Biology subjects

Chen, Z.

Publications and source records attributed to Chen, Z..

At least 541 records · Page 30Linked to original sources

bioRxiv2023

Hierarchical cortical and subcortical mechanisms underlying binocular rivalry

Conscious perception alternates between the two eyes images during binocular rivalry. How hierarchical processes in our brain interact to resolve visual competition to generate conscious perception remains unclear. Here we investigated the mesoscale neural circuitry for binocular rivalry in human cortical and subcortical areas using high-resolution functional MRI at 7 Tesla. Eye-specific response modulation in binocular rivalry was strongest in the superficial layers of V1 ocular dominance columns (ODCs), and more synchronized in the superficial and deep layers. The intraparietal sulcus (IPS) generated stronger eye-specific response modulation and increased effective connectivity to the early visual cortex during binocular rivalry compared to monocular "replay" simulations. Although there was no evidence of eye-specific rivalry modulation in the lateral geniculate nucleus (LGN) of the thalamus, strong perceptual rivalry modulation can be found in its parvocellular (P) subdivision. Finally, IPS and ventral pulvinar showed robust perceptual rivalry modulation and increased connectivity to the early visual cortex. These findings demonstrate that local interocular competition arises from lateral mutual inhibition between V1 ODCs, and feedback signals from IPS to visual cortex and visual thalamus further synchronize and resolve visual competition to generate conscious perception. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/528110v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@af6feaorg.highwire.dtl.DTLVardef@1dc8cd3org.highwire.dtl.DTLVardef@a1905forg.highwire.dtl.DTLVardef@10d7b75_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIEye-specific rivalry modulation is strongest in the superficial layers of V1 ODCs and more synchronized in superficial and deep layers C_LIO_LIIPS generates stronger eye-specific response modulation and increases connectivity to V1 during rivalry compared to replay C_LIO_LILGN activity shows no evidence of eye-specific rivalry modulation but strong perceptual rivalry modulation in its P subdivision C_LIO_LIIPS and ventral pulvinar show robust perceptual rivalry modulation and increased connectivity to the early visual cortex C_LI

neuroscience↗

bioRxiv2023

RNPS1 stabilizes NAT10 protein to facilitate translation in cancer via tRNA ac4C modification

NAT10 is dysregulated and plays an essential role in various types of cancers. However, the exact machenism of how NAT10 regulates cancer progression remains debatable. In this report, we show that NAT10 affects tumorigeneis mainly based on its acetylation function on tRNA. In addition, we found NAT10 regulate the ac4C of tRNA in cancer via interaction with RNPS1, which in turn protect NAT10 from degradation by E3 ubiquitin ligase ZSWIM6. We developed TRMC-seq method to compreshensively profile tRNA ac4C sites and uncovered the presence of ac4C in a broader range of tRNA isoacceptors than previous studies. Multi-omics analysis identified AP-1 signaling pathway as a major downstream mediator of NAT10. Mechanistically, we found NAT10 is responsible for the translation efficiency genes which contain higher ac4C-tRNA codon. Importantly, our genetic mouse model validated our in vitro findings of NAT10 in cancer. Our study highlights a role of NAT10 in mediating tRNA ac4C to regulate the translation and tumorigenesis of cancer.

molecular biology↗

bioRxiv2023

Structure-dependent spontaneous calcium dynamics in cultured neuronal networks on microcontact-printed substrates

Microcontact printing (CP) is widely used in neuroscience research. However, CP yields reduced cell-substrate adhesion compared with directly coating cell adhesion molecules. Here, we demonstrate that the reduced cell-substrate adhesion caused by CP, high seeding density, and the local restriction would separately contribute to more aggregated (neurons closer to each other in separate clusters) neuronal networks. Calcium recordings revealed that more aggregated networks presented fewer spontaneous calcium activity patterns, and were more likely dominated by synchronized network-wide calcium oscillation (network bursts). First, on a uniform microcontact-printed substrate, densely seeded neurons were reaggregated into a Petri dish-wide network consisting of small clusters, of which the calcium dynamics were dominated by network bursts. Next, further analysis revealed this dominance was maintained since its appearance, and the initiation and propagation of bursts in the small-cluster network shared a similar mechanism with that of homogeneous networks. Then, sparsely seeded neurons formed several networks with different aggregation degrees, in which the less clustered ones presented abundant time-varying subnetwork burst patterns. Finally, by printing locally restricted patterns, highly clustered networks formed, where dominant network bursts reappeared. These findings demonstrate the existence of structure-dependent spontaneous calcium dynamics in cultured networks on microcontact-printed substrates, which provide important insights into designing cultured networks by using CP, and into deciphering the onset and evolution of network bursts in developmental nerve systems.

