7 research outputs found
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IDOL regulates systemic energy balance through control of neuronal VLDLR expression.
Liver X receptors limit cellular lipid uptake by stimulating the transcription of Inducible Degrader of the LDL Receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose, endothelium, intestine, skeletal muscle), but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to control of metabolism. Finally, we identify VLDLR rather than LDLR as the primary mediator of IDOL effects on energy balance. These studies identify a role for the neuronal IDOL-VLDLR pathway in metabolic homeostasis and diet-induced obesity
Whiteness and diasporic Irishness: nation, gender and class
Whiteness is often detached from the notion of diaspora in the recent flurry of interest in the phenomenon, yet it is a key feature of some of the largest and oldest displacements. This paper explores the specific contexts of white racial belonging and status over two centuries in two main destinations of the Irish diaspora, the USA and Britain. Its major contribution is a tracing of the untold story of âHow the Irish became white in Britainâ to parallel and contrast with the much more fully developed narrative in the USA. It argues that, contrary to popular belief, the racialisation of the Irish in England did not fade away at the end of the nineteenth century but became transmuted in new forms which have continued to place the âwhiteâ Irish outside the boundaries of the English nation. These have been strangely ignored by social scientists, who conflate Irishness and working-class identities in England without acknowledging the distinctive contribution of Irish backgrounds to constructions of class difference. Gender locates Irish women and men differently in relation to these class positions, for example allowing mothers to be blamed for the perpetuation of the underclass. Class and gender are also largely unrecognised dimensions of Irish ethnicity in the USA, where the presence of âpoor whiteâ neighbourhoods continues to challenge the iconic story of Irish upward mobility. Irishness thus remains central to the construction of mainstream âwhiteâ identities in both the USA and Britain into the twenty-first century
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Sequential regression and simulation: a method for estimating causal effects from heterogeneous clinical trials without a common control group
BackgroundThe advent of clinical trial data sharing platforms has created opportunities for making new discoveries and answering important questions using already collected data. However, existing methods for meta-analyzing these data require the presence of shared control groups across studies, significantly limiting the number of questions that can be confidently addressed. We sought to develop a method for meta-analyzing potentially heterogeneous clinical trials even in the absence of a common control group.MethodsThis work was conducted within the context of a broader effort to study comparative efficacy in Crohn's disease. Following a search of clnicaltrials.gov we obtained access to the individual participant data from nine trials of FDA-approved treatments in Crohn's Disease (Nâ=â3392). We developed a method involving sequences of regression and simulation to separately model the placebo- and drug-attributable effects, and to simulate head-to-head trials against an appropriately normalized background. We validated this method by comparing the outcome of a simulated trial comparing the efficacies of adalimumab and ustekinumab against the recently published results of SEAVUE, an actual head-to-head trial of these drugs. This study was pre-registered on PROSPERO (#157,827) prior to the completion of SEAVUE.ResultsUsing our method of sequential regression and simulation, we compared the week eight outcomes of two virtual cohorts subject to the same patient selection criteria as SEAVUE and treated with adalimumab or ustekinumab. Our primary analysis replicated the corresponding published results from SEAVUE (pâ=â0.9). This finding proved stable under multiple sensitivity analyses.ConclusionsThis new method may help reduce the bias of individual participant data meta-analyses, expand the scope of what can be learned from these already-collected data, and reduce the costs of obtaining high-quality evidence to guide patient care