Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells

Chronic hyperglycaemia causes a dramatic decrease in mitochondrial metabolism and insulin content in pancreatic β-cells. This underlies the progressive decline in β-cell function in diabetes. However, the molecular mechanisms by which hyperglycaemia produces these effects remain unresolved. Using isolated islets and INS-1 cells, we show here that one or more glycolytic metabolites downstream of phosphofructokinase and upstream of GAPDH mediates the effects of chronic hyperglycemia. This metabolite stimulates marked upregulation of mTORC1 and concomitant downregulation of AMPK. Increased mTORC1 activity causes inhibition of pyruvate dehydrogenase which reduces pyruvate entry into the tricarboxylic acid cycle and partially accounts for the hyperglycaemia-induced reduction in oxidative phosphorylation and insulin secretion. In addition, hyperglycaemia (or diabetes) dramatically inhibits GAPDH activity, thereby impairing glucose metabolism. Our data also reveal that restricting glucose metabolism during hyperglycaemia prevents these changes and thus may be of therapeutic benefit. In summary, we have identified a pathway by which chronic hyperglycaemia reduces β-cell function

Beyond Prejudice as Simple Antipathy: Hostile and Benevolent Sexism Across Cultures

The authors argue that complementary hostile and benevolent componen:s of sexism exist ac ro.ss cultures. Male dominance creates hostile sexism (HS). but men's dependence on women fosters benevolent sexism (BS)-subjectively positive attitudes that put women on a pedestal but reinforce their subordination. Research with 15,000 men and women in 19 nations showed that (a) HS and BS are coherenl constructs th at correlate positively across nations, but (b) HS predicts the ascription of negative and BS the ascription of positive traits to women, (c) relative to men, women are more likely to reject HS than BS. especially when overall levels of sexism in a culture are high, and (d) national averages on BS and HS predict gender inequal ity across nations. These results challenge prevailing notions of prejudice as an antipathy in that BS (an affectionate, patronizing ideology) reflects inequality and is a cross-culturally pervasive complement to HS

Reelin regulates the maturation of dendritic spines, synaptogenesis and glial ensheathment of newborn granule cells

The Reelin pathway is essential for both neural migration and for the development and maturation of synaptic connections. However, its role in adult synaptic formation and remodeling is still being investigated. Here, we investigated the impact of the Reelin/Dab1 pathway on the synaptogenesis of newborn granule cells (GCs) in the young-adult mouse hippocampus. We show that neither Reelin overexpression nor the inactivation of its intracellular adapter, Dab1, substantially alters dendritic spine numbers in these neurons. In contrast, 3D-electron microscopy (focused ion beam milling/scanning electron microscope) revealed that dysregulation of the Reelin/Dab1 pathway leads to both transient and permanent changes in the types and morphology of dendritic spines, mainly altering mushroom, filopodial, and branched GC spines. We also found that the Reelin/Dab1 pathway controls synaptic configuration of presynaptic boutons in the dentate gyrus, with its dysregulation leading to a substantial decrease in multi-synaptic bouton innervation. Lastly, we show that the Reelin/Dab1 pathway controls astroglial ensheathment of synapses. Thus, the Reelin pathway is a key regulator of adult-generated GC integration, by controlling dendritic spine types and shapes, their synaptic innervation patterns, and glial ensheathment. These findings may help to better understanding of hippocampal circuit alterations in neurological disorders in which the Reelin pathway is implicated. Significance Statement: The extracellular protein Reelin has an important role in neurological diseases, including epilepsy, Alzheimer's disease and psychiatric diseases, targeting hippocampal circuits. Here we address the role of Reelin in the development of synaptic contacts in adult-generated granule cells (GCs), a neuronal population that is crucial for learning and memory and implicated in neurological and psychiatric diseases. We found that the Reelin pathway controls the shapes, sizes, and types of dendritic spines, the complexity of multisynaptic innervations and the degree of the perisynaptic astroglial ensheathment that controls synaptic homeostasis. These findings show a pivotal role of Reelin in GC synaptogenesis and provide a foundation for structural circuit alterations caused by Reelin deregulation that may occur in neurological and psychiatric disorders

