Biology subjects

Zhang, D.

Publications and source records attributed to Zhang, D..

At least 343 records · Page 19Linked to original sources

bioRxiv2021

Overlapping Representation of Basic Tastes in the Human Gustatory Cortex

The topological representation is a fundamental property of human primary sensory cortices. The human gustatory cortex (GC) responds to the five basic tastes: bitter, salty, sweet, umami, and sour. However, the topological representation of the human gustatory cortex remains controversial. Through functional magnetic resonance imaging(fMRI) measurements of human responses to the five basic tastes, the current study aimed to delineate the taste representations within the GC. During the scanning, the volunteers tasted solutions of the five basic tastes, then washed their mouths with the tasteless solution. The solutions were then sucked from the volunteers mouths, eliminating the action of swallowing. The results showed that the bilateral mid-insula activated most during the taste task, and the active areas were mainly in the precentral and central insular sulcus. However, the regions responding to the five basic tastes are substantially overlapped, and the analysis of contrasts between each taste response and the averaged response to the remaining tastes does not report any significant results. Furthermore, in the gustatory insular cortex, the multivariate pattern analysis (MVPA) was unable to distinguish the activation patterns of the basic tastes, suggesting the possibility of weakly clustered distribution of the taste-preference neural activities in the human insular cortex. In conclusion, the presented results suggest overlapping representations of the basic tastes in the human gustatory insular cortex.

neuroscience↗

bioRxiv2021

Maternal Ezh1/2 deficiency in oocyte delays H3K27me2/3 restoration and impairs epiblast development responsible for embryonic sub-lethality in mouse

Mammalian embryonic development is a complex process regulated by various epigenetic modifications. Recently, maternal histone H3 methylations were found to be inherited and reprogrammed in early embryos to regulate embryonic development. The enhancer of zest homolog 1 and 2 (Ezh1 and Ezh2) belong to the core components of Polycomb repressive complex 2 (PRC2) and are the histone methyltransferase of histone 3 lysine 27 (H3K27). How maternal Ezh1 and Ezh2 function on H3K27 methylation in in vivo preimplantation embryos and embryonic development are not clear. Here, we deleted Ezh1 or/and Ezh2 in growing oocytes using gene knockout mouse models, and found that H3K27me3 in oocytes was disappeared by loss of Ezh2 alone while H3K27me2 was absent upon deletion of both Ezh1 and Ezh2. The effects of Ezh1/2 were inherited in maternal knockout zygotes and early embryos, in which restoration of H3K27me3 was delayed until late blastocyte by loss of Ezh2 alone and H3K27me2 was reestablished until morulae by deletion of Ezh1 and Ezh2. However, the ablation of both Ezh1 and Ezh2, but not single Ezh1 or Ezh2, led to significantly decreased litter size due to growth retardation during post-implantation. Furthermore, maternal Ezh1/2 deficiency caused compromised H3K27me3 and pluripotent epiblast cells in late blastocyst, followed by defective development of epiblast. These results demonstrate that in oocytes, Ezh2 is indispensable for H3K27me3 while Ezh1 complements Ezh2 in H3K27me2. Also, maternal Ezh1/2-H3K27 methylation is inherited in descendant embryos and has a critical effect on fetus and placenta development. Thus, this work sheds light on maternal epigenetic modifications during embryonic development.

developmental biology↗

bioRxiv2021

Single-nucleus transcriptomic atlas of spinal cord neuron in human

Despite the recognized importance of spinal cord in sensory processing, motor behaviors and/or neural diseases, the underlying neuronal clusters remain elusive. Recently, several studies attempted to define the neuronal types and functional heterogeneity in spinal cord using single cell and/or single-nucleus RNA-sequencing in varied animal models. However, the molecular evidence of neuronal heterogeneity in human spinal cord has not been established yet. Here we sought to classify spinal cord neurons from human donors by high-throughput single-nucleus RNA-sequencing. The functional heterogeneity of identified cell types and signaling pathways that connecting neuronal subtypes were explored. Moreover, we also compared human results with previous single-cell transcriptomic profiles of mouse spinal cord. As a result, we generated the first comprehensive atlas of human spinal cord neurons and defined 18 neuronal clusters. In addition to identification of the new and functionally-distinct neuronal subtypes, our results also provide novel marker genes for previously known neuronal types. The comparation with mouse transcriptomic profiles revealed an overall similarity in the cellular composition of spinal cord between the two species. In summary, these results illustrate the complexity and diversity of neuronal types in human spinal cord and will provide an important resource for future researches to explore the molecular mechanism underlying several spinal cord physiology and diseases.

