Biology subjects

Tian, Z.

Publications and source records attributed to Tian, Z..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

SoyOmics: A deeply integrated database on soybean multi omics

As one of the most important crops to supply majority plant oil and protein for the whole world, soybean is facing an increasing global demand. Up to now, vast multi-omics data of soybean were generated, thereby providing valuable resources for functional study and molecular breeding. Nevertheless, it is tremendously challenging for researchers to deal with these big multi-omics data, particularly considering the unprecedented rate of data growth. Therefore, we collect the reported high-quality omics, including assembly genomes, graph pan-genome, resequencing and phenotypic data of representative germplasms, transcriptomic and epigenomic data from different tissues, organs and accessions, and construct an integrated soybean multi-omics database, named SoyOmics (https://ngdc.cncb.ac.cn/soyomics). By equipping with multiple analysis modules and toolkits, SoyOmics is of great utility to facilitate the global scientific community to fully use these big omics datasets for a wide range of soybean studies from fundamental functional investigation to molecular breeding.

bioinformatics↗

bioRxiv2022

Enhancing Mitochondrial Functions by Optogenetic Clustering

Known as the powerhouses of cells, mitochondria and its dynamics are important for their functions in cells. Herein, an optogenetic method that controlling mitochondria to form the clusters was developed. The plasmid named CRY2PHR-mCherry-Miro1TM was designed for the optogenetic system. The photoactivable protein CRY2PHR was anchored to mitochondria, via the specific organelle-targeting transmembrane domain Miro1TM. Under blue light illumination, CRY2PHR can form the oligomerization, called puncta. With the illuminated time extended, the puncta can interact, and the mitochondria were found to form clustering with reversibility and spatiotemporal controllability. The mitochondrial functions were found to enhance after the formation of optogenetic mitochondrial clusters. This method presented here provides a way to control mitochondrial clustering and raise mitochondrial functions up.

cell biology↗

bioRxiv2022

Spatial proteomics and iPSC modeling uncover mechanisms of axonal pathology in Alzheimer's disease

Axonal spheroids (dystrophic neurites) are commonly found around amyloid deposits in Alzheimers disease (AD). They impair electrical conduction, disrupt neural circuits, and correlate with AD severity. Despite their significance, the mechanisms underlying spheroid formation remain unknown. To address this, we developed a proximity labeling proteomics approach to uncover the proteome of spheroids in human postmortem and mouse brains. Additionally, we established a human iPSC-derived AD model allowing mechanistic investigation of spheroid pathology and optical electrophysiology. This approach revealed the subcellular molecular architecture of spheroids and identified abnormalities in key biological processes, including protein turnover, cytoskeleton dynamics, and lipid transport. Notably, the PI3K/AKT/mTOR pathway, which regulates these processes, was activated within spheroids. Furthermore, phosphorylated mTOR levels in spheroids strongly correlated with AD severity in humans. Importantly, inhibition of mTOR in iPSC-derived neurons and in mice ameliorated spheroid pathology. Altogether, our study provides a multidisciplinary toolkit for investigating mechanisms and novel targets for axonal pathology in neurodegeneration.

neuroscience↗

bioRxiv2022

Programming super DNA-enzyme molecules for on-demand enzyme activity modulation

Dynamic interactions of enzymes, including programmable configuration and cycling of enzymes, play important roles in the regulation of cellular metabolism. Here, we construct a super DNA-enzymes molecule (SDEM) that comprises at least two cascade enzymes and linked DNA strands to control and detect metabolism. We find that the programmable SDEM which comprises glucose oxidase (GOx) and horseradish peroxidase (HRP) has a 50-fold lower detection of limit and a 1.6-fold higher reaction rate than free enzymes. SDEM can be assembled and disassembled using a hairpin structure and a displacement DNA strand to complete multiple cycles. An entropically driven catalytic assembly (catassembly) enables different SDEMs to switch from SDEM with GOx and HRP cascades to SDEM with sarcosine oxidase (SOX) and HRP cascades by over six orders of magnitude less time than no catassembly to detect different metabolisms (glucose and sarcosine) on demand.

biochemistry↗

bioRxiv2022

Molecular basis for the pheromone-mediated feeding preference of early-instar Mythimna separata larvae

