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Zhao, L.

Publications and source records attributed to Zhao, L..

At least 343 records · Page 19Linked to original sources
bioRxiv2020

Mapping fetal brain development based on automated segmentation and 4D brain atlasing

Fetal brain MRI has become an important tool for in utero assessment of brain development and disorders. However, quantitative analysis of fetal brain MRI remains difficult, partially due to the limited tools for automated preprocessing and the lack of normative brain templates. In this paper, we proposed an automated pipeline for fetal brain extraction, super-resolution reconstruction, and fetal brain atlasing to quantitatively map in utero fetal brain development during mid-to-late gestation in a Chinese population. First, we designed a U-net convolutional neural network for automated fetal brain extraction, which achieved an average accuracy of 97%. We then generated a developing fetal brain atlas, using an iterative linear and nonlinear registration approach. Based on the 4D spatiotemporal atlas, we quantified the morphological development of the fetal brain between 23-36 weeks of gestation. The proposed pipeline enabled the fully-automated volumetric reconstruction for clinically available fetal brain MRI data, and the 4D fetal brain atlas provided normative templates for quantitative analysis of potential fetal brain abnormalities, especially in the Chinese population.

neuroscience↗
bioRxiv2020

Single-cell atlas of human developing and azoospermia patients' testicles reveals the roadmap and defects in somatic microenvironment

Non-obstructive azoospermia (NOA) affects 1% of men. However, the unknowns of NOA pathogenesis and even normal spermatogenic microenvironment establishment severely limit the clinical efficacy of NOA treatment. We profiled > 80,000 human testicular single-cell transcriptomes from 10 healthy donors spanning the range from infant to adult and 7 NOA patients. Sertoli cells, which form the scaffold in the testicular microenvironment, exhibited the most obvious damages in NOA patients. We identified the roadmap of Sertoli cell maturation. Notably, Sertoli cells of patients with congenital causes (Klinefelter syndrome and Y chromosome microdeletions) are mature but with abnormal immune response, while the cells in idiopathic NOA (iNOA) are basically physiologically immature. Furthermore, inhibition of Wnt signaling promotes the maturation of Sertoli cells from iNOA patients, allowing these cells to regain their ability to support germ cell survival. We provide a novel perspective on the development of diagnostic methods and therapeutic targets for NOA.

developmental biology↗
bioRxiv2020

Yellow-Fruited Phenotype is Caused by an Insertion Event at 5' UTR of YFT1 Allele in yft1 Mutant Tomato

The yft1 tomato mutant has a yellow-fruited phenotype controlled by a recessive gene (YFT1), which has been shown by map-based cloning to be a homolog of ETHYLENE INSENSITIVE 2 (EIN2). The genetic lesion of the YFT1 allele of yft1 is attributed to a 573 bp DNA fragment (IF573) insertion at 1,200 bp downstream of the transcription start site (TSS). Transcriptome analysis revealed that the mutation resulted in 5,053 differentially expressed genes (DEGs) in the fruit pericarp compared with the M82 wild type cultivar. These were annotated as being involved in ethylene synthesis, chromoplast development, and carotenoid synthesis. Genetic lesion in YFT1 caused a reduction in its own transcript levels in yft1 and impaired ethylene emission and signal transduction, delayed chromoplast development and decreased carotenoid accumulation. The molecular mechanism underlying the reduced expression of YFT1 in yft1 was examined at both the RNA and DNA levels. The IF573 event was shown to introduce two negative regulatory sequences located at -272 to -173 bp and -172 to -73 bp in the YFT1 allele promoter, causing alterative splicing due to aberrant splicing sites, and also altering the structure of the open reading frame in the 5-UTR. This study contributes to the understanding of color formation in tomato fruit. One-sentence summaryLesion happened in regulatory region impairs expression of a key gene of ethylene signal pathway, and alters fruit color in tomato due to effect of carotenoids accumulation and ethylene synthesis.

