Biology subjects

Cheng, F.

Publications and source records attributed to Cheng, F..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Identification of Host Restriction Factors Critical for Recombinant AAV Transduction of Polarized Human Airway Epithelium

Recombinant (r)AAV2.5T was selected from the directed evolution of an AAV capsid library in human airway epithelium (HAE). The capsid gene of rAAV2.5T is a chimera of the N-terminal unique coding sequence of AAV2 VP1 unique (VP1u) and the VP2- and VP3-coding sequence of AAV5 with a single amino acid mutation of A581T. We conducted two rounds of genome wide CRISPR gRNA library screening for host factors limiting rAAV2.5T transduction in HeLa S3 cells. The screen identified several genes that are critical for rAAV2.5T transduction in HeLa S3 cells, including previously reported genes KIAA0319L, TM9SF2, VPS51, and VPS54, as well as a novel gene WDR63. We verified the role of KIAA0319L and WDR63 in rAAV2.5T transduction of polarized HAE by utilizing CRISPR gene knockouts. Although KIAA0319L, a proteinaceous receptor for multiple AAV serotypes, played an essential role in rAAV2.5T transduction of polarized HAE either from apical or basolateral side, our findings demonstrated that the internalization of rAAV2.5T was independent of KIAA0319L. Importantly, we confirmed WDR63 is an important player in rAAV2.5T transduction of HAE, while not being involved in vector internalization and nuclear entry. Furthermore, we identified that the basal stem cells of HAE can be significantly transduced by rAAV2.5T. SignificanceThe essential steps of a successful gene delivery by rAAV include vector internalization, intracellular trafficking, nuclear import, uncoating, double-stranded (ds)DNA conversion, and transgene expression. rAAV2.5T has a chimeric capsid of AAV2 VP1u and AAV5 VP2 and VP3 with the mutation A581T. Our investigation revealed that KIAA0319L, the multiple AAV serotype receptor, is not essential for vector internalization but remains critical for efficient vector transduction to human airway epithelia. Additionally, we identified that a novel gene WDR63, whose cellular function is not well understood, plays an important role in vector transduction of human airway epithelia but not vector internalization and nuclear entry. Our study also discovered the substantial transduction potential of rAAV2.5T in basal stem cells of human airway epithelia, underscoring its utility in gene editing of human airways. Thus, the knowledge derived from this study holds promise for the advancement of gene therapy in the treatment of pulmonary genetic diseases.

microbiology↗

bioRxiv2023

Engineering cGAS-agonistic oligonucleotides as therapeutics and vaccine adjuvants for cancer immunotherapy

Current cancer immunotherapy (e.g., immune checkpoint blockade (ICB)) has only benefited a small subset of patients. Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation holds the potential to improve cancer immunotherapy by eliciting type-I interferon (IFN-I) responses in cancer cells and myeloid cells. Yet, current approaches to this end, mostly by targeting STING, have marginal clinical therapeutic efficacy. Here, we report a cGAS-specific agonistic oligonucleotide, Svg3, as a novel approach to cGAS-STING activation for versatile cancer immunotherapy. Featured with a hairpin structure with consecutive guanosines flanking the stem, Svg3 binds to cGAS and enhances cGAS-Svg3 phase separation to form liquid-like droplets. This results in cGAS activation by Svg3 for robust and dose-dependent IFN-I responses, which outperforms several state-of-the-art STING agonists in murine and human immune cells, and human tumor tissues. Nanocarriers efficiently delivers Svg3 to tissues, cells, and cytosol where cGAS is located. Svg3 reduces tumor immunosuppression and potentiates ICB therapeutic efficacy of multiple syngeneic tumors, in wildtype but neither cGas-/- nor goldenticket Sting-/- mice. Further, as an immunostimulant adjuvant, Svg3 enhances the immunogenicity of peptide antigens to elicit potent T cell responses for robust ICB combination immunotherapy of tumors. Overall, cGAS-agonistic Svg3 is promising for versatile cancer combination immunotherapy.

bioengineering↗

bioRxiv2023

Variations in Homoeologous Dosage and Epigenomics Mark the Early Evolution of Synthetic Brassica Tetraploids

