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

Hallmarks of aging: An expanding universe

Wed, 04/01/2023 - 12:00
Cell. 2022 Dec 26:S0092-8674(22)01377-0. doi: 10.1016/j.cell.2022.11.001. Online ahead of print.ABSTRACTAging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected among each other, as well as to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to stress.PMID:36599349 | DOI:10.1016/j.cell.2022.11.001

Diurnal transcriptome landscape of a multi-tissue response to time-restricted feeding in mammals

Wed, 04/01/2023 - 12:00
Cell Metab. 2023 Jan 3;35(1):150-165.e4. doi: 10.1016/j.cmet.2022.12.006.ABSTRACTTime-restricted feeding (TRF) is an emerging behavioral nutrition intervention that involves a daily cycle of feeding and fasting. In both animals and humans, TRF has pleiotropic health benefits that arise from multiple organ systems, yet the molecular basis of TRF-mediated benefits is not well understood. Here, we subjected mice to isocaloric ad libitum feeding (ALF) or TRF of a western diet and examined gene expression changes in samples taken from 22 organs and brain regions collected every 2 h over a 24-h period. We discovered that TRF profoundly impacts gene expression. Nearly 80% of all genes show differential expression or rhythmicity under TRF in at least one tissue. Functional annotation of these changes revealed tissue- and pathway-specific impacts of TRF. These findings and resources provide a critical foundation for future mechanistic studies and will help to guide human time-restricted eating (TRE) interventions to treat various disease conditions with or without pharmacotherapies.PMID:36599299 | DOI:10.1016/j.cmet.2022.12.006

Meta-hallmarks of aging and cancer

Wed, 04/01/2023 - 12:00
Cell Metab. 2023 Jan 3;35(1):12-35. doi: 10.1016/j.cmet.2022.11.001.ABSTRACTBoth aging and cancer are characterized by a series of partially overlapping "hallmarks" that we subject here to a meta-analysis. Several hallmarks of aging (i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis) are very similar to specific cancer hallmarks and hence constitute common "meta-hallmarks," while other features of aging (i.e., telomere attrition and stem cell exhaustion) act likely to suppress oncogenesis and hence can be viewed as preponderantly "antagonistic hallmarks." Disabled macroautophagy and cellular senescence are two hallmarks of aging that exert context-dependent oncosuppressive and pro-tumorigenic effects. Similarly, the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. The agonistic and antagonistic relationship between the processes that drive aging and cancer has bearings for the age-related increase and oldest age-related decrease of cancer morbidity and mortality, as well as for the therapeutic management of malignant disease in the elderly.PMID:36599298 | DOI:10.1016/j.cmet.2022.11.001

Immunoediting instructs tumor metabolic reprogramming to support immune evasion

Wed, 04/01/2023 - 12:00
Cell Metab. 2023 Jan 3;35(1):118-133.e7. doi: 10.1016/j.cmet.2022.12.003.ABSTRACTImmunoediting sculpts immunogenicity and thwarts host anti-tumor responses in tumor cells during tumorigenesis; however, it remains unknown whether metabolic programming of tumor cells can be guided by immunosurveillance. Here, we report that T cell-mediated immunosurveillance in early-stage tumorigenesis instructs c-Myc upregulation and metabolic reprogramming in tumor cells. This previously unexplored tumor-immune interaction is controlled by non-canonical interferon gamma (IFNγ)-STAT3 signaling and supports tumor immune evasion. Our findings uncover that immunoediting instructs deregulated bioenergetic programs in tumor cells to empower them to disarm the T cell-mediated immunosurveillance by imposing metabolic tug-of-war between tumor and infiltrating T cells and forming the suppressive tumor microenvironment.PMID:36599297 | DOI:10.1016/j.cmet.2022.12.003

Comparative transcriptomic and metabolomic analysis revealed molecular mechanism of two wheat near-isogenic lines response to nitrogen application

