Biology subjects

Xie, M.

Publications and source records attributed to Xie, M..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

RNAi-mediated HBV antigen shutdown enhances the antiviral immune effects of PEGIFNalpha via altering T and B cell crosstalk

PEGylated interferon- (PEGIFN) demonstrates promising therapeutic outcomes against chronic hepatitis B (CHB), whereas patient response to PEGIFN therapy remains unsatisfied. Shutdown of hepatitis B virus (HBV) antigens by RNA interference (RNAi) could enhance PEGIFN efficacy in CHB patients, whereas the underlying immunological mechanisms remain obscure. We performed studies by utilizing our newly established extracellular humanized IFNAR (IFNAR-hEC) mice. An in-house constructed small interfering RNAs (GalNac-siHBV) was administrated to mice either alone or in combination with PEGIFN. The phenotypic and functional characteristics of peripheral and organ-specific immune cells were assessed by flow cytometry, ELISpot, RNA sequencing (RNA-seq), and single-cell RNA-seq (scRNA-seq) analysis. Our results demonstrated that combined treatment with PEGIFN and RNAi exerted a synergistic and prolonged inhibition of HBsAg ([~]4log10 IU/mL, vs PBS) and induced a higher incidence of HBsAg seroconversion ([~]30%), comparing with either monotreatment. Mechanistically, combined therapy improved the functionality of global T and B cells, triggered increased anti-HBs producing B cells, and enhanced IFN{gamma}-producing T cells. scRNA-seq analysis revealed that the combined therapy reduced inhibitory B cell-B cell interaction, enhanced MHC-I signaling mediated T cell-T cell communication, and improved T cell-B cell crosstalk, thus improving the functionality of T and B cells. Enhanced MHC-II signaling networks across B cells and hepatocytes/Cd8+ T cells further promoted HBsAg seroconversion in the combined treatment groups. These results together provided scientific rationale and lessons for the combination of the two towards better therapeutic efficacy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/626539v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@84785aorg.highwire.dtl.DTLVardef@f984fborg.highwire.dtl.DTLVardef@189a966org.highwire.dtl.DTLVardef@d081f9_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIShutting down HBsAg through RNA interference augmented the antiviral immune effects of PEGIFN in chronic HBV-carrier IFNAR-hEC mice. C_LIO_LICombined RNAi plus PEGIFN augmented the functionality of T cells, promoted B cell activation and class switch, but also exerted some suppressive effects on B cells. C_LIO_LIReduced inhibitory B cell-B cell interaction, enhanced MHC-I signaling between T cells and T cells, and improved T cell-B cell crosstalk, improved the functionality of T cells and B cells. C_LIO_LIEnhanced MHC-II signaling networks across B cells and hepatocytes/ Cd8+ T cells further promoted HBsAg seroconversion in RNAi plus PEGIFN combined treatment groups. C_LI

microbiology↗

bioRxiv2024

Effects of Bacterial Wilt on Community Composition and Diversity of Culturable Endophytic Fungi in Alpinia galanga

