The linear ubiquitin assembly complex (LUBAC) is an essential component of the innate and adaptive immune system. Modification of cellular substrates with linear polyubiquitin chains is a key regulatory step in signal transduction that impacts cell death and inflammatory signaling downstream of various innate immunity receptors. Loss-of-function mutations in the LUBAC components HOIP and HOIL-1 yield a systemic autoinflammatory disease in humans, whereas their genetic ablation is embryonically lethal in mice. Deficiency of the LUBAC adaptor protein Sharpin results in a multi-organ inflammatory disease in mice characterized by chronic proliferative dermatitis (cpdm), which is propagated by TNFR1-induced and RIPK1-mediated keratinocyte cell death. We have previously shown that caspase-1 and -11 promoted the dermatitis pathology of cpdm mice and mediated cell death in the skin. Here, we describe a reciprocal regulation of caspase-1 and LUBAC activities in keratinocytes. We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. HOIP processing impeded substrate ubiquitination in the NF-κB pathway and resulted in enhanced apoptosis. These results highlight a regulatory mechanism underlying efficient apoptosis in keratinocytes and provide further evidence of a cross-talk between inflammatory and cell death pathways.

Tammie M. Johnson
Jan 1, 2010; 23:41-46
Feature Articles

Due to their peculiar mechanism of action, the evaluation of radiological response to immune checkpoint inhibitors (ICI) presents many challenges in solid tumors. We aimed to compare the evaluation of first response to Nivolumab by means of CT-based criteria with respect to fluorodeoxyglucose positron emission tomography (FDG-PET) response criteria in non-small-cell lung cancer (NSCLC) patients. Methods: 72 patients with advanced NSCLC were recruited in a mono-institutional ancillary trial within the expanded access program (EAP; NCT02475382) for Nivolumab. Patients underwent CT scan and FDG-PET at baseline and after 4 cycles (first evaluation). In case of progressive disease (PD), an additional evaluation was performed after two further cycles in order to confirm progression. We evaluated the response to treatment with CT scan by means of response evaluation criteria in solid tumors (RECIST) 1.1 and Immuno-related Response Criteria (IrRC) and with FDG-PET by means of PERCIST and immunotherapy-modified-PERCIST (imPERCIST) criteria. The concordance between CT- and PET-based criteria and the capability of each method to predict overall survival (OS) were evaluated. Results: 48/72 patients were evaluable for first response assessment with both PET- and CT-based criteria. We observed low concordance between CT- and PET-based criteria (Kappa value of 0.346 and 0.355 and Kappa value of 0.128 and 0.198 between PERCIST and imPERCIST versus RECIST and irRC respectively). Looking at OS, IrRC were more reliable to distinguish responders from non-responders. However thanks to the prognostic value of partial metabolic response assessed by both PERCIST and Immuno-PERCIST, PET-based response maintained prognostic significant in patients classified as progressive disease on the basis of irRC. Conclusion: Even though the present study did not support the routine use of FDG-PET in the general population of NSCLC patients treated with ICI, it suggests the added prognostic value of the metabolic response assessment, potentially improving the therapeutic decision-making.

2 March 2020

Shwetha K. Shetty
Apr 1, 2020; 61:546-559
Methods

It's a pop culture episode this week as we do a deep dive into dystopian fiction. Scott Carey is your host as he chats to Dominic Preston and Tamlin Magee about the best novels, films, TV shows and video games set in dystopian universes.

We talk about how the world is closer to fiction than ever before, and how this impacts the way we think about fictional dystopias, and end on a positive note to discuss our favourite utopian fiction too.