Polyploidization is important in plant evolution and is becoming increasingly important in crop breeding and material creation. Studies have provided evidence for structural variations and epigenomic repatterning in synthetic polyploidizations, but the relationships between structural and epigenomic variations, as well as their effects on gene expression and phenotypic variations are unknown. Here, we investigated the genome-wide large deletion/duplication regions (DelDups) and genomic methylation dynamics, in the leaf organ as a representative, of progenies from eight generations that derived from the synthetic tetraploidization between Brassica rapa and Brassica oleracea. We found that half or complete deletion/duplication of fragments ranging in size from 400 kb to 65.85 Mb, with a mean size of 5.70 Mb, occurred frequently from the first generation of selfing and thereafter. The genes located in these DelDups expressed at levels expected for a positive dosage effect, as indicated by the positive association between expression and the copy number of these genes. Plants containing these DelDups also showed distinct phenotypic variations. The whole genome methylation level experienced significant fluctuations in different generations and eventually decreased in the latter generations. Moreover, the DelDups did not show methylation changes from other individuals of the same generation, and the local regions with methylation alterations did not affect gene expression. Our findings provide new insights into the early evolution of polyploid genomes and guide the use of synthetic polyploidizations in breeding.

genomics↗

bioRxiv2023

Phenotypic Switching of Vascular Smooth Muscle Cells in Duchenne Muscular Dystrophy

BackgroundExtensive studies have been conducted in skeletal muscle and myocardium affected by Duchenne Muscular Dystrophy (DMD) disease but there is a significant gap of research in the role of vascular smooth muscle cells (VSMCs) in DMD. Here, we investigated the role of dystrophin deficiency in the maintenance of VSMCs contractile phenotype. Methods12-14 months old mdx mice and DMD induced pluripotent stem cells (iPSC) derived VSMCs were used as disease models. Morphological and immunohistochemistry analyses were performed to determine histological changes and the expression of contractile markers. Transmission Electron Microscopy (TEM) was used to assess ultrastructural changes in the VSMCs. Mito-tracker staining and TUNEL staining were performed to determine mitochondria fission-fusion and apoptosis respectively. mRNA Sequencing for normal iPSC derived VSMCs (WT-VSMCs) and DMD iPSC derived VSMCs (DMD-VSMCs) with or without oxidative stress was performed. KEGG signaling pathway enrichment, Go function enrichment and Gene set enrichment analysis (GESA) were conducted to explore the potential mechanism responsible for these changes. In addition, transcription factor enrichment analysis was performed to unravel mechanistic pathways of regulatory networks. ResultsSpontaneous abnormal VSMCs proliferation, loss of vascular structure and degenerative changes occurred in VSMCs in aorta from 12-14 months old mdx mice. The DMD-VSMCs showed maturation defect, loss of mitochondrial hemostasis, and increased vulnerability to oxidative stress compared with WT-VSMCs. Transcriptome analysis revealed dysregulation of smooth muscle proliferation, differentiation, and vascular development in DMD-VSMCs. Transcriptional factor, target, and motif discovery analysis of the dysregulated gene set suggested potential contributions of transcriptional factors GADD45A, SOX9, TIA1, RBBP9 and FOXM to the phenotypes of DMD-VSMCs. Under oxidative stress, initiation of apoptotic process was significantly enhanced in DMD-VSMCs while their response to hypoxia and oxidative stress was downregulated. ConclusionsDystrophin deficiency induced VSMCs phenotype switching and disrupted mitochondrial metabolism. The findings in this study underscore the importance of vascular dysfunction in DMD disease and therapeutic interventions to restore VSMC phenotype may ameliorate the propensity of disease progression. It is suggested that the transcriptome analysis may allow the discovery of potential signaling pathways involved in the dysregulation of transcription factors.

cell biology↗

bioRxiv2023

Reconstructing visual illusory experiences from human brain activity

Visual illusions provide significant insights into the brains interpretation of the world given sensory inputs. However, the precise manner in which brain activity translates into illusory experiences remains largely unknown. Here we leverage a brain decoding technique combined with deep neural network (DNN) representations to reconstruct illusory percepts as images from brain activity. The reconstruction model was trained on natural images to establish a link between brain activity and perceptual features and then tested on two types of illusions: illusory lines and neon color spreading. Reconstructions revealed lines and colors consistent with illusory experiences, which varied across the source visual cortical areas. This framework offers a way to materialize subjective experiences, shedding new light on the brains internal representations of the world.

