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Zhao, J.

Publications and source records attributed to Zhao, J..

At least 289 records · Page 16Linked to original sources

Structural and sequential regularities modulate phrase-rate neural tracking

Electrophysiological brain activity has been shown to synchronize with the quasi-regular repetition of grammatical phrases in connected speech - so-called phrase-rate neural tracking. Current debate centers around whether this phenomenon is best explained in terms of the syntactic properties of phrases or in terms of syntax-external information, such as the sequential repetition of parts of speech. As these two factors were confounded in previous studies, much of the literature is compatible with both accounts. Here, we used electroencephalography (EEG) to determine if and when the brain is sensitive to both types of information. Twenty native speakers of Mandarin Chinese listened to isochronously presented streams of monosyllabic words, which contained either grammatical two-word phrases (e.g., catch fish, sell house) or non-grammatical word combinations (e.g., full lend, bread far). Within the grammatical conditions, we varied two structural factors: the position of the head of each phrase and the type of attachment. Within the non-grammatical conditions, we varied the consistency with which parts of speech were repeated. Tracking was quantified through evoked power and inter-trial phase coherence, both derived from the frequency-domain representation of EEG responses. As expected, neural tracking at the phrase rate was stronger in grammatical sequences than in non-grammatical sequences without syntactic structure. Moreover, it was modulated by both attachment type and head position, revealing the structure-sensitivity of phrase-rate tracking. We additionally found that the brain tracks the repetition of parts of speech in non-grammatical sequences. These data provide an integrative perspective on the current debate about neural tracking effects, revealing that the brain utilizes regularities computed over multiple levels of linguistic representation in guiding rhythmic computation.

neuroscience↗

Analgesic targets identified in mouse sensory neuron somata and terminal pain translatomes

The relationship between transcription and protein expression is complex. We identified polysome-associated RNA transcripts in the somata and central terminals of mouse sensory neurons in control, painful (+ Nerve Growth Factor (NGF)) and pain-free conditions (Nav1.7 null mice). The majority (98%) of translated transcripts are shared between male and female mice in both the somata and terminals. Some transcripts are highly enriched in the somata or terminals. Changes in the translatome in painful and pain-free conditions include novel and known regulators of pain pathways. Antisense knockdown of selected somatic and terminal polysome-associated transcripts that correlate with pain states diminished pain behaviour. Terminal-enriched transcripts encoding synaptic proteins (e.g. Synaptotagmin), non-coding RNAs, transcription factors (e.g. Znf431), proteins associated with trans-synaptic trafficking (HoxC9), GABA generating enzymes (Gad1 and Gad2) and neuropeptides (Penk). Thus, central terminal translation may well be a significant regulatory locus for peripheral input from sensory neurons.

neuroscience↗

Annotations of four high-quality indigenous chicken genomes identify more than one thousand missing genes in sub-telomeric regions with high G/C contents

BackgroundAlthough multiple chicken genomes have been assembled and annotated, the number of protein-coding genes in chicken genomes is still uncertain due to the low quality of these genome assemblies and limited resources used in gene annotations. ResultsTo fill the gap, we annotated our four recently assembled high-quality genomes of four indigenous chickens with distinct traits using a combination of RNA-seq- and homology-based approach. Our annotated genes in the four chickens recovered 51 of the 274 "missing" genes in birds in general and 36 of the 174 "missing" genes in chickens in particular. Intriguingly, based on deeply sequenced RNA-seq data collected in multiple tissues in each chicken breed, we found a total of 1,420 new protein-coding genes in the four chicken genomes, which were missed in the reference chicken genome annotations. These newly annotated genes (NAGs) tend to have high G/C contents and be located in sub-telomeric regions of almost all assembled chromosomes and some unplaced contigs. The NAGs showed tissue-specific expression and we were able to verify 39 (92.9%) of 42 randomly selected ones in various tissues of the four chicken breeds using RT-qPCR experiments. We found that most of the NAGs also are encoded in previously assembled chicken genomes. The NAGs form functional modules with homology-supported genes that are involved in many important biological pathways. We also identified numerous unique genes in each indigenous chicken genome that might be related to the unique traits of each breed. ConclusionThe ubiquitous presence of the NAGs in various chicken genomes indicate that they might play critical roles in chicken physiology. Counting these new genes, chicken genomes harbor more genes than originally thought.