plant biology↗
bioRxiv2020

The conservation of a core virome in Aedes mosquitoes across different developmental stages and continents

Mosquitoes belonging to the genus Aedes can efficiently transmit many pathogenic arboviruses, placing a great burden on public health worldwide. In addition, they also carry a number of insect specific viruses (ISVs), and it was recently suggested that some of these ISVs might form a stable species-specific "core virome" in mosquito populations. However, little is known about such a core virome in laboratory colonies and if it is present across different developmental stages. In this study, we compared the viromes in eggs, larvae, pupae and adults of Aedes albopictus mosquitoes collected from the field as well as from a lab colony. The virome in lab-derived Ae. albopictus is very stable across all stages, consistent with a vertical transmission route of these viruses, forming a "vertically transmitted core virome". The different stages of field collected Ae. albopictus mosquitoes also contains this stable vertically transmitted core virome as well as another set of viruses shared by mosquitoes across different stages, which might be an "environment derived core virome". Both these vertically and environmentally transmitted core viromes in Ae. albopictus deserve more attention with respect to their effects on vector competence for important medically relevant arboviruses. To further study this core set of ISVs, we screened 46 publically available SRA viral metagenomic dataset of mosquitoes belonging to the genus Aedes. Some of the identified core ISVs are identified in the majority of SRAs. In addition, a novel virus, Aedes phasmavirus, is found to be distantly related to Yongsan bunyavirus 1, and the genomes of the core virus Phasi Charoen-like phasivirus is highly prevalent in the majority of the tested samples, with nucleotide identities ranging from 94% to 99%. Finally, Guadeloupe mosquito virus, and some related viruses formed three separated phylogenetic clades. How these core ISVs influence the biology of mosquito host, arboviruses infection and evolution deserve to be further explored.

microbiology↗
bioRxiv2020

Functional Interrogation of HOXA9 Regulome in MLLr Leukemia via Reporter-based CRISPR/Cas9 screen

Aberrant HOXA9 expression is a hallmark of most aggressive acute leukemias, including human acute myeloid leukemia (AML) and subtypes of acute lymphoblastic leukemia (ALL). HOXA9 overexpression not only predicts poor diagnosis and outcome but also plays a critical role in leukemia transformation and maintenance. However, our current understanding of HOXA9 regulation in leukemia is limited, hindering development of therapeutic strategies to treat HOXA9-driven leukemia. To mitigate these challenges, we generated the first HOXA9-mCherry knock-in reporter in an MLL-rearranged (MLLr) B-ALL cell line to dissect HOXA9 regulation. By utilizing the reporter and CRISPR/Cas9 mediated screens, we identified transcription factors controlling HOXA9 expression, including a novel regulator, USF2 and its homolog USF1. USF1/USF2 depletion significantly down-regulated HOXA9 expression and impaired MLLr leukemia cell proliferation. Ectopic expression of HOXA9-MEIS1 fusion protein rescued the impaired leukemia cell proliferation upon USF2 loss. Cut&Run analysis revealed the direct occupancy of USF2 onto HOXA9 promoter in MLLr leukemia cells. Collectively, the HOXA9 reporter facilitated the functional interrogation of the HOXA9 regulome and has advanced our understanding of the molecular regulation network in HOXA9-driven leukemia.

cancer biology↗
bioRxiv2020

Potential microenvironment of SARS-CoV-2 infection in airway epithelial cells revealed by Human Protein Atlas database analysis

The outbreak of COVID-19 has caused serious epidemic events in China and other countries. With the rapid spread of COVID-19, it is urgent to explore the pathogenesis of this novel coronavirus. However, the foundational research of COVID-19 is very weak. Although angiotensin converting enzyme 2 (ACE2) is the reported receptor of SARS-CoV-2, information about SARS-CoV-2 invading airway epithelial cells is very limited. Based on the analysis of the Human Protein Atlas database, we compared the virus-related receptors of epithelial-derived cells from different organs and found potential key molecules in the local microenvironment for SARS-CoV-2 entering airway epithelial cells. In addition, we found that these proteins were associated with virus reactive proteins in host airway epithelial cells, which may promote the activation of the immune system and the release of inflammatory factors. Our findings provide a new research direction for understanding the potential microenvironment required by SARS-CoV-2 infection in airway epithelial, which may assist in the discovery of potential drug targets against SARS-CoV-2 infection.