Hongdoukou plant (Alpinia galanga Willd.) is a perennial herbaceous plant that usually has a stable microflora living in the inter-root and stem and leaf tissues, which assists the host in normal growth and development. The bacterial wilt disease that had been investigated in planting bases of A. galanga, was a new soil-borne disease infected by pathogenic bacteria (Ralstonia solanacearum (Smith) Yabuuchi et al.), which disrupts the A. galanga-microbe-soil microecological balance. For this reason, it is important to study the changes of the community composition and diversity of endophytic fungi in healthy and diseased A. galanga (HDK_J and HDK_B), and to mine the active endophytic fungal resources in order to lay the foundation for exploring the functional microbial communities for artificial synthesis. All experimental materials were from the healthy and diseased plant clusters of A. galanga in the traditional planting areas in Guangdong Province. The endophytic fungi were isolated from the stems and leaves of A. galanga by separated plant tissue blocks cultured in PDA medium. The colonization rate (CR) was calculated, and the isolated strains were amplified by PCR with the ITS1/ITS4 genes as the fungal molecular markers, to identify the endophytic fungi species, and to analyze the diversity of endophytic fungi in the healthy and diseased clusters of HDK_J and HDK_B, and the indexes included: relative segregation frequency (SF), relative abundance (RA) plotted by ggplot2 under R language, Shannon-Wiener diversity index (H'), Simpson index (D), Margalef richness index (R) and Pielou uniformity index (J), and finally, a phylogenetic tree of the endophytic fungi of healthy and diseased A. galanga was constructed by MEGA. A total of 685 endophytic fungal strains were isolated from the stems and leaves of healthy (HDK_J) and diseased (HDK_B) A. galanga, of which 27 endophytic fungal species were identified in healthy A. galanga. and 8 in diseased A. galanga, which belonged to 3 Phyla, 6 Classes and 13 Families. At the genus level, the RA of HDK_B endophytic fungi were only 38.93% of HDK_J, with significant difference (P<0.05), indicating that the composition and abundance of endophytic fungi in HDK_B were lower than that in HDK_J. Meanwhile, the endophytic fungi species isolated from the stems and leaves of the HDK_J and HDK_B were the same, but the RA of leaf organs was higher than that of stems, with the RA in the leaves in HDK_J higher than that of stems by 124.23%, and the RA of leaves in HDK_B higher than that of stems by 78.23%. The RA of HDK_J leaves was 78.08% higher than that of stems. all the diversity indexes of HDK_J were higher than that of HDK_B, with significant differences (P<0.05), and the Shannon-Wiener index (H'), Simpsons index (D), and Margalefs index (R) behaved as follows: HDK_J leaves (1.16, 0.87, 5.12) > HDK_J stems (0.82, 0.72, 4.22) > HDK_B leaves (0.57, 0.24, 2.97) > HDK_B stems (0.33, 0.14, 2.25), whereas Pielous index (J) indicated that the endophytic fungal species were more uniformly distributed in HDK_J leaves, and there was not much difference in the homogeneity of the leaves of the HDK_J stems and the HDK_B stems. The mapping phylogenetic trees showed there were 4 major development branches of the species on endophytic fungi in HDK_J, and especially, there were many long development branches under the Ascomycota. The genetic relationships among different species were completely revealed in phylogenetic trees. The average genetic similarity among genera was 52.80%. Conversely, there only were1major branch (Ascomycota), and few sub-branches under the Ascomycota in HDK_B. The average genetic similarity among genera was 84.59%, and the difference was small. The bacterial wilt significantly affected the composition and RA of endophytic fungi in A. galanga. The diversity indices showed decreasing trend in A. galanga after infected by R. solanacearum. The dominant species were changed. The parts of sensitive endophytic fungi were disappeared. This result will be helpful for the study on the relationship between the artificial minimal microbial community and the role of the host as well as the study on synthetic microbiomics.

microbiology↗

bioRxiv2024

Task-induced internal bodily rather than brain states regulate human self-perception

A fundamental ability for us is to identify and distinguish with others, known as the self, whose neural substrate is hard to identify by external self-related stimuli because of possible interference from internal self-related states of both body and brain. Using the same stimuli, we ruled out this dilemma by manipulating human subjects performing own- and celebrity-face discrimination tasks to induce self-related and non-self-related states, respectively. Results showed that stimulus-driven sensory sensory differences among own-, celebrity-, and stranger-faces were independent of task-induced internal states, whereas their perceptual differences were strongly modulated by these states. Intriguingly, we further found that subjects bodily (indexed by heartbeat-evoked potentials) rather than brain (indexed by pre-stimulus -powers) states not only predicated their self-perception but also moderated the relationship between external stimuli and self-perception. Our results reveal for the first time an adaptive self-perception, shaped by not only external stimuli but also internal states, especially the interoception.

neuroscience↗

bioRxiv2024

Deficiency of Hv1 Proton Channel Enhances Macrophage Antigen Presentation and Anti-Tumor Responses in Glioma

