PubMed

Cell Biochem Biophys. 2024 Mar 18. doi: 10.1007/s12013-024-01249-1. Online ahead of print.ABSTRACTIn vitro cellular models provide valuable insights into the adaptive biochemical mechanisms triggered by cells to cope with the stress situation induced by hypoxia and reoxygenation cycles. The first biological data generated in studies based on this micrometric life-scale has the potential to provide us a global overview about the main biochemical phenomena presented in some reported preconditioning therapies in life-scale of higher dimensions. Thus, in this study, a cell incubator was designed and manufactured to produce a cellular model of heart hypoxia followed by reoxygenation (HfR) through consecutive repetitions of hypoxia-normoxia gas exchange. Samples of cellular extracts and culture media were obtained from non-proliferative cardiomyocytes (CMs) cultivated under challenging HfR (stressed CMs) and regular cultivation (unstressed CMs) in rounds of four days for each case. Metabolomic based on proton magnetic resonance spectroscopy (1H-MRS) was used as an analytical approach to identify and quantify the metabolomes of these samples, the endo- and exo-metabolome. Despite the stressed CMs presented over 90% higher cellular death rate compared to the unstressed CMs, the metabolic profiles indicates that the surviving cells up-regulate their amino acid metabolism either by active protein degradation or by the consumption of culture media components to increase coenzyme A-dependent metabolic pathways. This cell auto-regulation mechanism could be well characterized in the first two days when the difference smears off under once the metabolomes become similar. The metabolic adaptations of stressed CMs identified the relevance of the cyclic oxidation/reduction reactions of nicotinamide adenine dinucleotide phosphate molecules, NADP+/NADPH, and the increased tricarboxylic acid cycle activity in an environment overloaded with such a powerful antioxidant agent to survive an extreme HfR challenge. Thus, the combination of cellular models based on CMs, investigative methods, such as metabolomic and 1H-MRS, and the instrumental development of hypoxia incubator shown in this work were able to provide the first biochemical evidences behind therapies of gaseous exchanges paving the way to future assays.PMID:38498099 | DOI:10.1007/s12013-024-01249-1

J Cell Biol. 2024 May 6;223(5):e202302069. doi: 10.1083/jcb.202302069. Epub 2024 Mar 18.ABSTRACTCells utilize multiple mechanisms to maintain mitochondrial homeostasis. We recently characterized a pathway that remodels mitochondria in response to metabolic alterations and protein overload stress. This remodeling occurs via the formation of large membranous structures from the mitochondrial outer membrane called mitochondrial-derived compartments (MDCs), which are eventually released from mitochondria and degraded. Here, we conducted a microscopy-based screen in budding yeast to identify factors that regulate MDC formation. We found that two phospholipids, cardiolipin (CL) and phosphatidylethanolamine (PE), differentially regulate MDC biogenesis. CL depletion impairs MDC biogenesis, whereas blocking mitochondrial PE production leads to constitutive MDC formation. Additionally, in response to metabolic MDC activators, cellular and mitochondrial PE declines, and overexpressing mitochondrial PE synthesis enzymes suppress MDC biogenesis. Altogether, our data indicate a requirement for CL in MDC biogenesis and suggest that PE depletion may stimulate MDC formation downstream of MDC-inducing metabolic stress.PMID:38497895 | DOI:10.1083/jcb.202302069

J Proteome Res. 2024 Mar 18. doi: 10.1021/acs.jproteome.3c00860. Online ahead of print.ABSTRACTColitis has a multifactorial pathogenesis with a strong cross-talk among microbiota, hypoxia, and tissue metabolism. Here, we aimed to characterize the molecular signature of the disease in symptomatic and presymptomatic stages of the inflammatory process at the tissue and fecal level. The study is based on two different murine models for colitis, and HR-MAS NMR on "intact" colon tissues and LC-MS/MS on colon tissue extracts were used to derive untargeted metabolomics and proteomics information, respectively. Solution NMR was used to derive metabolomic profiles of the fecal extracts. By combining metabolomic and proteomic analyses of the tissues, we found increased anaerobic glycolysis, accompanied by an altered citric acid cycle and oxidative phosphorylation in inflamed colons; these changes associate with inflammation-induced hypoxia taking place in colon tissues. Different colitis states were also characterized by significantly different metabolomic profiles of fecal extracts, attributable to both the dysbiosis characteristic of colitis as well as the dysregulated tissue metabolism. Strong and distinctive tissue and fecal metabolomic signatures can be detected before the onset of symptoms. Therefore, untargeted metabolomics of tissues and fecal extracts provides a comprehensive picture of the changes accompanying the disease onset already at preclinical stages, highlighting the diagnostic potential of global metabolomics for inflammatory diseases.PMID:38497760 | DOI:10.1021/acs.jproteome.3c00860

