Biology subjects

He, Z.

Publications and source records attributed to He, Z..

At least 217 records · Page 12Linked to original sources

bioRxiv2021

Summary statistics knockoff inference empowers identification of putative causal variants in genome-wide association studies

Recent advances in genome sequencing and imputation technologies provide an exciting opportunity to comprehensively study the contribution of genetic variants to complex phenotypes. However, our ability to translate genetic discoveries into mechanistic insights remains limited at this point. In this paper, we propose an efficient knockoff-based method, GhostKnockoff, for genome-wide association studies (GWAS) that leads to improved power and ability to prioritize putative causal variants relative to conventional GWAS approaches. The method requires only Z-scores from conventional GWAS and hence can be easily applied to enhance existing and future studies. The method can also be applied to meta-analysis of multiple GWAS allowing for arbitrary sample overlap. We demonstrate its performance using empirical simulations and two applications: (1) analysis of 1,403 binary phenotypes from the UK Biobank data in 408,961 samples of European ancestry, and (2) a meta-analysis for Alzheimers disease (AD) comprising nine overlapping large-scale GWAS, whole-exome and whole-genome sequencing studies. The UK Biobank analysis demonstrates superior performance of the proposed method compared to conventional GWAS in both statistical power (2.05-fold more discoveries) and localization of putative causal variants at each locus (46% less proxy variants due to linkage disequilibrium). The AD meta-analysis identified 55 risk loci (including 31 new loci) with ~70% of the proximal genes at these loci showing suggestive signal in downstream single-cell transcriptomic analyses. Our results demonstrate that GhostKnockoff can identify putatively functional variants with weaker statistical effects that are missed by conventional association tests.

genetics↗

bioRxiv2021

Two decades of suspect evidence for adaptive molecular evolution - Negative selection confounding positive selection signals

There is a large literature in the last two decades affirming adaptive DNA sequences evolution between species. The main lines of evidence are from i) the McDonald-Kreitman (MK) test, which compares divergence and polymorphism data, and ii) the PAML test, which analyzes multi-species divergence data. Here, we apply these two tests concurrently on the genomic data of Drosophila and Arabidopsis. To our surprise, the >100 genes identified by the two tests do not overlap beyond random expectation. Because the non-concordance could be due to low powers leading to high false-negatives, we merge every 20 - 30 genes into a "supergene". At the supergene level, the power of detection is large but the calls still do not overlap. We rule out methodological reasons for the non-concordance. In particular, extensive simulations fail to find scenarios whereby positive selection can only be detected by either MK or PAML, but not both. Since molecular evolution is governed by positive and negative selection concurrently, a fundamental assumption for estimating one (say, positive selection) is that the other is constant. However, in a broad survey of primates, birds, Drosophila and Arabidopsis, we found that negative selection rarely stays constant for long in evolution. As a consequence, the variation in negative selection is often mis-construed as signals of positive selection. In conclusion, MK, PAML or any method that examines genomic sequence evolution has to explicitly address the variation in negative selection before estimating positive selection. In a companion study, we propose a possible path forward in two stages - first, by mapping out the changes in negative selection and then using this map to estimate positive selection. For now, the large literature on positive selection between species has to await the re-assessment.

evolutionary biology↗

bioRxiv2021

Sieve tube structural variation in Austrobaileya scandens and its significance for lianescence

