PubMed

Syst Biol Reprod Med. 2023 Apr 25:1-14. doi: 10.1080/19396368.2023.2195964. Online ahead of print.ABSTRACTInfertility is clinically defined as the inability to achieve pregnancy within 12 months of regular unprotected sexual intercourse and affects 15% of couples worldwide. Therefore, the identification of novel biomarkers that can accurately predict male reproductive health and couples' reproductive success is of major public health significance. The objective of this pilot study is to test whether untargeted metabolomics is capable of discriminating reproductive outcomes and understand associations between the internal exposome of seminal plasma and the reproductive outcomes of semen quality and live birth among ten participants undergoing assisted reproductive technology (ART) in Springfield, MA. We hypothesize that seminal plasma offers a novel biological matrix by which untargeted metabolomics is able to discern male reproductive status and predict reproductive success. The internal exposome data was acquired using UHPLC-HR-MS on randomized seminal plasma samples at UNC at Chapel Hill. Unsupervised and supervised multivariate analyses were used to visualize the differentiation of phenotypic groups classified by men with normal or low semen quality based on World Health Organization guidelines as well as by successful ART: live birth or no live birth. Over 100 exogenous metabolites, including environmentally relevant metabolites, ingested food components, drugs and medications, and metabolites relevant to microbiome-xenobiotic interaction, were identified and annotated from the seminal plasma samples, through matching against the NC HHEAR hub in-house experimental standard library. Pathway enrichment analysis indicated that fatty acid biosynthesis and metabolism, vitamin A metabolism, and histidine metabolism were associated sperm quality; while pathways involving vitamin A metabolism, C21-steroid hormone biosynthesis and metabolism, arachidonic acid metabolism, and Omega-3 fatty acid metabolism distinguished live birth groups. Taken together, these pilot results suggest that seminal plasma is a novel matrix to study the influence of the internal exposome on reproductive health outcomes. Future research aims to increase the sample size to validate these findings.PMID:37098216 | DOI:10.1080/19396368.2023.2195964

Cannabis Cannabinoid Res. 2023 Apr 25. doi: 10.1089/can.2022.0331. Online ahead of print.ABSTRACTIntroduction: Cannabidiol (CBD) has important pharmacological activity, which includes antispasmodic, antioxidant, antithrombotic, and antianxiety properties. CBD has been applied as a health supplement to atherosclerosis. However, CBDs effect on gut microbiota and metabolic phenotype is unclear. Materials and Methods: We constructed a high production of cardiovascular risk factors, such as trimethylamine-N-oxide (TMAO) and phenylacetylglutamine (PAGln), in a mouse model using Clostridium sporogenes colonization. We used 16S ribosomal RNA (rRNA) gene sequencing and ultra-high performance liquid chromatography-quadrupole time-of flight mass spectrometry-based metabolomics to evaluate the effect of CBD on gut microbiota and plasma metabolites. Results: CBD decreased the levels of creatine kinase (CK), alanine transaminase (ALT), and low-density lipoprotein cholesterol and markedly increased high-density lipoprotein cholesterol. Furthermore, CBD treatment increased the abundance of beneficial bacteria, which include Lachnospiraceae_NK4A136 and Blautia in the gut, but it decreased the levels of TMAO and PAGln in the plasma. Conclusion: CBD might have beneficial effects for cardiovascular protection.PMID:37098174 | DOI:10.1089/can.2022.0331