Microbiol Spectr. 2024 Mar 18:e0401223. doi: 10.1128/spectrum.04012-23. Online ahead of print.ABSTRACTEsophageal squamous cell carcinoma (ESCC) is one of the most predominant subtypes of esophageal cancer. The characteristics of the gut microbiome and its metabolites from patients with ESCC have not been adequately studied and discussed. In this study, 40 fecal samples (20 from ESCC patients and 20 from healthy controls) were analyzed by 16S rRNA gene sequencing and untargeted metabolomics. The data sets were analyzed individually and synthesized using various bioinformatics methods. Alpha and beta diversity indicated significant differences in microbial diversity and abundance between ESCC and healthy control feces. At the genus level, the abundance of Phascolarctobacterium, Sutterella, and Streptococcus was significantly increased in ESCC. At the genus level, linear discriminant analysis effect size identified two biomarkers: Bacteroides_stercoris and Prevotella_copri. Untargeted metabolomics analysis revealed 307 differential metabolites between ESCC and healthy control feces, with indoles and derivatives, tropane alkaloids, lipids, and lipid-like molecules in higher relative abundance in ESCC feces than in healthy control feces. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that unsaturated fatty acids (FAs), ascorbate and aldarate metabolism, and hypoxia-inducible factor 1 signaling pathway were significantly associated with differential metabolite. Phenylethanolamine and despropionyl p-fluoro fentanyl could be used as reliable biomarkers to differentiate ESCC from healthy control. The correlation analysis showed that Prevotella may be involved in the synthesis of fatty acyl, carboxylic acids and derivatives, benzenes and substituted derivatives, organic oxygenates, and indoles and derivatives as metabolites. Fusicatenibacter and Lachnospira may be involved in the degradation of indoles and derivatives. Alistipes, Agathobacter, and Parabacteroides may be involved in the synthesis of indoles and derivatives with strong contributions. There is an intricate relationship between the gut microbiome and the levels of several metabolites (e.g., fatty acyls, carboxylic acids and derivatives, indoles, and derivatives). Microbial-associated metabolites can be used as diagnostic biomarkers in therapeutic exploration. Further analysis revealed that Prevotella, Alistipes, Agathobacter, and Parabacteroides might promote ESCC by regulating the synthesis of indoles and their derivatives. The results of this study provide favorable evidence for the early diagnosis of ESCC and subsequent individualized treatment and targeted interventions.IMPORTANCEWe describe for the first time the differences in fecal microbiome composition and metabolites between patients with esophageal squamous cell carcinoma (ESCC) and healthy controls by 16S rRNA gene sequencing and untargeted metabolomics. The results of this study provide a favorable basis for the early diagnosis of ESCC and subsequent targeted interventional therapy.PMID:38497715 | DOI:10.1128/spectrum.04012-23