Lianas are characterized by large leaf areas and slender stems, a combination of features that require an efficient vascular system. The only extant member of the Austrobaileyaceae, is an endemic twining liana of the tropical Australian forests with well-known xylem hydraulic traits. However, the vascular phloem continuum through aerial organs remains understudied. We analyzed the structure of phloem conduits across leaf veins and stems of A. scandens, combining topological data obtained through light and electron microscopy, with current models of phloem transport. Leaves displayed a low xylem to phloem ratio compared with leaves of other angiosperms, with vascular elements invariant in diameter along the midrib, but tapered across vein hierarchies. Sieve plate pore radii were extremely small: 0.08 {micro}m in minor veins, increasing to 0.12{micro}m in the petiole and only to 0.20{micro}m at the base of the stem, tens of meters away. Searcher branches contained tube shaped phloem conduits with a pectin-rich wall, whereas twining stems displayed sieve elements with tangential connections that displayed a greater fraction of the tubes populated with an astonishing number of sieve plates. Hydraulic segmentation of the leaves in Austrobaileyaceae correlate with vesseless leaves that benefit photoassimilate export through volumetric scaling of the sieve tube elements. Yet, compared with canopy dominant trees, the geometrical properties of the sieve tube in twining stems, restrict considerably energy distribution in the sub-canopy layers, potentially favoring the allocation of assimilates toward the elongating branches. Thus, the conductive xylem of twining stems contrasts with a poorly conductive phloem that meets the mechanical constraints of lianescence.

plant biology↗

bioRxiv2021

Mapping of single-cell landscape of acral melanoma and analysis of molecular regulatory network of tumor microenvironment

Melanoma is a type of skin malignant tumor with high invasiveness, high metastasis, and poor prognosis. The incidence of melanoma continues to increase. Among them, the subtype of acral melanoma (AM) is more common in Asian populations. AM has higher degree, low immunotherapy response rate. With the help of single-cell sequencing technology provides new technical means for tumor microenvironment research, so that we can more easily explore specific tumor types suitable immunotherapy targets. However, no complete single-cell level differentiation map exists for the AM tumor microenvironment (TME). In this study, we used AM related sample and used the 10x Genomics single-cell transcriptome platform to draw a specific single-cell map of AM, understand the cell composition of AM, and analyze the interaction and molecular regulation of AM TME. Nine cell types were identified, of which malignant cells accounted for the largest proportion, followed by fibroblasts. And the cell interaction network shows that malignant cells, macrophages, B, T and fibroblasts play an important role in AM TME. Our research provides systematic theoretical guidance for the diagnosis and treatment of acral melanoma.

genomics↗

bioRxiv2021

Inferring and perturbing cell fate regulomes in human cerebral organoids

Self-organizing cerebral organoids grown from pluripotent stem cells combined with single-cell genomic technologies provide opportunities to explore gene regulatory networks (GRNs) underlying human brain development. Here we acquire single-cell transcriptome and accessible chromatin profiling data over a dense time course covering multiple phases of organoid development including neuroepithelial formation, patterning, brain regionalization, and neurogenesis. We identify temporally dynamic and brain region-specific regulatory regions, and cell interaction analysis reveals emergent patterning centers associated with regionalization. We develop Pando, a flexible linear model-based framework that incorporates multi-omic data and transcription binding site predictions to infer a global GRN describing organoid development. We use pooled genetic perturbation with single-cell transcriptome readout to assess transcription factor requirement for cell fate and state regulation in organoid. We find that certain factors regulate the abundance of cell fates, whereas other factors impact neuronal cell states after differentiation. We show that the zinc finger protein GLI3 is required for cortical fate establishment in humans, recapitulating previous work performed in mammalian model systems. We measure transcriptome and chromatin accessibility in normal or GLI3-perturbed cells and identify a regulome central to the dorsoventral telencephalic fate decision. This regulome suggests that Notch effectors HES4/5 are direct GLI3 targets, which together coordinate cortex and ganglionic eminence diversification. Altogether, we provide a framework for how multi-brain region model systems and single-cell technologies can be leveraged to reconstruct human brain developmental biology.

