Biology subjects

Lu, A.

Publications and source records attributed to Lu, A..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection

The innate immune system relies on pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and guard proteins to monitor pathogen disruption of host cell processes. How different immune cell types engage PRR- and guard protein-dependent defenses in response to infection is poorly understood. Here, we show that macrophages and dendritic cells (DCs) respond in distinct ways to bacterial virulence activities. In macrophages, the bacterial pathogen Legionella pneumophila deploys its Dot/Icm type IV secretion system (T4SS) to deliver effector proteins that facilitate its robust intracellular replication. In contrast, T4SS activity triggers rapid DC death that potently restricts Legionella replication within this cell type. Intriguingly, we found that infected DCs exhibit considerable heterogeneity at the single cell level. Initially, a subset of DCs activate caspase-11 and NLRP3 inflammasome-dependent pyroptosis and release IL-1{beta} early during infection. At later timepoints, a separate DC population undergoes apoptosis driven by T4SS effectors that block host protein synthesis, thereby depleting the levels of the pro-survival proteins Mcl-1 and cFLIP. Together, pyroptosis and effector-triggered apoptosis robustly restrict Legionella replication in DCs. Collectively, our work suggests a model where Mcl-1 and cFLIP guard host translation in DCs, and that macrophages and DCs distinctly employ innate immune sensors and guard proteins to mount divergent responses to Legionella infection.

immunology↗

bioRxiv2024

N1-methylpseudouridine mRNA modification enhances efficiency and specificity of gene overexpression by preventing Prkra-mediated global translation repression

In vitro transcribed messenger RNA (IVT mRNA) has emerged as a pivotal tool in mRNA-based therapies and has been extensively employed in gene function studies and genetic tool applications. However, the IVT process generates double-stranded RNA (dsRNA) by-products that are recognized by dsRNA sensors, triggering innate immune responses. In this study, we comprehensively analyzed the detrimental effects of dsRNA by-products on early zebrafish embryos, revealing that these by-products induce cell necrosis and delay maternal-zygotic transition by reducing global translation efficiency via Prkra, a recently identified dsRNA sensor in pluripotent cells. Importantly, we demonstrate that N1-methylpseudouridine (m1{varphi}) modification of IVT mRNAs effectively mitigates these adverse effects, as m1{varphi}-modified dsRNAs exhibit significantly lower binding affinity to the Prkra dimer. Our findings underscore a previously overlooked challenge in the use of IVT mRNA in early embryos and offer a robust solution to enhance the fidelity of mRNA applications. Furthermore, we elucidate that m1{varphi} modification minimizes the dsRNA-induced stress response in pluripotent cells through a distinct mechanism.

developmental biology↗

bioRxiv2024

GM-CSF engages multiple signaling pathways to enhance pro-inflammatory cytokine responses in human monocytes during Legionella infection

The proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is required for host defense against a wide range of pathogens. We previously found that GM-CSF enhances inflammatory cytokine production in murine monocytes and is required for in vivo control of the intracellular bacterial pathogen Legionella pneumophila. It is unclear whether GM-CSF similarly augments cytokine production in human monocytes during bacterial infection. Here, we find that GM-CSF enhances inflammatory cytokine expression in Legionella-infected human monocytes by engaging multiple signaling pathways. Legionella- and TLR-dependent NF-B signaling is a prerequisite signal for GM-CSF to promote cytokine expression. Then, GM-CSF-driven JAK2/STAT5 signaling is required to augment cytokine expression in Legionella-infected human monocytes. We also found a role for PI-3K/Akt/mTORC1 signaling in GM-CSF-dependent upregulation of cytokine expression. Finally, glycolysis and amino acid metabolism are also critical for GM-CSF to boost cytokine gene expression in human monocytes during infection. Our findings show that GM-CSF-mediated enhancement of cytokine expression in infected human monocytes is regulated by multiple signaling pathways, thereby allowing the host to fine tune antibacterial immunity.

