PubMed

Nat Commun. 2024 Oct 22;15(1):9110. doi: 10.1038/s41467-024-52213-9.ABSTRACTImaging mass spectrometry is a powerful technology enabling spatial metabolomics, yet metabolites can be assigned only to a fraction of the data generated. METASPACE-ML is a machine learning-based approach addressing this challenge which incorporates new scores and computationally-efficient False Discovery Rate estimation. For training and evaluation, we use a comprehensive set of 1710 datasets from 159 researchers from 47 labs encompassing both animal and plant-based datasets representing multiple spatial metabolomics contexts derived from the METASPACE knowledge base. Here we show that, METASPACE-ML outperforms its rule-based predecessor, exhibiting higher precision, increased throughput, and enhanced capability in identifying low-intensity and biologically-relevant metabolites.PMID:39438443 | DOI:10.1038/s41467-024-52213-9

Metabolomics. 2024 Oct 22;20(6):119. doi: 10.1007/s11306-024-02174-3.ABSTRACTINTRODUCTION: Plant hormonal mutants, which do not produce or are insensitive to hormones, are often affected in their growth and development, but other metabolic rearrangements might be involved. A trade-off between growth and stress response is necessary for the plant survival.OBJECTIVES: Here, we explore the metabolic profile and the pathogen resistance of a brassinosteroid-insensitive Hordeum vulgare L. semi-dwarf mutant, BW312.METHODS: We investigate BW312 metabolism through a chemical enrichment analysis, confirming a shifted metabolic profile towards pathogen resistance. The effective pathogen resistance of the mutant was tested in presence of Pyrenophora teres and Fusarium graminearum.RESULTS: Four compound families were increased in the mutant (pyrrolidines, basic amino acids, alkaloids, monounsaturated fatty acids), while two compound families were decreased (pyrrolidinones, anthocyanins). Dipeptides were also altered (increased and decreased). BW312 displayed a better resistance to Pyrenophora teres in the earliest stage of infection with a 21.5% decrease of the lesion length 10 days after infection. BW312 also exhibited a reduced lesion length (43.3%) and a reduced browning of the lesions (55.5%) when exposed to Fusarium graminearum at the seedling stage.CONCLUSION: The observed metabolomic shift strongly suggests that the BW312 semi-dwarf mutant is in a primed state, resulting in a standby state of alertness to pathogens.PMID:39438353 | DOI:10.1007/s11306-024-02174-3

Ann Rheum Dis. 2024 Oct 22:ard-2024-225925. doi: 10.1136/ard-2024-225925. Online ahead of print.ABSTRACTOBJECTIVES: Systemic sclerosis (SSc) is a heterogeneous disease, complicating its management. Its complexity and the insufficiency of clinical manifestations alone to delineate homogeneous patient groups further challenge this task. However, autoantibodies could serve as relevant markers for the pathophysiological mechanisms driving the disease. Identifying specific immunological mechanisms based on patients' serological statuses might facilitate a deeper understanding of the diversity of the disease.METHODS: A cohort of 206 patients with SSc enrolled in the PRECISESADS cross-sectional study was examined. Patients were stratified based on their anti-centromere (ACA) and anti-SCL70 (SCL70) antibody statuses. Comprehensive omics analyses including transcriptomic, flow cytometric, cytokine and metabolomic data were analysed to characterise the differences between these patient groups.RESULTS: Patients with SCL70 antibodies showed severe clinical features such as diffuse cutaneous sclerosis and pulmonary fibrosis and were biologically distinguished by unique transcriptomic profiles. They exhibit a pro-inflammatory and fibrotic signature associated with impaired tissue remodelling and increased carnitine metabolism. Conversely, ACA-positive patients exhibited an immunomodulation and tissue homeostasis signature and increased phospholipid metabolism.CONCLUSIONS: Patients with SSc display varying biological profiles based on their serological status. The findings highlight the potential utility of serological status as a discriminating factor in disease severity and suggest its relevance in tailoring treatment strategies and future research directions.PMID:39438128 | DOI:10.1136/ard-2024-225925

Clin Chim Acta. 2024 Oct 20:120012. doi: 10.1016/j.cca.2024.120012. Online ahead of print.NO ABSTRACTPMID:39437984 | DOI:10.1016/j.cca.2024.120012

