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Zhou, L.

Publications and source records attributed to Zhou, L..

At least 163 records · Page 9Linked to original sources

Shared and distinct neural signatures of feature and spatial attention

The debate on whether feature attention (FA) and spatial attention (SA) share a common neural mechanism remains unresolved. Previous neuroimaging studies have identified fronto-parietal-temporal attention-related regions that exhibited consistent activation during various visual attention tasks. However, these studies have been limited by small sample sizes and methodological constraints inherent in univariate analysis. Here, we utilized a between-subject whole-brain machine learning approach with a large sample size (N = 235) to investigate the neural signatures of FA (FAS) and SA (SAS). Both FAS and SAS showed cross-task predictive capabilities, though inter-task prediction was weaker than intra-task prediction, suggesting both shared and distinct mechanisms. Specifically, the frontoparietal network exhibited the highest predictive performance for FA, while the visual network excelled in predicting SA, highlighting their respective prominence in the two attention processes. Moreover, both signatures demonstrated distributed representations across large-scale brain networks, as each cluster within the signatures was sufficient for predicting FA and SA, but none of them were deemed necessary for either FA or SA. Our study challenges traditional network-centric models of attention, emphasizing distributed brain functioning in attention, and provides comprehensive evidence for shared and distinct neural mechanisms underlying FA and SA.

neuroscience↗

Cooperation between bacteriocytes and endosymbionts drives function and development of symbiotic cells in mussel holobionts

Symbiosis drives the adaptation and evolution in multicellular organisms. Modeling the function and development of symbiotic cells/organs in holobionts is yet challenging. Here, we surveyed the molecular function and developmental trajectory of bacteriocyte lineage in non-model deep-sea mussels by constructing a high-resolution single-cell expression atlas of gill tissue. We show that mussel bacteriocytes optimized immune processes to facilitate recognition, engulfment, and elimination of endosymbionts, and interacted with them intimately in sterol, carbohydrate, and ammonia metabolism. Additionally, the bacteriocytes could arise from three different stem cells as well as bacteriocytes themselves. In particular, we showed that the molecular functions and developmental process of bacteriocytes were guided by the same set of regulatory networks and dynamically altered regarding to symbiont abundance via sterol-related signaling. The coordination in the functions and development of bacteriocytes and between the host and symbionts underlies the interdependency of symbiosis, and drives the deep-sea adaptation of mussels.

ecology↗

YiNet: An Integrated Traditional Chinese and Western Medicine Platform for Viral Infectious Diseases

Viral infectious diseases (VIDs) impose a heavy burden on global public health. Traditional Chinese medicine (TCM) has previously and is currently contributing to the prevention and treatment of infectious diseases. Omics and information technology enable the precise identification of virus characteristics, virus-host interactions and TCM mechanisms. In this study, we constructed the YiNet platform to better integrate the novel techniques and historical experience of TCM in infectious diseases. YiNet comprises three modules: knowledge base, database and toolkit. The YiNet knowledge base involves 43 VIDs, thereby systematically integrating the knowledge regarding viruses, host symptoms and TCM and Western medicine (commonly used chemical drugs, 6,899 herbs and 2,481 formulas). The YiNet database module includes multiple databases, comprising 57,340 genome sequences of 45,791 viral strains and 5,726 multi-omics datasets such as RNA-seq, ChIP-seq and ATAC-seq from different tissues and cell models. It also integrates 1,105 real-world TCM clinical cases. We adopted visual analysis tool to investigate pathogen-host-herb relationships. To explore pharmacological mechanisms for the core herbs, we added formula data mining and network pharmacology analysis pipelines and visualisation tools. YiNet can facilitate the mechanistic study of TCM and drug development for VIDs. The YiNet platform is publicly available at http://yinet.gene.ac/.