Wed, 04/01/2023 - 12:00
Plant Physiol Biochem. 2022 Dec 30;195:47-57. doi: 10.1016/j.plaphy.2022.12.029. Online ahead of print.ABSTRACTNitrogen (N) is an essential nutrient element required for plant growth, and the development of wheat varieties with high nitrogen use efficiency (NUE) is an urgent need for sustainable crop production. However, the molecular mechanism of NUE between diverse wheat varieties in response to N application remains unclear. To reveal the possible molecular mechanisms underlying this complex phenomenon, we investigated the transcriptional and metabolic changes of flag leaves of two wheat near-isogenic lines (NILs) differing in NUE under two N fertilizer treatments. Comparative transcriptome analysis indicated that the expression levels of the genes responsible for carbon and nitrogen metabolism were significantly higher in high-NUE wheat. The metabolome comparison revealed that the activity of the tricarboxylic acid (TCA) cycle was enhanced in high-NUE wheat, while reduced in low-NUE wheat after the N fertilizer application. Additionally, amino acid metabolism increased in both wheat NILs but more increased in high-NUE wheat. In summary, more upregulated transcripts and metabolites were identified in high-NUE wheat, and this study provides valuable new insights for improving NUE in wheat.PMID:36599275 | DOI:10.1016/j.plaphy.2022.12.029

Mediterranean diet related metabolite profiles and cognitive performance

Wed, 04/01/2023 - 12:00
Clin Nutr. 2022 Dec 22;42(2):173-181. doi: 10.1016/j.clnu.2022.12.012. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Evidence suggests that adherence to the Mediterranean diet (MedDiet) affects human metabolism and may contribute to better cognitive performance. However, the underlying mechanisms are not clear.OBJECTIVE: We generated a metabolite profile for adherence to MedDiet and evaluated its cross-sectional association with aspects of cognitive performance.METHODS: A total of 1250 healthy Greek middle-aged adults from the Epirus Health Study cohort were included in the analysis. Adherence to the MedDiet was assessed using the 14-point Mediterranean Diet Adherence Screener (MEDAS); cognition was measured using the Trail Making Test, the Verbal Fluency test and the Logical Memory test. A targeted metabolite profiling (n = 250 metabolites) approach was applied, using a high-throughput nuclear magnetic resonance platform. We used elastic net regularized regressions, with a 10-fold cross-validation procedure, to identify a metabolite profile for MEDAS. We evaluated the associations of the identified metabolite profile and MEDAS with cognitive tests, using multivariable linear regression models.RESULTS: We identified a metabolite profile composed of 42 metabolites, mainly lipoprotein subclasses and fatty acids, significantly correlated with MedDiet adherence (Pearson r = 0.35, P-value = 5.5 × 10-37). After adjusting for known risk factors and accounting for multiple testing, the metabolite profile and MEDAS were not associated with the cognitive tests.CONCLUSIONS: A plasma metabolite profile related to better adherence to the MedDiet was not associated with the tested aspects of cognitive performance, in a middle-aged Mediterranean population.PMID:36599272 | DOI:10.1016/j.clnu.2022.12.012

Methods to identify protein targets of metal-based drugs

Wed, 04/01/2023 - 12:00
Curr Opin Chem Biol. 2023 Jan 2;73:102257. doi: 10.1016/j.cbpa.2022.102257. Online ahead of print.ABSTRACTMetal-based anticancer agents occupy a distinct chemical space due to their particular coordination geometry and reactivity. Despite the initial DNA-targeting paradigm for this class of compounds, it is now clear that they can also be tuned to target proteins in cells, depending on the metal and ligand scaffold. Since metallodrug discovery is dominated by phenotypic screenings, tailored proteomics strategies were crucial to identify and validate protein targets of several investigative and clinically advanced metal-based drugs. Here, such experimental approaches are discussed, which showed that metallodrugs based on ruthenium, gold, rhenium and even platinum, can selectively and specifically target proteins with clear-cut down-stream effects. Target identification strategies are expected to support significantly the mechanism-driven clinical translation of metal-based drugs.PMID:36599256 | DOI:10.1016/j.cbpa.2022.102257

The MADS-box transcription factor AoRlmA is involved in the regulation of mycelium development, conidiation, cell-wall integrity, stress response, and trap formation of Arthrobotrys oligospora

Wed, 04/01/2023 - 12:00
Microbiol Res. 2022 Dec 29;268:127299. doi: 10.1016/j.micres.2022.127299. Online ahead of print.ABSTRACTThe maintenance of cell-wall integrity (CWI) is important for mycelial growth, development, and pathogenicity in fungi. Arthrobotrys oligospora is a typical nematode-trapping (NT) fungus which can capture nematodes by producing adhesive networks. In this study, we characterized an orthologous MADS-box transcription factor RlmA (AoRlmA) downstream of the CWI regulatory pathway in A. oligospora. The deletion of AorlmA caused a reduction in mycelial growth, the number of nuclei, conidiation, and trap formation, as well as increased sensitivity to cell-wall synthesis-disrupting agents, osmotic agents, and oxidants; accordingly, the transcript levels of genes associated with sporulation, cell-wall biosynthesis, and DNA damage response were downregulated in the ΔAorlmA mutant. Furthermore, the absence of AorlmA resulted in a reduction in autophagy and endocytosis. Transcriptome analysis showed that differentially expressed genes in the absence of AorlmA were involved in membrane components, the oxidation-reduction process, transmembrane transport, metabolic processes, cellular components, organelles, cellular response to stress, and DNA damage response. In addition, metabolomic analysis showed that AoRlmA was involved in the regulation of secondary metabolites of A. oligospora. To summarize, our results highlighted the important roles of transcription factor RlmA in mycelial growth, conidiation, CWI, trap formation, stress response, autophagy, endocytosis, and secondary metabolism regulation in A. oligospora, providing a basis for elucidating the regulatory mechanism of the mycelial growth and development, pathogenicity, and stress response of NT fungi.PMID:36599176 | DOI:10.1016/j.micres.2022.127299

Dynamic metabolome profiling uncovers potential TOR signaling genes

Wed, 04/01/2023 - 12:00
Elife. 2023 Jan 4;12:e84295. doi: 10.7554/eLife.84295.ABSTRACTAlthough the genetic code of the yeast Saccharomyces cerevisiae was sequenced 25 years ago, the characterization of the roles of genes within it is far from complete. The lack of a complete mapping of functions to genes hampers systematic understanding of the biology of the cell. The advent of high-throughput metabolomics offers a unique approach to uncovering gene function with an attractive combination of cost, robustness, and breadth of applicability. Here, we used flow-injection time-of-flight mass spectrometry to dynamically profile the metabolome of 164 loss-of-function mutants in TOR and receptor or receptor-like genes under a time course of rapamycin treatment, generating a dataset with >7000 metabolomics measurements. In order to provide a resource to the broader community, those data are made available for browsing through an interactive data visualization app hosted at https://rapamycin-yeast.ethz.ch. We demonstrate that dynamic metabolite responses to rapamycin are more informative than steady-state responses when recovering known regulators of TOR signaling, as well as identifying new ones. Deletion of a subset of the novel genes causes phenotypes and proteome responses to rapamycin that further implicate them in TOR signaling. We found that one of these genes, CFF1, was connected to the regulation of pyrimidine biosynthesis through URA10. These results demonstrate the efficacy of the approach for flagging novel potential TOR signaling-related genes and highlight the utility of dynamic perturbations when using functional metabolomics to deliver biological insight.PMID:36598488 | DOI:10.7554/eLife.84295

Identification of a Novel Coumarins Biosynthetic Pathway in the Endophytic Fungus Fusarium oxysporum GU-7 with Antioxidant Activity