In the tumor microenvironment of glioblastoma, myeloid cells act as a double-edged sword--they are a major cellular component modulating the immune response while presenting a potential therapeutic target. Our study highlights the voltage-gated proton channel Hv1, predominantly expressed in myeloid cells, as a crucial regulator of their physiological functions. We discovered a strong correlation between increased Hv1 expression and poor prognosis in glioblastoma patients. Depleting Hv1 significantly extended survival in a mouse model of glioma. Employing multiple novel transgenic mouse lines, we demonstrated that Hv1 is upregulated in response to tumor presence, with glioma-associated macrophages as the principal contributors. Specifically, we identified that Hv1 in infiltrating macrophages as the major driver of survival phenotype differences. Through a combination of in vivo two-photon imaging, spectral flow cytometry, and spatial transcriptomic sequencing, we found that Hv1 depletion leads to reduced macrophage infiltration and enhanced antigen presentation, ultimately fostering a stronger adaptive immune response. These findings establish the Hv1 channel as a crucial new immune regulator within the brain tumor milieu, offering a promising target for reprogramming macrophage function to combat glioblastoma.

neuroscience↗

bioRxiv2024

The kinetics of bedaquiline diffusion in tuberculous cavities opens a window for emergence of resistance.

Cavitary tuberculosis (TB) is difficult to cure and a site of relapse. Bedaquiline has been a wonder drug in the treatment of multidrug resistant TB, but emergence of resistance threatens its sustained success. To investigate the role of drug distribution in resistance development, we designed a novel laser-capture microdissection scheme to spatially resolve the penetration of bedaquiline in the necrotic center (caseum) of cavities, a recalcitrant site of disease. Working with preclinical models that form large necrotic lesions, we profiled bedaquiline and two next generation diarylquinolines TBAJ-587 and TBAJ-876. Drug concentrations were measured in laser-captured areas of cavity caseum as a function of time and distance from blood supply. To simulate drug coverage in patient cavities, the data were modeled, and drug penetration parameter estimates were linked to clinical plasma pharmacokinetics for bedaquiline and the new diarylquinolines. Pharmacokinetic-pharmacodynamic (PK-PD) simulations revealed that bedaquiline reaches efficacious concentrations in outer and deep caseum after several weeks to months and lingers at subtherapeutic concentrations up to 3 years after therapy ends. TBAJ-587 and TBAJ-876, currently in clinical development, achieve bactericidal concentrations in caseum more rapidly and shorten the window of suboptimal concentrations post treatment compared to bedaquiline. Simulations of clinically plausible dosing schemes were conducted to guide the design of clinical trials for cavitary TB and help mitigate resistance development. In summary, the slow kinetics of diffusion of bedaquiline into and out of cavity caseum creates spatio-temporal windows of subtherapeutic concentrations. Site-of-disease simulations of TBAJ-587 and TBAJ-876 predict reduced opportunities for resistance development. SIGNIFICANCEClinical resistance to bedaquiline has emerged faster than anticipated. Understanding potential contributing factors could help curb further resistance development, not only for bedaquiline but also for the next generation diarylquinolines currently in phase 2, TBAJ-587 and TBAJ-876. Here we hypothesized and confirmed that the extended time to reach steady state and slow clearance of bedaquiline leads to extremely slow diffusion into and out of cavity caseum, a recalcitrant site of TB disease and relapse. Through modeling of experimental data in a preclinical model of cavitary TB and clinical simulations, we show that the next generation diarylquinolines may reduce spatio-temporal windows of resistance development compared to bedaquiline. Our results can inform dosing schemes of diarylquinoline-based therapies that limit resistance development.

pharmacology and toxicology↗

bioRxiv2024

Plant genotype and microbial strain combinations strongly influence the transcriptome under heavy metal stress conditions