developmental biology↗

bioRxiv2021

MetaLogo: a generator and aligner for multiple sequence logos

Sequence logos are used to visually display conservations and variations in short sequences. They can indicate the fixed patterns or conserved motifs in a batch of DNA or protein sequences. However, most of the popular sequence logo generators are based on the assumption that all the input sequences are from the same homologous group, which will lead to an overlook of the heterogeneity among the sequences during the sequence logo making process. Heterogeneous groups of sequences may represent clades of different evolutionary origins, or genes families with different functions. Therefore, it is essential to divide the sequences into different phylogenetic or functional groups to reveal their specific sequence motifs and conservation patterns. To solve these problems, we developed MetaLogo, which can automatically cluster the input sequences after multiple sequence alignment and phylogenetic tree construction, and then output sequence logos for multiple groups and aligned them in one figure. User-defined grouping is also supported by MetaLogo to allow users to investigate functional motifs in a more delicate and dynamic perspective. MetaLogo can highlight both the homologous and nonhomologous sites among sequences. MetaLogo can also be used to annotate the evolutionary positions and gene functions of unknown sequences, together with their local sequence characteristics. We provide users a public MetaLogo web server (http://metalogo.omicsnet.org), a standalone Python package (https://github.com/labomics/MetaLogo), and also a built-in web server available for local deployment. Using MetaLogo, users can draw informative, customized and publishable sequence logos without any programming experience to present and investigate new knowledge on specific sequence sets.

bioinformatics↗

bioRxiv2021

Construction of competing endogenous RNA interaction networks as prognostic markers in metastatic melanoma

Malignant melanoma (MM) is a highly aggressive, metastatic cancer originating from melanocytes. These tumors have an extremely poor prognosis. MM accounts for 4% of skin cancers with an 80% mortality rate. The median survival of patients with metastatic melanoma is approximately six months, with a five-year survival rate of less than 10%. In recent years, the incidence of melanoma has gradually increased and has become one of the deadliest cancers. Competitive endogenous RNA (ceRNA) models the mechanism by which long chain non-coding RNAs (lncRNAs) play a regulatory role in the disease. LncRNAs can act as a sponge, competitively attracting small RNAs (micoRNAs; miRNAs) and interfering with miRNA function. This can affect the expression of target gene messenger RNAs (mRNAs), ultimately promoting tumorigenesis and tumor progression. Bioinformatics analysis may identify potentially prognostic and therapeutically-relevant differentially expressed genes in MM, as well as lncRNAs, miRNAs and mRNAs that are interconnected through the ceRNA network. This may provide further insight into gene regulation and the prognosis of metastatic melanoma. Weighted co-expression networks were used to identify lncRNA and mRNA modules associated with the metastatic phenotype, as well as the co-expression genes contained in the modules. We used 17 lncRNAs, six miRNAs, and 11 mRNAs to construct a ceRNA interaction network with a regulatory role in patients with metastatic melanoma. The prognostic risk model was used as a sorter to classify the survival prognosis of melanoma patients. Four groups of ceRNA interaction triplets were obtained, and miR-3662 may be used in the treatment of metastatic melanoma patients. Experiments confirmed the regulating relationship and phenotype of this assumption. This study provides new targets to regulate the metastatic process, predict metastatic potential and determine that miR-3662 may be used in the treatment of melanoma.

cancer biology↗

bioRxiv2021

A new single-cell level R-index for EGFR-TKI resistance and survival prediction in LUAD

EGFR-TKIs achieved excellent efficacy in EGFR-mutated patients. Unfortunately, most patients would inevitably develop progressive disease within a median of 10 to 14 months. Predicting the resistance probability remains a challenge. Therefore, we created an R-index model trained by single-cell RNA data with the OCLR algorithm. This model can be applied to estimate the level of EGFR-TKI resistance in cell line and xenograft mice models and predict prognosis in multiple cohorts. Comparing the high and the low R-index group, we found that the glycolysis pathway and KRAS up-regulation pathway were related to resistance, and MDSC was the leading cause of immunosuppression in the tumor microenvironment. These results are consistent with previous studies indicating that the R-index provides an insight into resistance status and a new way to explore resistance mechanisms and clinical treatment by the combination of Glucose metabolism-targeted or MDSC-targeted therapies. This is the first quantification method of EGFR-TKI resistance based on single-cell sequencing data solving the problem of the mixed resistance state of tumor cells and helping explore transcriptome characteristics of drug-resistant cell populations.