Insect sex pheromones are important chemical signals in sexual communication, they are traditionally thought to be inactive to larvae. However, it was found that some lepidopteran larvae can be significantly attracted by sex pheromones of the same species in a food context. Here we reported that the host-feeding choice of early-instar Mythimna separata larvae can be effectively regulated by the sex pheromone component (Z)-11-hexadecenal (Z11-16: Ald). Further exploration revealed that two olfactory proteins, M. separata general odorant binding protein 2 (MsGOBP2) and olfactory receptor 3 (MsOR3), were molecular basis of the host-feeding choice regulation mediated by Z11-16: Ald. Silencing either MsGOBP2 or MsOR3 led to a sharply reduced preference for Z11-16: Ald-spiked hosts. It is possible that the Z11-16: Ald-based preference of the M. separata larvae for host is governed by the interplay between MsGOBP2 and MsOR3. In the present research, the interactions between MsGOBP2 and Z11-16: Ald were also discussed using molecular dynamics-based approaches. Our research explored insight into the Z11-16: Ald-mediated host-feeding choice regulation of M. separata larvae, all the results would aid in developing olfaction-based methods for controlling pests in larval stage.

ecology↗

bioRxiv2022

Triangulation fails when neither linguistic, genetic, nor archaeological data support the Transeurasian narrative

Robbeets et al.1 argue that the dispersal of the so-called "Transeurasian" languages, a highly disputed language superfamily comprising the Turkic, Mongolian, Tungusic, Koreanic, and Japonic language families, was driven by Neolithic farmers in the West Liao River region of China. They adduce evidence from linguistics, archaeology, and genetics to support their claim. An admirable feature of the Robbeets et al.s paper is that all their datasets can be accessed. However, a closer investigation of all three types of evidence reveals fundamental problems with each of them. Robbeets et al.s analysis of the linguistic data does not conform to the minimal standards required by traditional scholarship in historical linguistics and contradicts their own stated sound correspondence principles. A reanalysis of the genetic data finds that they do not conclusively support the farming-driven dispersal of Turkic, Mongolian, and Tungusic, nor the two-wave spread of farming to Korea. Their archaeological data contain little phylogenetic signal, and we failed to reproduce the results supporting their core hypotheses about migrations. Given the severe problems we identify in all three parts of the "triangulation" process, we conclude that there is neither conclusive evidence for a Transeurasian language family nor for associating the five different language families with the spread of Neolithic farmers from the West Liao River region.

genetics↗

bioRxiv2022

Multiplex CRISPR strategy targeting viral genome for agriculture and clinical use

African Swine Fever (ASF) is a viral disease with exceptionally high lethality in domestic pigs and wild boar worldwide1, 2, without any effective vaccine or drug to prevent its spread. In this study, we established a multiplexable CRISPR-Cas-gRNA system targeting 13 genomic loci in the ASF virus genome that could prevent viral replication by cutting its genome. Furthermore, we generated pig strains expressing the multiplexable CRISPR-Cas-gRNA via germline genome editing and demonstrated that the gene-edited pigs were more resistant to ASFV infection and less likely to spread the virus upon infection. As far as we know, our study presents the first living organism generated via germline editing to demonstrate resistance to viral infection via CRISPR-Cas. We anticipate our work to be helpful for both agricultural and biomedical applications, such as xenotransplantation.

bioengineering↗

bioRxiv2022

Unleashing the Potential of Noncanonical Amino Acid Biosynthesis for Creation of Cells with Site-Specific Tyrosine Sulfation

Incorporation of noncanonical amino acids (ncAAs) into proteins holds great promise for modulating the structure and function of those proteins and for influencing evolutionary dynamics in organisms. Despite significant progress in improving the efficiency of translational machinery needed for incorporating ncAAs, exogenous feeding of high concentrations of chemically-synthesized ncAAs, especially in the case of polar ncAAs, is required to ensure adequate intracellular ncAA levels. Here, we report the creation of autonomous cells, both prokaryotic and eukaryotic, with the ability to biosynthesize and genetically encode sulfotyrosine (sTyr), an important protein post-translational modification with low membrane permeability. We discovered the first enzyme catalyzing tyrosine sulfation, sulfotransferase 1C1 from Nipponia nippon (NnSULT1C1), using a sequence similarity network (SSN). The unique specificity of NnSULT1C1 for tyrosine has been systematically explored using both bioinformatics and computational methods. This NnSULT1C1 was introduced into both bacterial and mammalian cells so as to yield organisms capable of biosynthesizing high levels of intracellular sTyr. These engineered cells produced site-specifically sulfated proteins at a higher yield than cells fed exogenously even with the highest level of sTyr reported in literature. We have used these autonomous cells to prepare highly potent thrombin inhibitors with site-specific sulfation. By enhancing ncAA incorporation efficiency, this added ability of cells to biosynthesize ncAAs and genetically incorporate them into proteins greatly extends the utility of genetic code expansion methods. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/485857v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@2c3b08org.highwire.dtl.DTLVardef@1d7a914org.highwire.dtl.DTLVardef@19d9f91org.highwire.dtl.DTLVardef@156ee8c_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