neuroscience↗

bioRxiv2023

FarmGTEx TWAS-server: an interactive web server for customized TWAS analysis in both human and farm animals

Transcriptome-wide association study (TWAS) is a powerful strategy for elucidating the molecular mechanisms behind the genetic loci of complex phenotypes. However, TWAS analysis is still daunting in many species due to the complication of the TWAS analysis pipeline, including the construction of the gene expression reference panel, gene expression prediction, and the subsequent association analysis in the large cohorts of genome-wide association study (GWAS). Farm animals are major protein sources and biomedical models for humans. To facilitate the translation of genetic findings across species, here we provide an interactive and easy-to-use multi-species TWAS web server for the entire community, called the FarmGTEx TWAS-server (http://twas.farmgtex.org), which is based on the GTEx and FarmGTEx projects. It includes gene expression data from 49, 34, and 23 tissues in 838 humans, 5,457 pigs, and 4,889 cattle, representing 38,180, 21,037, and 17,942 distinct eGenes in prediction models for humans, pigs, and cattle, respectively. It allows users to conduct gene expression prediction for any individuals with genotypes, GWAS summary statistics imputation, customized TWAS, and popular downstream functional annotation. It also provides 479,203, 1,208, and 657 tissue-gene-trait association trios for the research community, representing 1,129 human traits, 41 cattle traits, and 11 pig traits. In summary, the FarmGTEx TWAS-server is a one-stop solution for performing TWAS analysis for researchers without programming skills in both human and farm animal research communities. It will be maintained and updated timely within the FarmGTEx project to facilitate gene mapping and phenotype prediction within and across species.

bioinformatics↗

bioRxiv2023

PLANET: A Multi-Objective Graph Neural Network Model for Protein-Ligand Binding Affinity Prediction

Predicting protein-ligand binding affinity is a central issue in drug design. Various deep learning models have been developed in recent years to tackle this issue, but many of them merely focus on reproducing the binding affinity of known binders. In this study, we have developed a graph neural network model called PLANET (Protein-Ligand Affinity prediction NETwork). This model takes the graph-represented 3D structure of the binding pocket on the target protein and the 2D chemical structure of the ligand molecule as input, and it was trained through a multi-objective process with three related tasks, including deriving the protein-ligand binding affinity, protein-ligand contact map, and intra-ligand distance matrix. To serve those tasks, a large number of decoy non-binders were selected and added to the standard PDBbind data set. When tested on the CASF-2016 benchmark, PLANET exhibited a scoring power comparable to other deep learning models that rely on 3D protein-ligand complex structures as input. It also showed notably better performance in virtual screening trials on the DUD-E and LIT-PCBA benchmark. In particular, PLANET achieved comparable accuracy on LIT-PCBA as the conventional docking program Glide. However, it only took less than 1% of the computation time required by Glide to finish the same job because it did not perform exhaustive conformational sampling. In summary, PLANET exhibited a decent performance in binding affinity prediction as well as virtual screening, which makes it potentially useful for drug discovery in practice.

bioinformatics↗

bioRxiv2023

Disrupted trans-placental thyroid hormone transport in a human model for MCT8 deficiency

Introduction ABSTRACT Introduction Results Discussion Materials and methods Author contributions Conflict of interest statement The Paper Explained Problem Results Impact Expanded View Figures References Thyroid hormones, the collective name for the prohormone T4 and the active hormone T3, are crucial for neurodevelopment. During prenatal neurodevelopment, maternal-to-fetal T4 transfer is critical, particularly during the first half of pregnancy with the fetal thyroid gland being immature (Patel et al, 2011). Therefore, maternal thyroid dysfunction negatively impacts brain structure and function in the offspring (Jansen et al, 2019; ...