bioinformatics↗

bioRxiv2021

Voxelated Bioprinting of Mechanically Robust Multiscale Porous Scaffolds for Pancreatic Islets

Three-dimensional (3D) bioprinting additively assembles bio-inks to manufacture tissue-mimicking biological constructs, but with the typical building blocks limited to one-dimensional filaments. Here, we develop a technique for the digital assembly of spherical particles (DASP), which are effectively zero-dimensional voxels - the basic unit of 3D structures. We show that DASP enables on-demand generation, deposition, and assembly of viscoelastic bio-ink droplets. We establish a phase diagram that outlines the viscoelasticity of bio-inks required for printing spherical particles of good fidelity. Moreover, we develop a strategy for engineering bio-inks with independently controllable viscoelasticity and mesh size. Using DASP, we create mechanically robust, multiscale porous scaffolds composed of interconnected yet distinguishable hydrogel particles. Finally, we demonstrate the application of the scaffolds in encapsulating human pancreatic islets for responsive insulin release. Together with the knowledge of bio-ink design, DASP might be used to engineer highly heterogeneous yet tightly organized tissue constructs for therapeutic applications. Table of ContentsA three-dimensional bioprinting technology is developed to enable on-demand generation, deposition, and assembly of viscoelastic bio-ink droplets in a biofriendly environment. A strategy is developed to independently control elasticity, viscosity, and mesh size of bio-inks. The technique allows for easy manufacturing mechanically robust multiscale porous scaffolds, which can be used to encapsulate human pancreatic islets for sustained responsive insulin release. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/449587v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@1c0f2eaorg.highwire.dtl.DTLVardef@8bf924org.highwire.dtl.DTLVardef@191bd3aorg.highwire.dtl.DTLVardef@11e5ce1_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2021

Essential role for Ggct in erythrocyte antioxidant defense

GGCT encodes {gamma}-glutamyl cyclotransferase enzyme activity, and its expression is up-regulated in various human cancers. {gamma}-glutamyl cyclotransferase enzyme activity was originally purified from human red blood cells (RBCs), however physiological function of GGCT in RBCs is still not clear. Here we reported that Ggct deletion in mouse leads to splenomegaly and progressive anemia phenotypes, due to elevated oxidative damage and shortened life span of Ggct-/- RBCs. Ggct-/- RBCs have increased reactive oxygen species (ROS), and are more sensitive to H2O2 induced damage compared to control RBCs. Glutathione (GSH) and GSH synthesis precursor L-cysteine are decreased in Ggct-/- RBCs. Our study suggests a critical function of Ggct in RBC redox balance and life span maintenance through regulating GSH metabolism.

genetics↗

bioRxiv2021

Cell atlas of the regenerating human liver after portal vein embolization

The liver has the remarkable capacity to regenerate. In the clinic, this capacity can be induced by portal vein embolization (PVE), which redirects portal blood flow resulting in liver hypertrophy in locations with increased blood supply, and atrophy of embolized segments. Here we apply single-cell and single-nucleus transcriptomics on healthy, hypertrophied, and atrophied patient-derived liver samples to explore cell states in the liver during regeneration. We first establish an atlas of cell subtypes from the healthy human liver using fresh and frozen tissues, and then compare post-PVE samples with their reference counterparts. We find that PVE alters portal-central zonation of hepatocytes and endothelial cells. Embolization upregulates expression programs associated with development, cellular adhesion and inflammation across cell types. Analysis of interlineage crosstalk revealed key roles for immune cells in modulating regenerating tissue responses. Altogether, our data provides a rich resource for understanding homeostatic mechanisms arising during human liver regeneration and degeneration.