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

Bone-Specific Enhancement of Antibody Therapy for Breast Cancer Metastasis to Bone

Therapeutic antibodies have gone a long way toward realizing their clinical potential and have become very useful for treating a variety of pathologies. Despite the rapid evolution of therapeutic antibodies, their clinical efficacy in treatment of bone tumors has been hampered by the inadequate pharmacokinetics and poor bone tissue accessibility of these large macromolecules. Here, we show that engineering therapeutic antibodies to include bone-homing peptide sequences dramatically enhances their concentration in the bone metastatic niche, resulting in significantly reduced survival and progression of breast cancer bone metastases. To enhance the bone tumor-targeting ability of engineered antibodies, we introduced varying numbers of a bone-homing peptide into permissive internal sites of the anti-HER2 antibody trastuzumab. Compared to the unmodified antibody, the engineered bone-targeting antibodies have similar pharmacokinetics and in vitro cytotoxic activity against HER2-positive cancer cells, but exhibit improved bone tumor distribution in vivo. Accordingly, in xenograft models of breast cancer metastasis to bone sites, engineered antibodies with enhanced bone specificity exhibit increased inhibition of both initial bone metastases and secondary multi-organ metastases from bone lesions. Furthermore, this engineering strategy is also applied to prepare bone-targeting antibody-drug conjugates with enhanced therapeutic efficacy. These results demonstrate that adding bone-specific targeting to antibody therapy results in robust delivery of therapeutic antibodies to the bone tumor niche. This provides a powerful strategy for overcoming inadequate treatment of bone cancer and the development of potentially acquired resistance to therapy.

bioengineering↗

bioRxiv2021

The maize hexokinase gene ZmHXK7 confers salt resistance in transgenic Arabidopsis plants

The hexokinase (HXK) gene family, whose members play vital roles in sugar induction signals and glycolysis in organisms, is widely found in plants. Although some hexokinase genes have been studied in maize, a systematic report of the gene family and its role in plant resistance is lacking. In this study, 10 hexokinase genes were systematically identified in maize based on the maize genome-wide database. Phylogenetic analysis divides the maize HXK protein family into four clusters. Prediction of cis-regulatory elements showed that a number of elements responding to abiotic stress exist in the promoter of hexokinase genes. The expression profile of these genes, originated from B73, showed that different members of hexokinase genes are highly expressed in roots and leaves of maize under salt or drought stress, which is similar to that of Mo17.The coding sequence of ZmHXK7 gene, isolated from maize B73, was constructed into plant expression vector pMDC45 and then transformed into athxk3 (Salk_022188C). By hyg resistance detection, PCR analysis, and western blot confirmation, the homozygous progenies of transgenic Arabidopsis lines were identified. Subcellular localization analysis showed that the ZmHXK7 gene was located in cytosol. Seedling growth and salt stress inhibition in complementary mutant plants of ZmHXK7 gene were significantly improved, and enhanced salt tolerance was displayed. Our study provides insights into the evolution and expression patterns of the hexokinase gene and show that maize ZmHXK7 proteins play an important role in resisting salt stress, which will be useful in plant breeding for abiotic stress resistance.

plant biology↗

bioRxiv2021

Harnessing the Power of Antibodies to Fight Bone Metastasis

Over the past 20 years, antibody-based therapies have proved to be of great value in cancer treatment. Despite the clinical success of these biopharmaceuticals, reaching targets in the bone micro-environment has proved to be difficult perhaps due to the relatively low vascularization of bone tissue and the presence of physical barriers that impair drug penetration. Here, we have used an innovative bone targeting (BonTarg) technology to generate a first-in-class bone-targeting anti-body. Moreover, we have used two xenograft models to demonstrate the enhanced therapeutic efficacy of this bone-targeting antibody against bone metastases, compared to the efficacy of traditional antibodies. Our strategy involves the use of pClick antibody conjugation technology to chemically couple the bone-targeting moiety bisphosphonate to the human epidermal growth factor receptor 2 (HER2)-specific antibody trastuzumab. Bisphosphonate modification of therapeutic antibodies results in delivery of higher conjugate concentrations to the bone metastatic niche, relative to other tissues. In both HER2-positive and negative xenograft mice models, this strategy provides enhanced inhibition of experimental bone metastases as well as multi-organ secondary metastases that arise from the bone lesions. Specific delivery of therapeutic antibodies to the bone therefore represents a promising strategy for the treatment of bone metastatic cancers and other bone diseases.

