Biology subjects

Hong, Y.

Publications and source records attributed to Hong, Y..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Metabolic and ribosomal dysregulation drive developmental arrest of Schistosoma japonicum in non-permissive rats

Parasitic flatworms of the genus Schistosoma infect a wide range of definitive hosts, which are categorized as permissive or non-permissive based on their capacity to support parasite development. Unlike permissive hosts such as mice, Schistosoma japonicum undergoes pronounced developmental arrest in non-permissive hosts like rats; however, the molecular mechanisms underlying this phenomenon remain largely unclear. In this study, we conducted a comprehensive morphological and transcriptomic comparison of S. japonicum derived from mouse and rat hosts at multiple time points post-infection, identifying the period between 12 and 24 days post-infection (dpi) as a critical window for developmental arrest in parasites from rats. Utilizing single-cell RNA sequencing, we constructed a high-resolution cellular atlas of S. japonicum at 14 and 24 dpi from both host species, revealing host-dependent alterations in cell composition and transcriptional programs during parasite development. Functional analyses further demonstrated that impairments in mitochondrial function and anaerobic glycolysis contribute to the developmental arrest observed in parasites from rats. Additionally, downregulation of ribosomal genes was associated with reduced protein synthesis and impaired cell proliferation. Together, these findings suggest that disruptions in energy metabolism and ribosomal function are key drivers of developmental arrest in non-permissive hosts. This study provides novel, parasite-centered insights into host permissiveness and identifies potential molecular targets for schistosomiasis control strategies.

developmental biology↗

bioRxiv2025

A community-consensus reconstruction of Chinese Hamster metabolism enables structural systems biology analyses to decipher metabolic rewiring in lactate-free CHO cells

Genome-scale metabolic models (GEMs) are indispensable for studying and engineering cellular metabolism. Here, we present iCHO3K, a community-consensus, manually-curated reconstruction of the Chinese Hamster metabolic network. In addition to accounting for 11004 reactions associated with 3597 genes, iCHO3K includes 3489 protein structures and structural descriptors for >70% of its 7377 metabolites, enabling deeper exploration of the link between molecular structure and cellular metabolism. We used iCHO3K to contextualize transcriptomics and metabolomics data from a CHO cell line in which lactate secretion is abolished. We found the reduced glycolytic flux and enhanced TCA cycle flux were accompanied by an elevated NADH and PEP levels in these cells, consistent with experimental measurements. Leveraging iCHO3Ks structural annotations, we identified candidate binding interactions of NADH and PEP with glycolytic enzymes showing model-predicted differential flux, suggesting novel allosteric regulation associated with the observed decrease in glucose uptake and glycolysis. Overall, iCHO3K offers a valuable framework for systematic integration of omics data, improved flux predictions, and structure-guided insights, thus advancing CHO cell engineering and enhancing biomanufacturing efficiency.

systems biology↗

bioRxiv2025

Advancing RNAi-Based Strategies Against Downy Mildews: Insights Into dsRNA Uptake and Gene Silencing

Downy mildew (DMs) dieases are caused by destructive obligate pathogens with limited control options, posing a significant threat to global agriculture. RNA interference (RNAi) has emerged as a promising, environmentally sustainable strategy for disease management. In this study, we evaluated the efficacy of dsRNA-mediated RNAi in suppressing key biological functions in DM pathogens of Arabidopsis thaliana, pea and lettuce DM pathogens, Hyaloperonospora arabidopsidis (Hpa), Peronospora viciae f. sp. pisi (Pvp) and Bremia lactucae (Bl), respectively. We specifically targeted the cellulose synthase 3 (CesA3) and the beta tubulin (BTUB) genes. Silencing CesA3 impaired spore germination and infection across multiple species, while BTUB silencing reinforced the potential of dsRNA-mediated inhibition. Reduction in gene expression levels correlated well with the sporulation assays confirming the effectiveness of dsRNA-mediated gene silencing. We used dsRNAs that were chemically synthesized, in vitro transcribed (IVT) or produced in E. coli. We found that the length and concentration of these dsRNAs significantly affected uptake efficiency, spore germination, and sporulation, with higher concentrations enhancing inhibitory effects. Confocal microscopy using Cy-5-labelled short-synthesized dsRNA (SS-dsRNA) provided direct evidence of spore uptake, confirming the potential of SS-dsRNA for pathogen control. However, species-specific sequence variations influenced dsRNA efficacy, underscoring the importance of target sequence design. Multiplexed RNAi impacted silencing synergisticly, further reducing germination and sporulation in Hpa. Additionally, we demonstrated that SS-dsRNA-mediated gene silencing is sustained over time, with a significant reduction in gene expression level at 4, 7, 10 and 11dpi. This indicates the durability and efficacy of this approach. Taken together, these findings demonstrate the potential of dsRNA-mediated gene silencing as a precision tool for managing DM pathogens.

