Biology subjects

Jiang, F.

Publications and source records attributed to Jiang, F..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Revealing a Correlation between Structure and in vitro Activity of mRNA Lipid Nanoparticles

mRNA-loaded lipid nanoparticles (mRNA-LNPs) represent a promising platform for disease prevention, cancer immunotherapy, and gene editing, etc. Despite the success of mRNA-LNPs based vaccines, the relationship between their structure and efficacy remains elusive. Here, we generated a series of mRNA-LNPs with varied structural properties and in vitro cellular activities by altering their processing and storage conditions to investigate the structure-activity relationship (SAR). Our findings revealed a moderate anticorrelation between particle size distribution and in vitro activity. Importantly, the intensity of a characteristic peak, as detected by small angle X-ray scattering (SAXS), demonstrated a strong correlation with in vitro activity while the encapsulation efficiency is high. Additionally, the peak width and area were moderately correlated and anticorrelated with activity, respectively. These observations suggest that a more ordered internal structure is likely associated with enhanced in vitro activity of mRNA-LNPs. Further analysis using 31P nuclear magnetic resonance indicated that lyophilization might induce phase separation of mRNA and lipids within the LNPs, leading to a diminished SAXS peak and reduced in vitro activity. Overall, our study establishes an SAR for mRNA-LNPs, highlighting that a more ordered internal structure correlates with higher efficacy, which could be instrumental in high-throughput screening of LNP libraries.

biophysics↗

bioRxiv2024

Localized in vivo prodrug activation using radionuclides

Radionuclides used for imaging and therapy can show high molecular specificity in the body with appropriate targeting ligands. We hypothesized that local energy delivered by molecularly targeted radionuclides could chemically activate prodrugs at disease sites while avoiding activation in off-target sites of toxicity. As proof-of-principle, we tested whether this strategy of "RAdionuclide induced Drug Engagement for Release" (RAiDER) could locally deliver combined radiation and chemotherapy to maximize tumor cytotoxicity while minimizing exposure to activated chemotherapy in off-target sites. MethodsWe screened the ability of radionuclides to chemically activate a model radiation-activated prodrug consisting of the microtubule destabilizing monomethyl auristatin E caged by a radiation-responsive phenyl azide ("caged-MMAE") and interpreted experimental results using the radiobiology computational simulation suite TOPAS-nBio. RAiDER was evaluated in syngeneic mouse models of cancer using fibroblast activation protein inhibitor (FAPI) agents 99mTc-FAPI-34 and 177Lu-FAPI-04, the prostate-specific membrane antigen (PSMA) agent 177Lu-PSMA-617, combined with caged-MMAE or caged-exatecan. Biodistribution in mice, combined with clinical dosimetry, estimated the relationship between radiopharmaceutical uptake in patients and anticipated concentrations of activated prodrug using RAiDER. ResultsRAiDER efficiency varied by 250-fold across radionuclides (99mTc>177Lu>64Cu>68Ga>223Ra>18F), yielding up to 1.22{micro}M prodrug activation per Gy of exposure from 99mTc. Computational simulations implicated low-energy electron-mediated free radical formation as driving prodrug activation. Clinically relevant radionuclide concentrations chemically activated caged-MMAE restored its ability to destabilize microtubules and increased its cytotoxicity by up to 600-fold compared to non-irradiated prodrug. Mice treated with 99mTc-FAPI-34 and caged-MMAE accumulated up to 3000x greater concentrations of activated MMAE in tumors compared to other tissues. RAiDER with 99mTc-FAPI-34 or 177Lu-FAPI-04 delayed tumor growth, while monotherapies did not (P<0.03). Clinically-guided dosimetry suggests sufficient radiation doses can be delivered to activate therapeutically meaningful levels of prodrug. ConclusionThis proof-of-concept study shows that RAiDER is compatible with multiple radionuclides commonly used in nuclear medicine and has the potential to improve the efficacy of radiopharmaceutical therapies to treat cancer safely. RAiDER thus shows promise as an effective strategy to treat disseminated malignancies and broadens the capability of radiopharmaceuticals to trigger diverse biological and therapeutic responses. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/606075v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@18aef37org.highwire.dtl.DTLVardef@5f36eforg.highwire.dtl.DTLVardef@10fa0ccorg.highwire.dtl.DTLVardef@105c416_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

