Biology subjects

Fan, Y.

Publications and source records attributed to Fan, Y..

At least 217 records · Page 12Linked to original sources

bioRxiv2021

Computing personalized brain functional networks from fMRI using self-supervised deep learning

A novel self-supervised deep learning (DL) method is developed for computing bias-free, personalized brain functional networks (FNs) that provide unique opportunities to better understand brain function, behavior, and disease. Specifically, convolutional neural networks with an encoder-decoder architecture are employed to compute personalized FNs from resting-state fMRI data without utilizing any external supervision by optimizing functional homogeneity of personalized FNs in a self-supervised setting. We demonstrate that a DL model trained on fMRI scans from the Human Connectome Project can identify canonical FNs and generalizes well across four different datasets. We further demonstrate that the identified personalized FNs are informative for predicting individual differences in behavior, brain development, and schizophrenia status. Taken together, self-supervised DL allows for rapid, generalizable computation of personalized FNs.

neuroscience↗

bioRxiv2021

The cause of on-target point mutations generated by CRISPR-Cas9 treatment in the yeast Xanthophyllomyces dendrorhous

Recognizing outcomes of DNA repair induced by CRISPR-Cas9 cutting is vital for precise genome editing. Reported DNA repair outcomes after Cas9 cutting include deletions/insertions and low frequency of genomic rearrangements and nucleotide substitutions. Thus far, substitution mutations caused by CRISPR-Cas9 has not attracted much attention. Here, we identified on-target point mutations induced by CRISPR-Cas9 treatment in the yeast Xanthophyllomyces dendrorhous by Sanger and Illumina sequencing. Different from previous studies, our findings suggested that the on-target mutations are not random and they cannot render the gRNA effective. Moreover, these point mutations showed strong sequence dependence that is not consistent with the observations in Hela cells, in which CRISPR-mediated substitutions were considered lacking sequence dependence and conversion preferences. Furthermore, this study demonstrated that the NHEJ components Ku70, Ku80, Mre11, or RAD50, and the overlapping roles of non-essential DNA polymerases were necessary for the emergence of point mutations, increasing the knowledge on CRISPR-Cas9 mediated DNA repair.

microbiology↗

bioRxiv2021

Linking Individual Differences in Personalized Functional Network Topography to Psychopathology in Youth

The spatial layout of large-scale functional brain networks differs between individuals and is particularly variable in association cortex that has been implicated in a broad range of psychiatric disorders. However, it remains unknown whether this variation in functional topography is related to major dimensions of psychopathology in youth. Capitalizing on a large sample with 27-minutes of high-quality functional MRI data (n=790, ages 8-23 years) and advances in machine learning, we examined associations between functional topography and four correlated dimensions of psychopathology (fear, psychosis, externalizing, anxious-misery) as well as an overall psychopathology factor. We found that functional topography significantly predicted individual differences in dimensions of psychopathology, driven mainly by robust associations between topography and overall psychopathology. Reduced cortical representations of association networks were among the most important features of the model. Our results emphasize the value of considering systematic differences in functional neuroanatomy for personalized diagnostics and therapeutics in psychiatry.

neuroscience↗

bioRxiv2021

Convergence of MCR-8.2 and chromosome-mediated resistance to colistin and tigecycline in an NDM-5-producing ST656 Klebsiella pneumoniae from a lung transplant patient