neuroscience↗

bioRxiv2021

Distinct cell adhesion signature defines glioblastoma myeloid-derived suppressor cell subsets

Increased myeloid-derived suppressor cell (MDSC) frequency is associated with worse outcomes and poor therapeutic response in glioblastoma (GBM). Monocytic (m) MDSCs represent the predominant subset in the GBM microenvironment. However, the molecular basis of mMDSC enrichment in the tumor microenvironment compared to granulocytic (g) MDSCs has yet to be determined. Here, we report that mMDSCs and gMDSCs display differences in their tumoraccelerating ability, with mMDSCs driving tumor growth in GBM models. Epigenetic assessments indicate enhanced gene accessibility for cell adhesion programs in mMDSCs and higher cellsurface integrin expression in mouse and human mMDSCs. Integrin {beta}1 blockage abrogated the tumor-promoting phenotype of mMDSCs and altered the immune profile in the tumor microenvironment. These findings suggest that integrin {beta}1 expression underlies the enrichment of mMDSCs in tumors and represents a putative immunotherapy target to attenuate myeloid cell-driven immune suppression in GBM. SummaryMyeloid-derived suppressor cells (MDSCs) drive glioblastoma growth; however, the function of specific MDSCs subsets is unclear. Bayik et al. demonstrate that adhesion programs are enhanced in monocytic MDSCs and responsible for their GBM-promoting function.

immunology↗

bioRxiv2021

A Purkinje cell to parabrachial nucleus pathway enables broad cerebellar influence over the forebrain and emotional valence

In addition to its well-known contributions to motor function, the cerebellum is involved in emotional regulation, anxiety, and affect1-4. We found that suppressing the firing of cerebellar Purkinje cells (PCs) rapidly excites forebrain areas that could contribute to such functions (including the amygdala, basal forebrain, and septum), but that the classic cerebellar outputs, the deep cerebellar nuclei (DCN), do not project to these forebrain regions. Here we show that PCs directly inhibit parabrachial nuclei (PBN) neurons that project to and influence numerous forebrain regions in a manner distinct from the DCN pathway. We also found that the PBN and DCN output pathways differentially influence behavior: suppressing the PC to PBN pathway is aversive and does not affect the speed of movement, whereas suppressing the PC to DCN pathway is not aversive and reduces speed. Molecular profiling shows that PCs inhibit numerous types of PBN neurons that control diverse nonmotor behaviors5-9. Therefore, the PBN pathway allows the cerebellum to regulate activity in many forebrain regions and may be an important substrate for nonmotor disorders related to cerebellar dysfunction.

neuroscience↗

bioRxiv2021

Transcriptome and miRNAome reveal components regulating primary thickening of bamboo shoots

Primary thickening determines bamboo yield and wood property. However, little is known about the regulatory networks involved in this process. The present study identified a total of 58,652 genes and 521 miRNAs via transcriptome and small RNA sequencing using the underground thickening shoot samples of wild type (WT) Moso bamboo (Phyllostachys edulis) and a thick wall (TW) variant (P. edulis cv. Pachyloen) at five developmental stages (WTS1/TWS1-WTS5/TWS5). A total of 11,636 (54.05%) differentially expressed genes (DEGs) and 515 (98.85%) differentially expressed miRNAs (DEmiRs) were identified from the WT, TW, and WTTW groups. The first two groups were composed of four pairwise combinations each between two successive stages (WTS2/TWS2_vs_WTS1/TWS1, WTS3/TWS3_vs_WTS2/TWS2, WTS4/TWS4_vs_WTS3/TWS3 and WTS5/TWS5_vs_WTS4/TWS4), and the WTTW group was composed of five between two relative stages (TWS1-5_vs_WTS1-5). Additionally, among the phytohormones, zeatin (ZT) showed more remarkable changes in concentrations than indole-3-acetic acid (IAA), gibberellic acid (GA3), and abscisic acid (ABA) throughout the five stages in the WT and the TW groups. Moreover, 118 sites were identified for 590 miRNA-mRNA pairs via degradome sequencing. The dual-luciferase reporter assay confirmed that 14 miRNAs bound to 12 targets. Fluorescence in situ hybridization (FISH) localized miR166 and miR160 in the shoot apical meristem (SAM) and the procambium of Moso bamboo shoots at the S1 stage. Thus, primary thickening is a complex process regulated by miRNA-gene-phytohormone networks, and the miRNAome and transcriptome dynamics regulate phenotypic plasticity. These findings provide insights into the molecular mechanisms underlying wood formation and properties and propose targets for bamboo breeding.

