Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

A study of the lipid profile of Coix seeds from four areas based on untargeted lipidomics combined with multivariate algorithms to enable tracing of their origin

Wed, 31/05/2023 - 12:00
Food Res Int. 2023 Jul;169:112740. doi: 10.1016/j.foodres.2023.112740. Epub 2023 Mar 21.ABSTRACTThe geographical traceability of food products is seen as a distinctive feature of the future of food which is increasingly becoming a concern for consumers. In this research, differences in the lipid composition of Coix seed samples from four major Chinese origins were investigated using non-targeted lipidomics. By multivariate statistical analysis, unsupervised PCA and OPLS-DA based differentiation between the four origins of Coix seed samples could be achieved. The OPLS-DA VIP > 1 screened 72 lipids out of 1211 lipids as potential markers to distinguish Coix seeds from different origins. In addition, the potential markers (SPH(d16:0), Cer(d18:2/20:0 + O) and PC(8:0e/8:0) were combined with statistical analysis algorithms to construct a discriminant function for rapid differentiation of Coix seed samples from different origins and a specific function for different origins with 100% discrimination accuracy. In general, a rapid and accurate method combining multivariate chemometrics and algorithms was developed based on untargeted lipidomics to determine the geographical origin of Coix seed samples, which can also be applied to other agricultural products.PMID:37254373 | DOI:10.1016/j.foodres.2023.112740

Association of lipidome evolution with the corresponding volatile characteristics of postmortem lamb during chilled storage

Wed, 31/05/2023 - 12:00
Food Res Int. 2023 Jul;169:112916. doi: 10.1016/j.foodres.2023.112916. Epub 2023 Apr 29.ABSTRACTThis investigation aims to elucidate the roles of lipids on the volatilome evolution of postmortem lamb and its possible modulated mechanism behind. Firstly, the physicochemical properties were evaluated as coordinating role of flavor quality, and results suggested that chilled storage improved tenderness of muscle tissue and induced color variation of lamb. According to multivariate results, the pattern shifts of volatile profile of chilled lamb could be differentiated successfully. Besides, the potential differential aroma-active compounds were identified, including up-regulated heptanol, 1-octen-3-ol, 6-methyl-2-heptanone, 3-heptanone, 2-pentyl furan and octanol in early stage of storage (days 0-3) and down-regulated hexanal, pentanal, hexanol, octanol, 6-methy-2-heptanone, heptanol, 1-octen-3-ol and benzaldehyde in later stage of storage (days 3-7). Then, discriminant analysis recognized the differential lipid species corresponding to different stages of lamb flavor development, involving phospholipids, sphingolipids, glycerolipids and fatty acyls. Herein, the degradation of acyl carnitine and diglyceride may be an important pathway that contributed to volatilome evolution of postmortem lamb in the early stage of storage. These results demonstrated a potential relationship between headspace volatilome and lipidome evolutions, providing a comprehensive understanding for development of lipid-derived volatile compounds of chilled lamb and useful for lamb characteristic flavor quality evaluation and control in future.PMID:37254350 | DOI:10.1016/j.foodres.2023.112916

Effect of miR-149-5p on intramuscular fat deposition in pigs based on metabolomics and transcriptomics

Wed, 31/05/2023 - 12:00
BMC Genomics. 2023 May 31;24(1):293. doi: 10.1186/s12864-023-09382-6.ABSTRACTAs one of the important traits in pig production, meat quality has important research significance and value. Intramuscular fat (IMF) content is one of the most important factors affecting pork quality. Many experimental studies have shown that IMF content is closely related to the flavor, tenderness, and juiciness of pork. Therefore, it is of great significance to study the mechanism of porcine IMF deposition. Previous research indicated that miR-149-5p promoted the proliferation of porcine intramuscular (IM) preadipocytes and decreased their ability to differentiate, albeit the exact mechanism of action is unknown. In vitro, foreign pigs showed increased miR-149-5p expression and reduced fat deposition when compared to Queshan Black pigs. This study conducted metabolomics and transcriptomics analyses of porcine IM preadipocytes overexpressing miR-149-5p to verify their effects on lipid formation. According to metabolomics analysis, the overexpression of miR-149-5p has significantly altered the lipid, organic acid, and organic oxygen metabolites of porcine IM preadipocytes. Specially speaking, it has changed 115 metabolites, including 105 up-regulated and 10 down-regulated ones, as well as the composition of lipid, organic acid, and organic oxygen metabolism-related metabolites. RNA-seq analysis showed that overexpression of miR-149-5p significantly altered 857 genes, of which 442 were up-regulated, and 415 were down-regulated, with enrichment to MAPK, IL-17, PI3K-Akt, and ErbB signaling pathways. We found that overexpression of miR-149-5p inhibited adipogenic differentiation by changing cAMP signaling pathway in porcine IM preadipocytes. In addition, the overexpression of miR-149-5p may affect the transport of Cu2+ by targeting ATP7A and inhibiting adipogenic differentiation. These findings elucidate the regulatory function of miR-149-5p in porcine IM preadipocytes, which may be a key target for controlling pork quality.PMID:37259030 | DOI:10.1186/s12864-023-09382-6

