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Chen, L.

Publications and source records attributed to Chen, L..

At least 595 records · Page 33Linked to original sources
bioRxiv2022

Visualizing somatic alterations in spatial transcriptomics data of skin cancer

Tools to visualize genetic alterations within tissues remain underdeveloped despite the growth of spatial transcriptomic technologies, which measure gene expression in different regions of tissues. Since genetic alterations can be detected in RNA-sequencing data, we explored the feasibility of observing somatic alterations in spatial transcriptomics data. Extracting genetic information from spatial transcriptomic data would illuminate the spatial distribution of clones and allow for correlations with regional changes in gene expression to support genotype-phenotype studies. Recent work demonstrates that copy number alterations can be inferred from spatial transcriptomics data1. Here, we describe new software to further enhance the inference of copy number from spatial transcriptomics data. Moreover, we demonstrate that single nucleotide variants are also detectable in spatial transcriptomic data. We applied these approaches to map the location of point mutations, copy number alterations, and allelic imbalances in spatial transcriptomic data of two cutaneous squamous cell carcinomas. We show that both tumors are dominated by a single clone of cells, suggesting that their regional variations in gene expression2 are likely driven by non-genetic factors. Furthermore, we observe mutant cells in histologically normal tissue surrounding one tumor, which were not discernible upon histopathologic evaluation. Finally, we detected mono-allelic expression of immunoglobulin heavy chains in B-cells, revealing clonal populations of plasma cells surrounding one tumor. In summary, we put forward solutions to add the genetic dimension to spatial transcriptomic datasets, augmenting the potential of this new technology.

genomics↗
bioRxiv2022

Ring-finger protein 34 facilitates nervous necrosis virus evading antiviral innate immunity by targeting TBK1 and IRF3 for ubiquitination and degradation

Ubiquitination, as one of the most prevalent posttranslational modifications of proteins, enables a tight control on host immune responses. Many viruses hijack the host ubiquitin system to regulate host antiviral responses for their survival. Here, we found that fish pathogen nervous necrosis virus (NNV) recruited an E3 ubiquitin ligase ring finger protein 34 (RNF34) to inhibit RLRs-mediated interferons (IFN) response via ubiquitinating TBK1 and IRF3. Ectopic expression of RNF34 greatly enhances NNV replication and prevents IFN production, while deficiency of RNF34 led to the opposite effect. Furthermore, RNF34 targets TBK1 and IRF3 via its RING domain. Of note, the interactions between RNF34 and TBK1 or IRF3 were conserved in different fish species. Mechanically, RNF34 promote K27-linked ubiquitination and degradation of TBK1 and IRF3, which in turn diminishing TBK1-induced translocation of IRF3 from cytoplasm to nucleus. Ultimately, NNV capsid protein (CP) was found directly bind with RNF34 and this interaction was conserved in different fishes, and CP induced TBK1 and IRF3 degradation and IFN suppression was depended on RNF34. Our finding demonstrated a novel mechanism by which NNV CP evaded host innate immunity via RNF34, and provided a potential drug target for the control of NNV infection. Author SummaryUbiquitination plays an essential role in the regulation of innate immune responses to pathogens. NNV, a kind of RNA virus, is the causal agent of a highly destructive disease in a variety of marine and freshwater fish. Previous study reported NNV could hijack the ubiquitin system to manipulate the hosts immune responses, however, how NNV utilizes ubiquitination to facilitate its own replication is not well understood. Here, we identified a novel distinct role of E3 ubiquitin ligase RNF34 as an IFN antagonist to promote NNV infection. Nervous necrosis virus capsid protein utilized RNF34 to target TBK1 and IRF3 for K27 and K48-linked ubiquitination degradation. Importantly, the interactions between RNF34 and CP, TBK1 or IRF3 are conserved in different fishes, suggesting it is a general immune evasion strategy exploited by NNV to target the IFN response via RNF34.

