Biology subjects

Liu, Y.

Publications and source records attributed to Liu, Y..

At least 1,207 records · Page 67Linked to original sources

bioRxiv2024

GeoAB: Towards Realistic Antibody Design and Reliable Affinity Maturation

Increasing works for antibody design are emerging to generate sequences and structures in Complementarity Determining Regions (CDRs), but problems still exist. We focus on two of them: (i) authenticity of the generated structure and (ii) rationality of the affinity maturation, and propose GEOAB as a solution. In specific, GeoABDesigner generates CDR structures with realistic internal geometries, composed of a generative geometry initializer (Geo-Initializer) and a position refiner (Geo-Refiner); GeoAB-Optimizer achieves affinity maturation by accurately predicting both the mutation effects and structures of mutant antibodies with the same network architecture as Geo-Refiner. Experiments show that GEOAB achieves state-of-the-art performance in CDR co-design and mutation effect predictions, and fulfills the discussed tasks effectively.

bioinformatics↗

bioRxiv2024

Phase synchrony between prefrontal noradrenergic and cholinergic signals indexes inhibitory control

Inhibitory control is a critical executive function that allows animals to suppress their impulsive behavior in order to achieve certain goals or avoid punishment. We investigated norepinephrine (NE) and acetylcholine (ACh) dynamics and population neuronal activity in the prefrontal cortex (PFC) during inhibitory control. Using fluorescent sensors to measure extracellular levels of NE and ACh, we simultaneously recorded prefrontal NE and ACh dynamics in mice performing inhibitory control tasks. The prefrontal NE and ACh signals exhibited strong coherence at 0.4-0.8 Hz. Although inhibition of locus coeruleus (LC) neurons projecting to the PFC impaired inhibitory control, inhibiting LC neurons projecting to the basal forebrain (BF) caused a more profound impairment, despite an approximately 30% overlap between LC neurons projecting to the PFC and BF, as revealed by our tracing studies. The inhibition of LC neurons projecting to the BF did not diminish the difference in prefrontal NE/ACh signals between successful and failed trials; instead, it abolished the difference in NE-ACh phase synchrony between successful and failed trials, indicating that NE-ACh phase synchrony is a task-relevant neuromodulatory feature. Chemogenetic inhibition of cholinergic neurons that project to the LC region did not impair inhibitory control, nor did it abolish the difference in NE-ACh phase synchrony between successful or failed trials, further confirming the relevance of NE-ACh phase synchrony to inhibitory control. To understand the possible effect of NE-ACh synchrony on prefrontal population activity, we employed Neuropixels to record from the PFC during inhibitory control. The inhibition of LC neurons projecting to the BF not only reduced the number of prefrontal neurons encoding inhibitory control, but also disrupted population firing patterns representing inhibitory control, as revealed by a demixed principal component (dPCA) analysis. Taken together, these findings suggest that the LC modulates inhibitory control through its collective effect with cholinergic systems on population activity in the prefrontal cortex. Our results further indicate that NE-ACh phase synchrony is a critical neuromodulatory feature with important implications for cognitive control.

neuroscience↗

bioRxiv2024

Recognition of RNA secondary structures with a programmable peptide nucleic acid-based platform

RNA secondary structures comprise double-stranded (ds) and single-stranded (ss) regions. Antisense peptide nucleic acids (asPNAs) enable the targeting of ssRNAs and weakly formed dsRNAs. Nucleobase-modified dsRNA-binding PNAs (dbPNAs) allow for targeting of relatively stable dsRNAs. A programmable RNA structure-specific targeting strategy is needed for simultaneous recognition of dsRNAs and ssRNAs. Here, we report on combining dbPNAs and asPNAs (designated as daPNAs) for the targeting of dsRNA-ssRNA junctions. Our binding and modeling data suggest that combining traditional asPNA (with a 4-letter code: T, C, A, and G) and dbPNA (with a 4-letter code: T or s2U, L, Q, and E) scaffolds facilitates RNA structure-specific tight binding (nM to M) under physiologically-relevant conditions. We further applied our daPNAs in substrate specific inhibition of Dicer acting on pre-miR-198 in a cell-free assay and regulating ribosomal frameshifting induced by model hairpins in both cell-free and cell culture assays. daPNAs would be a useful platform for developing chemical probes and therapeutic ligands targeting RNA. HighlightO_LIWe demonstrated that sequence- and structure-specific targeting of RNA can be facilitated by nucleobase-modified dsRNA-binding PNAs (dbPNAs) platform in combination with antisense PNAs (asPNAs). We name the novel PNAs as daPNAs. C_LIO_LIdaPNAs can be used in a programmable way for targeting RNAs by formation of a short triplex next to a short duplex at a dsRNA-ssRNA junction. C_LIO_LIWe applied our daPNAs in substrate specific inhibition of Dicer acting on pre-miR-198 in a cell-free assay and regulating ribosomal frameshifting induced by model hairpins in both cell-free and cell culture assays. C_LIO_LIThe daPNAs platform would serve as useful junction-specific molecular glues for the targeting of many biologically important RNA structures in transcriptomes. C_LI