developmental biology↗

bioRxiv2021

The Siberian wild apple, Malus baccata (L.) Borkh., is an additional contributor to the genomes of cultivated European and Chinese apples

It is crucial to understand domestication to unravel the evolutionary processes that shape the divergence of populations. Differences in life-history traits have probably led to marked differences in the mode and speed of evolution between trees and annuals, particularly the extent of crop-wild gene flow during domestication. Apple is an iconic tree and major fruit crop grown worldwide. The contribution of wild apple species to the genetic makeup of the cultivated apple genome remains a topic of intense investigations. We used population genomics in combination with SNPs to investigate the contributions of the two known wild apple relatives, Malus sylvestris and Malus sieversii, and a supposed contributor, Malus baccata, to European and Chinese rootstock and dessert genomes, with a focus on the extent of wild-crop gene flow during apple domestication. We showed that the European dessert and rootstock apples form a specific gene pool, whereas the Chinese dessert and rootstock apples were a mixture of three wild gene pools. Coalescent-based inferences and gene flow estimates indicated that M. baccata is an additional contributor to the genome of both European and Chinese cultivated apples through wild-to-crop introgressions. We also confirmed previous results on the contribution of M. sylvestris to the cultivated apple genome, and provided insights into the origin of the apple rootstock. This study further demonstrates the role of gene flow during apple domestication, as seen in other woody perennials, and show that domestication of the apple tree involved several wild apple species.

evolutionary biology↗

bioRxiv2021

iCn3D: from Web-based 3D Viewer to Structure Analysis Tool in Batch Mode

iCn3D was initially developed as a web-based 3D molecular viewer. It then evolved from visualization into a full-featured interactive structural analysis software. It became a collaborative research instrument through the sharing of permanent, shortened URLs that encapsulate not only annotated visual molecular scenes, but also all underlying data and analysis scripts in a FAIR manner. More recently, with the growth of structural databases, the need to analyze large structural datasets systematically led us to use Python scripts and convert the code to be used in Node.js scripts. We showed a few examples of Python scripts at https://github.com/ncbi/icn3d/tree/master/icn3dpython to export secondary structures or PNG images from iCn3D. Users just need to replace the URL in the Python scripts to export other annotations from iCn3D. Furthermore, any interactive iCn3D feature can be converted into a Node.js script to be run in batch mode, enabling an interactive analysis performed on one or a handful of protein complexes to be scaled up to analysis features of large ensembles of structures. Currently available Node.js analysis scripts examples are available at https://github.com/ncbi/icn3d/tree/master/icn3dnode. This development will enable ensemble analyses on growing structural databases such as AlphaFold or RoseTTAFold on one hand and Electron Microscopy on the other. In this paper, we also review new features such as DelPhi electrostatic potential, 3D view of mutations, alignment of multiple chains, assembly of multiple structures by realignment, dynamic symmetry calculation, 2D cartoons at different levels, interactive contact maps, and use of iCn3D in Jupyter Notebook as described at https://pypi.org/project/icn3dpy.

bioinformatics↗

bioRxiv2021

LIFE-Seq: A universal Large Integrated DNA Fragment Enrichment Sequencing strategy for transgene integration in genetically modified organisms