Plant Cell Environ. 2024 Mar 18. doi: 10.1111/pce.14889. Online ahead of print.ABSTRACTDamage caused by the rice striped stem borer (SSB), Chilo suppressalis (Walker) (Lepidoptera: Pyralidae), is much more severe on indica/xian rice than on japonica/geng rice (Oryza sativa) which matches pest outbreak data in cropping regions of China. The mechanistic basis of this difference among rice subspecies remains unclear. Using transcriptomic, metabolomic and genetic analyses in combination with insect bioassay experiments, we showed that japonica and indica rice utilise different defence responses to repel SSB, and that SSB exploited plant nutrition deficiencies in different ways in the subspecies. The more resistant japonica rice induced patterns of accumulation of methyl jasmonate (MeJA-part of a defensive pathway) and vitamin B1 (VB1 -a nutrition pathway) distinct from indica cultivars. Using gene-edited rice plants and SSB bioassays, we found that MeJA and VB1 jointly affected the performance of SSB by disrupting juvenile hormone levels. In addition, genetic variants of key biosynthesis genes in the MeJA and VB1 pathways (OsJMT and OsTH1, respectively) differed between japonica and indica rice and contributed to performance differences; in indica rice, SSB avoided the MeJA defence pathway and hijacked the VB1 nutrition-related pathway to promote development. The findings highlight important genetic and mechanistic differences between rice subspecies affecting SSB damage which could be exploited in plant breeding for resistance.PMID:38497544 | DOI:10.1111/pce.14889

J Cosmet Dermatol. 2024 Mar 18. doi: 10.1111/jocd.16259. Online ahead of print.ABSTRACTBACKGROUND: Research has demonstrated the anti-photoaging properties of glabridin and bakuchiol.METHODS: The impact of glabridin, glabridin + bakuchiol, and bakuchiol on the levels of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) in mice skin fibroblasts was observed. Furthermore, we investigated the potential roles of fibronectin (FN), interferon-γ (IFN-γ), interleukin-22 (IL-22), and transforming growth factor-β (TGF-β) in the tissues, and evaluated their impact on the enzymatic levels in the skin. In conjunction with transcriptomic analysis, metabolomic profiling, and network pharmacology, all samples underwent comprehensive metabolomic and principal component analysis. The Venny2.1 method was utilized to identify variances in shared metabolites between the treatment group and the UVB group, as well as between the UVB group and the control group. Subsequently, a cluster heat map was generated to forecast and analyze metabolic pathways and targets.RESULTS: The outcomes from the hematoxylin and eosin and toluidine blue staining revealed that glabridin and bakuchiol markedly decreased dermal thickness and suppressed mast cell infiltration in photoaged mice. Immunohistochemistry and Elisa analysis revealed that glabridin and bakuchiol effectively attenuated the levels of pro-inflammatory factors, including IL-1β, tumor necrosis factor-α, IL-22, and IFN-γ. Furthermore, an increase in the levels of anti-inflammatory factors such as FN and TGF-β was also observed. The determination of the contents of superoxide dismutase, hydroxypropyltransferase and malondialdehyde in mice dorsal skin revealed that glabridin and bakuchiol not only elevated the levels of superoxide dismutase and hydroxyproline, but also reduced malondialdehyde content. Due to the limited number of shared differential metabolites exclusively within Kyoto Encyclopedia of Genes and Genomes, comprehensive pathway enrichment analysis was not feasible.CONCLUSION: This study demonstrates that glabridin and bakuchiol effectively impede photoaging and alleviate skin inflammation in mice.PMID:38497297 | DOI:10.1111/jocd.16259

Philos Trans R Soc Lond B Biol Sci. 2024 May 6;379(1901):20230075. doi: 10.1098/rstb.2023.0075. Epub 2024 Mar 18.ABSTRACTThe gut microbiota is crucial for intestinal health, including gastrointestinal (GI) motility. How commensal bacterial species influence GI motility has not been fully elucidated. A major factor of GI motility is the gut contraction promoting the propulsive movement of orally ingested materials. Here, we developed a method to monitor and quantify gut contractions in living Drosophila melanogaster larvae. We found that the culture medium of an isolated strain Lactiplantibacillus plantarum Lsi promoted gut contraction in vivo, which was not observed in Leuconostoc sp. Leui nor Acetobacter persici Ai culture medium. To identify bacteria-derived metabolites, we performed metabolome analysis of the culture media by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Of the 66 metabolites detected, we found that some metabolites changed in a species-specific manner. Among them, acetylcholine was specifically produced by L. plantarum. Feeding exogenous acetylcholine increased the frequency of gut contractions, which was blocked by D-tubocurarine, an inhibitor of nicotinic acetylcholine receptors. In this study, we propose a mechanism by which the gut microbiota influences Drosophila gut motility. This article is part of the theme issue 'Sculpting the microbiome: how host factors determine and respond to microbial colonization'.PMID:38497270 | DOI:10.1098/rstb.2023.0075