biochemistry↗

bioRxiv2024

Specialized Pericyte Subtypes in the Pulmonary Capillary

Pericytes (PCs) play crucial roles in capillary maturation, stability, and homeostasis. Impaired PC coverage and function are implicated in various diseases, including pulmonary arterial hypertension (PAH). Challenges investigating PC biology are largely due to the lack of a concise marker, resulting in difficulty distinguishing PCs from other mural cell populations, including smooth muscle cells (SMCs) and fibroblasts (FBs). Utilizing bioinformatic analysis and RNAscope, we identified HIG hypoxia-inducible domain family member 1B (Higd1b) as a unique and conserved gene marker for PCs and generated a novel knockin mouse line, Higd1b-CreERT2, which precisely labels PCs in the lung and heart. Human lung single-cell RNAseq suggested the presence of two HIGD1B+ PC subtypes with different functions. By lineage tracing pulmonary Higd1b+ cells exposed to hypoxia in vivo, we identified Type 1 PCs remained in the capillary network, while Type 2 PCs accumulated in the arterioles and coexpressed SMC markers and increased levels of Vimentin, associated with focal adhesion pathways. These results suggest that Type 1 PCs are specialized for supporting capillary EC homeostasis and quiescent, while Type 2 PCs are lineage active and located close to the border zone of the arterioles and capillaries, which may be motile and transition to SMC-like cells in hypoxia-induced pulmonary hypertension. The discovery of PC-type specialization in capillaries transforms our understanding of the structure, function and regulation of pulmonary capillary circulation and their contribution to vascular remodeling.

cell biology↗

bioRxiv2024

Construction of a breast cancer predictive nomogram based on diverse cell death methods and reveal tumor microenvironment characterization

ObjectiveTo develop a robust predictive model and nomogram for breast cancer (BC) linked to genes associated with diverse cell death methods. MethodsThe prognostic model was constructed using the LASSO Cox method. Model performance was assessed using K-M analysis, ROC curves, and independent prognostic analysis. Subsequently, we constructed a nomogram and analyzed differences in tumor microenvironment and drug sensitivity between different subgroups. The enrichment of differentially expressed genes between different subgroups was assessed. Additionally, we overexpressed CD24 in BC cell lines to assess its impact on cellular proliferation using CCK8 assays, migration through scratch and transwell assays, and apoptosis via flow cytometry. ResultsA prognostic model comprising twelve genes (CREB3L1, SFRP1, SHARPIN, AIFM1, IL-18, CD24, EDA2R, CRIP1, XBP1, BCL2A1, NKX3-1, and NME5) was constructed. BC patients were categorized into different subgroups, with the low-risk subgroup demonstrating superior survival. Additionally, we constructed a nomogram. The nomogram was validated as a reliable independent predictor of outcome. The enrichment analyses imply a connection between patient risk and immune response. The low-risk subgroup had a higher TME score. Patients in the high-risk group had improved responses to lapatinib, BI-2536, OSI-027, and SB505124, while those in the low-risk subgroup showed improved sensitivity to axitinib, epirubicin, fulvestrant, and olaparib. Furthermore, CD24 overexpression was found to promote proliferation and migration, while inhibiting apoptosis. ConclusionThese findings contribute to the individualization of treatment and aid in uncovering the tumor microenvironment characterization for BC patients.

cancer biology↗

bioRxiv2024

LucaOne: Generalized Biological Foundation Model with Unified Nucleic Acid and Protein Language

