Biology subjects

Liu, Z.

Publications and source records attributed to Liu, Z..

At least 937 records · Page 52Linked to original sources

bioRxiv2021

Active oxygen transport in tissue by interstitial flow

The model of diffusive O2 transport from capillary to tissue was established by Krogh a century ago. This model is incomplete as it ignores the often inevitable convective O2 transport via fluid movement. Here, we propose a one-dimensional physical-phenomenological model to evaluate the contribution of fluid movement to the O2 transport in tissue. Both the O2 gradient and the total O2 flux are found to be sensitive to the fluid movement. For small flow rates with a Peclet number Pe < 1, a critical flow rate, udc, is introduced to characterize the contribution of fluid movement to the O2 transport, as well as to evaluate the fluid contribution in O2-deficient tissues and the cytoplasm movement inside muscle fibers. During hemostasis, the O2 flux contributed by the interstitial flow even below a rate of 2 m/s, although negligible near the capillary, can be significant for the tissue residing far from the capillary. For an isolated intramyocyte mitochondrion, the cytoplasm movement can play a key role in the O2 transport. These considerations point to the scenario of an external force to drive the fluid movement leading to an accelerated O2 transport to sustain the mitochondrial consumption. Our model offers a comprehensive picture of the O2 transport in tissue by including both the concentration gradient and the hydraulic pressure gradient. It predicts that even with a small external force, damaged tissues with higher permeability can yield larger rates of interstitial flow promoting O2 transport for tissue recovery. HighlightsO_LIThe fluid movement can play a significant role in O2 transport in tissue with high Prandtl number{nu} /D ~ 103; C_LIO_LIA critical flow rate, udc, is introduced to evaluate the convective transport flux by the fluid in tissue for Pe < 1. C_LIO_LIO2 transport in tissue is a result of the balance between hydraulic pressure gradient induced flux and concentration gradient induced flux. C_LIO_LIOur model indicates more O2 pumped by convective transport into the O2 -deficient region where the O2 diffusive flux cannot penetrate. C_LIO_LIThe cytoplasm movement can excite more O2 flux to the mitochondria with higher myoglobin concentration. C_LI

physiology↗

bioRxiv2021

Immune elicitation by sensing the conserved signature from phytocytokines and microbes via the Arabidopsis MIK2 receptor

Sessile plants encode a large number of small peptides and cell surface-resident receptor kinases, most of which have unknown functions. Here, we report that the Arabidopsis receptor kinase MALE DISCOVERER 1-INTERACTING RECEPTOR-LIKE KINASE 2 (MIK2) recognizes the conserved signature motif of SERINE RICH ENDOGENOUS PEPTIDEs (SCOOPs) from plants as well as proteins present in fungal Fusarium spp. and bacterial Comamonadaceae, and elicits potent immune responses. SCOOP signature peptides trigger diverse immune and physiological responses in a MIK2-dependent manner with a sub-nanomolar sensitivity and directly bind to the extracellular leucine rich-repeat domain of MIK2 in vivo and in vitro, indicating that MIK2 is the receptor of SCOOP peptides. Perception of SCOOP peptides induces the association of MIK2 and the coreceptors SOMATIC EMBRYOGENESIS RECEPTOR KINASE 3 (SERK3) and SERK4 and relays the signaling through the cytosolic receptor-like kinases BOTRYTIS-INDUCED KINASE 1 (BIK1) and AVRPPHB SUSCEPTIBLE1 (PBS1)-LIKE 1 (PBL1). Our study identified a unique plant receptor that bears a dual recognition capability sensing the conserved peptide motif from phytocytokines and microbial proteins via a convergent signaling relay to ensure a robust immune response.

plant biology↗

bioRxiv2021

Pre-stimulus alpha activities predict the confidence in subjective judgment by modulating post-stimulus theta oscillation

Even when making arbitrary decisions, people tend to feel varying levels of confidence, which is associated with the pre-stimulus neural oscillation of the brain. We investigated varying confidence in a pure subjective judgment task, and how this confidence was predicted by pre-stimulus alpha oscillations. Participants made pure subjective judgments where their prior experience seems to be helpful but actually useless, and their fluctuating confidence was related to the choice boundary process rather than the evidence accumulation process, suggesting participants underwent varying confidence resulting from the internal signals. With EEG and MEG analyses, we not only revealed the linkage between confidence and pre-stimulus alpha activities, but also successfully located this linkage onto decision-making relevant brain areas, i.e. MCC/PCC and SMA. Moreover, we unveiled a specific pathway underlying such linkage, that is, the influence of pre-stimulus alpha activities on decision confidence was fulfilled through modulating post-stimulus theta activities of SMA.

