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Pediatric obesity is a progressive, chronic disease that can lead to serious cardiometabolic complications. Here we investigated the peripheral lipidome in 958 children and adolescents with overweight or obesity and 373 with normal weight, in a cross-sectional study. We also implemented a family-based, personalized program to assess the effects of obesity management on 186 children and adolescents in a clinical setting. Using mass spectrometry-based lipidomics, we report an increase in ceramides, alongside a decrease in lysophospholipids and omega-3 fatty acids with obesity metabolism. Ceramides, phosphatidylethanolamines and phosphatidylinositols were associated with insulin resistance and cardiometabolic risk, whereas sphingomyelins showed inverse associations. Additionally, a panel of three lipids predicted hepatic steatosis as effectively as liver enzymes. Lipids partially mediated the association between obesity and cardiometabolic traits. The nonpharmacological management reduced levels of ceramides, phospholipids and triglycerides, indicating that lowering the degree of obesity could partially restore a healthy lipid profile in children and adolescents., Competing Interests: Competing interests: The data and paper were prepared while K.S. was employed at the Steno Diabetes Center Copenhagen. In the process of revision and publication, K.S. has started a position at Novo Nordisk. C.L.-Q. has received consultancy fees from Pfizer. C.L.-Q. has received honoraria, travel or speakers’ fees from Biogen and research funds from Pfizer and Novo Nordisk. C.L.-Q. is the director of the company BrainLogia. All of these activities are unrelated to this study. The other authors declare no competing interests., (© 2024. The Author(s).)

Background: Alzheimer's disease (AD) is a neurodegenerative condition for which there is currently no available medication that can stop its progression. Previous studies suggest that mild cognitive impairment (MCI) is a phase that precedes the disease. Therefore, a better understanding of the molecular mechanisms behind MCI conversion to AD is needed., Method: Here, we propose a machine learning-based approach to detect the key metabolites and proteins involved in MCI progression to AD using data from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Study. Proteins and metabolites were evaluated separately in multiclass models (controls, MCI and AD) and together in MCI conversion models (MCI stable vs converter). Only features selected as relevant by 3/4 algorithms proposed were kept for downstream analysis., Results: Multiclass models of metabolites highlighted nine features further validated in an independent cohort (0.726 mean balanced accuracy). Among these features, one metabolite, oleamide, was selected by all the algorithms. Further in-vitro experiments in rodents showed that disease-associated microglia excreted oleamide in vesicles. Multiclass models of proteins stood out with nine features, validated in an independent cohort (0.720 mean balanced accuracy). However, none of the proteins was selected by all the algorithms. Besides, to distinguish between MCI stable and converters, 14 key features were selected (0.872 AUC), including tTau, alpha-synuclein (SNCA), junctophilin-3 (JPH3), properdin (CFP) and peptidase inhibitor 15 (PI15) among others., Conclusions: This omics integration approach highlighted a set of molecules associated with MCI conversion important in neuronal and glia inflammation pathways., Competing Interests: Declaration of competing interest SL is named as an inventor on biomarker intellectual property protected by Proteome Sciences and Kings College London unrelated to the current study and within the past five years has advised for Optum labs, Merck, SomaLogic and been the recipient of funding from AstraZeneca and other companies via the IMI funding scheme. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, reMYND, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). AL has served at scientific advisory boards of Fujirebio Europe, Eli Lilly, Novartis, Nutricia and Otsuka and is the inventor of a patent on synaptic markers in CSF (all unrelated to this study). JP has served at scientific advisory boards of Fujirebio Europe, Eli Lilly and Nestle Institute of Health Sciences, all unrelated to this study. SE has received unrestricted research grants from Janssen Pharmaceutica and ADx Neurosciences and has served at scientific advisory boards of Biogen, Eisai, Novartis, Nutricia/Danone, all unrelated to this study. FB is a steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena. Consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics. Research agreements with Merck, Biogen, GE Healthcare, Roche. Co-founder and shareholder of Queen Square Analytics LTD, all unrelated to this study. CLQ has received funding related to this study from Pfizer and via the IMI funding scheme, in the past five years has been the recipient of funding from Novo Nordisk, unrelated to this study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cerebrospinal fluid (CSF) is a metabolically diverse biofluid and a key specimen for exploring biochemical changes in neurodegenerative diseases. Detecting lipid species in CSF using mass spectrometry (MS)-based techniques remains challenging because lipids are highly complex in structure, and their concentrations span over a broad dynamic range. This work aimed to develop a robust lipidomics and metabolomics method based on commonly used two-phase extraction systems from human CSF samples. Prioritizing lipid detection, biphasic extraction methods, Folch, Bligh and Dyer (B&D), Matyash, and acidified Folch and B&D (aFolch and aB&D) were compared using 150 μL of human CSF samples for the simultaneous extraction of lipids and metabolites with a wide range of polarity. Multiple chromatographical separation approaches, including reversed-phase liquid chromatography (RPLC), hydrophilic interaction liquid chromatography (HILIC), and gas chromatography (GC), were utilized to characterize human CSF metabolome. The aB&D method was found as the most reproducible technique (RSD < 15%) for lipid extraction. The aB&D and B&D yielded the highest peak intensities for targeted lipid internal standards and displayed superior extracting power for major endogenous lipid classes. A total of 674 unique metabolites with a wide polarity range were annotated in CSF using, combining RPLC-MS/MS lipidomics (n = 219), HILIC-MS/MS (n = 304), and GC-quadrupole time of flight (QTOF) MS (n = 151). Overall, our findings show that the aB&D extraction method provided suitable lipid coverage, reproducibility, and extraction efficiency for global lipidomics profiling of human CSF samples. In combination with RPLC-MS/MS lipidomics, complementary screening approaches enabled a comprehensive metabolite signature that can be employed in an array of clinical studies., (© 2023. The Author(s).)