bioinformatics↗

The circadian clock is a pacemaker of the axonal regenerative ability

Peripheral nervous system injuries lead to long-term neurological disability due to limited axonal regenerative ability. Injury-dependent and -independent physiological mechanisms have provided important molecular insight into neuronal regeneration. However, whether common molecular denominators underpin both injury-dependent and independent biological processes remain unclear. Here, we performed a comparative analysis of recently generated transcriptomic datasets associated with the regenerative ability of sciatic dorsal root ganglia (DRG). Surprisingly, circadian rhythms were identified as a the most significantly enriched biological process associated with regenerative capability. We demonstrate that DRG neurons possess an endogenous circadian clock with a 24h oscillations of circadian genes and that their regenerative ability displays a diurnal oscillation in a mouse model of sciatic nerve injury. Consistently, transcriptomic analysis of DRG neurons showed a significant time-of-day dependent enrichment for processes associated with axonal regeneration, development and growth, as well as circadian associated genes, including the core clock genes Bmal1 and Clock. Indeed, DRG-specific ablation of the non-redundant clock gene Bmal1 showed that it is required for regenerative gene expression, neuronal intrinsic circadian regeneration and target reinnervation. Lastly, lithium, a chrono-active compound, enhanced nerve regeneration, in wildtype but not in Bmal1 and Cry1/2-deficient mice. Together, these data demonstrate that daily rhythms and the molecular clock fine-tune the regenerative response of DRG neurons, and that chrono-active drugs, such as lithium, are a novel potential approach to nerve repair.

neuroscience↗

A 3D microtumour system that faithfully represents ovarian cancer minimal residual disease

BackgroundBulk cancer and minimal residual disease (MRD) are characterised by different molecular drivers and therefore necessitate different therapeutic strategies. However, there are currently no 3D models that can faithfully recapitulate MRD ex vivo for therapy development. MethodsA microfluidic technique was implemented to construct 3D microtumours, in which tumour cells, either by themselves or with fibroblasts, were encapsulated in viscous hydrogels. The 3D microtumours were analysed for their response to first-line chemotherapeutics and characterised through RNA-Seq, by comparing them to both 2D cultures and clinical samples. ResultsOur microfluidic platform guarantees the fabrication of 3D microtumours of tailorable size and cell content, which recreate key features of tumours such as hypoxia, characteristic organization of the cytoskeleton and a dose-response to chemotherapeutics close to the physiological range. The 3D microtumours were also used to examine non-genetic heterogeneity in ovarian cancer and could fully reflect the recently described "Oxford Classic" five molecular signatures. The gene expression profile of 3D microtumours following chemotherapy treatment closely resembled that of MRD in ovarian cancer patients, showing the upregulation of genes involved in fatty acid metabolism. We demonstrate that these 3D microtumours are ideal for drug development by showing how they support the identification of a promising inhibitor of fatty acid oxidation, perhexiline, which specifically targets chemotherapy-resistant MRD ovarian cancer cells and not bulk cancer cells. ConclusionWe have obtained the first 3D model of ovarian cancer MRD by using microtumours generated through microfluidics. This system is ideal for high-throughput drug screening and, given its versatility, it can be readily extended to additional types of cancer, as well as accommodate multiple cell types to generate complex tumour microenvironments.

cancer biology↗

Electrically Conductive DNA-Inspired Coating for Intracortical Neural Microelectrodes

Different from conventional electrodes, intracortical neural microelectrodes are the size of one or several neural cells. Due to the limited space for cell-electrode connections, the bio-integration between each neural cell and the electrode surface is critical. To improve bio-integration and electrode functions, various coating materials (such as conductive polymers (CPs), carbon nanotubes (CNTs), and natural hydrogels) have been developed aiming to provide an enhanced interface for neuron recruitment, bio-anchorage, and electrical function. However, synthetic materials usually have limited biocompatibility and/or relatively high cytotoxicity, while biological materials present poor electrical functions. Therefore, current coatings possess biological, functional or electrochemical limitations that are not optimal for intracortical neural microelectrodes. To overcome this obstacle, we developed an electrically conductive coating based on biological molecules, named Janus base nano-coating (JBNc). JBNc is formed by Janus base nanotubes (JBNts) which are a family of nanotubes assembled from engineered DNA base pair units. Based on the long-distance translocation ability of the {pi} electrons of JBNts, we developed them into an electrically conductive coating on the electrode surface. For the first time, we reported the DNA-inspired JBNc had an electrochemical performance that met and exceeded standard metal electrode surface in cyclic voltammetry, impedance spectroscopy, charge injection capacity tests, and neural recording. Moreover, we demonstrated enhanced bio-anchorage and microelectrode interface integration using SEM and AFM. Importantly, we demonstrated enhanced functional response to JBNc microelectrodes with immunohistochemical staining and RNA sequencing (RNAseq) analysis. Using cell viability assays, we also showed the benefits of DNA-mimicking chemistry of Janus base nanomaterials compared to conventional microelectrode coatings. We anticipate that these results will serve as a foundation for the continued development and study of JBNc to enhance interface dynamics and ultimately the performance and reliability of brain microelectrodes.