bioinformatics↗

RBM7 deficiency promotes breast cancer metastasis by coordinating MFGE8 splicing switch and NF-kB pathway

Aberrant alternative splicing is well-known to be closely associated with tumorigenesis of various cancers. However, the intricate mechanisms underlying breast cancer metastasis driven by deregulated splicing events remain largely unexplored. Here, we unveiled that RBM7 is decreased in lymph node and distant organ metastases of breast cancer as compared to primary lesions and low expression of RBM7 is correlated with the reduced disease-free survival of breast cancer patients. Breast cancer cells with RBM7 depletion exhibited an increased potential for lung metastasis compared to scramble control cells. The absence of RBM7 stimulated breast cancer cell migration, invasion, and angiogenesis. Mechanistically, RBM7 controlled the splicing switch of MFGE8, favoring the production of the predominant isoform of MFGE8, MFGE8-L. This resulted in the attenuation of STAT1 phosphorylation and alterations in cell adhesion molecules. MFGE8-L exerted an inhibitory effect on the migratory and invasive capability of breast cancer cells, while the truncated isoform MFGE8-S, which lack the second F5/8 type C domain had the opposite effect. In addition, RBM7 negatively regulates the NF-{kappa}B cascade and an NF-{kappa}B inhibitor could obstruct the increase in HUVEC tube formation caused by RBM7 silencing. Clinically, we noticed a positive correlation between RBM7 expression and MFGE8 exon7 inclusion in breast cancer tissues, providing new mechanistic insights for molecular-targeted therapy in combating breast cancer.

cancer biology↗

Direct interrogation of context-dependent GPCR activity with a universal biosensor platform

G protein-coupled receptors (GPCRs) are the largest family of druggable proteins in the human genome, but progress in understanding and targeting them is hindered by the lack of tools to reliably measure their nuanced behavior in physiologically-relevant contexts. Here, we developed a collection of compact ONE vector G-protein Optical (ONE-GO) biosensor constructs as a scalable platform that can be conveniently deployed to measure G-protein activation by virtually any GPCR with high fidelity even when expressed endogenously in primary cells. By characterizing dozens of GPCRs across many cell types like primary cardiovascular cells or neurons, we revealed new insights into the molecular basis for G-protein coupling selectivity of GPCRs, pharmacogenomic profiles of anti-psychotics on naturally-occurring GPCR variants, and G-protein subtype signaling bias by endogenous GPCRs depending on cell type or upon inducing disease-like states. In summary, this open-source platform makes the direct interrogation of context-dependent GPCR activity broadly accessible.

biochemistry↗

Structure of the minor spliceosomal U11 snRNP

The minor spliceosome catalyses the excision of U12-dependent introns from pre-mRNAs. These introns are rare, but their removal is critical for cell viability. We obtained a cryo-EM reconstruction of the 13-subunit U11 snRNP complex, revealing structures of U11 snRNA and five minor spliceosome-specific factors. U11 snRNP appears strikingly different from the equivalent major spliceosome U1 snRNP. SNRNP25 and SNRNP35 form a dimer, which specifically recognises U11 snRNA. PDCD7 forms extended helices, which bridge SNRNP25 and SNRNP48, located at the distal ends of the particle. SNRNP48 forms multiple interfaces with U11 snRNP and, together with ZMAT5, are positioned near the 5-end of the U11 snRNA and likely stabilise the binding of the incoming 5SS. Our structure provides mechanistic insights into U12-dependent intron recognition and the evolution of the splicing machinery.