Application of at-line two-dimensional liquid chromatography–mass spectrometry for identification of small hydrophilic angiotensin I-inhibiting peptides in milk hydrolysates

A two-dimensional chromatographic method with mass spectrometric detection has been developed for identification of small, hydrophilic angiotensin I-inhibiting peptides in enzymatically hydrolysed milk proteins. The method involves the further separation of the poorly retained hydrophilic fraction from a standard C18 reversed-phase column on a hydrophilic interaction liquid chromatography (HILIC) column. The latter column is specifically designed for the separation of hydrophilic compounds. Narrow fractions collected from the HILIC column were analysed for their angiotensin I-converting enzyme (ACE) inhibiting potential in an at-line assay. Fractions showing significant inhibition of ACE were analysed by LC–MS for structure elucidation. With this method the main peptides responsible for ACE-inhibition in the hydrophilic part of a milk hydrolysate could be determined. The ACE-inhibiting peptides RP, AP, VK, EK, and EW explained more than 85% of ACE-inhibition by the hydrophilic fraction

What are the beliefs of pediatricians and dietitians regarding complementary food introduction to prevent allergy?

<p>Abstract</p> <p>Background</p> <p>The timing of complementary food introduction is controversial. Providing information on the timing of dietary introduction is crucial to the primary prevention of food allergy. The American Academy of Pediatrics offers dietary recommendations that were updated in 2008.</p> <p>Objective</p> <p>Identify the recommendations that general pediatricians and registered dietitians provide to parents and delineate any differences in counselling.</p> <p>Methods</p> <p>A 9-item survey was distributed to pediatricians and dietitians online and by mail. Information on practitioner type, gender, length of practice and specific recommendations regarding complementary food introduction and exposure was collected.</p> <p>Results</p> <p>181 surveys were returned with a 54% response rate from pediatricians. It was not possible to calculate a meaningful dietitian response rate due to overlapping email databases. 52.5% of all respondents were pediatricians and 45.9% were dietitians. The majority of pediatricians and dietitians advise mothers that peanut abstinence during pregnancy and lactation is unnecessary. Dietitians were more likely to counsel mothers to breastfeed their infants to prevent development of atopic dermatitis than pediatricians. Hydrolyzed formulas for infants at risk of developing allergy were the top choice of formula amongst both practitioners. For food allergy prevention, pediatricians were more likely to recommend delayed introduction of peanut and egg, while most dietitians recommended no delay in allergenic food introduction.</p> <p>Conclusions</p> <p>In the prophylaxis of food allergy, pediatricians are less aware than dietitians of the current recommendation that there is no benefit in delaying allergenic food introduction beyond 4 to 6 months. More dietitians than pediatricians believe that breastfeeding decreases the risk of atopic dermatitis. Practitioners may benefit from increased awareness of current guidelines.</p

Power system dynamic state estimation: motivations, definitions, methodologies, and future work

This paper summarizes the technical activities of the Task Force on Power System Dynamic State and Parameter Estimation. This Task Force was established by the IEEE Working Group on State Estimation Algorithms to investigate the added benefits of dynamic state and parameter estimation for the enhancement of the reliability, security, and resilience of electric power systems. The motivations and engineering values of dynamic state estimation (DSE) are discussed in detail. Then, a set of potential applications that will rely on DSE is presented and discussed. Furthermore, a unified framework is proposed to clarify the important concepts related to DSE, forecasting-aided state estimation, tracking state estimation, and static state estimation. An overview of the current progress in DSE and dynamic parameter estimation is provided. The paper also provides future research needs and directions for the power engineering community

Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis

Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine whether gain of function in FAO (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1A (CPT1A) in TECs. Cpt1a-knockin (CPT1A-KI) mice subjected to 3 models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy [FAN], and adenine-induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted proinflammatory response, and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restored oxidative metabolism and mitochondrial number and enhanced bioenergetics, increasing palmitate oxidation and ATP levels, changes that were also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients showed decreased CPT1 levels and increased accumulation of short- and middle-chain acylcarnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD