A low-cost spectroscopic nutrient management system for Microscale Smart Hydroponic system.

Hydroponics offers a promising approach to help alleviate pressure on food security for urban residents. It requires minimal space and uses less resources, but management can be complex. Microscale Smart Hydroponics (MSH) systems leverage IoT systems to simplify hydroponics management for home users. Previous work in nutrient management has produced systems that use expensive sensing methods or utilized lower cost methods at the expense of accuracy. This study presents a novel inexpensive nutrient management system for MSH applications that utilises a novel waterproofed, IoT spectroscopy sensor (AS7265x) in a transflective application. The sensor is submerged in a hydroponic solution to monitor the nutrients and MSH system predicts the of nutrients in the hydroponic solution and recommends an adjustment quantity in mL. A three-phase model building process was carried out resulting in significant MLR models for predicting the mL, with an R2 of 0.997. An experiment evaluated the system's performance using the trained models with a 30-day grow of lettuce in a real-world setting, comparing the results of the management system to a control group. The sensor system successfully adjusted and maintained nutrient levels, resulting in plant growth that outperformed the control group. The results of the models in actual deployment showed a strong, significant correlation of 0.77 with the traditional method of measuring the electrical conductivity of nutrients. This novel nutrient management system has the potential to transform the way nutrients are monitored in hydroponics. By simplifying nutrient management, this system can encourage the adoption of hydroponics, contributing to food security and environmental sustainability.

Biological basis of critical illness subclasses: from the bedside to the bench and back again.

Critical illness syndromes including sepsis, acute respiratory distress syndrome, and acute kidney injury (AKI) are associated with high in-hospital mortality and long-term adverse health outcomes among survivors. Despite advancements in care, clinical and biological heterogeneity among patients continues to hamper identification of efficacious therapies. Precision medicine offers hope by identifying patient subclasses based on clinical, laboratory, biomarker and 'omic' data and potentially facilitating better alignment of interventions. Within the previous two decades, numerous studies have made strides in identifying gene-expression based endotypes and clinico-biomarker based phenotypes among critically ill patients associated with differential outcomes and responses to treatment. In this state-of-the-art review, we summarize the biological similarities and differences across the various subclassification schemes among critically ill patients. In addition, we highlight current translational gaps, the need for advanced scientific tools, human-relevant disease models, to gain a comprehensive understanding of the molecular mechanisms underlying critical illness subclasses.

Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns.

The immunological defects causing susceptibility to severe viral respiratory infections due to early-life dysbiosis remain ill-defined. Here, we show that influenza virus susceptibility in dysbiotic infant mice is caused by CD8+ T cell hyporesponsiveness and diminished persistence as tissue-resident memory cells. We describe a previously unknown role for nuclear factor interleukin 3 (NFIL3) in repression of memory differentiation of CD8+ T cells in dysbiotic mice involving epigenetic regulation of T cell factor 1 (TCF 1) expression. Pulmonary CD8+ T cells from dysbiotic human infants share these transcriptional signatures and functional phenotypes. Mechanistically, intestinal inosine was reduced in dysbiotic human infants and newborn mice, and inosine replacement reversed epigenetic dysregulation of Tcf7 and increased memory differentiation and responsiveness of pulmonary CD8+ T cells. Our data unveils new developmental layers controlling immune cell activation and identifies microbial metabolites that may be used therapeutically in the future to protect at-risk newborns.

Kruppel-like factor 2+ CD4 T cells avert microbiota-induced intestinal inflammation.

Intestinal colonization by antigenically foreign microbes necessitates expanded peripheral immune tolerance. Here we show commensal microbiota prime expansion of CD4 T cells unified by the Kruppel-like factor 2 (KLF2) transcriptional regulator and an essential role for KLF2+ CD4 cells in averting microbiota-driven intestinal inflammation. CD4 cells with commensal specificity in secondary lymphoid organs and intestinal tissues are enriched for KLF2 expression, and distinct from FOXP3+ regulatory T cells or other differentiation lineages. Mice with conditional KLF2 deficiency in T cells develop spontaneous rectal prolapse and intestinal inflammation, phenotypes overturned by eliminating microbiota or reconstituting with donor KLF2+ cells. Activated KLF2+ cells selectively produce IL-10, and eliminating IL-10 overrides their suppressive function in vitro and protection against intestinal inflammation in vivo. Together with reduced KLF2+ CD4 cell accumulation in Crohn's disease, a necessity for the KLF2+ subpopulation of T regulatory type 1 (Tr1) cells in sustaining commensal tolerance is demonstrated.