bioengineering↗

TRAIL agonists rescue mice from radiation-induced lung injury

Cancer therapy is often limited by toxicity from pneumonitis. This often-lethal side effect is known to be impacted by innate immunity, and in particular the pathways regulated by the TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from the lethal effects of radiation. We found that two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound #10 (TIC10/ONC201), could achieve this goal. Both compounds could completely protect mice from lethality by reducing pneumonitis, alveolar-wall thickness, and oxygen desaturation. At the molecular level, this protection appeared to be due to the inhibition of CCl22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from high doses of radiation exposure has important translational implications. One Sentence SummaryPrevention of lethality, pneumonitis, lung fibrosis and skin dermatitis post-{psi}-irradiation by short- term treatment with innate immune TRAIL pathway agonists

pathology↗

Deciphering deep-sea chemosynthetic symbiosis by single-nucleus RNA-sequencing

Bathymodioline mussels dominate deep-sea methane seep and hydrothermal vent habitats and obtain nutrients and energy primarily through chemosynthetic endosymbiotic bacteria in the bacteriocytes of their gill. However, the molecular mechanisms that orchestrate mussel host-symbiont interactions remain unclear. Here, we constructed a comprehensive cell atlas of the gill in the mussel Gigantidas platifrons from the South China Sea methane seeps (1100m depth) using single-nucleus RNA sequencing (snRNA-seq) and whole-mount in situ hybridisation. We identified 13 types of cells, including three previously unknown ones, and uncovered unknown tissue heterogeneity. Every cell type has a designated function in supporting the gills structure and function, creating an optimal environment for chemosynthesis, and effectively acquiring nutrients from the endosymbiotic bacteria. Analysis of snRNA-seq of in situ transplanted mussels clearly showed the shifts in cell state in response to environmental oscillations. Our findings provide insight into principles of host-symbiont interaction and the bivalves environmental adaption mechanisms.

ecology↗

Single-cell analysis of innate spinal cord regeneration identifies intersecting modes of neuronal repair.

Adult zebrafish have an innate ability to recover from severe spinal cord injury. Here, we report a comprehensive single nuclear RNA sequencing atlas that spans 6 weeks of regeneration. We identify cooperative roles for adult neurogenesis and neuronal plasticity during spinal cord repair. Neurogenesis of glutamatergic and GABAergic neurons restores the excitatory/inhibitory balance after injury. In addition, a transient population of injury-responsive neurons (iNeurons) show elevated plasticity between 1 and 3 weeks post-injury. We found iNeurons are injury-surviving neurons that acquire a neuroblast-like gene expression signature after injury. CRISPR/Cas9 mutagenesis showed iNeurons are required for functional recovery and employ vesicular trafficking as an essential mechanism that underlies neuronal plasticity. This study provides a comprehensive resource of the cells and mechanisms that direct spinal cord regeneration and establishes zebrafish as a model of plasticity-driven neural repair.

