Biology subjects

Guo, W.

Publications and source records attributed to Guo, W..

At least 217 records · Page 12Linked to original sources

bioRxiv2020

Hippocampal and cortical mechanisms at retrieval explain variability in episodic remembering in older adults

Age-related episodic memory decline is characterized by striking heterogeneity across individuals. Hippocampal pattern completion is a fundamental process supporting episodic memory. Yet, the degree to which this mechanism is impaired with age, and contributes to variability in episodic memory, remains unclear. We combine univariate and multivariate analyses of fMRI data from a large cohort of cognitively normal older adults (N=100; 60-82 yrs) to measure hippocampal activity and cortical reinstatement during retrieval of trial-unique associations. Trial-wise analyses revealed that hippocampal activity predicted cortical reinstatement strength, and these two metrics of pattern completion independently predicted retrieval success. However, increased age weakened cortical reinstatement and its relationship to memory behaviour. Critically, individual differences in the strength of hippocampal activity and cortical reinstatement explained unique variance in performance across multiple assays of episodic memory. These results indicate that fMRI indices of hippocampal pattern completion explain within- and across-individual memory variability in older adults.

neuroscience↗

bioRxiv2020

Prediction of meiosis-essential genes based upon the dynamic proteomes responsive to spermatogenesis

Mammalian meiosis is a specific cell division process during sexual reproduction, whereas a comprehensive proteome of the different meiotic stages has not been systematically investigated. Here, we isolated different types of spermatocytes from the testes of spermatogenesis-synchronized mice and quantified the corresponding proteomes with high-resolution mass spectrometry. A total of 8,002 proteins were identified in nine types of germ cells, and the protein signatures of spermatogenesis were characterized using the dynamic proteomes. A supervised machine learning package, FuncProFinder, was developed to predict meiosis-essential candidate genes based on changes in their protein abundance. Of the candidates without functional annotation, four of the ten genes with the highest prediction scores, Zcwpw1, Tesmin, 1700102P08Rik, and Kctd19, were validated as meiosis-essential genes using knockout mouse models. The proteomic analysis of spermatogenic cells provides a solid foundation for studying the mechanism of mammalian meiosis.

developmental biology↗

bioRxiv2020

Accumulation of ammonium owing to the metabolic imbalance of carbon and nitrogen might inhibit the central metabolism in Methylomonas sp. ZR1

The metabolic intermediates of nitrogen source have been proved to have multiple functions on the metabolism of mehthanotrophs. In this study, accumulation and assimilation mechanism of the nitrate metabolic intermediate ammonium in the fast growing Methylomonas sp. ZR1 was analyzed. Although, nitrate salt was the best nitrogen source supporting the growth of ZR1, its metabolic intermediate ammonium would accumulate and inhibit ZR1. Kinetic studies indicated that accumulation of NH4+ was deduced from the imbalance of nitrogen and carbon metabolism. Compensation of carbon skeleton -keto-glutaramate could effectively relieve the inhibition of NH4+ to ZR1, which further approved the assumption. qPCR analysis indicated a third ammonium assimilation pathway Glycine synthesis system may function in ZR1 under high ammonium tension. In the presence of ammonium, ZR1 might employ two strategies to relieve the ammonium stress, one was assimilating the excess ammonium, and another one was cutting off the nitrogen reduction reactions. Investigation of the nitrogen metabolism and its influence to the carbon metabolism is meaningful to systematically understand and control the C1 feedstock bioconversion process in methanotrophs. ImportanceThe nitrogen metabolism in methanotrophs has long been concerned. However, there are lots of research problems yet to be solved. In this study, the accumulation and assimilation mechanism of the nitrogen metabolic intermediate ammonium in the fast growing Methylomonas sp. ZR1 was analyzed. Owing to the imbalance metabolism of carbon and nitrogen source, ammonium would accumulate to high concentrations to inhibit cell growth. Compensation of carbon skeleton was an effective strategy to relieve the inhibition of NH4+. A third ammonium assimilation pathway related genes were proved actively expressing in ZR1 when it confronted with high ammonium tension. When confronted with ammonium tension, ZR1 might employ different strategies to relieve the ammonium stress according to the edible carbon source. Revealing the endogenous ammonium accumulation mechanism and its metabolic adjustment effect on the central metabolism of methanotrophs, was meaningful to reveal the complex coordination metabolic mechanism of nitrogen and carbon in methanotrophs.