For infection caused by NDM-5-producing Klebsiella pneumoniae, tigecycline and colistin are the last treatment options. In this study, we characterized the first NDM-5 and MCR-8.2 co-harboring K. pneumoniae clinical isolate, combining with chromosomal gene-mediated resistance to colistin and tigecycline. The K. pneumoniae KP32558 was isolated from the bronchoalveolar lavage fluid from a lung transplant male patient. Whole genome sequencing was carried out using Illumina HiSeq sequencing platform as well as nanopore sequencing method. The K. pneumoniae KP32558 was identified as a pan-drug resistant bacteria, belonged to ST656, and harbored plasmid-encoded blaNDM-5 and mcr-8.2 genes. The blaNDM-5 gene was located on an IncX3 type plasmid, which was successfully transferred to Escherichia coli strain J53 without visible fitness cost. The mcr-8.2 gene was located on a conjugative plasmid pKP32558-2-mcr8. It had two replicons, IncFII(K) and IncQ1, harbored previously by another two mcr-8.2-carrying plasmids pMCR8_020135 and pMCR8_095845. These three plasmids were clustered into the same clade and derived from K. pneumoniae isolates of the same clonal complex, indicating that pKP32558-2-mcr8 may come from pMCR8_020135 and pMCR8_095845 related ancestor. The MIC of KP32558 for colistin was 256 mg/L, the 6 amino acid substitutions in the two-component system may involve in the high-level colistin resistance. The truncation in acrR gene, related to tigecycline resistance, was also identified. K. pneumoniae has evolved a variety of complex resistance mechanisms to the last-resort antimicrobials, close surveillance is urgently needed to monitor the prevalence of this clone.

microbiology↗

bioRxiv2021

Dissociable Multi-scale Patterns of Development in Personalized Brain Networks

The brain is organized into networks at multiple resolutions, or scales, yet studies of functional network development typically focus on a single scale. Here, we derived personalized functional networks across 29 scales in a large sample of youths (n=693, ages 8-23 years) to identify multi-scale patterns of network re-organization related to neurocognitive development. We found that developmental shifts in inter-network coupling systematically adhered to and strengthened a functional hierarchy of cortical organization. Furthermore, we observed that scale-dependent effects were present in lower-order, unimodal networks, but not higher-order, transmodal networks. Finally, we found that network maturation had clear behavioral relevance: the development of coupling in unimodal and transmodal networks dissociably mediated the emergence of executive function. These results delineate maturation of multi-scale brain networks, which varies according to a functional hierarchy and impacts cognitive development.

neuroscience↗

bioRxiv2021

Sex Differences in Functional Topography of Association Networks

Prior work has shown that there is substantial interindividual variation in the spatial distribution of functional networks across the cerebral cortex, or functional topography. However, it remains unknown whether there are sex differences in the topography of individualized networks in youth. Here we leveraged an advanced machine learning method (sparsity-regularized nonnegative matrix factorization) to define individualized functional networks in 693 youth (ages 8-23 years) who underwent functional magnetic resonance imaging as part of the Philadelphia Neurodevelopmental Cohort. Multivariate pattern analysis using support vector machines classified participant sex based on functional topography with 83% accuracy (p<0.0001). Brain regions most effective in classifying participant sex belonged to association networks, including the ventral attention and default mode networks. Mass-univariate analyses using generalized additive models with penalized splines provided convergent results. Comparative analysis using transcriptomic data from the Allen Human Brain Atlas revealed that sex differences in multivariate patterns of functional topography correlated with the expression of genes on the X-chromosome. These results identify normative developmental sex differences in the functional topography of association networks and highlight the role of sex as a biological variable in shaping brain development in youth. SIGNIFICANCE STATEMENTWe identify normative developmental sex differences in the functional topography of personalized association networks including the ventral attention network and default mode network. Furthermore, chromosomal enrichment analyses revealed that sex differences in multivariate patterns of functional topography were spatially coupled to the expression of X-linked genes as well as astrocytic and excitatory neuronal cell-type signatures. These results highlight the role of sex as a biological variable in shaping functional brain development in youth.

neuroscience↗

bioRxiv2021

CovidExpress: an interactive portal for intuitive investigation on SARS-CoV-2 related transcriptomes

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans could cause coronavirus disease 2019 (COVID-19). Since its first discovery in Dec 2019, SARS-CoV-2 has become a global pandemic and caused 3.3 million direct/indirect deaths (2021 May). Amongst the scientific communitys response to COVID-19, data sharing has emerged as an essential aspect of the combat against SARS-CoV-2. Despite the ever-growing studies about SARS-CoV-2 and COVID-19, to date, only a few databases were curated to enable access to gene expression data. Furthermore, these databases curated only a small set of data and do not provide easy access for investigators without computational skills to perform analyses. To fill this gap and advance open-access to the growing gene expression data on this deadly virus, we collected about 1,500 human bulk RNA-seq datasets from publicly available resources, developed a database and visualization tool, named CovidExpress (https://stjudecab.github.io/covidexpress). This open access database will allow research investigators to examine the gene expression in various tissues, cell lines, and their response to SARS-CoV-2 under different experimental conditions, accelerating the understanding of the etiology of this disease to inform the drug and vaccine development. Our integrative analysis of this big dataset highlights a set of commonly regulated genes in SARS-CoV-2 infected lung and Rhinovirus infected nasal tissues, including OASL that were under-studied in COVID-19 related reports. Our results also suggested a potential FURIN positive feedback loop that might explain the evolutional advantage of SARS-CoV-2.

