Biology subjects

Zhou, L.

Publications and source records attributed to Zhou, L..

At least 217 records · Page 12Linked to original sources

bioRxiv2022

Heterotypic vaccination responses against SARS-CoV-2 Omicron BA.2

The Omicron sub-lineage BA.2 of SARS-CoV-2 has recently become dominant across many areas in the world in the on-going waves of COVID-19. Compared to the ancestral/wild-type (WT) virus, Omicron lineage variants, both BA.1 and BA.2, contain high number of mutations, especially in the spike protein, causing significant immune escape that leads to substantial reduction of vaccine and antibody efficacy. Because of this antigenic drift, BA.2 exhibited differential resistance profile to monoclonal antibodies than BA.1. Thus, it is important to understand whether the immunity elicited by currently available vaccines are effective against the BA.2 subvariant. We directly tested the heterotypic vaccination responses against Omicron BA.2, using vaccinated serum from animals receiving WT- and variant-specific mRNA vaccine in lipid nanoparticle (LNP) formulations. Omicron BA.1 and BA.2 antigen showed similar reactivity to serum antibodies elicited by two doses of WT, B.1.351 and B.1.617 LNP-mRNAs. Neutralizing antibody titers of B.1.351 and B.1.617 LNP-mRNA were ~2-fold higher than that of WT LNP-mRNA. Both homologous boosting with WT LNP-mRNA and heterologous boosting with BA.1 LNP-mRNA substantially increased waning immunity of WT vaccinated mice against both BA.1 and BA.2 subvariants. The BA.1 LNP-mRNA booster was ~3-fold more efficient than WT LNP-mRNA at elevating neutralizing antibody titers of BA.2. Together, these data provided a direct preclinical evaluation of WT and variant-specific LNP-mRNAs in standard two-dose and as boosters against BA.1 and BA.2 subvariants.

immunology↗

bioRxiv2022

Lyophilized mRNA-lipid nanoparticles vaccine with long-term stability and high antigenicity against SARS-CoV-2

Advanced mRNA vaccines play vital roles against SARS-CoV-2. However, due to their poor stability, most current mRNA delivery platforms need to be stored at -20{degrees}C or -70{degrees}C, which severely limits their distribution. Herein, we present lyophilized SARS-CoV-2 mRNA-lipid nanoparticle vaccines, which can be stored at room temperature with long-term thermostability. In the in vivo Delta virus challenge experiment, lyophilized Delta variant mRNA vaccine successfully protected mice from infection and cleared the virus. Lyophilized omicron mRNA vaccine enabled to elicit both potent humoral and cellular immunity. In booster immunization experiments in mice and old monkeys, lyophilized omicron mRNA vaccine could effectively increase the titers of neutralizing antibodies against wild-type coronavirus and omicron variants. In humans, lyophilized omicron mRNA vaccine as a booster shot could also engender excellent immunity and had less severe adverse events. This lyophilization platform overcomes the instability of mRNA vaccines without affecting their bioactivity, and significantly improved their accessibility, particularly in remote regions.

immunology↗

bioRxiv2022

Macromolecular crowding and supersaturation protect hemodialysis patients from the onset of dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA), a serious complication among long-term hemodialysis patients, is caused by amyloid fibrils of {beta}2-microglobulin ({beta}2m). Although high serum {beta}2m levels and a long dialysis vintage are the primary and secondary risk factors for the onset of DRA, respectively, patients with these do not always develop DRA, indicating that there are additional risk factors. To clarify these unknown factors, we investigated the effects of human sera on {beta}2m amyloid fibril formation. Although sera markedly inhibited amyloid fibril formation, the inhibitory effects were weaker for sera collected from dialysis patients than for control sera. When sera collected before and after maintenance dialysis treatments were compared, the latter inhibited amyloid fibril formation more than the former. These results indicate that, although the inhibitory effects of sera were deteriorated in long-term dialysis patients, they were ameliorated by maintenance dialysis treatments in the short term. Maintenance dialysis decreases the body weight by 5% and consequently increases the concentrations of serum components. Among these components, we found that serum albumin prevented amyloid fibril formation based on macromolecular crowding effects, and that the decreased serum albumin concentration in dialysis patients is a tertiary risk factor for the onset of DRA. The model was constructed assuming accumulative effects of three risk factors and may be useful for predicting the onset of DRA. Furthermore, the model suggested the importance of monitoring temporary and accumulated risks to prevent the development of amyloidoses in general, which occurs based on supersaturation-limited amyloid fibril formation in a crowded milieu.