neuroscience↗

bioRxiv2023

Direct interhemispheric cortical communication via thalamic commissures: a new white-matter pathway in the primate brain

Cortical neurons of eutherian mammals project to the contralateral hemisphere, crossing the midline primarily via the corpus callosum and the anterior, posterior, and hippocampal commissures. We recently reported an additional commissural pathway in rodents, termed the thalamic commissures (TCs), as another interhemispheric axonal fiber pathway that connects cortex to the contralateral thalamus. Here, we demonstrate that TCs also exist in primates and characterize the connectivity of these pathways with high-resolution diffusion-weighted magnetic resonance imaging, viral axonal tracing, and functional MRI. We present evidence of TCs in both New World (Callithrix jacchus and Cebus apella) and Old World primates (Macaca mulatta). Further, like rodents, we show that the TCs in primates develop during the embryonic period, forming anatomical and functionally active connections of the cortex with the contralateral thalamus. We also searched for TCs in the human brain, showing their presence in humans with brain malformations, although we could not identify TCs in healthy subjects. These results pose the TCs as an important fiber pathway in the primate brain, allowing for more robust interhemispheric connectivity and synchrony and serving as an alternative commissural route in developmental brain malformations. Significance statementBrain connectivity is a central topic in neuroscience. Understanding how brain areas can communicate allows for the comprehension of brain structure and function. We have described in rodents a new commissure pathway that connects the cortex to the contralateral thalamus. Here, we investigate whether this pathway exists in non-human primates and humans. The presence of these commissures poses the TCs as an important fiber pathway in the primate brain, allowing for more robust interhemispheric connectivity and synchrony and serving as an alternative commissural route in developmental brain malformations.

neuroscience↗

bioRxiv2023

FOXK2 amplification and overexpression promotes breast cancer development and chemoresistance

Activation of oncogenes through DNA amplification/overexpression plays an important role in cancer initiation and progression. Chromosome 17 has many cancer-associated genetic anomalies. This cytogenetic anomaly is strongly associated with poor prognosis of breast cancer. FOXK2 gene is located on 17q25 and encodes a transcriptional factor with a forkhead DNA binding domain. By integrative analysis of public genomic datasets of breast cancers, we found that FOXK2 is frequently amplified and overexpressed in breast cancers. FOXK2 overexpression in breast cancer patients is associated with poor overall survival. FOXK2 knockdown significantly inhibits cell proliferation, invasion and metastasis, and anchorage-independent growth, as well as causes G0/G1 cell cycle arrest in breast cancer cells. Moreover, inhibition of FOXK2 expression sensitizes breast cancer cells to frontline anti-tumor chemotherapies. More importantly, co-overexpression of FOXK2 and PI3KCA with oncogenic mutations (E545K or H1047R) induces cellular transformation in non-tumorigenic MCF10A cells, suggesting that FOXK2 is an oncogene in breast cancer and is involved in PI3KCA-driven tumorigenesis. Our study identified CCNE2, PDK1, and Estrogen receptor alpha (ESR1) as direct transcriptional targets of FOXK2 in MCF-7 cells. Blocking CCNE2- and PDK1-mediated signaling by using small molecule inhibitors has synergistic anti-tumor effects in breast cancer cells. Furthermore, FOXK2 inhibition by gene knockdown or inhibitors for its transcriptional targets (CCNE2 and PDK1) in combination with PI3KCA inhibitor, Alpelisib, showed synergistic anti-tumor effects on breast cancer cells with PI3KCA oncogenic mutations. In summary, we provide compelling evidence that FOXK2 plays an oncogenic role in breast tumorigenesis and targeting FOXK2-mediated pathways may be a potential therapeutic strategy in breast cancer.

cancer biology↗

bioRxiv2023

3D structural human interactome reveals proteome-wide perturbations by disease mutations