bioinformatics↗

bioRxiv2021

A novel cholinergic neural pathway and its role in the drug relapse

The lateral parabrachial nucleus (LPB) is critical hub implicated in the control of food intake, reward and aversion. Here, we identified a novel cholinergic projection from choline acetyltransferase (ChAT)-positive neurons in external portion of the lateral parabrachial nucleus (eLPBChAT) to {gamma}-aminobutyric acid (GABA) neurons in central nucleus of amygdala (CeAGABA), activation of which could block methamphetamine (METH)-primed conditioned place preference (CPP) in mice.

neuroscience↗

bioRxiv2021

YAP/TAZ Maintain the Proliferative Capacity and Structural Organization of Radial Glial Cells During Brain Development

The Hippo pathway regulates the development and homeostasis of many tissues and in many species. It controls the activity of two paralogous transcriptional coactivators, YAP and TAZ (YAP/TAZ). Although previous studies have established that aberrant YAP/TAZ activation is detrimental to mammalian brain development, whether and how endogenous levels of YAP/TAZ activity regulate brain development remain unclear. Here, we show that during mammalian cortical development, YAP/TAZ are specifically expressed in apical neural progenitor cells known as radial glial cells (RGCs). The subcellular localization of YAP/TAZ undergoes dynamic changes as corticogenesis proceeds. YAP/TAZ are required for maintaining the proliferative potential and structural organization of RGCs, and their ablation during cortical development reduces the numbers of cortical projection neurons and causes the loss of ependymal cells, resulting in hydrocephaly. Transcriptomic analysis using sorted RGCs reveals gene expression changes in YAP/TAZ-depleted cells that correlate with mutant phenotypes. Thus, our study has uncovered essential functions of YAP/TAZ during mammalian brain development and revealed the transcriptional mechanism of their action.

developmental biology↗

bioRxiv2021

A genetic mouse model with postnatal Nf1 and p53 loss recapitulates the histology and transcriptome of human malignant peripheral nerve sheath tumor

BackgroundMalignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas. Somatic inactivation of NF1 and cooperating tumor suppressors, including CDKN2A/B, PRC2, and p53, is found in most MPNST. Inactivation of the LATS1/2 kinases of the Hippo pathway was recently shown to cause tumors resembling MPNST histologically, although Hippo pathway mutations are rarely found in MPNST. Because existing genetically engineered mouse (GEM) models of MPNST do not recapitulate some of the key genetic features of human MPNST, we aimed to establish a mouse MPNST model that recapitulated the human disease genetically, histologically, and molecularly. MethodsWe combined two genetically modified alleles, an Nf1;Trp53 cis-conditional allele and an inducible Plp-CreER allele (NP-Plp), to model the somatic, possibly postnatal, mutational events in human MPNST. We also generated conditional Lats1;Lats2 knockout mice. We performed histopathologic analysis of mouse MPNST models and transcriptomic comparison of mouse models and human nerve sheath tumors. ResultsPostnatal Nf1;Trp53 cis-deletion resulted in GEM-MPNST that was histologically more similar to human MPNST than the widely used germline Nf1;Trp53 cis-heterozygous (NPcis) model and showed partial loss of H3K27me3. At the transcriptome level, Nf1;p53-driven GEM-MPNST were distinct from Lats-driven GEM-MPNST and resembled human MPNST more closely than do Lats-driven tumors. ConclusionsThe NP-Plp model recapitulates human MPNST genetically, histologically, and molecularly. Key PointsO_LIPostnatal Nf1;p53 cis-deletion in NP-Plp mice results in tumors similar to MPNST. C_LIO_LIThe transcriptomes of Nf1;p53-driven and Lats-driven MPNST models are distinct. C_LIO_LINP-Plp model resembles human MPNST genetically, histologically, and molecularly. C_LI Importance of the StudyMalignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with a poor prognosis and limited treatment options. Existing genetically engineered mouse (GEM) models of MPNST do not recapitulate some of the key genetic features of human MPNST. To model the somatic, possibly postnatal, mutational events seen in MPNST patients, we generated a GEM-MPNST model by combining two genetically modified alleles, an Nf1;Trp53 cis-conditional allele and a Plp-CreER allele. Our histologic and transcriptomic analyses showed that this NP-Plp model resembles human MPNST genetically, histologically, and molecularly--more so than the widely used NPcis model and the recently published Lats-driven model. The NP-Plp model is genetically simple, making it easy to maintain and an ideal platform for preclinical studies. Given its tamoxifen-inducible nature, this model can be used to study the time/stage dependency of the tumorigenic potential of Schwann cells.