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No abstract

The hydrolysis of triglycerides in triglyceride-rich lipoproteins by LPL is critical for the delivery of triglyceride-derived fatty acids to tissues, including heart, skeletal muscle, and adipose tissues. Physiologically active LPL is normally bound to the endothelial cell protein glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), which transports LPL across endothelial cells, anchors LPL to the vascular wall, and stabilizes LPL activity. Disruption of LPL-GPIHBP1 binding significantly alters triglyceride metabolism and lipid partitioning. In this study, we modified the NanoLuc® Binary Technology split-luciferase system to develop a novel assay that monitors the binding of LPL to GPIHBP1 on endothelial cells in real time. We validated the specificity and sensitivity of the assay using endothelial lipase and a mutant version of LPL and found that this assay reliably and specifically detected the interaction between LPL and GPIHBP1. We then interrogated various endogenous and exogenous inhibitors of LPL-mediated lipolysis for their ability to disrupt the binding of LPL to GPIHBP1. We found that angiopoietin-like (ANGPTL)4 and ANGPTL3-ANGPTL8 complexes disrupted the interactions of LPL and GPIHBP1, whereas the exogenous LPL blockers we tested (tyloxapol, poloxamer-407, and tetrahydrolipstatin) did not. We also found that chylomicrons could dissociate LPL from GPIHBP1 and found evidence that this dissociation was mediated in part by the fatty acids produced by lipolysis. These results demonstrate the ability of this assay to monitor LPL-GPIHBP1 binding and to probe how various agents influence this important complex.

The pancreatic islet is a highly-vascularized endocrine micro-organ. The unique architecture of rodent islets, a so-called core-mantle arrangement seen in 2D images, led researchers to seek functional implications for islet hormone secretion. Three models of islet blood flow were previously proposed, all based on the assumption that islet microcirculation occurs in an enclosed structure. Recent electrophysiological and molecular biological studies using isolated islets also presumed uni-directional flow. Using intravital analysis of the islet microcirculation in mice, we find that islet capillaries are continuously integrated to those in the exocrine pancreas, which makes the islet circulation rather open, not self-contained. Similarly in human islets, the capillary structure was integrated with pancreatic microvasculature in its entirety. Thus, islet microcirculation has no relation to islet cytoarchitecture, which explains its well-known variability throughout species. Furthermore, tracking fluorescent-labeled red blood cells at the endocrine-exocrine interface revealed bi-directional blood flow, with similar variability in blood flow speed in both the intra- and extra-islet vasculature. To date, the endocrine and exocrine pancreas have been studied separately by different fields of investigators. We propose that the open circulation model physically links both endocrine and exocrine parts of the pancreas as a single organ through the integrated vascular network.

Juli Bai
Jun 1, 2019; 68:1099-1108
Perspectives in Diabetes

Giants president of baseball operations Farhan Zaidi would prefer to stay mum when it comes to his forays into the free-agent market, but he realized there was no use in attempting to obscure the club's meeting with superstar Bryce Harper in Las Vegas earlier this week.

Invitation Only Research Event

Event participants

Sir Simon Fraser, Managing Partner of Flint Global; Deputy Chairman, Chatham House
Chair: Marianne Schneider-Petsinger, Senior Research Fellow, US and the Americas Programme, Chatham House

It took only two words for Alex Bregman to send 9-year-old Jax Nystrom into a frenzy, but this kind of reaction -- young people freaking out at the slightest bit of attention from him -- has become commonplace for the Astros' All-Star third baseman.

Markus Tiedge
Nov 1, 1997; 46:1733-1742
Original Article

Steven E Kahn
Nov 1, 1993; 42:1663-1672
Original Article

Development assistance may be a blunt tool for reshaping migration patterns—and indeed one that could increase flows over the short term. Shifting the focus away from increasing individuals’ skills and assets toward investments in the broader economic or governance structures that are a prerequisite for growth and stability may offer more alternatives to emigration in the long run.

Milwaukee Bucks star Giannis Antetokounmpo has apologized after he said someone hacked his Twitter account to send inappropriate tweets about several athletes, including LeBron James, Stephen Curry and Kobe Bryant.

Joseph Largay
Jan 1, 2012; 30:25-26
Case Studies

OBJECTIVE

To analyze the differences in health care costs according to glycemic control in people with type 2 diabetes.

Animal rescuers in Britain said a fox was rescued from the narrow gap between the external walls of a house and its garage.

Robert A. Ritzel
Mar 1, 2006; 29:717-718
BR Pathophysiology/Complications

OBJECTIVE

The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region.

Greater compliance with dietary guidelines may reduce the chance of untreated caries in adults, according to a study published in the February issue of The Journal of the American Dental Association.

The Dental Quality Alliance will help dentists learn more about how quality measure domains can be best used to drive quality improvement at the practice level through a free webinar in March.