Human genome sequencing studies have identified numerous loci associated with complex diseases. However, translating human genetic and genomic findings to disease pathobiology and therapeutic discovery remains a major challenge at multiscale interactome network levels. Here, we present a deep-learning-based ensemble framework, termed PIONEER (Protein-protein InteractiOn iNtErfacE pRediction), that accurately predicts protein binding partner-specific interfaces for all known protein interactions in humans and seven other common model organisms, generating comprehensive structurally-informed protein interactomes. We demonstrate that PIONEER outperforms existing state-of-the-art methods. We further systematically validated PIONEER predictions experimentally through generating 2,395 mutations and testing their impact on 6,754 mutation-interaction pairs, confirming the high quality and validity of PIONEER predictions. We show that disease-associated mutations are enriched in PIONEER-predicted protein-protein interfaces after mapping mutations from [~]60,000 germline exomes and [~]36,000 somatic genomes. We identify 586 significant protein-protein interactions (PPIs) enriched with PIONEER-predicted interface somatic mutations (termed oncoPPIs) from pan-cancer analysis of [~]11,000 tumor whole-exomes across 33 cancer types. We show that PIONEER-predicted oncoPPIs are significantly associated with patient survival and drug responses from both cancer cell lines and patient-derived xenograft mouse models. We identify a landscape of PPI-perturbing tumor alleles upon ubiquitination by E3 ligases, and we experimentally validate the tumorigenic KEAP1-NRF2 interface mutation p.Thr80Lys in non-small cell lung cancer. We show that PIONEER-predicted PPI-perturbing alleles alter protein abundance and correlates with drug responses and patient survival in colon and uterine cancers as demonstrated by proteogenomic data from the National Cancer Institutes Clinical Proteomic Tumor Analysis Consortium. PIONEER, implemented as both a web server platform and a software package, identifies functional consequences of disease-associated alleles and offers a deep learning tool for precision medicine at multiscale interactome network levels.

bioinformatics↗

bioRxiv2023

Degenerated CRISPRs widely regulate Cas expression to balance immunity and cost

CRISPR RNAs (crRNAs) and Cas proteins together provide prokaryotes with adaptive immunity against genetic invaders. How Cas expression is fine-tuned to avoid energy burden while satisfying the dynamic need of crRNAs remains poorly understood. Here we experimentally demonstrated widespread degenerated mini-CRISPRs encode CreR (Cas-regulating) RNAs to mediate autorepression of type I-B, I-E and V-A Cas proteins, based on their partial complementarity to cas promoters. This autorepression decreases energy burden and autoimmune risks, thus mitigating the fitness cost on host cell, and remarkably, senses and responds to alterations in the volume of canonical crRNAs, which compete with CreR for Cas proteins. Moreover, CreR-guided Cas autorepression can be subverted by diverse anti-CRISPR (Acr) proteins that destruct Cas proteins, which in turn replenishes the weapon depot. Our data unveil a general degenerated crRNA-guided autorepression paradigm for diverse Cas effectors, which highlights the intricate (self-)regulation of CRISPR-Cas and its transcriptional counterstrategy against Acr attack.

microbiology↗

bioRxiv2022

Identifying human islet microRNAs associated with donor sex, age and body mass index

ObjectivesHuman islets are widely researched to understand pathophysiological mechanisms leading to diabetes. Sex, age, and body mass index (BMI) are key donor traits influencing insulin secretion. Islet function is also regulated by an intricate network of microRNAs. MethodsHere, we profiled 754 microRNAs and 58,190 potential targets in up to 131 different human islet donor preparations (without diabetes) and assessed their association with donor traits. We further performed mechanistical studies to observe the causal role of the age-associated key microRNAs on relative telomere length in human islets. ResultsMicroRNA discovery analyses identified miR-199a-5p and miR-214-3p associated with sex, age and BMI; miR-147b with sex and age; miR-378a-5p with sex and BMI; miR-542-3p, miR-34a-3p, miR-34a-5p, miR-497-5p and miR-99a-5p with age and BMI. There were 959 mRNA transcripts associated with sex (excluding those from sex-chromosomes), 940 with age and 418 with BMI. MicroRNA-199a-5p and miR-214-3p levels inversely associate with transcripts critical in islet function, metabolic regulation, and senescence. Our functional studies verified that inhibition of these two microRNAs (miR-199a-5p/-214-3p) slowed down telomere length shortening in human islet cells maintained in vitro and demonstrating cellular senescence. ConclusionsOur analyses identify human islet cell microRNAs influenced by donor traits. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/512222v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1666c2org.highwire.dtl.DTLVardef@b4695forg.highwire.dtl.DTLVardef@720e99org.highwire.dtl.DTLVardef@1c78ae_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