cell biology↗
bioRxiv2020

A large effective population size for within-host influenza virus infection

Strains of the influenza virus form coherent global populations, yet exist at the level of single infections in individual hosts. The relationship between these scales is a critical topic for understanding viral evolution. Here we investigate the within-host relationship between selection and the stochastic effects of genetic drift, estimating an effective population size of infection Ne for influenza infection. Examining whole-genome sequence data describing a chronic case of influenza B in a severely immunocompromised child we infer an Ne of 2.5 x 107 (95% confidence range 1.0 x 107 to 9.0 x 107) suggesting the importance of genetic drift to be minimal. Our result, supported by the analysis of data from influenza A infection, suggests that positive selection during within-host infection is primarily limited by the typically short period of infection. Atypically long infections may have a disproportionate influence upon global patterns of viral evolution.

evolutionary biology↗
bioRxiv2020

The evolution of sex-biased gene expression in the Drosophila brain

Genes with sex-biased expression in Drosophila are thought to underlie sexually dimorphic phenotypes and have been shown to possess important evolutionary properties. However, the forces and constraints governing the evolution of sex-biased genes in the somatic tissues of Drosophila are largely unknown. Using population-scale RNA sequencing data we show that sex-biased genes in the Drosophila brain are highly enriched on the X Chromosome and that most are biased in a species-specific manner. We show that X-linked male-biased genes, and to a lesser extent female-biased genes, are enriched for signatures of directional selection at the gene expression level. By examining the evolutionary properties of gene flanking regions on the X Chromosome, we find evidence that adaptive cis-regulatory changes are more likely to drive the expression evolution of X-linked male-biased genes than other X-linked genes. Finally, we examine whether constraint due to broad expression across multiple tissues and genetic constraint due to the largely shared male and female genomes could be responsible for the observed patterns of gene expression evolution. We find that expression breadth does not constrain the directional evolution of gene expression in the brain. Additionally, we find that the shared genome between males and females imposes a substantial constraint on the expression evolution of sex-biased genes. Overall, these results significantly advance our understanding of the patterns and forces shaping the evolution of sexual dimorphism in the Drosophila brain.

evolutionary biology↗
bioRxiv2020

Assessment of whether published non-Cochrane systematic reviews of nursing follow the review protocols registered in the International Prospective Register of Systematic Reviews (PROSPERO): A comparative study

Purpose We compare published non-Cochrane reviews of nursing with their pre-registered protocols on PROSPERO to quantify the prevalence of differences and the extent to which the differences were explained.Methods We searched for protocols and their corresponding reviews in PROSPERO’s nursing group that were “completed and published” from inception to September 8th, 2019. Two authors independently identified differences and classified the difference as none, partial, or complete, and determined if the existed differences had been explained. Frequency (n), percentage (%), median, and inter-quartile ranges were used to analyze the extent of differences and explanations.Results We identified 22 pre-registered protocols and their reviews. All 22 pairs (100%) exhibited differences. Eighteen pairs (82%) showed differences in at least six methodological sections, while 21 pairs (95%) involved completed difference in at least one section. The median number of differences per review was 8.00 (upper quartile = 6.00, lower quartile = 9.75). The differences involved all 13 compared methodology-related sections. Only 5 (3%) of all differences were explained in the systematic reviews.Conclusions We observed widespread differences between non-Cochrane reviews of nursing and their protocols recorded in PROSPERO, with relatively few explanations for the changes. Measures including establishing a new item in the reporting guideline of systematic reviews to guide reporting and explaining the reasons for differences between protocols and systematic reviews or even requiring authors to do so at the Journal’s author guideline are recommended to improve transparency.View Full Text

scientific communication and education↗
bioRxiv2020

β-alanine or L-carnosine prevents the development of pale, soft and exudative pork by inhibiting the glycolysis of porcine longissimus dorsi muscle