biochemistry↗

Differential developmental blueprints of organ-intrinsic nervous systems

The organ-intrinsic nervous system is a major interface between visceral organs and the brain, mediating important sensory and regulatory functions in the body-brain axis and serving as critical local processors for organ homeostasis. Molecularly, anatomically, and functionally, organ-intrinsic neurons are highly specialized for their host organs. However, the underlying mechanism that drives this specialization is largely unknown. Here, we describe the differential strategies utilized to achieve organ-specific organization between the enteric nervous system (ENS)1 and the intrinsic cardiac nervous system (ICNS)2, a neuronal network essential for heart performance but poorly characterized. Integrating high-resolution whole-embryo imaging, single-cell genomics, spatial transcriptomics, proteomics, and bioinformatics, we uncover that unlike the ENS which is highly mobile and colonizes the entire gastrointestinal (GI) tract, the ICNS uses a rich set of extracellular matrix (ECM) genes that match with surrounding heart cells and an intermediate dedicated neuronal progenitor state to stabilize itself for a beads-on-the-necklace organization on heart atria. While ICNS- and ENS-precursors are genetically similar, their differentiation paths are influenced by their host-organs, leading to distinct mature neuron types. Co-culturing ENS-precursors with heart cells shifts their identity towards the ICNS and induces the expression of heart-matching ECM genes. Our cross-organ study thus reveals fundamental principles for the maturation and specialization of organ-intrinsic neurons.

neuroscience↗

Breakage fusion bridge cycles drive high oncogene copy number, but not intratumoral genetic heterogeneity or rapid cancer genome change

Oncogene amplification is a major driver of cancer pathogenesis. Breakage fusion bridge (BFB) cycles, like extrachromosomal DNA (ecDNA), can lead to high copy numbers of oncogenes, but their impact on intratumoral heterogeneity, treatment response, and patient survival are not well understood due to difficulty in detecting them by DNA sequencing. We describe a novel algorithm that detects and reconstructs BFB amplifications using optical genome maps (OGMs), called OM2BFB. OM2BFB showed high precision (>93%) and recall (92%) in detecting BFB amplifications in cancer cell lines, PDX models and primary tumors. OM-based comparisons demonstrated that short-read BFB detection using our AmpliconSuite (AS) toolkit also achieved high precision, albeit with reduced sensitivity. We detected 371 BFB events using whole genome sequences from 2,557 primary tumors and cancer lines. BFB amplifications were preferentially found in cervical, head and neck, lung, and esophageal cancers, but rarely in brain cancers. BFB amplified genes show lower variance of gene expression, with fewer options for regulatory rewiring relative to ecDNA amplified genes. BFB positive (BFB (+)) tumors showed reduced heterogeneity of amplicon structures, and delayed onset of resistance, relative to ecDNA(+) tumors. EcDNA and BFB amplifications represent contrasting mechanisms to increase the copy numbers of oncogene with markedly different characteristics that suggest different routes for intervention.

cancer biology↗

Extracellular Matrix Protein 1 Attenuates Hepatic Fibrosis by Inhibiting TSP-, ADAMTS-, and MMP-Mediated Latent TGF-β1 Activation

ObjectiveExtracellular Matrix Protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-{beta}1 (TGF-{beta}1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-{beta}1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-{beta}1 bioavailability and its impact on CLD progression. DesignRNAseq was performed to analyze hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1-KO and Fxr-KO mice, patient liver tissue, and computer simulations. ResultsExpression of LTGF-{beta}1 activators, including thrombospondins (TSPs), ADAMTS proteases, and matrix metalloproteinases (MMPs) increased along with pro-fibrotic gene expression in liver tissue of Ecm1-KO mice. In HSCs, overexpression of ECM1 prevented TSP-1-, ADAMTS1-, and MMP-2/9-mediated LTGF-{beta}1 activation. In vitro interaction assays demonstrated that ECM1 inhibited LTGF-{beta}1 activation by interacting with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid sequences, and by suppressing MMP-2/9 proteolytic activity. In mice, ECM1 overexpression attenuated KRFK-induced LTGF-{beta}1 activation, while KTFR treatment reversed Ecm1-KO- and Fxr-KO-mediated liver injury. In patients with CLD, ECM1 expression was inversely correlated with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-{beta}1 activation. And these results were complemented by a computational compartment model representing the key network of cellular phenotypes and predicted interactions in liver fibrogenesis. ConclusionOur findings underscore the hepatoprotective effect of ECM1, which interferes with mediators of LTGF-{beta}1 activation, suggesting ECM1 or its representative peptide as potential anti-fibrotic therapies in CLD. What is already known on this topic?[tpltrtarr] ECM1 expression is negatively correlated with CLD progression. [tpltrtarr]ECM1 maintains liver homeostasis by keeping TGF-{beta}1 latency. What this study adds?[tpltrtarr] ECM1 inhibits LTGF-{beta}1 activation through interfering with key activators, including TSP-1, ADAMTS1, MMP-2, and MMP-9. [tpltrtarr]ECM1 interacts with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid motifs, and suppresses MMP-2/9 proteolytic activity. [tpltrtarr]In vivo, ECM1 overexpression mitigates KRFK peptide-induced LTGF-{beta}1 activation, while KTFR peptide rescues Ecm1-KO- and Fxr-KO-induced liver injury. [tpltrtarr]ECM1 expression inversely correlates with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-{beta}1 activation in CLD patients. How might this study affect research, practice or policy?[tpltrtarr] Considering severe adverse effects associated with anti-fibrotic treatments utilizing TGF-{beta}1 receptor inhibitors, our findings indicate that restoration of ECM1 expression or phenocopying peptides might represent a novel and safe route to urgently needed anti-fibrotic therapies in CLD.