neuroscience↗

HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers

Incorporation of histone variant H3.3 comprises active territories of chromatin. Exploring the function of H3.3 in prostate cancer (PC), we found that knockout (KO) of H3.3 chaperone HIRA suppresses PC growth in vitro and in xenograft settings, deregulates androgen-induced gene expression and alters androgen receptor (AR) binding within enhancers of target genes. H3.3 affects transcription in multiple ways, including activation of p300 by phosphorylated H3.3 at Ser-31 (H3.3S31Ph), which results in H3K27 acetylation (H3K27Ac) at enhancers. In turn, H3K27Ac recruits bromodomain protein BRD4 for enhancer-promoter interaction and transcription activation. We observed that HIRA KO reduces H3.3 incorporation, diminishes H3.3S31Ph and H3K27Ac, modifies recruitment of BRD4. These results suggest that H3.3-enriched enhancer chromatin serves as a platform for H3K27Ac-mediated BRD4 recruitment, which interacts with and retains AR at enhancers, resulting in transcription reprogramming. AR KO reduced levels of H3.3 at enhancers, indicating feedback mechanism. In addition, HIRA KO deregulates glucocorticoid-driven transcription, suggesting a common H3.3/HIRA-dependent mechanism of nuclear receptors function. Expression of HIRA complex proteins is increased in PC compared with normal prostate tissue, especially in high-risk PC groups, and is associated with a negative prognosis. Collectively, our results demonstrate function of HIRA-dependent H3.3 pathway in regulation of nuclear receptors activity. Key points*H3.3 at enhancers promotes acetylation of H3K27Ac and retention of AR/BRD4 complex for transcription regulation *Knockout of H3.3 chaperone HIRA suppresses PC cells growth and deregulates androgen-induced transcription *H3.3/HIRA pathway regulates both AR and GR, suggesting a common HIRA/H3.3 mechanism of nuclear receptors function

molecular biology↗

Gene Expression and Splicing QTL Analysis of Blood Cells in African American Participants from the Jackson Heart Study

Most gene expression and alternative splicing quantitative trait loci (eQTL/sQTL) studies have been biased toward European ancestry individuals. Here, we performed eQTL and sQTL analysis using TOPMed whole genome sequencing-derived genotype data and RNA sequencing data from stored peripheral blood mononuclear cells in 1,012 African American participants from the Jackson Heart Study (JHS). At a false discovery rate (FDR) of 5%, we identified 4,798,604 significant eQTL-gene pairs, covering 16,538 unique genes; and 5,921,368 sQTL-gene-cluster pairs, covering 9,605 unique genes. About 31% of detected eQTL and sQTL variants with a minor allele frequency (MAF) > 1% in JHS were rare (MAF < 0.1%), and therefore unlikely to be detected, in European ancestry individuals. We also generated 17,630 eQTL credible sets and 24,525 sQTL credible sets for genes (gene-clusters) with lead QTL p < 5e-8. Finally, we created an open database, which is freely available online, allowing fast query and bulk download of our QTL results.

genetics↗

Designer DNA NanoGripper

DNA has shown great biocompatibility, programmable mechanical properties, and structural addressability at the nanometer scale, making it a versatile material for building high precision nanorobotics for biomedical applications. Herein, we present design principle, synthesis, and characterization of a DNA nanorobotic hand, called the "NanoGripper", that contains a palm and four bendable fingers as inspired by human hands, bird claws, and bacteriophages evolved in nature. Each NanoGripper finger has three phalanges connected by two flexible and rotatable joints that are bendable in response to binding to other entities. Functions of the NanoGripper have been enabled and driven by the interactions between moieties attached to the fingers and their binding partners. We showcase that the NanoGripper can be engineered to interact with and capture various objects with different dimensions, including gold nanoparticles, gold NanoUrchins, and SARS-CoV-2 virions. When carrying multiple DNA aptamer nanoswitches programmed to generate fluorescent signal enhanced on a photonic crystal platform, the NanoGripper functions as a sensitive viral biosensor that detects intact SARS-CoV-2 virions in human saliva with a limit of detection of [~] 100 copies/mL, providing RT-PCR equivalent sensitivity. Additionally, we use confocal microscopy to visualize how the NanoGripper-aptamer complex can effectively block viral entry into the host cells, indicating the viral inhibition. In summary, we report the design, synthesis, and characterization of a complex nanomachine that can be readily tailored for specific applications. The study highlights a path toward novel, feasible, and efficient solutions for the diagnosis and therapy of other diseases such as HIV and influenza. One-sentence summaryDesign, synthesis, characterization, and functional showcase of a human-hand like designer DNA nanobot

bioengineering↗

Functional divergences of natural variations of TaNAM-A1 controlling leaf senescence initiation during wheat grain filling

