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Biology subjects

Gao, H.

Publications and source records attributed to Gao, H..

At least 163 records · Page 9Linked to original sources

Generating Electricity from Water Evaporation Through Microbial Biofilms

Sustainable strategies for energy production are required to reduce reliance on fossil fuels and to power electronics without generating toxic waste.1-7 Generating electricity from water evaporation through engineered materials is a promising approach,8,9 but power outputs have been low and the materials employed were not sustainably produced. Microorganisms can be mass produced with renewable feedstocks. Here, we demonstrate that it is possible to engineer microbial biofilms as a cohesive, flexible material for long-term continuous electricity production from evaporating water. The biofilm sheets were the functional component in devices that continuously produced power densities ([~]1 W/cm2) higher than that achieved with non-biological materials. Current production scaled directly with biofilm-sheet size and skin-patch devices harvested sufficient electricity from the moisture on skin to continuously power wearable devices. The results demonstrate that appropriately engineered biofilms can perform as robust functional materials without the need for further processing or maintaining cell viability. Biofilm-based hydroelectric current production was comparable to that achieved with similar sized biofilms catalyzing current production in microbial fuel cells,10,11 without the need for an organic feedstock or maintaining cell viability. The ubiquity of biofilms in nature suggests the possibility of additional sources of biomaterial for evaporation-based electricity generation and the possibility of harvesting electricity from diverse aqueous environments.

microbiology↗

Glucocorticoids Unmask Silent Non-Coding Genetic Risk Variants for Common Diseases

Understanding the function of non-coding genetic variants represents a formidable challenge for biomedicine. We previously identified genetic variants that influence gene expression only after exposure to a hormone or drug. Using glucocorticoid signaling as a model system, we have now demonstrated, in a genome-wide manner, that exposure to glucocorticoids triggered disease risk variants with previously unclear function to influence the expression of genes involved in autoimmunity, metabolic and mood disorders, osteoporosis and cancer. Integrating a series of pharmacogenomic and pharmacoepigenomic datasets, we identified the cis-regulatory elements and 3-dimensional interactions underlying the ligand-dependent associations between those genetic variants and distant risk genes. These observations increase our understanding of mechanisms of non-coding genetic variant-chemical environment interactions and advance the fine-mapping of disease risk and pharmacogenomic loci.

genomics↗

Myeloid cell-driven nonregenerative pulmonary scarring is conserved in multiple nonhuman primate species regardless of SARS-CoV-2 infection modality

The novel coronavirus SARS-CoV-2 has caused a worldwide pandemic resulting in widespread efforts in development of animal models that recapitulate human disease for evaluation of medical countermeasures, and to dissect COVID-19 immunopathogenesis. We tested whether route of experimental infection substantially changes COVID-19 disease characteristics in two species (Macaca mulatta; rhesus macaques; RM, Chlorocebus atheiops; African green monkeys; AGM) of nonhuman primates. Species-specific cohorts of RM and AGM Rhesus macaques (Macaca mulatta, RMs) and African green monkeys (Chlorocebus aethiops, AGMs) were experimentally infected with homologous SARS-CoV-2 by either direct mucosal instillation or small particle aerosol in route-discrete subcohorts. Both species demonstrated equivalent infection initially by either exposure route although the magnitude and duration of viral loading was greater in AGMs than that of the RM. Clinical onset was nearly immediate (+1dpi) in mucosally-exposed cohorts whereas aerosol-infected animals began to show signs +7dpi. Myeloid cell responses indicative of the development of pulmonary scarring and extended lack of regenerative capacity in the pulmonary compartment was a conserved pathologic response in both species by either exposure modality. This pathological commonality may be useful in future anti-fibrosis therapeutic evaluations and expands our understanding of how SARS-CoV-2 infection leads to ARDS and functional lung damage.

microbiology↗

Diversity, function and evolution of marine invertebrate genomes

Invertebrates, animals (metazoans) without backbones, encompass [~]97% of all animal yet remains understudied. They have provided insights into molecular mechanisms underlying fundamentally identical mechanisms in phylogenetically diverse animals, including vertebrates. Marine invertebrates have long fascinated researchers due to their abundance, diversity, adaptations, and impact on ecosystems and human economies. Here, we report a compendium and appraisal of 190 marine invertebrate genomes spanning 21 phyla, 43 classes, 92 orders, and 134 families. We identify a high proportion and long unit size of tandem repeats, likely contributing to reported difficulties in invertebrate genome assembly. A well-supported phylogenetic tree of marine invertebrates from 974 single-copy orthologous genes resolved topological controversies. We show that Ctenophora is at the basal phylum and Porifera is the sister group of Parahoxozoa; that Xenacoelomorpha is within Bilateria and is the sister group to Protostomia, rejecting three out of four hypotheses in the field; and that Bryozoa is at the basal position of Lophotrochozoa, not grouped into Lophophorata. We also present insights into the genetic underpinnings of metazoans from Hox genes, innate immune gene families, and nervous system gene families. Our marine invertebrate genome compendium provides a unified foundation for studies on their evolution and effects on ecological systems and human life.