Wed, 04/01/2023 - 12:00
Appl Environ Microbiol. 2023 Jan 4:e0160122. doi: 10.1128/aem.01601-22. Online ahead of print.ABSTRACTCoumarins are generally considered to be produced by natural plants. Fungi have been reported to produce coumarins, but their biosynthetic pathways are still unknown. In this study, Fusarium oxysporum GU-7 and GU-60 were isolated from Glycyrrhiza uralensis, and their antioxidant activities were determined to be significantly different. Abundant dipeptide, phenolic acids, and the plant-derived coumarins fraxetin and scopoletin were identified in GU-7 by untargeted metabolomics, and these compounds may account for its stronger antioxidant activity compared to GU-60. Combined with metabolome and RNA sequencing analysis, we identified 24 potentially key genes involved in coumarin biosynthesis and 6 intermediate metabolites. Interestingly, the best hit of S8H, a key gene involved in hydroxylation at the C-8 position of scopoletin to yield fraxetin, belongs to a plant species. Additionally, nondestructive infection of G. uralensis seeds with GU-7 significantly improved the antioxidant activity of seedlings compared to the control group. This antioxidant activity may depend on the biological characteristics of endophytes themselves, as we observed a positive correlation between the antioxidant activity of endophytic fungi and that of their nondestructively infected seedlings. IMPORTANCE Plant-produced coumarins have been shown to play an important role in assembly of the plant microbiomes and iron acquisition. Coumarins can also be produced by some microorganisms. However, studies on coumarin biosynthesis in microorganisms are still lacking. We report for the first time that fraxetin and scopoletin were simultaneously produced by F. oxysporum GU-7 with strong free radical scavenging abilities. Subsequently, we identified intermediate metabolites and key genes in the biosynthesis of these two coumarins. This is the first report on the coumarin biosynthesis pathway in nonplant species, providing new strategies and perspectives for coumarin production and expanding research on new ways for plants to obtain iron.PMID:36598487 | DOI:10.1128/aem.01601-22

The oomycete MAMP, arachidonic acid, and an <em>Ascophyllum nodosum</em>-derived plant biostimulant induce defense metabolome remodeling in tomato

Wed, 04/01/2023 - 12:00
Phytopathology. 2023 Jan 4. doi: 10.1094/PHYTO-10-22-0368-R. Online ahead of print.ABSTRACTArachidonic acid (AA) is an oomycete-derived MAMP capable of eliciting robust defense responses and inducing resistance in plants. Similarly, extract (ANE) from the brown seaweed Ascophylum nodosum, a plant biostimulant that contains AA, can also prime plants for defense against pathogen challenge. A previous parallel study comparing the transcriptomes of AA and ANE root-treated tomato demonstrated significant overlap in transcriptional profiles, a shared induced resistance phenotype, and changes in accumulation of various defense-related phytohormones. In this work, untargeted metabolomic analysis via liquid chromatography-mass spectrometry was conducted to investigate the local and systemic metabolome-wide remodeling events elicited by AA- and ANE-root treatment in tomato. Our study demonstrated AA and ANE's capacity to locally and systemically alter the metabolome of tomato with enrichment of chemical classes and accumulation of metabolites associated with defense-related secondary metabolism. AA and ANE root-treated plants showed enrichment of fatty acyl-glycosides and strong modulation of hydroxycinnamic acids and derivatives. Identification of specific metabolites whose accumulation was affected by AA and ANE treatment revealed shared metabolic changes related to ligno-suberin biosynthesis and the synthesis of phenolic compounds. This study highlights the extensive local and systemic metabolic changes in tomato induced by treatment with a fatty acid MAMP and a seaweed-derived plant biostimulant with implications for induced resistance and crop improvement.PMID:36598344 | DOI:10.1094/PHYTO-10-22-0368-R

Central Role of Sibling Small RNAs NgncR_162 and NgncR_163 in Main Metabolic Pathways of Neisseria gonorrhoeae