ACS Omega. 2024 Feb 29;9(10):11200-11216. doi: 10.1021/acsomega.3c05591. eCollection 2024 Mar 12.ABSTRACTMedicinally valuable components derived from natural resources are highly desirable as prospective alternatives to synthetic drugs to treat fatal diseases, such as cancer and diabetes mellitus. Suaeda maritima (L.) Dumort (Amaranthaceae) (S. maritima) is a halophyte plant that can thrive in saline environments and possesses excellent medicinal properties. Hence, for the present investigation, S. maritima has been chosen, and its phytochemical constituents have been extracted utilizing various solvents, including hexane, acetone, and methanol, and identified by GC-MS, LC-MS, and HPLC analyses. The antioxidant activity of the compounds using DPPH, ABTS, and reducing power assays demonstrated that all three extracts of S. maritima possessed significant radical scavenging activity comparable to standard ascorbic acid with lower IC50 values (69.20-95.58 μg/mL). In addition, the evaluation of antidiabetic activity by α-amylase inhibition and α-glucosidase inhibition methods revealed that the acetone extract of S. maritima (SMAE) displayed equipotent activity of standard acarbose with an IC50 of 32.6 μg/mL. Advantageously, SMAE also exhibited better inhibition activity against the growth of lung cancer cells with an IC50 of 78.19. μg/mL and less toxicity on the noncancerous HUVEC cells with a high IC50 of 300 μg/mL. In addition, the cancer cell death mechanism via the apoptotic pathway induced by SMAE was confirmed by DAPI staining and ROS analysis. The analysis of ADME properties, including absorption, distribution, metabolism, and excretion, witnessed that the physicochemical and druglikeness factors were best catered by stigmasterol, γ-sitosterol, and vitamin E. Further, the key phytochemicals identified from SMAE were docked with CtBP1 and SOX2 bound to importin-α target proteins associated with carcinogenic pathways using Schrodinger software. The results showed that the phytochemicals, scilicet, stigmasterol, γ-sitosterol, octadecadienoic acid, and vitamin E, showed a good binding affinity with Glide scores in the range -2.845-4.018 kcal/mol. Overall, the findings support that the least investigated traditional edible medicinal mangrove-related S. maritima is high in pharmacologically active constituents and might be one of the finest sources of naturally derived molecules for drug development and delivery systems.PMID:38496978 | PMC:PMC10938337 | DOI:10.1021/acsomega.3c05591

ACS Omega. 2024 Feb 26;9(10):11987-11997. doi: 10.1021/acsomega.3c09742. eCollection 2024 Mar 12.ABSTRACTThe influence of enrichment of culturable microorganisms in in situ coal seams on biomethane production potential of other coal seams has been rarely studied. In this study, we enriched culturable microorganisms from three in situ coal seams with three coal ranks and conducted indoor anaerobic biomethane production experiments. Microbial community composition, gene functions, and metabolites in different culture units by 16S rRNA high-throughput sequencing combined with liquid chromatography-mass spectrometry-time-of-flight (LC-MS-TOF). The results showed that biomethane production in the bituminous coal group (BC)cc resulted in the highest methane yield of 243.3 μmol/g, which was 12.3 times higher than that in the control group (CK). Meanwhile, Methanosarcina was the dominant archaeal genus in the three experimental groups (37.42 ± 11.16-52.62 ± 2.10%), while its share in the CK was only 2.91 ± 0.48%. Based on the functional annotation, the relative abundance of functional genes in the three experimental groups was mainly related to the metabolism of nitrogen-containing heterocyclic compounds such as purines and pyrimidines. Metabolite analysis showed that enriched microorganisms promoted the degradation of a total of 778 organic substances in bituminous coal, including 55 significantly different metabolites (e.g., purines and pyrimidines). Based on genomic and metabolomic analyses, this paper reconstructed the heterocyclic compounds degradation coupled methane metabolism pathway and thereby preliminarily elucidated that enriched culturable bacteria from different coal-rank seams could promote the degradation of bituminous coal and intensify biogenic methane yields.PMID:38496961 | PMC:PMC10938392 | DOI:10.1021/acsomega.3c09742