cancer biology↗

bioRxiv2021

Aminooxadiazolyl kainic acid reveals that kainic acid receptors contribute to astrocytoma glutamate signaling

The excitatory neurotransmitter glutamate triggers a Ca2+ rise and the extension of processes in astrocytes. Our results suggest that kainic acid receptors (KAR) can independently initiate glutamate signaling in astrocytoma U118-MG cells. The natural product kainic acid triggered glioexcitablity in cells and was inhibited by the KAR antagonist CNQX, but its activity was lower than glutamate on KARs. We created a new heteroaryl kainoid based on rational design: aminooxadiazolyl kainic acid 1 (AODKA). AODKA induced a larger calcium influx and a faster processes extension than kainic acid in U118-MG cells. AODKA is a new tool to study KAR activity in the nervous system. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/426948v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1b63f72org.highwire.dtl.DTLVardef@1ff92c4org.highwire.dtl.DTLVardef@1fcb212org.highwire.dtl.DTLVardef@10ed76e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Kaposi's Sarcoma Herpesvirus Is Associated with Osteosarcoma in Xinjiang Uyghur Population

Osteosarcoma is the most common malignant tumor of bone predominately affecting adolescents and young adults. Viral etiology of osteosarcoma has been proposed more than a half-century ago but never been proven by identifying any virus authentically associated with human osteosarcoma. The Uyghur ethnic population in Xinjiang China has an unusually high prevalence of Kaposis sarcoma-associated herpesvirus (KSHV) infection and elevated incidence of osteosarcoma. In the current study, we explored the possible association of KSHV infection and osteosarcoma occurrence. Our seroepidemiological study revealed that KSHV prevalence was significantly elevated in osteosarcoma patients versus the general population in the Xinjiang Uyghur population (OR, 10.23; 95%CI, 4.25, 18.89). The KSHV DNA genome and viral latent nuclear antigen LANA were detected in most osteosarcoma tumor cells. Gene expression profiling analysis showed that KSHV positive osteosarcoma represents a distinct subtype of osteosarcomas with viral gene-driven signaling pathways that are important for osteosarcoma development. We conclude that KSHV infection is a risk factor for osteosarcoma and KSHV is associated with some osteosarcomas, representing a newly identified viral-associated endemic cancer. SignificanceViral etiology of osteosarcoma was proposed previously but has never been proven by identifying any virus that is authentically associated with human osteosarcoma. The current study revealed an association of human osteosarcoma with KSHV infection in Uyghur osteosarcoma patients. First, this study provides the first evidence that supports the possible viral etiology of human osteosarcoma. The gene expression profiling study showed that KSHV-positive osteosarcoma represents a distinct subtype of osteosarcomas, which is of diagnostic, prognostic and therapeutic significance. Second, KSHV-associated osteosarcomas preferentially occur in children and young adults, predicting that KSHV-positive children in KSHV endemic region may be at great risk for osteosarcoma. Third, the finding extended the range of human cancers associated with viruses.

microbiology↗

bioRxiv2020

Insulin Resistance Mediates Crosstalk between Skeletal Muscle and the Heart to Prevent Cardiac Dysfunction

Obesity and type 2 diabetes milieus (T2DM) are the leading causes of cardiovascular morbidity and mortality. Although insulin resistance is believed to underlie these disorders, a paradox exists that obese patients with cardiovascular diseases have better prognoses relative to leaner patients with the same diagnoses, whereas improvement of insulin sensitivity by thiazolidines significantly increases the risk of heart failure in T2DM patients. Using mice with skeletal muscle-specific deletion of the insulin receptor gene (MIRKO), we resolved this dilemma by demonstrating that insulin resistance in the skeletal muscle prevents myocardial hypertrophy and dysfunction in response to diet-induced obesity. In spite of aggregating obesity, insulin resistance selectively protected the heart, but not other metabolic tissues, from mitochondrial dysfunction and insulin resistance in MIRKO mice, leading to significant attenuation of inflammation and apoptosis of cardiomyocytes. Together, our findings revealed an unexpected role of insulin resistance as a double edge sword, calling for reevaluation of ongoing efforts for targeting insulin resistance for the treatment of metabolic diseases. Significance statementInsulin resistance is commonly recognized as one of the major causes of T2DM and other aging-related chronic diseases. However, cumulative efforts in targeting insulin resistance for the treatment of T2DM and other metabolic disorders have not met with great success due to unwanted side effects on heart failure. Here we report that insulin resistance in skeletal muscle is a double edge sword. On one hand, insulin resistance in skeletal muscle aggregates obesity and its related metabolic syndromes, and on the other it protects the heart from the development of myocardial hypertrophy, dysfunction, and apoptosis in response to DIO. Our findings call for reevaluation of the ongoing strategies in targeting insulin resistance as a novel treatment for T2DM and other metabolic diseases.