J Agric Food Chem. 2023 Apr 25. doi: 10.1021/acs.jafc.3c00301. Online ahead of print.ABSTRACTTransgenic soybean is the commercial crop with the largest cultivation area worldwide. During transgenic soybean cultivation, exogenous genes may be transferred to wild relatives through gene flow, posing unpredictable ecological risks. Accordingly, an environmental risk assessment should focus on fitness changes and underlying mechanisms in hybrids between transgenic and wild soybeans (Glycine soja). Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) was used for in situ detection and imaging of protein changes in the seeds of transgenic herbicide-resistant soybean harboring epsps and pat genes, non-transgenic soybean, wild soybean, and their F2 hybrid. Protein data clearly distinguished wild soybeans, while the F2 seeds had protein characteristics of both parents and were distinguished from wild soybean seeds. Using UPLC-Q-TOF-MS, 22 differentially expressed proteins (DEPs) were identified, including 13 specific to wild soybean. Sucrose synthase and stress response-related DEPs were differentially expressed in parental and offspring. Differences in these may underpin the greater adaptability of the latter. MSI revealed DEP distribution in transgenic, wild, and F2 seeds. Identifying DEPs related to fitness may elucidate mechanisms underlying fitness differences among the studied varieties. Our study shows that MALDI-MSI has the potential to become a visual method for transgenic soybean analysis.PMID:37098110 | DOI:10.1021/acs.jafc.3c00301

J Biomol Struct Dyn. 2023 Apr 25:1-10. doi: 10.1080/07391102.2023.2197074. Online ahead of print.ABSTRACTFluoroquinolones (FQs) are the most commonly used antimicrobial drugs and regardless of their advantages in the healthcare sector, the pollution of these antimicrobial drugs in the environment has big concerns about human and environmental health. The presence of these antibiotic drugs even at the lowest concentrations in the environment has resulted in the emergence and spread of antibiotic resistance. Hence, it is necessary to remediate these pollutants from the environment. Previously alkaline laccase (SilA) from Streptomyces ipomoeae has been demonstrated to show degrading potentials against two of the FQs, Ciprofloxacin (CIP) and Norfloxacin (NOR); however, the molecular mechanism was not elucidated in detail. In this study, we have analyzed the possible molecular catalytic mechanism of FQ degrading SilA-laccase for the degradation of the FQs, CIP, NOR and Ofloxacin (OFL) using three-dimensional protein structure modeling, molecular docking and molecular dynamic (MD) studies. The comparative protein sequence analysis revealed the presence of tetrapeptide conserved catalytic motif, His102-X-His104-Gly105. After evaluating the active site of the enzyme in depth using CDD, COACH and S-site tools, we have identified the catalytic triad composed of three conserved amino acid residues, His102, Val103 and Tyr108 with which ligands interacted during the catalysis process. By analyzing the MD trajectories, it is revealed that the highest degradation potential of SilA is for CIP followed by NOR and OFL. Ultimately, this study provides the possible comparative catalytic mechanism for the degradation of CIP, NOR and OFL by the SilA enzyme.Communicated by Ramaswamy H. Sarma.PMID:37096761 | DOI:10.1080/07391102.2023.2197074

Microb Biotechnol. 2023 Apr 25. doi: 10.1111/1751-7915.14262. Online ahead of print.ABSTRACTSanghuangporus baumii is a medicinal fungi with anti-inflammatory, liver protection and antitumour effects. Terpenoids are one of the main medicinal ingredients of S. baumii. However, terpenoid production by wild-type S. baumii cannot meet the market demand, which affects its application in medical care. Therefore, exploring how to increase terpenoid content in S. baumii is a promising path in this research field. Salicylic acid (SA) is a secondary metabolite. In this study, a concentration of 350 μmol/L SA was added into fungal cultivations for 2 and 4 days, and then the transcriptome and metabolome of untreated mycelia and treated with SA were analysed. The expression of some genes in the terpenoids biosynthesis pathway increased in SA-induced cultivations, and the content of isopentenyl pyrophosphate (IPP) and geranylgeranyl-PP (GGPP) increased significantly as well as the contents of triterpenoids, diterpenoids, sesquiterpenoids and carotenoids. The gene FPS was considered to be a key gene regulating terpenoid biosynthesis. Therefore, FPS was overexpressed in S. baumii by Agrobacterium tumefaciens-mediated genetic transformation. The gene FPS and its downstream gene (LS) expression levels were confirmed to be increased in the FPS overexpressing transformant, and terpenoid content was 36.98% higher than that of the wild-type strain in the evaluated cultivation conditions.PMID:37096757 | DOI:10.1111/1751-7915.14262