Comprehensive profiling of transcriptional regulation in cartilage reveals pathogenesis of osteoarthritis

Cartilage damage is a leading cause of osteoarthritis (OA) etiology, however, the underlying mechanism governing gene expression regulation in this progress is poorly understood. Here, we described a comprehensive profiling of transcriptional regulation of 235 primary human cartilage samples. We identified 3,352 independent significant expression quantitative trait loci (eQTLs) for 3,109 genes. We explored the candidate casual SNP and its underlying regulatory mechanism using our established functional fine-mapping pipeline by integrating the cartilage-specific ATAC-seq data. We identified 117 causal eQTLs that display allele-specific open chromatin (ASoC) and 547 transcription factor binding-disruption (TBD) eQTLs. We conducted cell type-interaction eQTL (ci-eQTL) analyses based on speculated chondrocyte subtype proportions and revealed the regulation relationship of 120 eQTL-gene pairs showed cell type dependency. Further, by integrating with genome-wide association studies (GWASs) data of OA, we nominated 43 candidate effector genes for OA risk loci. We verified that the T allele of the OA risk variant rs11750646 increased the AR binding affinity to an open chromatin region and promoted the expression of an OA-related gene PIK3R1. Altogether, our findings provide new insights into the unique regulatory landscape of cartilage and elucidate potential mechanisms underlying the OA pathogenesis.

genetics↗

bioRxiv2024

Proteome analysis provides insights into sex differences in Holothuria Scabra

Sex-determining mechanism is still ambiguous for sea cucumber Holothuria scabra which only manifests gonochorism in gonad. In this study, proteomic analysis was employed to delineate sex-related proteins and genes in gonads of H. scabra, subsequently validated through Quantitative real-time polymerase chain reaction (qRT-PCR). A total of 5,313 proteins were identified via proteome sequencing. Among these, 817 proteins exhibited expression in both the ovary and testis, with 445 proteins displaying up-regulation and 372 proteins showing down-regulation. Furthermore, 136 and 69 proteins were identified as ovary-specific and testis-specific Differentially Abundant Proteins (DAPs), respectively. For the validation of 75 DAP coding genes, 9 genes were considered to be reliable. Notably, 25 ovary-bias proteins enriched in ribosome pathway strongly indicated the crucial role of ribosome in ovary. And 5S/18S rRNA ratio in H. Scabra may have potencial to establish a nondestructive method to distinguish sexes unambiguously. This study serves to furnish novel evidence pertaining to sex differences in H. scabra.

molecular biology↗

bioRxiv2024

Single-cell multiomics reveals a gene regulatory circuit promoting leukemia cell differentiation

Cancer differentiation therapy aims to induce maturation of neoplastic cells, yet how cell fate is determined in oncogenic cellular contexts is poorly understood. Here we integrate chromatin accessibility and transcriptome analysis at single-cell levels to investigate the mechanism driving the differentiation trajectory of the PML/RAR+ acute promyeloid leukemia (APL) cell line model, NB4, under the induction of all-trans-retinoid acid (ATRA). We show that differentiating NB4 cells navigate through an intermediate cell fate decision point that leads to either terminal granulopoiesis or a transient immature-lymphocyte-like state. Functional perturbation studies indicate that ATRA signaling activates discrete PML/RAR-target enhancers to induce a positive feedforward gene regulatory circuit involving two myeloid-lineage transcription factors, SPI1 and CEBPE, which is both necessary and sufficient to activate a myelocytic gene expression program in NB4. Further, ectopic expression of SPI1 and CEBPE also promotes myelocytic differentiation in non-APL leukemia cell lines HL60 and K562. Together, these results shed light on the differentiation trajectory of therapy-induced cell decisions of APL and suggest a gene regulatory circuit that may be broadly exploited to promote terminal differentiation of leukemia.