TRAF6 modulates PD-L1 expression through YAP1-TFCP2 signaling in melanoma

BackgroundImmunotherapy represented by the programmed death-1 (PD-1)/ligand 1 (PD-L1) monoclonal antibodies has led tumor treatment into a new era. However, the low overall response rate and high incidence of drug resistance largely damage the clinical benefits of existing immune checkpoint therapies. Recent studies correlate the response to PD-1/PD-L1 blockade with PD-L1 expression levels in tumor cells. Hence, identifying molecular targets and pathways controlling PD-L1 protein expression and stability in tumor cells is a major priority. MethodsIn this study, we first performed a Stress and Proteostasis CRISPR interference library-based screening to identify PD-L1 positive modulators. We then used in vitro and in vivo assays to investigate the biological function and mechanism of TRAF6 and its downstream YAP1/TFCP2 signaling in malignant melanoma. ResultsHere, we identified TRAF6 as a critical regulator of PD-L1 in melanoma cells. Suppression of TRAF6 expression down-regulates PD-L1 expression on the membrane surface of melanoma cells. We also found that PD-L1 protein abundance is regulated by YAP1/TFCP2 transcriptional complex. TRAF6 stabilizes YAP1 by K63 poly-ubiquitination modification, subsequently promoting the formation of YAP1/TFCP2 and PD-L1 transcription. Furthermore, inhibition of TRAF6 by Bortezomib enhanced cytolytic activity of CD8+ T cells by reduction of endogenous PD-L1. Notably, Bortezomib enhances anti-tumor immunity to an extent that is comparable to anti-PD-1 mAb therapies with no obvious toxicity. ConclusionsThese findings uncover a novel molecular mechanism for regulating PD-L1 protein abundance by a E3 ligase in cancer cells and reveal the potential of using TRAF6 inhibitors to stimulate internal anti-tumor immunological effect for TRAF6-PD-L1 overexpressing cancers.

cancer biology↗

bioRxiv2022

Comprehensive characterization of multi-omic landscapes between gut-microbiota metabolites and the G-protein-coupled receptors in Alzheimer's disease

Accumulating evidence suggests that gut-microbiota metabolites contribute to human disease pathophysiology, yet the host receptors that sense these metabolites are largely unknown. Here, we developed a systems pharmacogenomics framework that integrates machine learning (ML), AlphaFold2-derived structural pharmacology, and multi-omics to identify disease-relevant metabolites derived from gut-microbiota with non-olfactory G-protein-coupled receptors (GPCRome). Specifically, we evaluated 1.68 million metabolite-protein pairs connecting 408 human GPCRs and 516 gut metabolites using an Extra Trees algorithm-improved structural pharmacology strategy. Using genetics-derived Mendelian randomization and multi-omics (including transcriptomic and proteomic) analyses, we identified likely causal GPCR targets (C3AR, FPR1, GALR1 and TAS2R60) in Alzheimers disease (AD). Using three-dimensional structural fingerprint analysis of the metabolite-GPCR complexome, we identified over 60% of the allosteric pockets of orphan GPCR models for gut metabolites in the GPCRome, including AD-related orphan GPCRs (GPR27, GPR34, and GPR84). We additionally identified the potential targets (e.g., C3AR) of two AD-related metabolites (3-hydroxybutyric acid and Indole-3-pyruvic acid) and four metabolites from AD-related bacterium Eubacterium rectale, and also showed that tridecylic acid is a candidate ligand for orphan GPR84 in AD. In summary, this study presents a systems pharmacogenomics approach that serves to uncover the GPCR molecular targets of gut microbiota in AD and likely many other human diseases if broadly applied.

systems biology↗

bioRxiv2022

Single-cell network biology characterizes cell-type gene regulation for drug repurposing and phenotype prediction in Alzheimer's disease