plant biology↗

bioRxiv2025

Nitric oxide donor sodium nitroprusside serves as a source of iron supporting Pseudomonas aeruginosa growth and biofilm formation

Biofilm dispersal agents, like nitric oxide (NO), restore antimicrobial effectiveness against biofilm infections by inducing bacteria to shift from a biofilm to a planktonic state, thereby overcoming the antimicrobial tolerance typically associated with biofilms. Sodium nitroprusside (SNP) is a widely used NO donor for investigating the molecular mechanisms underlying NO-mediated biofilm dispersal in the nosocomial pathogen Pseudomonas aeruginosa. However, the biofilm effects of SNP are variable depending on the in vitro experimental conditions, with some studies reporting enhanced growth in both planktonic and biofilm forms instead of dispersal. These discrepancies suggest that SNP affects P. aeruginosa biofilm-residing cells beyond the release of NO. In this study, we compared SNP with another NO donor, Spermine NONOate, to systematically contrast their effects on biofilm and planktonic cultures of P. aeruginosa. We found that SNP, but not Spermine NONOate, increased the biomass of P. aeruginosa biofilms in microplate cultures. This effect was also observed when biofilms were supplemented with iron. Additionally, supplementation with SNP rescued the planktonic growth of P. aeruginosa in iron-depleted media, similar to FeSO4 supplementation, suggesting that SNP may serve as an iron source. Our findings suggest that SNPs potential as an NO agent used for biofilm dispersal may be confounded by its role in promoting both biofilm and planktonic growth through its iron centre. Our study cautions investigators using SNP for studying NO-mediated biofilm dispersal.

microbiology↗

bioRxiv2025

SARS-CoV-2 Infects Peripheral Sensory Neurons and Promotes Axonal Degeneration via TRPV1 Activation

Common neurological symptoms of COVID-19, such as anosmia, headaches, and cognitive dysfunction, depend on interactions between the peripheral and central nervous systems. However, the molecular mechanisms by which SARS-CoV-2 affects the peripheral nervous system remain poorly understood, with ongoing debate about whether sensory neurons can be directly infected by the virus. In this study, human iPSC-derived sensory neurons were exposed to the SARS-CoV-2 BA.5 variant, a mutant virus, or viral S1 proteins. Under control conditions, sensory neurons exhibited low expression of ACE2. However, exposure to BA.5 or S1 proteins significantly upregulated ACE2 expression in peripherin-positive sensory neurons. Virological analysis confirmed that SARS-CoV-2 directly infects TRPV1-expressing sensory neurons, including olfactory neurons. Moreover, exposure to the live virus or S1 proteins induced TRPV1 upregulation and translocation from the nucleus to the cytosol, resulting in axonal destruction. Single-nucleus transcriptomic analysis revealed that viral exposure enhanced cAMP signaling, virus receptor and transmembrane transporter activities, and inflammatory regulation of TRP channels, which collectively contributed to synaptic and axonal damage. Importantly, treatment with a TRPV1 antagonist demonstrated neuroprotective effects. These findings underscore the need for further research into the interaction between SARS-CoV-2 and TRPV1, as well as its downstream signaling pathways, to develop therapeutic strategies for preventing sensory neuron loss during viral infections. HighlightsO_LIiPSC technology was employed to generate peripheral sensory neurons from human induced pluripotent stem cells (iPSCs), providing a valuable platform for studying the impact of SARS-CoV-2 on peripheral sensory neurons. C_LIO_LIOur findings demonstrated that the SARS-CoV-2 Omicron BA.5 variant exerted both direct and indirect effects on peripheral sensory neurons. Virus exposure upregulated the angiotensin-converting enzyme 2 (ACE2) receptor in peripherin-positive neurons. Additionally, exposure to the virus or its S1 spike protein increased transient receptor potential vanilloid 1 (TRPV1) expression and trafficking, leading to axonal degeneration. C_LIO_LISingle-nucleus RNA sequencing revealed that BA.5 exposure enhanced cAMP signaling pathway, virus receptor and transmembrane transporter activities, and inflammatory regulation of TRP channels that led to the significantly damage on synapses and axon guidance. C_LIO_LIThe TRPV1 antagonist capsazepine inhibited TRPV1 activation and mitigated axonal damage, offering neuroprotective effects for sensory neurons exposed to SARS-CoV-2. C_LI