immunology↗

bioRxiv2024

Dynamic metabolic modeling of ATP allocation during viral infection

Viral pathogens, like SARS-CoV-2, hijack the hosts macromolecular production machinery, imposing an energetic burden that is distributed across cellular metabolism. To explore the dynamic metabolic tension between the hosts survival and viral replication, we developed a computational framework that uses genome-scale models to perform dynamic Flux Balance Analysis of human cell metabolism during virus infections. Relative to previous models, our framework addresses the physiology of viral infections of non-proliferating host cells through two new features. First, by incorporating the lipid content of SARS-CoV-2 biomass, we discovered activation of previously overlooked pathways giving rise to new predictions of possible drug targets. Furthermore, we introduce a dynamic model that simulates the partitioning of resources between the virus and the host cell, capturing the extent to which the competition depletes the human cells from essential ATP. By incorporating viral dynamics into our COMETS framework for spatio-temporal modeling of metabolism, we provide a mechanistic, dynamic and generalizable starting point for bridging systems biology modeling with viral pathogenesis. This framework could be extended to broadly incorporate phage dynamics in microbial systems and ecosystems.

systems biology↗

bioRxiv2024

Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in the C. elegans uaDf5 animal model.

Single large scale mitochondrial DNA (mtDNA) deletions (SLSMD) underlie a range of sporadic or maternally inherited primary mitochondrial diseases having significant morbidity and mortality, including Pearson syndrome, Kearns-Sayre Syndrome, or Chronic Progressive External Ophthalmoplegia. Therapeutic development has been hindered by limited existing knowledge on mtDNA quality control and a lack of SLSMD animal models. To address this challenge, we utilized the C. elegans heteroplasmic SLSMD strain, uaDf5, to objectively screen for potential therapies. As mitophagy modulation has been implicated in mtDNA homeostasis, we screened a library of mitophagy modulating compounds to determine their comparative effects to rescue mitochondrial unfolded protein (UPRmt) stress induction in in uaDf5 SLSMD worms. Interestingly, Thiamine was discovered to be an effective positive control, significantly reducing mitochondrial stress in this model. Two lead therapeutic candidates from the mitophagy library screen were Hemin and Celastrol (Tripterin). Celastrol is a mitophagy activating anti-inflammatory and metabolic modifying natural product derived compound, that rescued multiple fitness outcomes (thrashing, development, survival) and reduced the mitochondrial stress in uaDf5 animals in a mitophagy-dependent fashion. This study highlights the utility of the uaDf5 worm model to enable preclinical identification of therapeutic candidate leads for SLSMD-based heteroplasmic mtDNA diseases and identifies possible therapeutic candidates that serve as mitophagy modulators to improve health and specifically reduce heteroplasmy levels in SLSMD diseases.

cell biology↗

bioRxiv2024

Synthesis and Evaluation of Carmofur Analogs as Antiproliferative Agents, Inhibitors to the Main Protease (Mpro) of SARS-CoV-2, and Membrane Rupture-Inducing Agents

Initially developed as a derivatized analog of 5-fluorouracil for the treatment of colorectal cancer, carmofur has more recently demonstrated potent covalent inhibition of the main protease (Mpro) of SARS-CoV-2. Harnessing our previously described workflow for the optimized preparation of carmofur using benchtop 19F NMR spectroscopy, here, we prepared and evaluated a synthetic library of nine carmofur analogs with a selection of side chain motifs or single-atom substitution to explore the diversifiability of these compounds as Mpro inhibitors, where we discovered that a hexyl carbamate analog outperformed carmofur, and as antiproliferative agents in model human cell lines to identify differences in potency when the carbonyl electrophilicity and/or alkyl side chains are modified. Finally, we describe a novel workflow for the evaluation of membrane-rupturing small molecules through imaging of fluorescently labeled giant unilamellar vesicles (GUVs), and through this, we identified two lipophilic urethane analogs of carmofur bearing dodecyl urethane and octadecyl urethane side chains that have potent membrane-rupturing capability in the nanomolar range, providing insight into a potential mechanism for the in vitro activities of lipidated 5-fluorouracil analogs.