Heliyon. 2024 Mar 8;10(6):e27472. doi: 10.1016/j.heliyon.2024.e27472. eCollection 2024 Mar 30.ABSTRACTAngiotensin-converting enzyme 2 (ACE2) polymorphisms are associated with increased risk of type 2 diabetes mellitus (T2DM), obesity and dyslipidemia, which have been determined in various populations. Consistently, ACE2 knockout (ACE2 KO) mice display damaged energy metabolism in multiple tissues, especially the key metabolic tissues such as liver, skeletal muscle and epididymal white adipose tissue (eWAT) and show even more severe phenotype under high-fat diet (HFD) induced metabolic stress. However, the effects of ACE2 on global metabolomics profiling and the tissue sensitivity remain unclear. To understand how tissues independently and collectively respond to ACE2, we performed untargeted metabolomics in serum in ACE2 KO and control wild type (WT) mice both on normal diet (ND) and HFD, and in three key metabolic tissues (liver, skeletal muscle and eWAT) after HFD treatment. The results showed significant alterations in metabolic profiling in ACE2 KO mice. We identified 275 and 168 serum metabolites differing significantly between WT and ACE2 KO mice fed on ND and HFD, respectively. And the altered metabolites in the ACE2 KO group varied from 90 to 196 in liver, muscle and eWAT. The alterations in ND and HFD serum were most similar. Compared with WT mice, ACE2 KO mice showed an increase in N-phenylacetylglutamine (PAGln), methyl indole-3-acetate, 5-hydroxytryptophol, cholic acid, deoxycholic acid and 12(S)-HETE, while LPC (19:0) and LPE (16:1) decreased. Moreover, LPC (20:0), LPC (20:1) and PC (14:0e/6:0) were reduced in both ND and HFD serum, paralleling the decreases identified in HFD skeletal muscle. Interestingly, DL-tryptophan, indole and Gly-Phe decreased in both ND and HFD serum but were elevated in HFD liver of ACE2 KO mice. A low level of l-ergothioneine was observed among liver, muscle, and epididymal fat tissue of ACE2 KO mice. Pathway analysis demonstrated that different tissues exhibited different dysregulated metabolic pathways. In conclusion, these results revealed that ACE2 deficiency leads to an overall state of metabolic distress, which may provide a new insight into the underlying pathogenesis in metabolic disorders in both ACE2 KO mice and in patients with certain genetic variant of ACE2 gene.PMID:38496880 | PMC:PMC10944221 | DOI:10.1016/j.heliyon.2024.e27472

bioRxiv [Preprint]. 2024 Mar 9:2024.03.08.584156. doi: 10.1101/2024.03.08.584156.ABSTRACTSpecies of the Bacteroidales order are among the most abundant and stable bacterial members of the human gut microbiome with diverse impacts on human health. While Bacteroidales strains and species are genomically and functionally diverse, order-wide comparative analyses are lacking. We cultured and sequenced the genomes of 408 Bacteroidales isolates from healthy human donors representing nine genera and 35 species and performed comparative genomic, gene-specific, mobile gene, and metabolomic analyses. Families, genera, and species could be grouped based on many distinctive features. However, we also show extensive DNA transfer between diverse families, allowing for shared traits and strain evolution. Inter- and intra-specific diversity is also apparent in the metabolomic profiling studies. This highly characterized and diverse Bacteroidales culture collection with strain-resolved genomic and metabolomic analyses can serve as a resource to facilitate informed selection of strains for microbiome reconstitution.PMID:38496653 | PMC:PMC10942478 | DOI:10.1101/2024.03.08.584156

