Cysteine and iron accelerate the formation of ribose-5-phosphate, providing insights into the evolutionary origins of the metabolic network structure.

The structure of the metabolic network is highly conserved, but we know little about its evolutionary origins. Key for explaining the early evolution of metabolism is solving a chicken-egg dilemma, which describes that enzymes are made from the very same molecules they produce. The recent discovery of several nonenzymatic reaction sequences that topologically resemble central metabolism has provided experimental support for a "metabolism first" theory, in which at least part of the extant metabolic network emerged on the basis of nonenzymatic reactions. But how could evolution kick-start on the basis of a metal catalyzed reaction sequence, and how could the structure of nonenzymatic reaction sequences be imprinted on the metabolic network to remain conserved for billions of years? We performed an in vitro screening where we add the simplest components of metabolic enzymes, proteinogenic amino acids, to a nonenzymatic, iron-driven reaction network that resembles glycolysis and the pentose phosphate pathway (PPP). We observe that the presence of the amino acids enhanced several of the nonenzymatic reactions. Particular attention was triggered by a reaction that resembles a rate-limiting step in the oxidative PPP. A prebiotically available, proteinogenic amino acid cysteine accelerated the formation of RNA nucleoside precursor ribose-5-phosphate from 6-phosphogluconate. We report that iron and cysteine interact and have additive effects on the reaction rate so that ribose-5-phosphate forms at high specificity under mild, metabolism typical temperature and environmental conditions. We speculate that accelerating effects of amino acids on rate-limiting nonenzymatic reactions could have facilitated a stepwise enzymatization of nonenzymatic reaction sequences, imprinting their structure on the evolving metabolic network.

Cytosine-5 RNA methylation links protein synthesis to cell metabolism.

Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt protein synthesis rates to a dynamically changing microenvironment. However, the precise cellular mechanisms linking the extrinsic stimulus to the intrinsic RNA modification pathways remain largely unclear. Here, we identified the cytosine-5 RNA methyltransferase NSUN2 as a sensor for external stress stimuli. Exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Using metabolic profiling, we showed that loss of tRNA methylation captured cells in a distinct catabolic state. Mechanistically, loss of NSUN2 altered the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of protein synthesis. The intracellular accumulation of a specific subset of tRFs correlated with the dynamic repression of global protein synthesis. Finally, NSUN2-driven RNA methylation was functionally required to adapt cell cycle progression to the early stress response. In summary, we revealed that changes in tRNA methylation profiles were sufficient to specify cellular metabolic states and efficiently adapt protein synthesis rates to cell stress.

Alphavirus-induced hyperactivation of PI3K/AKT directs pro-viral metabolic changes.

Virus reprogramming of cellular metabolism is recognised as a critical determinant for viral growth. While most viruses appear to activate central energy metabolism, different viruses have been shown to rely on alternative mechanisms of metabolic activation. Whether related viruses exploit conserved mechanisms and induce similar metabolic changes is currently unclear. In this work we investigate how two alphaviruses, Semliki Forest virus and Ross River virus, reprogram host metabolism and define the molecular mechanisms responsible. We demonstrate that in both cases the presence of a YXXM motif in the viral protein nsP3 is necessary for binding to the PI3K regulatory subunit p85 and for activating AKT. This leads to an increase in glucose metabolism towards the synthesis of fatty acids, although additional mechanisms of metabolic activation appear to be involved in Ross River virus infection. Importantly, a Ross River virus mutant that fails to activate AKT has an attenuated phenotype in vivo, suggesting that viral activation of PI3K/AKT contributes to virulence and disease.

Cyclooxygenase-2, Asymmetric Dimethylarginine, and the Cardiovascular Hazard From Nonsteroidal Anti-Inflammatory Drugs.