cell biology↗

bioRxiv2025

De novo biosynthesis of cannabinoid and its analogs in Yarrowia lipolytica

Cannabis sativa has long been a cornerstone of both medicinal and cultural practices, with its therapeutic use spanning over 2,700 years. Central to its therapeutic effects are cannabinoids, which interact with the endocannabinoid system to influence various physiological processes such as anxiety, pain, and inflammation. Despite its benefits, cannabinoid production faces challenges and scarcity from plant extraction. This work leverages Yarrowia lipolytica as a platform for cannabinoid biosynthesis. By optimizing precursor supply, engineering biomolecular condensate-like dual prenyltransferase expression and expanding endogenous metabolism with a noncanonical polyketide synthase, we achieved the de novo biosynthesis of various cannabinoid and its analogs. Our engineered Y. lipolytica produced [~]3.5 mg/L of cannabigerolic acid, 18.8 mg/L of orsellinic acid, and 0.5 mg/L of cannabigerorcinic acid. Additionally, CBGA titer reached 15.7 mg/L with olivetolic acid supplement. This work demonstrates Y. lipolyticas versatility as a promising host for cannabinoid and its analogs production, which opens avenues for further research and medicinal applications.

synthetic biology↗

bioRxiv2025

Emergence of cooperation promoted by higher-order strategy updates

Cooperation is fundamental to human societies, and the interaction structure among individuals profoundly shapes its emergence and evolution. In real-world scenarios, cooperation prevails in multi-group (higher-order) populations, beyond just dyadic behaviors. Despite recent studies on group dilemmas in higher-order networks, the exploration of cooperation driven by higher-order strategy updates remains limited due to the intricacy and indivisibility of group-wise interactions. Here we investigate four categories of higher-order mechanisms for strategy updates in public goods games and establish their mathematical conditions for the emergence of cooperation. Such conditions uncover the impact of both higher-order strategy updates and network properties on evolutionary outcomes, notably highlighting the enhancement of cooperation by overlaps between groups. Interestingly, we discover that the group-mutual comparison update - selecting a high-fitness group and then imitating a random individual within this group - can prominently promote cooperation. Our analyses further unveil that, compared to pairwise interactions, higher-order strategy updates generally improve cooperation in most higher-order networks. These findings underscore the pivotal role of higher-order strategy updates in fostering collective cooperation in complex social systems. Author summaryHuman societies often organize and cooperate within social groups, where relatives, friends, neighbors, and colleagues influence behavior at both group and individual levels. Individuals may exhibit biased or neutral attitudes when selecting a neighboring group and a peer within it for imitation or comparison, a process termed as higher-order strategy update. These selection preferences originate from four personality types: aggressive, open-minded, myopic, and passive. This work demonstrates that the open-minded type - indiscriminately imitating a peer within a well-functioning group - significantly promotes cooperation. The mathematical framework proposed in this study deepens the understanding of how decision-making within higher-order structures affects the emergence and spread of cooperative behaviors.