physiology↗

bioRxiv2020

In vitro activities of the tetrazole SHR8008 compared to itraconazole and fluconazole against Candida and Cryptococcus species

Candida and Cryptococcus are the main pathogens of clinical fungal infection associated with high morbidity and mortality. SHR8008 (in fact, this is the only official name in China and it is called VT-1161 by FDA) is a novel tetrazole agent that selectively inhibits fungal CYP51A compared to mammalian cytochrome P450 enzymes to achieve a better antifungal effect. The in vitro activities of SHR8008 and its comparators itraconazole and fluconazole were determined in 127 Candida and 50 Cryptococcus strains isolated from Chinese patients in the last 2 years by Invasive Fungal Infection Group. The MICs of SHR8008 and other triazoles were measured by the Clinical and Laboratory Standards Institute guidelines M27-E4. For Candida spp., SHR8008 (geometric mean MIC=0.078 g/mL) was 6.5-fold and 11.2-fold more potent than itraconazole and fluconazole, respectively. There is a good correlation of MICs between SHR8008 and itraconazole/fluconazole. The MIC values of SHR8008 against Candida glabrata and Candida tropicalis were significantly lower than those of fluconazole, while for Candida albicans and Candida parapsilosis, the differences between SHR8008 and fluconazole were not statistically significant, either. For Cryptococcus spp., SHR8008 (geometric mean MIC=0.024 g/mL) was 21.7-fold and 104.5-fold more potent than itraconazole and fluconazole, respectively. Against the seven Cryptococcus neoformans isolates with elevated fluconazole MICs ([≥]8g/mL based on the MIC90 value for this azole), SHR8008 maintained potent activity, with MICs ranging between 0.031 and 0.5 g/mL. The results showed that tetrazole SHR8008 was more promising in the treatment of Candida and Cryptococcus infection than itraconazole and fluconazole.

microbiology↗

bioRxiv2020

Genomic analyses provide insights into peach local adaptation and responses to climate change

The environment has constantly shaped plant genomes, but the genetic bases underlying how plants adapt to environmental influences remain largely unknown. We constructed a high-density genomic variation map by re-sequencing genomes of 263 geographically representative peach landraces and wild relatives. A combination of whole-genome selection scans and genome-wide environmental association studies (GWEAS) was performed to reveal the genomic bases of peach local adaptation to diverse climates comprehensively. A total of 2,092 selective sweeps that underlie local adaptation to both mild and extreme climates were identified, including 339 sweeps conferring genomic pattern of adaptation to high altitudes. Using GWEAS, a total of 3,496 genomic loci strongly associated with 51 specific environmental variables were detected. The molecular mechanism underlying adaptive evolution of high drought, strong UV-B, cold hardiness, sugar content, flesh color, and bloom date were revealed. Finally, based on 30 years of observation, a candidate gene associated with bloom date advance, representing peach responses to global warming, was identified. Collectively, our study provides insights into molecular bases of how environments have shaped peach genomes by natural selection and adds valuable genome resources and candidate genes for future studies on evolutionary genetics, adaptation to climate changes, and future breeding.

genomics↗

bioRxiv2019

Single-Cell Map of Diverse Immune Phenotypes in the Metastatic Brain Tumor Microenvironment of Non Small Cell Lung Cancer