neuroscience↗

bioRxiv2021

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

Mammalian cochlear outer hair cells (OHCs) are essential for hearing. OHC degeneration causes severe hearing impairment. Previous attempts of regenerating new OHCs from cochlear supporting cells (SCs) had yielded cells lacking Prestin, a key motor protein for OHC function. Thus, regeneration of Prestin+ OHCs remains a challenge for repairing OHC damage in vivo. Here, we reported that successful in vivo conversion of adult cochlear SCs into Prestin+ OHC-like cells could be achieved by simultaneous expression of Atoh1 and Ikzf2, two key transcriptional factors necessary for OHC development. New OHC-like cells exhibited upregulation of hundreds of OHC genes and downregulation of SC genes. Single cell transcriptomic analysis demonstrated that the differentiation status of these OHC-like cells was much more advanced than previously achieved. Thus, we have established an efficient approach to promote regeneration of Prestin+ OHCs and paved the way for repairing damaged cochlea in vivo via transdifferentiation of SCs.

developmental biology↗

bioRxiv2021

Mutation rate variations in the human genome are encoded in DNA shape

Single nucleotide mutation rates have critical implications for human evolution and genetic diseases. Accurate modeling of these mutation rates has long remained an open problem since the rates vary substantially across the human genome. A recent model, however, explained much of the variation by considering higher order nucleotide interactions in the local (7-mer) sequence context around mutated nucleotides. Despite this models predictive value, we still lack a biophysically-grounded understanding of genome-wide mutation rate variations. DNA shape features are geometric measurements of DNA structural properties, such as helical twist and tilt, and are known to capture information on interactions between neighboring nucleotides within a local context. Motivated by this characteristic of DNA shape features, we used them to model mutation rates in the human genome. The DNA shape feature based models show up to 15% higher accuracy than the current nucleotide sequence-based models and pinpoint DNA structural properties predictive of mutation rates in the human genome. Further analyzing the mutation rates of individual positions of transcription factor (TF) binding sites in the human genome, we found a strong association between DNA shape and the position-specific mutation rates. The trend holds for hundreds of TFs and is even stronger in evolutionarily conserved regions. To our knowledge, this is the first attempt that demonstrates the structural underpinnings of nucleotide mutations in the human genome and lays the groundwork for future studies to incorporate DNA shape information in modeling genetic variations.

genomics↗

bioRxiv2021

A novel Wnt/beta-catenin signaling driven adipocyte population that is required for beiging

Wnt/{beta}-catenin signaling has been well established as a potent inhibitor of adipogenesis. Here, we identified a population of adipocytes that exhibit persistent activity of Wnt/{beta}-catenin signaling, as revealed by the Tcf/Lef-Gfp reporter allele, in embryonic and adult mouse fat depots, named as Wnt+ adipocytes. We showed that the {beta}-catenin-mediated signaling activation in these cells is Wnt ligand- and receptor-independent but relies on AKT/mTOR pathway and is essential for cell survival. Such adipocytes are distinct from classical ones in transcriptomic and genomic signatures and can be induced from various sources of mesenchymal stromal cells including human cells. Genetic lineage-tracing and targeted cell ablation studies revealed that these adipocytes convert into beige adipocytes directly and are also required for beige fat recruitment under thermal challenge, demonstrating both cell autonomous and non-cell autonomous roles in adaptive thermogenesis. Furthermore, mice bearing targeted ablation of these adipocytes exhibited glucose intolerance, while mice receiving exogenously supplied such cells manifested enhanced glucose utilization. Our studies uncover a unique adipocyte population in regulating beiging in adipose tissues and systemic glucose homeostasis.

physiology↗

bioRxiv2021

N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

SARS-CoV-2 entry into host cells is orchestrated by the spike (S) glycoprotein that contains an immunodominant receptor-binding domain (RBD) targeted by the largest fraction of neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge. SARS-CoV-2 variants, including the 501Y.V2 and B.1.1.7 lineages, harbor frequent mutations localized in the NTD supersite suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs to protective immunity.

immunology↗

bioRxiv2021

Analysis of next- and third-generation RNA-Seq data reveals the structures of alternative transcription units in bacterial genomes

Alternative transcription units (ATUs) are dynamically encoded under different conditions or environmental stimuli in bacterial genomes, and genome-scale identification of ATUs is essential for studying the emergence of human diseases caused by bacterial organisms. However, it is unrealistic to identify all ATUs using experimental techniques, due to the complexity and dynamic nature of ATUs. Here we present the first-of-its-kind computational framework, named SeqATU, for genome-scale ATU prediction based on next-generation RNA-Seq data. The framework utilizes a convex quadratic programming model to seek an optimum expression combination of all of the to-be-identified ATUs. The predicted ATUs in E. coli reached a precision of 0.77/0.74 and a recall of 0.75/0.76 in the two RNA-Sequencing datasets compared with the benchmarked ATUs from third-generation RNA-Seq data. We believe that the ATUs identified by SeqATU can provide fundamental knowledge to guide the reconstruction of transcriptional regulatory networks in bacterial genomes.

bioinformatics↗

bioRxiv2021

DenovoProfiling: a webserver for de novo generated molecule library profiling

With the advances of deep learning techniques, various architectures for molecular generation have been proposed for de novo drug design. Successful cases from academia and industrial demonstrated that the deep learning based de novo molecular design could efficiently accelerate the drug discovery process. The flourish of the de novo molecular generation methods and applications created great demand for the visualization and functional profiling for the de novo generated molecules. The rising of publicly available chemogenomic databases lays good foundations and create good opportunities for comprehensive profiling of the de novo library. In this paper, we present DenovoProfiling, a web server dedicated for de novo library visualization and functional profiling. Currently, DenovoProfiling contains six modules: (1) identification & visualization, (2) chemical space, (3) scaffold analysis, (4) molecular alignment, (5) target & pathways, and (6) drugs mapping. DenovoProfiling could provide structural identification, chemical space exploration, drugs mapping, and targets & pathways. The comprehensive annotated information could give user a clear picture of their de novo library and could provide guidance in the further selection of candidates for synthesis and biological confirmation. DenovoProfiling is freely available at http://denovoprofiling.xielab.net.

bioinformatics↗

bioRxiv2020

Process Development and Scale-up Optimization of the SARS-CoV-2 Receptor Binding Domain-Based Vaccine Candidate, RBD219-N1C1

A SARS-CoV-2 RBD219-N1C1 (RBD219-N1C1) recombinant protein antigen formulated on Alhydrogel(R) has recently been shown to elicit a robust neutralizing antibody response against SARS-CoV-2 pseudovirus in mice. The antigen has been produced under current good manufacturing practices (cGMP) and is now in clinical testing. Here, we report on process development and scale-up optimization for upstream fermentation and downstream purification of the antigen. This includes production at the 1 and 5 L scale in the yeast, Pichia pastoris, and the comparison of three different chromatographic purification methods. This culminated in the selection of a process to produce RBD219-N1C1 with a yield of >400 mg per liter of fermentation with >92% purity and >39% target product recovery after purification. In addition, we show the results from analytical studies, including SEC-HPLC, DLS, and an ACE2 receptor binding assay that were performed to characterize the purified proteins to select the best purification process. Finally, we propose an optimized upstream fermentation and downstream purification process that generates quality RBD219-N1C1 protein antigen and is fully scalable at a low cost.

immunology↗

bioRxiv2020

Amphipathic Bax core dimer forms part of apoptotic pore wall in the mitochondrial membrane

Bax proteins form pores in the mitochondrial outer membrane to initiate apoptosis. They may embed in the cytosolic leaflet of the lipid bilayer generating tension to induce a lipid pore with radially arranged lipids forming the wall. Alternatively, they may comprise part of the pore wall. However, there is no unambiguous structural evidence for either hypothesis. Using NMR, we determine a high-resolution structure of the Bax core region that forms a dimer with the nonpolar surface covering the lipid bilayer edge and the polar surface exposed to water. The dimer tilts from the bilayer normal, not only maximizing nonpolar interactions with lipid tails but creating polar interactions between charged residues and lipid heads. Structure-guided mutations demonstrate the importance of both protein-lipid interactions in Bax pore assembly and core dimer configuration. Therefore, the Bax core dimer forms part of the proteolipid pore wall to permeabilize mitochondria.

biophysics↗

bioRxiv2020

The 3'tsRNAs are aminoacylated: Implications for their biogenesis

Emerging evidence indicates that tRNA-derived small RNAs (tsRNAs) are involved in fine-tuning gene expression and become dysregulated in various cancers. We recently showed that the 22nt LeuCAG tsRNA from 3 end of tRNALeu is required for efficient translation of a ribosomal protein mRNA and ribosome biogenesis. Inactivation of this tsRNA induced apoptosis in rapidly dividing cells and suppressed the growth of a patient derived orthotopic hepatocellular carcinoma in mice. The mechanism involved in the generation of the 3-tsRNAs remains elusive and it is unclear if the 3-ends of 3-tsRNAs are aminoacylated. Here we report an enzymatic method utilizing exonuclease T to determine the 3charging status of tRNAs and tsRNAs. Our results showed that the LeuCAG 3-tsRNA is fully charged and originated solely from charged mature tRNA. When the leucyl-tRNA synthetase was knocked down, less tsRNA was generated while the mature tRNA was not reduced further supporting that tsRNA generation is regulated. The fact that the 3-tsRNA is aminoacylated has implications for their biogenesis and provides additional insights into their biological role in post-transcriptional gene regulation.

molecular biology↗

bioRxiv2020

Non-coding loci without epigenomic signals can be essential for maintaining global chromatin organization and cell viability

The majority of the non-coding regions in the human genome do not harbor any annotated element and are even not marked with any epigenomic signal or protein binding. An understudied aspect of these regions is their possible roles in stabilizing the 3D chromatin organization. To illuminate their "structural importance", we chose to start with the non-coding regions forming many 3D contacts (referred to as hubs) and identified dozens of hubs essential for cell viability. Hi-C and single cell transcriptomic analyses showed that their deletion could significantly alter chromatin organization and impact gene expression located distal in the genome. This study revealed the 3D structural importance of non-coding loci that are not associated with any functional element, providing a new mechanistic understanding of the disease-associated genetic variations (GVs). Furthermore, our analyses also suggested a powerful approach to develop "one-drug-multiple-targets" therapeutics targeting the disease-specific non-coding regions.

genetics↗

bioRxiv2020

Regulatory elements can be essential for maintaining broad chromatin organization and cell viability

Increasing evidence shows that promoters and enhancers could be related to 3D chromatin structure, thus affecting cellular functions. Except for functioning through the canonical chromatin loops formed by promoters and enhancers, their roles in maintaining broad chromatin organization have not been well studied. Here, we focused on the active promoters/enhancers (referred to as hotspots) predicted to form many 3D contacts with other active promoters/enhancers, and identified dozens of loci critical for cell survival. While the essentiality of hotspots is not resulted from their association with essential genes, deletion of an essential hotspot could lead to change of broad chromatin organization and expressions of distal genes. We demonstrated that multiple affected genes that are individually non-essential could have synergistic effects to cause cell death.

bioinformatics↗

bioRxiv2020

High-throughput, low-cost and rapid DNA sequencing using surface-coating techniques

The speed1-3, expense1-4 and throughput2 of genomic sequencing impose limitations on its use for time-sensitive acute cases, such as rare4,5 or antibiotic resistant infections6, and large-scale testing that is necessary for containing COVID-19 outbreaks using source-tracing7-9. The major bottleneck for increasing the bandwidth and decreasing operating costs of next-generation sequencers (NGS) is the flow cell that supplies reagents for the biochemical processes; this subsystem has not significantly improved since 200510-12. Here we report a new method for sourcing reagents based on surface coating technology (SCT): the DNA adhered onto the biochip is directly contacted by a reagent-coated polymeric strip. Compared with flow cells the reagent layers are an order of magnitude thinner while both the reagent exchange rate and biochip area are orders of magnitude greater. These improvements drop the turn-around time from days to twelve hours and the cost for whole genome sequencing (WGS) from about $1000 to $15, as well as increase data production by several orders of magnitude. This makes NGS more affordable than many blood tests while rapidly providing detailed genomic information about microbial and viral pathogens6,13, cancers14 and genetic disorders for targeted treatments6 and personalized medicine6,15. This data can be pooled in population-wide databases for accelerated research and development as well providing detailed real-time data for tracking and containing outbreaks, such as the current COVID-19 pandemic.

bioengineering↗

bioRxiv2020

Automatic Assessment of Human Gastric Motility and Emptying from Dynamic 3D Magnetic Resonance Imaging

BackgroundTime-sequenced magnetic resonance imaging (MRI) of the stomach is an emerging technique for non-invasive assessment of gastric emptying and motility. However, an automated and systematic image processing pipeline for analyzing dynamic 3D (i.e., 4D) gastric MRI data is not yet available. This study introduces an MRI protocol for imaging the stomach with high spatiotemporal isotropic resolution and provides an integrated pipeline for assessing gastric emptying and motility simultaneously. MethodsDiet contrast-enhanced MRI images were acquired from seventeen healthy humans after they consumed a naturalistic contrast meal. An automated image processing pipeline was developed to correct for respiratory motion, to segment and compartmentalize the lumen-enhanced stomach, to quantify total gastric and compartmental emptying, and to compute and visualize gastric motility on the surface of the stomach. Key ResultsThe gastric segmentation reached an accuracy of 91.10{+/-}0.43% with the Type-I error and Type-II error being 0.11{+/-}0.01% and 0.22{+/-}0.01%, respectively. Gastric volume decreased 34.64{+/-}2.8% over 1 hour where the emptying followed a linear-exponential pattern. The gastric motility showed peristaltic patterns with a median = 4 wave-fronts (range 3 - 6) and a mean frequency of 3.09{+/-}0.07 cycles per minute (CPM). Further, the contractile amplitude was stronger in the antrum than in the corpus (antrum vs. corpus: 5.18{+/-}0.24 vs. 3.30{+/-}0.16 mm; p < .001). Conclusions & InferencesThe automated, streamlined software can process dynamic 3D MRI images and produce comprehensive and personalized profiles of gastric motility and emptying. This software will facilitate the application of MRI for monitoring gastric dynamics in research and clinical settings.

bioengineering↗

bioRxiv2020

Bone marrow adipocytes drive the development of tissue invasive Ly6Chigh monocytes during obesity

During obesity and high fat-diet (HFD) feeding in mice, sustained low-grade inflammation includes not only increased pro-inflammatory macrophages in the expanding adipose tissue, but also bone marrow (BM) production of invasive Ly6Chigh monocytes. As BM adiposity also accrues with HFD, we explored the relationship between the gains in BM white adipocytes and invasive Ly6Chigh monocytes in vivo and through ex vivo paradigms. We find a temporal and causal link between BM adipocyte whitening and the Ly6Chigh monocyte surge, preceding the adipose tissue macrophage rise during HFD. Phenocopying this, ex vivo treatment of BM cells with conditioned media from BM adipocytes or from bona fide white adipocytes favoured Ly6Chigh monocyte preponderance. Notably, the switch towards the Ly6Chigh subset was preceded by monocyte metabolic reprogramming towards glycolysis, reduced oxidative potential and increased mitochondrial fission. In sum, short-term HFD changes BM cellularity, resulting in local adipocyte whitening driving a gradual increase and activation of invasive Ly6Chigh monocytes.

immunology↗

bioRxiv2020

Single-Cell RNA Sequencing Reveals Endothelial Cell Transcriptome Heterogeneity under Homeostatic Laminar Flow

ObjectiveEndothelial cells that form the innermost layer of all vessels exhibit heterogeneous cell behaviors and responses to pro-angiogenic signals that are critical for vascular sprouting and angiogenesis. Once vessels form, remodeling and blood flow lead to endothelial cell quiescence, and homogeneity in cell behaviors and signaling responses. These changes are important for the function of mature vessels, but whether and at what level endothelial cells regulate overall expression heterogeneity during this transition is poorly understood. Here we profiled endothelial cell transcriptomic heterogeneity, and expression heterogeneity of selected proteins, under homeostatic laminar flow. Approach and ResultsSingle-cell RNA sequencing and fluorescence microscopy were used to characterize heterogeneity in RNA and protein gene expression levels of human endothelial cells under homeostatic laminar flow compared to non-flow conditions. Analysis of transcriptome variance, Gini coefficient, and coefficient of variation showed that more genes increased RNA heterogeneity under laminar flow relative to genes whose expression became more homogeneous. Analysis of a subset of genes for relative protein expression revealed that most protein profiles showed decreased heterogeneity under flow. In contrast, the magnitude of expression level changes in RNA and protein was coordinated among endothelial cells in flow vs. non-flow conditions. ConclusionsEndothelial cells exposed to homeostatic laminar flow showed increased cohort heterogeneity in RNA expression levels, while cohort expression heterogeneity of selected cognate proteins decreased under laminar flow. These findings suggest that EC homeostasis is imposed at the level of protein translation and/or stability rather than transcriptionally.

cell biology↗