BMC Genomics. 2023 Apr 25;24(1):213. doi: 10.1186/s12864-023-09292-7.ABSTRACTBACKGROUND: Understanding the mechanisms underlining forage production and its biomass nutritive quality at the omics level is crucial for boosting the output of high-quality dry matter per unit of land. Despite the advent of multiple omics integration for the study of biological systems in major crops, investigations on forage species are still scarce.RESULTS: Our results identified substantial changes in gene co-expression and metabolite-metabolite network topologies as a result of genetic perturbation by hybridizing L. perenne with another species within the genus (L. multiflorum) relative to across genera (F. pratensis). However, conserved hub genes and hub metabolomic features were detected between pedigree classes, some of which were highly heritable and displayed one or more significant edges with agronomic traits in a weighted omics-phenotype network. In spite of tagging relevant biological molecules as, for example, the light-induced rice 1 (LIR1), hub features were not necessarily better explanatory variables for omics-assisted prediction than features stochastically sampled and all available regressors.CONCLUSIONS: The utilization of computational techniques for the reconstruction of co-expression networks facilitates the identification of key omic features that serve as central nodes and demonstrate correlation with the manifestation of observed traits. Our results also indicate a robust association between early multi-omic traits measured in a greenhouse setting and phenotypic traits evaluated under field conditions.PMID:37095447 | DOI:10.1186/s12864-023-09292-7

Mol Neurobiol. 2023 Apr 25. doi: 10.1007/s12035-023-03343-6. Online ahead of print.ABSTRACTHair is a noninvasive valuable biospecimen for the long-term assessment of endogenous metabolic disturbance. Whether the hair is suitable for identifying biomarkers of the Alzheimer's disease (AD) process remains unknown. We aim to investigate the metabolism changes in hair after β-amyloid (Aβ1-42) exposure in rats using ultra-high-performance liquid chromatography-high-resolution mass spectrometry-based untargeted and targeted methods. Thirty-five days after Aβ1-42 induction, rats displayed significant cognitive deficits, and forty metabolites were changed, of which twenty belonged to three perturbed pathways: (1) phenylalanine metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis-L-phenylalanine, phenylpyruvate, ortho-hydroxyphenylacetic acid, and phenyllactic acid are up-regulated; (2) arachidonic acid (ARA) metabolism-leukotriene B4 (LTB4), arachidonyl carnitine, and 5(S)-HPETE are upregulation, but ARA, 14,15-DiHETrE, 5(S)-HETE, and PGB2 are opposite; and (3) unsaturated fatty acid biosynthesis- eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), FA 18:3 + 1O, and FA 18:3 + 2O are downregulated. Linoleic acid metabolism belonging to the biosynthesis of unsaturated fatty acid includes the upregulation of 8-hydroxy-9,10-epoxystearic acid, 13-oxoODE, and FA 18:2 + 4O, and downregulation of 9(S)-HPODE and dihomo-γ-linolenic acid. In addition, cortisone and dehydroepiandrosterone belonging to steroid hormone biosynthesis are upregulated. These three perturbed metabolic pathways also correlate with cognitive impairment after Aβ1-42 stimulation. Furthermore, ARA, DHA, EPA, L-phenylalanine, and cortisone have been previously implicated in the cerebrospinal fluid of AD patients and show a similar changing trend in Aβ1-42 rats' hair. These data suggest hair can be a useful biospecimen that well reflects the expression of non-polar molecules under Aβ1-42 stimulation, and the five metabolites have the potential to serve as novel AD biomarkers.PMID:37095368 | DOI:10.1007/s12035-023-03343-6