evolutionary biology↗

bioRxiv2025

Comparative molecular landscapes of immature neurons in the mammalian dentate gyrus across species reveal special features in humans

Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity, learning and memory, but their evolutionary changes across species and specialized features in humans remain poorly understood. Here we performed machine learning-augmented analysis of published single-cell RNA-sequencing datasets and identified macaque imGCs with transcriptome-wide immature neuronal characteristics. Our cross-species comparisons among humans, monkeys, pigs, and mice showed few shared (such as DPYSL5), but mostly species-specific gene expression in imGCs that converged onto common biological processes regulating neuronal development. We further identified human-specific transcriptomic features of imGCs and demonstrated functional roles of human imGC-enriched expression of a family of proton-transporting vacuolar-type ATPase subtypes in development of imGCs derived from human pluripotent stem cells. Our study reveals divergent gene expression patterns but convergent biological processes in the molecular characteristics of imGCs across species, highlighting the importance of conducting independent molecular and functional analyses for adult neurogenesis in different species.

neuroscience↗

bioRxiv2025

Structure-based analysis unveils co-origin of LPOR and nitrogenase-like proteins

Structures of nitrogenases, dark-operative protochlorophyllide oxidoreductases, and light-dependent protochlorophyllide oxidoreductases (LPOR) have been resolved. However, their evolutionary relatedness remains elusive. Here, we show, through structural alignment, that all subunits of nitrogenase-like proteins originated from a co-ancestral archaic one-subdomain precursor. LPOR evolved from the BchX/BchY subunits of nitrogenase-like chlorophyllide a oxidoreductase (COR), and the intermediary retinol dehydrogenase through possible genetic recombination. We thus establish previously unknown structural links among key enzymes involved in biological nitrogen-fixation (BNF) and photosynthesis, unraveling structure-guided functional evolution from a single-subunit iron protein to multi-subunit nitrogenase-like COR, and to the single-subunit LPOR for phototrophic metabolism via bacteriochlorophyll, retinal, and chlorophyll. This work also demonstrates structural similarities are imperative for inferring distant origins of functionally divergent proteins, particularly those lacking primary amino-acid sequence identity. Moreover, our findings coupled with AI may be exploited to design innovative light-driven CORs and/or light-utilizing nitrogenases with enhanced efficacy of photosynthesis and BNF. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/634645v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@9f9a2aorg.highwire.dtl.DTLVardef@4243ecorg.highwire.dtl.DTLVardef@796b4corg.highwire.dtl.DTLVardef@17373da_HPS_FORMAT_FIGEXP M_FIG C_FIG Video abstracthttps://www.youtube.com/watch?v=b0qBE1JMaH0 HighlightsO_LILPOR evolves from BchX and BchY subunits of the nitrogenase-like protein (NGLP) COR C_LIO_LIAll subunits of NGLPs can be traced back to the ancestral one-subdomain precursor C_LIO_LIRetinol dehydrogenase acts as a crucial intermediate in the COR to LPOR evolution C_LIO_LIStructure-based design of LUN is showcased to revolutionize protein engineering C_LI

evolutionary biology↗

bioRxiv2025

Evaluating the toxicity of methanol, formaldehyde and formate on the growth fitness of Yarrowia lipolytica

Liquid C1 feedstock, including methanol, formaldehyde and formic acid can be easily manufactured from greenhouse gases CO2 and CH4. Yarrowia lipolytica, isolated from marine ecosystem, is a non-conventional yeast which is capable of assimilating multiple range of hydrophobic compounds including alcohols, lipids, hydrocarbons, and volatile fatty acids et al. This yeast has been extensively engineered to produce lipids, carotenoids, squalene and other natural products. Herein we tested the growth fitness of Y. lipolytica when exposed to various one-carbon (C1) liquid feedstocks (methanol, formaldehyde, and formic acid). We firstly captured the cell growth kinetics with an automatic Cell Growth Analyzer and fitted the data with a Monod-type growth model. We obtained the inhibition constants of the three liquid C1s from the growth fitness dose-response curves. We found that the lagging phase duration is exponentially correlated with the toxicity of the tested C1 solvents. Notably, Y. lipolytica exhibited tolerance to methanol (IC50 871 mM) and formic acid (IC50 42.6 mM), but showed sensitivity to formaldehyde (IC50 3.8 mM). We next chose fromate as the co-substrate to cultivate Y. lipolytica, confirmed that Y. lipolytica can upcycle formic acid to improve lipid yields and biomass in fed-batch culture. This work broadens Y. lipolyticas substrate scope and facilitates sustainable and cost-efficient production of fuels and chemicals.