BACKGROUND: Large-scale, placebo-controlled trials established that nonsteroidal anti-inflammatory drugs confer a cardiovascular hazard: this has been attributed to depression of cardioprotective products of cyclooxygenase (COX)-2, especially prostacyclin. An alternative mechanism by which nonsteroidal anti-inflammatory drugs might constrain cardioprotection is by enhancing the formation of methylarginines in the kidney that would limit the action of nitric oxide throughout the vasculature. METHODS: Targeted and untargeted metabolomics were used to investigate the effect of COX-2 deletion or inhibition in mice and in osteoarthritis patients exposed to nonsteroidal anti-inflammatory drugs on the l-arginine/nitric oxide pathway. RESULTS: Analysis of the plasma and renal metabolome was performed in postnatal tamoxifen-inducible Cox-2 knockout mice, which exhibit normal renal function and blood pressure. This revealed no changes in arginine and methylarginines compared with their wild-type controls. Moreover, the expression of genes in the l-arginine/nitric oxide pathway was not altered in the renal medulla or cortex of tamoxifen inducible Cox-2 knockout mice. Therapeutic concentrations of the selective COX-2 inhibitors, rofecoxib, celecoxib, and parecoxib, none of which altered basal blood pressure or renal function as reflected by plasma creatinine, failed to elevate plasma arginine and methylarginines in mice. Finally, plasma arginine or methylarginines were not altered in osteoarthritis patients with confirmed exposure to nonsteroidal anti-inflammatory drugs that inhibit COX-1 and COX-2. By contrast, plasma asymmetrical dimethylarginine was increased in mice infused with angiotensin II sufficient to elevate blood pressure and impair renal function. Four weeks later, blood pressure, plasma creatinine, and asymmetrical dimethylarginine were restored to normal levels. The increase in asymmetrical dimethylarginine in response to infusion with angiotensin II in celecoxib-treated mice was also related to transient impairment of renal function. CONCLUSIONS: Plasma methylarginines are not altered by COX-2 deletion or inhibition but rather are elevated coincident with renal compromise.

UPLC-ESI-QTOF-MS²-Based Identification and Antioxidant Activity Assessment of Phenolic Compounds from Red Corn Cob (Zea mays L.).

In this study, the extraction of phenolic antioxidants from red corn cob was carried out using ultrasound-assisted extraction (UAE). The solid:liquid ratio and extraction time were evaluated when obtaining these bioactive compounds. The total phenolic contents were evaluated using the Folin Ciocalteu method, while the antioxidant activity was measured by ABTS•+ and DPPH• assays. The amount of phenolic compounds ranged from 215.17 ± 33.49 to 527.33 ± 103.79 GAE mg/100 g and, overall, high solid:liquid ratios and time periods release more phenolic compounds. Moreover, the red corn cob extracts showed higher radical scavenging capacity according to the results obtained using the ABTS•+ technique compared to the DPPH• test. The coupling of liquid chromatography and mass spectrometry assay allowed the determination of 11 phenolic compounds, including phenolic acids and flavonoids. Thus, our results demonstrated for the first time the potential of red corn cob as a source of bioactive compounds, which might be included in food and pharmacological preparations.

A role for vaccinia virus protein C16 in reprogramming cellular energy metabolism.

Vaccinia virus (VACV) is a large DNA virus that replicates in the cytoplasm and encodes about 200 proteins of which approximately 50 % may be non-essential for viral replication. These proteins enable VACV to suppress transcription and translation of cellular genes, to inhibit the innate immune response, to exploit microtubule- and actin-based transport for virus entry and spread, and to subvert cellular metabolism for the benefit of the virus. VACV strain WR protein C16 induces stabilization of the hypoxia-inducible transcription factor (HIF)-1α by binding to the cellular oxygen sensor prolylhydroxylase domain-containing protein (PHD)2. Stabilization of HIF-1α is induced by several virus groups, but the purpose and consequences are unclear. Here, (1)H-NMR spectroscopy and liquid chromatography-mass spectrometry are used to investigate the metabolic alterations during VACV infection in HeLa and 2FTGH cells. The role of C16 in such alterations was examined by comparing infection to WT VACV (strain WR) and a derivative virus lacking gene C16L (vΔC16). Compared with uninfected cells, VACV infection caused increased nucleotide and glutamine metabolism. In addition, there were increased concentrations of glutamine derivatives in cells infected with WT VACV compared with vΔC16. This indicates that C16 contributes to enhanced glutamine metabolism and this may help preserve tricarboxylic acid cycle activity. These data show that VACV infection reprogrammes cellular energy metabolism towards increased synthesis of the metabolic precursors utilized during viral replication, and that C16 contributes to this anabolic reprogramming of the cell, probably via the stabilization of HIF-1α.

Post-developmental microRNA expression is required for normal physiology, and regulates aging in parallel to insulin/IGF-1 signaling in C. elegans.