Wed, 04/01/2023 - 12:00
mBio. 2023 Jan 4:e0309322. doi: 10.1128/mbio.03093-22. Online ahead of print.ABSTRACTSmall bacterial regulatory RNAs (sRNAs) have been implicated in the regulation of numerous metabolic pathways. In most of these studies, sRNA-dependent regulation of mRNAs or proteins of enzymes in metabolic pathways has been predicted to affect the metabolism of these bacteria. However, only in a very few cases has the role in metabolism been demonstrated. Here, we performed a combined transcriptome and metabolome analysis to define the regulon of the sibling sRNAs NgncR_162 and NgncR_163 (NgncR_162/163) and their impact on the metabolism of Neisseria gonorrhoeae. These sRNAs have been reported to control genes of the citric acid and methylcitric acid cycles by posttranscriptional negative regulation. By transcriptome analysis, we now expand the NgncR_162/163 regulon by several new members and provide evidence that the sibling sRNAs act as both negative and positive regulators of target gene expression. Newly identified NgncR_162/163 targets are mostly involved in transport processes, especially in the uptake of glycine, phenylalanine, and branched-chain amino acids. NgncR_162/163 also play key roles in the control of serine-glycine metabolism and, hence, probably affect biosyntheses of nucleotides, vitamins, and other amino acids via the supply of one-carbon (C1) units. Indeed, these roles were confirmed by metabolomics and metabolic flux analysis, which revealed a bipartite metabolic network with glucose degradation for the supply of anabolic pathways and the usage of amino acids via the citric acid cycle for energy metabolism. Thus, by combined deep RNA sequencing (RNA-seq) and metabolomics, we significantly extended the regulon of NgncR_162/163 and demonstrated the role of NgncR_162/163 in the regulation of central metabolic pathways of the gonococcus. IMPORTANCE Neisseria gonorrhoeae is a major human pathogen which infects more than 100 million people every year. An alarming development is the emergence of gonococcal strains that are resistant against virtually all antibiotics used for their treatment. Despite the medical importance and the vanishing treatment options of gonococcal infections, the bacterial metabolism and its regulation have been only weakly defined until today. Using RNA-seq, metabolomics, and 13C-guided metabolic flux analysis, we here investigated the gonococcal metabolism and its regulation by the previously studied sibling sRNAs NgncR_162/163. The results demonstrate the regulation of transport processes and metabolic pathways involved in the biosynthesis of nucleotides, vitamins, and amino acids by NgncR_162/163. In particular, the combination of transcriptome and metabolic flux analyses provides a heretofore unreached depth of understanding the core metabolic pathways and their regulation by the neisserial sibling sRNAs. This integrative approach may therefore also be suitable for the functional analysis of a growing number of other bacterial metabolic sRNA regulators.PMID:36598194 | DOI:10.1128/mbio.03093-22

Vending-Machine-Style Skin Excretion Sensing

Wed, 04/01/2023 - 12:00
ACS Sens. 2023 Jan 4. doi: 10.1021/acssensors.2c02325. Online ahead of print.ABSTRACTSkin metabolites show huge potential for use in clinical diagnostics. However, skin sampling and analysis workflows are tedious and time-consuming. Here, we demonstrate a vending-machine-style skin excretion sensing platform based on hydrogel-assisted sampling of skin metabolites. In this sensing platform, a sampling probe with hydrogel is held by a robotic arm. The robotic arm manoeuvres the probe to press it onto the forearm of a human subject. Due to the highly hydrophilic nature of the hydrogel, water-soluble metabolites─released by skin─are collected into the hydrogel, leaving behind the nonpolar metabolites. The probe is then inserted into a custom-made open port sampling interface coupled to an electrospray ion source of a high-resolution quadrupole-time-of-flight mass spectrometer. Metabolites in the hydrogel are immediately extracted by a solvent liquid junction in the interface and analyzed using the mass spectrometer. The ion current of the target analyte is displayed on a customized graphical user interface, which can also be used to control the key components of the analytical platform. The automated sampling and analysis workflow starts after the user inserts coins or presents an insurance card, presses a button, and extends an arm on the sampling area. The platform relies on low-cost mechanical and electronic modules (a robotic arm, a single-board computer, and two microcontroller boards). The limits of detection for standard analytes─arginine, citrulline, and histidine─embedded in agarose gel beds were 148, 205, and 199 nM, respectively. Various low-molecular-weight metabolites from human skin have been identified with the high-resolution mass spectrometer.PMID:36598150 | DOI:10.1021/acssensors.2c02325