Heavy metals such as cadmium (Cd) and mercury (Hg) pose significant threats to plant health and food safety as they are absorbed from the environment. Legumes are generally considered sensitive to heavy metals but possess standing genetic variation for accumulation and tolerance to toxic ions. We conducted a transcriptomic analysis on hydroponically and soil grown Medicago truncatula plants to investigate gene expression responses to Cd and Hg exposure in roots, leaves, and nodules. By using plant genotypes with varying metal tolerance or accumulation levels, we observed distinct clustering of gene ontologies, indicating tissue-specific, genotype-specific, and metal-specific gene expression patterns. Considering the symbiotic relationship between legumes and nitrogen-fixing bacteria, we further examined plant phenotypes and transcriptomes of plant genotypes with contrasting Hg accumulation levels and inoculated them with high or low Hg-tolerant Sinorhizobium medicae strains that have presence-absence variation for a mercury reductase (Mer) operon. Host plants inoculated with the Hg-tolerant rhizobia strain possessing a Mer operon exhibited less reduction in nodule number and plant biomass. A smaller reduction in iron (Fe) distribution in nodules after Hg stress was measured using X-ray Fluorescence (XRF) imaging. Dual transcriptome (host plant and bacteria) analysis of nodules revealed a remarkable decrease in the number of differentially expressed genes (DEGs) and clustering of gene ontologies in plants inoculated with the Hg-tolerant rhizobia strain, including symbiosis related genes. This suggests the Hg-tolerant rhizobia strain has the potential to mitigate Hg stress in host plants. Furthermore, we observed genotype-by-genotype interactions between the high Hg accumulating plant genotype and the Hg-tolerant rhizobia strain. These findings provide insights into enhancing plant resilience in contaminated environments through optimizing legume-rhizobia interactions for heavy metal tolerance, as well as identification of genetic mechanisms that can reduce transport to edible plant parts. HighlightsO_LIGenetic variation in tolerance to heavy metals affects responses in plant tissues C_LIO_LISymbiosis with Hg tolerant rhizobia strain reduced stress response in host plant C_LIO_LIDual-transcriptomics in nodules identified metal stress and symbiosis responses C_LIO_LIGenotype by genotype interaction significantly affected symbiosis gene expression C_LIO_LIRhizobia strain possessing Mer operon suggests genetic basis affecting responses C_LI

plant biology↗

bioRxiv2024

MiniXL: An open-source, large field-of-view epifluorescence miniature microscope for mice capable of single-cell resolution and multi-brain region imaging

Capturing the intricate dynamics of neural activity in freely behaving animals is essential for understanding the neural mechanisms underpinning specific behaviors. Miniaturized microscopy enables investigators to track population activity at cellular level, but the field of view (FOV) of these microscopes have been limited and does not allow multiple-brain region imaging. To fill this technological gap, we have developed the eXtra Large field-of-view Miniscope (MiniXL), a 3.5g lightweight miniaturized microscope with an FOV measuring 3.5 mm in diameter and an electrically adjustable working distance of 1.9 mm {+/-} 200 m. We demonstrated the capability of MiniXL recording the activity of large neuronal population in both subcortical area (hippocampal dorsal CA1) and deep brain regions (medial prefrontal cortex, mPFC and nucleus accumbens, NAc). The large FOV allows simultaneous imaging of multiple brain regions such as bilateral mPFCs or mPFC and NAc during complex social behavior and tracking cells across multiple sessions. As with all microscopes in the UCLA Miniscope ecosystem, the MiniXL is fully open-source and will be shared with the neuroscience community to lower the barriers for adoption of this technology.

neuroscience↗

bioRxiv2024

Iron deprivation activates aboveground cell wall biosynthesis in Populus and the role of PtrbHLH011

Lack of mechanistic understanding of the environmental plasticity of secondary cell wall (SCW) biosynthesis hinders the massive bioenergy production on marginal lands. Growing bioenergy crops on marginal lands is appealing to minimize competition for arable land. However, abiotic stresses, particularly iron deficiency stress, are widespread to perturb SCW biosynthesis. In poplar, a major bioenergy crop, we demonstrated that iron deprivation activates stem SCW biosynthesis and identified transcription factor PtrbHLH011 as a possible underlying regulator. PtrbHLH011 is a potent repressor of SCW, whose overexpression resulted in a reduction of stem SCW by over 65%. Our genomic and molecular studies discovered that PtrbHLH011 binds to the AAAGACA sequence and represses essential genes for SCW biosynthesis, flavonoid biosynthesis, and iron homeostasis. Wood formation and iron deprivation downregulates PtrbHLH011 to release the transcriptional repression. Our findings reveal a regulatory mechanism coordinating SCW biosynthesis in response to environmental iron availability and suggest that PtrbHLH011 manipulation may help engineer bioenergy crops with improved performance under marginal conditions.

plant biology↗

bioRxiv2024

Rod-shaped microglia interact with neuronal dendrites to regulate cortical excitability in TDP-43 related neurodegeneration