cancer biology↗

bioRxiv2024

CACIMAR: Cross-species Analysis of Cell Identities, Markers, Regulations and Interactions Using Single-cell RNA Sequencing Data

Transcriptomic analysis across species is increasingly used to reveal conserved gene regulations which implicate crucial regulators. Cross-species analysis of single-cell RNA sequencing (scRNA-seq) data provides new opportunities to identify the cellular and molecular conservations especially for cell types and cell type-specific gene regulations. However, few methods have been developed to analyze cross-species scRNA-seq data to uncover both molecular and cellular conservation patterns. Here, we built a tool called CACIMAR, which can perform cross-species analysis of cell identities, markers, regulations and interactions using scRNA-seq profiles. Based on the weighted sum models of the conserved features, we developed different conservation scores to measure the conservation of cell types, regulatory networks and intercellular interactions. Using publicly available scRNA-seq data on retinal regeneration in mice and zebrafish, we demonstrated four main functions of CACIMAR. First, CACIMAR allows to identify evolutionarily conserved cell types, including poorly conserved cell types. Second, the tool facilitates the identification of evolutionarily conserved or species-specific marker genes. Third, CACIMAR enables the identification of conserved intracellular regulations, including cell type-specific regulatory subnetworks and regulators. Lastly, CACIMAR provides a unique feature on the identification of conserved intercellular interactions. Overall, CACIMAR facilitates the identification of evolutionarily conserved cell types, marker genes, intracellular regulations and intercellular interactions, providing insights on the cellular and molecular mechanisms of species evolution.

bioinformatics↗

bioRxiv2024

Identification of a distinct cluster of GDF15high macrophages exhibiting anti-inflammatory activities

Macrophage-mediated inflammatory response may have crucial roles in the pathogenesis of a variety of human diseases. Growth differentiation factor 15 (GDF15) is a cytokine of the transforming growth factor-{beta} superfamily, with potential anti-inflammatory activities. Previous studies observed in human lungs some macrophages which expressed a high level of GDF15. In the present study, we employed multiple techniques, including immunofluorescence, flow cytometry, and single-cell RNA sequencing, in order to further clarify the identity of such GDF15high macrophages. We demonstrated that macrophages derived from human peripheral blood mononuclear cells and rat bone marrow mononuclear cells by in vitro differentiation with granulocyte-macrophage colony stimulating factor contained a minor population ([~]1%) of GDF15high cells. GDF15high macrophages did not exhibit a typical M1 or M2 phenotype, but had a unique molecular signature as revealed by single-cell RNA sequencing. Functionally, GDF15high macrophages were associated with reduced responsiveness to pro-inflammatory activation; furthermore, GDF15high macrophages could inhibit the pro-inflammatory functions of other macrophages via a paracrine mechanism. We further confirmed that GDF15 per se was a key mediator of the anti-inflammatory effects of GDF15high macrophage. Also, we provided direct evidence showing that GDF15high macrophages were also present in other macrophage-residing human tissues in addition to the lungs. Our results suggest that the GDF15high macrophage may represent a distinct cluster of macrophage cells with intrinsic anti-inflammatory functions. The (patho)physiological importance of these cells in vivo warrants further investigation.