biophysics↗

bioRxiv2022

Clonal dynamics of SARS-CoV-2-specific T cells in children and adults with COVID-19

Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop less severe coronavirus disease 2019 (COVID-19) than adults. The mechanisms for the age-specific differences and the implications for infection-induced immunity are beginning to be uncovered. We show by longitudinal multimodal analysis that SARS-CoV-2 leaves a small footprint in the circulating T cell compartment in children with mild/asymptomatic COVID-19 compared to adult household contacts with the same disease severity who had more evidence of systemic T cell interferon activation, cytotoxicity and exhaustion. Children harbored diverse polyclonal SARS-CoV- 2-specific naive T cells whereas adults harbored clonally expanded SARS-CoV-2-specific memory T cells. More naive interferon-activated CD4+ T cells were recruited into the memory compartment and recovery was associated with the development of robust CD4+ memory T cell responses in adults but not children. These data suggest that rapid clearance of SARS-CoV-2 in children may compromise their cellular immunity and ability to resist reinfection. HIGHLIGHTSO_LIChildren have diverse polyclonal SARS-CoV-2-specific naive T cells C_LIO_LIAdults have clonally expanded exhausted SARS-CoV-2-specific memory T cells C_LIO_LIInterferon-activated naive T cells differentiate into memory T cells in adults but not children C_LIO_LIAdults but not children develop robust memory T cell responses to SARS-CoV-2 C_LI O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/478400v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@e9586org.highwire.dtl.DTLVardef@17aaf37org.highwire.dtl.DTLVardef@18575e0org.highwire.dtl.DTLVardef@fde4ae_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses

As the SARS-CoV-2 pandemic enters its third year, vaccines that not only prevent disease, but also prevent transmission are needed to help reduce global disease burden. Currently approved parenteral vaccines induce robust systemic immunity, but poor immunity at the respiratory mucosa. Here we describe the development of a novel vaccine strategy, Prime and Spike, based on unadjuvanted intranasal spike boosting that leverages existing immunity generated by primary vaccination to elicit mucosal immune memory within the respiratory tract. We show that Prime and Spike induces robust T resident memory cells, B resident memory cells and IgA at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, Prime and Spike enables induction of cross-reactive immunity against sarbecoviruses without invoking original antigenic sin. One-sentence summaryBroad sarbecovirus protective mucosal immunity is generated by unadjuvanted intranasal spike boost in preclinical model.

immunology↗

bioRxiv2022

SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a novel mechanism by which the SARS-CoV-2 virus co-opts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-{beta}. We reveal that the SARS-CoV-2 encoded Non-Structural Protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-{beta} production, leading to reduced viral infection. Our findings reveal a new target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

microbiology↗

bioRxiv2022

Teasing apart the joint effect of demography and natural selection in the birth of a contact zone

Vast population movements induced by recurrent climatic cycles have shaped the genetic structure of plant species. This is especially true in Scandinavia that was repeatedly glaciated. During glacial periods trees were confined to refugia, south and east of the ice sheet, from which they recolonized Scandinavia as the ice melted away. This multi-pronged recolonization led to large contact zones in most species. We leverage large genomic data from 5000 trees to reconstruct the demographic history of Norway spruce (Picea abies) and test for the presence of natural selection during the recolonization process and the establishment of the contact zone. Sweden is today made up of two large genetic clusters, a southern one originating from the Baltics and a Northern one originating from Northern Russia. The contact zone delineating these two clusters closely matches the limit between two major climatic regions. This suggests that natural selection contributed to the establishment and the maintenance of the contact zone. To test this hypothesis we first used Approximate Bayesian Computation; an Isolation-with migration model with genome-wide linked selection fits the data better than a purely neutral one. Secondly, we identified loci characterized by both extreme allele frequency differences between geographic regions and association to the variables defining the climatic zones. These loci, many of which are related to phenology, form clusters present on all linkage groups. Altogether, the current genetic structure reflects the joint effect of climatic cycles, recolonization and selection on the establishment of strong local adaptation and contact zones. Significance StatementUnderstanding how past climatic events, human actions and evolutionary forces contributed to the present distribution of genetic diversity is crucial to predict their reaction to the current climate crisis. Vast distribution shifts induced by past environmental changes, local ecological processes, natural selection and human transfers contributed to the current distribution of Norway spruce across Northern Europe. Genome-wide polymorphisms from thousands of individuals show that Scandinavia was recolonized after the Last Glacial from both south and north. This two-pronged recolonization established a contact zone between two genetic clusters that matches the limit between two major climate zones. The contact zone is shaped and maintained by natural selection on a large number of loci that form blocks of co-adapted loci spread genome-wide.