AbstractThe language of biology, encoded in DNA, RNA, and proteins, forms the foundation of life but remains challenging to decode due to its complexity. Traditional computational methods often struggle to integrate information across these molecules, limiting a comprehensive understanding of biological systems. Advances in Natural Language Processing (NLP) with pre-trained models offer new possibilities for interpreting biological language. Here, we introduce LucaOne, a pre-trained foundation model trained on nucleic acid and protein sequences from 169,861 species. Through large-scale data integration and semisupervised learning, LucaOne demonstrates an understanding of key biological principles, such as DNA-Protein translation. Using few-shot learning, it effectively comprehends the central dogma of molecular biology and performs competitively on tasks involving DNA, RNA, or protein inputs. Our results highlight the potential of unified foundation models to address complex biological questions, providing an adaptable framework for bioinformatics research and enhancing the interpretation of lifes complexity.

bioinformatics↗

bioRxiv2024

Multiple Unfolded Protein Response pathways cooperate to link cytosolic dsDNA release to Stimulator of Interferon Gene (STING) activation

The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to "sterile" endogenous threats and pathogens without nominal DNA or cyclic di-nucleotide stimuli. Previous work showed an endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR), activates STING. Herein, we sought to determine if ER stress generated a STING ligand, and to identify the UPR pathways involved. Induction of IFN-{beta} expression following stimulation with the UPR inducer thapsigargin (TPG) or oxygen glucose deprivation required both STING and the dsDNA-sensing cyclic GMP-AMP synthase (cGAS). Furthermore, TPG increased cytosolic mitochondrial DNA, and immunofluorescence visualized dsDNA punctae in murine and human cells, providing a cGAS stimulus. N-acetylcysteine decreased IFN-{beta} induction by TPG, implicating reactive oxygen species (ROS). However, mitoTEMPO, a mitochondrial oxidative stress inhibitor did not impact TPG-induced IFN. On the other hand, inhibiting the inositol requiring enzyme 1 (IRE1) ER stress sensor and its target transcription factor XBP1 decreased the generation of cytosolic dsDNA. iNOS upregulation was XBP1-dependent, and an iNOS inhibitor decreased cytosolic dsDNA and IFN-{beta}, implicating ROS downstream of the IRE1-XBP1 pathway. Inhibition of the PKR-like ER kinase (PERK) pathway also attenuated cytoplasmic dsDNA release. The PERK-regulated apoptotic factor Bim was required for both dsDNA release and IFN-{beta} mRNA induction. Finally, XBP1 and PERK pathways contributed to cytosolic dsDNA release and IFN-induction by the RNA virus, Vesicular Stomatitis Virus (VSV). Together, our findings suggest that ER stressors, including viral pathogens without nominal STING or cGAS ligands such as RNA viruses, trigger multiple canonical UPR pathways that cooperate to activate STING and downstream IFN-{beta} via mitochondrial dsDNA release.

immunology↗

bioRxiv2024

Opto-chemogenetic inhibition of L-type CaV1 channels in neurons through a membrane-assisted molecular linkage

Acute, specific, and robust inhibition of L-type Ca2+ (CaV1) channels has been sought after for both research and therapeutic applications. Compared to other available CaV1 antagonists, genetically-encoded modulators, such as CMI (C-terminus mediated inhibition) peptides encoded by CaV1 DCT (distal C-terminus), hold great potentials due to its affirmative mechanisms of action on both gating and signaling. Here, we find that membrane-anchoring with a Ras tag could essentially help form a type of intramolecular-equivalent linkage, by which the tag anchored-peptide appears to dimerize with another protein or peptide on the membrane, supported by the evidence from patch-clamp electrophysiology and FRET imaging. We then design and implement the constitutive and inducible CMI modules, with appropriate dynamic ranges targeting the short and long variants of CaV1.3, both naturally occurring in neurons. Upon optical (infrared-responsive nanoparticles) and/or chemical (rapamycin) induction of FRB/FKBP binding, DCT peptides with no CMI in the cytosol acutely translocate onto the membrane via FRB-Ras, where the physical linkage requirement could be fulfilled. The peptides robustly produce acute and potent inhibitions on both recombinant CaV1.3 channels and neuronal CaV1 activities, and thus the Ca2+ influx-neuritogenesis coupling. Validated through opto-chemogenetic induction, this prototype demonstrates channel modulation via membrane-assisted molecular linkage, promising broad applicability to diverse membrane proteins.