immunology↗

bioRxiv2023

Systematic comparison of sequencing-based spatial transcriptomic methods

Recent advancements of sequencing-based spatial transcriptomics (sST) have catalyzed significant advancements by facilitating transcriptome-scale spatial gene expression measurement. Despite this progress, efforts to comprehensively benchmark different platforms are currently lacking. The extant variability across technologies and datasets poses challenges in formulating standardized evaluation metrics. In this study, we established a collection of reference tissues and regions characterized by well-defined histological architectures, and used them to generate data to compare six sST methods. We highlighted molecular diffusion as a variable parameter across different methods and tissues, significantly impacting the effective resolutions. Furthermore, we observed that spatial transcriptomic data demonstrate unique attributes beyond merely adding a spatial axis to single-cell data, including an enhanced ability to capture patterned rare cell states along with specific markers, albeit being influenced by multiple factors including sequencing depth and resolution. Our study assists biologists in sST platform selection, and helps foster a consensus on evaluation standards and establish a framework for future benchmarking efforts that can be used as a gold standard for the development and benchmarking of computational tools for spatial transcriptomic analysis.

genomics↗

bioRxiv2023

Targeted Deletion of All Known Thyroid Hormone Receptors Causes Maturation Retardation and Early-onset Degeneration of Cochlear Outer Sulcus

Thyroid hormone (TH) and its receptors (TRs) are crucial for cochlear late-stage development and endocochlear potential (EP) maintenance. However, the mechanism underlying EP reduction in the absence of TH or TRs remains elusive. Cochlear outer sulcus root cells undergo significant morphological changes during late-stage cochlear development and are believed to play a role in maintaining endolymph homeostasis and EP. Yet, it is unknown whether TH and/or TRs are necessary for root cell differentiation and function. Here, we elucidate the essential role of TH or TRs in postnatal root cell development and survival in mice. TH deficiency significantly delayed root cell differentiation. Otocyst-selective deletion of both Thra and Thrb, but not Thrb alone, leads to a similar impairment, accompanied by early degeneration of root cells, with the stria vascularis remaining unaffected. Furthermore, a 22% reduction in mean EP magnitudes was observed in conditional TRs double knockout mice at 4 months of age, less pronounced than in global TRs knockout mice. Transcriptome analysis reveals that TH deficiency downregulates a significant portion of root cell-enriched genes. These findings underscore the redundant roles of TR and TR{beta} in promoting the late-stage differentiation and survival of root cells. Additionally, they suggest that the expression of TRs in cochlear epithelium is crucial for maintaining an optimal EP magnitude, while TRs expressed in areas outside cochlear epithelium, particularly in spiral ligament fibrocytes, may also significantly contribute to EP maintenance. This study advances our understanding of TH in cochlear outer sulcus development and EP maintenance.

developmental biology↗

bioRxiv2023

PCMD: A Multilevel Comparison Database of Intra- and Cross-species Metabolic Profiling in 530 Plant Species

Comparative metabolomics plays a crucial role in understanding gene function, exploring metabolite evolution, and improving crop genetic breeding. However, a systematic platform for comparing intra- and cross-species metabolites is currently lacking. In this study, we present the plant comparative metabolome database (PCMD; http://yanglab.hzau.edu.cn/PCMD), a comprehensive multi-level comparison database encompassing intra- and cross-species metabolic profiling in 530 plants. Remarkably, PCMD offers a multi-level platform for comparative metabolite analysis, allowing for the examination of metabolite characteristics across species at various levels including species, metabolites, pathways, and biological taxonomy. In addition, PCMD standardizes metabolite numbering, establishing a uniform system based on existing metabolite-related databases. The database also provides a range of user-friendly online tools, such as Species-comparison, Metabolites-enrichment, and ID conversion, enabling users to perform comparisons and enrichment analyses of metabolites across different species. PCMD stands out as the most comprehensive and species-rich comparative plant metabolomics database currently available, as demonstrated by two case studies that highlight its ability to supplement phylogenetic similarity mining among species through phylogenetic trees and offer new insights into the diversity and species-specificity of metabolites.

bioinformatics↗

bioRxiv2023

De novo generation of T-cell receptors with desired epitope-binding property by leveraging a pre-trained large language model