Dysregulation of gene expression in Alzheimers disease (AD) remains elusive, especially at the cell type level. Gene regulatory network, a key molecular mechanism linking transcription factors (TFs) and regulatory elements to govern target gene expression, can change across cell types in the human brain and thus serve as a model for studying gene dysregulation in AD. However, it is still challenging to understand how cell type networks work abnormally under AD. To address this, we integrated single-cell multi-omics data and predicted the gene regulatory networks in AD and control for four major cell types, excitatory and inhibitory neurons, microglia and oligodendrocytes. Importantly, we applied network biology approaches to analyze the changes of network characteristics across these cell types, and between AD and control. For instance, many hub TFs target different genes between AD and control (rewiring). Also, these networks show strong hierarchical structures in which top TFs (master regulators) are largely common across cell types, whereas different TFs operate at the middle levels in some cell types (e.g., microglia). The regulatory logics of enriched network motifs (e.g., feed-forward loops) further uncover cell-type-specific TF-TF cooperativities in gene regulation. The cell type networks are highly modular. Several network modules with cell-type-specific expression changes in AD pathology are enriched with AD-risk genes and putative targets of approved and pending AD drugs, suggesting possible cell-type genomic medicine in AD. Finally, using the cell type gene regulatory networks, we developed machine learning models to classify and prioritize additional AD genes. We found that top prioritized genes predict clinical phenotypes (e.g., cognitive impairment). Overall, this single-cell network biology analysis provides a comprehensive map linking genes, regulatory networks, cell types and drug targets and reveals mechanisms on cell-type gene dyregulation in AD.

bioinformatics↗

bioRxiv2021

Genome Assembly and Population Resequencing Reveal the Geographical Divergence of 'Shanmei'(Rubus corchorifolius)

Rubus corchorifolius ( Shanmei or mountain berry, 2n =14) is widely distributed in China, and its fruit has high nutritional and medicinal values. Here, we report a high-quality chromosome-scale genome assembly of Shanmei, with a size of 215.69 Mb and encompassing 26,696 genes. Genome comparisons among Rosaceae species show that Shanmei and Fupenzi (Rubus chingii Hu) are most closely related, and then is blackberry (Rubus occidentalis). Further resequencing of 101 samples of Shanmei collected from four regions in provinces of Yunnan, Hunan, Jiangxi, and Sichuan in South China reveals that the Hunan population of Shanmei possesses the highest diversity and may represent the relatively more ancestral population. Moreover, the Yunnan population undergoes strong selection based on nucleotide diversity, linkage disequilibrium, and the historical effective population size analyses. Furthermore, genes from candidate genomic regions that show strong divergence are significantly enriched in flavonoid biosynthesis and plant hormone signal transduction, indicating the genetic basis of adaptation of Shanmei to the local environments. The high-quality genome sequences and the variome dataset of Shanmei provide valuable resources for breeding applications and for elucidating the genome evolution and ecological adaptation of Rubus species.

genomics↗

bioRxiv2021

A Network-based Deep Learning Framework Catalyzes GWAS and Multi-Omics Findings to Biology and Drug Repurposing for Alzheimer's Disease

Human genome sequencing studies have identified numerous loci associated with complex diseases, including Alzheimers disease (AD). Translating human genetic findings (i.e., genome-wide association studies [GWAS]) to pathobiology and therapeutic discovery, however, remains a major challenge. To address this critical problem, we present a network topology-based deep learning framework to identify disease-associated genes (NETTAG). NETTAG is capable of integrating multigenomics data along with the protein-protein interactome to infer putative risk genes and drug targets impacted by GWAS loci. Specifically, we leverage non-coding GWAS loci effects on expression quantitative trait loci (eQTLs), histone-QTLs, and transcription factor binding-QTLs, enhancers and CpG islands, promoter regions, open chromatin, and promoter flanking regions. The key premises of NETTAG are that the disease risk genes exhibit distinct functional characteristics compared to non-risk genes and therefore can be distinguished by their aggregated genomic features under the human protein interactome. Applying NETTAG to the latest AD GWAS data, we identified 156 putative AD-risk genes (i.e., APOE, BIN1, GSK3B, MARK4, and PICALM). We showed that predicted risk genes are: 1) significantly enriched in AD-related pathobiological pathways, 2) more likely to be differentially expressed regarding transcriptome and proteome of AD brains, and 3) enriched in druggable targets with approved medicines (i.e., choline and ibudilast). In summary, our findings suggest that understanding of human pathobiology and therapeutic development could benefit from a network-based deep learning methodology that utilizes GWAS findings under the multimodal genomic analyses.