Cancer immunotherapies have shown sustained clinical success in treating primary non-small-cell lung cancer (NSCLC). However, patients with brain metastasis are excluded from the trials because the brain is viewed traditionally as an immune-privileged organ. The composition and properties of tumor-infiltrating myeloid cells in metastatic brain tumors are mostly unknown. To depict the baseline landscape of the composition, gene signature, and functional states of these immune cells, we performed - single-cell RNA sequencing (scRNAseq) for 12,196cellsafter data preprocessing, including 2,241 immunecells from three surgically removed brain lesions of treatment-naive NSCLC patients. We found a lack of T lymphocyte infiltration and activation, as well as the vast expansion of tumor-associated macrophage(TAM) in the brain lesions of NSCLC patients. By comparing our scRNAseq dataset with published data from early and late-stage primary NSCLC tumors, we showed that this compromised T cell response is unique to brain lesions. We identified a unique alternative activation (M2) gene expression pattern of the TAM in the brain metastasis and a lack of known T cell co-stimulator expression. Accumulation of M2 polarized TAM may, therefore, cause the comprised anti-tumor T cell response in metastatic brain lesions. These findings can contribute to the design of new immunotherapy strategies for NSCLC patients with brain metastasis.

cancer biology↗

bioRxiv2019

Niacin Stimulates Mammary Gland Development in Pubertal Mice through Activation of the AKT/mTOR and ERK1/2 Signaling Pathways

Previous studies have shown the effects of vitamins on the development of the mammary gland. However, the role of niacin in this process has not been reported. Therefore, the aim of this study was to investigate the effects of niacin on mammary gland development in pubertal mice and to use a mouse mammary epithelial cell line to study the underlying mechanism. The results showed that niacin could activate the AKT/mTOR and ERK signaling pathways by the Gi protein-coupled receptor and increase phosphorylation of 4EBP1 to promote the synthesis of cell proliferation markers, leading to the dissociation of the Rb-E2F1 complex in mMECs. In addition, 0.5% niacin promoted mammary duct development, increased the expression of cyclin D1/D3 and PCNA, and activated Akt/mTOR and ERK1/2 in the mammary glands of pubertal mice. These results strongly suggest that niacin stimulates mammary gland development in pubertal mice through the Akt/mTOR and ERK1/2 signaling pathways and that the Gi protein-coupled receptor is essential for this function.

developmental biology↗

bioRxiv2019

Lateral mechanical impedance rather than frontal, promotes cortical expansion of roots

It has long been considered that mechanical impedance on root will restrict root elongation and consequently promote radial growth. However, we did observe radial expansion but not elongation restriction in maize seedlings after short growth in sands. Mechanical impedance of soil can be classified into frontal- and lateral-type based on the interaction site of root. Therefore, we suspected that radial expansion might be mainly stimulated by lateral rather than frontal impedance. To verify our speculation, frontal and lateral impedance was provided separately. Small plastic caps were used to provide unique frontal impedance on root tip and cylindrical plastic containers were used to provide lateral impedance. Plastic caps could reduce root length remarkably. However, the radial expansion of plastic-cap-fitted roots was significantly inferior to that of the sand-cultured roots. Microstructural analysis revealed that sand-condition thickened root largely dependents on cortical expansion, whereas plastic cap did it mainly by thickening stele. In cylindrical plastic containers, mechanical impedance came only from the lateral direction and promoted the expansion of cortex just as sand-condition. Thus, we proposed that the expansion of the cortex and the consequent radial growth is mainly due to lateral impedance when growing in sands.