cell biology↗

Toward Best Practice in Identifying Subtle Differential Expression with RNA-seq: A Real-World Multi-Center Benchmarking Study Using Quartet and MAQC Reference Materials

Translating RNA-seq into clinical diagnostics requires ensuring the reliability of detecting clinically relevant subtle differential expressions, such as those between different disease subtypes or stages. Moreover, cross-laboratory reproducibility and consistency under diverse experimental and bioinformatics workflows urgently need to be addressed. As part of the Quartet project, we presented a comprehensive RNA-seq benchmarking study utilizing Quartet and MAQC RNA reference samples spiked with ERCC controls in 45 independent laboratories, each employing their in-house RNA-seq workflows. We assessed the data quality, accuracy and reproducibility of gene expression and differential gene expression and compared over 40 experimental processes and 140 combined differential analysis pipelines based on multiple ground truths. Here we show that real-world RNA-seq exhibited greater inter-laboratory variations when detecting subtle differential expressions between Quartet samples. Experimental factors including mRNA enrichment methods and strandedness, and each bioinformatics step, particularly normalization, emerged as primary sources of variations in gene expression and have a more pronounced impact on the subtle differential expression measurement. We underscored the pivotal role of experimental execution over the choice of experimental protocols, the importance of strategies for filtering low-expression genes, and optimal gene annotation and analysis tools. In summary, this study provided best practice recommendations for the development, optimization, and quality control of RNA-seq for clinical diagnostic purposes.

genomics↗

MPRAbase: A Massively Parallel Reporter Assay Database

Massively parallel reporter assays (MPRAs) represent a set of high-throughput technologies that measure the functional effects of thousands of sequences/variants on gene regulatory activity. There are several different variations of MPRA technology and they are used for numerous applications, including regulatory element discovery, variant effect measurement, saturation mutagenesis, synthetic regulatory element generation or characterization of evolutionary gene regulatory differences. Despite their many designs and uses, there is no comprehensive database that incorporates the results of these experiments. To address this, we developed MPRAbase, a manually curated database that currently harbors 129 experiments, encompassing 17,718,677 elements tested across 35 cell types and 4 organisms. The MPRAbase web interface (http://www.mprabase.com) serves as a centralized user-friendly repository to download existing MPRA data for independent analysis and is designed with the ability to allow researchers to share their published data for rapid dissemination to the community.