Introduction: Microglia and macrophages can influence the evolution of myelin lesions through the production of extracellular vesicles (EVs). While microglial EVs promote in vitro differentiation of oligodendrocyte precursor cells (OPCs), whether EVs derived from macrophages aid or limit OPC maturation is unknown., Methods: Immunofluorescence analysis for the myelin protein MBP was employed to evaluate the impact of EVs from primary rat macrophages on cultured OPC differentiation. Raman spectroscopy and liquid chromatography-mass spectrometry was used to define the promyelinating lipid components of myelin EVs obtained in vitro and isolated from human plasma., Results and Discussion: Here we show that macrophage-derived EVs do not promote OPC differentiation, and those released from macrophages polarized towards an inflammatory state inhibit OPC maturation. However, their lipid cargo promotes OPC maturation in a similar manner to microglial EVs. We identify the promyelinating endocannabinoids anandamide and 2-arachidonoylglycerol in EVs released by both macrophages and microglia in vitro and circulating in human plasma. Analysis of OPC differentiation in the presence of the endocannabinoid receptor antagonists SR141716A and AM630 reveals a key role of vesicular endocannabinoids in OPC maturation. From this study, EV-associated endocannabinoids emerge as important mediators in microglia/macrophage-oligodendrocyte crosstalk, which may be exploited to enhance myelin repair., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lombardi, Scaroni, Gabrielli, Raffaele, Bonfanti, Filipello, Giussani, Picciolini, de Rosbo, Uccelli, Golia, D’Arrigo, Rubino, Hooshmand, Legido-Quigley, Fenoglio, Gualerzi, Fumagalli and Verderio.)

Thyroid cancer is the most common malignancy of the endocrine system and the seventh most prevalent cancer in women worldwide. It is a complex and diverse disease characterized by heterogeneity, underscoring the importance of understanding the underlying metabolic alterations within tumor cells. Metabolomics technologies offer a powerful toolset to explore and identify endogenous and exogenous biochemical reaction products, providing crucial insights into the intricate metabolic pathways and processes within living cells. Metabolism plays a central role in cell function, making metabolomics a valuable reflection of a cell's phenotype. In the OMICs era, metabolomics analysis of cells brings numerous advantages over existing methods, propelling cell metabolomics as an emerging field with vast potential for investigating metabolic pathways and their perturbation in pathophysiological conditions. This review article aims to look into recent developments in applying metabolomics for characterizing and interpreting the cellular metabolome in thyroid cancer cell lines, exploring their unique metabolic characteristics. Understanding the metabolic alterations in tumor cells can lead to the identification of critical nodes in the metabolic network that could be targeted for therapeutic intervention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Studies have demonstrated that pigment-epithelium-derived factor (PEDF) is a robust inhibitor of tumour growth and development, implying that this may serve as a promising target for therapeutic intervention. However, the precise impact of PEDF on cancerous cell metabolic pathways remains uncertain despite ongoing research. In this light, this study aimed to employ a metabolomics approach for understanding the metabolic reprogramming events in breast cancer across different glycaemic loads and their response to PEDF. Gas chromatography-quadrupole mass spectrometry (GC/Q-MS) analysis revealed metabolic alterations in ER + human cell line MCF-7 cells treated with PEDF under varying glycaemic conditions. The identification of significantly altered metabolites was accomplished through MetaboAnalyst (v.5.0) and R packages, which enabled both multivariate and univariate analyses. Out of the 48 metabolites identified, 14 were chosen based on their significant alterations in MCF-7 cells under different glycaemic conditions and PEDF treatment ( p < 0.05, VIP > 0.8). Dysregulation in pathways associated with amino acid metabolism, intermediates of the TCA cycle, nucleotide metabolism, and lipid metabolism were detected, and they exhibited different responses to PEDF. Our results suggest that PEDF has a diverse influence on the metabolism of MCF-7 cells in both normo- and hyperglycaemic environments, thereby warranting studies using patient samples to correlate our findings with clinical response in the future.