pathology↗

bioRxiv2023

Gastrodin ameliorates synaptic impairment, reestablishes mitochondrial membrane potential and reduces oxidative stress in N2a/APP cells through the ERK1/2 and GSK-3beta pathways

Alzheimers disease (AD) is featured by abnormal {beta}-amyloid (A{beta}) deposition, neurofibrillary tangle formation, downstream mitochondrial dysfunction, oxidative stress, and synaptic loss. Gastrodin, a phenolic glycoside, has shown neuroprotective effect and used in the treatment of a range of brain diseases. Here we aim to assess the mechanisms and signaling pathways involved in the neuroprotective effect of gastrodin in murine neuroblastoma N2a cells expressing human Swedish mutant amyloid precursor protein (N2a/APP). The levels of pre- and postsynaptic proteins, amyloid precursor protein C-terminal fragments (APP-CTFs), levels of tau, glycogen synthase kinase-3 {beta} (GSK-3{beta}), extracellular regulated kinase (ERK), and c-Jun N-terminal Kinase (JNK) were assessed by Western blotting. Flow cytometry assays for mitochondrial membrane potential (JC1) and reactive oxidative stress, as well as immunofluorescence staining for lipid peroxidation (4{square}hydroxynonenal) and DNA oxidation (8{square}hydroxy{square}2{square}deoxyguanosine), were performed. We found that gastrodin treatment increased the levels of presynaptic SNAP25, synaptophysin, and postsynaptic PSD95, reduced phosphorylated tau protein Ser396, and APP-CTFs in N2a/APP cells. In addition, gastrodin reduced the levels of reactive oxygen species generation, lipid peroxidation, and DNA oxidation, reestablished mitochondrial membrane potential. Upregulated levels of phosphorylated-GSK-3{beta}, reduced levels of phosphorylated-ERK, and phosphorylated-JNK were involved the protective effect of gastrodin. In conclusion, we demonstrated a neuroprotective effect of gastrodin in N2a/APP cell line.

neuroscience↗

bioRxiv2023

Genetics of Latin American Diversity (GLAD) Project: insights into population genetics and association studies in recently admixed groups in the Americas

Latin America is underrepresented in genetic studies, which can exacerbate disparities in personalized genomic medicine. However, genetic data of thousands of Latin Americans are already publicly available, but require a bureaucratic maze to navigate all the data access and consenting issues. We present the Genetics of Latin American Diversity (GLAD) Project, a platform that compiles genome-wide information of 54,077 Latin Americans from 39 studies representing 45 geographical regions. Through GLAD, we identified heterogeneous ancestry composition and recent gene-flow across the Americas. Also, we developed a simulated-annealing-based algorithm to match the genetic background of external samples to our database and share summary statistics without transferring individual-level data. Finally, we demonstrate the potential of GLAD as a critical resource for evaluating statistical genetic softwares in the presence of admixture. By making this resource available, we promote genomic research in Latin Americans and contribute to the promises of personalized medicine to more people.

genetics↗

bioRxiv2023

The mechanosensitive ion channel Piezo1 contributes to ultrasound neuromodulation

Transcranial low-intensity ultrasound is a promising neuromodulation modality, with the advantages of non-invasiveness, deep penetration, and high spatiotemporal accuracy. However, the underlying biological mechanism of ultrasonic neuromodulation remains unclear, hindering the development of efficacious treatments. Here, the well-known Piezo1, was studied through a conditional knockout mouse model as a major molecule for ultrasound neuromodulation ex vivo and in vivo. We showed that Piezo1 knockout in the right motor cortex of mice significantly reduced ultrasound-induced neuronal calcium responses, limb movement and muscle EMG responses. We also detected higher Piezo1 in the central amygdala (CEA) which were found more sensitive to ultrasound stimulation than that of cortex. Knocking out the Piezo1 in CEA neurons showed a significant reduction of response under ultrasound stimulation while knocking out astrocytic Piezo1 showed no obvious changes in neuronal responses. Additionally, we excluded an auditory confound by monitoring auditory cortical activation and using smooth waveform ultrasound with randomized parameters to stimulate P1KO ipsilateral and contralateral regions of the same brain and recording evoked movement in the corresponding limb. Thus, we demonstrate that Piezo1 is functionally expressed in different brain regions, and that it is an important mediator of ultrasound neuromodulation in the brain, laying the ground for further mechanistic studies of ultrasound.