cancer biology↗

bioRxiv2021

Effects of straw returning with potassium fertilizer on the stem lodging resistance, grain quality and yield of spring maize (Zea mays L.)

The effects of straw returning with potassium fertilizer on the stem lodging resistance, grain quality and yield of spring maize were investigated to provide a scientific basis for the rational utilization of Inner Mongolia spring maize straw and potassium fertilizer resources. This study utilized Xianyu 335 as the test material, and a split plot design was carried out in three ecological regions from eastern to western Inner Mongolia (Tumochuan Plain irrigation area, Hetao Plain irrigation area and Lingnan warm dry zone), with the straw returning method as the main plot and potassium fertilizer dosage as the subplot. The stem resistance index, grain quality and yield were systematically identified. Both application of potassium fertilizer and straw returning improved the resistance and yield indicators of spring maize. Straw returning increased the effectiveness of potassium fertilizer application on spring maize plant height, ear height, fresh weight of stems, brix of stems and stem puncture strength by 2.82%-5.22%, 3.11%-5.90%, 15.96%-19.78%, 4.35%-4.50% and 8.89%-14.82%, respectively. Straw returning increased the effectiveness of potassium fertilizer application on the spring maize grain protein content, spring maize grain crude fat content, maize yield and yield variation coefficient by 3.49%-6.50%, 2.09%-4.43%, 4.87%-12.50% and 5.07%-7.55%, respectively. Straw returning can be combined with reasonable application of potassium fertilizer to increase the effectiveness of potassium fertilizer and enhance lodging resistance. Along with increased maize yield, straw returning also improves grain quality and enhances yield stability, providing a theoretical basis for high-yield and stress-resistant cultivation of Inner Mongolia spring maize, which can be popularized and applied in the spring maize planting areas of Inner Mongolia.

plant biology↗

bioRxiv2021

Focused Ultrasound Modulation of Hepatic Neural Plexus Restores Glucose Homeostasis in Diabetes

While peripheral glucose sensors are known to relay signals of substrate availability to integrative nuclei in the brain, the importance of these pathways in maintaining energy homeostasis and their contribution to disease remain unknown. Herein, we demonstrate that selective activation of the hepatoportal neural plexus via transient peripheral focused ultrasound (pFUS) induces glucose homeostasis in models of well-established insulin resistant diabetes. pFUS modulates sensory projections to the hindbrain and alters hypothalamic concentrations of neurotransmitters that regulate metabolism, resulting in potentiation of hypothalamic insulin signaling, leptin-independent inhibition of the orexigenic neuropeptide Y system, and therapeutic alteration in autonomic output to peripheral effector organs. Multiomic profiling confirms pFUS-induced modifications of key metabolic functions in liver, pancreas, muscle, adipose, kidney, and intestines. Activation of the hepatic nutrient sensing pathway not only restores nervous system coordination of peripheral metabolism in three different species but does so across these organ systems; several of which are current targets of antidiabetic drug classes. These results demonstrate the potential of hepatic pFUS as a novel/non-pharmacologic therapeutic modality to restore glucose homeostasis in metabolic diseases, including type II diabetes. One Sentence SummaryWe utilize a non-invasive ultrasound technique to activate a liver-brain sensory pathway and demonstrate its potential to induce durable normalization of glucose homeostasis in models of well-established insulin resistant diabetes.