immunology↗
bioRxiv2022

High-throughput Approaches to Uncover Synergistic Drug Combinations in Leukemia

We report a comprehensive drug synergy study in acute myeloid leukemia (AML). In this work, we investigate 11 cell lines spanning both MLL-rearranged and non-rearranged subtypes. The work comprises a resource for the community, with many synergistic drug combinations that could not have been predicted a priori, and open source code for automation and analyses. We base our definitions of drug synergy on the Chou-Talalay method, which is useful for visualizations of synergy experiments in isobolograms, and median-effects plots, among other representations. Our key findings include drug synergies affecting the chromatin state, specifically in the context of regulation of the modification state of histone H3 lysine-27. We report open source high throughput methodology such that multidimensional drug screening can be accomplished with equipment that is accessible to most laboratories. This study will enable preclinical investigation of new drug combinations in a lethal blood cancer, with data analysis and automation workflows freely available to the community. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/518409v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1e85ef9org.highwire.dtl.DTLVardef@b3369eorg.highwire.dtl.DTLVardef@1c6d705org.highwire.dtl.DTLVardef@14ec6b2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗
bioRxiv2022

Quantitatively mapping local quality of super-resolution microscopy by rolling Fourier ring correlation

In fluorescence microscopy, computational algorithms have been developed to suppress noise, enhance contrast, and even enable super-resolution (SR). However, the local quality of the images may vary on multiple scales, and these differences can lead to misconceptions, which is especially intractable in emerging deep-learning ones. Current mapping methods fail to finely estimate the local quality, challenging to associate the SR scale content. Here, we develop a rolling Fourier ring correlation (rFRC) framework to evaluate the reconstruction uncertainties down to SR scale. To visually pinpoint regions with low reliability, a filtered rFRC is combined with a modified resolution scaled error map (RSM), offering a comprehensive and concise map for further examination. We demonstrate their performances on various SR imaging modalities, and the resulting quantitative maps enable better SR images integrated from different reconstructions. Beyond that, we provide a strategy for learning-based restorations, allowing a direct detection of both data and model uncertainties, and expect the representative cases can inspire further advances in this rapidly developing field.

biophysics↗
bioRxiv2022

N6-methyladenosine (m6A) and reader protein YTHDF2 enhance innate immune response by mediating DUSP1 mRNA degradation and activating mitogen-activated protein kinases during bacterial and viral infections

Mitogen-activated protein kinases (MAPKs) play critical roles in the induction of numerous cytokines, chemokines, and inflammatory mediators that mobilize the immune system to counter pathogenic infections. Dual-specificity phosphatase-1 (DUSP1) is a member of dual-specificity phosphatases, which inactivates MAPKs through a negative feedback mechanism. Here we report that in response to viral and bacterial infections, not only DUSP1 transcript but also its N6-methyladenosine (m6A) level rapidly increase together with the m6A reader protein YTHDF2, resulting in enhanced YTHDF2-mediated DUSP1 transcript degradation. Knockdown of DUSP1 promotes p38 and JNK phosphorylation and activation, thus increasing the expression of innate immune response genes including IL1{beta}, CSF3, TGM2 and SRC. Similarly, knockdown of m6A eraser ALKBH5 increases DUSP1 transcript m6A level resulting in accelerated transcript degradation, activation of p38 and JNK, and enhanced expression of IL1{beta}, CSF3, TGM2 and SRC. These results demonstrate that m6A and reader protein YTHDF2 orchestrate optimal innate immune response during viral and bacterial infections by downregulating the expression of a negative regulator DUSP1 of the p38 and JNK pathways that are central to innate immune response against pathogenic infections. IMPORTANCEInnate immunity is central for controlling pathogenic infections and maintaining the homeostasis of the host. In this study, we have revealed a novel mechanism regulating innate immune response during viral and bacterial infections. We have found that N6-methyladenosine (m6A) and the reader protein YTHDF2 regulate dual-specificity phosphatase-1, a negative regulator of mitogen-activated protein kinases p38 and JNK, to maximize innate immune response during viral and bacterial infections. These results provide novel insights into the mechanism regulating innate immunity, which could help the development of novel approaches for controlling pathogenic infections.

microbiology↗
bioRxiv2022

Soft and stretchable organic bioelectronics for continuous intra-operative neurophysiological monitoring during microsurgery

Continuous intra-operative neurophysiological monitoring (CINM) that provides precise mapping of neural anatomy through the entire microsurgery process is essential to preserve the structural and functional integrity of the nerve. However, bulky and rigid electrodes used currently in clinics are usually unable to reliably maintain continuous and stable contacts with the vulnerable and complex nerve networks, thus often resulting in detrimental post-operative complications, such as hemiplegia and sensory disturbances. Here, we describe a biomechanically compatible, suture-free, and individually reconfigurable CINM based on soft and stretchable organic electronic materials. Due to both low impedance and modulus of our conducting polymer electrodes, we achieved for the first time continuous recording of near-field action potential with high signal-to-noise ratio and minimal invasiveness during microsurgeries. Utilizing this unprecedented CINM modality, in conjunction with localized neurostimulation, we further demonstrated our approach in enabling optimal post-operative prognosis in preclinical animal models by preserving normal neural functions after a variety of tumor resection surgeries.