Sci Total Environ. 2024 Oct 20:177071. doi: 10.1016/j.scitotenv.2024.177071. Online ahead of print.ABSTRACTThe tire antioxidant 6PPD has garnered extensive attention due to its widespread presence in the environment and the harmful effects of its transformation products on aquatic organisms. 6PPD has been detected in airborne dust, and it can enter mammals through inhalation exposure. While the toxic effects of 6PPD exposure have been reported in mammals, its effects on hepatic metabolism still remain poorly understood. Here, we collected the serum and liver samples at 1, 6, and 72 h following a single oral exposure of 100 mg/kg body weight (bw) 6PPD, respectively. We also investigated changes in serum and hepatic physiological indicators and metabolites, correspondingly. Results indicated that single time oral exposure a high dose of 6PPD did not significantly affect the physiological indexes of rats within a short time frame. However, untargeted metabolomics analysis of the metabolites in the liver at 1, 6, and 72 h revealed that the number of differential expression metabolites gradually increased over time and the most affected substances were lipids and lipid-like molecules. Interestingly, the KEGG pathway enrichment analysis indicated that 6PPD disrupted the riboflavin metabolism, leading to a significant decrease in FMN levels at all time points. In addition, the hepatic glucose metabolism was significantly affected at 6 and 72 h after oral administration. Taken together, short-term exposure to 6PPD disturbed lipid and riboflavin metabolism and gradually affected glucose metabolism in the liver of rats. These findings revealed the impacts of 6PPD on the hepatic metabolism in animals, and also offered some important insights into its toxicology and health risk.PMID:39437917 | DOI:10.1016/j.scitotenv.2024.177071

Sci Total Environ. 2024 Oct 20:177064. doi: 10.1016/j.scitotenv.2024.177064. Online ahead of print.ABSTRACTThe restoration of mangroves in urban environments can increase the risk of contaminant exposure and subsequent health effects to resident biota, yet this risk is rarely considered in mangrove restoration programs. Here we assessed the influence of sediment chemistry on contaminant bioaccumulation in shore crabs from restored and natural mangroves in urban environments compared to a reference site. The concentrations of some trace elements were several-fold higher in the sediment and crab tissues of the urban restored site compared to the natural reference site (Cd = 6×, Co = 7×, Cr = 4×, Mn = 30×, and Ni = 18× greater in sediments, while Cd = 4×, Co = 2×, Cr = 2×, Mn = 6×, and Ni = 3× greater in crab tissues). NMR-based metabolomics on crabs revealed higher abundances of proline and glutamate at urban sites, which may be indicative of physiological stress from trace element contamination. Choice experiments were used to test habitat selectivity by crabs from each population, and showed that crabs avoided sediments from the contaminated urban sites. Our results suggest that restoring mangroves in contaminated environments could create ecological sinks, where animals take residence in the new habitat but are exposed to sediment-based contaminants, with potential implications for organism and population health.PMID:39437910 | DOI:10.1016/j.scitotenv.2024.177064

Neurochem Int. 2024 Oct 20:105886. doi: 10.1016/j.neuint.2024.105886. Online ahead of print.ABSTRACTOxygen support plays a critical role in the management of preterm infants in neonatal intensive care units. On the other hand, the possible effects of oxygen supplementation on cellular functions, specifically glucose metabolism, have been less understood. PURPOSE: of the study is to investigate whether supplemental oxygen alters glucose metabolism and pentose phosphate pathway (PPP) activity in the brain tissue and its relevance with silent information regulator proteins (SIRT) pathway. For this purpose, newborn C57BL/6 pups were exposed to 90% oxygen from birth until postnatal day 7 (PN7) and metabolites of glysolysis and PPP were investigated through metabolomics analysis. SIRT1, glucose-6-phosphate dehydrogenase (G6PD) and transaldolase (TALDO) proteins were examined immunohistochemically and molecularly in the prefrontal and hippocampus regions of the brain. Later on, SIRT1 inhibition was carried out. Our results indicate that supplemental oxygen causes an increase in PPP metabolites as well as activation of G6PD enzyme in the brain tissue, which is reversed by SIRT1 inhibition. Our study underlines a connection between supplemental oxygen, glucose metabolism, PPP pathway and the SIRT signaling. Understanding these intricate relationships not only deepens our knowledge of cellular physiology but also holds promise for therapeutic interventions for creating neuroprotective strategies in preterm brain.PMID:39437895 | DOI:10.1016/j.neuint.2024.105886