A metabolomic signature of decelerated physiological aging in human plasma

Wed, 31/05/2023 - 12:00
Geroscience. 2023 May 31. doi: 10.1007/s11357-023-00827-0. Online ahead of print.ABSTRACTThe degenerative processes that occur during aging increase the risk of disease and impaired health. Meanwhile, interventions that target aging to promote healthy longevity are gaining interest, both academically and in the public. While nutritional and physical interventions exist, efficacy is often difficult to determine. It is therefore imperative that an aging score measuring the biological aging process is available to the wider public. However, simple, interpret, and accessible biological aging scores are lacking. Here, we developed PhysiAge, a physiological aging score based on five accessible parameters that have influence on or reflect the aging process: (1) average daily step count, (2) blood glucose, (3) systolic blood pressure, (4) sex, and (5) age. Here, we found that compared to calendar age alone, PhysiAge better predicts mortality, as well as established muscle aging markers such as decrease in NAD+ levels, increase in oxidative stress, and decline in physical functioning. In order to demonstrate the usefulness of PhysiAge in identifying relevant factors associated with decelerated aging, we calculated PhysiAges for a cohort of aged individuals and obtained mass spectrometry-based blood plasma metabolomic profiles for each individual. Here, we identified a metabolic signature of decelerated aging, which included components of the TCA cycle, including malate, citrate, and isocitrate. Higher abundance of these metabolites was associated with decelerated aging, in line with supplementation studies in model organisms. PhysiAge represents an accessible way for people to track and intervene in their aging trajectories, and identifies a metabolic signature of decelerated aging in human blood plasma, which can be further studied for its causal involvement in human aging.PMID:37259015 | DOI:10.1007/s11357-023-00827-0

Metabolite Analyses Using Nuclear Magnetic Resonance (NMR) Spectroscopy in Plasma of Patients with Prostate Cancer

Wed, 31/05/2023 - 12:00
Methods Mol Biol. 2023;2675:195-204. doi: 10.1007/978-1-0716-3247-5_15.ABSTRACTNuclear magnetic resonance (NMR) spectroscopy enables the detection and the quantification of a large range of molecules, including low-molecular-weight metabolites and lipids. NMR spectroscopy is a powerful approach when applied to the high-throughput analysis of plasma or serum samples allowing, in addition, the detection of total proteins, lipoproteins, and signals arising from the glycosylation of circulating acute-phase proteins. Here, we describe the usage of NMR spectroscopy for profiling the plasma or serum of patients with prostate cancer.PMID:37258765 | DOI:10.1007/978-1-0716-3247-5_15

Tracer-Based Metabolic Analysis by NMR in Intact Perfused Human Liver Tissue

Wed, 31/05/2023 - 12:00
Methods Mol Biol. 2023;2675:167-180. doi: 10.1007/978-1-0716-3247-5_13.ABSTRACTHuman metabolic liver disease is dramatically increasing globally and presents an urgent clinical unmet need. Rodent models of non-alcoholic fatty liver disease (NAFLD) are available, but they fail to fully recreate the metabolic and cellular features of human disease. Thus, it is imperative to understand the metabolic interplay in human cells in the context of disease. We have applied nuclear magnetic resonance (NMR) spectroscopy approaches to enable the detection of numerous metabolites in human cells and within intact tissue in a single measurement. In this chapter, we describe the challenges of using isolated human hepatocytes vs perfused human liver tissue for metabolic tracer experiments and how experimental parameters can be refined to interrogate signals from intact tissue and cells.PMID:37258763 | DOI:10.1007/978-1-0716-3247-5_13

Allantoic fluid metabolome reveals specific metabolic signatures in chicken lines different for their muscle glycogen content

Wed, 31/05/2023 - 12:00
Sci Rep. 2023 May 31;13(1):8867. doi: 10.1038/s41598-023-35652-0.ABSTRACTNutrient availability in eggs can affect early metabolic orientation in birds. In chickens divergently selected on the Pectoralis major ultimate pH, a proxy for muscle glycogen stores, characterization of the yolk and amniotic fluid revealed a different nutritional environment. The present study aimed to assess indicators of embryo metabolism in pHu lines (pHu+ and pHu-) using allantoic fluids (compartment storing nitrogenous waste products and metabolites), collected at days 10, 14 and 17 of embryogenesis and characterized by 1H-NMR spectroscopy. Analysis of metabolic profiles revealed a significant stage effect, with an enrichment in metabolites at the end of incubation, and an increase in interindividual variability during development. OPLS-DA analysis discriminated the two lines. The allantoic fluid of pHu- was richer in carbohydrates, intermediates of purine metabolism and derivatives of tryptophan-histidine metabolism, while formate, branched-chain amino acids, Krebs cycle intermediates and metabolites from different catabolic pathways were more abundant in pHu+. In conclusion, the characterization of the main nutrient sources for embryos and now allantoic fluids provided an overview of the in ovo nutritional environment of pHu lines. Moreover, this study revealed the establishment, as early as day 10 of embryo development, of specific metabolic signatures in the allantoic fluid of pHu+ and pHu- lines.PMID:37258592 | DOI:10.1038/s41598-023-35652-0

Gut microbiome determines therapeutic effects of OCA on NAFLD by modulating bile acid metabolism

Wed, 31/05/2023 - 12:00
NPJ Biofilms Microbiomes. 2023 May 31;9(1):29. doi: 10.1038/s41522-023-00399-z.ABSTRACTNon-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease, had no approved pharmacological agents yet. Obeticholic acid (OCA), a novel bile acid derivative, was demonstrated to ameliorate NAFLD-related manifestations. Regarding the role of gut-liver axis in liver disease development, this study aimed to explore the potential role of gut microbiota in the treatment of OCA in NAFLD mice induced by the high-fat diet (HFD). Antibiotic-induced microbiome depletion (AIMD) and fecal microbiota transplantation (FMT) confirmed the critical role of gut microbiota in OCA treatment for NAFLD by effectively alleviating histopathological lesions and restoring liver function impaired by HFD. Metagenomic analysis indicated that OCA intervention in HFD mice remarkably increased the abundance of Akkermansia muciniphila, Bifidobacterium spp., Bacteroides spp., Alistipes spp., Lactobacillus spp., Streptococcus thermophilus, and Parasutterella excrementihominis. Targeted metabolomics analysis indicated that OCA could modulate host bile acids pool by reducing levels of serum hydrophobic cholic acid (CA) and chenodeoxycholic acid (CDCA), and increasing levels of serum-conjugated bile acids, such as taurodeoxycholic acid (TDCA) and tauroursodesoxycholic acid (TUDCA) in the HFD-fed mice. Strong correlations were observed between differentially abundant microbes and the shifted bile acids. Furthermore, bacteria enriched by OCA intervention exhibited much greater potential in encoding 7alpha-hydroxysteroid dehydrogenase (7α-HSDs) producing secondary bile acids rather than bile salt hydrolases (BSHs) mainly responsible for primary bile acid deconjugation. In conclusion, this study demonstrated that OCA intervention altered gut microbiota composition with specially enriched gut microbes modulating host bile acids, thus effectively alleviating NAFLD in the mice.PMID:37258543 | DOI:10.1038/s41522-023-00399-z

Red light-induced inhibition of maize (Zea mays) mesocotyl elongation: evaluation of apoplastic metabolites

Wed, 31/05/2023 - 12:00
Funct Plant Biol. 2023 Jun 1. doi: 10.1071/FP22181. Online ahead of print.ABSTRACTLight is a crucial factor affecting plant growth and development. Besides providing the energy for photosynthesis, light serves as a sensory cue to control the adaptation of plants to environmental changes. We used the etiolated maize (Zea mays) seedlings as a model system to study the red light-regulated growth. Exposure of the maize seedlings to red light resulted in growth inhibition of mesocotyls. We demonstrate for the first time (to the best our knowledge) that red light affected the patterns of apoplastic fluid (AF) metabolites extracted from the mesocotyl segments. By means of the untargeted gas chromatography-mass spectrometry (GC-MS)-based metabolomics approach, we identified 44 metabolites in the AF of maize mesocotyls and characterised the dynamics of their relative tissue abundances. The characteristic metabolite patterns of mesocotyls dominated with mono- and disaccharides, organic acids, amino acids, and other nitrogen-containing compounds. Upon red light irradiation, the contents of β-alanine, putrescine and trans-aconitate significantly increased (P-value<0.05). In contrast, there was a significant decrease in the total ascorbate content in the AF of maize mesocotyls. The regulatory role of apoplastic metabolites in the red light-induced inhibition of maize mesocotyl elongation is discussed.PMID:37258494 | DOI:10.1071/FP22181

Investigating the impact of condomless vaginal intercourse and lubricant use on the vaginal metabolome: a pre-post observational study

Wed, 31/05/2023 - 12:00
Sex Transm Infect. 2023 May 31:sextrans-2022-055667. doi: 10.1136/sextrans-2022-055667. Online ahead of print.ABSTRACTOBJECTIVE: The vaginal metabolome is a significant factor in the vaginal microenvironment, and data are emerging on its independent role in urogenital health. Condomless vaginal intercourse and personal lubricant use are common practices that may affect the vaginal metabolome. The aim of the present study is to describe the associations between condomless intercourse and lubricant use on the vaginal metabolome.METHODS: This study used archived mid-vaginal swabs from a 10-week observational cohort of reproductive age women who self-collected samples and recorded behavioural diaries daily. Cases and controls were defined as participants who self-reported condomless vaginal intercourse with or without lubricant use, respectively. Samples were drawn prior to and following condomless vaginal intercourse. Twenty-two case participants were race/ethnicity matched to 22 control participants. Mid-vaginal swabs were subjected to 16S rRNA gene amplicon sequencing and untargeted ultrahigh performance liquid chromatography tandem mass spectroscopy metabolomics. Bayesian mixed-effects regression (unadjusted and adjusted for the vaginal microbiota) was used to evaluate differences in metabolite concentration associated with vaginal intercourse and lubricant use.RESULTS: Both condomless penile-vaginal intercourse and lubricant use were independently associated with higher (up to 8.3-fold) concentrations of metabolites indicative of epithelial damage (eg, sarcosine) and many host-produced antioxidants. Lubricant use was significantly associated with increases in lipids related to cellular damage, host-produced sphingolipids (antimicrobials), antioxidants and salicylate, a cooling agent common to lubricants, in a study design which controls for the independent effect of intercourse. Metabolites involved in oxidative stress and salicylate were strongly correlated with several molecular bacterial vaginosis-associated bacteria.CONCLUSIONS: This study provides important foundational data on how condomless vaginal-penile intercourse and lubricant use affect the vaginal metabolome and may affect the protective mechanisms in the vaginal microenvironment.PMID:37258272 | DOI:10.1136/sextrans-2022-055667

Screening strategy for 1210 exogenous chemicals in serum by two-dimensional liquid chromatography-mass spectrometry

Wed, 31/05/2023 - 12:00
Environ Pollut. 2023 May 29:121914. doi: 10.1016/j.envpol.2023.121914. Online ahead of print.ABSTRACTHumans are at risk of exogenous exposure to exogenous chemicals. Challenges exist for the comprehensive monitoring of residues with different physical and chemical properties in serum. Here, an on-line two-dimensional liquid chromatography (2D-LC) - high resolution mass spectrometry system (HRMS) was developed, expanding the range of the partition coefficient in octanol/water of the residue analysis from -8 to 12. A high-coverage serum residue screening strategy was further designed by integrating 2D-LC system with HRMS full MS/data independent acquisition and automatic spectral library searching. This strategy enables to simultaneously screen 1210 pesticides, veterinary/human drugs, other chemical pollutants and their metabolites in serum with a single analysis. Method validation showed 92% and 81% of 1022 residues spiked in serum could be detected at 50 ng/mL and 5 ng/mL, respectively. The developed method was applied to the analysis of 24 separately pooled serum samples, 58 suspect residues were found, some of them were detected at high frequencies over than 50%. Among them, 4,6-Dinitro-O-cresol and probable carcinogenic folpet are highly toxic, and cimaterol is banned in China. Collectively, this study developed a 2D-LC-HRMS -based screening strategy for screening pesticides, veterinary/human drugs, and other chemical pollutants in serum, it is helpful for studying the effect of exogenous exposures on human health.PMID:37257806 | DOI:10.1016/j.envpol.2023.121914

Integrated lncRNA transcriptomics, proteomics, and metabolomics to identify early cellular response variation in deoxynivalenol-treated IPEC-J2 cells

Wed, 31/05/2023 - 12:00
Food Chem Toxicol. 2023 May 29:113863. doi: 10.1016/j.fct.2023.113863. Online ahead of print.ABSTRACTMycotoxins, especially deoxynivalenol (DON), are common contaminants of food and feed, which also has serious threaten to human health and livestock production. Moreover, DON severely impair intestinal epithelial barrier function. Therefore, it is necessary to investigate the mechanism of intestinal epithelial cell injury induced by DON. Here, intestinal porcine enterocyte cell (IPEC-J2) was incubated with 200 ng/ml or 2000ng/ml DON for 6 h, then lncRNA sequencing, metabolomics and proteomics were applied. Combined with long coding transcriptomics, and proteomics, 200 ng/ml DON treatment (LDON group) significantly upregulated ribosome biogenesis in eukaryotes, spliceosome, and ubiquitin mediated proteolysis, RNA transport, and downregulated metabolic pathways in IPEC-J2, 2000 ng/ml of DON treatment (HDON group) significantly upregulated ribosome biogenesis in eukaryotes, and spliceosome, and downregulated base excision repair, cell cycle, DNA replication, homologous recombination, and mismatch repair in IPEC-J2. Combined with long coding transcriptomics, and proteomics, as compared with LDON group, HDON group significantly upregulated adherens junction, hippo signaling pathway, and pathways in cancer, and downregulated DNA replication pathways in IPEC-J2. In metabolomics, LDON group and HDON group was mainly downregulated biosynthesis of unsaturated fatty acids, and fatty acid metabolism. These results provide a new insight to prevent and treat DON induced intestinal epithelial cell injury.PMID:37257635 | DOI:10.1016/j.fct.2023.113863

An alien metabolite vs. a synthetic chemical hazard: An ecotoxicological comparison in the Mediterranean blue mussel

Wed, 31/05/2023 - 12:00
Sci Total Environ. 2023 May 29:164476. doi: 10.1016/j.scitotenv.2023.164476. Online ahead of print.ABSTRACTBioactive natural products from marine invasive species may dramatically impact native communities, while many synthetic pharmaceutical drugs are released into the marine environment and have long-lasting harmful effects on aquatic life. Sometimes, metabolites from alien species and synthetic compounds share similar mechanisms of action, suggesting comparable ecotoxicological impacts. This applies to the alkaloid caulerpin (CAU) from the green alga Caulerpa cylindracea, highly invasive in the Mediterranean Sea, and to the synthetic lipid-lowering drug fenofibrate (FFB), both acting as agonists of peroxisome proliferator-activated receptors (PPARs). Analogies with FFB, which is widely considered hazardous to the aquatic environment, have led to concerns about the ecotoxicological potential of CAU. The problem has implications for public health as CAU is well known to enter the food web accumulating in fish of commercial importance. Here, we compared the effects of FFB and CAU through biochemical and histopathological analysis on a relevant bioindicator molluscan species, the mussel Mytilus galloprovincialis. Under laboratory conditions, mussels were fed with food enriched with CAU or FFB. After treatment, biochemical markers were analyzed revealing metabolic capacity impairments, cellular damage, and changes in acetylcholinesterase activity in mussels fed with FFB-enriched food. NMR-based metabolomic studies also showed significant alterations in the metabolic profiles of FFB-treated mussels. In addition, dietary administration of FFB produced morphological alterations in the mussels' gills and digestive tubules. Obtained results confirm that FFB is harmful to aquatic life and that its release into the environment should be avoided. Conversely, dietary treatment with CAU did not produce any significant alterations in the mussels. Overall, our results pave the way for the possible valorization of the huge biomass from one of the world's worst invasive species to obtain CAU, a natural product of interest in drug discovery.PMID:37257616 | DOI:10.1016/j.scitotenv.2023.164476

Forages and Pastures Symposium: Forage biodegradation: Advances in ruminal microbial ecology

Wed, 31/05/2023 - 12:00
J Anim Sci. 2023 May 31:skad178. doi: 10.1093/jas/skad178. Online ahead of print.ABSTRACTThe rumen microbial ecosystem provides ruminants a selective advantage, the ability to utilize forages, allowing them to flourish worldwide in various environments. For many years, our understanding of the ruminal microbial ecosystem was limited to understanding the microbes (usually only laboratory-amenable bacteria) grown in pure culture, meaning that much of our understanding of ruminal function remained a "black box." However, the ruminal degradation of plant cell walls is performed by a consortium of bacteria, archaea, protozoa, and fungi that produces a wide variety of carbohydrate active enzymes (CAZymes) that are responsible for the catabolism of cellulose, hemicellulose, and pectin. The past 15 years have seen the development and implementation of numerous next-generation sequencing (NGS) approaches (e.g., pyrosequencing, Illumina, and shotgun sequencing), which have contributed significantly to a greater level of insight regarding the microbial ecology of ruminants fed a variety of forages. There has also been an increase in the utilization of liquid chromatography (LC) and mass spectrometry (MS) that revolutionized transcriptomic approaches, and further improvements in the measurement of fermentation intermediates and end products have advanced with metabolomics. These advanced NGS techniques along with other analytic approaches, such as metaproteomics, have been utilized to elucidate the specific role of microbial CAZymes in forage degradation. Other methods have provided new insights into dynamic changes in the ruminal microbial population fed different diets and how these changes impact the assortment of products presented to the host animal. As more omics-based data has accumulated on forage-fed ruminants, the sequence of events that occur during fiber colonization by the microbial consortium has become more apparent, with fungal populations and fibrolytic bacterial populations working in conjunction, as well as expanding understanding of the individual microbial contributions to degradation of plant cell walls and polysaccharide components. In the future, the ability to predict microbial population and enzymatic activity and end products will be able to support the development of dynamic predictive models of rumen forage degradation and fermentation. Consequently, it is imperative to understand the rumen's microbial population better to improve fiber degradation in ruminants and, thus, stimulate more sustainable production systems.PMID:37257501 | DOI:10.1093/jas/skad178

Multi-omics blood atlas reveals unique features of immune and platelet responses to SARS-CoV-2 Omicron breakthrough infection

Wed, 31/05/2023 - 12:00
Immunity. 2023 May 16:S1074-7613(23)00224-8. doi: 10.1016/j.immuni.2023.05.007. Online ahead of print.ABSTRACTAlthough host responses to the ancestral SARS-CoV-2 strain are well described, those to the new Omicron variants are less resolved. We profiled the clinical phenomes, transcriptomes, proteomes, metabolomes, and immune repertoires of >1,000 blood cell or plasma specimens from SARS-CoV-2 Omicron patients. Using in-depth integrated multi-omics, we dissected the host response dynamics during multiple disease phases to reveal the molecular and cellular landscapes in the blood. Specifically, we detected enhanced interferon-mediated antiviral signatures of platelets in Omicron-infected patients, and platelets preferentially formed widespread aggregates with leukocytes to modulate immune cell functions. In addition, patients who were re-tested positive for viral RNA showed marked reductions in B cell receptor clones, antibody generation, and neutralizing capacity against Omicron. Finally, we developed a machine learning model that accurately predicted the probability of re-positivity in Omicron patients. Our study may inspire a paradigm shift in studying systemic diseases and emerging public health concerns.PMID:37257450 | DOI:10.1016/j.immuni.2023.05.007

Tracer metabolomics reveals the role of aldose reductase in glycosylation

Wed, 31/05/2023 - 12:00
Cell Rep Med. 2023 May 23:101056. doi: 10.1016/j.xcrm.2023.101056. Online ahead of print.ABSTRACTAbnormal polyol metabolism is predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol metabolism has been implicated in phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG) and an AR inhibitor, epalrestat, proposed as a potential therapy. Considering that the PMM2 enzyme is not directly involved in polyol metabolism, the increased polyol production and epalrestat's therapeutic mechanism in PMM2-CDG remained elusive. PMM2-CDG, caused by PMM2 deficiency, presents with depleted GDP-mannose and abnormal glycosylation. Here, we show that, apart from glycosylation abnormalities, PMM2 deficiency affects intracellular glucose flux, resulting in polyol increase. Targeting AR with epalrestat decreases polyols and increases GDP-mannose both in patient-derived fibroblasts and in pmm2 mutant zebrafish. Using tracer studies, we demonstrate that AR inhibition diverts glucose flux away from polyol production toward the synthesis of sugar nucleotides, and ultimately glycosylation. Finally, PMM2-CDG individuals treated with epalrestat show a clinical and biochemical improvement.PMID:37257447 | DOI:10.1016/j.xcrm.2023.101056

Exposure to copper nanoparticles or copper sulfate dysregulated the hypothalamic-pituitary-gonadalaxis, gonadal histology, and metabolites in Pelteobagrus fulvidraco

Wed, 31/05/2023 - 12:00
J Hazard Mater. 2023 May 26;457:131719. doi: 10.1016/j.jhazmat.2023.131719. Online ahead of print.ABSTRACTThis study evaluated the effects of chronic exposure to copper nanoparticles (Cu-NPs) and waterborne copper (CuSO4) on the reproductive system of yellow catfish (Pelteobagrus fulvidraco). Juvenile yellow catfish were exposed to 100 and 200 μg Cu/L Cu-NPs and 100 μg Cu/L CuSO4 for 42 days. The results showed clear reproductive defects in both female and male yellow catfish in the 200 μg Cu/L Cu-NPs and 100 μg Cu/L CuSO4 groups. Exposure to Cu-NPs or CuSO4 inhibited folliculogenesis and vitellogenesis in the ovaries, and spermatogenesis in the testes, accompanied by elevation of the apoptotic signal. Ultrastructural observations also revealed damaged organelles of gonadal cells in both testes and ovaries. Most of the hypothalamic-pituitary-gonadal (HPG) axis genes examined and serum sex steroid hormones tended to be downregulated after Cu exposure. Metabolomic analysis suggested that gonadal estradiol level is sensitive to Cu-NPs or CuSO4. The heat map of gonadal metabolomics suggested a similar effect of 200 μg Cu/L Cu-NPs and 100 μg Cu/L CuSO4 in both the ovaries and testes. Additionally, metabolomics data showed that the reproductive toxicity due to Cu-NPs and CuSO4 may occur via different metabolic pathways. Cu-NPs tend to dysregulate the metabolic pathways of sphingolipid and linoleic acid metabolism in the ovary and the biosynthesis of amino acids and pantothenate and CoA in the testis. Overall, these findings revealed the toxicological effects of Cu-NPs and CuSO4 on the HPG axis and gonadal metabolism in yellow catfish.PMID:37257385 | DOI:10.1016/j.jhazmat.2023.131719

Neurosteroid pathway derangement in asphyctic infants treated with hypothermia: an untargeted metabolomic approach

Wed, 31/05/2023 - 12:00
EBioMedicine. 2023 May 29;92:104636. doi: 10.1016/j.ebiom.2023.104636. Online ahead of print.ABSTRACTBACKGROUND: The pathobiological mechanisms associated with perinatal asphyxia and hypoxic-ischemic encephalopathy are complex and poorly understood. The metabolic effects of therapeutic hypothermia have been partially explored.METHODS: We conducted a single-center longitudinal study to investigate the metabolic effects of perinatal asphyxia and hypoxic-ischemic encephalopathy on the urinary metabolome of a group of 12 asphyctic infants over time compared to 22 matched healthy newborns, using untargeted metabolomics based on mass spectrometry.FINDINGS: Over-representation pathway analysis identified the steroidogenesis pathway as being significantly disrupted, with reduced steroid levels in the first three days of life despite treatment with hypothermia. Comparison with matched healthy newborns showed that the urinary steroid content was lower in asphyctic infants before hypothermia. The lysine degradation and carnitine synthesis pathways were also significantly affected.INTERPRETATION: Steroidogenesis is significantly disrupted in asphyctic infants compared to healthy newborns. Given how neurosteroids are involved in neuromodulation and neuroprotection, translational research is warranted on the potential role of neurosteroid-based intervention in asphyctic infants.FUNDING: None.PMID:37257315 | DOI:10.1016/j.ebiom.2023.104636

Targeted Mutagenesis of the Vacuolar H+ Translocating Pyrophosphatase Gene Reduces Grain Chalkiness in Rice

Wed, 31/05/2023 - 12:00
Plant J. 2023 May 31. doi: 10.1111/tpj.16317. Online ahead of print.ABSTRACTGrain chalkiness is a major concern in rice production as it impacts milling yield and cooking quality, eventually reducing market value of the rice. A gene encoding the vacuolar H+ translocating pyrophosphatase (V-PPase) is a major quantitative trait locus in indica rice, controlling grain chalkiness. Higher transcriptional activity of this gene is associated with increased chalk content. However, whether the suppression of V-PPase could reduce chalkiness is not clear. Further, natural variation in the chalkiness of japonica rice has not been linked with V-PPase. Here, we describe promoter targeting of the japonica V-PPase allele that led to reduced grain chalkiness and development of more translucent grains. Disruption of a putative GATA element by CRISPR/Cas9 suppressed V-PPase activity, reduced grain chalkiness, and impacted post-germination growth that could be rescued by the exogenous supply of sucrose. The mature grains of the targeted lines showed a much lower percentage of large or medium chalk. Interestingly, the targeted lines developed a significantly lower chalk under heat stress, a major inducer of grain chalk. Metabolomic analysis showed that pathways related to starch and sugar metabolism were affected in the developing grains of the targeted lines that correlated with higher inorganic pyrophosphate and starch contents and upregulation of starch biosynthesis genes. In summary, we show a biotechnology approach of reducing grain chalkiness in rice by downregulating the transcriptional activity of V-PPase that presumably leads to altered metabolic rates including starch biosynthesis, resulting in more compact packing of starch granules and formation of translucent rice grains.PMID:37256847 | DOI:10.1111/tpj.16317

The pennate diatom Pseudo-nitzschia multistriata as a model for diatom life cycles, from the laboratory to the sea

Wed, 31/05/2023 - 12:00
J Phycol. 2023 May 9. doi: 10.1111/jpy.13342. Online ahead of print.ABSTRACTPhytoplankton dynamics are regulated by external cues, such as light and nutrients, as well as by biotic interactions and endogenous controls linked to life cycle characteristics. The planktonic pennate diatom Pseudo-nitzschia multistriata, with a heterothallic mating system with two opposite mating types (MTs), represents a model for the study of diatom life cycles. P. multistriata is a toxic species, able to produce the neurotoxin domoic acid. First described in Japan in 1993, it was detected at the long-term monitoring station MareChiara (Gulf of Naples, Italy) in 1995. Since then, P. multistriata has been reported from several worldwide coastal sites. A large body of knowledge has been produced on its ecology, genetic diversity, and life cycle characteristics. The availability of these data, the ecological relevance of the Pseudo-nitzschia genus, and its controllable life cycle with a short generation time made it an ideal species to develop a genetic model system for diatoms. To enable functional studies, a 59 Mb genome sequence and several transcriptomic data were produced, and genetic transformation was optimized. These tools allowed the discovery of the first mating-type determining gene for diatoms. Gene expression studies and metabolomics analyses defined genes and molecules underpinning different phases of the process of sexual reproduction. This model system, developed to explore the genetics of diatom life cycles, offers the opportunity to parallel experimental observations in the laboratory using in situ meta-omics analyses along space and time, empowering knowledge on the biology and ecology of the genus.PMID:37256710 | DOI:10.1111/jpy.13342

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