Hepatology. 2023 Apr 26. doi: 10.1097/HEP.0000000000000420. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Purines are building blocks for cellular genome and excessive purine nucleotides are seen in tumors. However, how purine metabolism is dysregulated in tumor and impacting tumorigenesis remains elusive.APPROACH AND RESULTS: Transcriptomic and metabolomic analysis of purine biosynthesis and purine degradation pathways were performed in the tumor and associated non-tumor liver tissues obtained from 62 patients with hepatocellular carcinoma (HCC), one of the most lethal cancers worldwide. We found that most genes in purine synthesis are upregulated while genes in purine degradation are inhibited in HCC tumors. High purine anabolism is associated with unique somatic mutational signatures linked to patient prognosis. Mechanistically, we discover that increasing purine anabolism promotes epitranscriptomic dysregulation of DDR machinery through upregulating RNA N6-methyladenosine modification. High purine anabolic HCC is sensitive to DDR-targeting agents but not to standard HCC treatments, correlating with the clinical outcomes in five independent HCC cohorts containing 724 patients. We further showed that high purine anabolism determines the sensitivity to DDR-targeting agents in 5 HCC cell lines in vitro and in vivo.CONCLUSION: Our results reveal a central role of purine anabolism in regulating DDR, which could be therapeutically exploited in HCC.PMID:37094826 | DOI:10.1097/HEP.0000000000000420

BMC Complement Med Ther. 2023 Apr 24;23(1):130. doi: 10.1186/s12906-023-03944-7.ABSTRACTBACKGROUND: With fast rising incidence, papillary thyroid carcinoma (PTC) is the most common head and neck cancer. Parthenolide, isolated from traditional Chinese medicine, inhibits various cancer cells, including PTC cells. The aim was to investigate the lipid profile and lipid changes of PTC cells when treated with parthenolide.METHODS: Comprehensive lipidomic analysis of parthenolide treated PTC cells was conducted using a UHPLC/Q-TOF-MS platform, and the changed lipid profile and specific altered lipid species were explored. Network pharmacology and molecular docking were performed to show the associations among parthenolide, changed lipid species, and potential target genes.RESULTS: With high stability and reproducibility, a total of 34 lipid classes and 1736 lipid species were identified. Lipid class analysis indicated that parthenolide treated PTC cells contained higher levels of fatty acid (FA), cholesterol ester (ChE), simple glc series 3 (CerG3) and lysophosphatidylglycerol (LPG), lower levels of zymosterol (ZyE) and Monogalactosyldiacylglycerol (MGDG) than controlled ones, but with no significant differences. Several specific lipid species were changed significantly in PTC cells treated by parthenolide, including the increasing of phosphatidylcholine (PC) (12:0e/16:0), PC (18:0/20:4), CerG3 (d18:1/24:1), lysophosphatidylethanolamine (LPE) (18:0), phosphatidylinositol (PI) (19:0/20:4), lysophosphatidylcholine (LPC) (28:0), ChE (22:6), and the decreasing of phosphatidylethanolamine (PE) (16:1/17:0), PC (34:1) and PC (16:0p/18:0). Four key targets (PLA2G4A, LCAT, LRAT, and PLA2G2A) were discovered when combining network pharmacology and lipidomics. Among them, PLA2G2A and PLA2G4A were able to bind with parthenolide confirmed by molecular docking.CONCLUSIONS: The changed lipid profile and several significantly altered lipid species of parthenolide treated PTC cells were observed. These altered lipid species, such as PC (34:1), and PC (16:0p/18:0), may be involved in the antitumor mechanisms of parthenolide. PLA2G2A and PLA2G4A may play key roles when parthenolide treated PTC cells.PMID:37095470 | PMC:PMC10123985 | DOI:10.1186/s12906-023-03944-7