genomics↗

NLRP3 Cys126 palmitoylation by ZDHHC7 Promotes Inflammasome Activation

NACHT-, leucine-rich-repeat- (LRR), and pyrin domain-containing protein 3 (NLRP3) mediates inflammasome activation in response to multiple pathogen and damage-associated molecular patterns in macrophages. Hyperactivation of NLRP3 inflammasome contributes to many human chronic inflammatory diseases. Understanding how NLRP3 inflammasome is regulated can potentially provide new strategies to treat inflammatory diseases. Here, we demonstrated that NLRP3 is palmitoylated on Cys126 by palmitoyl-acyltransferase ZDHHC7 in macrophages, which is critical for NLRP3-mediated inflammasome activation. Perturbating NLRP3 Cys126 palmitoylation by ZDHHC7 knockout, pharmacological inhibition, or modification site mutation, diminishes NLRP3 activation and the consequential Caspase-1 and Gasdermin D (GSDMD) cleavage, and IL-1{beta} and IL-18 secretion in mouse primary macrophages and human macrophages. Furthermore, NLRP3 Cys126 palmitoylation is vital for inflammasome activation in vivo, as Zdhhc7 knockout, pharmacological inhibition, or NLRP3 C126A mutation protects mice from LPS-induced endotoxic shock and monosodium urate (MSU)-induced peritonitis. Mechanistically, ZDHHC7-mediated NLRP3 Cys126 palmitoylation promotes resting NLRP3 localizing on the trans-Golgi network (TGN) and activated NLRP3 on the dispersed TGN (dTGN), which is indispensable for the recruitment and oligomerization of adaptor protein ASC after inflammasome activation. The activation of NLRP3 by ZDHHC7-mediated Cys126 palmitoylation is different from the previously reported inhibitory effect by ZDHHC12-mediated Cys841 palmitoylation, highlighting the versatile regulatory roles of S-palmitoylation. Therefore, our study identifies a new regulatory mechanism of NLRP3 activation and suggests targeting ZDHHC7 or NLRP3 Cys126 residue as a potential therapeutic strategy to treat NLRP3-related human disorders. HighlightsO_LINLRP3 Cys126 is palmitoylated by ZDHHC7. C_LIO_LIZDHHC7 promotes NLRP3 activation in macrophages, which can be inhibited by ZDHHCs inhibitors, 2-bromopalmitate and MY-D4. C_LIO_LICys126 palmitoylation of NLRP3 is critical for NLRP3 activation. C_LIO_LINLRP3 TGN/dTGN localization depends on ZDHHC7-mediated Cys126 palmitoylation, which is crucial for ASC recruitment and inflammasome assembly. C_LIO_LINLRP3 inflammasome activation by ZDHHC7 differs from ZDHHC12-mediated NLRP3 inhibition. C_LI

immunology↗

Antibodies utilizing VL6-57 light chains target a convergent cryptic epitope on SARS-CoV-2 spike protein driving the genesis of Omicron variants

Continued evolution of SARS-CoV-2 generates variants to challenge antibody immunity established by infection and vaccination. A connection between population immunity and genesis of virus variants has long been suggested but its molecular basis remains poorly understood. Here, we identify a class of SARS-CoV-2 neutralising public antibodies defined by their shared usage of VL6-57 light chains. Although heavy chains of diverse genotypes are utilized, convergent HCDR3 rearrangements have been observed among these public antibodies to cooperate with germline VL6-57 LCDRs to target a convergent epitope defined by RBD residues S371-S373-S375. Antibody repertoire analysis identifies that this class of VL6-57 antibodies is present in SARS-CoV-2-naive individuals and is clonally expanded in most COVID-19 patients. We confirm that Omicron specific substitutions at S371, S373 and S375 mediate escape of antibodies of the VL6-57 class. These findings support that this class of public antibodies constitutes immune pressure promoting the introduction of S371L/F-S373P-S375F in Omicron variants. The results provide further molecular evidences to support that antigenic evolution of SARS-CoV-2 is driven by antibody mediated population immunity.

biochemistry↗

Causal Role of the Frontal Eye Field in Attention-induced Ocular Dominance Plasticity