bioengineering↗

bioRxiv2024

Compositional Shifts and Co-occurrence Patterns of Topsoil Bacteria and Micro-Eukaryotes Across a Permafrost Thaw Gradient in Alpine Meadows of the Qilian Mountains, China

Soil microorganisms play a pivotal role in the biogeochemical cycles of alpine meadow ecosystems, especially in the context of permafrost thaw. However, the mechanisms driving microbial community responses to environmental changes, such as variations in active layer thickness (ALT) of permafrost, remain poorly understood. This study utilized next-generation sequencing to explore the composition and co-occurrence patterns of soil microbial communities, focusing on bacteria and micro-eukaryotes along a permafrost thaw gradient. Results showed a decline in bacterial alpha diversity with increasing permafrost thaw, while micro-eukaryotic diversity exhibited an opposite trend. Although changes in microbial community composition were observed in permafrost and seasonally frozen soils, these shifts were not statistically significant. Bacterial communities exhibited greater differentiation between frozen and seasonally frozen soils, a pattern not mirrored in eukaryotic communities. LEfSe analysis revealed a higher number of potential biomarkers in bacterial communities compared to micro-eukaryotes. Bacterial co-occurrence networks were more complex, with more nodes, edges, and positive linkages than those of micro-eukaryotes. Key factors such as soil texture, ALT, and bulk density significantly influenced bacterial community structures, particularly affecting the relative abundances of the Acidobacteria, Proteobacteria, and Actinobacteria phyla. In contrast, fungal communities (e.g., Nucletmycea, Rhizaria, Chloroplastida, and Discosea groups) were more affected by electrical conductivity, vegetation coverage, and ALT. This study highlights the distinct responses of soil bacteria and micro-eukaryotes to permafrost thaw, offering insights into microbial community stability under global climate change. ImportanceThis study sheds light on how permafrost thaw affects microbial life in the soil, with broader implications for understanding climate change impacts. As permafrost degrades, it alters the types and numbers of microbes in the soil. These microbes play essential roles in environmental processes, such as nutrient cycling and greenhouse gas emissions. By observing shifts from bacteria-dominated to fungi-dominated communities as permafrost thaws, the study highlights potential changes in these processes. Importantly, this research suggests that the stability of microbial networks decreases with permafrost degradation, potentially disrupting the delicate balance of these ecosystems. The findings not only deepen our understanding of microbial responses to changing climates but also support the development of strategies to monitor and potentially mitigate the effects of climate change on fragile high-altitude ecosystems.

microbiology↗

bioRxiv2024

Deconvolution of polygenic risk score in single cells unravels cellular and molecular heterogeneity of complex human diseases

Polygenic risk scores (PRSs) are commonly used for predicting an individuals genetic risk of complex diseases. Yet, their implication for disease pathogenesis remains largely limited. Here, we introduce scPRS, a geometric deep learning model that constructs single-cell-resolved PRS leveraging reference single-cell chromatin accessibility profiling data to enhance biological discovery as well as disease prediction. Real-world applications across multiple complex diseases, including type 2 diabetes (T2D), hypertrophic cardiomyopathy (HCM), and Alzheimers disease (AD), showcase the superior prediction power of scPRS compared to traditional PRS methods. Importantly, scPRS not only predicts disease risk but also uncovers disease-relevant cells, such as hormone-high alpha and beta cells for T2D, cardiomyocytes and pericytes for HCM, and astrocytes, microglia and oligodendrocyte progenitor cells for AD. Facilitated by a layered multi-omic analysis, scPRS further identifies cell-type-specific genetic underpinnings, linking disease-associated genetic variants to gene regulation within corresponding cell types. We substantiate the disease relevance of scPRS-prioritized HCM genes and demonstrate that the suppression of these genes in HCM cardiomyocytes is rescued by Mavacamten treatment. Additionally, we establish a novel microglia-specific regulatory relationship between the AD risk variant rs7922621 and its target genes ANXA11 and TSPAN14. We further illustrate the detrimental effects of suppressing these two genes on microglia phagocytosis. Our work provides a multi-tasking, interpretable framework for precise disease prediction and systematic investigation of the genetic, cellular, and molecular basis of complex diseases, laying the methodological foundation for single-cell genetics.

genetics↗

bioRxiv2024

Fast adaptive super-resolution lattice light-sheet microscopy for rapid, long-term, near-isotropic subcellular imaging