Molecular characterisation of genetically modified organisms (GMOs) yields basic information on exogenous DNA integration, including integration sites, entire inserted sequences and structures, flanking sequences and copy number, providing key data for biosafety assessment. However, there are few effective methods for deciphering transgene integration, especially for large DNA fragment integration with complex rearrangement, inversion, and tandem repeats. Herein, we developed a universal Large Integrated DNA Fragments Enrichment strategy combined with PacBio Sequencing (LIFE-Seq) for deciphering transgene integration in GMOs. Universal tilling DNA probes targeting transgenic elements and exogenous genes facilitate specific enrichment of large inserted DNA fragments associated with transgenes from plant genomes, followed by PacBio sequencing. LIFE-Seq were evaluated using six GM events and four crop species. Target DNA fragments averaging [~]6275 bp were enriched and sequenced, generating [~]26,352 high fidelity reads for each sample. Transgene integration structures were determined with high repeatability and sensitivity. Compared with whole-genome sequencing, LIFE-Seq achieved better data integrity and accuracy, greater universality, and lower cost, especially for transgenic crops with complex inserted DNA structures. LIFE-Seq could be applied in molecular characterisation of transgenic crops and animals, and complex DNA structure analysis in genetics research.

plant biology↗

bioRxiv2021

Mismatch repair deficiency is not sufficient to increase tumor immunogenicity

DNA mismatch repair deficiency (MMRd) in human cancer is associated with high tumor mutational burden (TMB), frameshift mutation-derived neoantigens, increased T cell infiltration, and remarkable responsiveness to immune checkpoint blockade (ICB) therapy. Nevertheless, about half of MMRd tumors do not respond to ICB for unclear reasons. While tumor cell line transplant models of MMRd have reinforced the importance of TMB in immune response, critical questions remain regarding the role of immunosurveillance in the evolution of MMRd tumors induced in vivo. Here, we developed autochthonous mouse models of lung and colon cancer with highly efficient ablation of MMR genes via in vivo CRISPR/Cas9 targeting. Surprisingly, MMRd in these models did not result in increased immunogenicity or response to ICB. Mechanistically, we showed this lack of immunogenicity to be driven by profound intratumoral heterogeneity (ITH). Studies in animals depleted of T cells further demonstrated that immunosurveillance in MMRd tumors has no impact on TMB but shapes the clonal architecture of neoantigens by exacerbating ITH. These results provide important context for understanding immune evasion in cancers with high TMB and have major implications for therapies aimed at increasing TMB.

cancer biology↗

bioRxiv2021

The rs1421085 variant within FTO promotes but not inhibits thermogenesis and is potentially associated with human migration

Disease-associated GWAS loci are predominantly scattered among noncoding regions of the human genome, which impedes causality estimation. One lead risk signal of obesity-rs1421085 T>C within the FTO gene-is reported to functional in vitro but lack of organismal evidence. Here, we established global and the brown-adipocyte specific locus-knock-in mice to recapitulate this homologous variant in humans, and discovered the minor allele (C-allele) as one candidate thermogenic locus. Mice carrying the C-alleles showed increased thermogenic capacity and a resistance to high-fat diet-induced adiposity. In terms of mechanism, the knock-in models showed enhanced FTO expression, while FTO knockdown or inhibition effectively eliminated the increased thermogenic ability of brown adipocytes. In humans, the C-allele was associated with lower birthweight, and its allele frequency increases following the environmental temperature decreases. Cumulatively, these findings demonstrated rs1421085 T>C as a functional variant regulating whole-body thermogenesis, and this variation was possibly related to early human migration from hot to cold environments.