plant biology↗

bioRxiv2019

C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we use human induced pluripotent stem cell-derived motor neurons to show that C9orf72 repeat expansions impair microtubule-based transport of mitochondria, a process critical for maintenance of neuronal function. Cargo transport defects are recapitulated by treating healthy neurons with the arginine-rich dipeptide repeat proteins (DPRs) that are produced by the hexanucleotide repeat expansions. Single-molecule imaging shows that these DPRs perturb motility of purified kinesin-1 and cytoplasmic dynein-1 motors along microtubules in vitro. Additional in vitro and in vivo data indicate that the DPRs impair transport by interacting with both microtubules and the motor complexes. We also show that kinesin-1 is enriched in DPR inclusions in patient brains and that increasing the level of this motor strongly suppresses the toxic effects of arginine-rich DPR expression in a Drosophila model. Collectively, our study implicates an inhibitory interaction of arginine-rich DPRs with the axonal transport machinery in C9orf72-associated ALS/FTD and thereby points to novel potential therapeutic strategies.

neuroscience↗

bioRxiv2019

DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging

There are numerous hallmarks of aging in mammals, but no unifying cause has been identified. In budding yeast, aging is associated with a loss of epigenetic information that occurs in response to genome instability, particularly DNA double-strand breaks (DSBs). Mammals also undergo predictable epigenetic changes with age, including alterations to DNA methylation patterns that serve as epigenetic \"age\" clocks, but what drives these changes is not known. Using a transgenic mouse system called \"ICE\" (for inducible changes to the epigenome), we show that a tissues response to non-mutagenic DSBs reorganizes the epigenome and accelerates physiological, cognitive, and molecular changes normally seen in older mice, including advancement of the epigenetic clock. These findings implicate DSB-induced epigenetic drift as a conserved cause of aging from yeast to mammals.\n\nOne Sentence SummaryDNA breaks induce epigenomic changes that accelerate the aging clock in mammals

molecular biology↗

bioRxiv2019

Length-dependent accumulation of double-stranded RNAs in plastids affects RNA interference efficiency in the Colorado potato beetle

Transplastomic potato plants expressing double-stranded RNA (dsRNA) targeted against essential genes of the Colorado potato beetle (CPB) can be lethal to larvae by triggering an RNA interference (RNAi) response. High accumulation levels of dsRNAs in plastids are crucial to confer an efficient RNAi response in the insects. However, whether length and sequence of the dsRNA determine the efficacy of RNAi and/or influence the level of dsRNA accumulation in plastids is not known. Here we compared the RNAi efficacy of different lengths of dsRNA targeted against the CPB {beta}-Actin gene (ACT) by feeding in vitro-synthesized dsRNAs to larvae. We show that, while the 60 bp dsRNA induced only a relatively low RNAi response in CPB, dsRNAs of 200 bp and longer caused high mortality and similar larval growth retardation. When the dsRNAs were expressed from the plastid (chloroplast) genome of potato plants, we found that their accumulation levels were correlated with length. dsRNA accumulation levels were positively associated with the observed mortality, suppression of larval growth and suppression of target gene expression. Importantly, transplastomic potato plants expressing the 200 bp dsRNA were better protected from CPB than plants expressing the 297 bp dsRNA, the best-performing line in our previous study. Our results suggest that the length of dsRNAs is an important factor that influences their accumulation levels in plastids and thus determines the strength of the insecticidal RNAi effect. Our findings will aid the design of optimized dsRNA expression constructs for plant protection by plastid-mediated RNAi.

bioengineering↗

bioRxiv2019

scCancer: a package for automated processing of single cell RNA-seq data in cancer

SummaryMolecular heterogeneities bring great challenges for cancer diagnosis and treatment. Recent advance in single cell RNA-sequencing (scRNA-seq) technology make it possible to study cancer transcriptomic heterogeneities at single cell level. Here, we develop an R package named scCancer which focuses on processing and analyzing scRNA-seq data for cancer research. Except basic data processing steps, this package takes several special considerations for cancer-specific features. Firstly, the package introduced comprehensive quality control metrics. Secondly, it used a data-driven machine learning algorithm to accurately identify major cancer microenvironment cell populations. Thirdly, it estimated a malignancy score to classify malignant (cancerous) and non-malignant cells. Then, it analyzed intra-tumor heterogeneities by key cellular phenotypes (such as cell cycle and stemness) and gene signatures. Finally, a user-friendly graphic report was generated for all the analyses.\n\nAvailabilityhttp://lifeome.net/software/sccancer/.\n\nContactjgu@tsinghua.edu.cn

bioinformatics↗

bioRxiv2019

Metabolic remodeling by TIGAR overexpression is a therapeutic target in esophageal squamous-cell carcinoma