biochemistry↗

bioRxiv2024

Analyzing Biodiversity in Protected vs. Unprotected Tide Pools

This study assessed the efficacy of marine protected areas (MPAs) by comparing tide pool biodiversity in Half Moon Bay, California between a protected site (Fitzgerald Marine Reserve) and an unprotected site (Mavericks Beach). Samples were collected through random quadrat surveys. ImageJ and RStudio were used to analyze data through three methods utilizing the Simpsons Diversity Index along with three metrics. The unprotected Mavericks Beach displayed greater biodiversity through two metrics while the third did not find significant difference in biodiversity between sites. 30 unique species were present at each site with 43 species between both. These mixed findings prevent us from drawing definitive conclusions on the effectiveness of Half Moon Bays tide pool MPAs but suggest the MPA is less biodiverse. Potential explanations include the Intermediate Disturbance Hypothesis, lack of sample size, or that the MPA is not effective in maintaining biodiversity.

ecology↗

bioRxiv2024

IRF5 mediates adaptive immunity via altered glutamine metabolism, mTORC1 signaling and post-transcriptional regulation following T cell receptor activation

Although dynamic alterations in transcriptional, translational, and metabolic programs have been described in T cells, the factors and pathways guiding these molecular shifts are poorly understood, with recent studies revealing a disassociation between transcriptional responses and protein expression following T cell receptor (TCR) stimulation. Previous studies identified interferon regulatory factor 5 (IRF5) in the transcriptional regulation of cytokines, chemotactic molecules and T effector transcription factors following TCR signaling. In this study, we identified T cell intrinsic IRF5 regulation of mTORC1 activity as a key modulator of CD40L protein expression. We further demonstrated a global shift in T cell metabolism, with alterations in glutamine metabolism accompanied by shifts in T cell populations at the single cell level due to loss of Irf5. T cell conditional Irf5 knockout mice in a murine model of experimental autoimmune encephalomyelitis (EAE) demonstrated protection from clinical disease with conserved defects in mTORC1 activity and glutamine regulation. Together, these findings expand our mechanistic understanding of IRF5 as an intrinsic regulator of T effector function(s) and support the therapeutic targeting of IRF5 in multiple sclerosis. Sentence SummaryFindings provide new insight into the mechanisms by which T cell intrinsic IRF5 regulates the adaptive immune response via modulation of mTORC1 signaling, glutamine metabolism, and protein translation.

immunology↗

bioRxiv2024

Pre-Assembly NGS Correction of ONT Reads Achieves HiFi-Level Assembly Quality

BackgroundRecently developed hybrid assemblies can achieve Telomere-to-Telomere (T2T) completeness of some chromosomes. However, such approaches involve sequencing a large volume of both Pacific Biosciences high-fidelity (HiFi) and Oxford Nanopore Technologies (ONT) sequencing reads. Along with this, third-generation sequencing techniques are rapidly advancing, increasing the available length and accuracy. To reduce the final cost of genome assembly, here we investigated the possibility of assembly from low-coverage samples and with only ONT corrected by Next-Generation Sequencing (NGS) sequencing reads. We demonstrated that ONT-based assembly approaches corrected by NGS can achieve performance metrics comparable to more expensive hybrid approaches based on HiFi sequencing. ResultsWe investigated the assembly of different chromosomes of HG002 and the low-coverage performance of state-of-the-art hybrid assembly tools, including Verkko and Hifiasm, and ONT-based assemblers Shasta and Flye. Our study shows that even with the best NG50, Hifiasm has many misassemblies in the centromere region, raising doubts about its T2T capabilities. Additionally, ONT-based assemblies perform well at low coverage, offering a cost-effective solution. To achieve better assembly quality, we evaluated the performance of different NGS technologies across various aspects of hybrid genome assembly, including pre-assembly correction, haplotype phasing, and polishing, and found them to be similarly effective. For the NGS technology stLFR, we proposed two-round assembly methods that utilize stLFR linked-read data to achieve assembly phasing performance comparable to that obtained with trio data. ConclusionWe found that assemblies based on ONT corrected by NGS can match or exceed HiFi-based assemblies in accuracy. It appears that no assembly tool investigated here can achieve T2T completeness, even with 50X coverage. Therefore, we recommend using a combination of regular R9 or R10 simplex ONT reads and accurate NGS reads for assembly without aiming for T2T completeness. These ONT-based assemblies perform well even at low coverage, offering a cost-effective solution.