Metabolomic Signatures Associated With Pulmonary Arterial Hypertension Outcomes

Wed, 04/01/2023 - 12:00
Circ Res. 2023 Jan 4. doi: 10.1161/CIRCRESAHA.122.321923. Online ahead of print.ABSTRACTBACKGROUND: Pulmonary arterial hypertension (PAH) is a complex disease characterized by progressive right ventricular (RV) failure leading to significant morbidity and mortality. Investigating metabolic features and pathways associated with RV dilation, mortality, and measures of disease severity can provide insight into molecular mechanisms, identify subphenotypes, and suggest potential therapeutic targets.METHODS: We collected data from a prospective cohort of PAH participants and performed untargeted metabolomic profiling on 1045 metabolites from circulating blood. Analyses were intended to identify metabolomic differences across a range of common metrics in PAH (eg, dilated versus nondilated RV). Partial least squares discriminant analysis was first applied to assess the distinguishability of relevant outcomes. Significantly altered metabolites were then identified using linear regression, and Cox regression models (as appropriate for the specific outcome) with adjustments for age, sex, body mass index, and PAH cause. Models exploring RV maladaptation were further adjusted for pulmonary vascular resistance. Pathway enrichment analysis was performed to identify significantly dysregulated processes.RESULTS: A total of 117 participants with PAH were included. Partial least squares discriminant analysis showed cluster differentiation between participants with dilated versus nondilated RVs, survivors versus nonsurvivors, and across a range of NT-proBNP (N-terminal probrain natriuretic peptide) levels, REVEAL 2.0 composite scores, and 6-minute-walk distances. Polyamine and histidine pathways were associated with differences in RV dilation, mortality, NT-proBNP, REVEAL score, and 6-minute walk distance. Acylcarnitine pathways were associated with NT-proBNP, REVEAL score, and 6-minute walk distance. Sphingomyelin pathways were associated with RV dilation and NT-proBNP after adjustment for pulmonary vascular resistance.CONCLUSIONS: Distinct plasma metabolomic profiles are associated with RV dilation, mortality, and measures of disease severity in PAH. Polyamine, histidine, and sphingomyelin metabolic pathways represent promising candidates for identifying patients at high risk for poor outcomes and investigation into their roles as markers or mediators of disease progression and RV adaptation.PMID:36597887 | DOI:10.1161/CIRCRESAHA.122.321923

The potential of metabolomics as a predictive guide for clinical management in autoimmunity against red blood cells

Wed, 04/01/2023 - 12:00
Br J Haematol. 2023 Jan 4. doi: 10.1111/bjh.18633. Online ahead of print.ABSTRACTAutoimmune-responses leading to increased destruction of red blood cells occur in autoimmune haemolytic anaemia (AIHA). The pathophysiology of AIHA is multifactorial and not fully understood, and clinically it remains challenging to manage relapsed and treatment-refractory cases. Rabelo and colleagues conduct metabolomic profiling in plasma of 26 patients with primary warm AIHA, with consideration of haemolytic activity and relapse occurrence. They identify distinct metabolites to be increased in primary warm AIHA patients, thereby providing an encouraging basis for further validation and exploration of metabolomic profiling as a predictive tool for the management of AIHA. Commentary on: Rabelo et al. Metabolomic profile in patients with primary warm autoimmune haemolytic anaemia. Br J Haematol 2022 (Online ahead of print). doi: 10.1111/bjh.18584.PMID:36597858 | DOI:10.1111/bjh.18633

Fusion of Quality Evaluation Metrics and Convolutional Neural Network Representations for ROI Filtering in LC-MS

Wed, 04/01/2023 - 12:00
Anal Chem. 2023 Jan 4. doi: 10.1021/acs.analchem.2c01398. Online ahead of print.ABSTRACTRegion of interest (ROI) extraction is a fundamental step in analyzing metabolomic datasets acquired by liquid chromatography-mass spectrometry (LC-MS). However, noises and backgrounds in LC-MS data often affect the quality of extracted ROIs. Therefore, developing effective ROI evaluation algorithms is necessary to eliminate false positives meanwhile keep the false-negative rate as low as possible. In this study, a deep fused filter of ROIs (dffROI) was proposed to improve the accuracy of ROI extraction by combining the handcrafted evaluation metrics with convolutional neural network (CNN)-learned representations. To evaluate the performance of dffROI, dffROI was compared with peakonly (CNN-learned representation) and five handcrafted metrics on three LC-MS datasets and a gas chromatography-mass spectrometry (GC-MS) dataset. Results show that dffROI can achieve higher accuracy, better true-positive rate, and lower false-positive rate. Its accuracy, true-positive rate, and false-positive rate are 0.9841, 0.9869, and 0.0186 on the test set, respectively. The classification error rate of dffROI (1.59%) is significantly reduced compared with peakonly (2.73%). The model-agnostic feature importance demonstrates the necessity of fusing handcrafted evaluation metrics with the convolutional neural network representations. dffROI is an automatic, robust, and universal method for ROI filtering by virtue of information fusion and end-to-end learning. It is implemented in Python programming language and open-sourced at https://github.com/zhanghailiangcsu/dffROI under BSD License. Furthermore, it has been integrated into the KPIC2 framework previously proposed by our group to facilitate real metabolomic LC-MS dataset analysis.PMID:36597722 | DOI:10.1021/acs.analchem.2c01398