Regulation of gene expression by microRNAs (miRNAs) is essential for normal development, but the roles of miRNAs in the physiology of adult animals are poorly understood. We have isolated a conditional allele of DGCR8/pash-1, which allows reversible and rapid inactivation of miRNA synthesis in vivo in Caenorhabditis elegans. This is a powerful new tool that allows dissection of post-developmental miRNA functions. We demonstrate that continuous synthesis of miRNAs is dispensable for cellular viability but critical for the physiology of adult animals. Loss of miRNA synthesis in the adult reduces lifespan and results in rapid aging. The insulin/IGF-1 signaling pathway is a critical determinant of lifespan, and is modulated by miRNAs. We find that although miRNA expression is required for some mechanisms of lifespan extension, it is not essential for the longevity of animals lacking insulin/IGF-1 signaling. Further, misregulated insulin/IGF-1 signaling cannot account for the reduced lifespan caused by disruption of miRNA synthesis. We show that miRNAs act in parallel with insulin/IGF-1 signaling to regulate a shared set of downstream genes important for physiological processes that determine lifespan. We conclude that coordinated transcriptional and post-transcriptional regulation of gene expression promotes longevity.

Safety, Efficacy, and Visual Performance of an Orthokeratology Lens with Increased Compression Factor.

The aim was to evaluate the safety, efficacy, and visual performance of an orthokeratology lens with an increased compression factor (ICF) of 1.25 D in a 3-month follow-up. Thirty-six myopic patients (5 males and 31 females; 24.2 ± 5.8 years) were fitted with Alexa AR (Tiedra Farmacéutica S.L., Madrid, Spain) contact lenses (CLs) and twenty participants finished the follow-up. Visual acuity (VA), subjective refraction, primary spherical and primary coma aberrations, keratometry, central pachymetry, and ocular surface evaluation were performed at baseline and after 1 night, 1 week, 1 month, and 3 months of CL wear. The differences among visits were analyzed using a repeated-measures analysis of variance or the Friedman test. The spherical equivalent decreased (p ≤ 0.005), and the uncorrected VA improved (p < 0.001) until the first week. Corneal and ocular aberrations showed a significant increase (p ≤ 0.02). A significant decrease (p < 0.001) was found for keratometry values. No significant changes were observed in either central pachymetry or ocular surface parameters among study visits. In conclusion, an orthokeratology CL with an ICF of 1.25 D provides good safety, efficacy, and visual performance in a 3-month follow-up. Seven days of orthokeratology wear are enough to achieve the full myopic compensation, resulting in satisfactory VA.

An IoT-fuzzy intelligent approach for holistic management of COVID-19 patients.

In this study, an internet of things (IoT)-enabled fuzzy intelligent system is introduced for the remote monitoring, diagnosis, and prescription of treatment for patients with COVID-19. The main objective of the present study is to develop an integrated tool that combines IoT and fuzzy logic to provide timely healthcare and diagnosis within a smart framework. This system tracks patients' health by utilizing an Arduino microcontroller, a small and affordable computer that reads data from various sensors, to gather data. Once collected, the data are processed, analyzed, and transmitted to a web page for remote access via an IoT-compatible Wi-Fi module. In cases of emergencies, such as abnormal blood pressure, cardiac issues, glucose levels, or temperature, immediate action can be taken to monitor the health of critical COVID-19 patients in isolation. The system employs fuzzy logic to recommend medical treatments for patients. Sudden changes in these medical conditions are remotely reported through a web page to healthcare providers, relatives, or friends. This intelligent system assists healthcare professionals in making informed decisions based on the patient's condition.

Evaluation of hemostatic devices in a randomized porcine model of junctional hemorrhage and 72-hour prolonged field care.