Modifying Surface Charges of a Thermophilic Laccase Toward Improving Activity and Stability in Ionic Liquid.

The multicopper oxidase enzyme laccase holds great potential to be used for biological lignin valorization alongside a biocompatible ionic liquid (IL). However, the IL concentrations required for biomass pretreatment severely inhibit laccase activity. Due to their ability to function in extreme conditions, many thermophilic enzymes have found use in industrial applications. The thermophilic fungal laccase from Myceliophthora thermophila was found to retain high levels of activity in the IL [C2C1Im][EtSO4], making it a desirable biocatalyst to be used for lignin valorization. In contrast to [C2C1Im][EtSO4], the biocompatibility of [C2C1Im][OAC] with the laccase was markedly lower. Severe inhibition of laccase activity was observed in 15% [C2C1Im][OAc]. In this study, the enzyme surface charges were modified via acetylation, succinylation, cationization, or neutralization. However, these modifications did not show significant improvement in laccase activity or stability in [C2C1Im][OAc]. Docking simulations show that the IL docks close to the T1 catalytic copper, likely interfering with substrate binding. Although additional docking locations for [OAc]- are observed after making enzyme modifications, it does not appear that these locations play a role in the inhibition of enzyme activity. The results of this study could guide future enzyme engineering efforts by showing that the inhibition mechanism of [C2C1Im][OAc] toward M. thermophila laccase is likely not dependent upon the IL interacting with the enzyme surface.

The balance between protective and pathogenic immune responses to pneumonia in the neonatal lung is enforced by gut microbiota.

Although modern clinical practices such as cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how the gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system, as assessed by single-cell proteomic and transcriptomic analyses. Early-life antibiotic exposure rendered newborn macaques more susceptible to bacterial pneumonia, concurrent with increases in neutrophil senescence and hyperinflammation, broad inflammatory cytokine signaling, and macrophage dysfunction. This pathogenic reprogramming of pulmonary immunity was further reflected by a hyperinflammatory signature in all pulmonary immune cell subsets coupled with a global loss of tissue-protective, homeostatic pathways in the lungs of dysbiotic newborns. Fecal microbiota transfer was associated with partial correction of the broad immune maladaptations and protection against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity and support the idea that gut microbiota promote the balance between pathways driving tissue repair and inflammatory responses associated with clinical recovery from infection in infants. Our results highlight a potential role for microbial transfer for immune support in these at-risk infants.

Critical evaluation of stents in coronary angioplasty: a systematic review.