Previous research has found that prolonged eye-based attention can bias ocular dominance. If one eye long-termly views a regular movie meanwhile the opposite eye views a backward movie of the same episode, perceptual ocular dominance will shift towards the eye previously viewing the backward movie. Yet it remains unclear whether the role of eye-based attention in this phenomenon is causal or not. To address this issue, the present study relied on both the functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) techniques. We found robust activation of the frontal eye field (FEF) and intraparietal sulcus (IPS) when participants were watching the dichoptic movie while focusing their attention on the regular movie. Interestingly, we found a robust effect of attention-induced ocular dominance shift when the cortical function of vertex or IPS was transiently inhibited by continuous theta burst stimulation (cTBS), yet the effect was significantly attenuated to a negligible extent when cTBS was delivered to FEF. A control experiment verified that the attenuation of ocular dominance shift after inhibitory stimulation of FEF was not due to any impact of the cTBS on the binocular rivalry measurement of ocular dominance. These findings suggest that the fronto-parietal attentional network is involved in controlling eye-based attention in the "dichoptic-backward-movie" adaptation paradigm, and in this network, FEF plays a crucial causal role in generating the attention-induced ocular dominance shift.

neuroscience↗

NeuroMotion: Open-source Simulator with Neuromechanical and Deep Network Models to Generate Surface EMG signals during Voluntary Movement

Neuromechanical studies investigate how the nervous system interacts with the musculoskeletal (MSK) system to generate volitional movements. Such studies have been supported by simulation models that provide insights into variables that cannot be measured experimentally and allow a large number of conditions to be tested before the experimental analysis. However, current simulation models of electromyography (EMG), a core physiological signal in neuromechanical analyses, are mainly limited to static contractions and cannot fully represent the dynamic modulation of EMG signals during volitional movements. Here, we overcome these limitations by presenting NeuroMotion, an open-source simulator that provides a full-spectrum synthesis of EMG signals during voluntary movements. NeuroMotion is comprised of three modules. The first module is an upper-limb MSK model with OpenSim API to estimate the muscle fibre lengths and muscle activations during movements. The second module is BioMime, a deep neural network-based EMG generator that receives nonstationary physiological parameter inputs, such as muscle fibre lengths, and efficiently outputs motor unit action potentials (MUAPs). The third module is a motor unit pool model that transforms the muscle activations into discharge timings of motor units. The discharge timings are convolved with the output of BioMime to simulate EMG signals during the movement. Here we also provide representative applications of NeuroMotion. We first show how simulated MUAP waveforms change during different levels of physiological parameter variations and different movements. We then show that the synthetic EMG signals during two-degree-of-freedom hand and wrist movements can be used to augment experimental data for regression. Ridge regressors trained on the synthetic dataset were directly used to predict joint angles from experimental data. NeuroMotion is the first full-spectrum EMG generative model to simulate human forearm electrophysiology during voluntary hand, wrist, and forearm movements. All intermediate variables are available, which allows the user to study cause-effect relationships in the complex neuromechanical system, fast iterate algorithms before collecting experimental data, and validate algorithms that estimate non-measurable parameters in experiments. We expect this full-spectrum model will complement experimental approaches and facilitate neuromechanical research. Author summaryNeuromechanical studies investigate how the nervous system and musculoskeletal system interact to generate movements. Such studies heavily rely on simulation models, which provide non-measurable variables to complement the experimental analyses. However, the simulation models of surface electromyography (EMG), the core physiological signal widely used in neuromechanical analyses, are limited to static conditions. We bridged this gap by proposing NeuroMotion, the first full-spectrum EMG simulator that can be used to generate EMG signals during voluntary movements. NeuroMotion integrates a musculoskeletal model, a neural network-based EMG generator, and an advanced motoneuron model. With representative applications of this simulator, we show that it can be used to investigate the variabilities of EMG signals during voluntary movement. We also demonstrate that the synthetic signals generated by NeuroMotion can be used to augment experimental data for regressing joint angles. We expect the functionality provided by NeuroMotion, which is provided open-source, will stimulate progress in neuromechanics.

bioengineering↗

Prognostic implications and biological roles of EMT-related lncRNAs in lung squamous cell carcinoma: an in-depth analysis utilizing a novel prognostic signature and classification system