Yeast. 2023 Apr 24. doi: 10.1002/yea.3852. Online ahead of print.ABSTRACTYeast-insect interactions are increasingly becoming an attractive source of discovery for previously unknown, unique, diverse, and industrially relevant yeast species. Despite a wealth of studies that have recently focused on yeasts in symbiotic association with Hymenopteran insects, yeasts associated with Coleopteran insects, such as lignocellulosic-rich dung-dependent beetles, remain poorly studied. Trends in yeast discovery suggest that species richness and diversity can be attributed to the ecological niche of the insect. Here, we considered the potential of dung beetles inhabiting the extreme environments of Botswana, characterized by desert-like conditions (semi-arid to arid and hot) as well as protected pristine environments, as possible attribute niches that can shape the extremophilic and diverse life history strategies of yeasts. We obtained a total of 97 phylogenetically diverse yeast isolates from six species of dung beetles from Botswana's unexplored environments, representing 19 species belonging to 11 genera. The findings suggest that the guts of dung beetles are a rich niche for non-Saccharomyces yeast species. Meyerozyma and Pichia were the most dominant genera associated with dung beetles, representing 55% (53 out of 97) of the yeast isolates in our study. Trichosporon and Cutaneotrichosporon genera represented 32% (31 out of 97) of the isolates. The remaining isolates belonged to Apiotrichum, Candida, Diutina, Naganishia, Rhodotorula, and Wickerhamiella genera (12 out of 97). We found out that about 62% (60 out of 97) of the isolates were potentially new species because of their low internal transcribed spacer (ITS) sequence similarity when compared to the most recent optimal species delineation threshold. A single isolate was unidentifiable using the ITS sequences. Using an in silico polymerase chain reaction-restriction fragment length polymorphism approach, we revealed that there was genetic diversity within isolates of the same species. Our results contribute to the knowledge and understanding of the diversity of dung beetle-associated yeasts.PMID:37096317 | DOI:10.1002/yea.3852

J Transl Med. 2023 Apr 24;21(1):277. doi: 10.1186/s12967-023-04137-z.ABSTRACTBACKGROUND: Icariin (ICA), an active ingredient extracted from Epimedium species, has shown promising results in the treatment of Alzheimer's disease (AD), although its potential therapeutic mechanism remains largely unknown. This study aimed to investigate the therapeutic effects and the underlying mechanisms of ICA on AD by an integrated analysis of gut microbiota, metabolomics, and network pharmacology (NP).METHODS: The cognitive impairment of mice was measured using the Morris Water Maze test and the pathological changes were assessed using hematoxylin and eosin staining. 16S rRNA sequencing and multi-metabolomics were performed to analyze the alterations in the gut microbiota and fecal/serum metabolism. Meanwhile, NP was used to determine the putative molecular regulation mechanism of ICA in AD treatment.RESULTS: Our results revealed that ICA intervention significantly improved cognitive dysfunction in APP/PS1 mice and typical AD pathologies in the hippocampus of the APP/PS1 mice. Moreover, the gut microbiota analysis showed that ICA administration reversed AD-induced gut microbiota dysbiosis in APP/PS1 mice by elevating the abundance of Akkermansia and reducing the abundance of Alistipe. Furthermore, the metabolomic analysis revealed that ICA reversed the AD-induced metabolic disorder via regulating the glycerophospholipid and sphingolipid metabolism, and correlation analysis revealed that glycerophospholipid and sphingolipid were closely related to Alistipe and Akkermansia. Moreover, NP indicated that ICA might regulate the sphingolipid signaling pathway via the PRKCA/TNF/TP53/AKT1/RELA/NFKB1 axis for the treatment of AD.CONCLUSION: These findings indicated that ICA may serve as a promising therapeutic approach for AD and that the ICA-mediated protective effects were associated with the amelioration of microbiota disturbance and metabolic disorder.PMID:37095548 | DOI:10.1186/s12967-023-04137-z

