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"Johnson, James"
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On the causal relationships between hyperinsulinaemia, insulin resistance, obesity and dysglycaemia in type 2 diabetes
Hundreds of millions of people are affected by hyperinsulinaemia, insulin resistance, obesity and the dysglycaemia that mark a common progression from metabolic health to type 2 diabetes. Although the relative contribution of these features and the order in which they appear may differ between individuals, the common clustering and seemingly progressive nature of type 2 diabetes aetiology has guided research and clinical practice in this area for decades. At the same time, lively debate around the causal relationships between these features has continued, as new data from human trials and highly controlled animal studies are presented. This ‘For debate’ article was prompted by the review in Diabetologia by Esser, Utzschneider and Kahn (https://doi.org/10.1007/s00125-020-05245-x), with the purpose of reviewing established and emerging data that provide insight into the relative contributions of hyperinsulinaemia and impaired glucose-stimulated insulin secretion in progressive stages between health, obesity and diabetes. It is concluded that these beta cell defects are not mutually exclusive and that they are both important, but at different stages.
Journal Article
Models-As-Fables: An Alternative to the Standard Rationale for Using Formal Models in Political Science
Political scientists invoke the standard rationale to justify making and using formal models. It goes like this: (1) we rely on formal models to generate predictions, (2) we treat these predictions as empirical hypotheses, and (3) we seek to test these hypotheses against evidence derived from the “real world.” I show that this interpretation of formal models as directly empirical is inadequate just insofar as it fails to capture the way we actually use them. I then offer an alternative rationale for making and using formal models. Specifically, I argue that we use models, like we use fables, for conceptual purposes.
Journal Article
B12 cofactors directly stabilize an mRNA regulatory switch
The crystal structures of two different cobalamin (vitamin B
12
)-binding riboswitches are determined; the structures reveal how cobalamin facilitates interdomain interactions to regulate gene expression.
An alternative structure for riboswitches
Small metabolites and ligands can affect gene expression by binding to a structured part of an RNA known as a riboswitch. Although the structures of many riboswitch receptor domains have been solved, the complete riboswitch structure with regulatory domain had not been determined. Robert Batey and colleagues have now solved the structure of two different cobalamin (vitamin B
12
) riboswitches that include the downstream regulatory domain. Ligand recognition occurs largely as a result of shape complementarity, rather than the more typical hydrogen bonding.
Structures of riboswitch receptor domains bound to their effector have shown how messenger RNAs recognize diverse small molecules, but mechanistic details linking the structures to the regulation of gene expression remain elusive
1
,
2
. To address this, here we solve crystal structures of two different classes of cobalamin (vitamin B
12
)-binding riboswitches that include the structural switch of the downstream regulatory domain. These classes share a common cobalamin-binding core, but use distinct peripheral extensions to recognize different B
12
derivatives. In each case, recognition is accomplished through shape complementarity between the RNA and cobalamin, with relatively few hydrogen bonding interactions that typically govern RNA–small molecule recognition. We show that a composite cobalamin–RNA scaffold stabilizes an unusual long-range intramolecular kissing-loop interaction that controls mRNA expression. This is the first, to our knowledge, riboswitch crystal structure detailing how the receptor and regulatory domains communicate in a ligand-dependent fashion to regulate mRNA expression.
Journal Article
A profane wit : the life of John Wilmot, Earl of Rochester
\"Of the glittering, licentious court around King Charles II, John Wilmot the second Earl of Rochester was the most notorious. Simultaneously admired and vilified, he personified the rake-hell. Libertine, profane, promiscuous, he shocked his pious contemporaries with his doubts about religion and his blunt verses that dealt with sex or vicious satiric assaults on the high and mighty of the court. This account of Rochester and his times provides the facts behind his legendary reputation as a rake and his deathbed repentance. However, it also demonstrates that he was a loving if unfaithful husband, a devoted father, a loyal friend, a serious scholar, a social critic, and an aspiring patriot.\"--Jacket.
Urban-Rural Differences in Childhood and Adolescent Obesity in the United States: A Systematic Review and Meta-Analysis
Abstract
Background:
A systematic literature review and subsequent meta-analysis were performed to investigate differences in childhood obesity between urban and rural areas in the United States.