Motor cortical hyperexcitability is well-documented in the presymptomatic stage of amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying this early dysregulation are not fully understood. Microglia, as the principal immune cells of the central nervous system, have emerged as important players in sensing and regulating neuronal activity. Here we investigated the role of microglia in the motor cortical circuits in a mouse model of TDP-43 neurodegeneration (rNLS8). Utilizing multichannel probe recording and longitudinal in vivo calcium imaging in awake mice, we observed neuronal hyperactivity at the initial stage of disease progression. Spatial and single-cell RNA sequencing revealed that microglia are the primary responders to motor cortical hyperactivity. We further identified a unique subpopulation of microglia, rod-shaped microglia, which are characterized by a distinct morphology and transcriptional profile. Notably, rod-shaped microglia predominantly interact with neuronal dendrites and excitatory synaptic inputs to attenuate motor cortical hyperactivity. The elimination of rod-shaped microglia through TREM2 deficiency increased neuronal hyperactivity, exacerbated motor deficits, and further decreased survival rates of rNLS8 mice. Together, our results suggest that rod-shaped microglia play a neuroprotective role by attenuating cortical hyperexcitability in the mouse model of TDP-43 related neurodegeneration.

neuroscience↗

bioRxiv2024

Network pharmacological evaluation of active ingredients and potential targets of San Huang Decoction in the treatment of breast cancer

ObjectiveUsing the method of network pharmacology, the possible targets and related signaling pathways of San Huang Decoction against breast cancer were explored. MethodsThe active ingredients of San Huang Decoction were screened in Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). All targets of San Huang Decoction and breast cancer were obtained through five databases, and R software was used to obtain their common targets. Then, Cytoscape software was used to construct the active ingredient-target network map. The protein-protein interaction network (PPI) was obtained with the help of the STRING database, and key targets were screened out through network topology analysis. Common targets were subjected to gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis using R software. ResultsA total of 39 active ingredients were screened from San Huang Decoction, of which 20 belonged to Huangqi, 16 belonged to Dahuang, and 3 belonged to Jianghuang. After taking the intersection of all the targets of San Huang Decoction and breast cancer, a total of 185 potential targets of San Huang Decoction against breast cancer were obtained. PPI network analysis screened out 16 targets that may be the key targets of San Huang Decoction against breast cancer. The enrichment analysis of GO and KEGG suggested that the common targets were involved in various biological processes and functions through PI3K-Akt signaling pathway, MAPK signaling pathway, TNF signaling pathway, IL-17 signaling pathway, and HIF-1 signaling pathway, including oxidation stress, transcription-related functions, and nuclear receptor functions. ConclusionThis study predicted the potential targets and signaling pathways of San Huang Decoction against breast cancer, and provided scientific guidance for the further study on the anti-breast cancer mechanism of San Huang Decoction.

bioinformatics↗

bioRxiv2024

Single-nucleus multiomic analysis of Beckwith-Wiedemann syndrome liver reveals PPARA signaling enrichment and metabolic dysfunction

Beckwith-Wiedemann Syndrome (BWS) is an epigenetic overgrowth syndrome caused by methylation changes in the human 11p15 chromosomal locus. Patients with BWS exhibit tissue overgrowth, as well as an increased risk of childhood neoplasms in the liver and kidney. To understand the impact of these 11p15 changes, specifically in the liver, we performed single-nucleus RNA sequencing (snRNA-seq) and single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) to generate paired, cell-type-specific transcriptional and chromatin accessibility profiles of both BWS-liver and nonBWS-liver nontumorous tissue. Our integrated RNA+ATACseq multiomic approach uncovered hepatocyte-specific enrichment and activation of the peroxisome proliferator-activated receptor (PPARA) - a liver metabolic regulator. To confirm our findings, we utilized a BWS-induced pluripotent stem cell (iPSC) model, where cells were differentiated into hepatocytes. Our data demonstrates the dysregulation of lipid metabolism in BWS-liver, which coincided with observed upregulation of PPARA during hepatocyte differentiation. BWS liver cells exhibited decreased neutral lipids and increased fatty acid {beta}-oxidation, relative to controls. We also observed increased reactive oxygen species (ROS) byproducts in the form of peroxidated lipids in BWS hepatocytes, which coincided with increased oxidative DNA damage. This study proposes a putative mechanism for overgrowth and cancer predisposition in BWS liver due to perturbed metabolism.