BACKGROUND: Hemorrhage control in prolonged field care (PFC) presents unique challenges that drive the need for enhanced point of injury treatment capabilities to maintain patient stability beyond the Golden Hour. To address this, two hemostatic agents, Combat Gauze (CG) and XSTAT, were evaluated in a porcine model of uncontrolled junctional hemorrhage for speed of deployment and hemostatic efficacy over 72 hours. METHODS: The left subclavian artery and subscapular vein were isolated in anesthetized male Yorkshire swine (70-85 kg) and injured via 50% transection, followed by 30 seconds of hemorrhage. Combat Gauze (n = 6) or XSTAT (n = 6) was administered until bleeding stopped and remained within subjects for observation over 72 hours. Physiologic monitoring, hemostatic efficacy, and hematological parameters were measured throughout the protocol. Gross necropsy and histology were performed following humane euthanasia. RESULTS: Both CG and XSTAT maintained hemostasis throughout the full duration of the protocol. There were no significant differences between groups in hemorrhage volume (CG: 1021.0 ± 183.7 mL vs. XSTAT: 968.2 ± 243.3 mL), total blood loss (CG: 20.8 ± 2.7% vs. XSTAT: 20.1 ± 5.1%), or devices used (CG: 3.8 ± 1.2 vs. XSTAT: 5.3 ± 1.4). XSTAT absorbed significantly more blood than CG (CG: 199.5 ± 50.3 mL vs. XSTAT: 327.6 ± 71.4 mL) and was significantly faster to administer (CG: 3.4 ± 1.6 minutes vs. XSTAT: 1.4 ± 0.5 minutes). There were no significant changes in activated clot time, prothrombin time, or international normalized ratio between groups or compared with baseline throughout the 72-hour protocol. Histopathology revealed no evidence of microthromboemboli or disseminated coagulopathies across evaluated tissues in either group. CONCLUSION: Combat Gauze and XSTAT demonstrated equivalent hemostatic ability through 72 hours, with no overt evidence of coagulopathies from prolonged indwelling. In addition, XSTAT offered significantly faster administration and the ability to absorb more blood. Taken together, XSTAT offers logistical and efficiency advantages over CG for immediate control of junctional noncompressible hemorrhage, particularly in a tactical environment. In addition, extension of indicated timelines to 72 hours allows translation to PFC.

An Epidemiological Analysis for Assessing and Evaluating COVID-19 Based on Data Analytics in Latin American Countries.

This research provides a detailed analysis of the COVID-19 spread across 14 Latin American countries. Using time-series analysis and epidemic models, we identify diverse outbreak patterns, which seem not to be influenced by geographical location or country size, suggesting the influence of other determining factors. Our study uncovers significant discrepancies between the number recorded COVID-19 cases and the real epidemiological situation, emphasizing the crucial need for accurate data handling and continuous surveillance in managing epidemics. The absence of a clear correlation between the country size and the confirmed cases, as well as with the fatalities, further underscores the multifaceted influences on COVID-19 impact beyond population size. Despite the decreased real-time reproduction number indicating quarantine effectiveness in most countries, we note a resurgence in infection rates upon resumption of daily activities. These insights spotlight the challenge of balancing public health measures with economic and social activities. Our core findings provide novel insights, applicable to guiding epidemic control strategies and informing decision-making processes in combatting the pandemic.

Similarity-Based Predictive Models: Sensitivity Analysis and a Biological Application with Multi-Attributes.

Predictive models based on empirical similarity are instrumental in biology and data science, where the premise is to measure the likeness of one observation with others in the same dataset. Biological datasets often encompass data that can be categorized. When using empirical similarity-based predictive models, two strategies for handling categorical covariates exist. The first strategy retains categorical covariates in their original form, applying distance measures and allocating weights to each covariate. In contrast, the second strategy creates binary variables, representing each variable level independently, and computes similarity measures solely through the Euclidean distance. This study performs a sensitivity analysis of these two strategies using computational simulations, and applies the results to a biological context. We use a linear regression model as a reference point, and consider two methods for estimating the model parameters, alongside exponential and fractional inverse similarity functions. The sensitivity is evaluated by determining the coefficient of variation of the parameter estimators across the three models as a measure of relative variability. Our results suggest that the first strategy excels over the second one in effectively dealing with categorical variables, and offers greater parsimony due to the use of fewer parameters.

On the Use of Machine Learning Techniques and Non-Invasive Indicators for Classifying and Predicting Cardiac Disorders.

This research aims to enhance the classification and prediction of ischemic heart diseases using machine learning techniques, with a focus on resource efficiency and clinical applicability. Specifically, we introduce novel non-invasive indicators known as Campello de Souza features, which require only a tensiometer and a clock for data collection. These features were evaluated using a comprehensive dataset of heart disease cases from a machine learning data repository. Our findings highlight the ability of machine learning algorithms to not only streamline diagnostic procedures but also reduce diagnostic errors and the dependency on extensive clinical testing. Three key features-mean arterial pressure, pulsatile blood pressure index, and resistance-compliance indicator-were found to significantly improve the accuracy of machine learning algorithms in binary heart disease classification. Logistic regression achieved the highest average accuracy among the examined classifiers when utilizing these features. While such novel indicators contribute substantially to the classification process, they should be integrated into a broader diagnostic framework that includes comprehensive patient evaluations and medical expertise. Therefore, the present study offers valuable insights for leveraging data science techniques in the diagnosis and management of cardiovascular diseases.