Generating T-cell receptors (TCRs) with desired epitope-binding properties is a fundamental step in the development of immunotherapies, yet heavily relies on laborious and expensive wet experiments. Recent advancements in generative artificial intelligence have demonstrated promising power in protein design and engineering. In this regard, we propose a large language model, termed Epitope-Receptor-Transformer (ERTransformer), for the de novo generation of TCRs with the desired epitope-binding property. ERTransformer is built on EpitopeBERT and ReceptorBERT, which are trained using 1.9 million epitope sequences and 33.1 million TCR sequences, respectively. To demonstrate the model capability, we generate 1000 TCRs for each of the five epitopes with known natural TCRs. The artificial TCRs exhibit low sequence identity (average Bit-score 27.64 with a standard deviation of 1.50) but high biological function similarity (average BLOSUM62 score 32.32 with a standard deviation of 12.01) to natural TCRs. Furthermore, the artificial TCRs are not very structurally identical to natural ones (average RMSD 2.84 [A] with a standard deviation of 1.21 [A]) but exhibit a comparable binding affinity towards the corresponding epitopes. Our work highlights the tremendous potential of applying ERTransformer to generate novel TCRs with desired epitope-binding ability.

bioinformatics↗

bioRxiv2023

Folding correctors can restore CFTR posttranslational folding landscape by allosteric domain-domain coupling

AbstractThe folding/misfolding and pharmacological rescue of multidomain ATP-binding cassette (ABC) C-subfamily transporters, essential for organismal health, remain incompletely understood. The ABCC transporters core consists of two nucleotide binding domains (NBD1,2) and transmembrane domains (TMD1,2). Using molecular dynamic simulations, biochemical and hydrogen deuterium exchange approaches, we show that the mutational uncoupling or stabilization of NBD1-TMD1/2 interfaces can compromise or facilitate the CFTR(ABCC7)-, MRP1(ABCC1)-, and ABCC6-transporters posttranslational coupled domain-folding in the endoplasmic reticulum. Allosteric or orthosteric binding of VX-809 and/or VX-445 folding correctors to TMD1/2 can rescue kinetically trapped CFTR post-translational folding intermediates of cystic fibrosis (CF) mutants of NBD1 or TMD1 by global rewiring inter-domain allosteric-networks. We propose that dynamic allosteric domain-domain communications not only regulate ABCC-transporters function but are indispensable to tune the folding landscape of their post-translational intermediates. These allosteric networks can be compromised by CF-mutations, and reinstated by correctors, offering a framework for mechanistic understanding of ABCC-transporters (mis)folding. One-Sentence SummaryAllosteric interdomain communication and its modulation are critical determinants of ABCC-transporters post-translational conformational biogenesis, misfolding, and pharmacological rescue.

biophysics↗

bioRxiv2023

A chromosome-level reference genome of a Fabaceae species yam bean (Pachyrhizus erosus)

Yam bean (Pachyrhizus erosus L.), belonging to the family Fabaceae, is an important but underutilized root crop. Here, we generated a high-quality chromosome-level reference genome of yam bean by PacBio HiFi and Hi-C sequencing, with assembly size of 539.0 Mb, contig N50 of 25.6 Mb, and BUSCO complete rate of 99.3%. Then, we anchored 94.4% of the contig sequences into 11 pseudo-chromosomes, and assembled the telomeres at 86.4% (19/22) of the chromosome-ends. A total of 44,692 protein-coding genes were predicted, with the BUSCO complete rate of 99.3%, comparable to that of the genome assembly. Compared to the previously reported yam bean genome, the current assembly has a 1,388-fold increase in contig N50 size, and 12.2% and 24.3% increase in BUSCO complete rate for the genome sequence and gene set, respectively. Evolutionary analysis revealed that yam bean diverged from the clade of soybean and Pueraria lobata var. montana 22.5 MYA. This high-quality genome assembly will greatly facilitate the breeding of yam bean based on the genetic and genomic methods.

genomics↗

bioRxiv2023

Cardiomyocyte-specific Loss of Glutamyl-prolyl-tRNA Synthetase Leads to Disturbed Protein Homeostasis and Dilated Cardiomyopathy