genetics↗

bioRxiv2021

Humanoid robots are perceived as an evolutionary threat

Studying how we perceive humanoid robots will provide insights for a deeper understanding of human-robot interaction. Our ideas about humanoid robots are mainly informed by science fiction, and humanoid robots are generally described as an evolutionary threat in science fiction that has not been tested. The preparedness model has emphasized that the fear module is automatically activated by evolutionary threats, and its underlying neural circuit is centered on the amygdala. We hypothesized that if humanoid robots are perceived as an evolutionary threat even though humanoid robots are manmade, modern objects, we would expect to observe a monocular advantage for humanoid robots and an amygdala response to unconsciously presented humanoid robots that were previously only evident in evolutionary threats. Here, we observed a monocular advantage for the perception of humanoid robots the same as an evolutionary threat (i.e., snakes). Our neuroimaging analysis indicated that unconscious presentation of humanoid robot vs. human images led to significant amygdala activation. Despite a positive humanoid robot-related association had been established by associative learning (as evidenced by results of successfully weakening the negative implicit attitude to humanoid robots and enhancing functional connectivity between the amygdala and hippocampus), the amygdala could still automatically and quickly detect humanoid robots. Our results reveal that processing of information about humanoid robots displays automaticity with regard to recruitment of visual pathway and amygdala activation. Our findings that humans apparently perceive humanoid robots as an evolutionary threat may help inform redefinition of human-robot interaction and robot ethics.

neuroscience↗

bioRxiv2021

Three conserved hydrophobic residues in the CC domain of Pit contribute to its plasma membrane localization and immune induction

Nucleotide-binding leucine-rich repeat (NLR) proteins work as crucial intracellular immune receptors. N-terminal domains of NLRs fall into two groups, namely coiled-coil (CC) and Toll-interleukin 1 receptor (TIR) domains, which play critical roles in signal transduction and disease resistance. However, the activation mechanisms of NLRs, and how their N-termini are involved in immune induction, remain largely unknown. Here, we revealed that the rice NLR Pit self-associates through its CC domain. The CC domain of Pit possesses three conserved hydrophobic residues that are known to be involved in homodimer formation in two NLRs, barley MLA10 and Arabidopsis RPM1. Interestingly, the function of these residues in Pit is different from that in MLA10 and RPM1. Although the three hydrophobic residues are important for Pit-induced disease resistance against rice blast fungus, they do not participate in self-association or in binding to downstream signaling molecules. Based on homology modeling of Pit using the structure of the Arabidopsis NLR ZAR1, we tried to clarify the role of the three conserved hydrophobic residues and found that they are involved in the plasma membrane localization. Our findings provide novel insights for understanding the mechanisms of NLR activation as well as the relationship between subcellular localization and immune induction.

plant biology↗

bioRxiv2021

Ribosomal protein L23 drives the metastasis of hepatocellular carcinoma via upregulating MMP9

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally and tumor metastasis is one of the major causes of high mortality. To identify novel molecules contributing to HCC metastasis is critical to understanding the underlining mechanism of cancer metastasis. Here, combining the analyze based on published database and liver tissues from HCC patients, we identified that RNA binding protein L23 (RPL23) as a tumor metastasis driver in HCC. RPL23 was elevated in HCC and closely related to poor clinical outcomes. Furthermore, RPL23 depletion inhibited HCC cell proliferation, migration and invasion, while RPL23 overexpression promoted HCC cell metastasis. Mechanistically, RPL23 positively regulated MMP9 expression by stabilizing its mRNA. And increased MMP9 is involved in RPL23-mediated HCC metastasis. Importantly, RPL23 silencing reduced tumor growth and metastasis in vivo. In summary, we identified that RPL23 play an important role in HCC metastasis in an MMP9-dependent manner and may be a novel potential therapeutic target for HCC tumorigenesis and metastasis.

cancer biology↗

bioRxiv2021

Vision-based monitoring and measurement of bottlenose dolphins' daily habitat use and kinematics

This research presents a framework to enable computer-automated observation and monitoring of bottlenose dolphins (Tursiops truncatus) in a professionally managed environment. Results from this work provide insight into the dolphins movement patterns, kinematic diversity, and how changes in the environment affect their dynamics. Fixed overhead cameras were used to collect [~]100 hours of observations, recorded over multiple days including time both during and outside of formal training sessions. Animal locations were estimated using convolutional neural network (CNN) object detectors and Kalman filter post-processing. The resulting animal tracks were used to quantify habitat use and animal dynamics. Additionally, Kolmogorov-Smirnov analyses of the swimming kinematics were used for high-level behavioral mode classification. The detectors achieved a minimum Average Precision of 0.76. Performing detections and post-processing yielded 1.24x107 estimated dolphin locations. Animal kinematic diversity was found to be lowest in the morning and peaked immediately before noon. Regions of the habitat displaying the highest activity levels correlated to locations associated with animal care specialists, conspecifics, or enrichment. The work presented here demonstrates that CNN object detection is not only viable for large-scale marine mammal tracking, it also enables automated analyses of dynamics that provide new insight into animal movement and behavior.