Objective: To determine if clustering methods can use a holistic assessment of health-related quality-of-life after bladder cancer diagnosis to predict survival outcomes independent of clinical characteristics. In the United States, an estimated 81,180 cases of bladder cancer will be diagnosed in 2022. We aim to help address the knowledge gap concerning the impact of patient functional status on outcomes., Materials and Methods: This is a cross-sectional, retrospective cohort study of patients in the End Results-Medicare Health Outcomes Survey Registry. Age and 36-Item Short Form Survey (SF-36) responses were used as K-means inputs to identify homogenous clusters of older patients with bladder cancer. We analyzed the association between the identified clusters, patient and disease characteristics, and outcomes. We used Cox proportional hazard regression to compare overall survival., Results: We identified 5 homogenous clusters that exhibited differences in patient characteristics and survival. There was no significant difference in cancer stage or surgery type among the clusters. The Cox proportional hazard regression demonstrated significant associations of cluster with gender, age, education, marital status, smoking status, type of surgery, and cancer stage on overall survival. Cluster independently predicted overall survival., Conclusion: Using unsupervised machine learning, we identified clusters of patients with bladder cancer who had similar mental and physical function scores. Cluster grouping suggests that patients' mental and physical function may not be based on disease or treatment. There are significant survival differences between all clusters, demonstrating that a holistic assessment of patient-reported health-related quality-of-life has the potential to predict survival and possible modifiable risk factors in older patients with bladder cancer., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein that belongs to the serine protease inhibitor (serpin) family. An increase in PEDF activity has been shown to be a potent inhibitor of tumour progression and proliferation, suggesting a possible therapeutic target. There is still a great deal to learn about how PEDF controls metabolic pathways in breast cancer and its metastatic form. Given this, the primary purpose of this study was to use a metabolomics approach to gain a better understanding of the mechanisms driving the reprogramming of metabolic events involved in breast cancer pertaining to PEDF under various glycaemic loads. We employed gas chromatography-quadrupole mass spectrometry (GC-Q-MS) to investigate metabolic changes in the triple-negative breast cancer (TNBC) cell line MDA-MB-231 treated with PEDF under glycaemic loading. Multivariate and univariate analyses were carried out as indicative tools via MetaboAnalyst (V.5.0) and R packages to identify the significantly altered metabolites in the MDA-MB-231 cell line after PEDF exposure under glycaemic loading. A total of 61 metabolites were found, of which nine were selected to be distinctively expressed in MDA-MB-231 cells under glycaemic conditions and exhibited differential responses to PEDF ( p < 0.05, VIP > 1). Abnormalities in amino acid metabolism pathways were observed. In particular, glutamic acid, glutamine, and phenylalanine showed different levels of expression across different treatment groups. The lactate and glucose-6-phosphate production significantly increased in high-glucose vs. normal conditions while it decreased when the cells were exposed to PEDF, confirming the positive influence on the Warburg effect. The TCA cycle intermediates, including malate and citric acid, showed different patterns of expression. This is an important finding in understanding the link of PEDF with metabolic perturbation in TNBC cells in response to glycaemic conditions. Our findings suggest that PEDF significantly influenced the Warburg effect (as evidenced by the significantly lower levels of lactate), one of the well-known metabolic reprogramming pathways in cancer cells that may be responsive to metabolic-targeted therapeutic strategies. Moreover, our results demonstrated that GC-MS-based metabolomics is an effective tool for identifying metabolic changes in breast cancer cells after glycaemic stress or in response to PEDF treatment., Competing Interests: The authors declare no conflict of interest.