J Proteome Res. 2024 Oct 22. doi: 10.1021/acs.jproteome.3c00634. Online ahead of print.ABSTRACTOrthogonal separations of data from high-resolution mass spectrometry can provide insight into sample composition and address challenges of complete annotation of molecules in untargeted metabolomics. "Molecular networks" (MNs), as used in the Global Natural Products Social Molecular Networking platform, are a prominent strategy for exploring and visualizing molecular relationships and improving annotation. MNs are mathematical graphs showing the relationships between measured multidimensional data features. MNs also show promise for using network science algorithms to automatically identify targets for annotation candidates and to dereplicate features associated with a single molecular identity. This paper introduces "molecular hypernetworks" (MHNs) as more complex MN models able to natively represent multiway relationships among observations. Compared to MNs, MHNs can more parsimoniously represent the inherent complexity present among groups of observations, initially supporting improved exploratory data analysis and visualization. MHNs also promise to increase confidence in annotation propagation, for both human and analytical processing. We first illustrate MHNs with simple examples, and build them from liquid chromatography- and ion mobility spectrometry-separated MS data. We then describe a method to construct MHNs directly from existing MNs as their "clique reconstructions", demonstrating their utility by comparing examples of previously published graph-based MNs to their respective MHNs.PMID:39437798 | DOI:10.1021/acs.jproteome.3c00634

Cell Stem Cell. 2024 Oct 14:S1934-5909(24)00328-X. doi: 10.1016/j.stem.2024.09.014. Online ahead of print.ABSTRACTSenescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role in disease pathobiology and contribution to the lesion environment remains unclear. By establishing directly induced neural stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied their senescent phenotype in vitro. Senescence was strongly associated with inflammatory signaling, hypermetabolism, and the senescence-associated secretory phenotype (SASP). PMS-derived iNSCs displayed increased glucose-dependent fatty acid and cholesterol synthesis, which resulted in the accumulation of lipid droplets. A 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR)-mediated lipogenic state was found to induce a SASP in PMS iNSCs via cholesterol-dependent transcription factors. SASP from PMS iNSC lines induced neurotoxicity in mature neurons, and treatment with the HMGCR inhibitor simvastatin altered the PMS iNSC SASP, promoting cytoprotective qualities and reducing neurotoxicity. Our findings suggest a disease-associated, cholesterol-related, hypermetabolic phenotype of PMS iNSCs that leads to neurotoxic signaling and is rescuable pharmacologically.PMID:39437792 | DOI:10.1016/j.stem.2024.09.014

Plant Physiol Biochem. 2024 Oct 18;217:109209. doi: 10.1016/j.plaphy.2024.109209. Online ahead of print.ABSTRACTBarley (Hordeum vulgare L.) is widely cultivated across diverse soil types, including acidic soils where aluminum (Al) toxicity is the major limiting factor. The relative Al sensitivity of barley highlights the need for a deeper understanding of early molecular responses in root tip (the primary target of Al toxicity) to develop Al-tolerant cultivars. Integrative N6-methyladenosine (m6A) modification, transcriptomic, and metabolomic analyses revealed that elevated auxin and jasmonic acid (JA) levels modulated Al-induced root growth inhibition by repressing genes involved in cell elongation and proliferation. Additionally, these pathways promoted pectin demethylation via up-regulation of genes encoding pectin methylesterases (PMEs). The up-regulation of citrate efflux transporter genes including Al-activated citrate transporter 1 (HvAACT1), and ATP-binding cassette (ABC) transporters like HvABCB25, facilitated Al exclusion and vacuolar sequestration. Enhanced activity within the phenylpropanoid pathway supported antioxidant defenses and internal chelation through the production of specific flavonoids and altered cell wall composition via lignin unit modulation. Notably, several Al-responsive genes, including HvABCB25 and transcription factors (TFs), exhibited m6A modification changes, with two microtubule associated protein 65 (MAP65) members displaying opposing regulatory patterns at both transcriptional and m6A levels, underscoring the crucial role of m6A modification in gene expression regulation. This comprehensive study provides valuable insights into the epitranscriptomic regulation of gene expression and metabolite accumulation in barley root tip under Al stress.PMID:39437666 | DOI:10.1016/j.plaphy.2024.109209