synthetic biology↗

bioRxiv2025

Disruptions in Outer Membrane-Peptidoglycan Interactions Enhance Bile Salt Resistance in O-antigen-Producing E. coli

Bile salts (BS) are derived from cholesterol in the liver and act as antimicrobial agents in the intestines by disrupting bacterial cell membranes and inducing oxidative stress. The gut bacterium E. coli is naturally resistant to BS, including the model strain K12 that produces a truncated LPS without O-antigen (OAg). Paradoxically, restoring a wild-type like LPS with OAg sensitises E. coli K12 to exogenous BS. In this study, we investigate this phenomenon. We show that mutations causing truncation of the LPS core oligosaccharide render these strains even more susceptible to BS, similar to the mutant strain MG1655-S{Delta}waaL defective in OAg ligase, primarily due to the accumulation of the lipid-linked intermediate UndPP-OAg. Through the characterisation of BS-resistant suppressor mutants of MG1655-S{Delta}waaL, we identify key genetic disruptions involved in resistance. Notably, we observed the highest BS resistance in strains with a weaker connection between the outer membrane (OM) and peptidoglycan (PG), including strains lacking the major OM-anchored, PG-binding proteins OmpA or Lpp, or expressing versions of these that lack PG-binding. Our data suggest that BS-induced stress in OAg-producing E. coli is due to the spatial constraints between OM and PG, and that mutations disrupting OM-PG interactions alleviate this stress, enhancing BS resistance. These findings provide new insights into a major challenge E. coli faces in the gut environment where it needs to produce OAg for stable colonisation and resists BS. E. coli can only survive BS exposure by fine-tuning the connectivity between its cell envelope layers, which highlights a potential target for modulating bacterial responses to BS in the gut. Author summaryEnteric bacteria residing in the human gut must withstand the host-derived antimicrobial agents, bile salts (BS), but the underlying resistance mechanisms are not fully elucidated. This study investigates the BS resistance mechanisms in O-antigen (OAg)-producing Escherichia coli K-12. We show that truncation of lipopolysaccharide (LPS) core oligosaccharides or restoration of OAg production increases BS sensitivity due to the accumulation of UndPP-OAg intermediates. By analysing suppressor mutants, we identify key genetic disruptions, particularly affecting the level of outer membrane-peptidoglycan (OM-PG) interactions involving OmpA and Lpp, which confer heightened BS resistance. Our findings highlight how BS-induced stress is linked to spatial constraints between the OM and PG layer, offering new insights into bacterial adaptation to BS stress. This research may provide new targets for therapeutic interventions to modulate gut microbial responses to BS.

microbiology↗

bioRxiv2025

DAZAP2 functions as a pan-coronavirus restriction factor by inhibiting viral entry and genomic replication