BackgroundLung squamous cell carcinoma (LUSC) represents a major subtype of non-small cell lung cancer (NSCLC), a leading contributor to cancer-related mortality. Epithelial-mesenchymal transition (EMT)-associated genes have been implicated in poor survival and metastatic gene expression in LUSC. Long non-coding RNAs (lncRNAs) are known to facilitate tumor progression and metastasis via EMT regulation. However, the prognostic significance and biological functions of EMT-associated lncRNAs in LUSC remain to be elucidated. MethodsIn this study, we aimed to develop an EMT-related lncRNA prognostic signature (EMT-LPS) utilizing RNA transcription data from LUSC patients in The Cancer Genome Atlas (TCGA) database, along with corresponding clinical characteristics. Kaplan-Meier analysis, receiver operating characteristic (ROC) curves, and Cox regression were employed to validate and assess the model. Furthermore, we confirmed the independent prognostic value of key genes in EMT-LPS using Gene Expression Profiling Interactive Analysis (GEPIA). Additionally, we proposed a novel LUSC classification system based on EMT-related lncRNA expression patterns, evaluating the prognostic profile, tumor microenvironment, and immunotherapy sensitivity of each subtype. ResultsA prognostic signature comprising twelve genes was constructed, and patients were stratified into high and low-risk groups according to their risk scores. Cox regression analysis revealed that the risk score served as an independent prognostic factor. A nomogram was generated to predict LUSC patient survival rates. Distinct subtypes exhibited varying tumor purity, immunogenicity, and immunotherapy drug sensitivity. ConclusionsOur findings underscore the relevance of EMT-related lncRNAs in LUSC and their potential utility in guiding immunotherapy strategies. The EMT-LPS and novel LUSC typing scheme provide a new perspective for understanding the biological functions and prognostic role of EMT-related lncRNAs in LUSC.

bioinformatics↗

Resident memory T cell development is associated with AP-1 transcription factor upregulation across anatomical niches.

Tissue-resident memory T (TRM) cells play a central role in immune responses to pathogens across all barrier tissues after infection. However, the underlying mechanisms that drive TRM differentiation and priming for their recall effector function remains unclear. In this study, we leveraged both newly generated and publicly available single-cell RNA-sequencing (scRNAseq) data generated across 10 developmental time points to define features of CD8 TRM across both skin and small-intestine intraepithelial lymphocytes (siIEL). We employed linear modeling to capture temporally-associated gene programs that increase their expression levels in T cell subsets transitioning from an effector to a memory T cell state. In addition to capturing tissue-specific gene programs, we defined a consensus TRM signature of 60 genes across skin and siIEL that can effectively distinguish TRM from circulating T cell populations, providing a more specific TRM signature than what was previously generated by comparing bulk TRM to naive or non-tissue resident memory populations. This updated TRM signature included the AP-1 transcription factor family members Fos, Fosb and Fosl2. Moreover, ATACseq analysis detected an enrichment of AP-1-specific motifs at open chromatin sites in mature TRM. CyCIF tissue imaging detected nuclear co-localization of AP-1 members Fosb and Junb in resting CD8 TRM >100 days post-infection. Taken together, these results reveal a critical role of AP-1 transcription factor members in TRM biology and suggests a novel mechanism for rapid reactivation of resting TRM in tissue upon antigen encounter.

immunology↗

Pan-genome of pear provides insights into the differentiation of fruit quality traits between Asian and European pears

The pear (Pyrus spp.) is a remarkable fruit, well known for its diverse flavors, textures, culinary versatility, and global horticultural importance. However, the genetic diversity responsible for its extensive phenotypic variations remains largely unexplored. Here, we de novo assembled and annotated the genomes of the maternal (PsbM) and paternal (PsbF) lines of the hybrid Yuluxiang pear and constructed the first pear pangenome of 1.15Gb by combining these two genomes with five previously published pear genomes. Using the constructed pangenome, we identified 21,224 gene PAVs and 1,158,812 SNPs in the non-reference genome that were absent in the PsbM reference genome. Compared with SNP markers, we found that PAV-based analysis provides additional insights into the pear population structure. In addition, we also revealed that some genes associated with pear fruit quality traits have differential occurrence frequencies and differential gene expression between Asian and European populations. Moreover, our analysis of the pear pangenome revealed a mutated SNP and an insertion in the promoter region of the gene PsbMGH3.1 potentially enhances sepal shedding in Xuehuali which is vital for pear quality. This research helps further capture the genetic diversity of pear populations and provides valuable genomic resources for accelerating pear breeding.

genomics↗