bioengineering↗
bioRxiv2022

Structural and Computational Design of a SARS-CoV-2 Spike Antigen with Increased Receptor Binding Domain Exposure and Improved Immunogenicity

Emerging SARS-CoV-2 variants of concern challenge the efficacy of approved vaccines and emphasize the need for improved antigens. Using an evolutionary-based design approach starting from the widely used engineered Spike antigen, S-2P, we sought to increase antigen production levels and the exposure of highly conserved and neutralization sensitive receptor-binding domain (RBD) epitopes. Thirty-six prototypes were generated in silico, of which fifteen were produced and tested in biochemical assays. Design S2D14, which contains 20 mutations within the Spike S2 domain, showed a 6-fold increase in expression while preserving similar thermal stability and antigenicity as S-2P. Cryo-EM structures indicate that the dominant populations of S2D14 particles have RBDs in exposed states, and analysis of these structures revealed how modifications within the S2 domain balance trimer stability and RBD accessibility through formation and removal of hydrogen bonds and surface charge alterations. Importantly, vaccination of mice with adjuvanted S2D14 resulted in higher levels of neutralizing antibodies than adjuvanted S-2P against SARS-CoV-2 Wuhan strain and four variants of concern. These results can guide the design of next generation vaccines to combat current, and future coronaviruses and the approaches used may be broadly applicable to streamline the successful design of vaccine antigens.

immunology↗
bioRxiv2022

Host translation machinery is not a barrier to phages that infect both CPR and non-CPR bacteria

Within human microbiomes, Gracilibacteria, Absconditabacteria, and Saccharibacteria, members of Candidate Phyla Radiation (CPR), are increasingly correlated with human oral health and disease. We profiled the diversity of CRISPR-Cas systems in the genomes of these bacteria and sought phages that are capable of infecting them by comparing their spacer inventories to large phage sequence databases. Gracilibacteria and Absconditabacteria recode the typical TGA stop codon to glycine and are infected by phages that share their hosts alternate genetic code. Unexpectedly, however, other predicted phages of Gracilibacteria and Absconditabacteria do not use an alternative genetic code. Some of these phages are predicted to infect both alternatively coded CPR bacteria and standard coded bacteria. These phages rely on other stop codons besides TGA, and thus should be capable of producing viable gene products in either bacterial host type. Interestingly, we predict that phages of Saccharibacteria can replicate in Actinobacteria, which have been shown to act as episymbiotic hosts for Saccharibacteria. Overall, the broad host range of some CPR phages may be advantageous for the production of these phages for microscopic characterization or use as therapy agents, given the current difficulty of CPR cultivation. Absconditabacteria phages and Gracilibacteria phages may have avoided acquisition of in-frame stop codons to increase the diversity of bacteria in which they can replicate.

microbiology↗
bioRxiv2022

Default But Not Rest: Topological Discrimination Defines the Default Mode Network

The default mode network (DMN), a set of transmodal cortical regions, has historically been argued to serve the internal functions of brain. The discovery of this network highlighted the brains intrinsic operations. The DMN generally decreases its activity during tasks and increases its activity during relaxed non-task states. It is important to investigate the nature of the DMN in order to understand the human brain in health and disease. In the current study, we discovered a task-related cortical network we called the Topological Discrimination Network (TDN), which was consistently revealed by contrasting activations from topological discrimination tasks with local geometric discrimination tasks. The TDN and the DMN consist of essentially the same group of brain regions and the fMRI response of topological discrimination in those regions exhibited consistent temporal dynamics with resting state. The robustness of the TDN is supported by multiple experiments performed at different field strengths (3T and 7T MRI scanner) as well as different types of signals measured (BOLD and CBF). The collective results suggest that the process of topological discrimination could almost be considered as a functional "default mode" of our brain. The TDN, like the DMN, could define the functional baseline of brain, with the advantage of functional consistency across participants and experimental sessions.