Stress can have long-lasting impacts on plants. Here we report the long-term effects of the stress hormone jasmonic acid (JA) on the defence phenotype, transcriptome and DNA methylome of Arabidopsis. Three weeks after transient JA signalling, 5-week-old plants retained induced resistance (IR) against herbivory but showed increased susceptibility to pathogens. Transcriptome analysis revealed long-term priming and/or upregulation of JA-dependent defence genes but repression of ethylene- and salicylic acid-dependent genes. Long-term JA-IR was associated with shifts in glucosinolate composition and required MYC2/3/4 transcription factors, RNA-directed DNA methylation, the DNA demethylase ROS1 and the small RNA (sRNA)-binding protein AGO1. Although methylome analysis did not reveal consistent changes in DNA methylation near MYC2/3/4-controlled genes, JA-treated plants were specifically enriched with hypomethylated ATREP2 transposable elements (TEs). Epigenomic characterization of mutants and transgenic lines revealed that ATREP2 TEs are regulated by RdDM and ROS1 and produce 21 nt sRNAs that bind to nuclear AGO1. Since ATREP2 TEs are enriched with sequences from IR-related defence genes, our results suggest that AGO1-associated sRNAs from hypomethylated ATREP2 TEs trans-regulate long-lasting memory of JA-dependent immunity., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Genetic risk factors for chemotherapy-induced peripheral neuropathy (CIPN), a major dose-limiting side-effect of paclitaxel, are not well understood., Methods: We performed a genome-wide association study (GWAS) in 183 paclitaxel-treated patients to identify genetic loci associated with CIPN assessed via comprehensive neuropathy phenotyping tools (patient-reported, clinical and neurological grading scales). Bioinformatic analyses including pathway enrichment and polygenic risk score analysis were used to identify mechanistic pathways of interest., Results: In total, 77% of the cohort were classified with CIPN (n = 139), with moderate/severe neuropathy in 36%. GWAS was undertaken separately for the three measures of CIPN. GWAS of patient-reported CIPN identified 4 chromosomal regions that exceeded genome-wide significance (rs9846958, chromosome 3; rs117158921, chromosome 18; rs4560447, chromosome 4; rs200091415, chromosome 10). rs4560447 is located within a protein-coding gene, LIMCH1, associated with actin and neural development and expressed in the dorsal root ganglia (DRG). There were additional risk loci that exceeded the statistical threshold for suggestive genome-wide association (P < 1 × 10 -5 ) for all measures. A polygenic risk score calculated from the top 46 ranked SNPs was highly correlated with patient-reported CIPN (r 2  = 0.53; P = 1.54 × 10 -35 ). Overlap analysis was performed to identify 3338 genes which were in common between the patient-reported CIPN, neurological grading scale and clinical grading scale GWAS. The common gene set was subsequently analysed for enrichment of gene ontology (GO) and Reactome pathways, identifying a number of pathways, including the axon development pathway (GO:0061564; P = 1.78 × 10 -6 ) and neuronal system (R-HSA-112316; adjusted P = 3.33 × 10 -7 )., Conclusions: Our findings highlight the potential role of axon development and regeneration pathways in paclitaxel-induced CIPN., (© 2022. The Author(s).)

Metabolomic studies on root uptake and transformation of bioactive compounds, like cereal benzoxazinoids (BXs) in non-BX producing plants, are very limited. Therefore, a targeted mass-spectrometry-based metabolomics study was performed to elucidate the root uptake of BXs in white clover ( Trifolium repens L.) and the impact of absorbed BXs on intrinsic clover secondary metabolites. Clover plants grew in a medium containing 100 μM of individual BXs (five aglycone and one glycoside BXs) for 3 weeks. Subsequently, plant tissues were analyzed by liquid chromatography-tandem mass spectrometry to quantify the BXs and clover secondary metabolite concentrations. All BXs were taken up by clover roots and translocated to the shoots. Upon uptake of 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA), 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA), 2-hydroxy-1,4-benzoxazin-3-one (HBOA), and 2-β-d-glucopyranosyloxy-1,4-benzoxazin-3-one (HBOA-glc), the parent compounds and a range of transformation products were seen in the roots and shoots. The individual BX concentrations ranged from not detected (nd) to 469 μg/g of dry weight (dw) and from nd to 170 μg/g of dw in the roots and shoots, respectively. The root uptake of BXs altered the composition of intrinsic clover secondary metabolites. In particular, the concentration of flavonoids and the hormone abscisic acid increased substantially in comparison to control plants.