Microbiome. 2023 Apr 24;11(1):88. doi: 10.1186/s40168-023-01506-0.ABSTRACTBACKGROUND: Psychological health risk is one of the most severe and complex risks in manned deep-space exploration and long-term closed environments. Recently, with the in-depth research of the microbiota-gut-brain axis, gut microbiota has been considered a new approach to maintain and improve psychological health. However, the correlation between gut microbiota and psychological changes inside long-term closed environments is still poorly understood. Herein, we used the "Lunar Palace 365" mission, a 1-year-long isolation study in the Lunar Palace 1 (a closed manned Bioregenerative Life Support System facility with excellent performance), to investigate the correlation between gut microbiota and psychological changes, in order to find some new potential psychobiotics to maintain and improve the psychological health of crew members.RESULTS: We report some altered gut microbiota that were associated with psychological changes in the long-term closed environment. Four potential psychobiotics (Bacteroides uniformis, Roseburia inulinivorans, Eubacterium rectale, and Faecalibacterium prausnitzii) were identified. On the basis of metagenomic, metaproteomic, and metabolomic analyses, the four potential psychobiotics improved mood mainly through three pathways related to nervous system functions: first, by fermenting dietary fibers, they may produce short-chain fatty acids, such as butyric and propionic acids; second, they may regulate amino acid metabolism pathways of aspartic acid, glutamic acid, tryptophan, etc. (e.g., converting glutamic acid to gamma-aminobutyric acid; converting tryptophan to serotonin, kynurenic acid, or tryptamine); and third, they may regulate other pathways, such as taurine and cortisol metabolism. Furthermore, the results of animal experiments confirmed the positive regulatory effect and mechanism of these potential psychobiotics on mood.CONCLUSIONS: These observations reveal that gut microbiota contributed to a robust effect on the maintenance and improvement of mental health in a long-term closed environment. Our findings represent a key step towards a better understanding the role of the gut microbiome in mammalian mental health during space flight and provide a basis for future efforts to develop microbiota-based countermeasures that mitigate risks to crew mental health during future long-term human space expeditions on the moon or Mars. This study also provides an essential reference for future applications of psychobiotics to neuropsychiatric treatments. Video Abstract.PMID:37095530 | DOI:10.1186/s40168-023-01506-0

Lipids Health Dis. 2023 Apr 24;22(1):54. doi: 10.1186/s12944-023-01817-z.ABSTRACTEndotoxemia and sepsis induce neuroinflammation and increase the risk of neurodegenerative disorders although the mechanism by which peripheral infection leads to brain inflammation is not well understood. While circulating serum lipoproteins are known immunometabolites with the potential to modulate the acute phase response and cross the blood brain barrier, their contribution to neuroinflammation during systemic infection is unknown. The objective of this study was to elucidate the mechanisms by which lipoprotein subclasses modulate lipopolysaccharide (LPS)-induced neuroinflammation. Adult C57BL/6 mice were divided into 6 treatment groups, including a sterile saline vehicle control group (n = 9), an LPS group (n = 11), a premixed LPS + HDL group (n = 6), a premixed LPS + LDL group (n = 5), a HDL only group (n = 6) and an LDL only group (n = 3). In all cases injections were administered intraperitoneally. LPS was administered at 0.5 mg/kg, and lipoproteins were administered at 20 mg/kg. Behavioural testing and tissue collection was performed 6 h post-injection. The magnitude of peripheral and central inflammation was determined by qPCR of pro-inflammatory genes in fresh liver and brain. Metabolite profiles of liver, plasma and brain were determined by 1H NMR. Endotoxin concentration in the brain was measured by the Limulus Amoebocyte Lysate (LAL) assay. Co-administration of LPS + HDL exacerbated both peripheral and central inflammation, whilst LPS + LDL attenuated this inflammation. Metabolomic analysis identified several metabolites significantly associated with LPS-induced inflammation, which were partially rescued by LDL, but not HDL. Endotoxin was detected at significantly greater concentrations in the brains of animals that received LPS + HDL compared to LPS + saline, but not those that received LPS + LDL. These results suggest that HDL may promote neuroinflammation through direct shuttling of endotoxin to the brain. In contrast, LDL was shown to have anti-neuroinflammatory properties in this study. Our results indicate that lipoproteins may be useful targets in neuroinflammation and neurodegeneration associated with endotoxemia and sepsis.PMID:37095493 | DOI:10.1186/s12944-023-01817-z