Lattice light-sheet microscopy (LLSM) provides a crucial observation window into intra- and inter-cellular physiology of living specimens with high speed and low phototoxicity, however, at the diffraction-limited resolution or anisotropic super-resolution with structured illumination. Here we present the meta-learning-empowered reflective lattice light-sheet virtual structured illumination microscopy (Meta-rLLS-VSIM), which instantly upgrades LLSM to a near-isotropic super resolution of [~]120-nm laterally and [~]160-nm axially, more than twofold improvement in each dimension, without any modification of the optical system or sacrifice of other imaging metrics. Moreover, to alleviate the tremendous demands on training data and time necessitated by existing deep-learning (DL) methods, we devised an adaptive online training approach by synergizing the front-end imaging system and back-end meta-learning framework, which reduced the total time for data acquisition and model training down to tens of seconds. With this method, a new model can be well-trained with tenfold less data and three orders of magnitude less time than current standard supervised learning. We demonstrate the versatile functionalities of Meta-rLLS-VSIM by imaging a variety of bioprocesses with ultrahigh spatiotemporal resolution for long duration of hundreds of multi-color volumes, characterizing the dynamic regulation of contractile ring filaments during mitosis and the growth of pollen tubes, and delineating the nanoscale distributions, dispersion, and interaction pattern of multiple organelles in embryos and eukaryotic cells.

biophysics↗

bioRxiv2024

Super Enhancer-driven LncRNA UNC5B-AS1 Inhibits Inflammatory Phenotypic Transition in Smooth Muscle Cells via Lactylation Modification

BackgroundThe phenotypic transition of pulmonary artery smooth muscle cells (PASMCs) is a central pathological alteration in pulmonary artery remodeling that contributes to pulmonary hypertension (PH). The specific role of long noncoding RNAs (lncRNAs), especially super enhancer (SE)-driven lncRNAs, in the phenotypic transformation of PASMCs induced by hypoxia remains unclear. The objective of this study is to determine the mechanistic role of the super enhancer-driven LncRNA UNC5B-AS1 in phenotypic transformation of PASMCs and hypoxia-induced vascular remodeling. MethodsThe lncRNA UNC5B-AS1 regulated by super-enhancers was identified in hypoxic human PASMCs through RNA sequencing and H3K27ac ChIP sequencing. Overexpression of lncRNA UNC5B-AS1 in human PASMCs was performed to elucidate its role in the pathogenesis of PH. A conserved functional fragment of lncRNA UNC5B-AS1 was used for the treatment of mouse PH. ResultsIn PASMCs, we have identified a SE-driven lncRNA called UNC5B-AS1 that regulates phenotype transition. It is transcriptionally activated by the transcription factor FOXP3. We demonstrate that UNC5B-AS1, as a molecular scaffold in mitochondria, stabilizes the interaction between LRPPRC, which is rich in leucine, and oxidative respiratory chain complex IV. This complex regulates the lactylation modification level of upstream promoter regions of inflammatory genes IL-1{beta}, IL-6, and TNF- by influencing the glycolytic pathway in PASMCs under hypoxic conditions, ultimately affecting the inflammatory phenotype transition of PASMCs. ConclusionsOur findings identify the SE-driven lncRNA UNC5B-AS1 as a novel regulatory factor in hypoxia-induced phenotypic switch of PASMCs, and suggest that overexpression of UNC5B-AS1 may represent a promising therapeutic strategy for PH. HighlightsThe long non-coding RNA UNC5B-AS1, regulated by super-enhancers (SE), is downregulated in hypoxic PASMCs, and regulates PASMC phenotype transition through glycolysis. The super-enhancer region of lncRNA UNC5B-AS1 recruits the transcription factor FOXP3 to its promoter region, forming a chromatin loop to regulate its expression. The lncRNA UNC5B-AS1 acts as a molecular scaffold stabilizing the interaction between LRPPRC and mitochondrial complex IV. The lactate generated by glycolysis activation induces lactylation modification of histones at the IL-1{beta}, IL-6, and TNF- promoters, leading to the inflammatory phenotype transition of PASMCs. Overexpression of lncRNA UNC5B-AS1 conserved fragment reversed SuHx-induced PH in mice. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/593065v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@864576org.highwire.dtl.DTLVardef@13a5fe4org.highwire.dtl.DTLVardef@16d7884org.highwire.dtl.DTLVardef@35d50_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Microfluidic-enabled production of DNA barcoded APC library (MEDAL) for high throughput T cell epitope screening