Whole-genome sequencing has identified many amplified genes in esophageal squamous-cell carcinoma (ESCC); however, their roles and the clinical relevance have yet elucidated. Here we show TP53-induced glycolysis and apoptosis regulator (TIGAR) is a major player in ESCC progression and chemoresistance. TIGAR reprograms glucose metabolism from glycolysis to the glutamine pathway through AMP-activated kinase, and its overexpression is correlated with poor disease outcomes. Tigar knockout mice have reduced ESCC growth and tumor burden. Treatment of TIGAR-overexpressed ESCC cell xenografts and patient-derived tumor xenografts in mice with combination of glutaminase inhibitor and chemotherapeutic agents achieves significant more efficacy than chemotherapy alone. These findings shed light on an important role of TIGAR in ESCC and provide evidence for targeted treatment of TIGAR-overexpressed ESCC.\n\nSignificanceEffective and target therapies are required for ESCC, one of the most common types of digestive OR cancer. Little has been known about the biology of ESCC progression or potential molecular targets OR for treatment. Whole-genome sequencing and RNA sequencing studies in ESCC have identified OR many recurrent copy number gain genes; however, the roles and druggable relevance of these OR genes remains poorly understood. Herein we demonstrate that TIGAR overexpression leads to OR metabolic remodeling, promoting ESCC progression and resistance to chemotherapeutic agents. OR Inhibiting the glutamine pathway significantly represses TIGAR-overexpressing ESCC growth and OR enhances tumor cell sensitization to cytotoxic agents. These findings might provide the rationale OR for clinical trials testing glutamine pathway inhibitors in combination with chemotherapy in OR TIGAR-expressing ESCC.

cancer biology↗

bioRxiv2019

Direct microRNA sequencing using Nanopore Induced Phase-Shift Sequencing (NIPSS)

MicroRNAs (miRNAs) are a class of short non-coding RNAs that function in RNA silencing and post-transcriptional gene regulation. Besides their participation in regulating normal physiological activities, specific miRNA types could act as oncogenes, tumor suppressors or metastasis regulators, which are critical biomarkers for cancer. However, direct characterization of miRNA is challenging due to its unique properties such as its low abundance, sequence similarities and short length. Nanopore Induced Phase Shift Sequencing (NIPSS), which is a variant form of nanopore sequencing, could directly sequence any short analytes including miRNA. In practice, NIPSS clearly discriminates between different identities, isoforms and epigenetic variants of model miRNA sequences. This work demonstrates the first report of direct miRNA sequencing, which serves as a complement to existing miRNA sensing routines by the introduction of single molecule resolution. Future engineering of this technique may assist miRNA based early stage diagnosis or inspire novel cancer therapeutics.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC=\"FIGDIR/small/747113v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (33K):\norg.highwire.dtl.DTLVardef@216b4borg.highwire.dtl.DTLVardef@b1e88org.highwire.dtl.DTLVardef@1b04aorg.highwire.dtl.DTLVardef@dcdbb7_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2019

Universal activation mechanism of class A GPCRs

Class A G protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. GPCR activation is an allosteric process that links agonist binding to G protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue-level changes of this trigger remain less well understood. Here, by analyzing over 230 high-resolution structures of class A GPCRs, we discovered a modular, universal GPCR activation pathway that unites previous findings into a common activation mechanism, directly linking the bottom of ligand-binding pocket with G protein-coupling region. We suggest that the modular nature of the universal GPCR activation pathway allowed for the decoupling of the evolution of the ligand binding site, G protein binding region and the residues important for receptor activation. Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature.