Platelet-derived TLT-1 promotes tumor progression by suppressing CD8+ T cells.

Current understanding of tumor immunosuppressive mechanisms forms the basis for modern day immunotherapies. Immunoregulatory role of platelets in cancer remains largely elusive. Platelets from non-small cell lung cancer (NSCLC) patients revealed a distinct activation phenotype. TREM-like transcript 1 (TLT-1), a platelet protein, was increased along with enhanced extracellular release from NSCLC platelets. The increased platelet TLT-1 was also evident in humanized mice with patient-derived tumors. In immunocompetent mice with syngeneic tumors, TLT-1 binding to T cells, in vivo, led to suppression of CD8 T cells, promoting tumor growth. We identified direct interaction between TLT-1 and CD3ε on T cells, implicating the NF-κB pathway in CD8 T cell suppression. Anti-TLT-1 antibody rescued patients' T cells from platelet-induced suppression ex vivo and reduced tumors in mice in vivo. Clinically, higher TLT-1 correlated with reduced survival of NSCLC patients. Our findings thus identify TLT-1 as a platelet-derived immunosuppressor that suppresses CD8 T cells and demonstrate its therapeutic and prognostic significance in cancer.

Parent Perception of School Meals in the San Joaquin Valley during COVID-19: A Photovoice Project.

School-based nutrition programs are crucial to reducing food insecurity. The COVID-19 pandemic adversely impacted students' school meal participation. This study seeks to understand parent views of school meals during COVID-19 to inform efforts to improve participation in school meal programs. Photovoice methodology was used to explore parental perception of school meals in San Joaquin Valley, California, a region of predominately Latino farmworker communities. Parents in seven school districts photographed school meals for a one-week period during the pandemic and then participated in focus group discussions and small group interviews. Focus group discussions and small group interviews were transcribed, and data were analyzed using a team-based, theme-analysis approach. Three primary domains emerged: benefits of school meal distribution, meal quality and appeal, and perceived healthfulness. Parents perceived school meals as beneficial to addressing food insecurity. However, they noted that meals were unappealing, high in added sugar, and unhealthy, which led to discarded meals and decreased participation in the school meal program. The transition to grab-and-go style meals was an effective strategy for providing food to families during pandemic school closures, and school meals remain an important resource for families experiencing food insecurity. However, negative parental perceptions of the appeal and nutritional content of school meals may have decreased school meal participation and increased food waste that could persist beyond the pandemic.

A metabolomic strategy defines the regulation of lipid content and global metabolism by Δ9 desaturases in Caenorhabditis elegans.

BACKGROUND: Caenorhabditis elegans provides a genetically tractable model organism to investigate the network of genes involved in fat metabolism and how regulation is perturbed to produce the complex phenotype of obesity. C. elegans possess the full range of desaturases, including the Δ9 desaturases expressed by fat-5, fat-6 and fat-7. They regulate the biosynthesis of monounsaturated fatty acids, used for the synthesis of lipids including phospholipids, triglycerides and cholesteryl esters. RESULTS: Liquid chromatography mass spectrometry (LC-MS), gas chromatography mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy were used to define the metabolome of all the possible knock-outs for the Δ9 desaturases, including for the first time intact lipids. Despite the genes having similar enzymatic roles, excellent discrimination was achievable for all single and viable double mutants highlighting the distinctive roles of fat-6 and fat-7, both expressing steroyl-CoA desaturases. The metabolomic changes extend to aqueous metabolites demonstrating the influence Δ9 desaturases have on regulating global metabolism and highlighting how comprehensive metabolomics is more discriminatory than classically used dyes for fat staining. CONCLUSIONS: The propagation of metabolic changes across the network of metabolism demonstrates that modification of the Δ9 desaturases places C.elegans into a catabolic state compared with wildtype controls.

ß-hydroxybutyrate accumulates in the rat heart during low-flow ischaemia with implications for functional recovery.