neuroscience↗
bioRxiv2022

Discovery of benzophenanthridine derivatives with potent activity against multidrug resistant Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb), the pathogen responsible for tuberculosis (TB), is the leading cause of bacterial disease-related death worldwide. Current antibiotic regimens for the treatment of TB remain dated and suffer from long treatment times as well as the development of drug-resistance. As such, the search for novel chemical modalities that have selective or potent anti-Mtb properties remains an urgent priority, particularly against multidrug resistant (MDR) Mtb strains. Herein, we design and synthesize 35 novel benzo[c]phenanthridine derivatives (BPD). The two most potent compounds, BPD-6 and BPD-9, accumulated within the bacterial cell and exhibited strong inhibitory activity (MIC90 [~] 2-10 M) against multiple Mycobacterium strains, while remaining inactive against a range of other Gram-negative and Gram-positive bacteria. BPD-6 and BPD-9 were also effective in reducing Mtb viability within infected macrophages. The two BPD compounds displayed comparable efficacy to rifampicin, a critical frontline antibiotic used for the prevention and treatment of TB. Importantly, BPD-6 and BPD-9 inhibited the growth of multiple MDR Mtb clinical isolates, suggesting a completely novel mechanism of action compared to existing frontline TB dugs. The discovery of BPDs provides novel chemical scaffolds for anti-TB drug discovery. TOC/GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/515485v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1536acaorg.highwire.dtl.DTLVardef@1881e83org.highwire.dtl.DTLVardef@18b2f58org.highwire.dtl.DTLVardef@d15f1a_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗
bioRxiv2022

STAMarker: Determining spatial domain-specific variable genes with saliency maps in deep learning

Spatial transcriptomics characterizes gene expression profiles while retaining the information of the spatial context, providing an unprecedented opportunity to understand cellular systems. One of the essential tasks in such data analysis is to determine spatially variable genes (SVGs), which demonstrate spatial expression patterns. Existing methods only consider genes individually and fail to model the inter-dependence of genes. To this end, we present an analytic tool STAMarker for robustly determining spatial domain-specific SVGs with saliency maps in deep learning. STAMarker is a three-stage ensemble framework consisting of graphattention autoencoders, multilayer perceptron (MLP) classifiers, and saliency map computation by the backpropagated gradient. We illustrate the effectiveness of STAMarker and compare it with three competing methods on four spatial transcriptomic data generated by various platforms. STAMarker considers all genes at once and is more robust when the dataset is very sparse. STAMarker could identify spatial domain-specific SVGs for characterizing spatial domains and enable in-depth analysis of the region of interest in the tissue section.

bioinformatics↗
bioRxiv2022

Dual RNA-Seq profiling unveils mycoparasitic activities of Trichoderma atroviride against haploid Armillaria ostoyae in antagonistic interaction assays

Armillaria ostoyae, a species among the destructive forest pathogens from the genus Armillaria, causes root rot disease on woody plants worldwide. Efficient control measures to limit the growth and impact of this severe underground pathogen are currently under investigation. In a previous study, a new soilborne fungal isolate, Trichoderma atroviride SZMC 24276, exhibited high antagonistic efficacy, which suggested that it could be utilized as a biocontrol agent. The dual culture assay results indicated that the haploid A. ostoyae derivative SZMC 23085 (C18/9) is highly susceptible to the mycelial invasion of T. atroviride SZMC 24276. In the present study we analyzed the transcriptome of A. ostoyae SZMC 23085 (AO) and that of T. atroviride SZMC 24276 (TA) in in vitro dual culture assays to test the molecular arsenal of Trichoderma antagonism and the defense mechanisms of Armillaria. We conducted time-course analysis, functional annotation, analyzed enriched pathways, and differentially expressed genes (DEGs) including biocontrol-related candidate genes from TA and defense-related candidate genes from AO. The results indicated that TA deployed several biocontrol mechanisms when confronted with AO. In response, AO initiated multiple defense mechanisms to protect against the fungal attack. To our knowledge, the present study offers the first transcriptome analysis of a biocontrol fungus attacking A. ostoyae. Overall, this study provides insights that aid the further exploration of plant pathogen - biocontrol agent interaction mechanisms. IMPORTANCEArmillaria species can survive for decades in the soil on dead woody debris, develop rapidly under favourable conditions, and harmfully infect newly planted forests. Our previous study found Trichoderma atroviride to be highly effective in controlling Armillaria growth; therefore, our current work explored the molecular mechanisms that might play a key role in Trichoderma-Armillaria interactions. Direct confrontation assays combined with time course-based dual transcriptome analysis provided a reliable system for uncovering the interactive molecular dynamics between the fungal plant pathogen and its mycoparasitic partner. Furthermore, using a haploid Armillaria isolate allowed us to survey the deadly prey-invading activities of the mycoparasite and the ultimate defensive strategies of its prey. Our current study provides detailed insights into the essential genes and mechanisms involved in Armillaria defense against Trichoderma and the genes potentially involved in the efficiency of Trichoderma to control Armillaria. In addition, using a sensitive haploid Armillaria strain (C18/9), with its complete genome data already available, also offers the opportunity to test possible variable molecular responses of Armillaria ostoyae towards diverse Trichoderma isolates with varying biocontrol abilities. Initial molecular tests of the dual interactions may soon help to develop a targeted biocontrol intervention with mycoparasites against plant pathogens.