bioinformatics↗

bioRxiv2019

Widespread positive selection for mRNA secondary structure at synonymous sites in domesticated yeast

mRNA secondary structure assumes a critical role in gene regulation, especially for translational efficiency. Previous studies have a growing appreciation of purifying selection for the conserved mRNA structure across lineages of different species. However, the effect of mRNA structure on positive evolution remains unclear. Here, we construct a large-scale dataset of single nucleotide polymorphisms (SNPs) at synonymous sites in the population of Saccharomyces cerevisiae, combined with the experimental assessment of mRNA structure, and perform empirical population genetics data analysis through unfolded site-frequency spectra. Our results suggest that functional mRNA stem drives faster evolution of increasing GC contents itself with the purpose of regulating translational speed, which is greatly influenced by length. At the synonymous site without codon usage bias, this kind of positive selection still exists. Furthermore, mRNA secondary structure is subject to positive selection widespread among the yeast genome, particularly related to mitochondria activities, which is possibly aimed to achieve a balance between cellular respiration and alcoholic fermentation precisely at a non-protein level. It is conducive to the adaption of the dramatic environment alterations from wild to man-made environments during the domestication.

evolutionary biology↗

bioRxiv2019

Loss of SHMT2 mediates 5-FU chemoresistance by inducing autophagy in colorectal cancer

Serine hydroxymethyltransferase 2 (SHMT2) plays a vital role in one-carbon metabolism and drives colorectal carcinogenesis. In our study, loss of SHMT2 induced 5-Fluorouracil (5-FU) chemoresistance and was associated with poor prognosis in colorectal cancer (CRC). To elucidate the possible mechanism and generate a strategy to sensitize CRC to 5-FU chemotherapy, we first identified the binding proteins of SHMT2 in cancer cells by mass spectrometry. We found that SHMT2 inhibited autophagy through binding cytoplasmic p53. In fact, SHMT2 prevented cytoplasmic p53 degradation by inhibiting the binding of p53 and HDM2. Under treatment with 5-FU, depletion of SHMT2 promoted autophagy and inhibited apoptosis. Autophagy inhibitors CQ decreased low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, we enhanced the lethality of 5-FU treatment to CRC cells through the autophagy inhibitor or knockdown of SHMT2 in patient-derived and CRC cell xenograft models. Our findings identified the low SHMT2-induced autophagy on 5-FU resistance in CRC. These results reveal SHMT2-p53 as a novel cancer therapeutic target to reduce chemotherapeutic drug resistance.

cancer biology↗

bioRxiv2019

APOC2 accelerates colorectal cancer progression via modulating lipid metabolism and transcriptional activity of PHF8

The apolipoproteins (APOs) are the major proteins in blood lipid transportation. Emerging evidence has demonstrated that APOs might exert important function in tumor cells, but the underlying mechanism remains inclusive. In this study, we aim to explore the relationship between APOC2 dysfunction and colorectal cancer (CRC) malignancy. By analyzing the expression of APOC2 in 507 patients with CRC, we demonstrated that the APOC2 was overexpressed and associated with poor prognosis in CRC. We then found that high levels of APOC2 resulted in proliferation, invasion and metastasis of CRC cells in vitro and in vivo. Mechanistically, we revealed that APOC2 directly interacted with FASN which resulted in decreased levels of omega-3 fatty acids and increased levels of alpha-ketoglutarate (-KG). Both RNA-seq and ChIP-seq analysis revealed that APOC2 overexpression resulted accumulation of -KG leads to activation on the transcriptional program of PHF8 and thereby contributed to activation on genes involved in cell proliferation, invasion and metastasis. Together, our study unveiled the oncogenic role of APOC2 in tumor cells, which sheds new light on the potential of APOC2 as a biomarker in the prognosis of CRC.

cancer biology↗