Res Sq [Preprint]. 2024 Mar 5:rs.3.rs-3921099. doi: 10.21203/rs.3.rs-3921099/v1.ABSTRACTMultiomics analyses have identified multiple potential biomarkers of the incidence and prevalence of complex diseases. However, it is not known which type of biomarker is optimal for clinical purposes. Here, we make a systematic comparison of 90 million genetic variants, 1,453 proteins, and 325 metabolites from 500,000 individuals with complex diseases from the UK Biobank. A machine learning pipeline consisting of data cleaning, data imputation, feature selection, and model training using cross-validation and comparison of the results on holdout test sets showed that proteins were most predictive, followed by metabolites, and genetic variants. Only five proteins per disease resulted in median (min-max) areas under the receiver operating characteristic curves for incidence of 0.79 (0.65-0.86) and 0.84 (0.70-0.91) for prevalence. In summary, our work suggests the potential of predicting complex diseases based on a limited number of proteins. We provide an interactive atlas (macd.shinyapps.io/ShinyApp/) to find genomic, proteomic, or metabolomic biomarkers for different complex diseases.PMID:38496611 | PMC:PMC10942575 | DOI:10.21203/rs.3.rs-3921099/v1

medRxiv [Preprint]. 2024 Mar 8:2024.03.07.24303907. doi: 10.1101/2024.03.07.24303907.ABSTRACTDespite the high prevalence of neurodevelopmental disorders, there are a lack of clinical studies examining the impact of pregnancy diet on child neurodevelopment. This observational clinical study examined the associations between pregnancy dietary patterns and neurodevelopmental diagnoses, as well as their symptoms, in a prospective cohort of 10-year-old children (n=508). Data-driven dietary patterns were derived from self-reported food frequency questionnaires. An Unhealthy dietary pattern in pregnancy (per SD change) was significantly associated with attention deficit hyperactivity disorder (ADHD) OR 1.66 [1.21 - 2.27], p=0.002 and autism diagnosis OR 2.22 [1.33 - 3.74], p=0.002 and associated symptoms p<0.001. Findings for ADHD were validated in two large (n=656, n=348), independent mother-child cohorts via blood metabolome modelling. Objective metabolite scores, assessed at five timepoints in mothers and children in two independent mother-child cohorts, indicated that the strongest association with ADHD was during early-to mid-pregnancy. These results provide evidence for targeted prenatal dietary interventions to prevent neurodevelopmental disorders in children.PMID:38496582 | PMC:PMC10942528 | DOI:10.1101/2024.03.07.24303907

bioRxiv [Preprint]. 2024 Feb 22:2024.02.21.581486. doi: 10.1101/2024.02.21.581486.ABSTRACTOne of the most important properties of human embryonic stem cells (hESCs) is related to their pluripotent states. In our recent study, we identified a previously unrecognized pluripotent state induced by RSeT medium. This state makes primed hESCs resistant to conversion to naïve pluripotent state. In this study, we have further characterized the metabolic features in these RSeT hESCs, including metabolic gene expression, metabolomic analysis, and various functional assays. The commonly reported metabolic modes include glycolysis or both glycolysis and oxidative phosphorylation (i.e., metabolic bivalency) in pluripotent stem cells. However, besides the presence of metabolic bivalency, RSeT hESCs exhibited a unique metabolome with additional fatty acid oxidation and imbalanced nucleotide metabolism. This metabolic quadrivalency is linked to hESC growth independent of oxygen tension and restricted capacity for naïve reprogramming in these cells. Thus, this study provides new insights into pluripotent state transitions and metabolic stress-associated hPSC growth in vitro .PMID:38496581 | PMC:PMC10942463 | DOI:10.1101/2024.02.21.581486

bioRxiv [Preprint]. 2024 Mar 4:2024.02.29.582775. doi: 10.1101/2024.02.29.582775.ABSTRACTWe previously reported that in the absence of Prostaglandin D2 synthase (L-PGDS) peripheral nerves are hypomyelinated in development and that with aging they present aberrant myelin sheaths. We now demonstrate that L-PGDS expressed in Schwann cells is part of a coordinated program aiming at preserving myelin integrity. In vivo and in vitro lipidomic, metabolomic and transcriptomic analyses confirmed that myelin lipids composition, Schwann cells energetic metabolism and key enzymes controlling these processes are altered in the absence of L-PGDS. Moreover, Schwann cells undergo a metabolic rewiring and turn to acetate as the main energetic source. Further, they produce ketone bodies to ensure glial cell and neuronal survival. Importantly, we demonstrate that all these changes correlate with morphological myelin alterations and describe the first physiological pathway implicated in preserving PNS myelin. Collectively, we posit that myelin lipids serve as a reservoir to provide ketone bodies, which together with acetate represent the adaptive substrates Schwann cells can rely on to sustain the axo-glial unit and preserve the integrity of the PNS.PMID:38496560 | PMC:PMC10942270 | DOI:10.1101/2024.02.29.582775