genomics↗

bioRxiv2024

TIR domains produce histidine-ADPR conjugates as immune signaling molecules in bacteria

TIR domains are central components of pattern recognition immune proteins across all domains of life. In both bacteria and plants, TIR-domain proteins were shown to recognize pathogen invasion and then produce immune signaling molecules exclusively comprising nucleotide moieties. Here we show that the TIR domain protein of the type II Thoeris defense system in bacteria produces a unique signaling molecule comprising the amino acid histidine conjugated to ADP-ribose (His-ADPR). His-ADPR is generated in response to phage infection and activates the cognate Thoeris effector by binding a Macro domain located at the C-terminus of the effector protein. By determining the crystal structure of a ligand-bound Macro domain, we describe the structural basis for His-ADPR recognition. Our analyses furthermore reveal a family of phage proteins that bind and sequester His-ADPR signaling molecules, allowing phages to evade TIR- mediated immunity. These data demonstrate diversity in bacterial TIR signaling and reveal a new class of TIR-derived immune signaling molecules combining nucleotide and amino acid moieties.

microbiology↗

bioRxiv2023

Complete genome of the Medicago anthracnose fungus, Colletotrichum destructivum, reveals a mini-chromosome-like region within a core chromosome.

Colletotrichum destructivum (Cd) is a phytopathogenic fungus causing significant economic losses on forage legume crops (Medicago and Trifolium species) worldwide. To gain insights into the genetic basis of fungal virulence and host specificity, we sequenced the genome of an isolate from M. sativa using long-read (PacBio) technology. The resulting genome assembly has a total length of 51.7 Mb and comprises 10 core chromosomes and two accessory chromosomes, all of which were sequenced from telomere to telomere. A total of 15,631 gene models were predicted, including genes encoding potentially pathogenicity-related proteins such as candidate secreted effectors (484), secondary metabolism key enzymes (110) and carbohydrate-active enzymes (619). Synteny analysis revealed extensive structural rearrangements in the genome of Cd relative to the closely-related Brassicaceae pathogen, C. higginsianum. In addition, a 1.2 Mb species-specific region was detected within the largest core chromosome of Cd that has all the characteristics of fungal accessory chromosomes (transposon-rich, gene-poor, distinct codon usage), providing evidence for exchange between these two genomic compartments. This region was also unique in having undergone extensive intra-chromosomal segmental duplications. Our findings provide insights into the evolution of accessory regions and possible mechanisms for generating genetic diversity in this asexual fungal pathogen. Impact statementColletotrichum is a large genus of fungal phytopathogens that cause major economic losses on a wide range of crop plants throughout the world. These pathogens vary widely in their host specificity and may have either broad or narrow host ranges. Here, we report the first complete genome of the alfalfa (Medicago sativa) pathogen, Colletotrichum destructivum, which will facilitate the genomic analysis of host adaptation and comparison with other members of the Destructivum species complex. We identified a species-specific 1.2 Mb region within chromosome 1 displaying all the hallmarks of fungal accessory chromosomes, which may have arisen through the integration of a mini-chromosome into a core chromosome and could be linked to the pathogenicity of this fungus. We show this region is also a focus for segmental duplications, which may contribute to generating genetic diversity for adaptive evolution. Finally, we report infection by this fungus of the model legume, Medicago truncatula, providing a novel pathosystem for studying fungal-plant interactions. Data summaryAll RNA-seq data were submitted to the NCBI GEO portal under the GEO accession GSE246592. C. destructivum genome assembly and annotation are available under the NCBI BioProject PRJNA1029933 with sequence accessions CP137305-CP137317. Supplementary data (genomic and annotation files, genome browser) are available from the INRAE BIOGER Bioinformatics platform (https://bioinfo.bioger.inrae.fr/). Transposable Elements consensus sequences are also available from the French national data repository, research.data.gouv.fr with doi 10.57745/TOO1JS.