neuroscience↗

bioRxiv2023

Structure of the ISW1a complex bound to the dinucleosome

Nucleosomes are basic repeating units of chromatin, and form regularly spaced arrays in cells. Chromatin remodelers alter the positions of nucleosomes, and are vital in regulating chromatin organization and gene expression. Here we report the cryoEM structure of chromatin remodeler ISW1a complex bound to the dinucleosome. Each subunit of the complex recognizes a different nucleosome. The motor subunit binds to the mobile nucleosome and recognizes the acidic patch through two arginine residues, and the DNA-binding module interacts with the entry DNA at the nucleosome edge. This nucleosome-binding mode provides the structural basis for linker DNA sensing of the motor. Notably, the Ioc3 subunit recognizes the disk face of the adjacent nucleosome through the H4 tail, the acidic patch and the nucleosomal DNA, which is important for the spacing activity in vitro, and for nucleosome organization and cell fitness in vivo. Together, these findings support the nucleosome spacing activity of ISW1a, and add a new mode of nucleosome remodeling in the context of a chromatin environment.

biochemistry↗

bioRxiv2022

ROS signaling-induced mitochondrial Sgk1 regulates epithelial cell plasticity

Many types of differentiated cells can reenter the cell cycle upon injury or stress. The mechanisms underlying this cell plasticity are still poorly understood. Here we investigated cell plasticity regulation using a zebrafish model, in which a population of differentiated epithelial cells are reactivated under a physiological context. We observed a robust and sustained increase in mitochondrial membrane potential in reactivated cells. Genetic and pharmacological perturbations show that elevated mitochondrial metabolism and ATP synthesis are critical for cell reactivation. Elevated mitochondrial metabolism increases mitochondrial ROS levels, which induces Sgk1 expression in the mitochondria. Deletion and inhibition of Sgk1 in zebrafish abolished cell reactivation. Similarly, ROS-dependent mitochondrial expression of SGK1 promotes S phase entry in human breast cancer cells. Mechanistically, Sgk1 coordinates mitochondrial activity with ATP synthesis by modulating F1Fo-ATP synthase phosphorylation. These findings suggest a conserved intramitochondrial signaling loop regulating epithelial cell renewal. One sentence highlightThis study reports a new intramitochondrial signaling loop regulating epithelial cell renewal.

cell biology↗

bioRxiv2022

Soft multimodal opto-electric biointerfaces for co-localized optical and electrical recording of cell function

Optical fluorescence and electrical monitoring of cell activity are two powerful approaches to study organ functions. Simultaneous recording of optical and electrical data types will provide complementary information from and take advantage of each approach. However, devices that can concurrently record optical signals from the same cell population underneath the microelectrodes have not been widely explored and remain a grand technical challenge. This work presents an innovative flexible opto-electric device that monolithically integrates transparent gold nanogrid microelectrodes directly above microscale light-emitting diodes, photodetectors, and optical filters to achieve co-localized crosstalk-free optical fluorescence and electrical recording. The optimized gold nanogrid microelectrodes show excellent optical transparency (>81%) and low normalized 1 kHz electrochemical impedance (6.3 {Omega} cm2). The optical recording subsystem offers high wavelength selectivity (>1,300) and linearity (R2 >0.99) for exciting and capturing green fluorescence from various fluorescent reporters in measurement ranges relevant to in vivo applications with minimal thermal effects. The opto-electric device exhibits remarkable durability under soaking for 40 days and repetitive mechanical bending for 5,000 cycles. The work may provide a versatile approach for constructing mechanically compliant biointerfaces containing crosstalk-free optical and electrical modalities with widespread application potentials in basic and clinical research.