Glutamyl-prolyl-tRNA synthetase (EPRS1), an aminoacyl-tRNA synthetase (ARS) ligating glutamic acid and proline to their corresponding tRNAs, plays an essential role in decoding proline codons during translation elongation. The physiological function of EPRS1 in cardiomyocytes (CMs) and the potential effects of CM-specific loss of EPRS1 remain unknown. Here, we found that heterozygous Eprs1 knockout in CMs does not cause any significant changes in CM hypertrophy induced by pressure overload, while homozygous knockout leads to dilated cardiomyopathy, heart failure, and lethality at around 1 month after Eprs1 deletion. Transcriptomic profiling of early-stage Eprs1 knockout hearts suggests a significantly decreased expression of multiple ion channel genes and an increased gene expression in proapoptotic pathways and integrated stress response. Proteomic analysis shows decreased protein expression of multi-aminoacyl-tRNA synthetase complex components, fatty acid, and branched-chain amino acid metabolic enzymes, as well as a compensatory increase in cytosolic translation machine-related proteins. Immunoblot analysis indicated that multiple proline-rich proteins were reduced at the early stage, which might contribute to cardiac dysfunction of Eprs1 knockout mice. Taken together, this study demonstrates the physiological and molecular outcome of loss-of-function of EPRS1 in vivo and provides valuable insights into the potential side effects on CMs resulting from the EPRS1-targeting therapeutic approach.

pathology↗

bioRxiv2023

Improved chromosome-level genome assembly for marigold (Tagetes erecta)

Marigold (Tagetes erecta L.) is a popular ornamental plant of the Asteraceae family, and its petals are considered the most abundant source of lutein. A low-continuity chromosome-level genome sequence of marigold was published recently, with poor annotation of the protein-coding genes, which hinders the studies of lutein biosynthesis. Here, we generated a near telomere-to-telomere level genome assembly of marigold based on highly accurate high-fidelity (HiFi) long reads and Hi-C sequencing data. Compared to the previously reported marigold genome, the current assembly had obviously higher contiguity and higher completeness of gene set. The current genome assembly has a 27-fold increase in contig N50 size, a 12.1% increase in chromosome anchoring rate, and a 9.0% increase in BUSCO complete rate for the gene set. Besides, the current assembly has much fewer assembly errors. Based on this high-quality genome assembly, we found that the 170-bp repeats are the most abundant centromeric unit and all centromeric regions are distributed along the whole chromosomes for all 12 centromeres, indicating the existence of the holocentromeres in marigold. In addition, we analyzed the structure and phylogenetic relationship of the four PSY genes, and revealed that these genes have diversified and possibly executed different functions in various tissues. Our near telomere-to-telomere level genome assembly and comprehensive gene annotation will greatly facilitate the breeding of marigold and researches aimed at improving lutein production.

genomics↗

bioRxiv2023

Mn2+-Induced Structural Flexibility Enhances the Entire Catalytic Cycle and the Cleavage of Mismatches in Prokaryotic Argonaute Proteins

Prokaryotic Argonaute (pAgo) proteins, a class of DNA/RNA-guided programmable endonucleases, have been extensively utilized in nucleic acid biosensors. The specific binding and cleavage of nucleic acids by pAgo proteins, which are crucial processes for their applications, are dependent on the presence of Mn2+ bound in the pockets, as verified through X-ray crystallography. However, a comprehensive understanding of how dissociated Mn2+ in the solvent affects the catalytic cycle, and its underlying regulatory role in this structure-function relationship, remains underdetermined. By combining experimental and computational methods, this study reveals that unbound Mn2+ in solution enhances the flexibility of diverse pAgo proteins. This increase in flexibility through decreasing the number of hydrogen bonds, induced by Mn2+, leads to higher affinity for substrates, thus facilitating cleavage. More importantly, Mn2+-induced structural flexibility increases the mismatch tolerance between guide-target pairs by increasing the conformational states, thereby enhancing the cleavage of mismatches. Further simulations indicated that the enhanced flexibility in linkers triggers conformational changes in the PAZ domain for recognizing various lengths of nucleic acids. Additionally, Mn2+-induced dynamic alterations of the protein cause a conformational shift in the N domain and catalytic sites towards their functional form, resulting in a decreased energy penalty for target release and cleavage. These findings demonstrate that the dynamic conformations of pAgo proteins, resulting from the presence of the unbound Mn2+ in solution, significantly promote the catalytic cycle of endonucleases and the tolerance of cleavage to mismatches. This flexibility enhancement mechanism serves as a general strategy employed by Ago proteins from diverse prokaryotes to accomplish their catalytic functions and provide useful information for Ago-based precise molecular diagnostics.