bioinformatics↗

bioRxiv2021

Differential effects of intra-modal and cross-modal reward value on visual perception: ERP evidence

Stimuli associated with high reward modulate perception and such value-driven effects have been shown to originate from the modulation of the earliest stages of sensory processing in the brain. In natural environments objects comprise multiple features (imagine a rolling soccer ball, with its black and white patches and the swishing sound made during its motion), where each feature may signal different associations with previously encountered rewards. How perception of such an object is affected by the value associations of its constituent parts is unknown. The present study compares intra- and cross-modal value-driven effects on behavioral and electrophysiological correlates of visual perception. Human participants first learned the reward associations of visual and auditory cues. Subsequently, they performed a visual orientation discrimination task in the presence of previously rewarded visual or auditory cues (intra- and cross-modal cues, respectively) that were concurrently presented with the target stimulus. During the conditioning phase, when reward associations were learned and reward cues were the target of the task, reward value of both modalities enhanced the electrophysiological correlates of sensory processing in visual cortex. During the post-conditioning phase, when reward delivery was halted and previously rewarded stimuli were task-irrelevant, cross-modal value-enhanced behavioral measures of visual sensitivity whereas intra-modal value led to a trend for suppression. A similar pattern of modulations was found in the simultaneously recorded event-related potentials (ERPs) of posterior electrodes. We found an early (90-120 ms) suppression of ERPs evoked by high-value, intra-modal stimuli. Cross-modal cues led to a later value-driven modulation, with an enhancement of response positivity for high-compared to low-value stimuli starting at the N1 window (180-250 ms) and extending to the P3 (300-600 ms) responses of the posterior electrodes. These results indicate that visual cortex is modulated by the reward value of visual as well as auditory cues. Previously rewarded, task-irrelevant cues from the same or different sensory modality have a different effect on visual perception, as intra-modal high-value cues may interfere with the target processing, whereas cross-modal high-value cues boost the perception of the target.

neuroscience↗

bioRxiv2021

Network-based prediction and functional validation of metformin for potential treatment of atrial Fibrillation using human inducible pluripotent stem cell-derived atrial-like cardiomyocytes

Atrial fibrillation (AF) is a significant cause of morbidity and mortality, and effective therapeutic interventions are lacking. Here, we harness an integrative, network medicine approach to repurpose FDA-approved drugs for AF. We hypothesize that the use of an unbiased method for prioritizing AF drugs using patient transcriptomics data can help to identify alternative therapeutic strategies and mechanism-of-action for these drugs. To achieve this, we first characterized the molecular networks specific to AF by incorporating transcriptomic data of left atrial tissue. We quantified the network proximity of genes differentially expressed in AF to drug targets to identify putative drugs for repurposing. We identified nine high-confidence drug candidates that were validated using enrichment analysis of drug-gene signatures in human cell lines. We identified metformin for the potential treatment of AF and validated its use in human inducible pluripotent stem cell-derived atrial-like cardiomyocytes. We identified AF-specific dysregulated networks enriched in cardiac metabolism, ion transport, and immune pathways that were improved following metformin treatment. In summary, this study utilized network-based approaches for rapid identification of drugs that may be repurposed for AF treatment and validated metformin as a candidate drug using a robust human atrial cell model.

systems biology↗

bioRxiv2021

Horizontal mitochondrial transfer from the microenvironment increases glioblastoma tumorigenicity

While dynamic microenvironmental interactions drive tumor growth and therapeutic resistance, the underlying direct cell-cell communication mechanisms remain poorly understood. We identified horizontal mitochondrial transfer as a mechanism that enhances tumorigenesis in glioblastoma. This transfer occurs primarily from brain-resident cells, including astrocytes, and can be appreciated in vitro and in vivo through intercellular connections between GBM cells and non-malignant host cells. The acquisition of astrocyte mitochondria drives an overall enhancement of mitochondrial membrane potential and metabolic capacity, while increasing glioblastoma cell self-renewal and tumor-initiating capacity. Collectively, our findings demonstrate that mitochondrial transfer augments the tumorigenic capacity of glioblastoma cells and reveals a previously unknown cell-cell communication mechanism that drives tumor growth. One-Sentence SummaryMitochondrial transfer from astrocytes to glioblastoma alters metabolic profile and enhances the tumor-initiation capacity.

cancer biology↗