Carnosine plays an important role in regulating muscle buffering capacity and glycolysis. In order to investigate the effects of dietary {beta}-alanine, L-histidine, and L-carnosine supplementation on the pH value, glycolytic potential, the activities of AMP-activated protein kinase (AMPK) and pyruvate kinase (PK) activities in the porcine longissimus dorsi muscle, a total of 60 barrows with an average body weight (BW) of 50.5 {+/-} 1.7 kg were assigned into five groups which received diets containing basal diet (control, CON), 0.04% {beta}-alanine ({beta}-ALA), 0.06% L-histidine (L-HIS), 0.04% {beta}-alanine+0.06% L-histidine ({beta}-ALA+L-HIS), or 0.1% L-carnosine (L-CAR). The results showed that dietary supplementation of the combination of {beta}-ALA and L-HIS or L-CAR significantly increased (P < 0.05) the average daily gain (ADG) of pigs with 50-75 kg BW, compared with other three groups. Compared with L-CAR group, L-HIS supplementation significantly decreased (P < 0.05) the average daily feed intake (ADFI) of pigs. There were no significant difference (P > 0.05) in back fat thickness and loin eye area among treatments. At 0, 1 and 24 h postmortem (PM) the pH values in the longissimus dorsi muscle (LM) of pigs receiving L-CAR were higher (P < 0.05) than that of pigs receiving CON diet. The redness (a*) values of LM of pigs in the {beta}-ALA+L-HIS or L-CAR group were higher (P < 0.05) than those in other three groups. The glycolytic potential of LM was not significantly different (P > 0.05) among treatments. At 1, 24 h PM the AMPK activities in LM of pigs receiving {beta}-ALA, {beta}-ALA+L-HIS and L-CAR were much lower (P < 0.05) than those of pigs receiving CON diet or L-HIS. 0.1% L-carnosine or 0.04% {beta}-alanine supplemented to pigs diet was effective in regulating AMPK and PK activities in the porcine longissimus dorsi muscle and preventing the development of pale, soft and exudative (PSE) pork.

physiology↗
bioRxiv2020

KMT2D Links TGF-β Signalling to Non-Canonical Activin Pathway and Regulates Pancreatic Cancer Cell Plasticity

Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-{beta} to the activin A pathway. We found that TGF-{beta} upregulates a microRNA, miR-147b, which in turn leads to post-transcriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a non-canonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the pro-tumoral role of KMT2D. These findings reveal a tumor-suppressive role of KMT2D and identify miR-147b and activin A as novel therapeutic targets in pancreatic cancer.

cancer biology↗
bioRxiv2020

VPTMdb: a viral post-translational modification database

In viruses, post-translational modifications (PTMs) are essential for their life cycle. Recognizing viral PTMs is very important for better understanding the mechanism of viral infections and finding potential drug targets. However, few studies have investigated the roles of viral PTMs in virus-human interactions using comprehensive viral PTM datasets. To fill this gap, firstly, we developed a viral post-translational modification database (VPTMdb) for collecting systematic information of viral PTM data. The VPTMdb contains 912 PTM sites that integrate 414 experimental-confirmed PTM sites with 98 proteins in 45 human viruses manually extracted from 162 publications and 498 PTMs extracted from UniProtKB/Swiss-Prot. Secondly, we investigated the viral PTM sequence motifs, the function of target human proteins, and characteristics of PTM protein domains. The results showed that (i) viral PTMs have the consensus motifs with human proteins in phosphorylation, SUMOylation and N-glycosylation. (ii) The function of human proteins that targeted by viral PTM proteins are related to protein targeting, translation, and localization. (iii) Viral PTMs are more likely to be enriched in protein domains. The findings should make an important contribution to the field of virus-human interaction. Moreover, we created a novel sequence-based classifier named VPTMpre to help users predict viral protein phosphorylation sites. Finally, an online web server was implemented for users to download viral protein PTM data and predict phosphorylation sites of interest. Author summaryPost-translational modifications (PTMs) plays an important role in the regulation of viral proteins; However, due to the limitation of data sets, there has been no detailed investigation of viral protein PTMs characteristics. In this manuscript, we collected experimentally verified viral protein post-translational modification sites and analysed viral PTMs data from a bioinformatics perspective. Besides, we constructed a novel feature-based machine learning model for predicting phosphorylation site. This is the first study to explore the roles of viral protein modification in virus infection using computational methods. The valuable viral protein PTM data resource will provide new insights into virus-host interaction.