biophysics↗

bioRxiv2021

Spike Protein Targeting "Nano-Glue" that Captures and Promotes SARS-CoV-2 Elimination

The global emergency caused by the SARS-CoV-2 pandemics can only be solved with adequate preventive and therapeutic strategies, both currently missing. The electropositive Receptor Binding Domain (RBD) of SARS-CoV-2 spike protein with abundant {beta}-sheet structure serves as target for COVID-19 therapeutic drug design. Here, we discovered that ultrathin 2D CuInP2S6 (CIPS) nanosheets as a new agent against SARS-CoV-2 infection, which also able to promote viral host elimination. CIPS exhibits extremely high and selective binding capacity with the RBD of SARS-CoV-2 spike protein, with consequent inhibition of virus entry and infection in ACE2-bearing cells and human airway epithelial organoids. CIPS displays nano-viscous properties in selectively binding with spike protein (KD < 1 pM) with negligible toxicity in vitro and in vivo. Further, the CIPS-bound SARS-CoV-2 was quickly phagocytosed and eliminated by macrophages, suggesting CIPS could be successfully used to capture and facilitate the virus host elimination with possibility of triggering anti-viral immunization. Thus, we propose CIPS as a promising nanodrug for future safe and effective anti-SARS-CoV-2 therapy, as well as for use as disinfection agent and surface coating material to constrain the SARS-CoV-2 spreading.

immunology↗

bioRxiv2021

Effects of potassium fertilizer on dry matter accumulation and potassium absorption characteristics of maize (Zea mays L.) inbred lines with different yield types

In this experiment, 20 different maize inbred lines were used as basic materials, which were divided into high-yield type, middle-yield type and low-yield type by yield cluster analysis. A 3-year long-term positioning field experiment (2016-2018) was carried out to assess the effects of potassium fertilizer on dry matter, potassium absorption and potassium absorption efficiency of maize inbred lines with different yield types. The results showed that the dry matter, potassium absorption and potassium absorption efficiency of leaf, stem, bract, rachis and grain of maize inbred lines have been significantly increased with potassium application in comparison with no potassium application. Potassium fertilizer could improve the dry matter accumulation capacity and potassium absorption characteristics of maize, promote the potassium absorption by maize plants, influence the growth and development of maize, and then improve the maize yield. The decrease of dry matter, potassium absorption and potassium absorption efficiency of high-yield maize inbred lines was smaller under low potassium stress. The high-yield maize inbred lines had stronger ability to maintain higher dry matter accumulation and potassium absorption characteristics under low potassium stress. The study provided a theoretical basis for the breeding of potassium-efficient maize materials.

plant biology↗

bioRxiv2021

Generation of human blastocyst-like structures from pluripotent stem cells

Human blastocysts are comprised of the first three cell lineages of the embryo: trophectoderm, epiblast, and primitive endoderm, all of which are essential for early development and organ formation1,2. However, due to ethical concerns and restricted access to human blastocysts, we lack a comprehensive understanding of early human embryogenesis. To bridge this knowledge gap, we need a reliable model system that recapitulates early stages of human embryogenesis. Here we report a [~]three-dimensional (3D), two-step induction protocol for generating blastocyst-like structures (EPS-blastoids) from human extended pluripotent stem (EPS) cells. Morphological and single-cell transcriptomic analyses revealed that EPS-blastoids contain key cell lineages and are transcriptionally similar to human blastocysts. Furthermore, EPS-blastoids also exhibited the developmental potential to undergo post-implantation morphogenesis in vitro to form structures with a cellular composition and transcriptome signature similar to human embryos that had been cultured in vitro for 8 or 10 days. In conclusion, human EPS-blastoids provide a new experimental platform for studying early developmental stages of the human embryo. HighlightsA method for generating human blastoids from EPS cells. Human blastoids resemble blastocysts in terms of morphology and cell lineage composition. Single-cell transcriptomic analyses reveal EPI, PE, and TE cell lineages in human blastoids. Human blastoids mimic in vitro the morphogenetic events of pre- and early post-implantation stages.