genomics↗

bioRxiv2021

Neuronal mitochondria transport Pink1 mRNA via Synaptojanin 2 to support local mitophagy

PTEN-induced kinase 1 (PINK1) is a very short-lived protein that is required for the removal of damaged mitochondria through Parkin translocation and mitophagy. Because the short half-life of PINK1 limits its ability to be trafficked into neurites, local translation is required for this mitophagy pathway to be active far from the soma. The Pink1 transcript is associated with and cotransported with neuronal mitochondria. In concert with translation, the mitochondrial outer membrane protein Synaptojanin 2 binding protein (SYNJ2BP) and Synaptojanin 2 (SYNJ2) are required for tethering Pink1 mRNA to mitochondria via an RNA-binding domain in SYNJ2. This neuron-specific adaptation for local translation of PINK1 provides distal mitochondria with a continuous supply of PINK1 for activation of mitophagy.

neuroscience↗

bioRxiv2021

Inferring the timing and strength of natural selection and gene migration in the evolution of chicken from ancient DNA data

With the rapid growth of the number of sequenced ancient genomes, there has been increasing interest in using this new information to study past and present adaptation. Such an additional temporal component has the promise of providing improved power for the estimation of natural selection. Over the last decade, statistical approaches for detection and quantification of natural selection from ancient DNA (aDNA) data have been developed. However, most of the existing methods do not allow us to estimate the timing of natural selection along with its strength, which is key to understanding the evolution and persistence of organismal diversity. Additionally, most methods ignore the fact that natural populations are almost always structured, which can result in overestimation of the effect of natural selection. To address these issues, we introduce a novel Bayesian framework for the inference of natural selection and gene migration from aDNA data with Markov chain Monte Carlo techniques, co-estimating both timing and strength of natural selection and gene migration. Such an advance enables us to infer drivers of natural selection and gene migration by correlating genetic evolution with potential causes such as the changes in the ecological context in which an organism has evolved. The performance of our procedure is evaluated through extensive simulations, with its utility shown with an application to ancient chicken samples.

genetics↗

bioRxiv2021

Sex- and context-dependent effects of acute isolation on vocal and non-vocal social behaviors in mice

Humans are extraordinarily social, and social isolation has profound effects on our behavior, ranging from increased social motivation following short periods of social isolation to increased anti-social behaviors following long-term social isolation. Mice are frequently used as a model to understand how social isolation impacts the brain and behavior. While the effects of chronic social isolation on mouse social behavior have been well studied, much less is known about how acute isolation impacts mouse social behavior and whether these effects vary according to the sex of the mouse and the behavioral context of the social encounter. To address these questions, we characterized the effects of acute (3-day) social isolation on the vocal and non-vocal social behaviors of male and female mice during same-sex and opposite-sex social interactions. Our experiments uncovered pronounced effects of acute isolation on social interactions between female mice, while revealing more subtle effects on the social behaviors of male mice during same-sex and opposite-sex interactions. Our findings advance the study of same-sex interactions between female mice as an attractive paradigm to investigate neural mechanisms through which acute isolation enhances social motivation and promotes social behavior.

animal behavior and cognition↗

bioRxiv2021

Establishment and Resilience of Transplanted Gut Microbiota in Aged Mice

Fecal microbiota transplantation (FMT), a procedure in which fecal material is transferred from a donor to a recipient, has been increasingly used as a treatment to restore healthy gut microbiota. There is a substantial difference in the composition of gut microbiota between young and aged hosts, but little is known about whether age matching between the FMT donor and recipient affects microbiota restoration and long-term maintenance. In the present investigation, we aimed to study the establishment and resilience of transplanted gut microbiota in aged recipients. We treated naturally aged mice (20 months old) with a broad-spectrum antibiotic cocktail and monitored the restoration of gut microbiota over 8 weeks. The diversity of gut microbiota in aged mice failed to reach the baseline level via spontaneous recovery; in contrast, FMT from either (age-)matched or unmatched donors facilitated the recovery of gut microbiota diversity. The microbiota transplanted from different donors successfully established in the aged recipients and had long-term effects on the gene expression profiles of the host colon. Finally, we evaluated the long-term maintenance of transplanted microbiota via intentional disruption of gut homeostasis. We found that lack of age matching between FMT donors and recipients may decrease the resilience of transplanted gut microbiota against colonic inflammation. The results from our study systematically examining the effects of FMT on the gut homeostasis of aged hosts suggest that the compatibility between donors and recipients should be taken into account when implementing FMT.