BACKGROUND: Coronary stents are routinely placed in the treatment and prophylaxis of coronary artery disease (CAD). Current coronary stent designs are prone to developing blockages: in-stent thrombosis (IST) and in-stent re-stenosis (ISR). This is a systematic review of the design of current coronary stent models, their structural properties and their modes of application, with a focus on their associated risks of IST and ISR. The primary aim of this review is to identify the best stent design features for reducing the risk of IST and ISR. To review the three major types of stents used in clinical settings today, determining best and relevant clinical practice by exploring which types and features of offer improved patient outcomes regarding coronary angioplasty. This information can potentially be used to increase the success rate of coronary angioplasty and stent technology in the future taking into account costs and benefits. METHODS: Scientific databases were searched to find studies concerning stents. After the exclusion criteria were applied, 19 of the 3192 searched literature were included in this review. Studies investigating three major types of stent design were found: bare-metal stents (BMS), drug-eluting stents (DES) and bioresorbable stents (BRS). The number of participants varied between 14 and 1264. On average 77.4% were male, with a mean age of 64 years. RESULTS: From the findings of these studies, it is clear that DES are superior in reducing the risk of ISR when compared to BMS. Conflicting results do not clarify whether BRS are superior to DES at reducing IST occurrence, although studies into newer BRS technologies show reducing events of IST to 0, creating a promising future for BRS showing them to be non-inferior. Thinner stents were shown to reduce IST rates, due to better re-endothelialisation. Scaffold material has also been shown to play a role with cobalt alloy stents reducing the risk of IST. This study found that thinner stents that release drugs were better at preventing re-blockages. Some dissolvable stents might be better at stopping blood clots blocking the arteries when compared to metal stents. The method and procedure of implanting the stent during coronary angioplasty influences success rate of these stents, meaning stent design is not the only significant factor to consider. CONCLUSIONS: Positive developments in coronary angioplasty could be made by designing new stents that encompass all the most desirable properties of existing stent technology. Further work is needed to investigate the benefits of BRS in reducing the risk of IST compared to DES, as well as to investigate the effects of different scaffold materials on IST and ISR outcomes.

Muscle-Specific Deletion of Toll-like Receptor 4 Impairs Metabolic Adaptation to Wheel Running in Mice.

PURPOSE: Toll-like receptor 4 (TLR4) is an inflammatory receptor expressed ubiquitously in immune cells as well as skeletal muscle and other metabolic tissues. Skeletal muscle develops favorable inflammation-mediated metabolic adaptations from exercise training. Multiple inflammatory myokines, downstream from TLR4, are proposed links to the metabolic benefits of exercise. In addition, activation of TLR4 alters skeletal muscle substrate preference. The role of skeletal muscle TLR4 (mTLR4) in exercise metabolism has not previously been investigated. Herein, we aimed to specifically test the significance of mTLR4 to exercise-induced metabolic adaptations. METHODS: We developed a novel muscle-specific TLR4 knockout (mTLR4-/-) mouse model on C57BL/6J background. Male mTLR4-/- mice and wild-type (WT) littermates were compared under sedentary (SED) and voluntary wheel running (WR) conditions for 4 wk. RESULTS: mTLR4 deletion revealed marked reductions in downstream interleukin-1 receptor-associated kinase-4 (IRAK4) phosphorylation. In addition, the disruption of mTLR4 signaling prominently blunted the metabolic adaptations in WR-mTLR4-/- mice as opposed to substantial improvements exhibited by the WT counterparts. Voluntary WR in WT mice, relative to SED, resulted in significant increases in skeletal muscle fatty acid oxidation, glucose oxidation, and associated mitochondrial enzyme activities, all of which were not significantly changed in mTLR4-/- mice. CONCLUSIONS: This study introduces a novel mTLR4-/- mouse model and identifies mTLR4 as an immunomodulatory effector of exercise-induced metabolic adaptations in skeletal muscle.

Evaluation of a novel lower radiation computed tomography protocol for assessment of tunnel position post anterior cruciate ligament reconstruction.

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction is a common orthopaedic procedure. We developed a novel, low dose computed tomography (LDCT) protocol to assess tunnel position post-operatively. The effective radiation dose of this protocol is < 0.5millisieverts (mSv), which is significantly less than the 2 mSv dose for a conventional CT protocol. The aim of this study was to assess the accuracy of the LDCT protocol for determining tunnel position. METHODS: Twenty-six patients who underwent primary ACL reconstruction were included in the study. A LDCT scan was performed 6 weeks post-operatively. Femoral and tibial tunnel positions were measured on three dimensional (3D) reconstructions using previously validated techniques. Measurements were performed independently by three observers at two time points, 4 weeks apart. RESULTS: There was excellent intra- and inter-rater reliability for all measurements using the images obtained from the LDCT protocol. Intra-class correlation coefficient (ICC) values were > 0.9 for all measurements. CONCLUSIONS: The LDCT protocol described in this study accurately demonstrates femoral and tibial tunnels post ACL reconstruction, while exposing the patient to a quarter of the radiation dose of a conventional CT. This protocol could be used by orthopaedic surgeons for routine post-operative imaging, in place of plain film radiographs.

Hepatocyte expression of the micropeptide adropin regulates the liver fasting response and is enhanced by caloric restriction.

The micropeptide adropin encoded by the clock-controlled energy homeostasis-associated gene is implicated in the regulation of glucose metabolism. However, its links to rhythms of nutrient intake, energy balance, and metabolic control remain poorly defined. Using surveys of Gene Expression Omnibus data sets, we confirm that fasting suppresses liver adropin expression in lean C57BL/6J (B6) mice. However, circadian rhythm data are inconsistent. In lean mice, caloric restriction (CR) induces bouts of compulsive binge feeding separated by prolonged fasting intervals, increasing NAD-dependent deacetylase sirtuin-1 signaling important for glucose and lipid metabolism regulation. CR up-regulates adropin expression and induces rhythms correlating with cellular stress-response pathways. Furthermore, adropin expression correlates positively with phosphoenolpyruvate carboxokinase-1 (Pck1) expression, suggesting a link with gluconeogenesis. Our previous data suggest that adropin suppresses gluconeogenesis in hepatocytes. Liver-specific adropin knockout (LAdrKO) mice exhibit increased glucose excursions following pyruvate injections, indicating increased gluconeogenesis. Gluconeogenesis is also increased in primary cultured hepatocytes derived from LAdrKO mice. Analysis of circulating insulin levels and liver expression of fasting-responsive cAMP-dependent protein kinase A (PKA) signaling pathways also suggests enhanced responses in LAdrKO mice during a glucagon tolerance test (250 µg/kg intraperitoneally). Fasting-associated changes in PKA signaling are attenuated in transgenic mice constitutively expressing adropin and in fasting mice treated acutely with adropin peptide. In summary, hepatic adropin expression is regulated by nutrient- and clock-dependent extrahepatic signals. CR induces pronounced postprandial peaks in hepatic adropin expression. Rhythms of hepatic adropin expression appear to link energy balance and cellular stress to the intracellular signal transduction pathways that drive the liver fasting response.

Biocatalysis in ionic liquids for lignin valorization: Opportunities and recent developments.

Lignin holds tremendous potential as a renewable feedstock for upgrading to a number of high-value chemicals and products that are derived from the petroleum industry at present. Since lignin makes up a significant fraction of lignocellulosic biomass, co-utilization of lignin in addition to cellulose and hemicelluloses is vital to the economic viability of cellulosic biorefineries. The recalcitrant nature of lignin, originated from the molecule's compositional and structural heterogeneity, however, poses great challenges toward effective and selective lignin depolymerization and valorization. Ionic liquid (IL) is a powerful solvent that has demonstrated high efficiency in fractionating lignocellulosic biomass into sugar streams and a lignin stream of reduced molecular weight. Compared to thermochemical methods, biological lignin deconstruction takes place at mild temperature and pressure while product selectivity can be potentially improved via the specificity of biocatalysts (lignin degrading enzymes, LDEs). This review focuses on a lignin valorization strategy by harnessing the biomass fractionating capabilities of ILs and the substrate and product selectivity of LDEs. Recent advances in elucidating enzyme-IL interactions as well as strategies for improving enzyme activity in IL are discussed, with specific emphases on biocompatible ILs, thermostable and IL-tolerant enzymes, enzyme immobilization, and surface charge engineering. Also reviewed is the protein engineering toolsets (directed evolution and rational design) to improve the biocatalysts' activity, stability and product selectivity in IL systems. The alliance between IL and LDEs offers a great opportunity for developing a biocatalytic route for lignin valorization.

The peptide hormone adropin regulates signal transduction pathways controlling hepatic glucose metabolism in a mouse model of diet-induced obesity.