Extrahepatic tissues which oxidise ketone bodies also have the capacity to accumulate them under particular conditions. We hypothesised that acetyl-coenzyme A (acetyl-CoA) accumulation and altered redox status during low-flow ischaemia would support ketone body production in the heart. Combining a Langendorff heart model of low-flow ischaemia/reperfusion with liquid chromatography coupled tandem mass spectrometry (LC-MS/MS), we show that ß-hydroxybutyrate (ß-OHB) accumulated in the ischaemic heart to 23.9 nmol/gww and was secreted into the coronary effluent. Sodium oxamate, a lactate dehydrogenase (LDH) inhibitor, increased ischaemic ß-OHB levels 5.3-fold and slowed contractile recovery. Inhibition of ß-hydroxy-ß-methylglutaryl (HMG)-CoA synthase (HMGCS2) with hymeglusin lowered ischaemic ß-OHB accumulation by 40%, despite increased flux through succinyl-CoA-3-oxaloacid CoA transferase (SCOT), resulting in greater contractile recovery. Hymeglusin also protected cardiac mitochondrial respiratory capacity during ischaemia/reperfusion. In conclusion, net ketone generation occurs in the heart under conditions of low-flow ischaemia. The process is driven by flux through both HMGCS2 and SCOT, and impacts on cardiac functional recovery from ischaemia/reperfusion.

Nrf2 activation does not affect adenoma development in a mouse model of colorectal cancer.

Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator, Kelch-like ECH associated protein 1 (Keap1), are at the interface between redox and intermediary metabolism. Nrf2 activation is protective in models of human disease and has benefits in clinical trials. Consequently, the Keap1/Nrf2 protein complex is a drug target. However, in cancer Nrf2 plays a dual role, raising concerns that Nrf2 activators may promote growth of early neoplasms. To address this concern, we examined the role of Nrf2 in development of colorectal adenomas by employing genetic, pharmacological, and metabolomic approaches. We found that colorectal adenomas that form in Gstp-/-: ApcMin/+ mice are characterized by altered one-carbon metabolism and that genetic activation, but not disruption of Nrf2, enhances these metabolic alterations. However, this enhancement is modest compared to the magnitude of metabolic differences between tumor and peri-tumoral tissues, suggesting that the metabolic changes conferred by Nrf2 activation may have little contribution to the early stages of carcinogenesis. Indeed, neither genetic (by Keap1 knockdown) nor pharmacological Nrf2 activation, nor its disruption, affected colorectal adenoma formation in this model. We conclude that pharmacological Nrf2 activation is unlikely to impact the early stages of development of colorectal cancer.

Downregulation of Keap1 Confers Features of a Fasted Metabolic State.

Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator, Kelch-like ECH-associated protein 1 (Keap1), are at the interface between redox and intermediary metabolism, allowing adaptation and survival under conditions of oxidative, inflammatory, and metabolic stress. Nrf2 is the principal determinant of redox homeostasis, and contributes to mitochondrial function and integrity and cellular bioenergetics. Using proteomics and lipidomics, we show that genetic downregulation of Keap1 in mice, and the consequent Nrf2 activation to pharmacologically relevant levels, leads to upregulation of carboxylesterase 1 (Ces1) and acyl-CoA oxidase 2 (Acox2), decreases triglyceride levels, and alters the lipidome. This is accompanied by downregulation of hepatic ATP-citrate lyase (Acly) and decreased levels of acetyl-CoA, a trigger for autophagy. These findings suggest that downregulation of Keap1 confers features of a fasted metabolic state, which is an important consideration in the drug development of Keap1-targeting pharmacologic Nrf2 activators.

Adiposity is associated with endothelial activation in healthy 2-3 year-old children.

Adiposity is associated with C-reactive protein level in healthy 2-3 year-old children and with other markers of endothelial activation in adults, but data are lacking in very young children. Data from 491 healthy Hispanic children were analyzed. Mean age was 2.7 years (SD 0.5, range 2-3 years); mean body mass index (BMI) was 17.2 kg/m2 (SD 1.9) among boys and 17.1 kg/m2 (SD 2.1) among girls. E-selectin level was associated with BMI (R = 0.11; p < 0.02), ponderal index (p < 0.02), waist circumference (p = 0.02), fasting insulin (p < 0.02), and insulin resistance (p < or = 0.05); these associations remained significant after adjustment for age, sex and fasting glucose. sVCAM was also associated with BMI (R = 0.12; p < 0.05). These observations indicate that adiposity is associated with inflammation and endothelial activation in very early childhood.