Recent evidence and progress for developing precision nursing in symptomatology: A scoping review

Wed, 04/01/2023 - 12:00
Int Nurs Rev. 2023 Jan 3. doi: 10.1111/inr.12816. Online ahead of print.ABSTRACTAIM: To summarize the omics results of symptomatic research that can help nurses identify intervention targets and design precision interventions for pain, mental health, cognitive impairment, sleep disorder, fatigue, lymphedema, and quality of life, so as to provide a comprehensive summary of help and inspire to precision nursing.METHODS: CINAHL, PubMed, Web of Science, and ScienceDirect databases were searched. Retrieval time was from January 2012 to December 2021. Symptomatology research applying omics that can be used to guide nurses in designing targeted interventions was included.RESULTS: Forty-six studies were included in the final review. Symptomatology research that can be integrated with nursing science to develop precision nursing focused on pain, mental health, cognitive impairment, sleep disorder, fatigue, lymphedema, and quality of life. Most studies were related to cognitive impairment (n = 10; 21.74%), pain (n = 9; 19.57%), and mental health (n = 8; 17.39%). Moreover, the included studies involved various omics technologies, such as whole genome, epigenome, transcriptome, proteome, and metabolome.CONCLUSION: The rapid development of various omic technologies promotes symptomatology research, which can help nurses fully understand the information of patients. Phenotypic characteristics and biomarkers shown in symptomatology research help nurses identify intervention targets and develop individualization interventions, so as to prevent and reduce symptoms and improve the quality of life.IMPLICATION FOR NURSING AND HEALTH POLICY: This scoping review is the first synthesis of all peer-reviewed literature to summarize and provide important information and references from the omic results of symptomatology studies to develop precision nursing, highlighting the status and development of precision nursing. Nursing education policies should introduce the development and importance of precision nursing. Further research could consider investing more attention in precision nursing. Nursing researchers can carry out some studies applying omics technology to explore more biomarkers, helping guide the formulation of clinical intervention for symptoms.PMID:36597558 | DOI:10.1111/inr.12816

The dynamic changes of flavors and UPLC-Q-Exactive-Orbitrap-MS based lipidomics in mackerel (Scomberomorus niphonius) during dry-cured processing

Tue, 03/01/2023 - 12:00
Food Res Int. 2023 Jan;163:112273. doi: 10.1016/j.foodres.2022.112273. Epub 2022 Nov 30.ABSTRACTDry-cured mackerel is favored by consumers for its suitable salty flavor. Herein, the dynamic changes of volatile compounds and lipids in the mackerel, and the lipidomics based on UPLC-Orbitrap/MS technique during dry-cured processing were investigated. The results showed that endogenous lipases activities in dry-cured mackerel decreased. The dry-cured processing of mackerel had significant effects on its lipid classes and content. The contents of Arachidonic acid (C20:4n6), docosapentaenoic acid (C22:5n3), linoleic acid (LA, C18:2n6), alpha-linolenic acid (C18:3n3), eicosatrienoic acid (C20:3n3) and docosahexaenoic acid (DHA, C22:6n3) increased during dry-cured processing. A total of 38 kinds of volatile compounds were detected in the dry-cured mackerel, 12 of which were derived from fatty acid oxidation. Among 30 lipid metabolites (FC ≥ 2 and VIP > 2), phosphatidylethanolamine (PE, 19:0/22:6) accounted for the highest content, and its difference between three stages was the most obvious. Glycerophospholipid and sphingolipid metabolisms were the most important metabolic pathways involved in dry-cured processing.PMID:36596184 | DOI:10.1016/j.foodres.2022.112273