The peptide hormone adropin regulates energy metabolism in skeletal muscle and plays important roles in the regulation of metabolic homeostasis. Besides muscle, the liver has an essential role in regulating glucose homeostasis. Previous studies have reported that treatment of diet-induced obese (DIO) male mice with adropin34-76 (the putative secreted domain) reduces fasting blood glucose independently of body weight changes, suggesting that adropin suppresses glucose production in the liver. Here, we explored the molecular mechanisms underlying adropin's effects on hepatic glucose metabolism in DIO mice. Male DIO B6 mice maintained on a high-fat diet received five intraperitoneal injections of adropin34-76 (450 nmol/kg/injection) over a 48-h period. We found that adropin34-76 enhances major intracellular signaling activities in the liver that are involved in insulin-mediated regulation of glucose homeostasis. Moreover, treatment with adropin34-76 alleviated endoplasmic reticulum stress responses and reduced activity of c-Jun N-terminal kinase in the liver, explaining the enhanced activities of hepatic insulin signaling pathways observed with adropin34-76 treatment. Furthermore, adropin34-76 suppressed cAMP activated protein kinase A (PKA) activities, resulting in reduced phosphorylation of inositol trisphosphate receptor, which mediates endoplasmic reticulum calcium efflux, and of cAMP-responsive element-binding protein, a key transcription factor in hepatic regulation of glucose metabolism. Adropin34-76 directly affected liver metabolism, decreasing glucose production and reducing PKA-mediated phosphorylation in primary mouse hepatocytes in vitro Our findings indicate that major hepatic signaling pathways contribute to the improved glycemic control achieved with adropin34-76 treatment in situations of obesity.

Low plasma adropin concentrations increase risks of weight gain and metabolic dysregulation in response to a high-sugar diet in male nonhuman primates.

Mouse studies linking adropin, a peptide hormone encoded by the energy homeostasis-associated (ENHO) gene, to biological clocks and to glucose and lipid metabolism suggest a potential therapeutic target for managing diseases of metabolism. However, adropin's roles in human metabolism are unclear. In silico expression profiling in a nonhuman primate diurnal transcriptome atlas (GSE98965) revealed a dynamic and diurnal pattern of ENHO expression. ENHO expression is abundant in brain, including ventromedial and lateral hypothalamic nuclei regulating appetite and autonomic function. Lower ENHO expression is present in liver, lung, kidney, ileum, and some endocrine glands. Hepatic ENHO expression associates with genes involved in glucose and lipid metabolism. Unsupervised hierarchical clustering identified 426 genes co-regulated with ENHO in liver, ileum, kidney medulla, and lung. Gene Ontology analysis of this cluster revealed enrichment for epigenetic silencing by histone H3K27 trimethylation and biological processes related to neural function. Dietary intervention experiments with 59 adult male rhesus macaques indicated low plasma adropin concentrations were positively correlated with fasting glucose, plasma leptin, and apolipoprotein C3 (APOC3) concentrations. During consumption of a high-sugar (fructose) diet, which induced 10% weight gain, animals with low adropin had larger increases of plasma leptin and more severe hyperglycemia. Declining adropin concentrations were correlated with increases of plasma APOC3 and triglycerides. In summary, peripheral ENHO expression associates with pathways related to epigenetic and neural functions, and carbohydrate and lipid metabolism, suggesting co-regulation in nonhuman primates. Low circulating adropin predicts increased weight gain and metabolic dysregulation during consumption of a high-sugar diet.

Stereoselective Synthesis of Diverse Lactones through a Cascade Reaction of Rhodium Carbenoids with Ketoacids.

A convergent cascade approach for the stereoselective synthesis of diverse lactones is described. The Rh2(TFA)4-catalyzed cascade reaction proceeds via a carboxylic acid O-H insertion/aldol cyclization with high chemo-, regio-, and diastereoselectivity. The cascade reaction provides quick access to highly functionalized γ-butyro- and δ-valerolactones from readily accessible ketoacid and diazo synthons. To demonstrate the utility of this approach, a thermally induced oxy-Cope ring-expansion strategy has been incorporated in the cascade sequence to access medium-sized lactones, which can undergo a serendipitous rearrangement to form spiro-lactones through an intramolecular aldol/trans-lactonization sequence. The reaction has proven to be general, with a range of ketoacids and diazo carbonyls to provide functionalized lactones of varying ring sizes.