bioinformatics↗
bioRxiv2020

High-quality chromosome-level genomes of two tilapia species reveal their evolution of repeat sequences and sex chromosomes

BackgroundTilapias are one of the most farmed fishes that are coined as aquatic chicken by the food industry. Like many other teleosts, Nile tilapia and blue tilapia exhibit very recent transition of sex chromosome systems since their divergence about 5 million years ago, making them a great model for elucidating the molecular and evolutionary mechanisms of sex chromosome turnovers. Studies into their sex-determining pathways are also critical for developing genetic sex control in aquaculture. ResultsWe report here the newly produced genomes of Nile tilapia and blue tilapia that integrate long-read sequencing and chromatin conformation data. The two nearly complete genomes have anchored over 97% of the sequences into linkage groups (LGs), and assembled majorities of complex repetitive regions including telomeres, centromeres and rDNA clusters. In particular, we inferred two episodes of repeat expansion at LG3 respectively in the ancestor of cichlids and that of tilapias. The consequential large heterochromatic region concentrated at one end of LG3 comprises tandem arrays of mRNA and small RNA genes, among which we have identified a candidate female determining gene Paics in blue tilapia. Paics show female-specific patterns of single-nucleotide variants, copy numbers and expression patterns in gonads during early gonadogenesis. ConclusionsOur work provide a very important genomic resource for functional studies of cichlids, and suggested that unequal distribution of repeat content that impacts the local recombination rate might make some chromosomes more likely to become sex chromosomes.

genomics↗
bioRxiv2020

Reinfection could not occur in SARS-CoV-2 infected rhesus macaques

A global pandemic of Corona Virus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is ongoing spread. It remains unclear whether the convalescing patients have a risk of reinfection. Rhesus macaques were rechallenged with SARS-CoV-2 during an early recovery phase from initial infection characterized by weight loss, interstitial pneumonia and systemic viral dissemination mainly in respiratory and gastrointestinal tracts. The monkeys rechallenged with the identical SARS-CoV-2 strain have failed to produce detectable viral dissemination, clinical manifestations and histopathological changes. A notably enhanced neutralizing antibody response might contribute the protection of rhesus macaques from the reinfection by SARS-CoV-2. Our results indicated that primary SARS-CoV-2 infection protects from subsequent reinfection. One Sentence SummaryNeutralizing antibodies against SARS-CoV-2 might protect rhesus macaques which have undergone an initial infection from reinfection during early recovery days.

microbiology↗
bioRxiv2020

Deep learning-based adaptive detection of fetal nucleated red blood cells

Aimthis study, we established an artificial intelligence system for rapid identification of fetal nucleated red blood cells (fNRBCs). MethodDensity gradient centrifugation and magnetic-activated cell sorting were used for the separation of fNRBCs from umbilical cord blood. The cell block technique was used for fixation. We proposed a novel preprocessing method based on imaging characteristics of fNRBCs for region of interest (ROI) extraction, which automatically segmented individual cells in peripheral blood cell smears. The discriminant information from ROIs was encoded into a feature vector and pathological diagnosis were provided by the prediction network. ResultsFour umbilical cord blood samples were collected and validated based on a large dataset containing 260 samples. Finally, the dataset was classified into 3,720 and 1,040 slides for training and testing, respectively. In the test set, classifier obtained 98.5% accuracy and 96.5% sensitivity. ConclusionTherefore, this study offers an effective and accurate method for fNRBCs preservation and identification.