EBioMedicine. 2024 Oct 21;109:105375. doi: 10.1016/j.ebiom.2024.105375. Online ahead of print.ABSTRACTBACKGROUND: SLC7A9 is responsible for the exchange of dibasic amino acids and cystine (influx) for neutral amino acids (efflux). Cystine/cysteine transport is related to ferroptosis.METHODS: Sanger sequencing detected TP53 status of cancer cells. Transcriptomic sequencing and untargeted metabolome profiling were used to identify differentially expressed genes and metabolites, respectively, upon SLC7A9 overexpression. CCK8, cell clonality, and EdU assays were used to observe cell proliferation. Cystine probes, glutathione (GSH) probes, and lipid ROS probes were used to examine cystine, GSH, and lipid ROS levels. 13C metabolic flow assays were used to monitor cellular cystine and GSH metabolism. Patient-derived organoids (PDO), immunocompetent MFC mice allograft models and patient-derived xenograft (PDX) models were used to evaluate SLC7A9 impact on chemotherapeutic response and to observe therapeutic effect of SLC7A9 knockdown.FINDINGS: Elevated SLC7A9 expression levels in gastric cancer cells were attributed to p53 loss. SLC7A9 knockdown suppressed the proliferation and increased the chemotherapy sensitivity of the cells. Chemotherapy was more effective in PDX and immunocompetent mice models upon SLC7A9 knockdown. Differentially expressed genes and metabolites between the SLC7A9 overexpression and control groups were associated with ferroptosis and GSH metabolism. SLC7A9 knockdown reduced cystine transport into cells, hampered intracellular cystine and GSH metabolic flow, decreased GSH synthesis, and increased lipid ROS levels in gastric cancer cells. Erastin was more effective at inducing ferroptosis in PDO and PDX models upon SLC7A9 knockdown.INTERPRETATION: SLC7A9 promotes gastric cancer progression by acting as a suppressor of ferroptosis, independent of SLC7A11, which is negatively regulated by p53.FUNDING: This work was supported by National Natural Science Foundation of China, Innovation Promotion Program of NHC and Shanghai Key Labs SIBPT, and Shanghai Academy of Science & Technology.PMID:39437660 | DOI:10.1016/j.ebiom.2024.105375

Physiol Genomics. 2024 Oct 22. doi: 10.1152/physiolgenomics.00011.2024. Online ahead of print.ABSTRACTThe availability of large scale multi-omics data requires development of computational models to infer valuable biological insights for the implementation of precision medicine. Artificial intelligence (AI) refers to a host of computational algorithms that is becoming a major tool capable of integrating large genomic, transcriptomic, proteomic, and metabolomic data. Machine learning (ML) is the most significant AI algorithm in health sciences have exploded, specifically due to the recent progress made by deep learning. Although the use of AI/ML tools in GBM-omics is still at an early stage, a comprehensive discussion of how AI can be used to unravel various aspects of GBM (intratumor heterogeneity, biomarker discovery, survival prediction, and treatment optimization) would be highly relevant to both researchers and clinicians. Here, we aim to review the different AI-based techniques that have been used to study GBM pathogenesis using multi-omics data over the last decade. We first summarize different types of GBM related omics resources that can be used to develop AI models. We then discuss various AI applications for multi-omics data in order to enhance GBM precision medicine. Finally, we discuss the technical and ethical challenges that limit its application and ways to improve its implementation in clinics.PMID:39437552 | DOI:10.1152/physiolgenomics.00011.2024