Circulating levels of perfluorodecanoic acid, a type of perfluoroalkyl acid, may be associated with dental caries in children, according to a study published in the fall 2019 issue of the Journal of Public Health Dentistry.

This webinar, organized by MPI and the Zolberg Institute on Migration and Mobility at The New School, discussed the state of play around the globe surrounding COVID-19 and examined where migration management and enforcement tools may be useful and where they may be ill-suited to advancing public health goals. 

President Obama appears serenely confident as he goes about fixing the worst global financial crisis in more than half a century while simultaneously revamping the national health-care system, changing the way Americans use and produce energy, giving tax breaks to 95 percent of all households, an...

OBJECTIVE

We sought to confirm a bidirectional association between severe hypoglycemic events (SHEs) and cardiovascular (CV) event risk and to characterize individuals at dual risk.

OBJECTIVE

This study aimed to reveal the associations between the risk of new-onset type 2 diabetes and the duration of antidepressant use and the antidepressant dose, and between antidepressant use after diabetes onset and clinical outcomes.

OBJECTIVE

To investigate the role of epigenetics in statins’ diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood.

This webinar, organized by MPI and the Zolberg Institute on Migration and Mobility at The New School, discussed migration policy responses around the globe in response to the COVID-19 pandemic, and examined where migration management and enforcement tools may be useful and where they may be ill-suited to advancing public health goals. 

Michael Sentance, who would oversee ESSA implementation as state superintendent, is less than a year into the job and under fire by the state board for his communication and leadership style.

A statewide survey of educators in Tennessee provides critical insights into connections that exist between standards, curriculum, professional development, and ultimately student success.

Australian author Trish Morey returns with a compelling and moving story about broken friendships and the rocky road of forgiveness. Coming home was never going to be easy ... With a failed marriage behind her, and her career dreams in tatters, Sarah returns home to Lord Howe Island to run the family store. Paradise to most, Lord Howe is the last place Sarah wants to be, trapped on an island with her two ex-best friends, Floss and Jules. Floss has the life she always wanted: married to her high school sweetheart, Andy, with five gorgeous children. But something is missing from her marriage. And now she has a secret that threatens to tear her happy family apart, and the only person she can talk to is the woman who pushed her away. For Jules, forgetting the past is impossible. Her four-year-old daughter is an everyday reminder of the friendships she has lost. But when a discovery turns her life upside down, she knows this is an opportunity to set things right. This summer, can these women overcome the pain of the past and find their way back to the friendship they once had?

Germans -- Victoria -- History.

London (5 Haymarket) : Published ... by J. Hogarth, June 1 1849.

[London] : [publisher not identified], [2019]

Zhonghua Liu, Ian Barnett, Xihong Lin.

Source: The Annals of Applied Statistics, Volume 14, Number 1, 433--451.

Abstract:
Principal component analysis (PCA) is a popular method for dimension reduction in unsupervised multivariate analysis. However, existing ad hoc uses of PCA in both multivariate regression (multiple outcomes) and multiple regression (multiple predictors) lack theoretical justification. The differences in the statistical properties of PCAs in these two regression settings are not well understood. In this paper we provide theoretical results on the power of PCA in genetic association testings in both multiple phenotype and SNP-set settings. The multiple phenotype setting refers to the case when one is interested in studying the association between a single SNP and multiple phenotypes as outcomes. The SNP-set setting refers to the case when one is interested in studying the association between multiple SNPs in a SNP set and a single phenotype as the outcome. We demonstrate analytically that the properties of the PC-based analysis in these two regression settings are substantially different. We show that the lower order PCs, that is, PCs with large eigenvalues, are generally preferred and lead to a higher power in the SNP-set setting, while the higher-order PCs, that is, PCs with small eigenvalues, are generally preferred in the multiple phenotype setting. We also investigate the power of three other popular statistical methods, the Wald test, the variance component test and the minimum $p$-value test, in both multiple phenotype and SNP-set settings. We use theoretical power, simulation studies, and two real data analyses to validate our findings.

Christian Gaser
Oct 8, 2003; 23:9240-9245
BehavioralSystemsCognitive

MN Shadlen
Feb 15, 1996; 16:1486-1510
Articles

M Niethammer
Apr 1, 1996; 16:2157-2163
Articles