genomics↗

bioRxiv2023

Bio-Mol:Pretraining Multimodality Bioactivity Profile for Enhancing Small Molecule Property Prediction

Non-optimized pharmacokinetic parameters serve as the primary cause of failure in clinical trials of drugs. Therefore, the successful prediction of pharmacokinetic parameters during the pre-clinical stage is crucial for the success of drug candidates. Conventional methods primarily rely on 2D structural information, while advanced models extend the features to other structural-related information or use advanced computational models to improve prediction accuracy. However, to gain a comprehensive understanding of small molecules, integrating bioactivity profiles with chemical structural information is essential. One significant challenge in this integration is the high proportion of missing values within experimentally validated bioactivity profiles for most small molecules. To address this challenge, we introduce Bio-Mol, an artificial intelligence model designed to effectively handle this issue. Bio-Mol utilizes a pretrain and finetune strategy, enabling the incorporation of a large proportion of missing bioactivity profiles during the small molecule representation learning process. Comprehensive evaluations of Bio-Mol demonstrate a notable improvement in predicting molecule properties. The integration of missing bioactivity profiles enhances the AUROC of average 5.2% compared to the previous state-of-the-art models predictions. Furthermore, we explore the potential of Bio-Mol in predicting synergistic drug combinations, highlighting its versatility and broader applications in the field of drug discovery. The successful implementation of Bio-Mol showcases its efficacy in over-coming the challenges posed by missing bioactivity profile data. This model paves the way for optimizing small molecule pharmacokinetics prediction, providing valuable insights for drug development and discovery processes.

bioinformatics↗

bioRxiv2023

Bushfire alters the gut microbiome in endangered Kangaroo Island echidnas (Tachyglossus aculeatus multiaculeatus)

Kangaroo Island experienced extensive bushfires in December 2019 and January 2020, affecting almost half of the island. This impacted several threatened species including the Kangaroo Island echidnas (Tachyglossus aculeatus multiaculeatus). Echidnas can often survive fires, however, changes in soil chemistry and food availability raises questions about the impact on echidna gut health and foraging behaviours. Due to local participation in the citizen science project, EchidnaCSI, echidna scats were collected before and after the fires to directly assess how fire affects their gut microbiomes. Metabarcoding of scat microbiota (n = 13) revealed substantial changes in bacterial composition of echidna faeces post-bushfire when compared to samples collected prior to bushfires. Before the fires, echidna gut microbiomes were more variable and contained mostly soil-associated bacteria, whereas post-fire samples shifted to uniform bacterial communities consisting of lactic acid and gut commensal bacteria. Interestingly, changes were observed in scats collected in both burnt and unburnt regions of the island, suggesting echidnas are foraging between these areas. This is the first study to document changes in gut microbiome of any mammal following bushfires. More work is needed to investigate if the gut bacterial communities continue to change as areas recover from fires.