Clinical endocrinology entails an understanding of the mechanisms involved in the regulation of tumors that occur in the endocrine system. The exact cause of endocrine cancers remains an enigma, especially when discriminating malignant lesions from benign ones and early diagnosis. In the past few years, the concepts of personalized medicine and metabolomics have gained great popularity in cancer research. In this systematic review, we discussed the clinical metabolomics studies in the diagnosis of endocrine cancers within the last 12 years. Cancer metabolomic studies were largely conducted using nuclear magnetic resonance (NMR) and mass spectrometry (MS) combined with separation techniques such as gas chromatography (GC) and liquid chromatography (LC). Our findings revealed that the majority of the metabolomics studies were conducted on tissue, serum/plasma, and urine samples. Studies most frequently emphasized thyroid cancer, adrenal cancer, and pituitary cancer. Altogether, analytical hyphenated techniques and chemometrics are promising tools in unveiling biomarkers in endocrine cancer and its metabolism disorders.

While the plant host metabolome drives distinct enrichment of detrimental and beneficial members of the microbiome, the mechanistic interomics relationships remain poorly understood. Here, we studied microbiome and metabolome profiles of two Arabidopsis thaliana accessions after Fusarium oxysporum f.sp. mathioli (FOM) inoculation, Landsberg erecta (Ler-0) being susceptible and Col-0 being resistant against FOM. By using bacterial and fungal amplicon sequencing and targeted metabolite analysis, we observed highly dynamic microbiome and metabolome profiles across FOM host progression, while being markedly different between FOM-inoculated and noninoculated Col-0 and Ler-0. Co-occurrence network analysis revealed more robust microbial networks in the resistant Col-0 compared to Ler-0 during FOM infection. Correlation analysis revealed distinct metabolite-OTU correlations in Ler-0 compared with Col-0 which could possibly be explained by missense variants of the Rfo 3 and Rlp 2 genes in Ler-0. Remarkably, we observed positive correlations in Ler-0 between most of the analyzed metabolites and the bacterial phyla Proteobacteria, Bacteroidetes, Planctomycetes, Acidobacteria, and Verrucomicrobia, and negative correlations with Actinobacteria, Firmicutes, and Chloroflexi. The glucosinolates 4-methyoxyglucobrassicin, glucoerucin and indole-3 carbinol, but also phenolic compounds were strongly correlating with the relative abundances of indicator and hub OTUs and thus could be active in structuring the A. thaliana root-associated microbiome. Our results highlight interactive effects of host plant defense and root-associated microbiota on Fusarium infection and progression. Our findings provide significant insights into plant interomic dynamics during pathogen invasion and could possibly facilitate future exploitation of microbiomes for plant disease control. IMPORTANCE Plant health and fitness are determined by plant-microbe interactions which are guided by host-synthesized metabolites. To understand the orchestration of this interaction, we analyzed the distinct interomic dynamics in resistant and susceptible Arabidopsis ecotypes across different time points after infection with Fusarium oxysporum (FOM). Our results revealed distinct microbial profiles and network resilience during FOM infection in the resistant Col-0 compared with the susceptible Ler-0 and further pinpointed specific microbe-metabolite associations in the Arabidopsis microbiome. These findings provide significant insights into plant interomics dynamics that are likely affecting fungal pathogen invasion and could possibly facilitate future exploitation of microbiomes for plant disease control.

Medullary thyroid cancer (MTC) is a rare tumor that arises from parafollicular cells within the thyroid gland. The molecular mechanism underlying MTC has not yet been fully understood. Here, we aimed to perform plasma metabolomics profiling of MTC patients to explore the perturbation of metabolic pathways contributing to MTC tumorigenesis. Plasma samples from 20 MTC patients and 20 healthy subjects were obtained to carry out an untargeted metabolomics by gas chromatography-mass spectrometry. Multivariate and univariate analyses were employed as diagnostic tools via MetaboAnalyst and SIMCA software. A total of 76 features were structurally annotated; among them, 13 metabolites were selected to be differentially expressed in MTC patients compared to controls (P < 0.05). These metabolites were mainly associated with the biosynthesis of unsaturated fatty acids and amino acid metabolisms, mostly leucine, glutamine, and glutamate, tightly responsible for tumor cells' energy production. Moreover, according to the receiver operating characteristic curve analysis, metabolites with the area under the curve (AUC) value up to 0.90, including linoleic acid (AUC = 0.935), linolenic acid (AUC = 0.92), and leucine (AUC = 0.948) could discriminate MTC from healthy individuals. This preliminary work contributes to existing knowledge of MTC metabolism by providing evidence of a distinctive metabolic profile in MTC patients relying on the metabolomics approach., (© 2022. The Author(s).)