Leaf senescence is an essential physiological process related to grain yield potential and nutritional quality. Green leaf duration (GLD) after anthesis directly reflects the leaf senescence process and exhibits large genotypic differences in common wheat; however, the underlying gene regulatory mechanism is still lacking up to now. Here, we report TaNAM-A1 as the causal gene of major loci qGLD-6A for GLD during grain filling by map-based cloning. The role of TaNAM-A1 in regulating leaf senescence, spike length, and grain size was proved by transgenic assay and TILLING mutants analyses. Furthermore, the functional divergences among TaNAM-A1 three haplotypes were systematically evaluated. Wheat varieties with TaNAM-A1d (containing two mutations in CDS of TaNAM-A1) had longer GLD and advantages in yield-related traits than those with the wild type TaNAM-A1a. All three haplotypes were functional in transactivating the expression of genes involved in macromolecular degradation and mineral nutrient remobilization, with TaNAM-A1a the strongest activity and TaNAM-A1d the weakest. TaNAM-A1 modulates the expression of TaNAC016-3A and TaNAC-S-7A to trigger senescence initiation. TaNAC016-3A enhances TaNAM-A1 transcriptional activation ability by protein-protein interaction. Our study provides new insights into fine-tuning the leaf functional period and grain yield formation for wheat breeding under different geographical climatic conditions.

plant biology↗

Progesterone is an Inducement of Heritable Pulmonary Arterial Hypertension with BMPR2 Mutation

BackgroundBone morphogenetic protein type II receptor (BMPR2) gene mutation accounts for 80% of patients with heritable pulmonary artery hypertension (HPAH), and female mutation carriers have significantly higher penetrance rate than males. The inducement of HPAH penetrance and the mechanism of sex differential penetrance are still elusive. MethodsWe infected or transfected pulmonary artery smooth muscle cells (PASMCs) with shBMPR2 lentivirus or siBMPR2 to simulate the pathologic condition of BMPR2 heterozygous mutation and treated them with progesterone. The HPAH patient-derived induced pluripotent stem cells (iPSCs) were induced into vascular smooth muscle cells (VSMCs) to further verify the cellular phenotype. Wild-type flox+/- female mice and SM22-cre BMPR2 flox+/- female mice (CKO mice) were administered with 1-month progesterone, and their phenotype of PAH was evaluated by right heart catheterization and histopathological examination. ResultsProgesterone promoted the proliferation of PASMCs with BMPR2-knockdownby activating ERK pathway via progesterone receptor (PGR). Activated ERK not only upregulated the phosphorylation and elevation of cMYC, but also induced the transcription of endothelin (EDN1) by promoting the nuclear entry of c-JUN and combination on the its promoter region. Similar results were confirmed by iPSCs-VSMCs experiment. CKO mice developed PAH spontaneously and had increased expression of EDN1, which was further aggravated by exogenous progesterone. ConclusionsProgesterone might be an inducement of HPAH penetrance caused by BMPR2 mutation, accounting for sex differential penetrance.

molecular biology↗

BATF relieves hepatic steatosis by inhibiting PD1 and promoting energy metabolism

The rising prevalence of nonalcoholic fatty liver disease (NAFLD) has become a global health threat that needs to be addressed urgently. Basic leucine zipper ATF-like transcription factor (BATF) is commonly thought to be involved in immunity, but its effect on lipid metabolism is not clear. Here, we investigated the function of BATF in hepatic lipid metabolism. BATF alleviated high-fat diet (HFD)-induced hepatic steatosis and inhibited elevated programmed cell death protein (PD)1 expression induced by HFD. A mechanistic study confirmed that BATF regulated fat accumulation by inhibiting PD1 expression and promoting energy metabolism. PD1 antibodies alleviated hepatic lipid deposition. In conclusion, we identified the regulatory role of BATF in hepatic lipid metabolism and that PD1 is a target for alleviation of NAFLD. This study provides new insights into the relationship between BATF, PD1 and NAFLD.