bioRxiv [Preprint]. 2024 Mar 10:2024.03.08.583994. doi: 10.1101/2024.03.08.583994.ABSTRACTFungal pathogens exhibit extensive strain heterogeneity, including variation in virulence. Whether closely related non-pathogenic species also exhibit strain heterogeneity remains unknown. Here, we comprehensively characterized the pathogenic potentials (i.e., the ability to cause morbidity and mortality) of 16 diverse strains of Aspergillus fischeri , a non-pathogenic close relative of the major pathogen Aspergillus fumigatus . In vitro immune response assays and in vivo virulence assays using a mouse model of pulmonary aspergillosis showed that A. fischeri strains varied widely in their pathogenic potential. Furthermore, pangenome analyses suggest that A. fischeri genomic and phenotypic diversity is even greater. Genomic, transcriptomic, and metabolomic profiling identified several pathways and secondary metabolites associated with variation in virulence. Notably, strain virulence was associated with the simultaneous presence of the secondary metabolites hexadehydroastechrome and gliotoxin. We submit that examining the pathogenic potentials of non-pathogenic close relatives is key for understanding the origins of fungal pathogenicity.PMID:38496489 | PMC:PMC10942418 | DOI:10.1101/2024.03.08.583994

bioRxiv [Preprint]. 2024 Mar 7:2024.03.05.583545. doi: 10.1101/2024.03.05.583545.ABSTRACTTuberculosis (TB), caused by Mycobacterium tuberculosis ( Mtb ), continues to be a major public health problem worldwide. The human immunodeficiency virus (HIV) is another equally important life-threatening pathogen. Further, co-infections with HIV and Mtb have severe effects in the host, with people infected with HIV being fifteen to twenty-one times more likely to develop active TB. The use of an appropriate animal model for HIV/ Mtb co-infection that can recapitulate the diversity of the immune response in humans would be a useful tool for conducting basic and translational research in HIV/ Mtb infections. The present study was focused on developing a humanized mouse model for investigations on HIV- Mtb co-infection. Using NSG-SGM3 mice that can engraft human stem cells, our studies showed that they were able to engraft human CD34+ stem cells which then differentiate into a full-lineage of human immune cell subsets. After co-infection with HIV and Mtb , these mice showed decrease in CD4+ T cell counts overtime and elevated HIV load in the sera, similar to the infection pattern of humans. Additionally, Mtb caused infections in both lungs and spleen, and induced the development of granulomatous lesions in the lungs, detected by CT scan and histopathology. Distinct metabolomic profiles were also observed in the tissues from different mouse groups after co-infections. Our results suggest that the humanized NSG-SGM3 mice are able to recapitulate the effects of HIV and Mtb infections and co-infection in the human host at pathological, immunological and metabolism levels, providing a dependable small animal model for studying HIV/ Mtb co-infection.PMID:38496484 | PMC:PMC10942347 | DOI:10.1101/2024.03.05.583545