Screening for peptide fragments that can be displayed on antigen-presenting cells is an essential step in vaccine development. The current approach for this process is slow and costly as it involves separately pulsing cells with chemically synthesized peptides. We present Microfluidic-Enabled production of DNA-barcoded APC Library (MEDAL), a high throughput microfluidic droplet platform for parallel production of DNA-barcoded APCs loaded with enzymatically synthesized peptides. Droplets containing peptides and their encoding DNA are produced from microfluidic PCR-IVTT reaction. APCs presenting both peptides and DNA barcodes are obtained by injecting cells into these droplets. Up to 9,000 different APCs can be produced and screened within a 10-hour workflow. This approach allowed us to identify peptide sequences that bind to APCs expressing H-2Kb MHC class 1 molecule with next-generation sequencing of DNA barcodes.

immunology↗

bioRxiv2024

mRNA psi profiling using nanopore DRS reveals cell-type-specific pseudouridylation

Pseudouridine (psi) is one of the most abundant human mRNA modifications yet its functional impact on translation has remained unclear. Using direct RNA nanopore sequencing coupled with our Mod-p ID analytical framework, we mapped psi at single-nucleotide resolution across six immortalized human cell lines derived from diverse tissue types. Psi sites identified by nanopore sequencing were cross-validated using Illumina-based methods, confirming both positional accuracy and reproducibility. Unlike prior short-read approaches, nanopore sequencing provided the unique ability to quantify relative occupancy at each site and to detect multiple modifications on the same RNA molecule, revealing combinatorial modification patterns that cannot be captured otherwise. Integrating these psi maps with matched proteomic and ribosome profiling datasets, we find that psi modulates translation through two mechanistic modes: (i) single high-occupancy psi sites enhance translational efficiency and protein output, whereas (ii) clustered psi modifications promote ribosome pausing, decoupling translation efficiency from protein yield. This integrative, multi-omics framework provides a quantitative model of how psi stoichiometry and distribution along transcripts shape ribosome dynamics and proteome composition across human cell types.

genomics↗

bioRxiv2024

Repeat and haplotype aware error correction in nanopore sequencing reads with DeChat

Error self-correction is a pivotal first step in the analysis of long-read sequencing data. However, most existing methods for this purpose are primarily tailored for noisy sequencing data with error rates exceeding 5%, often collapsing true variants in repeats and haplotypes. Alternatively, some methods are heavily optimized for PacBio HiFi reads, leaving a gap in methods specifically designed for Nanopore R10 reads basecalled with high accuracy or super accuracy models, which typically have error rates below 2%. Here, we introduce DeChat, a novel approach specifically designed for Nanopore R10 reads. DeChat enables repeat- and haplotype-aware error correction, leveraging the strengths of both de Bruijn graphs and variant-aware multiple sequence alignment to create a synergistic approach. This approach avoids read overcorrection, ensuring that variants in repeats and haplotypes are preserved while sequencing errors are accurately corrected. Benchmarking experiments reveal that reads corrected using DeChat exhibit substantially fewer errors, ranging from several times to two orders of magnitude lower, compared to the current state-of-the-art approaches. Furthermore, the application of DeChat for error correction significantly improves genome assembly across various aspects. DeChat is implemented as a highly efficient, standalone, and user-friendly software and is publicly available at https://github.com/LuoGroup2023/DeChat.

bioinformatics↗

bioRxiv2024

Hypergraph Cortical Cytoarchitectonic Parcellation with Multimodal Canine Brain Atlas

Brain atlases are vital tools in exploring the brain structure-function relationship. The burgeoning cross-species atlases have significantly accelerated our understanding of human brain development, evolution, function, and diseases. However, the existing coarse-grained macroscopic canine brain atlases greatly constrain their utility as an animal model for neurocognition research. Finer-grained brain atlas and partitions are crucial for decoding brain spatial heterogeneity and topology at different scales. Therefore, we conduct macroscopic and microscopic brain imaging to construct an interactive online dataset of multimodal canine brain atlas. Additionally, we develop a pioneering method for cortical cytoarchitectonic partitioning based on hypergraph learning. By integrating high-dimensional cytoarchitectonic features and spatial connections between cortical columns, the method leads to fine-grained partitioning patterns. This innovative approach aims to decode the biological heterogeneity of cortical microstructures, contributing to the structural annotation of canine atlas as well as public human brain atlases. The study not only offers valuable resources but also presents a novel zonation approach to investigate the cellular organization pattern and topology of the cortex.