Extending Remission and Reversing New-Onset Type 1 Diabetes by Targeted Ablation of Autoreactive T Cells.

Preserving endogenous insulin production is clinically advantageous and remains a vital unmet challenge in the treatment and reversal of type 1 diabetes. Although broad immunosuppression has had limited success in prolonging the so-called remission period, it comes at the cost of compromising beneficial immunity. Here, we used a novel strategy to specifically deplete the activated diabetogenic T cells that drive pathogenesis while preserving not only endogenous insulin production but also protective immunity. Effector T (Teff) cells, such as diabetogenic T cells, are naturally poised on the edge of apoptosis because of activation-induced DNA damage that stresses the p53 regulation of the cell cycle. We have found that using small molecular inhibitors that further potentiate p53 while inhibiting the G2/M cell cycle checkpoint control drives apoptosis of activated T cells in vivo. When delivered at the onset of disease, these inhibitors significantly reduce diabetogenic Teff cells, prolong remission, preserve functional islets, and protect islet allografts while leaving naive, memory, and regulatory T-cell populations functionally untouched. Thus, the targeted manipulation of p53 and cell cycle checkpoints represents a new therapeutic modality for the preservation of islet ß-cells in new-onset type 1 diabetes or after islet transplant.

A Convergent Approach to Diverse Spiroethers through Stereoselective Trapping of Rhodium Carbenoids with Gold-Activated Alkynols.

A convergent approach for the stereoselective synthesis of diverse spiroethers is described. The reaction involves stereoselective trapping of diazo-derived rhodium carbenoids with gold-activated alkynols for the installation of spiro cores. The reaction has proven general with a range of readily accessible homopropargylic alcohols and diazo carbonyls to provide functionalized spiroether cores of bioactive scaffolds such as spirobarbiturates, spirooxindoles, and pseurotin natural products.

Adropin: An endocrine link between the biological clock and cholesterol homeostasis.

OBJECTIVE: Identify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function. METHODS: Associations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models. RESULTS: In humans, plasma adropin concentrations are inversely related to atherogenic LDL-cholesterol (LDL-C) levels in men (n = 349), but not in women (n = 401). Analysis of hepatic Enho expression in male mice suggests control by the biological clock. Expression is rhythmic, peaking during maximal food consumption in the dark correlating with transcriptional activation by RORα/γ. The nadir in the light phase coincides with the rest phase and repression by Rev-erb. Plasma adropin concentrations in nonhuman primates (rhesus monkeys) also exhibit peaks coinciding with feeding times (07:00 h, 15:00 h). The ROR inverse agonists SR1001 and the 7-oxygenated sterols 7-ß-hydroxysterol and 7-ketocholesterol, or the Rev-erb agonist SR9009, suppress ENHO expression in cultured human HepG2 cells. Consumption of high-cholesterol diets suppress expression of the adropin transcript in mouse liver. However, adropin over expression does not prevent hypercholesterolemia resulting from a high cholesterol diet and/or LDL receptor mutations. CONCLUSIONS: In humans, associations between plasma adropin concentrations and LDL-C suggest a link with hepatic lipid metabolism. Mouse studies suggest that the relationship between adropin and cholesterol metabolism is unidirectional, and predominantly involves suppression of adropin expression by cholesterol and 7-oxygenated sterols. Sensing of fatty acids, cholesterol and oxysterols by the RORα/γ ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism. Furthermore, the nuclear receptors RORα/γ and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism.

Melanocortin-3 receptors expressed in Nkx2.1(+ve) neurons are sufficient for controlling appetitive responses to hypocaloric conditioning.