bioengineering↗

bioRxiv2022

Metal-driven anaerobic oxidation of methane as an important methane sink in methanic cold seep sediments

Anaerobic oxidation of methane (AOM) coupled with reduction of metal oxides is supposed to be a globally important bioprocess in marine sediments. However, the responsible microorganisms and their contributions to methane budget are not clear in deep sea cold seep sediments. Here, we combined geochemistry, muti-omics and numerical modeling to study metal-dependent AOM in methanic cold seep sediments in the northern continental slope of the South China Sea. Geochemical data based on methane concentrations, carbon stable isotope, solid-phase sediment analysis and pore water measurements indicate the occurrence of anaerobic methane oxidation coupled to metal oxides reduction in the methanic zone. The 16S rRNA gene amplicons and transcripts, along with metagenomic and metatranscriptomic data suggest that diverse ANME groups actively mediated methane oxidation in the methanic zone either independently or in syntrophy with e.g. ETH-SRB1 as potential metal reducers. Modeling results suggest that the estimated rates of methane consumption via Fe-AOM and Mn-AOM were both 0.3 mol cm-2 yr-1, which account for [~]3% of total CH4 removal in sediments. Overall, our results highlight metal-driven anaerobic oxidation of methane as an important methane sink in methanic cold seep sediments.

microbiology↗

bioRxiv2022

The compact CasPi (Cas12l) bracelet "provides" a unique structural platform for DNA manipulation

CRISPR-Cas modules serve as the adaptive nucleic-acid immune systems for prokaryotes, and provide versatile tools for nucleic-acid manipulation in various organisms. Here, we discovered a new miniature type V system, CRISPR-Cas{pi} (Cas12l) ([~]860 aa), from the environmental metagenome. Complexed with a large guide-RNA ([~]170 nt) comprising the tracrRNA and crRNA, Cas{pi} (Cas12l) recognizes a unique 5 C-rich PAM for DNA cleavage under a broad range of biochemical conditions, and generates gene editing in mammalian cells. Cryo-EM study reveals a bracelet architecture of Cas{pi} effector encircling the DNA target at 3.4-[A] resolution, substantially different from the canonical two-lobe architectures of Cas12 and Cas9 nucleases. And the large guide-RNA serves as a two-arm scaffold for effector assembly. Our study expands the knowledge of DNA targeting mechanisms by CRISPR effectors, and offers an efficient but compact platform for DNA manipulations.

biophysics↗

bioRxiv2022

Fortuitous Somatic Mutations during Antibody Evolution Endow Broad Neutralization against SARS-CoV-2 Omicron Variants

Striking antibody evasion by emerging circulating SARS-CoV-2 variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identified a clonally-related antibody family from a convalescent individual. One of the members, XG005, exhibited potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members showed significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface revealed how crucial somatic mutations endowed XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality, exhibited a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provided a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.

immunology↗

bioRxiv2022

Sketch the Organoids from Birth to Death Development of an Intelligent OrgaTracker System for Multi-Dimensional Organoid Analysis and Recreation

Organoids are three-dimensional in vitro models that recreate the structure and physiology of their source organs or tissues in remarkable detail. Due to the diversity of organoids in shape and size and the three-dimensional growth environment, it is challenging to observe and analyze organoids periodically in the microscope to obtain their morphological or growth characteristics, especially in high-throughput experiments. Here, this paper first proposes OrgaTracker, a novel assembled architecture combining Yolov5 for object detection and U-net for semantic segmentation. The deep learning algorithm can track and segment organoids over time and effectively avoid the influence of bubbles and accurately capture and analyze organoid fusion. A two-stage object detection methodology was performed to achieve the crypt count of each mouse small intestinal organoid, and the skeleton of intestinal organoids was further extracted to describe the structural relationship between the absorption villi and the crypt. Next, we used the "sketch" to convey visual concepts, which led to the clear identification of organoids at different growth/treatment stages. Lastly, based on our designed GAN network, various organoid images could be generated by drawing sketches, which for the first time provided a direct and practical approach for biologists and researchers to create "artificial organoids" simulating organoid morphology and allowing the exchange of ideas on organoid development. In sum, this research reported and provided a comprehensive novel organoid analysis and generation methodology for organoid research. HighlightsOrgaTracker can track organoids and capture and analyze the integration of organoids. The system was also able to identify the number of crypts in each intestinal organoid, as well as extract the skeleton of the organoid. It also allowed, for the first time, recreating "artificial organoids" from hand-drawn sketches.

cell biology↗

bioRxiv2022

Fingerprint SRS Imaging Unveils Ergosteryl Ester as a Metabolic Signature of Azole-Resistant Candida albicans

Candida albicans (C. albicans), a major fungal pathogen, causes life-threatening infections in immunocompromised individuals. Fluconazole (FLC) is recommended as first-line therapy for treatment of invasive fungal infections. Yet, the widespread use of FLC has resulted in increased antifungal resistance among different strains of Candida, especially C. albicans, which is a leading source of hospital-acquired infections. Here, by hyperspectral stimulated Raman scattering (hSRS) imaging of single fungal cells in the fingerprint window and pixel-wise spectral unmixing, we report aberrant ergosteryl ester accumulation in azole-resistant C. albicans compared to azole-susceptible species. This accumulation was a consequence of de novo lipogenesis. Lipid profiling by mass spectroscopy identified ergosterol oleate to be the major species stored in azole-resistant C. albicans. Blocking ergosterol esterification by oleate and suppressing sterol synthesis by FLC synergistically suppressed the viability of C. albicans in vitro and limited the growth of biofilm on mouse skin in vivo. Our findings highlight a metabolic marker and a new therapeutic strategy for targeting azole-resistant C. albicans by interrupting the esterified ergosterol biosynthetic pathway. Significance StatementInvasive fungal infections and increasing antifungal resistance are emerging threats to public health with high morbidity and mortality. Despite the advances in azole resistance mechanisms, it remains unclear why some fungal species are intrinsically resistant to or easily acquire resistance to multiple antifungal drugs. Here, using fingerprint SRS microscopy, we uncovered a molecular signature, aberrant ergosteryl ester accumulation, linked to the azole resistance of Candida species. An antifungal treatment strategy combining oleate (inhibitor of ersgosteryl esterification) and azole significantly attenuates the azole resistance and the viability of C. albicans in vitro and in vivo. Our work opens a new way to detect and treat azole-resistant fungal infections by targeting ergosterol metabolism.

microbiology↗

bioRxiv2022

Boosting wheat functional genomics via indexed EMS mutant library of KN9204

A better understanding of wheat functional genomics could facilitate the targeted breeding for agronomic traits improvement and environmental adaptation. With the release of reference genomes and extensive re-sequencing data of wheat and relatives, wheat functional genomics enters a new era. However, limited transformation efficiency in wheat hampers in-depth gene functional study and genetic manipulation for breeding. Here, we generated an EMS mutagenesis library of KN9204, a widely grown elite wheat variety in northern China, with available reference genome, transcriptome, and epigenome of various tissues. The library harbors enormous developmental diversity covering important tissues and transition stages. Exome capture sequencing of 2,090 mutant lines, with probes designed by KN9204 genome, revealed that 98.79% of coding genes have mutations and 1,383 EMS-type SNPs per line averagely. Novel allelic variations for important agronomic trait-related genes, such as Rht-D1, Q, TaTB1, and WFZP, were identified. We tested 100 lines with severe mutations in 80 NAC TFs under drought and salinity stresses, and found 13 lines with altered sensitivity. Three lines were further analyzed for the regulation insight of NAC TFs in stress response by combing transcriptome and available chromatin accessibility data. Hundreds of direct targets of NAC with altered transcriptional pattern in mutant lines under salt or drought stress induction were identified, including SNAC1, DREB2B, CML16 and ZFP182, knowing factors in abiotic stresses response. Thus, we have generated and indexed KN9204 EMS mutant library which would facilitate functional genomics study and provide resources for genetic manipulation in wheat.

plant biology↗