molecular biology↗

An allocentric human odometer for perceiving distances on the ground plane

We reliably judge locations of static objects when we walk despite the retinal images of these objects moving with every step we take. Here, we showed our brains solve this optical illusion by adopting an allocentric spatial reference frame. We measured perceived target location after the observer walked a short distance from the home base. Supporting the allocentric coding scheme, we found the intrinsic bias1, 2, which acts as a spatial reference frame for perceiving location of a dimly lit target in the dark, remained grounded at the home base rather than traveled along with the observer. The path-integration mechanism responsible for this can utilize both active and passive (vestibular) translational motion signals, but only along the horizontal direction. This anisotropic path-integration finding in human visual space perception is reminiscent of the anisotropic spatial memory finding in desert ants3, pointing to natures wondrous and logically simple design for terrestrial creatures.

neuroscience↗

6mA-Sniper: Quantifying 6mA Sites in Eukaryotes at Single-Nucleotide Resolution

While N6-methyldeoxyadenine (6mA) modification has been linked to fundamental regulatory processes in prokaryotes, its prevalence and functional implications in eukaryotes are controversial. Here, we report 6mA-Sniper to quantify 6mA sites in eukaryotes at single-nucleotide resolution. With 6mA-Sniper, we delineated an accurate 6mA profile in C. elegans with 2,034 sites, significantly enriched on sequences of [GC]GAG motif. Twenty-six of 39 6mA events with MnlI restriction endonuclease sites were experimentally verified, demonstrating the feasibility of this method. Notably, the enrichment of these 6mA sites on a specific sequence motif, their within-population conservation and the combinatorial patterns, and the selective constrains on them jointly support an active model for the shaping of the profile by some undiscovered methyltransferases. In a joint study (Cell Research, in revision), Ma et al. reported METL-9 as a new methyltransferase in shaping the basal and stress-dependent 6mA profile in C. elegans. Notably, with the 6mA profile identified by 6mA-Sniper at single-nucleotide resolution, we found that the levels of 6mAs are significantly decreased in strains with the removal of METL-9 (METL-9 KO-OP50), while generally increased after P. aeruginosa infection, further verified the efficiency of 6mA-Sniper in accurately pinpointing 6mA sites. Moreover, for the regions marked by 998 6mA sites emerged specifically after the infection, we identified an enrichment of the upregulated genes after the infection. The gene upregulations are likely mediated through a mutual exclusive crosstalk between 6mA and H3K27me3 modification, as supported by their co-occurrence, and the signal of increased H3K27me3 at regions marked by 6mAs depleted in METL-9 KO-OP50 strains. Notably, in different C. elegans strains, the cross-strain genetic variants removing 6mA sites are associated with the decreased expression of their host genes, and the removal of two randomly-selected 6mA events with genome editing directly decreased the expression of their host genes. We thus highlight 6mA regulation as a previously-neglected regulator of transcriptome in eukaryotes.

genomics↗

Audit to Forget: A Unified Method to Revoke Patients' Private Data in Intelligent Healthcare

Revoking personal private data is one of the basic human rights, which has already been sheltered by several privacy-preserving laws in many countries. However, with the development of data science, machine learning and deep learning techniques, this right is usually neglected or violated as more and more patients data are being collected and used for model training, especially in intelligent healthcare, thus making intelligent healthcare a sector where technology must meet the law, regulations, and privacy principles to ensure that the innovation is for the common good. In order to secure patients right to be forgotten, we proposed a novel solution by using auditing to guide the forgetting process, where auditing means determining whether a dataset has been used to train the model and forgetting requires the information of a query dataset to be forgotten from the target model. We unified these two tasks by introducing a new approach called knowledge purification. To implement our solution, we developed AFS, a unified open-source software, which is able to evaluate and revoke patients private data from pre-trained deep learning models. We demonstrated the generality of AFS by applying it to four tasks on different datasets with various data sizes and architectures of deep learning networks. The software is publicly available at https://github.com/JoshuaChou2018/AFS.

bioinformatics↗