genomics↗

Investigating lead removal at trace concentrations from water by inactive yeast cells

Traces of heavy metals found in water resources, due to mining activities and e-waste discharge, pose a global threat. Conventional treatment processes fail to remove toxic heavy metals, such as lead, from drinking water in a resource-efficient manner when their initial concentrations are low. Here, we show that by using the yeast Saccharomyces cerevisiae we can effectively remove trace lead from water via a rapid mass transfer process, achieving an uptake of up to 12 mg lead per gram of biomass in solutions with initial lead concentrations below 1 part per million. We found that the yeast cell wall plays a crucial role in this process, with its mannoproteins and {beta}-glucans being the key potential lead adsorbents. Furthermore, we discovered that biosorption is linked to a significant increase in cell wall stiffness. These findings open new opportunities for using environmentally friendly and abundant biomaterials for advanced water treatment targeting emerging contaminants. One-Sentence SummaryRemoving toxic heavy metals from water at challenging trace levels in an environmentally friendly, resource-efficient manner.

bioengineering↗

A General Framework for Representing and Annotating Multifaceted Cell Heterogeneity in Human Cell Atlas

A universal coordinate system that can ensemble the huge number of cells and capture their heterogeneities is of vital importance for constructing large-scale cell atlases as references for future molecular and cellular studies. Studies have shown that cells in complex organs exhibit multifaceted heterogeneities in their transcriptomic features at multiple resolutions. This nature of complexity makes it hard to design a fixed coordinate system through a combination of known features. It is desirable to build a learnable universal coordinate model that can capture major heterogeneities and serve as a controlled generative model for data argumentation. We developed UniCoord, a specially tuned joint-VAE model to represent single-cell transcriptomic data in a lower-dimensional latent space with high interpretability. Each latent dimension can represent either discrete or continuous feature, and either supervised by prior knowledge or unsupervised. The original transcriptomic profiles can be regenerated from the latent dimensions. The latent dimensions can be easily reconfigured to generate transcriptomic profiles of pseudo cells with desired properties. UniCoord can also be used as a pre-trained model to analyze new data with unseen cell types and thus can serve as a feasible framework for cell annotation and comparison. UniCoord provides a prototype for a learnable universal coordinate framework to enable better analysis and generation of cells with highly orchestrated functions and heterogeneities.

bioinformatics↗

The pigtail macaque (Macaca nemestrina) model of COVID-19 reproduces diverse clinical outcomes and reveals new and complex signatures of disease

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 disease, has killed over four million people worldwide as of July 2021 with infections rising again due to the emergence of highly transmissible variants. Animal models that faithfully recapitulate human disease are critical for assessing SARS-CoV-2 viral and immune dynamics, for understanding mechanisms of disease, and for testing vaccines and therapeutics. Pigtail macaques (PTM, Macaca nemestrina) demonstrate a rapid and severe disease course when infected with simian immunodeficiency virus (SIV), including the development of severe cardiovascular symptoms that are pertinent to COVID-19 manifestations in humans. We thus proposed this species may likewise exhibit severe COVID-19 disease upon infection with SARS-CoV-2. Here, we extensively studied a cohort of SARS-CoV-2-infected PTM euthanized either 6- or 21-days after respiratory viral challenge. We show that PTM demonstrate largely mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, including CD4+ T cells that upregulate CD8 and express cytotoxic molecules, as well as virus-targeting T cells that were predominantly CD4+. We also noted increases in inflammatory and coagulation markers in blood, pulmonary pathologic lesions, and the development of neutralizing antibodies. Together, our data demonstrate that SARS-CoV-2 infection of PTM recapitulates important features of COVID-19 and reveals new immune and viral dynamics and thus may serve as a useful animal model for studying pathogenesis and testing vaccines and therapeutics.

immunology↗

Single-shot rAAV5-based Vaccine Provides Long-term Protective Immunity against SARS-CoV-2 and Its Variants