Investigation of dichlorodiphenyltrichloroethane (DDT) on xenobiotic enzyme disruption and metabolomic bile acid biosynthesis in DDT-sprayed areas using wild rats

Tue, 03/01/2023 - 12:00
J Vet Med Sci. 2023 Jan 2. doi: 10.1292/jvms.22-0490. Online ahead of print.ABSTRACTDichlorodiphenyltrichloroethane (DDT) is an organochlorine insecticide used worldwide. Several studies have reported the toxic effects of DDT and its metabolites on steroid hormone biosynthesis; however, its environmental effects are not well understood. This study examined wild rats collected in DDT-sprayed areas of South Africa and quantified plasma metabolites using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS). Fold change analysis of the metabolome revealed the effect of DDT on bile acid biosynthesis. Gene expression of the related enzyme in rat liver samples was also quantified. Significant association was found between DDT and gene expression levels related to constitutive androstane receptor mediated enzymes, such as Cyp2b1 in rat livers. However, our results could not fully demonstrate that enzymes related to bile acid biosynthesis were strongly affected by DDT. The correlation between DDT concentration and gene expression involved in steroid hormone synthesis in testis was also evaluated; however, no significant correlation was found. The disturbance of metabolic enzymes occurred in rat liver in the target area. Our results suggest that DDT exposure affects gene expression in wild rats living in DDT-sprayed areas. Therefore, there is a need for DDT toxicity evaluation in mammals living in DDT-sprayed areas. We could not find an effective biomarker that could reflect the mechanism of DDT exposure; however, this approach can provide new insights for future research to evaluate DDT effects in sprayed areas.PMID:36596564 | DOI:10.1292/jvms.22-0490

Integrated proteomic and Phosphoproteomic analysis for characterization of colorectal cancer

Tue, 03/01/2023 - 12:00
J Proteomics. 2022 Dec 31:104808. doi: 10.1016/j.jprot.2022.104808. Online ahead of print.ABSTRACTProteins and translationally modified proteins like phosphoproteins have essential regulatory roles in tumorigenesis. This study attempts to elucidate the dysregulated proteins driving colorectal cancer (CRC). To explore the differential proteins, we performed iTRAQ labeling proteomics and TMT labeling phosphoproteomics analysis of CRC tissues and adjacent non-cancerous tissues. The functions of quantified proteins were analyzed using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and Subcellular localization analysis. Depending on the results, we identified 330 differential proteins and 82 phosphoproteins in CRC. GO and KEGG analyses demonstrated that protein changes were primarily associated with regulating biological and metabolic processes through binding to other molecules. Co-expression relationships between proteomic and phosphoproteomic analysis revealed that TMC5, SMC4, SLBP, VSIG2, and NDRG2 were significantly dysregulated differential proteins. Additionally, based on the predicted co-expression proteins, we identified that the stem-loop binding protein (SLBP) was up-regulated in CRC cells and promoted the proliferation and migration of CRC. This study reports an integrated proteomic and phosphoproteomic analysis of CRC to discern the functional impact of protein alterations and provides a candidate diagnostic biomarker or therapeutic target for CRC. SIGNIFICANCE: Combining one or more high-throughput omics technologies with bioinformatics to analyze biological samples and explore the links between biomolecules and their functions can provide more comprehensive and multi-level insights for disease mechanism research. Proteomics, phosphoproteomics, metabolomics and their combined analysis play an important role in the auxiliary diagnosis, the discovery of biomarkers and novel therapeutic targets for colorectal cancer. In this integrated proteomic and phosphoproteomic analysis, we identified proteins and phosphoproteins in colorectal cancer tissue and analyzed potential mechanisms contributing to progression in colorectal cancer. The results of this study provide a foundation to focus future experiments on the contribution of altered protein and phosphorylation patterns to prevention and treatment of colorectal cancer.PMID:36596410 | DOI:10.1016/j.jprot.2022.104808

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