genomics↗

bioRxiv2023

The SARM1 TIR domain produces glycocyclic ADPR molecules as minor products

Sterile alpha and TIR motif-containing 1 (SARM1) is a protein involved in programmed death of injured axons. Following axon injury or a drug-induced insult, the TIR domain of SARM1 degrades the essential molecule nicotinamide adenine dinucleotide (NAD+), leading to a form of axonal death called Wallerian degeneration. Degradation of NAD+ by SARM1 is essential for the Wallerian degeneration process, but accumulating evidence suggest that other activities of SARM1, beyond the mere degradation of NAD+, may be necessary for programmed axonal death. In this study we show that the TIR domains of both human and fruit fly SARM1 produce 1''-2' and 1''-3' glycocyclic ADP-ribose (gcADPR) molecules as minor products. As previously reported, we observed that SARM1 TIR domains mostly convert NAD+ to ADPR (for human SARM1) or cADPR (in the case of SARM1 from Drosophila melanogaster). However, we now show that human and Drosophila SARM1 additionally convert [~]0.1-0.5% of NAD+ into gcADPR molecules. We find that SARM1 TIR domains produce gcADPR molecules both when purified in vitro and when expressed in bacterial cells. Given that gcADPR is a second messenger involved in programmed cell death in bacteria and likely in plants, we propose that gcADPR may play a role in SARM1-induced programmed axonal death in animals.

molecular biology↗

bioRxiv2023

Exosome-mediated release of bis(monoacylglycerol)phosphate is regulated by LRRK2 and Glucocerebrosidase activity

The endolysosomal phospholipid, bis(monoacylglycerol)phosphate (BMP), is aberrantly elevated in the urine of Parkinsons patients with mutations in genes encoding leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GCase). Because BMP resides on and regulates the biogenesis of endolysosomal intralumenal membranes that become extracellular vesicles (EVs) upon release, we hypothesized that elevated urinary BMP may be driven by increased exocytosis of BMP-enriched EVs. To test this hypothesis, we analyzed BMP metabolism and EV-associated release of BMP in wild type (WT) and R1441G LRRK2-expressing mouse embryonic fibroblast (MEF) cells. Using immunofluorescence microscopy and transmission electron microscopy we detected structural alterations in endolysosomes and antibody-accessible BMP pool, indicating that mutant LRRK2 affects endolysosomal homeostasis. Biochemical analyses of isolated EV fractions confirmed the effect on endolysosomes by showing an increase in LAMP2-positive EVs in mutant cells, which was partially restored by LRRK2 kinase inhibition but further augmented, albeit to a more variable extent, by GCase inhibition. Using mass spectrometry, we detected an overall increase in total di-22:6-BMP and total di-18:1-BMP in cell lysates from mutant LRRK2 MEFs compared to WT cells. Inhibition of LRRK2 kinase partially restored cellular BMP levels, whereas inhibition of GCase further increased the BMP content. In isolated EVs from LRRK2 mutant cells, LRRK2 inhibition decreased BMP content whereas GCase inhibition tended to increase it. Using metabolic labeling experiments, we demonstrated that the increase in cellular BMP content is not due to an increase in BMP synthesis, even though we observed an increase in BMP synthesizing enzyme, CLN5, in LRRK2 mutant MEFs and patient-derived fibroblasts. Finally, pharmacological modulation of EV release and live total internal reflection fluorescence (TIRF) microscopy of endolysosomal exocytosis in human G2019S LRRK2 fibroblasts, further confirmed that BMP release is associated with EV secretion. Together, these results establish LRRK2 as a regulator of BMP levels in cells and its release through EVs and suggest that GCase activity further modulates this process in LRRK2 mutant cells. Mechanistic insights from these studies have implications for the potential use of BMP-positive EVs as a biomarker for Parkinsons disease and associated treatments.

neuroscience↗

bioRxiv2023

Stoichiometric expression of messenger polycistrons by eukaryotic ribosomes (SEMPER) for compact, ratio-tunable multi-gene expression from single mRNAs