Most neurodegenerative disorders take decades to develop, and their early detection is challenged by confounding non-pathological ageing processes. Therefore, the discovery of genes and molecular pathways in both peripheral and brain tissues that are highly predictive of disease evolution is necessary. To find genes that influence Alzheimer's disease (AD) and Parkinson's disease (PD) pathogenesis, human RNA-Seq transcriptomic data from Brodmann Area 9 (BA9) of the dorsolateral prefrontal cortex (DLPFC), whole blood (WB), and peripheral blood mononuclear cells (PBMC) were analysed using a combination of differential gene expression and a random forest-based machine learning algorithm. The results suggest that there is little overlap between PD and AD, and the AD brain signature is unique mainly compared to blood-based samples. Moreover, the AD-BA9 was characterised by changes in 'nervous system development' with Myocyte-specific enhancer factor 2C ( Mef2C ), encoding a transcription factor that induces microglia activation, a prominent feature. The peripheral AD transcriptome was associated with alterations in 'viral process', and FYN , which has been previously shown to link amyloid-beta and tau, was the prominent feature. However, in the absence of any overlap with the central transcriptome, it is unclear whether peripheral FYN levels reflect AD severity or progression. In PD, central and peripheral signatures are characterised by anomalies in 'exocytosis' and specific genes related to the SNARE complex, including Vesicle-associated membrane protein 2 ( VAMP2 ), Syntaxin 1A ( STX1A ), and p21-activated kinase 1 ( PAK1 ). This is consistent with our current understanding of the physiological role of alpha-synuclein and how alpha-synuclein oligomers compromise vesicle docking and neurotransmission. Overall, the results describe distinct disease-specific pathomechanisms, both within the brain and peripherally, for the two most common neurodegenerative disorders.

Background: The prevalence of current or past coronavirus disease 2019 in skilled nursing facility (SNF) residents is unknown because of asymptomatic infection and constrained testing capacity early in the pandemic. We conducted a seroprevalence survey to determine a more comprehensive prevalence of past coronavirus disease 2019 in Los Angeles County SNF residents and staff members., Methods: We recruited participants from 24 facilities; participants were requested to submit a nasopharyngeal swab sample for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) testing and a serum sample for detection of SARS-CoV-2 antibodies. All participants were cross-referenced with our surveillance database to identify persons with prior positive SARS-CoV-2 results., Results: From 18 August to 24 September 2020, we enrolled 3305 participants (1340 residents and 1965 staff members). Among 856 residents providing serum samples, 362 (42%) had current or past SARS-CoV-2 infection. Of the 346 serology-positive residents, 199 (58%) did not have a documented prior positive SARS-CoV-2 PCR result. Among 1806 staff members providing serum, 454 (25%) had current or past SARS-CoV-2 infection. Of the 447 serology-positive staff members, 353 (79%) did not have a documented prior positive SARS-CoV-2 PCR result., Conclusions: Past testing practices and policies missed a substantial number of SARS-CoV-2 infections in SNF residents and staff members., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective, early degeneration of motor neurons in the brain and spinal cord. Motor neurons have long axonal projections, which rely on the integrity of neuronal cytoskeleton and mitochondria to regulate energy requirements for maintaining axonal stability, anterograde and retrograde transport, and signaling between neurons. The formation of protein aggregates which contain cytoskeletal proteins, and mitochondrial dysfunction both have devastating effects on the function of neurons and are shared pathological features across several neurodegenerative conditions, including ALS, Alzheimer's disease, Parkinson's disease, Huntington's disease and Charcot-Marie-Tooth disease. Furthermore, it is becoming increasingly clear that cytoskeletal integrity and mitochondrial function are intricately linked. Therefore, dysregulations of the cytoskeletal network and mitochondrial homeostasis and localization, may be common pathways in the initial steps of neurodegeneration. Here we review and discuss known contributors, including variants in genetic loci and aberrant protein activities, which modify cytoskeletal integrity, axonal transport and mitochondrial localization in ALS and have overlapping features with other neurodegenerative diseases. Additionally, we explore some emerging pathways that may contribute to this disruption in ALS., (© 2021. The Author(s).)

Thyroid cancers (TCs) are the most prevalent malignancy of the endocrine system and the seventh most common cancer in women. According to estimates from the Global Cancer Observatory (GCO) in 2020, the incidence of thyroid cancer globally was 586,000 cases. As thyroid cancer incidences have dramatically increased, identifying the most important metabolic pathways and biochemical markers involved in thyroid tumorigenesis can be critical strategies for controlling the prevalence and ultimately treatment of this disease. Cancer cells undergo cellular metabolism and energy alteration in order to promote cell proliferation and invasion. Glutamine is one of the most abundant free amino acids in the human body that contributes to cancer metabolic remodeling as a carbon and nitrogen source to sustain cell growth and proliferation. In the present review, glutamine metabolism and its regulation in cancer cells are highlighted. Thereafter, emphasis is given to the perturbation of glutamine metabolism in thyroid cancer, focusing on metabolomics studies., (Copyright © 2021 Abooshahab et al.)