animal behavior and cognition↗

bioRxiv2021

GM1 mediates the formation and maintenance of cytotoxic Aβ oligomers

The aggregation of amyloid beta (A{beta}) peptide is associated with Alzheimers disease (AD) pathogenesis. Cell membrane composition, especially monosialotetrahexosylganglioside (GM1), is known to promote the formation of A{beta} fibrils, yet little is known about the roles of GM1 in the early steps of A{beta} oligomer formation. Here, by using GM1-contained liposomes as a mimic of neuronal cell membrane, we demonstrate that GM1 is a critical trigger of A{beta} oligomerization and aggregation. We find that GM1 not only promotes the formation of A{beta} fibrils, but also facilitates the maintenance of A{beta} oligomers on liposome membranes. We structurally characterize the A{beta} oligomers formed on the membrane and find that GM1 captures A{beta} by binding to its arginine-5 residue. To interrogate the mechanism of A{beta} oligomer toxicity, we design a new liposome-based Ca2+-encapsulation assay and provide new evidence for the A{beta} ion channel hypothesis. Finally, we conduct cell viability assay to determine the toxicity of A{beta} oligomers formed on membranes. Overall, by uncovering the roles of GM1 in mediating early A{beta} oligomer formation and maintenance, our work provides a novel direction for pharmaceutical research for AD.

biophysics↗

bioRxiv2021

Cell minor-axis length is a critical feature for breast cancer cell migration on straight, wavy, loop and grid microfibre patterns

Cell migration plays an important role in physiological and pathological processes where the fibrillar morphology of extracellular matrice (ECM) could regulate the migration dynamics. To mimic the morphological characteristics of fibrillar matrix structures, low-voltage continuous electrospinning was adapted to construct straight, wavy, looped and gridded fibre patterns made of polystyrene (of fibre diameter ca. 3 m). With microfibres deposited onto non-passivated surfaces, cells were permitted to explore their different shapes in response to the directly-adhered fibre, as well as to the neighbouring patterns. For all the patterns studied, analysing cellular migration dynamics of MDA-MB-231 (a highly migratory breast cancer cell line) demonstrated a switch in behaviour when the pattern features approach the upper limit of the cell minor axis. Our findings suggest that, although cells dynamically adjust their shapes in response to different fibrillar environments during migration, their ability to divert from an existing fibre track is limited by the size along the cell minor axis. We therefore conclude that the upper limit of cell minor axis might act as a guide for the design of microfibre patterns for different purposes of cell migration.

bioengineering↗

bioRxiv2021

A connectome-based neuromarker of the non-verbal number acuity and arithmetic skills

The approximate number system (ANS) is vital for survival and reproduction in animals and crucial in constructing abstract mathematical abilities in humans. Most previous neuroimaging studies focused on identifying discrete brain regions responsible for the ANS and characterizing their functions in numerosity perception. However, there lacks a neuromarker to characterize an individuals ANS acuity, especially one based on the whole-brain functional connectivity (FC). Here, we identified a distributed brain network (i.e., numerosity network) using a connectome-based predictive modeling (CPM) analysis on the resting-state functional magnetic resonance imaging (rs-fMRI) data based on a large sample size. The summed strength of all FCs within the numerosity network could reliably predict individual differences of the ANS acuity in behavior. Furthermore, in an independent dataset from the Human Connectome Project (HCP), we found that the summed FC strength within the numerosity network could also predict individual differences in arithmetic skills. Our findings illustrate that the numerosity network we identified could be an applicable neuromarker of the non-verbal number acuity and might serve as the neural basis underlying the known link between the non-verbal number acuity and mathematical abilities.

neuroscience↗