Eur J Clin Nutr. 2023 Apr 24. doi: 10.1038/s41430-023-01287-7. Online ahead of print.ABSTRACTBACKGROUND AND OBJECTIVES: Body composition (BC) assessment in cirrhosis has a wide variety of methods with no consensus on the best tools for each body component in patients with Liver Cirrhosis (LC). We aimed to conduct a systematic scoping review of the most frequent body composition analysis methods and nutritional findings published in liver cirrhosis patients.METHODS: We searched for articles in PubMed, Scopus, and ISI Web of Science databases. Keywords selected the BC methods and parameters in LC.RESULTS: Eleven methods were found. The most frequently used were computed tomography (CT) 47.5%, Bioimpedance Analysis 35%, DXA 32.5%, and anthropometry 32.5%. Up to 15 BC parameters were reported from each method.CONCLUSIONS: The vast heterogeneity in the results found during the qualitative analysis and imaging methods must reach a consensus to achieve a better clinical practice and improve nutritional treatment, as the physiopathology in LC compromises the nutritional status directly.PMID:37095222 | DOI:10.1038/s41430-023-01287-7

Nat Microbiol. 2023 Apr 24. doi: 10.1038/s41564-023-01374-2. Online ahead of print.ABSTRACTThe deep ocean (>200 m depth) is the largest habitat on Earth. Recent evidence suggests sulfur oxidation could be a major energy source for deep ocean microbes. However, the global relevance and the identity of the major players in sulfur oxidation in the oxygenated deep-water column remain elusive. Here we combined single-cell genomics, community metagenomics, metatranscriptomics and single-cell activity measurements on samples collected beneath the Ross Ice Shelf in Antarctica to characterize a ubiquitous mixotrophic bacterial group (UBA868) that dominates expression of RuBisCO genes and of key sulfur oxidation genes. Further analyses of the gene libraries from the 'Tara Oceans' and 'Malaspina' expeditions confirmed the ubiquitous distribution and global relevance of this enigmatic group in the expression of sulfur oxidation and dissolved inorganic carbon fixation genes across the global mesopelagic ocean. Our study also underscores the unrecognized importance of mixotrophic microbes in the biogeochemical cycles of the deep ocean.PMID:37095175 | DOI:10.1038/s41564-023-01374-2

Nat Commun. 2023 Apr 24;14(1):2356. doi: 10.1038/s41467-023-38027-1.ABSTRACTAccumulating evidence suggests mitochondria as key modulators of normal and premature aging, yet whether primary oxidative phosphorylation (OXPHOS) deficiency can cause progeroid disease remains unclear. Here, we show that mice with severe isolated respiratory complex III (CIII) deficiency display nuclear DNA damage, cell cycle arrest, aberrant mitoses, and cellular senescence in the affected organs such as liver and kidney, and a systemic phenotype resembling juvenile-onset progeroid syndromes. Mechanistically, CIII deficiency triggers presymptomatic cancer-like c-MYC upregulation followed by excessive anabolic metabolism and illicit cell proliferation against lack of energy and biosynthetic precursors. Transgenic alternative oxidase dampens mitochondrial integrated stress response and the c-MYC induction, suppresses the illicit proliferation, and prevents juvenile lethality despite that canonical OXPHOS-linked functions remain uncorrected. Inhibition of c-MYC with the dominant-negative Omomyc protein relieves the DNA damage in CIII-deficient hepatocytes in vivo. Our results connect primary OXPHOS deficiency to genomic instability and progeroid pathogenesis and suggest that targeting c-MYC and aberrant cell proliferation may be therapeutic in mitochondrial diseases.PMID:37095097 | DOI:10.1038/s41467-023-38027-1