Entomopathogenic fungi (EPF) can display a plant-associated lifestyle as endophytes. Seed application of EPF can affect insect herbivory above ground, but the mechanisms behind this are not documented. Here we applied three EPF isolates, Beauveria bassiana, Metarhizium brunneum and M. robertsii, as seed inoculation of wheat and bean, and evaluated the effects on population growth of aphids, Rhopalosiphum padi and Aphis fabae, respectively. In wheat and bean leaves, we quantified benzoxazinoids and flavonoids, respectively, in response to EPF inoculation and aphid infestation to elucidate the role of specific plant secondary metabolites (PSMs) in plant-fungus-herbivore interactions. Inoculations of wheat and bean with M. robertsii and B. bassiana reduced aphid populations compared with control treatments, whereas M. brunneum unexpectedly increased the populations of both aphids. Concentrations of the majority of PSMs were differentially altered in EPF-treated plants infested with aphids. Changes in aphid numbers were associated with PSMs regulation rather than EPF endophytic colonisation capacity. This study links the effects of EPF seed inoculations against aphids with unique PSM accumulation patterns in planta. The understanding of PSM regulation in tri-trophic interactions is important for the future development of EPF for pest management., (© 2020 The Authors New Phytologist © 2020 New Phytologist Foundation.)

Glucosinolates are biologically active secondary metabolites in Brassicaceae plants that play a critical role in positive and negative interactions between plants and root-associated microbial communities. The aim of this study was to develop a reversed-phase liquid chromatography method to quantify and identify intact glucosinolates in the root of Arabidopsis thaliana ( Arabidopsis ) grown in non-sterile natural soil by using liquid chromatography-hybrid triple quadruple-linear ion trap (LC-QqQ(LIT)) mass spectrometry. The Synergi Fusion C18-based column was found to be effective for sufficient retention and separation of nine intact glucosinolates without the need for time-consuming desulfation or ion-pairing steps. Method validation results showed satisfactory inter-day and intra-day precision for all glucosinolates except for 4-hydroxyglucobrassicin. Good inter-day and intra-day accuracy and recovery results were observed for glucoiberin, gluconapin, glucobrassicin, 4-methoxyglucobrassicin and neoglucobrassicin. However, for 4-hydroxyglucobrassicin, glucoraphanin and glucoerucin corrections to quantification results might be necessary since the recovery and accuracy results were not optimal. Matrix effects were shown to have a negligible effect on the ionization of all target analytes. The established liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to quantify target intact glucosinolates in Arabidopsis root crude extract of four different wild-type accessions where differences in terms of concentration and composition of intact glucosinolates were observed. Employment of sensitive and selective precursor ion survey scan of m / z 97 in combination with the information-dependent acquisition (IDA) of the enhanced product ion (EPI) dependent scan (Prec97-IDA-EPI) using LC-QqQ(LIT) provided high confidence in structural characterization of diverse intact glucosinolate profiles in complex Arabidopsis root crude extract.

Fusarium oxysporum is a destructive root-infecting plant pathogen that causes significant yield losses in many economically important crop species. Hence, a deeper understanding of pathogen infection strategies is needed. With liquid chromatography-tandem mass spectrometry and gas chromatography-time of flight mass spectrometry platforms, we analyzed the metabolic changes in a time-course experiment with Arabidopsis accessions either resistant (Col-0) or susceptible (Ler-0) to isolates of Fusarium oxysporum forma specialis matthioli infection. We showed a concurrent effect of Fusarium -derived polyols and the mycotoxin beauvericin in the suppression of the immune response of susceptible hosts. A significant increase in oxidized glutathione in the resistant host was probably associated with effective reactive oxygen species-mediated resistance responses. Through a combination of targeted and untargeted metabolomics, we demonstrated the concurrent action of several Arabidopsis defense systems as well as the concurrent action of several virulence systems in the fungal attack of susceptible Arabidopsis .