developmental biology↗

bioRxiv2021

Self-organization of Tissue Growth by Interfacial Mechanical Interactions in Multi-layered Systems

Morphogenesis is a spatially and temporally regulated process involved in various physiological and pathological transformations. In addition to the associated biochemical factors, the physical regulation of morphogenesis has attracted increasing attention. However, the driving force of morphogenesis initiation remains elusive. Here, we show that during the growth of multi-layered tissues, morphogenetic process can be self-organized by the progression of compression gradient stemmed from the interfacial mechanical interactions between layers. In tissues with low fluidity, the compression gradient is progressively strengthened during growth and induces stratification by triggering symmetric-to-asymmetric cell division reorientation at the critical tissue size. In tissues with high fluidity, compression gradient is dynamic and induces cell junction remodelling regulated cell rearrangement leading to 2D in-plane morphogenesis instead of 3D deformation. Morphogenesis can be tuned by manipulating tissue fluidity, cell adhesion forces and mechanical properties to influence the progression of compression gradient during the development of cultured cell sheets and chicken embryos. Together, the dynamics of compression gradient arised from interfacial mechanical interaction provides a conserved mechanism underlying morphogenesis initiation and size control during tissue growth.

biophysics↗

bioRxiv2021

Brazil Nut Effect Drives Pattern Formation in Early Mammalian Embryos

The formation of three-dimensional ordered spatial patterns, which is essential for embryonic development, tissue regeneration, and cancer metastasis, is mainly guided by the chemical concentration gradient of morphogens. However, since no chemical concentration gradient has been observed in the early embryonic development (pre-implantation) of mammals, the pattern formation mechanism has been unsolved for a long time. During the second cell fate decision of mouse embryos, the inner cell mass (ICM) segregates into topographically regionalized epiblast (EPI) and primitive endoderm (PrE) layers. Here, we report that the segregation process of PrE/EPI precursors coincides with an emerged periodic expansion-contraction vibration of the blastocyst cavity, which induces phase transition in the ICM compartment to a higher fluidity state and generates directional tissue flows. By experiments and modeling, we demonstrate that the spatial segregation of PrE and EPI precursors is mediated by a "Brazil nut effect"-like viscous segregation mechanism in which PrE precursors with low affinity gradually migrate to the surface of ICM along with the tissue flow, while EPI precursors with high affinity remains inside ICM under cavity vibration. Artificially manipulation of the frequency and amplitude of cavity vibration could control the process of spatial separation as well as lineage specification of PrE/EPI. Furthermore, disruption of the cavity vibration in the initial stage after segregation could reverse the ICM cells back to a mixed state. Therefore, this study reveals a fundamental mechanism that guarantees the robustness of cell segregation and pattern formation without specific morphogens in early mammalian embryos. Our model also emphasizes a conserved function of cavity structure that widely exists in organisms as an energy reservoir and converter between different forms, such as chemical and mechanical energy.

developmental biology↗

bioRxiv2021

Mechanically Sensitive HSF1 is a Key Regulator of Left-Right Symmetry Breaking in Zebrafish Embryos

The left-right symmetry breaking of vertebrate embryos requires fluid flow (called nodal flow in zebrafish). However, the molecular mechanisms that mediate the asymmetric gene expression regulation under nodal flow remain elusive. In this paper, we report that heat shock factor 1 (HSF1) is asymmetrically activated in the Kuppfers vesicle at the early stage of zebrafish embryos in the presence of nodal flow. Deficiency in HSF1 expression caused a significant situs inversus and disrupted gene expression asymmetry of nodal signaling proteins in zebrafish embryos. Further studies demonstrated that HSF1 could be immediately activated by fluid shear stress. The mechanical sensation ability of HSF1 is conserved in a variety of mechanical stimuli in different cell types. Moreover, cilia and the Ca2+-Akt signaling axis are essential for the activation of HSF1 under mechanical stress in vitro and in vivo. Considering the conserved expression of HSF1 in organisms, these findings unveil a fundamental mechanism of gene expression regulation triggered by mechanical clues during embryonic development and other physiological and pathological transformations.

developmental biology↗