biophysics↗

bioRxiv2023

Secondary structures that regulate mRNA translation provide insights for ASO-mediated modulation of cardiac hypertrophy

Translation of upstream open reading frames (uORFs) typically abrogates translation of main (m)ORFs. The molecular mechanism of uORF regulation in cells is not well understood. Here, we identified a double-stranded RNA (dsRNA) structure residing within the GATA4 uORF that augments uORF translation and inhibits mORF translation. Antisense oligonucleotides (ASOs) that disrupt this dsRNA structure promote mORF translation, while ASOs that base-pair immediately downstream (i.e., forming a bimolecular double-stranded region) of either the uORF or mORF start codon enhance uORF or mORF translation, respectively. Human cardiomyocytes and mice treated with a uORF-enhancing ASO showed reduced cardiac GATA4 protein levels and increased resistance to cardiomyocyte hypertrophy. We further show the general utility of uORF-dsRNA- or mORF- targeting ASO to regulate mORF translation for other mRNAs. Our work demonstrates a regulatory paradigm that controls translational efficiency and a useful strategy to alter protein expression and cellular phenotypes by targeting or generating dsRNA downstream of a uORF or mORF start codon. Bullet points for discoveriesO_LIdsRNA within GATA4 uORF activates uORF translation and inhibits mORF translation. C_LIO_LIASOs that target the dsRNA can either inhibit or enhance GATA4 mORF translation. C_LIO_LIASOs can be used to impede hypertrophy in human cardiomyocytes and mouse hearts. C_LIO_LIuORF- and mORF-targeting ASOs can be used to control translation of multiple mRNAs. C_LI

molecular biology↗

bioRxiv2023

Bayesian Inference of a Spectral Graph Model for Brain Oscillations

The relationship between brain functional connectivity and structural connectivity has caught extensive attention of the neuroscience community, commonly inferred using mathematical modeling. Among many modeling approaches, spectral graph model (SGM) is distinctive as it has a closed-form solution of the wide-band frequency spectra of brain oscillations, requiring only global biophysically interpretable parameters. While SGM is parsimonious in parameters, the determination of SGM parameters is non-trivial. Prior works on SGM determine the parameters through a computational intensive annealing algorithm, which only provides a point estimate with no confidence intervals for parameter estimates. To fill this gap, we incorporate the simulation-based inference (SBI) algorithm and develop a Bayesian procedure for inferring the posterior distribution of the SGM parameters. Furthermore, using SBI dramatically reduces the computational burden for inferring the SGM parameters. We evaluate the proposed SBI-SGM framework on the resting-state magnetoencephalography recordings from healthy subjects and show that the proposed procedure has similar performance to the annealing algorithm in recovering power spectra and the spatial distribution of the alpha frequency band. In addition, we also analyze the correlations among the parameters and their uncertainty with the posterior distribution which can not be done with annealing inference. These analyses provide a richer understanding of the interactions among biophysical parameters of the SGM. In general, the use of simulation-based Bayesian inference enables robust and efficient computations of generative model parameter uncertainties and may pave the way for the use of generative models in clinical translation applications.

neuroscience↗