microbiology↗
bioRxiv2022

COMBINATION THERAPIES TARGETING ALK-ABERRANT NEUROBLASTOMA IN PRECLINICAL MODELS.

BackgroundALK activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1-2% of cases. Lorlatinib, a third generation ALK inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data has suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. AimsTo study the preclinical activity of ALK inhibitors alone and in combination with chemotherapy or idasanutlin. MethodsWe compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient derived xenografts (PDX). ResultsLorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with the highest ALK expression. In this PDX lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth. ConclusionOur study suggests that in neuroblastoma, high ALK expression could be associated with response to lorlatinib and either chemotherapy or idasanutlin. The synergy between MDM2 inhibition and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma. STATEMENT OF TRANSLATIONAL RELEVANCENeuroblastoma is a pediatric tumor of the developing sympathetic nervous system. Around 50% of high-risk neuroblastoma patients are curable. Mutations or amplification of Anaplastic Lymphoma Kinase (ALK) have emerged as a marker with which to further risk-stratify patients. The ALK inhibitor lorlatinib will soon be used alongside chemotherapy in upfront treatment of high-risk patients with ALK-aberrant disease. In this preclinical study, we used a panel of ALK aberrant neuroblastoma models to evaluate ALK inhibitors focusing on lorlatinib in combination with conventional chemotherapy and the small molecule MDM2 inhibitor idasanutlin. In both approaches we found synergy in models with high basal ALK expression without MAPK pathway alterations. We conclude that in neuroblastoma the level of ALK expression could be an additional biomarker predictive of clinical response to ALK inhibitors.

cancer biology↗
bioRxiv2022

Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions

Transcription factors (TFs) activate enhancers to drive cell-specific gene programs in response to signals, but our understanding of enhancer assembly during signaling events is incomplete. Here, we show that Androgen Receptor (AR), a steroid hormone-regulated transcription factor, forms condensates through multivalent interactions in response to androgen signaling to orchestrate enhancer assembly. We demonstrate that the intrinsically disordered N-terminal domain (NTD) of AR drives 1,6-Hexanediol-sensitive condensate formation and that NTD deletion or aromatic residue mutation reduces AR self-association and abolishes AR transcriptional activity. AR NTD can be substituted by intrinsically disordered regions (IDRs) from selective proteins for AR condensation capacity and transactivation function. Surprisingly, strengthened AR condensation capacity caused by extending the polyQ tract within AR NTD also leads to impaired transcriptional activity without affecting AR binding on enhancers. Furthermore, either NTD deletion or polyQ extension reduces heterotypic multivalent interactions between AR and other enhancer components. These results suggest the importance of an optimal level of AR condensation in mediating AR-AR homotypic and AR-cofactor heterotypic interactions to regulate enhancer assembly in response to signals. Our study supports the notion that alteration of the fine-tuned multivalent IDR-IDR interactions might underlie AR-related human pathologies, thereby providing novel molecular insights for potential therapeutic strategies to treat prostate cancer and other AR-involved diseases by targeting AR multivalent interactions.

molecular biology↗
bioRxiv2022

Proliferative Exhausted CD8 T Cells Exacerbate Long-lasting Anti-tumor Effects in Human Papillomavirus Positive Head and Neck Squamous Cell Carcinoma

