Toward a Grand Vision: Early Implementation of California's Local Control Funding Formula

California has taken the first steps down an historic path that fundamentally alters how its public schools are financed, education decisions are made, and traditionally underserved students' needs are met. The Local Control Funding Formula (LCFF), passed with bipartisan legislative support and signed into law by Governor Jerry Brown on July 1, 2013, represents the most comprehensive transformation of California's school funding system in 40 years. The LCFF significantly loosens the reins of state control over education. It all but eliminates categorical funding streams, subsituting a base of funding for all distraicts and adding dollars for low-income students, English language learners, and foster youth. The new system empowers school districts to determine how to allocate their dollars to best meet the needs of their students. Finally, by requiring all districts to engage parents and other education stakeholders in decisions about how to spend newly flexible funds, the LCFF represents a remarkable experiment in local democracy

ATX-101 for reduction of submental fat: A phase III randomized controlled trial

BackgroundATX-101, an injectable form of deoxycholic acid, causes adipocytolysis when injected subcutaneously into fat.ObjectiveWe sought to evaluate the efficacy and safety of ATX-101.MethodsIn this phase III trial (REFINE-2), adults dissatisfied with their moderate or severe submental fat (SMF) were randomized to ATX-101 or placebo. Coprimary end points, evaluated at 12 weeks after last treatment, were composite improvements of 1 or more grades and 2 or more grades in SMF observed on both the validated Clinician- and Patient-Reported SMF Rating Scales. Other end points included magnetic resonance imaging–based assessment of submental volume, assessment of psychological impact of SMF, and additional patient-reported outcomes.ResultsAmong those treated with ATX-101 or placebo (n = 258/treatment group), 66.5% versus 22.2%, respectively, achieved a composite improvement of 1 or more grades (Mantel-Haenszel risk ratio 2.98; 95% confidence interval 2.31-3.85) and 18.6% versus 3.0% achieved a composite improvement of 2 or more grades in SMF (Mantel-Haenszel risk ratio 6.27; 95% confidence interval 2.91-13.52; P < .001 for both). Those treated with ATX-101 were more likely to achieve submental volume reduction confirmed by magnetic resonance imaging, greater reduction in psychological impact of SMF, and satisfaction with treatment (P < .001 for all). Overall, 85.7% of adverse events in the ATX-101 group and 76.9% in the placebo group were localized to the injection site.LimitationsFollow-up was limited to 44 weeks.ConclusionATX-101 is an alternative treatment for SMF reduction

Insulin Tolerance Test under Anaesthesia to Measure Tissue-specific Insulin-stimulated Glucose Disposal.

Insulin resistance is a pathophysiological state defined by impaired responses to insulin and is a risk factor for several metabolic diseases, most notably type 2 diabetes. Insulin resistance occurs in insulin target tissues including liver, adipose and skeletal muscle. Methods such as insulin tolerance tests and hyperinsulinaemic-euglycaemic clamps permit assessment of insulin responses in specific tissues and allow the study of the progression and causes of insulin resistance. Here we detail a protocol for assessing insulin action in adipose and muscle tissues in anesthetized mice administered with insulin intravenously

Heterogeneity in Preferences towards Complexity

We analyze lottery-choice data in a way that separately estimates the effects of risk aversion and complexity aversion. Complexity is represented by the number of different outcomes in the lottery. A finite mixture random effects model is estimated which assumes that a proportion of the population are complexity-neutral. We find that around 33% of the population are complexity-neutral, around 50% complexity-averse, and the remaining 17% are complexity-loving. Subjects who do react to complexity appear to have a bias towards complexity aversion at the start of the experiment, but complexity aversion reduces with experience, to the extent that the average subject is (almost) complexity-neutral by the end of the experiment. Complexity aversion is found to increase with age and to be higher for non-UK students than for UK students. We also find some evidence that, when evaluating complex lotteries, subjects perceive probabilities in accordance with Prospective Reference Theory

Akt phosphorylates insulin receptor substrate to limit PI3K-mediated PIP3 synthesis.

The phosphoinositide 3-kinase (PI3K)-Akt network is tightly controlled by feedback mechanisms that regulate signal flow and ensure signal fidelity. A rapid overshoot in insulin-stimulated recruitment of Akt to the plasma membrane has previously been reported, which is indicative of negative feedback operating on acute timescales. Here, we show that Akt itself engages this negative feedback by phosphorylating insulin receptor substrate (IRS) 1 and 2 on a number of residues. Phosphorylation results in the depletion of plasma membrane-localised IRS1/2, reducing the pool available for interaction with the insulin receptor. Together these events limit plasma membrane-associated PI3K and phosphatidylinositol (3,4,5)-trisphosphate (PIP3) synthesis. We identified two Akt-dependent phosphorylation sites in IRS2 at S306 (S303 in mouse) and S577 (S573 in mouse) that are key drivers of this negative feedback. These findings establish a novel mechanism by which the kinase Akt acutely controls PIP3 abundance, through post-translational modification of the IRS scaffold

Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance.

Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance

Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance

Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance

Insulin signaling requires glucose to promote lipid anabolism in adipocytes

Adipose tissue is essential for metabolic homeostasis, balancing lipid storage and mobilization based on nutritional status. This is coordinated by insulin, which triggers kinase signaling cascades to modulate numerous metabolic proteins, leading to increased glucose uptake and anabolic processes like lipogenesis. Given recent evidence that glucose is dispensable for adipocyte respiration, we sought to test whether glucose is necessary for insulin-stimulated anabolism. Examining lipogenesis in cultured adipocytes, glucose was essential for insulin to stimulate the synthesis of fatty acids and glyceride–glycerol. Importantly, glucose was dispensable for lipogenesis in the absence of insulin, suggesting that distinct carbon sources are used with or without insulin. Metabolic tracing studies revealed that glucose was required for insulin to stimulate pathways providing carbon substrate, NADPH, and glycerol 3-phosphate for lipid synthesis and storage. Glucose also displaced leucine as a lipogenic substrate and was necessary to suppress fatty acid oxidation. Together, glucose provided substrates and metabolic control for insulin to promote lipogenesis in adipocytes. This contrasted with the suppression of lipolysis by insulin signaling, which occurred independently of glucose. Given previous observations that signal transduction acts primarily before glucose uptake in adipocytes, these data are consistent with a model whereby insulin initially utilizes protein phosphorylation to stimulate lipid anabolism, which is sustained by subsequent glucose metabolism. Consequently, lipid abundance was sensitive to glucose availability, both during adipogenesis and in Drosophila flies in vivo. Together, these data highlight the importance of glucose metabolism to support insulin action, providing a complementary regulatory mechanism to signal transduction to stimulate adipose anabolism