J Proteome Res. 2024 Oct 22. doi: 10.1021/acs.jproteome.4c00646. Online ahead of print.ABSTRACTRecent advancements in single-cell (sc) resolution analyses, particularly in sc transcriptomics and sc proteomics, have revolutionized our ability to probe and understand cellular heterogeneity. The study of metabolism through small molecules, metabolomics, provides an additional level of information otherwise unattainable by transcriptomics or proteomics by shedding light on the metabolic pathways that translate gene expression into functional outcomes. Metabolic heterogeneity, critical in health and disease, impacts developmental outcomes, disease progression, and treatment responses. However, dedicated approaches probing the sc metabolome have not reached the maturity of other sc omics technologies. Over the past decade, innovations in sc metabolomics have addressed some of the practical limitations, including cell isolation, signal sensitivity, and throughput. To fully exploit their potential in biological research, however, remaining challenges must be thoroughly addressed. Additionally, integrating sc metabolomics with orthogonal sc techniques will be required to validate relevant results and gain systems-level understanding. This perspective offers a broad-stroke overview of recent mass spectrometry (MS)-based sc metabolomics advancements, focusing on ongoing challenges from a biologist's viewpoint, aimed at addressing pertinent and innovative biological questions. Additionally, we emphasize the use of orthogonal approaches and showcase biological systems that these sophisticated methodologies are apt to explore.PMID:39437423 | DOI:10.1021/acs.jproteome.4c00646

J Food Sci. 2024 Oct 22. doi: 10.1111/1750-3841.17476. Online ahead of print.ABSTRACTDiabetes is marked by postprandial hyperglycemia (PHG), an abnormal rise in blood glucose after meals. A key therapeutic goal to reduce PHG is the inhibition of α-amylase (αAM) and α-glucosidase (αGL), enzymes that break down carbohydrates into sugars. Cucurbita moschata has been shown to inhibit both enzymes. However, its inhibition mechanism has not been explored. This study investigated the in vitro inhibition mechanisms of αAM and αGL and conducted a metabolomic analysis of C. moschata (edible part) water-extract (CME), aiming to preliminarily identify its bioactive compounds (BCs). The inhibitory mechanisms were determined using Lineweaver-Burk plots. The BCs were identified and quantified using HPLC-QTOF-MS, employing both targeted and untargeted metabolomic approaches. CME had a significant higher effect (p < 0.05) on αAM activity than against αGL with IC50 of 28.99 and 698.42 mg/mL, respectively. The extract showed mixed and uncompetitive type inhibitions on αAM and αGL, respectively. The lowest inhibition constant (Ki) was 47.68 mg/mL on αAM activity at 20 mg/mL. Untargeted metabolic profiling by UPLC-MS-ESI-QTOF putatively identified 30 compounds in CME, such as amino acids, vitamins, phytohormones, fatty acids, cucurbitacins and phenolic acids, and flavonoids. Functional analysis of CME identified significant pathways, including pantothenate and CoA biosynthesis and phenylpropanoids, among others. The targeted analysis by UPLC-MS-ESI-QqQ allowed us to identify 12 compounds, with l-phenylalanine, p-hydroxybenzoic, and p-coumaric acid as majors. This study demonstrated the inhibitory potential of CME on αAM and αGL activities, which may be attributed to its metabolites. Thus, this plant represents a valuable source of BC against PHG. Practical Application: The research highlights that Cucurbita moschata has significant potential in managing postprandial hyperglycemia in diabetic patients by inhibiting enzymes like α-amylase and α-glucosidase. In addition, the identification of its compounds emphasizes its importance as a source of bioactive compounds. Therefore, C. moschata could be effectively utilized in the development of nutraceuticals or as an ingredient in functional foods specifically designed for postprandial hyperglycemia management. Thus, integrating C. moschata as part of the daily diet could offer patients with diabetes a natural alternative to control their blood glucose levels after eating.PMID:39437304 | DOI:10.1111/1750-3841.17476

J Agric Food Chem. 2024 Oct 22. doi: 10.1021/acs.jafc.4c05325. Online ahead of print.ABSTRACTLippia citriodora and Olea europaea are known for their shared common bioactivities. Although both matrices are rich in similar families of bioactive compounds, their specific phytochemical compounds are mostly different. Since these compounds can be metabolized in the organism, this study hypothesized that common bioavailable metabolites may contribute to their similar bioactive effects. To test this, an acute double-blind intervention study in humans was conducted with blood samples collected at multiple time points. Using an untargeted metabolomic approach based on HPLC-ESI-QTOF-MS, 66 circulating metabolites were detected, including 9 common to both extracts, such as homovanillic acid sulfate and glucuronide derivates, hydroxytyrosol sulfate, etc. These common metabolites displayed significantly different Tmax values depending on the source, suggesting distinct metabolization pathways for each extract. The study highlights how shared bioavailable metabolites may underlie similar bioactivities observed between these two plant sources.PMID:39437164 | DOI:10.1021/acs.jafc.4c05325

Plant Biotechnol J. 2024 Oct 22. doi: 10.1111/pbi.14487. Online ahead of print.ABSTRACTWood of broad-leaf tree species is a valued source of renewable biomass for biorefinery and a target for genetic improvement efforts to reduce its recalcitrance. Glucuronoxylan (GX) plays a key role in recalcitrance through its interactions with cellulose and lignin. To reduce recalcitrance, we modified wood GX by expressing GH10 and GH11 endoxylanases from Aspergillus nidulans in hybrid aspen (Populus tremula L. × tremuloides Michx.) and targeting the enzymes to cell wall. The xylanases reduced tree height, modified cambial activity by increasing phloem and reducing xylem production, and reduced secondary wall deposition. Xylan molecular weight was decreased, and the spacing between acetyl and MeGlcA side chains was reduced in transgenic lines. The transgenic trees produced hypolignified xylem having thin secondary walls and deformed vessels. Glucose yields of enzymatic saccharification without pretreatment almost doubled indicating decreased recalcitrance. The transcriptomics, hormonomics and metabolomics data provided evidence for activation of cytokinin and ethylene signalling pathways, decrease in ABA levels, transcriptional suppression of lignification and a subset of secondary wall biosynthetic program, including xylan glucuronidation and acetylation machinery. Several candidate genes for perception of impairment in xylan integrity were detected. These candidates could provide a new target for uncoupling negative growth effects from reduced recalcitrance. In conclusion, our study supports the hypothesis that xylan modification generates intrinsic signals and evokes novel pathways regulating tree growth and secondary wall biosynthesis.PMID:39436777 | DOI:10.1111/pbi.14487

J Clin Invest. 2024 Oct 22:e183984. doi: 10.1172/JCI183984. Online ahead of print.ABSTRACTBACKGROUND: In type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism.METHODS: Young adults with T1D (n = 30) and healthy controls (HC, n = 20) underwent hyperinsulinemic-euglycemic clamp studies, MRI, 11C-acetate PET, kidney biopsies, single-cell RNA sequencing, and spatial metabolomics to assess this relationship.RESULTS: Participants with T1D had significantly higher glomerular basement membrane thickness compared to HC. T1D participants exhibited lower insulin sensitivity and cortical oxidative metabolism, correlating with higher insulin sensitivity. Proximal tubular transcripts of TCA cycle and oxidative phosphorylation enzymes were lower in T1D. Spatial metabolomics showed reductions in tubular TCA cycle intermediates, indicating mitochondrial dysfunction. The Slingshot algorithm identified a lineage of proximal tubular cells progressing from stable to adaptive/maladaptive subtypes, using pseudotime trajectory analysis, which computationally orders cells along a continuum of states. This analysis revealed distinct distribution patterns between T1D and HC, with attenuated oxidative metabolism in T1D attributed to a greater proportion of adaptive/maladaptive subtypes with low expression of TCA cycle and oxidative phosphorylation transcripts. Pseudotime progression associated with higher HbA1c, BMI, GBM, and lower insulin sensitivity and cortical oxidative metabolism.CONCLUSION: These early structural and metabolic changes in T1D kidneys may precede clinical DKD.CLINICALTRIALS: gov NCT04074668.PMID:39436695 | DOI:10.1172/JCI183984

Geroscience. 2024 Oct 22. doi: 10.1007/s11357-024-01391-x. Online ahead of print.ABSTRACTThe 1-HMR metabolomics-based MetaboHealth score, comprised of 14 serum metabolic markers, associates with disease-specific mortality, but it is unclear whether the score also reflects cognitive changes and functional impairment. We aimed to assess the associations between the MetaboHealth score with cognitive function and functional decline in older adults at increased cardiovascular risk. A total of 5292 older adults free of dementia at baseline with mean age 75.3 years (SD = 3.4) from the Prospective Study of Pravastatin in the Elderly (PROSPER). MetaboHealth score were measured at baseline, and cognitive function and functional independence were measured at baseline and every 3 months during up to 2.5 years follow-up. Cognitive function was assessed using the Stroop test (selective attention), the Letter Digit Coding test (LDCT) (processing speed), and the two versions of the Picture Learning test (delayed and immediate; memory). Two tests of functional independence were used: Barthel Index (BI) and instrumental activities at daily living (IADL). A higher MetaboHealth score was associated with worse cognitive function (in all domains) and with worse functional independence. For example, after full adjustments, a 1-SD higher MetaboHealth score was associated with 9.02 s (95%CI 7.29, 10.75) slower performance on the Stroop test and 2.79 (2.21, 3.26) less digits coded on the LDCT. During follow-up, 1-SD higher MetaboHealth score was associated with an additional decline of 0.53 s (0.23, 0.83) on the Stroop test and - 0.08 (- 0.11, - 0.06) points on the IADL. Metabolic disturbance, as reflected by an increased metabolomics-based health score, may mark future cognitive and functional decline.PMID:39436550 | DOI:10.1007/s11357-024-01391-x

J Gen Physiol. 2024 Nov 4;156(11):e202313530. doi: 10.1085/jgp.202313530. Epub 2024 Oct 22.ABSTRACTThe phototransduction cascade enables the photoreceptor to detect light over a wide range of intensities without saturation. The main second messenger of the cascade is cGMP and the primary regulatory mechanism is calcium feedback. However, some experimental data suggest that cAMP may also play a role in regulating the phototransduction cascade, but this would require changes in cAMP on a time scale of seconds. Currently, there is a lack of data on the dynamics of changes in intracellular cAMP levels on this timescale. This is largely due to the specificity of the sensory modality of photoreceptors, which makes it practically impossible to use conventional experimental approaches based on fluorescence methods. In this study, we employed the method of rapid cryofixation of retinal samples after light stimulation and subsequent isolation of outer segment preparations. The study employed highly sensitive metabolomics approaches to measure levels of cAMP. Additionally, PKA activity was measured in the samples using a western blot. The results indicate that when exposed to near-saturating but still moderate light, cAMP levels increase transiently within the first second and then return to pre-stimulus levels. The increase in cAMP activates PKA, resulting in the phosphorylation of PKA-specific substrates in frog retinal outer segments.PMID:39436404 | DOI:10.1085/jgp.202313530

mSystems. 2024 Oct 22:e0081224. doi: 10.1128/msystems.00812-24. Online ahead of print.ABSTRACTIndividuals with latent tuberculosis infection (LTBI) account for almost 30% of the population worldwide and have the potential to develop active tuberculosis (ATB). Despite this, the current understanding of the pathogenesis of LTBI is limited. The gut microbiome can be altered in tuberculosis patients, and an understanding of the changes associated with the progression from good health to LTBI to ATB can provide novel perspectives for understanding the pathogenesis of LTBI by identifying microbial and molecular biomarkers associated therewith. In this study, fecal samples from healthy controls (HC), individuals with LTBI and ATB patients were collected for gut microbiome and metabolomics analyses. Compared to HC and LTBI subjects, participants with ATB showed a significant decrease in gut bacterial α-diversity. Additionally, there were significant differences in gut microbial communities and metabolism among the HC, LTBI, and ATB groups. PICRUSt2 analysis revealed that microbiota metabolic pathways involving the degradation of purine and pyrimidine metabolites were upregulated in LTBI and ATB individuals relative to HCs. Metabolomic profiling similarly revealed that purine and pyrimidine metabolite levels were decreased in LTBI and ATB samples relative to those from HCs. Further correlation analyses revealed that the levels of purine and pyrimidine metabolites were negatively correlated with those of gut microbial genera represented by Ruminococcus_gnavus_group (R. gnavus), and the levels of R. gnavus were also positively correlated with adenosine nucleotide degradation II, which is a purine degradation pathway. Moreover, a combined signature including hypoxanthine and xanthine was found to effectively distinguish between LTBI and HC samples (area under the curve [AUC] of training set = 0.796; AUC of testing set = 0.924). Therefore, through gut microbiome and metabolomic analyses, these findings provide valuable clues regarding how alterations in gut purine and pyrimidine metabolism are linked to the pathogenesis of LTBI.IMPORTANCEThis study provides valuable insight into alterations in the gut microbiome and metabolomic profiles in a cohort of adults with LTBI and ATB. Perturbed gut purine and pyrimidine metabolism in LTBI was associated with the compositional alterations of gut microbiota, which may be an impetus for developing novel diagnostic strategies and interventions targeting LTBI.PMID:39436103 | DOI:10.1128/msystems.00812-24