Methods:
A search of published studies comparing childhood obesity in urban and rural settings was undertaken by probing PubMed and Cumulative Index to Nursing and Allied Health Literature (CINAHL) for articles that met predetermined inclusion criteria. A subsequent meta-analysis was conducted to determine the combined effect size and significance of differences in childhood obesity between urban and rural areas.
Results:
Ten studies were identified for systematic review, five of which contributed to the meta-analysis. All but one study suggested that residence in rural areas was associated with higher prevalence or increased odds of childhood obesity, compared to children living in urban areas. A meta-analysis of 74,168 pooled participants ages 2–19 found that rural children have 26% greater odds of obesity, compared to urban children (odds ratio=1.26; 95% confidence interval, 1.21–1.32).
Conclusions:
Obesity rates are higher among rural children than urban children in the United States. To ensure successful targeted interventions and effective resource allocation, practitioners and policy makers alike should be cognizant of this disparity in childhood obesity.
Journal Article
White House burning : our national debt and why it matters to you
\"America is mired in debt--more than $30,000 for every man, woman, and child. Bitter fighting over deficits, taxes, and spending bedevils Washington, D.C., even as partisan gridlock has brought the government to the brink of default. Yet the more politicians on both sides of the aisle rant and the citizenry fumes, the more things seem to remain the same. In White House Burning, Simon Johnson and James Kwak--authors of the national best seller 13 Bankers and cofounders of The Baseline Scenario, a widely cited blog on economics and public policy--demystify the national debt, explaining whence it came and, even more important, what it means to you and to future generations. They tell the story of the Founding Fathers' divisive struggles over taxes and spending. They chart the rise of the almighty dollar, which makes it easy for the United States to borrow money. They account for the debasement of our political system in the 1980s and 1990s, which produced today's dysfunctional and impotent Congress. And they show how, if we persist on our current course, the national debt will harm ordinary Americans by reducing the number of jobs, lowering living standards, increasing inequality, and forcing a sudden and drastic reduction in the government services we now take for granted. But Johnson and Kwak also provide a clear and compelling vision for how our debt crisis can be solved while strengthening our economy and preserving the essential functions of government. They debunk the myth that such crucial programs as Social Security and Medicare must be slashed to the bone. White House Burning looks squarely at the burgeoning national debt and proposes to defuse its threat to our wellbeing without forcing struggling middle-class families and the elderly into poverty. Carefully researched and informed by the same compelling storytelling and lucid analysis as 13 Bankers, White House Burning is an invaluable guide to the central political and economic issue of our time. It is certain to provoke vigorous debate\"-- Provided by publisher.
Book
Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus
Diabetes mellitus is characterized by the failure of insulin-secreting pancreatic β-cells (or β-cell death) due to either autoimmunity (type 1 diabetes mellitus) or failure to compensate for insulin resistance (type 2 diabetes mellitus; T2DM). In addition, mutations of critical genes cause monogenic diabetes. The endoplasmic reticulum (ER) is the primary site for proinsulin folding; therefore, ER proteostasis is crucial for both β-cell function and survival under physiological and pathophysiological challenges. Importantly, the ER is also the major intracellular Ca2+ storage organelle, generating Ca2+ signals that contribute to insulin secretion. ER stress is associated with the pathogenesis of diabetes mellitus. In this Review, we summarize the mutations in monogenic diabetes that play causal roles in promoting ER stress in β-cells. Furthermore, we discuss the possible mechanisms responsible for ER proteostasis imbalance with a focus on T2DM, in which both genetics and environment are considered important in promoting ER stress in β-cells. We also suggest that controlled insulin secretion from β-cells might reduce the progression of a key aspect of the metabolic syndrome, namely nonalcoholic fatty liver disease. Finally, we evaluate potential therapeutic approaches to treat T2DM, including the optimization and protection of functional β-cell mass in individuals with T2DM.This Review summarizes the mechanisms by which endoplasmic reticulum (ER) stress contributes to β-cell dysfunction and cell death in monogenic diabetes and type 2 diabetes mellitus (T2DM). In addition, the potential therapeutic strategies for T2DM and metabolic syndrome that target ER stress in β-cells are discussed.
Journal Article