evolutionary biology↗

bioRxiv2021

Genome Assemblies of the Warthog and Kenyan Domestic Pig Provide Insights into Suidae Evolution and Candidate Genes for African Swine Fever Tolerance

As warthog (Phacochoerus africanus) has innate immunity against African swine fever (ASF), it is critical to understand the evolutionary novelty of warthog to explain its specific ASF resistance. Here, we present two completed new genomes of one warthog and one Kenyan domestic pig, as the fundamental genomic references to decode the genetic mechanism on ASF tolerance. Our results indicated, multiple genomic variations, including gene losses, independent contraction and expansion of specific gene families, likely moulded warthogs genome to adapt the environment. Importantly, the analysis of the presence and absence of genomic sequences revealed that, the warthog genome had a DNA sequence absence of the lactate dehydrogenase B (LDHB) gene on chromosome 2 compared to the reference genome. The overexpression and siRNA of LDHB indicated that its inhibition on the replication of ASFV. Combining with large-scale sequencing data of 123 pigs from all over the world, contraction and expansion of TRIM genes families revealed that TRIM family genes in the warthog genome were potentially responsible for its tolerance to ASF. Our results will help further improve the understanding of genetic resistance ASF in pigs.

genetics↗

bioRxiv2021

Non-rapid eye movement sleep and wake neurophysiology in schizophrenia

Motivated by the potential of objective neurophysiological markers to index thalamocortical function in patients with severe psychiatric illnesses, we comprehensively characterized key NREM sleep parameters across multiple domains, their interdependencies, and their relationship to waking event-related potentials and symptom severity. In 130 schizophrenia (SCZ) patients and controls, we confirmed a marked reduction in sleep spindle density in SCZ and extended these findings to show that only slow spindles predicted symptom severity, and that fast and slow spindle properties were largely uncorrelated. We also describe a novel measure of slow oscillation and spindle interaction that was attenuated in SCZ. The main sleep findings were replicated in a demographically distinct sample, and a joint model, based on multiple NREM components, predicted disease status in the replication cohort. Although also altered in patients, auditory event-related potentials elicited during wake were unrelated to NREM metrics. Consistent with a growing literature implicating thalamocortical dysfunction in SCZ, our characterization identifies independent NREM and wake EEG biomarkers that may index distinct aspects of SCZ pathophysiology and point to multiple neural mechanisms underlying disease heterogeneity. This study lays the groundwork for evaluating these neurophysiological markers, individually or in combination, to guide efforts at treatment and prevention as well as identifying individuals most likely to benefit from specific interventions.

neuroscience↗

bioRxiv2021

MitoVisualize: A resource for analysis of variants in human mitochondrial RNAs and DNA

We present MitoVisualize, a new tool for analysis of the human mitochondrial DNA (mtDNA). MitoVisualize enables visualization of: (1) the position and effect of variants in mitochondrial transfer RNA (tRNA) and ribosomal RNA (rRNA) secondary structures alongside curated variant annotations, (2) data across RNA structures, such as to show all positions with disease-associated variants or with post-transcriptional modifications, and (3) the position of a base, gene or region in the circular mtDNA map, such as to show the location of a large deletion. All visualizations can be easily downloaded as figures for reuse. MitoVisualize can be useful for anyone interested in exploring mtDNA variation, though is designed to facilitate mtDNA variant interpretation in particular. MitoVisualize can be accessed via https://www.mitovisualize.org/. The source code is available at https://github.com/leklab/mito_visualize/.

genetics↗

bioRxiv2021

Proteomic Characterization of Serum Small Extracellular Vesicles in Human Breast Cancer

There is a lack of comprehensive understanding of breast cancer (BC) specific sEVs characteristics and composition on BC unique proteomic information from human samples. Here, we interrogated the proteomic landscape of sEVs in 167 serum samples from patients with BC, benign mammary disease (BD) and from healthy donors (HD). The analysis provides a comprehensive landscape of serum sEVs with totally 9,589 proteins identified, considerably expanding the panel of sEVs markers. Of note, serum BC-sEVs protein signatures were distinct from those of BD and HD, representing stage- and molecular subtype-specific patterns. We constructed specific sEVs protein identifiers that could serve as a liquid biopsy tool for diagnosis and classification of BC from benign mammary disease, molecular subtypes, as well as assessment of lymph node metastasis. We also identified 11 potential survival biomarkers for distant metastasis. This work may provide reference value for the accurate diagnosis and monitoring of BC progression using serum sEVs.

bioinformatics↗

bioRxiv2021

Cryo-EM structure of the Smc5/6 holo-complex

The Smc5/6 complex plays an essential role in the resolution of recombination intermediates formed during mitosis or meiosis, or as a result of the cellular response to replication stress. It also functions as a restriction factor preventing viral integration. Here, we report the cryo-EM structure of the six-subunit budding yeast Smc5/6 holo-complex, reconstituted from recombinant proteins expressed in insect cells - providing a full overview of the complex in its apo / non-liganded form, and revealing how the Nse1/3/4 subcomplex binds to the hetero-dimeric SMC protein core. In addition, we demonstrate that a region within the head domain of Smc5, equivalent to the W-loop of Smc4 or F-loop of Smc1, mediates an essential interaction with Nse1. Taken together, these data confirm a degree of functional equivalence between the structurally unrelated KITE and HAWK accessory subunits associated with SMC complexes.

biochemistry↗

bioRxiv2021

Diversity, function and evolution of marine microbe genomes

Trillions of marine bacterial, archaeal and viral species contribute to the majority diversity of life on Earth. In the current study, we have done a comprehensive review of all the published studies of marine microbiome by re-analyzing most of the available high throughput sequencing data. We collected 17.59 Tb sequencing data from 8,165 metagenomic and prokaryotic samples, and systematically evaluated the genome characters, including genome size, GC content, phylogeny, and the functional and ecological roles of several typical phyla. A genome catalogue of 9,070 high quality genomes and a gene catalogue including 156,209,709 genes were constructed, representing the most integrate marine prokaryotic datasets till now. The genome size of Alphaproteobacteria and Actinobacteria was significant correlated to their GC content. A total of 44,322 biosynthetic gene clusters distributed in 53 types were detected from the reconstructed marine prokaryotic genome catalogue. Phylogenetic annotation of the 8,380 bacterial and 690 archaeal species revealed that most of the known bacterial phyla (99/111), including 62 classes and 181 orders, and four extra unclassified genomes from two candidate novel phyla were detected. In addition, taxonomically unclassified species represented a substantial fraction of 64.56% and 80.29% of the phylogenetic diversity of Bacteria and Archaea respectively. The genomic and ecological features of three groups of Cyanobacteria, luminous bacteria and methane-metabolizing archaea, including inhabitant preference, geolocation distribution and others were through discussed. Our database provides a comprehensive resource for marine microbiome, which would be a valuable reference for studies of marine life origination and evolution, ecology monitor and protection, bioactive compound development.

microbiology↗

bioRxiv2021

Kinetic Explanations for the Sequence Biases Observed in the Nonenzymatic Copying of RNA Templates

The identification of nonenzymatic pathways for nucleic acid replication is a key challenge in understanding the origin of life. We have previously shown that nonenzymatic RNA primer extension using 2-aminoimidazole (2AI) activated nucleotides occurs primarily through an imidazolium-bridged dinucleotide intermediate. The reactive nature and preorganized structure of the intermediate increase the efficiency of primer extension but remain insufficient to drive extensive copying of RNA templates containing all four canonical nucleotides. To understand the factors that limit RNA copying, we synthesized all ten 2AI-bridged dinucleotide intermediates and measured the kinetics of primer extension in a model. The affinities of the ten dinucleotides for the primer/template/helper complexes vary by over 7,000-fold, consistent with nearest neighbor energetic predictions. Surprisingly, the reaction rates at saturating intermediate concentrations still vary by over 15-fold, with the most weakly binding dinucleotides exhibiting a lower maximal reaction rate. Certain noncanonical nucleotides can decrease sequence dependent differences in affinity and primer extension rate, while monomers bridged to short oligonucleotides exhibit enhanced binding and reaction rates. We suggest that more uniform binding and reactivity of imidazolium-bridged intermediates may lead to the ability to copy arbitrary template sequences under prebiotically plausible conditions.

biochemistry↗

bioRxiv2021

Reference genomes of 545 silkworms enable high-throughput exploring genotype-phenotype relationships

The silkworm Bombyx mori is a domestic insect for silk production and a lepidopteran model. The currently available genomes limit a full understanding of its genetic and phenotypic diversity. Here we assembled long-read genomes of 545 domestic and wild silkworms and constructed a high-resolution pan-genome dataset. We found that the silkworm population harbors extremely variable genomes containing 7,308 new gene families, 4,260 (22%) core gene families, and 3,432,266 non-redundant SVs. We deciphered a series of causal genes and variants associated with domestication, breeding, and ecological adaptation traits, and experimentally validated two of those genes using CRISPR-Cas9 or RNA interference. This unprecedented large-scale genomic resource allows for high-throughput screening of interesting traits for functional genomic research and breeding improvement of silkworms and may serve as a guideline for traits decoding in other species.

genomics↗

bioRxiv2021

Myostatin is a negative regulator of adult neurogenesis in zebrafish

Intrinsic and extrinsic inhibition of axonal and neuronal regeneration obstruct spinal cord (SC) repair in mammals. In contrast, adult zebrafish achieve functional recovery after SC damage. While studies of innate SC regeneration have focused on axon regrowth as a primary repair mechanism, how local neurogenesis impacts functional recovery is unknown. We uncovered dynamic expression of myostatin b (mstnb) in a niche of dorsal ependymal progenitors after complete SC transection in zebrafish. Genetic loss-of-function in mstnb impaired functional recovery, although glial and axonal bridging across the lesion were unaffected. Using a series of transgenic reporter lines, we quantified the numbers of stem, progenitor, and neuronal cells in the absence of mstnb. We found neural stem cell proliferation was reduced, while newborn neurons were increased in mstnb null tissues, suggesting mstnb is a negative regulator of neurogenesis. Molecularly, neuron differentiation genes were upregulated, while the neural stem cell maintenance gene fgf1b was downregulated in mstnb mutants. Finally, we show that human FGF1 treatment rescued neuronal gene expression in mstnb mutants. These studies uncover unanticipated neurogenic functions for mstnb in adult zebrafish, and establish the importance of local neurogenesis for functional SC repair.

neuroscience↗

bioRxiv2021

Broad neutralizing nanobody against SARS-CoV-2 engineered from pre-designed synthetic library

SARS-CoV-2 infection is initiated with Spike glycoprotein binding to the receptor of human angiotensin converting enzyme 2 via its receptor binding domain. Blocking this interaction is considered as an effective approach to inhibit virus infection. Here we report the discovery of a neutralizing nanobody, VHH60, directly produced from a humanized synthetic nanobody library. VHH60 competes with human ACE2 to bind the receptor binding domain of the Spike protein with a KD of 2.56 nM, inhibits infections of both live SARS-CoV-2 and pseudotyped viruses harboring wildtype, escape mutations and prevailing variants at nanomolar level. VHH60 also suppresses SARS-CoV-2 infection and propagation 50-fold better and protects mice from death two times longer than that of control group after live virus inoculation on mice. VHH60 therefore is a powerful synthetic nanobody with a promising profile for disease control against COVID19.

microbiology↗

bioRxiv2021

Constructing a warhead of PROTAC with aptamer for tumor-selective degradation of nucleolin

PROteolysis TArgeting Chimeras (PROTACs) induce targeted protein degradation by hijacking the intracellular ubiquitin proteasome system, thus emerging as a new strategy for drug development. However, most PROTACs generated lack cell-type selectivity and have poorly soluble in water. To address this drawback, we developed a novel PROTAC ZL216 using aptamer AS1411 as a targeting ligand of nucleolin to conjugate with a small molecule ligand of E3 ligase VHL, which shows high aqueous solubility and serum stability. Based on the differential expression of nucleolin on the cell surface, ZL216 could bind to and internalize into breast cancer cells, but not normal breast cells. Furthermore, we revealed that ZL216 promoted the formation of a nucleolin-ZL216-VHL ternary complex in breast cancer cells and potently induced nucleolin degradation in vitro and in vivo. As a result, ZL216 inhibited the proliferation and migration of breast cancer cells. These studies demonstrate that in addition to peptides and small molecule compounds, nuclei acid aptamers can also be used to generate PROTACs, which broadens the toolbox constructing PROTACs and provides a promising strategy for development of tumor-selective PROTACs.

biochemistry↗