The COVID-19 pandemic and the SARS-CoV-2 with its variants have posed unprecedented challenges worldwide. Existing vaccines have limited effectiveness against the SARS-CoV-2 variants. Therefore, novel vaccines to match current mutated viral lineages with long-term protective immunity are urgently in demand. In the current study, we for the first time designed a recombinant Adeno-Associated Virus 5 (rAAV5)-based vaccine named as rAAV-COVID-19 vaccine (Covacinplus) by using RBD-plus of spike protein with both the single-stranded and the self-complementary AAV5 delivering vectors (ssAAV5 and scAAAV5), which provides excellent protection from SARS-CoV-2 infection. A single dose vaccination induced the strong immune response against SARS-CoV-2. The induced neutralizing antibodies (NAs) titers were maintained at a high peak level of over 1:1024 even after more than one year of injection and accompanied with functional T-cells responses in mice. Importantly, both ssAAV- and scAAV-based RBD-plus vaccines exhibited high levels of serum NAs against current circulating variants including variants Alpha, Beta, Gamma and Delta. SARS-CoV-2 virus challenge test showed that ssAAV5-RBD-plus vaccine protected both young and old age mice from SARS-CoV-2 infection in the upper and the lower respiratory tracts. Moreover, whole genome sequencing demonstrated that AAV vector DNA sequences were not found in the genome of the vaccinated mice after one year vaccination, demonstrating excellent safety of the vaccine. Taken together, this study suggests that rAAV5-based vaccine is powerful against SARS-CoV-2 and its variants with long-term protective immunity and excellent safety, which has great potential for development into prophylactic vaccination in human to end this global pandemic.

immunology↗

Diterpenoid Vinigrol activates ATF4/DDIT3-mediated PERK/eIF2 arm of unfolded protein response to drive breast cancer cell death

Vinigrol is a natural diterpenoid with unprecedented chemical structure, driving great efforts into its total synthesis and the chemical analogs in the past decades. Despite its pharmacological efficacies reported on anti-hypertension and anti-clot, comprehensive functional investigations on Vinigrol and the underlying molecular mechanisms are entirely missing. In this study, we carried out a complete functional prediction of Vinigrol using a transcriptome-based strategy, Connectivity Map, and identified "anti-cancer" as the most prominent biofunction ahead of anti-hypertension and anti-depression/psychosis. A broad cytotoxicity was subsequently confirmed on multiple cancer types. Further mechanistic investigation on MCF7 cells revealed that its anti-cancer effect is mainly through activating PERK/eIF2 arm of unfolded protein response (UPR) and subsequent upregulation of p53/p21 to halt the cell cycle. The other two branches of UPR, IRE1 and ATF6, are functionally irrelevant to Vinigrol-induced cell death. CRISPR/Cas9-based gene activation, repression, and knockout systems identified essential contribution of ATF4/DDIT3 not ATF6 to the death process. This study unraveled a broad anti-cancer function of Vinigrol and its underlying targets and regulatory mechanisms, and also paved the way for further inspection on the structure-efficacy relationship of the whole compound family, making them a novel cluster of chemical hits for cancer therapy.

pharmacology and toxicology↗

Development of a compact alkynyl-enrichable crosslinker for in-depth in-vivo crosslinking analysis

Chemical crosslinking coupled with mass spectrometry (CXMS) has emerged as a powerfl technique to capture the dynamic information of protein complexes with high sensitivity, throughput and sample universality. To advance the study of in-vivo protein structures and protein-protein interactions on the large scale, a new alkynyl-enrichable crosslinker was developed with high efficiency of membrane penetration, reactivity and enrichment. The crosslinker was successfully used for in-vivo crosslinking of intact human cells, reslting in 6820 non-redundant crosslinks identified at a false discovery rate (FDR) of 1% using pLink 2.0, which 4898 (71.8%) of the cross-links were assigned as intraprotein and 1922 (28.2%) were interprotein links. To our knowledge, this is also the first time to realize the in-vivo crosslinking with a non-cleavable crosslinker for homo species cells.

biochemistry↗

A human ensemble cell atlas (hECA) enables in data cell sorting

Single-cell omics data can characterize multifaceted features of massive cells and bring significant insights to biomedical researches. The accumulation of single-cell data provides growing resources for constructing atlases for all cells of a human organ or the whole body. The true assembly of a cell atlas should be cell-centric rather than file-centric. We proposed a unified information framework enabling seamless cell-centric data assembly and developed a human Ensemble Cell Atlas (hECA) as an instance. hECA version 1.0 assembled scRNA-seq data across multiple studies into one orchestrated data repository. It contains 1,093,299 labeled cells and metadata from 116 published human single-cell studies, covering 38 human organs and 11 systems. We invented three methods of applications based on the cell-centric assembly: "In data" cell sorting enables targeted data retrieval in the full atlas with customizable logic expressions; The "quantitative portraiture" system provides a multi-view presentation of biological entities (organs, cell types, and genes) of multiple granularities; The customizable reference creation allows users to use the cell-centric assembly to generate references for their own cell type annotations. Case studies on agile construction of user-defined sub-atlases and "in data" investigation of CAR-T off-targets in multiple organs showed the great potential of cell-centric atlas assembly.

bioinformatics↗

Wuschel2 enables highly efficient CRISPR/Cas-targeted genome editing during rapid de novo shoot regeneration in sorghum

For many important crops, including sorghum, the use of CRISPR/Cas technology is limited not only by the delivery of the gene-modification components into a plant cell, but more critically, by the ability to regenerate a fertile plant from the engineered cell through conventional tissue culture methods. Here, we report that Wuschel2 (Wus2)-enabled sorghum (Sorghum bicolor L.) transformation increases not only the efficiency of transgenic plant recovery, but also increases the observed efficiency of CRISPR/Cas-targeted genome editing within the population of T0 plants. Using Agrobacterium-mediated transformation, we have demonstrated Wus2-induced direct somatic embryo formation and regeneration, bypassing genotype-dependent callus formation and significantly shortening the tissue culture cycle time. This method also increased regeneration capacity, resulting in higher transformation efficiency across different sorghum genotypes. Subsequently, advanced excision systems and "altruistic" transformation technology have been developed to generate high-quality morphogenic gene-free and/or selectable marker-free sorghum events. Finally, we demonstrated up to an additional 6.8-fold increase in CRISPR/Cas9-mediated gene dropout frequency using Wus2-enabled, Agrobacterium-mediated transformation (compared to the control treatment with no Wus2), across various targeted loci in different sorghum genotypes. Wus2-enabled genome editing may be applicable to other crops and increasingly popular in planta transformation strategies.

developmental biology↗

Effective prophylaxis of COVID-19 in rhesus macaques using a combination of two parentally-administered SARS-CoV-2 neutralizing antibodies

SARS-CoV-2 is a respiratory borne pathogenic beta coronavirus that is the source of a worldwide pandemic and the cause of multiple pathologies in man. The rhesus macaque model of COVID-19 was utilized to test the added benefit of combinatory parenteral administration of two high-affinity anti-SARS-CoV-2 monoclonal antibodies (mAbs; C144-LS and C135-LS) expressly developed to neutralize the virus and modified to extend their pharmacokinetics. After completion of kinetics study of mAbs in the primate, combination treatment was administered prophylactically to mucosal viral challenge. Results showed near complete virus neutralization evidenced by no measurable titer in mucosal tissue swabs, muting of cytokine/chemokine response, and lack of any discernable pathologic sequalae. Blocking infection was a dose-related effect, cohorts receiving lower doses (6, 2 mg/kg) resulted in low grade viral infection in various mucosal sites compared to that of a fully protective dose (20 mg/kg). A subset of animals within this cohort whose infectious challenge was delayed 75 days later after mAb administration were still protected from disease. Results indicate this combination mAb effectively blocks development of COVID-19 in the rhesus disease model and accelerates the prospect of clinical studies with this effective antibody combination.

microbiology↗

SARS-CoV-2 Vaccines Elicit Durable Immune Responses in Infant Rhesus Macaques

Early life SARS-CoV-2 vaccination has the potential to provide lifelong protection and achieve herd immunity. To evaluate SARS-CoV-2 infant vaccination, we immunized two groups of 8 infant rhesus macaques (RMs) at weeks 0 and 4 with stabilized prefusion SARS-CoV-2 S-2P spike (S) protein, either encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or mixed with 3M-052-SE, a TLR7/8 agonist in a squalene emulsion (Protein+3M-052-SE). Neither vaccine induced adverse effects. High magnitude S-binding IgG and neutralizing infectious dose 50 (ID50) >103 were elicited by both vaccines. S-specific T cell responses were dominated by IL-17, IFN-{gamma}, or TNF-. Antibody and cellular responses were stable through week 22. The S-2P mRNA-LNP and Protein-3M-052-SE vaccines are promising pediatric SARS-CoV-2 vaccine candidates to achieve durable protective immunity. One-Sentence SummarySARS-CoV-2 vaccines are well-tolerated and highly immunogenic in infant rhesus macaques

immunology↗

A malaria parasite phospholipid flippase safeguards midgut traversal of ookinetes for mosquito transmission