pathology↗
bioRxiv2020

Global Profiling of 2-hydroxyisobutyrylome in Common Wheat

As a novel post-translational modification (PTM), lysine 2-hydroxyisobutyrylation (Khib) has been found to play a role in active gene transcription in mammalian cells and yeast, but the function of Khib proteins in plants remains unknown. In this study, we used western blot to demonstrate that Khib is an evolutionarily-conserved PTM in wheat and its donators, with the highest Khib abundance occurring in hexaploidy wheat. Additionally, global profiling using affinity purification and mass spectroscopy of 2-hydroxyisobutyrylome revealed that there were 3348 lysine modification sites from 1074 proteins in common wheat (Triticum aestivum L.). Moreover, bioinformatic data indicated that Khib proteins participate in a wide variety of biological and metabolic pathways. Immunoprecipitation and western blot confirmed that Khib proteins had an in vivo origin. A comparison of Khib and other major PTMs revealed that Khib proteins were simultaneously modified by multiple PTMs. Using mutagenesis experiments and Co-IP, we demonstrated that Khib on K206 is a key regulatory modification of phosphoglycerate kinase enzymatic activity and found that de-Khib on K206 affects protein interactions. Furthermore, Khib production of low-molecular-weight proteins was a response to the deacetylase inhibitors nicotinamide and trichostatin A. This study provides evidence that enhances our current understanding of Khib in wheat plants, including the cooperation between this PTM and metabolic regulation.

plant biology↗
bioRxiv2020

Dynamic Changes in Fecal Bacterial Microbiota of Dairy Cattle across the Production Line

Bacteria play important roles in the gastrointestinal tract (GIT) of dairy cattle as the communities are responsible for host health, growth and production performance. However, a systematic characterization and comparison of microbial communities in the GIT of cattle housed in different management units on a modern dairy are still lacking. In this study, we used 16S rRNA sequencing to evaluate the fecal bacterial communities of 90 dairy cattle raised and housed in 12 clearly defined management units on a modern dairy farm. We found that -diversity differed between several pairs of management units, especially between the hutch calves (management unit 1) and the other units except post weaned heifers (management unit 2). Although {beta}-diversity revealed that most of the samples did not cluster according to their management unit membership except management unit 1, in which the samples grouped and separated from others, we observed three major clusters. Besides the hutch calves (management unit 1), most samples from the other 11 units formed two distinct clusters and the relative abundance of Patescibacteria might be the reason for the separation. Moreover, we identified 212 amplicon sequence variants (ASVs) with relative abundances > 0.1% in more than 10% of the total samples that had significantly different abundances in these units. Furthermore, we found that, as the calves aged, 19 ASVs that were exclusively detected in unit 1, gradually degraded and never reoccurred in other management units. Lastly, we recognized 181 pairs of interactions between 61 ASVs with possibly strong synergistic or antagonistic relationships. These results suggest the enteric microbial communities of dairy cattle housed in different management units are quite dynamic. IMPORTANCEBacterial communities of GIT are crucial for ruminants, such as dairy cattle since they contribute to not only the cattles physiology and health but also milk production and food safety that are closely related to human health. Both scientifically and agriculturally, it is necessary to have deep insights into the composition and changes of the bacteria on modern dairy farms. In this study, we provided the profiles of fecal bacterial communities of dairy cattle in each management unit on a modern dairy and described how the enteric microbial communities changed across these management units. The findings have implications for improving animal health, dairy production, farm management, and food safety.

microbiology↗