shows predominantly the gene signature of one of the daughter fates, with the other daughter being induced by subsequent signaling. Our data further indicated that the asymmetric segregation of mitochondria in some of these divisions does not depend on the concurrent fate inducing FGF-MAPK signaling. In the notochord, which is an evolutionary novelty of chordates, the convergence of cell fate from two disparate lineages revealed modular structure in the gene regulatory network beyond the known master regulator T/Brachyury. Comparison to single cell transcriptomes of the early mouse embryo showed a clear match of cell types at the tissue level and supported the hypothesis of developmental-genetic toolkit. This study provides a high-resolution single cell dataset to understand chordate embryogenesis and the relationship between fate trajectories and the cell lineage. HighlightsO_LITranscriptome profiles of 47 cell types across 8 stages in early chordate embryo C_LIO_LIBipotent mother in asymmetric division shows the default daughter fate C_LIO_LIModular structure of the notochord GRN beyond the known function of T C_LIO_LIInvariant lineage and manual cell isolation provide truth to trajectory analysis C_LI

developmental biology↗