Mosquito midgut epithelium traversal is an essential component of transmission of malaria parasites. Phospholipid flippases are eukaryotic type IV ATPases (P4-ATPases), which in association with CDC50 cofactors, translocate phospholipids across lipid bilayers to maintain the membrane asymmetry. In this study, we investigated the function of a putative P4-ATPase, ATP7, from the rodent malaria parasite P. yoelii. Disruption of ATP7 results in block of parasite infection of mosquitoes. ATP7 is localized on the ookinete plasma membrane. While ATP7-depleted ookinetes are motile and capable of invading the midgut, they are quickly eliminated within the epithelial cells by a process that is independent from the mosquito complement-like immunity. ATP7 colocalizes and interacts with the flippase co-factor CDC50C. Importantly, depletion of CDC50C phenocopies ATP7 deficiency. ATP7-depleted ookinetes fail to translocate phosphatidylcholine (PC) across the plasma membrane, resulting in PC exposure at the ookinete surface. Lastly, ookinete microinjection into the mosquito hemocoel reverses the ATP7 deficiency phenotype. Our study identifies Plasmodium flippase as a novel mechanism of parasite survival in the midgut epithelium that is required for mosquito transmission.

microbiology↗

Insights into the susceptibility of rice to a floral disease

Crop floral diseases are economically important as they reduce grain yield and quality and even introduce food toxins. Rice false smut has emerged as a serious floral disease producing mycotoxins. However, very little is known on the interaction mechanisms between rice flower and the causal fungus Ustilaginoidea virens. Here we show that a conserved anti-fungal immunity in rice flower is disarmed by U. virens via a secreted protein UvChi1. UvChi1 functioned as an essential virulence factor and directly interacted with the chitin receptor CEBiP and co-receptor CERK1 in rice to disrupt their oligomerizations and subsequent immune responses. Moreover, intraspecific-conserved UvChi1 could target OsCEBiP/OsCERK1 receptor complex in at least 98.5% of 5232 surveyed rice accessions. These results demonstrate that U. virens utilizes a crucial virulence factor to subvert chitin-triggered flower immunity in most rice varieties, providing new insights into the susceptibility of rice to false smut disease. One Sentence SummaryThe fungal pathogen Ustilaginoidea virens disarms chitin-triggered immunity in rice flower via a secreted chitinase.

plant biology↗

Disrupted circadian core-clock oscillations in Type 2 Diabetes are linked to altered rhythmic mitochondrial metabolism

Circadian rhythms are generated by an auto-regulatory feedback loop composed of transcriptional activators and repressors. Disruption of circadian rhythms contributes to Type 2 diabetes (T2D) pathogenesis. We elucidated whether altered circadian rhythmicity of clock genes is associated with metabolic dysfunction in T2D. Transcriptional cycling of core clock genes ARNTL, CLOCK, CRY1 and NR1D1 was altered in skeletal muscle from individuals with T2D and this was coupled with reduced number and amplitude of cycling genes and disturbed circadian oxygen consumption. Mitochondrial associated genes were enriched for differential circadian amplitudes in T2D, and positively correlated with insulin sensitivity. ChIP- sequencing identified CLOCK and BMAL1 binding to circadian mitochondrial genes associated with insulin sensitivity, implicating regulation by the core clock. Mitochondria disruption altered core-clock gene expression and free-radical production, phenomena that were restored by resveratrol treatment. We identify bi-directional communication between mitochondrial function and rhythmic gene expression, processes which are disturbed in diabetes.

physiology↗

Nurse cell-derived small RNAs define paternal epigenetic inheritance in Arabidopsis

The plant male germline undergoes DNA methylation reprogramming, which methylates genes de novo and thereby alters gene expression and facilitates meiosis. Why reprogramming is limited to the germline and how specific genes are chosen is unknown. Here, we demonstrate that genic methylation in the male germline, from meiocytes to sperm, is established by germline-specific siRNAs transcribed from transposons with imperfect sequence homology. These siRNAs are synthesized by meiocyte nurse cells (tapetum) via activity of the tapetum-specific chromatin remodeler CLASSY3. Remarkably, tapetal siRNAs govern germline methylation throughout the genome, including the inherited methylation patterns in sperm. Finally, we demonstrate that these nurse cell-derived siRNAs (niRNAs) silence germline transposons, thereby safeguarding genome integrity. Our results reveal that tapetal niRNAs are sufficient to reconstitute germline methylation patterns and drive extensive, functional methylation reprogramming analogous to piRNA-mediated reprogramming in animal germlines. O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/428150v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1e985c0org.highwire.dtl.DTLVardef@4c065corg.highwire.dtl.DTLVardef@1358a5forg.highwire.dtl.DTLVardef@f9c03_HPS_FORMAT_FIGEXP M_FIG C_FIG

plant biology↗