Res Sq [Preprint]. 2024 Mar 8:rs.3.rs-3952944. doi: 10.21203/rs.3.rs-3952944/v1.ABSTRACTBackground Patients with COVID-19 under invasive mechanical ventilation are at higher risk of developing ventilator-associated pneumonia (VAP), associated with increased healthcare costs, and unfavorable prognosis. The underlying mechanisms of this phenomenon have not been thoroughly dissected. Therefore, this study attempted to bridge this gap by performing a lung microbiota analysis and evaluating the host immune responses that could drive the development of VAP. Materials and methods In this prospective cohort study, mechanically ventilated patients with confirmed SARS-CoV-2 infection were enrolled. Nasal swabs (NS), endotracheal aspirates (ETA), and blood samples were collected initially within 12 hours of intubation and again at 72 hours post-intubation. Plasma samples underwent cytokine and metabolomic analyses, while NS and ETA samples were sequenced for lung microbiome examination. The cohort was categorized based on the development of VAP. Data analysis was conducted using RStudio version 4.3.1. Results In a study of 36 COVID-19 patients on mechanical ventilation, significant differences were found in the nasal and pulmonary microbiome, notably in Staphylococcus and Enterobacteriaceae , linked to VAP. Patients with VAP showed a higher SARS-CoV-2 viral load, elevated neutralizing antibodies, and reduced inflammatory cytokines, including IFN-δ, IL-1β, IL-12p70, IL-18, IL-6, TNF-α, and CCL4. Metabolomic analysis revealed changes in 22 metabolites in non-VAP patients and 27 in VAP patients, highlighting D-Maltose-Lactose, Histidinyl-Glycine, and various phosphatidylcholines, indicating a metabolic predisposition to VAP. Conclusions This study reveals a critical link between respiratory microbiome alterations and ventilator-associated pneumonia in COVID-19 patients, with elevated SARS-CoV-2 levels and metabolic changes, providing novel insights into the underlying mechanisms of VAP with potential management and prevention implications.PMID:38496464 | PMC:PMC10942552 | DOI:10.21203/rs.3.rs-3952944/v1

Mol Ther Nucleic Acids. 2024 Feb 16;35(2):102155. doi: 10.1016/j.omtn.2024.102155. eCollection 2024 Jun 11.ABSTRACTEndometrial cancer (EC), the second most common malignancy in the female reproductive system, has garnered increasing attention for its genomic heterogeneity, but understanding of its metabolic characteristics is still poor. We explored metabolic dysfunctions in EC through a comprehensive multi-omics analysis (RNA-seq datasets from The Cancer Genome Atlas [TCGA], Cancer Cell Line Encyclopedia [CCLE], and GEO datasets; the Clinical Proteomic Tumor Analysis Consortium [CPTAC] proteomics; CCLE metabolomics) to develop useful molecular targets for precision therapy. Unsupervised consensus clustering was performed to categorize EC patients into three metabolism-pathway-based subgroups (MPSs). These MPS subgroups had distinct clinical prognoses, transcriptomic and genomic alterations, immune microenvironment landscape, and unique patterns of chemotherapy sensitivity. Moreover, the MPS2 subgroup had a better response to immunotherapy. Finally, three machine learning algorithms (LASSO, random forest, and stepwise multivariate Cox regression) were used for developing a prognostic metagene signature based on metabolic molecules. Thus, a 13-hub gene-based classifier was constructed to predict patients' MPS subtypes, offering a more accessible and practical approach. This metabolism-based classification system can enhance prognostic predictions and guide clinical strategies for immunotherapy and metabolism-targeted therapy in EC.PMID:38495844 | PMC:PMC10943971 | DOI:10.1016/j.omtn.2024.102155

Biomed Opt Express. 2024 Feb 22;15(3):1798-1812. doi: 10.1364/BOE.504954. eCollection 2024 Mar 1.ABSTRACTWith applications ranging from metabolomics to histopathology, quantitative phase microscopy (QPM) is a powerful label-free imaging modality. Despite significant advances in fast multiplexed imaging sensors and deep-learning-based inverse solvers, the throughput of QPM is currently limited by the pixel-rate of the image sensors. Complementarily, to improve throughput further, here we propose to acquire images in a compressed form so that more information can be transferred beyond the existing hardware bottleneck of the image sensor. To this end, we present a numerical simulation of a learnable optical compression-decompression framework that learns content-specific features. The proposed differentiable quantitative phase microscopy (∂-QPM) first uses learnable optical processors as image compressors. The intensity representations produced by these optical processors are then captured by the imaging sensor. Finally, a reconstruction network running on a computer decompresses the QPM images post aquisition. In numerical experiments, the proposed system achieves compression of × 64 while maintaining the SSIM of ∼0.90 and PSNR of ∼30 dB on cells. The results demonstrated by our experiments open up a new pathway to QPM systems that may provide unprecedented throughput improvements.PMID:38495703 | PMC:PMC10942716 | DOI:10.1364/BOE.504954