One of the challenges in the area of diagnostics of human thyroid cancer is a preoperative diagnosis of thyroid nodules with indeterminate cytology. Herein, we report an untargeted metabolomics analysis to identify circulating thyroid nodule metabolic signatures, to find new novel metabolic biomarkers. Untargeted gas chromatography-quadrupole-mass spectrometry was used to ascertain the specific plasma metabolic changes of thyroid nodule patients, which consisted of papillary thyroid carcinoma (PTC; n = 19), and multinodular goiter (MNG; n = 16), as compared to healthy subjects ( n = 20). Diagnostic models were constructed using multivariate analyses such as principal component analysis, orthogonal partial least squares-discriminant analysis, and univariate analysis including One-way ANOVA and volcano plot by MetaboAnalyst and SIMCA software. Because of the multiple-testing issue, false discovery rate p -values were also computed for these functions. A total of 60 structurally annotated metabolites were subjected to statistical analysis. A combination of univariate and multivariate statistical analyses revealed a panel of metabolites responsible for the discrimination between thyroid nodules and healthy subjects, with variable importance in the projection (VIP) value greater than 0.8 and p -value less than 0.05. Significantly altered metabolites between thyroid nodules versus healthy persons are those associated with amino acids metabolism, the tricarboxylic acid cycle, fatty acids, and purine and pyrimidine metabolism, including cysteine, cystine, glutamic acid, α-ketoglutarate, 3-hydroxybutyric acid, adenosine-5-monophosphate, and uracil, respectively. Further, sucrose metabolism differed profoundly between thyroid nodule patients and healthy subjects. Moreover, according to the receiver operating characteristic (ROC) curve analysis, sucrose could discriminate PTC from MNG (area under ROC curve value = 0.92). This study enhanced our understanding of the distinct metabolic pathways associated with thyroid nodules, which enabled us to distinguish between patients and healthy subjects. In addition, our study showed extensive sucrose metabolism in the plasma of thyroid nodule patients, which provides a new metabolic signature of the thyroid nodule's tumorigenesis. Accordingly, it suggests that sucrose can be considered as a circulating biomarker for differential diagnosis between malignancy and benignity in indeterminate thyroid nodules., (Copyright © 2020 Abooshahab, Hooshmand, Razavi, Gholami, Sanoie and Hedayati.)

The biosynthesis of starch granules in plant plastids is coordinated by the orchestrated action of transferases, hydrolases, and dikinases. These enzymes either contain starch-binding domain(s) themselves, or are dependent on direct interactions with co-factors containing starch-binding domains. As a means to competitively interfere with existing starch-protein interactions, we expressed the protein module Carbohydrate-Binding Motif 20 (CBM20), which has a very high affinity for starch, ectopically in barley plastids. This interference resulted in an increase in the number of starch granules in chloroplasts and in formation of compound starch granules in grain amyloplasts, which is unusual for barley. More importantly, we observed a photosystem-independent inhibition of CO2 fixation, with a subsequent reduced growth rate and lower accumulation of carbohydrates with effects throughout the metabolome, including lower accumulation of transient leaf starch. Our results demonstrate the importance of endogenous starch-protein interactions for controlling starch granule morphology and number, and plant growth, as substantiated by a metabolic link between starch-protein interactions and control of CO2 fixation in chloroplasts., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Bio-plastics and bio-materials are composed of natural or biomass derived polymers, offering solutions to solve immediate environmental issues. Polysaccharide-based bio-plastics represent important alternatives to conventional plastic because of their intrinsic biodegradable nature. Amylose-only (AO), an engineered barley starch with 99% amylose, was tested to produce cross-linked all-natural bioplastic using normal barley starch as a control. Glycerol was used as plasticizer and citrate cross-linking was used to improve the mechanical properties of cross-linked AO starch extrudates. Extrusion converted the control starch from A-type to Vh- and B-type crystals, showing a complete melting of the starch crystals in the raw starch granules. The cross-linked AO and control starch specimens displayed an additional wide-angle diffraction reflection. Phospholipids complexed with Vh-type single helices constituted an integrated part of the AO starch specimens. Gas permeability tests of selected starch-based prototypes demonstrated properties comparable to that of commercial Mater-Bi © plastic. The cross-linked AO prototypes had composting characteristics not different from the control, indicating that the modified starch behaves the same as normal starch. The data shows the feasibility of producing all-natural bioplastic using designer starch as raw material., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

In this study, we examined cytotoxic effect of GL-9 peptide on A459 cell line through studying the changes in TNF-α and CD44 gene expression and ROS production. Real-time PCR analysis showed that the treated A549 cells highly over expressed TNF-α, which was associated with a significant reduction of CD44 gene expression levels (p  <  0.05). ROS production rate was measured through the usage of DCFH-DA primer. Results demonstrated that GL-9 peptide could also induce cell death via ROS production. The effect of GL-9 peptide on human erythrocytes and leukocytes was analyzed. GL-9 peptide showed no significant toxic effect on human blood cells. Our results suggested that the GL-9 peptide as a potent natural agent could modulate gene expression of cancer cell markers.