Nat Commun. 2023 Apr 24;14(1):2339. doi: 10.1038/s41467-023-37875-1.ABSTRACTDifferential diagnosis of pulmonary nodules detected by computed tomography (CT) remains a challenge in clinical practice. Here, we characterize the global metabolomes of 480 serum samples including healthy controls, benign pulmonary nodules, and stage I lung adenocarcinoma. The adenocarcinoma demonstrates a distinct metabolomic signature, whereas benign nodules and healthy controls share major similarities in metabolomic profiles. A panel of 27 metabolites is identified in the discovery cohort (n = 306) to distinguish between benign and malignant nodules. The discriminant model achieves an AUC of 0.915 and 0.945 in the internal validation (n = 104) and external validation cohort (n = 111), respectively. Pathway analysis reveals elevation in glycolytic metabolites associated with decreased tryptophan in serum of lung adenocarcinoma vs benign nodules and healthy controls, and demonstrates that uptake of tryptophan promotes glycolysis in lung cancer cells. Our study highlights the value of the serum metabolite biomarkers in risk assessment of pulmonary nodules detected by CT screening.PMID:37095081 | DOI:10.1038/s41467-023-37875-1

Proc Natl Acad Sci U S A. 2023 May 2;120(18):e2212685120. doi: 10.1073/pnas.2212685120. Epub 2023 Apr 24.ABSTRACTCircadian rhythms influence physiology, metabolism, and molecular processes in the human body. Estimation of individual body time (circadian phase) is therefore highly relevant for individual optimization of behavior (sleep, meals, sports), diagnostic sampling, medical treatment, and for treatment of circadian rhythm disorders. Here, we provide a partial least squares regression (PLSR) machine learning approach that uses plasma-derived metabolomics data in one or more samples to estimate dim light melatonin onset (DLMO) as a proxy for circadian phase of the human body. For this purpose, our protocol was aimed to stay close to real-life conditions. We found that a metabolomics approach optimized for either women or men under entrained conditions performed equally well or better than existing approaches using more labor-intensive RNA sequencing-based methods. Although estimation of circadian body time using blood-targeted metabolomics requires further validation in shift work and other real-world conditions, it currently may offer a robust, feasible technique with relatively high accuracy to aid personalized optimization of behavior and clinical treatment after appropriate validation in patient populations.PMID:37094145 | DOI:10.1073/pnas.2212685120

J Intern Med. 2023 Apr 24. doi: 10.1111/joim.13640. Online ahead of print.ABSTRACTComplex diseases are caused by a combination of genetic, lifestyle, and environmental factors and comprise common noncommunicable diseases, including allergies, cardiovascular disease, and psychiatric and metabolic disorders. More than 25% of Europeans suffer from a complex disease, and together these diseases account for 70% of all deaths. The use of genomic, molecular, or imaging data to develop accurate diagnostic tools for treatment recommendations and preventive strategies, and for disease prognosis and prediction, is an important step toward precision medicine. However, for complex diseases, precision medicine is associated with several challenges. There is a significant heterogeneity between patients of a specific disease-both with regards to symptoms and underlying causal mechanisms-and the number of underlying genetic and nongenetic risk factors is often high. Here, we summarize precision medicine approaches for complex diseases and highlight the current breakthroughs as well as the challenges. We conclude that genomic-based precision medicine has been used mainly for patients with highly penetrant monogenic disease forms, such as cardiomyopathies. However, for most complex diseases-including psychiatric disorders and allergies-available polygenic risk scores are more probabilistic than deterministic and have not yet been validated for clinical utility. However, subclassifying patients of a specific disease into discrete homogenous subtypes based on molecular or phenotypic data is a promising strategy for improving diagnosis, prediction, treatment, prevention, and prognosis. The availability of high-throughput molecular technologies, together with large collections of health data and novel data-driven approaches, offers promise toward improved individual health through precision medicine.PMID:37093654 | DOI:10.1111/joim.13640

J Am Soc Nephrol. 2023 Apr 24. doi: 10.1681/ASN.0000000000000137. Online ahead of print.NO ABSTRACTPMID:37093635 | DOI:10.1681/ASN.0000000000000137