genetics↗

bioRxiv2024

New isolates refine the ecophysiology of the Roseobacter CHAB-I-5 lineage

The CHAB-I-5 cluster is a pelagic lineage that can comprise a significant proportion of all roseobacters in surface oceans and have predicted roles in biogeochemical cycling via heterotrophy, aerobic anoxygenic photosynthesis (AAnP), CO oxidation, DMSP degradation, and other metabolisms. Though cultures of CHAB-I-5 have been reported, none have been explored and the best known representative, strain SB2, was lost from culture after obtaining the genome sequence. We have isolated two new CHAB-I-5 representatives, strains US3C007 and FZCC0083, and assembled complete, circularized genomes with 98.7% and 92.5% average nucleotide identities with the SB2 genome. Comparison of these three with 49 other unique CHAB-I-5 metagenome-assembled and single-cell genomes indicated that the cluster represents a genus with two species, and we identified subtle differences in genomic content between the two species subclusters. Metagenomic recruitment from over fourteen hundred samples expanded their known global distribution and highlighted both isolated strains as representative members of the clade. FZCC0083 grew over twice as fast as US3C007 and over a wider range of temperatures. The axenic culture of US3C007 occurs as pleomorphic cells with most exhibiting a coccobacillus/vibrioid shape. We propose the name Thalassovivens spotae, gen nov., sp. nov. for the type strain US3C007T.

microbiology↗

bioRxiv2024

Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis. Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. To demonstrate that this translates to more effective cure, we first confirmed the role of rifampin, with or without pyrazinamide, as essential to achieve effective bactericidal responses and sterilizing cure in the current standard of care regimen in chronically infected C3HeB/FeJ mice compared to BALB/c mice. Thus, demonstrating added value in testing clinically relevant regimens in murine models of increasing pathologic complexity. Next we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models including mice exhibiting advanced pulmonary disease can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

microbiology↗

bioRxiv2024

A recurrent neural circuit in Drosophila deblurs visual inputs

A critical goal of vision is to detect changes in light intensity, even when these changes are blurred by the spatial resolution of the eye and the motion of the animal. Here we describe a recurrent neural circuit in Drosophila that compensates for blur and thereby selectively enhances the perceived contrast of moving edges. Using in vivo, two-photon voltage imaging, we measured the temporal response properties of L1 and L2, two cell types that receive direct synaptic input from photoreceptors. These neurons have biphasic responses to brief flashes of light, a hallmark of cells that encode changes in stimulus intensity. However, the second phase was often much larger than the first, creating an unusual temporal filter. Genetic dissection revealed that recurrent neural circuitry strongly shapes the second phase of the response, informing the structure of a dynamical model. By applying this model to moving natural images, we demonstrate that rather than veridically representing stimulus changes, this temporal processing strategy systematically enhances them, amplifying and sharpening responses. Comparing the measured responses of L2 to model predictions across both artificial and natural stimuli revealed that L2 tunes its properties as the model predicts in order to deblur images. Since this strategy is tunable to behavioral context, generalizable to any time-varying sensory input, and implementable with a common circuit motif, we propose that it could be broadly used to selectively enhance sharp and salient changes.

neuroscience↗

bioRxiv2024

Gra-CRC-miRTar: The pre-trained nucleotide-to-graph neural networks to identify potential miRNA targets in colorectal cancer