Melanocortin-3 receptors (MC3R) have a contextual role in appetite control that is amplified with hypocaloric conditioning. C57BL/6J (B6) mice subjected to hypocaloric feeding schedules (HFS) exhibit compulsive behavioral responses involving food anticipatory activity (FAA) and caloric loading following food access. These homeostatic responses to calorie-poor environs are attenuated in B6 mice in which Mc3r transcription is suppressed by a lox-stop-lox sequence in the 5'UTR (Mc3rTB/TB). Here, we report that optimization of caloric loading in B6 mice subject to HFS, characterized by increased meal size and duration, is not observed in Mc3rTB/TB mice. Analysis of hypothalamic and neuroendocrine responses to HFS throughout the light-dark cycle suggests uncoupling of hypothalamic responses involving appetite-stimulating fasting-responsive hypothalamic neurons expressing agouti-related peptide (AgRP) and neuropeptide Y (Npy). Rescuing Mc3rs expression in Nkx2.1(+ve) neurons is sufficient to restore normal hypothalamic responses to negative energy balance. In addition, Mc3rs expressed in Nkx2.1(+ve) neurons are also sufficient to restore FAA and caloric loading of B6 mice subjected to HFS. In summary, MC3Rs expressed in Nkx2.1(+ve) neurons are sufficient to coordinate hypothalamic response and expression of compulsive behavioral responses involving meal anticipation and consumption of large meals during situations of prolonged negative energy balance.

Acute low-dose endotoxin treatment results in improved whole-body glucose homeostasis in mice.

BACKGROUND: Obese individuals present with an increased inflammatory tone as compared to healthy, normal-weight individuals, which is associated with insulin resistance. One factor hypothesized to contribute to increased inflammation in obese and diabetic states is elevated blood endotoxin levels, a condition known as metabolic endotoxemia. In non-obese and insulin sensitive individuals, circulating endotoxin concentrations fluctuate over the course of the day with elevations in the post-prandial state that return to baseline levels in the post-absorptive state. Evidence suggests that high-fat feeding alters these fluctuations causing endotoxin levels to remain high throughout the day. The effects of alterations in endotoxin levels on glucose metabolism are not clearly understood. PURPOSE/PROCEDURES: The goal of this study was to determine the effects of both short-term and long-term increases in endotoxin (lipopolysaccharide, LPS) of a low magnitude on the glucose tolerance and insulin signaling in a human primary cell line as well as the effects of short-term endotoxin treatments on glucose homeostasis in a C57/Bl6 mouse model. First, we tested the hypothesis that short-term low-dose endotoxin treatments would augment insulin signaling and glycogen synthesis while long-term treatments would be disruptive in the cell culture model. Second, we examined if these short-term low dose treatments of endotoxin would contribute to similar improvements in whole-body glucose homeostasis in a mouse model. MAIN FINDINGS: Contrary to our initial hypothesis, short-term endotoxin treatment had no effect on insulin signaling or glycogen synthesis, however long-term treatment indeed decreased glycogen synthesis (P<.05). Interestingly, short-term endotoxin treatment resulted in significant improvements in glucose homeostasis in the mouse model (P<.01); which is believed to be at least partly attributed to an inhibitory action of LPS on liver glucose production. CONCLUSIONS: This research shows that low-magnitude, short-term changes in LPS can have significant effects on whole body glucose metabolism and this likely occurs through its direct actions on the liver. Additional studies are necessary to understand the mechanisms responsible for altered glucose metabolism in response to low magnitude changes in LPS levels.

The Interaction of Learning Disability Status and Student Demographic Characteristics on Mathematics Growth.

This study examined mathematics achievement growth of students without disabilities (SWoD) and students with learning disabilities (LD) and tested whether growth and LD status interacted with student demographic characteristics. Growth was estimated in a statewide sample of 79,554 students over Grades 3 to 7. The LD group was significantly lower in achievement in each grade and had less growth than the SWoD group. We also found that student demographic characteristics were significantly related to mathematics growth, but only three demographic characteristics were statistically significant as interactions. We found that LD-SWoD differences at Grade 3 were moderated by student sex, while Black race/ethnicity and free or reduced lunch (FRL) status moderated LD-SWoD differences at all grades. These results provide practitioners and policy makers with more specific information about which particular LD students show faster or slower growth in mathematics. Our results show that simply including predictors in a regression equation may produce different results than direct testing of interactions and achievement gaps may be larger for some LD subgroups of students than previously reported.