Applications of mammalian synthetic biology increasingly require the ability to express multiple proteins at user-determined stoichiometries from single, compactly encoded transcripts. Here we present an approach for expressing multiple open reading frames (ORFs) from a single transcript, taking advantage of the leaky scanning model of translation initiation. In this method, adjacent ORFs are translated from a single messenger RNA at tunable ratios determined by their order in the sequence and the strength of their translation initiation sites. We call this approach Stoichiometric Expression of Messenger Polycistrons by Eukaryotic Ribosomes (SEMPER). We demonstrate the principles of this approach by expressing up to three fluorescent proteins from one plasmid in two different cell lines. We then use it to encode a stoichiometrically tuned polycistronic construct encoding gas vesicle acoustic reporter genes, showing that enforcing the optimal ratio in every cell enables efficient formation of the multi-protein complex while minimizing cellular toxicity. Finally, we demonstrate the polycistronic expression of two fluorescent proteins from single mRNAs made through in vitro transcription and delivered to cells. SEMPER will enable a broad range of applications requiring tunable expression from compact eukaryotic constructs.

synthetic biology↗

bioRxiv2023

Phages overcome bacterial immunity via diverse anti-defense proteins

It was recently shown that bacteria employ, apart from CRISPR-Cas and restriction systems, a considerable diversity of phage resistance systems, but it is largely unknown how phages cope with this multilayered bacterial immunity. Here, we analyzed groups of closely related Bacillus phages that showed differential sensitivity to bacterial defense systems, and identified multiple families of anti-defense proteins that inhibit the Gabija, Thoeris, and Hachiman systems. We show that these proteins efficiently cancel the defensive activity when co-expressed with the respective defense system or introduced into phage genomes. Homologs of these anti-defense proteins are found in hundreds of phages that infect taxonomically diverse bacterial species. We show that an anti-Gabija protein, denoted Gad1, blocks the ability of the Gabija defense complex to cleave phage-derived DNA. Our data further reveal an anti-Thoeris protein, denoted Tad2, which is a "sponge" that sequesters the immune signaling molecules produced by Thoeris TIR-domain proteins in response to phage. Our results demonstrate that phages encode an arsenal of anti-defense proteins that can disable a variety of bacterial defense mechanisms.

genetics↗

bioRxiv2023

An explainable artificial intelligence-based typification of chronic inflammatory responses enhances glioma prognosis

Glioma is one of the most aggressive solid brain tumors with a poor prognosis. A chronic tumor inflammatory microenvironment drives glioma promotion and progression. The neutrophil-to-lymphocyte ratio and other clinicopathological variables usually serve as prognostic glioma markers. However, they are not ubiquitous prognostic markers for glioma as they fail to reveal the intricacy between the glioma-specific tumor inflammatory microenvironment and the systemic inflammatory responses, especially those chronic inflammatory responses, which vary among individuals fabricating diverse prognostic outcomes. Here, we introduced an explainable artificial intelligence model to typify chronic inflammatory responses as prognostic markers for glioma using 694-patients data from The Cancer Genome Atlas. We characterized the glioma-specific personalized inflammatory mediators using multi-layered regulators such as transcriptional networks, cellular infiltration markers, and cellular senescence markers, which identified five unique chronic inflammatory responses (p-value<0.0001). We defined its prognostic significance using overall survival analyses. The chronic inflammatory responses were positively correlated with poor overall survival in glioma. The patients with higher chronic inflammatory responses showed significantly shorter overall survival than those with lower chronic inflammatory responses. Interestingly, optimizing those chronic inflammatory responses improved the overall survival of glioma patients. We identified the effector genes within the personalized inflammatory mediators networks, indicating them as the targets for optimizing individualized chronic inflammatory response profiles through co-drug intervention. SignificanceExplainable artificial intelligence-based typification of chronic inflammatory responses accelerates glioma prognosis and supports co-drug discovery to modulate inflammatory responses alongside cancer therapy, suggested by 694-glioma patients data analysis.

systems biology↗