neuroscience↗

bioRxiv2024

Identification of Candidate Diagnostic gene CDC25C for Trametinib-induced Cardiotoxicity by Integrating Bioinformatics and Machine Learning

Trametinib is a MEK inhibitor that has been shown to have considerable efficacy in retarding melanoma progression. However, the exact mechanism of cardiotoxicity induced by trametinib remains unclear. Our study was designed to investigate the underlying mechanisms by which trametinib-induced cardiotoxicity (TIC) might exist, offering novel perspectives and guidance for potential prediction, diagnosis, and treatment of TIC. The GSE217421 dataset indicated 574 up-regulated and 705 down-regulated DEGs. According to the KEGG analysis, these genes were implicated in several pathways and functions, including Cell Cycle, Axon Guidance, Cellular Senescence, and Dilated Cardiomyopathy. The GO analysis suggested their association with Mitotic Cell Cycle, Microtubule Cytoskeleton and Adenyl Nucleotide Binding. The hub genes (CDC25C) for TIC were screened through Multiple machine learning algorithms. Next, The expression level of CDC25C was verified using the GSE217423 validation set. Nomogram model based on CDC25C demonstrated excellent diagnostic capability according to three different evaluation measures. To further explore the regulatory mechanism of CDC25C in TIC, we constructed a multi-regulatory network using miRNAs-lncRNAs-TFs-CDC25C and conducted an immunoinfiltration analysis. Our study suggests that CDC25C may be a candidate diagnostic gene and a potential therapeutic target for the early occurrence and development of TIC. This provides new ideas for the prediction, diagnosis and treatment strategies for TIC.

cancer biology↗

bioRxiv2024

Colorectal ALOX15 as a host factor determinant of EPA and DHA effects on colorectal carcinogenesis

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), omega-3 polyunsaturated fatty acids ({omega}-3 PUFAs) derived from fish oil, are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. However, studies investigating the effects of EPA and DHA on colorectal carcinogenesis (CRC) have yielded conflicting results. The factors that determine these discrepant results remain unknown. Resolvins, oxidative metabolites of EPA and DHA, inhibit key pro-tumorigenic cytokine and chemokine signaling of colorectal cancer (e.g., IL-6, IL-1{beta}, and CCL2). 15-lipoxygenase-1 (ALOX15), a critical enzyme for resolvin generation is commonly lost during human CRC. Whether ALOX15 expression, as a host factor, modulates the effects of EPA and DHA on CRC remains unknown. Therefore, we evaluated the effects of ALOX15 transgenic expression in colonic epithelial cells on resolvin generation by EPA and DHA and CRC in mouse models representative of human CRC. Our results revealed that 1) EPA and DHA effects on CRC were diverse, ranging from suppressive to promotive, and these effects were occasionally altered by the formulations of EPA and DHA (free fatty acid, ethyl ester, triglyceride); 2) EPA and DHA uniformly suppressed CRC in the presence of intestinal ALOX15 transgenic expression, which induced the production of resolvins, decreased colonic CCL3-5 and CXCL-5 expression and tumor associated macrophages while increasing CD8 T cell abundance in tumor microenvironment; and 3) RvD5, the predominant resolvin produced by ALOX15, inhibited macrophage generation of pro-tumorigenic cytokines. These findings demonstrate the significance of intestinal ALOX15 expression as a host factor in determining the effects of EPA and DHA on CRC. SignificanceEicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are widely used as dietary supplements and FDA-approved treatments for hypertriglyceridemia. Studies of EPA and DHA effects on colorectal carcinogenesis (CRC) have revealed inconsistencies; factors determining the direction of their impact on CRC have remained unidentified. Our data show that EPA and DHA effects on CRC were divergent and occasionally influenced by their formulations. More importantly, intestinal 15-lipoxgenase-1 (ALOX15) expression modulated EPA and DHA effects on CRC, leading to their consistent suppression of CRC. ALOX15 promoted EPA and DHA oxidative metabolism to generate resolvins, which inhibited key pro-tumorigenic inflammatory cytokines and chemokines, including IL-6. IL-1{beta}, and CCL2. ALOX15 is therefore an important host factor in determining EPA and DHA effects on CRC.

cancer biology↗