The SARS-CoV-2 pandemic and the emergence of novel variants underscore the need to understand host-virus interactions and identify host factors that restrict viral infection. Here, we perform a genome-wide CRISPR knockout screen to identify host restriction factors for SARS-CoV-2, revealing DAZAP2 as a potent antiviral gene. DAZAP2, previously implicated in SARS-CoV-2 restriction, is found to inhibit viral entry by blocking virion fusion with both endolysosomal and plasma membranes. Additionally, DAZAP2 suppresses genomic RNA replication without affecting the primary translation of viral replicases. We demonstrate that DAZAP2 functions as a pan-coronavirus restriction factor across four genera of coronaviruses. Importantly, knockout of DAZAP2 enhances SARS-CoV-2 infection in mouse models and in human primary airway epithelial cells, confirming its physiological relevance. Mechanistically, antiviral activity of DAZAP2 appears to be indirect, potentially through the regulation of host gene expression, as it primarily localizes to the nucleus. Our findings provide new insights into the host defense system against coronaviruses and highlight DAZAP2 as a potential target for host-directed antiviral therapies. IMPORTANCEDuring viral infection, the host defense response is mediated by a variety of host factors through distinct mechanisms that have yet to be fully elucidated. Although DAZAP2 was previously implicated in SARS-CoV-2 restriction, its mechanisms of action and in vivo relevance remain unclear. In this study, we identify the DAZAP2 as a potent pan-coronavirus restriction factor that inhibits viral infection through dual mechanisms: blocking virion fusion with both endolysosomal and plasma membranes, and suppressing genomic RNA replication. We confirm its physiological relevance in host defense using mouse models and primary cell cultures. This study advances our understanding of host-pathogen interactions. Targeting DAZAP2 or its regulatory pathways could provide a new approach to enhance host defense against current and future coronavirus threats.

microbiology↗

bioRxiv2025

Identifying JNK-regulated phosphoproteome markers of anxiety-like behaviour in mouse hippocampus

JNKs mediate neuronal damage in neurodegenerative disease and inhibitors of JNK1 have shown anxiolytic and anti-depressive effects in mice. Here, we analyze the phosphoproteomes of hippocampus and nucleus accumbens from DJNKI-1 (JNK inhibitor)-infused mice. We correlate phospho-site changes with anxiety-like behaviours in the elevated plus maze and light-dark test and identify unique changes in responder mice. Among the DJNKI-1 regulated phosphosites, several lie within GSK3 motifs and are exclusively down-regulated. Consistent with this, GSK3{beta} is inhibited and AKT activated. Importantly, we detect multilevel regulation of glucose metabolism enzymes including increased PDPK1-S241 phosphorylation, and a 5-fold increase in pyruvate dehydrogenase (PDHA1)-S-293 phosphorylation, signifying its inhibition. This suggests that JNK inhibitor drives a metabolic transformation to the neuronal Warburg response. This and a range of identified synaptic and cytoskeletal protein phosphosite changes are discussed in the context of JNK-regulated anxiety responses. The annotated hippocampal and nucleus accumbens phosphoproteomes described here will support a mechanistic understanding of the JNK pathway for future studies of brain disorders.

neuroscience↗

bioRxiv2025

Confounder-free Predictive Models for Microbiome-based Host Phenotype Prediction

As in many fields, the presence of confounding effects (or biases) presents a significant challenge in micro-biome research, including using microbiome data to predict host phenotypes. If not properly addressed, confounders can lead to spurious associations, biased predictions and misleading interpretations. One notable example is the medication metformin, which is commonly prescribed to treat type 2 diabetes (T2D) and is known to influence the gut microbiome. In this study, we propose confounder-free predictive models for human phenotype prediction using microbiome data. These models utilize an end-to-end approach within an adversarial min-max optimization framework to derive features that are invariant to confounding factors, while accounting for the intrinsic correlations between confounders and prediction outcomes. We implemented two versions of confounder-free predictors using different network architectures: one based on a fully connected network (referred as FNN CF) and another incorporating prior biological knowledge (referred as MicroKPNN CF). We evaluated our models on microbiome datasets associated with T2D, where metformin acts as a confounder. Our results demonstrate that confounder-free predictors achieve higher accuracy compared to models that do not account for confounders and more effectively identify microbial markers associated with the phenotype, rather than markers influenced by metformin. Between the two confounder-free models, although the prior-knowledge-guided approach showed slightly lower prediction accuracy compared to the fully connected model, it offered greater interpretability, providing additional insights into the underlying biological mechanisms.