cell biology↗

bioRxiv2020

Double-transmembrane domain reduces fusion rate by increasing lipid-protein mismatch

SNARE is the essential mediator of membrane fusion that highly relies on the molecular structure of SNAREs. For instance, the protein syntaxin-1 involving in neuronal SNAREs, has a single transmembrane domain (sTMD) leading to fast fusion, while the syntaxin 17 has a V-shape double TMDs (dTMDs), taking part in the autophagosome maturation. However, it is not clear how the TMD structure influences the fusion process. Here, we demonstrate that the dTMDs significantly reduce fusion rate compared with the sTMD by using an in vitro reconstitution system. Through theoretical analysis, we reveal that the V-shape dTMDs can significantly increase protein-lipid mismatch, thereby raising the energy barrier of the fusion, and that increasing the number of SNAREs can reduce the energy barrier or protein-lipid mismatch. This study provides a physical-chemical mechanistic understanding of SNARE-regulated membrane fusion.

biophysics↗

bioRxiv2020

Mechanism of duplex unwinding by coronavirus nsp13 helicases

The current COVID-19 pandemic urges in-depth investigation into proteins encoded with coronavirus (CoV), especially conserved CoV replicases. The nsp13 of highly pathogenic MERS-CoV, SARS-CoV-2, and SARS-CoV exhibit the most conserved CoV replicases. Using single-molecule FRET, we observed that MERS-CoV nsp13 unwound DNA in discrete steps of approximately 9 bp when ATP was used. If another NTP was used, then the steps were only 4 to 5 bp. In dwell time analysis, we detected 3 or 4 hidden steps in each unwinding process, which indicated the hydrolysis of 3 or 4 dTTP. Based on crystallographic and biochemical studies of CoV nsp13 helicases, we modeled an unwinding mechanism similar to the spring-loaded mechanism of HCV NS3 helicase, although our model proposes that flexible 1B and stalk domains, by allowing a lag greater than 4 bp during unwinding, cause the accumulated tension on the nsp13-DNA complex. The hinge region between two RecA-like domains in SARS-CoV-2 nsp13 is intrinsically more flexible than in MERS-CoV nsp13 due to the difference of a single amino acid, which causes the former to induce significantly greater NTP hydrolysis. Our findings thus establish a blueprint for determining the unwinding mechanism of a unique helicase family. O_LIWhen dTTP was used as the energy source, 4 hidden steps in each individual unwinding step after 3 - 4 NTP hydrolysis were observed. C_LIO_LIAn unwinding model of MERS-CoV-nsp13 which is similar to the spring-loaded mechanism of HCV NS3 helicase, except the accumulation of tension on nsp13/DNA complex is caused by the flexible 1B and stalk domains that allow a lag of 4-bp in unwinding. C_LIO_LIComparing to MERS-CoV nsp13, the hinge region between two RecA-like domains in SARS-CoV-2 nsp13 is intrinsically more flexible due to a single amino acid difference, which contributes to the significantly higher NTP hydrolysis by SARS-CoV-2 nsp13. C_LI

biophysics↗

bioRxiv2020

A high-quality de novo genome assembly from a single parasitoid wasp

Sequencing and assembling a genome with a single individual have several advantages, such as lower heterozygosity and easier sample preparation. However, the amount of genomic DNA of some small sized organisms might not meet the standard DNA input requirement for current sequencing pipelines. Although few studies sequenced a single small insect with about 100 ng DNA as input, it may still be challenging for many small organisms to obtain such amount of DNA from a single individual. Here, we use 20 ng DNA as input, and present a high-quality genome assembly for a single haploid male parasitoid wasp (Habrobracon hebetor) using Nanopore and Illumina. Because of the low input DNA, a whole genome amplification (WGA) method is used before sequencing. The assembled genome size is 131.6 Mb with a contig N50 of 1.63 Mb. A total of 99% Benchmarking Universal Single-Copy Orthologs are detected, suggesting the high level of completeness of the genome assembly. Genome comparison between H. hebetor and its relative Bracon brevicornis shows a high-level genome synteny, indicating the genome of H. hebetor is highly accurate and contiguous. Our study provides an example for de novo assembling a genome from ultra-low input DNA, and will be used for sequencing projects of small sized species and rare samples, haploid genomics as well as population genetics of small sized species.

genomics↗