Colorectal cancer (CRC) is the third most diagnosed cancer and the second deadliest cancer worldwide representing a major public health problem. In recent years, increasing evidence has shown that microRNA (miRNA) can control the expression of targeted human messenger RNA (mRNA) by reducing their abundance or translation, acting as oncogenes or tumor suppressors in various cancers, including CRC. Due to the significant up-regulation of oncogenic miRNAs in CRC, elucidating the underlying mechanism and identifying dysregulated miRNA targets may provide a basis for improving current therapeutic interventions. In this paper, we proposed Gra-CRC-miRTar, a pre-trained nucleotide-to-graph neural network framework, for identifying potential miRNA targets in CRC. Different from previous studies, we constructed two pre-trained models to encode RNA sequences and transformed them into de Bruijn graphs. We employed different graph neural networks to learn the latent representations. The embeddings generated from de Bruijn graphs were then fed into a Multilayer Perceptron (MLP) to perform the prediction tasks. Our extensive experiments show that Gra-CRC-miRTar achieves better performance than other deep learning algorithms and existing predictors. In addition, our analyses also successfully revealed 172 out of 201 functional interactions through experimentally validated miRNA-mRNA pairs in CRC. Collectively, our effort provides an accurate and efficient framework to identify potential miRNA targets in CRC, which can also be used to reveal miRNA target interactions in other malignancies, facilitating the development of novel therapeutics.

bioinformatics↗

bioRxiv2024

Benchmarking clustering, alignment, and integration methods for spatial transcriptomics

Spatial transcriptomics (ST) is advancing our understanding of complex tissues and organisms. However, building a robust clustering algorithm to define spatially coherent regions in a single tissue slice, and aligning or integrating multiple tissue slices originating from diverse sources for essential downstream analyses remain challenging. Numerous clustering, alignment, and integration methods have been specifically designed for ST data by leveraging its spatial information. The absence of benchmark studies complicates the selection of methods and future method development. Here we systematically benchmark a variety of state-of-the-art algorithms with a wide range of real and simulated datasets of varying sizes, technologies, species, and complexity. Different experimental metrics and analyses, like adjusted rand index (ARI), uniform manifold approximation and projection (UMAP) visualization, layer-wise and spot-to-spot alignment accuracy, spatial coherence score (SCS), and 3D reconstruction, are meticulously designed to assess method performance as well as data quality. We analyze the strengths and weaknesses of each method using diverse quantitative and qualitative metrics. This analysis leads to a comprehensive recommendation that covers multiple aspects for users. The code used for evaluation is available on GitHub. Additionally, we provide jupyter notebook tutorials and documentation to facilitate the reproduction of all benchmarking results and to support the study of new methods and new datasets (https://benchmarkst-reproducibility.readthedocs.io/en/latest/).

bioinformatics↗

bioRxiv2024

HER2 Prognostic Significance and Therapeutic Implications in Gastric Cardia Adenocarcinoma: Insights from Multi-Omics Profiling

Therapeutic targets for Gastric Cardia Adenocarcinoma (GCA), particularly for HER2- negative patients, are lacking. Here, we conducted multi-omics profiling on 128 GCA patients using mass spectrometry, whole-exome sequencing, RNA-Seq, and metabolomics. We found HER2 to be a favorable prognostic marker for GCA. Employing molecular counting, we categorized patients into HER2-high, -low, and -negative groups. We uncovered an enrichment of DNA repair features in the HER2-high group, while HER2-low and -negative groups exhibited strong inflammation. We found that tumor mutation burden may not be the distinguishing factor among these three groups. We revealed that the HER2-negative and -low groups have a tumor-suppressive immune microenvironment, and HER2 expression is associated with fatty acid metabolic profiles and inflammation in the blood of patients. Our study revealed anti-inflammatory and immune checkpoint inhibition, targeting PD-L2 and the CD47/SIRPA pair, as therapeutic strategies for HER2-negative GCA patients. These findings highlight promising avenues for personalized treatment for GCA.

cancer biology↗

bioRxiv2024

Structural insights into sphingosine 1-phosphate receptor 4 activation

S1PR4 is one of five subtypes of sphingosine 1-phosphate receptors (S1PRs) that regulate immune cell functioning, with functional distinctions to other subtypes. S1PR1-targeted modulators caused serious cardiac and vascular adverse effects because S1PR1 was expressed throughout the whole body. Since S1PR4 was only expressed in lung and lymphoid cells, S1PR4-targeted modulators might not trigger these side effects. However, the development of S1PR4-specific agonists is greatly hindered because of the lack of activated S1PR4 structure. Here, we resolved cryo-EM structures of activated S1PR4 and revealed the structural mechanism of ligand recognition, receptor activation, and Gi coupling. Our results offered structural templates for the development of selective S1PR4 agonists with improved safety profiles.

biochemistry↗