microbiology↗

bioRxiv2021

Identification of putative causal loci in whole-genome sequencing data via knockoff statistics

The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimers Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.

genetics↗

bioRxiv2021

Platinum nanoparticles inhibit intracellular ROS generation and protect against Cold Atmospheric Plasma-induced cytotoxicity

Platinum nanoparticles (PtNPs) have been investigated for their antioxidant abilities in a range of biological and other applications. The ability to reduce off-target CAP cytotoxicity would be useful in Plasma Medicine, however, little has been published to date about the ability of PtNPs to reduce or inhibit the effects of CAP. Here we investigate whether PtNPs can protect against CAP-induced cytotoxicity in cancerous and non-cancerous cell lines. PtNPs were shown to dramatically reduce intracellular reactive species (RONS) production in human U-251 MG cells. However, RONS generation was unaffected by PtNPs in medium without cells. PtNPs protect against CAP induced mitochondrial membrane depolarization, but not cell membrane permeabilization which is a CAP-induced RONS-independent event. PtNPs act as potent intracellular scavengers of reactive species and can protect both cancerous U-251 MG cells and non-cancerous HEK293 cells against CAP induced cytotoxicity. PtNPs may be useful as a catalytic antioxidant for healthy tissue and for protecting against CAP-induced tissue damage. Graphical AbstractPtNPs are potent catalase and superoxide dismutase mimetics which makes them strong antioxidant candidates for the protection of cells against oxidative stress. CAP was generated using a Dielectric Barrier Device (DBD) system with a voltage output of 75 kV at a frequency of 50 Hz. A range of concentrations of 3nm uncoated PtNPs combined with CAP were examined in human U-251 MG Glioblastoma (GBM) cells and non-cancerous human embryonic kidney HEK293 cells. The protective effects of PtNPs against CAP were explored using several biochemical indicators of oxidative stress and cytotoxicity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/431888v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@128a9f9org.highwire.dtl.DTLVardef@af1f21org.highwire.dtl.DTLVardef@124d6dborg.highwire.dtl.DTLVardef@196040c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Synergistic Cytotoxicity Between Cold Atmospheric Plasma and Pyrazolopyrimidinones Against Glioblastoma Cells

Pyrazolopyrimidinone is a fused nitrogen-containing heterocyclic system, which acts as a core scaffold in many pharmaceutically relevant compounds. Pyrazolopyrimidinones have been demonstrated to be efficient in treating several diseases, including cystic fibrosis, obesity, viral infection and cancer. We have tested the synergistic anti-cancer effects of 15 pyrazolopyrimidinones, synthesised in a two-step process, combined with cold atmospheric plasma (CAP), a novel innovation generating reactive species with other unique chemical and physical effects. We identify two pyrazolopyrimidinones that act as prodrugs and display enhanced reactive-species dependent cytotoxicity when used in combination with cold atmospheric plasma. Synergistic activation was evident for both direct CAP treatment on prodrug loaded tumour cells and indirect CAP treatment of prodrug in media prior to adding to tumour cells. Our results demonstrate the potential of CAP combined with pyrazolopyrimidinones as a programmable cytotoxic therapy against cancer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/429831v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@56c8aeorg.highwire.dtl.DTLVardef@1913ea9org.highwire.dtl.DTLVardef@a8f522org.highwire.dtl.DTLVardef@75a529_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