bioinformatics↗

bioRxiv2025

Optimal membrane fluidity modulates biofilm formation in Escherichia coli

IMPACT STATEMENTMembrane fluidity plays a crucial role in bacterial fitness and adaptation to cope rapid environmental changes. While high membrane fluidity promotes robust biofilm formation in Klebsiella pneumoniae, studies in several other species, including Salmonella enterica, suggest that biofilm formation is associated with reduced fluidity. This paradox may reflect the complex relationship between lipid composition and biofilm formation. Our findings demonstrated that both low and high extremes of lipid fluidity restrict biofilm formation. We propose that the required fluidity for biofilm growth, relative to that required for planktonic growth, may differ between species and are readily adjusted during lifestyle transitions.

microbiology↗

bioRxiv2024

FIDDLE: a deep learning method for chemical formulas prediction from tandem mass spectra

Molecular identification through tandem mass spectrometry is fundamental in small molecule analysis, with formula identification serving as an initial step in the process. Current computational methods often struggle with accuracy, speed, and scalability for relatively larger molecules, limiting high-throughput workflows. We present FIDDLE (Formula IDentification by Deep LEarning), a deep learning-based method trained on over 38,000 molecules and 1 million MS/MS spectra from various Quadrupole Time-of-Flight (Q-TOF) and Orbitrap instruments. FIDDLE accelerates formula identification by more than 10-fold and achieves top-1 and top-5 accuracies of 88.3% and 93.6%, respectively, outperforming state-of-the-art methods based on top-down (SIRIUS) and bottom-up (BUDDY) approaches by over 10%. On external metabolomics datasets, FIDDLE achieves top-5 accuracies of 75.1% (positive ion mode) and 66.2% (negative ion mode), with further improvements to 80.0% and 73.8% when combined with SIRIUS and BUDDY.

bioinformatics↗

bioRxiv2024

Sirt5 preserves cardiac function in ischemia-reperfusion injury by inhibiting ANT2 lactylation

Myocardial ischemia-reperfusion (IR) injury is the most common type of heart disease. IR-disrupted mitochondrial homeostasis affects heart energy metabolism and function, but the mechanism remains poorly understood. Here we report a cardioprotective role of the mitochondrial protein Sirt5 in a mouse model of cardiac IR injury. The down-regulation of Sirt5 in IR-injured heart is associated with an increased protein lactylation and impaired mitochondrial function. Overexpression of Sirt5 alleviates, whereas conditional knockout of Sirt5 aggravates, mitochondrial damage and cardiac injury. Mechanistically, Sirt5 interacts with the inner mitochondrial membrane protein adenine nucleotide translocase 2 (ANT2), inhibiting its lysine lactylation to promote its association with the outer mitochondrial membrane protein voltage-dependent anion-selective channel 1 (VDAC1). Lactylation-resistant ANT2 efficiently complexes with VDAC1 and improves cardiac function after injury. Therefore, we uncover a Sirt5-regulated interaction of ANT2 and VDAC1 in maintaining mitochondrial homeostasis, highlighting the potential of targeting ANT2 lactylation as a therapeutic strategy in the treatment of cardiac injury. TeaserSirt5 promotes the interaction of mitochondrial proteins to protect mitochondrial homeostasis and improve heart function in ischemia-reperfusion injury.

pathology↗

bioRxiv2024

The circadian gene Dec2 promotes pancreatic cancer dormancy by regulating tumor cell antigen presentation to facilitate immune evasion

The mechanisms that regulate cancer dormancy remain poorly understood. Using a mouse model of resectable pancreatic adenocarcinoma (PDAC), we identified Dec2 as a gene that was upregulated in metastatic dormant tumor cells. Deletion of Dec2 from tumor cells substantially increased mouse survival after resection due to an immune-mediated mechanism as the survival benefit was abrogated in immunodeficient conditions. Dec2 promoted immune evasion by repressing multiple components of the MHC-I dependent antigen presentation pathway in tumor cells. Dec2 is a regulator of circadian rhythms, and we found several components of the antigen presentation pathway oscillated in a circadian manner that was lost upon deletion of Dec2. Moreover, T-cell mediated tumor cell killing varied depending on the time of day. We suggest that lowered MHC-I presentation of antigens during rest phase is a natural effect of the circadian clock, which is exploited by Dec2-overexpressing pancreatic tumors to evade the immune system.

cancer biology↗