The survival prognosis of human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) is largely different, and little is known about the anti-tumor mechanism of tumor-infiltrated CD8+ exhausted T cells (Tex) in HNSCC. We performed cell level multi-omics sequencing on human HNSCC samples to decipher the multi-dimensional characteristics of Tex cells. A proliferative exhausted CD8+ T cell cluster (P-Tex) which was beneficial to survival outcomes of patients with HPV-positive HNSCC was identified. Interestingly, P-Tex cells expressed CDK4 genes as high as cancer cells, which could be simultaneously inhibited by CDK4 inhibitors and might be a potential reason for the ineffectiveness of CDK4 inhibitors in treating HPV-positive HNSCC. P-Tex cells could aggregate in the antigen presenting cell niches and activate certain signaling pathways. Together, our findings suggest a promising role for P-Tex cells in the prognosis of patients with HPV-positive HNSCC by providing modest but persistent anti-tumor effects. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/513993v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1f8810forg.highwire.dtl.DTLVardef@1e11d84org.highwire.dtl.DTLVardef@58fb6aorg.highwire.dtl.DTLVardef@1e20a13_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗
bioRxiv2022

Mapping genetic variants for nonsense-mediated mRNA decay regulation across human tissues

BackgroundNonsense-mediated mRNA decay (NMD) was originally conceived as an mRNA surveillance mechanism to prevent the production of potentially deleterious truncated proteins. Recent research shows NMD is an important post-transcriptional gene regulation mechanism selectively targeting many non-aberrant mRNAs. However, how natural genetic variants affect NMD and modulate gene expressions remains elusive. ResultsHere we elucidate NMD regulation of individual genes across human tissues through genetical genomics. Genetic variants corresponding to NMD regulation are identified based on the GTEx data through unique and robust transcript expression modelling. We identify genetic variants that influence the percentage of NMD-targeted transcripts (pNMD-QTLs), as well as genetic variants regulating the decay efficiency of NMD-targeted transcripts (dNMD-QTLs). Many such variants are missed in traditional expression quantitative trait locus (eQTL) mapping. NMD-QTLs show strong tissue specificity especially in the brain. They are more likely to colocalize with disease single-nucleotide polymorphisms (SNPs). Compared to eQTLs, NMD-QTLs are more likely to be located within gene bodies and exons, especially the penultimate exons from the 3 end. Furthermore, NMD-QTLs are more likely to be found in the binding sites of miRNAs and RNA binding proteins (RBPs). ConclusionsWe reveal the genome-wide landscape of genetic variants associated with NMD regulation across human tissues. Our analysis results indicate important roles of NMD in the brain. The preferential genomic positions of NMD-QTLs suggest key attributes for NMD regulation. Furthermore, the colocalization with disease-associated SNPs and post-transcriptional regulatory elements implicate regulatory roles of NMD-QTLs in disease manifestation and their interactions with other post-transcriptional regulators.

genetics↗
bioRxiv2022

Electro-acupuncture alleviates ACE-increased anxiety-like behaviors in mice of adulthood by targeting claustrum D1R CaMKII

Adolescent cocaine exposure (ACE) increases risk of developing psychiatric problems such as anxiety, which may drive relapse in later life, however, its underlying molecular mechanism remains poorly understood. Methods: ACE male mice model were established by exposing to cocaine during adolescent period. Elevated plus maze (EPM) were used to assess anxiety-like behaviors in mice. Within claustrum, local injection of SCH-23390, a specific antagonist for dopamine receptor 1 (D1R), or D1R knocking-down virus were used to regulate D1R function or expression on CaMKII-positive neurons (D1RCaMKII) in vivo. Electro-acupuncture (EA) treatment was performed at acupoints of Baihui and Yintang during withdrawal period. Results: We found that ACE mice exhibited anxiety-like behaviors, along with more activated CaMKII-positive neurons and increased D1RCaMKII levels in claustrum during adulthood. Inhibiting D1R function or knocking-down D1RCaMKII levels in claustrum efficiently reduced claustrum activation, and ultimately suppressed anxiety-like behaviors in ACE mice during adulthood. EA treatment alleviated ACE-evoked claustrum activation and anxiety-like behaviors by suppressing claustrum D1RCaMKII. Conclusion: Our findings identified a novel role of claustrum in ACE-induced anxiety-like behaviors, and put new insight into the D1RCaMKII in the claustrum. The claustrum D1RCaMKII might be a promising pharmacological target, such as EA treatment, to treat drugs-induced anxiety-like behaviors. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/512685v5_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1b22744org.highwire.dtl.DTLVardef@12fed83org.highwire.dtl.DTLVardef@1924caforg.highwire.dtl.DTLVardef@1e896ca_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