Phospholipases A₂ (PLA₂s) catalyze hydrolysis of the sn-2 substituent from glycerophospholipids to yield a free fatty acid (i.e., arachidonic acid), which can be metabolized to pro- or anti-inflammatory eicosanoids. Macrophages modulate inflammatory responses and are affected by Ca²⁺-independent phospholipase A₂ (PLA₂)β (iPLA₂β). Here, we assessed the link between iPLA₂β-derived lipids (iDLs) and macrophage polarization. Macrophages from WT and KO (iPLA₂β–/–) mice were classically M1 pro-inflammatory phenotype activated or alternatively M2 anti-inflammatory phenotype activated, and eicosanoid production was determined by ultra-performance LC ESI-MS/MS. As a genotypic control, we performed similar analyses on macrophages from RIP.iPLA₂β.Tg mice with selective iPLA₂β overexpression in β-cells. Compared with WT, generation of select pro-inflammatory prostaglandins (PGs) was lower in iPLA₂β^–/–, and that of a specialized pro-resolving lipid mediator (SPM), resolvin D2, was higher; both changes are consistent with the M2 phenotype. Conversely, macrophages from RIP.iPLA₂β.Tg mice exhibited an opposite landscape, one associated with the M1 phenotype: namely, increased production of pro-inflammatory eicosanoids (6-keto PGF₁α, PGE₂, leukotriene B₄) and decreased ability to generate resolvin D2. These changes were not linked with secretory PLA₂ or cytosolic PLA₂α or with leakage of the transgene. Thus, we report previously unidentified links between select iPLA₂β-derived eicosanoids, an SPM, and macrophage polarization. Importantly, our findings reveal for the first time that β-cell iPLA₂β-derived signaling can predispose macrophage responses. These findings suggest that iDLs play critical roles in macrophage polarization, and we posit that they could be targeted therapeutically to counter inflammation-based disorders.

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.

Acne is one of the most common dermatological conditions, but the details of its pathology are unclear, and current management regimens often have adverse effects. Cutibacterium acnes is known as a major acne-associated bacterium that derives energy from lipase-mediated sebum lipid degradation. C. acnes is commensal, but lipase activity has been observed to differ among C. acnes types. For example, higher populations of the type IA strains are present in acne lesions with higher lipase activity. In the present study, we examined a conserved lipase in types IB and II that was truncated in type IA C. acnes strains. Closed, blocked, and open structures of C. acnes ATCC11828 lipases were elucidated by X-ray crystallography at 1.6–2.4 Å. The closed crystal structure, which is the most common form in aqueous solution, revealed that a hydrophobic lid domain shields the active site. By comparing closed, blocked, and open structures, we found that the lid domain-opening mechanisms of C. acnes lipases (_CAlipases) involve the lid-opening residues, Phe-179 and Phe-211. To the best of our knowledge, this is the first structure-function study of _CAlipases, which may help to shed light on the mechanisms involved in acne development and may aid in future drug design.

Lipid droplets (LDs) are frequently increased when excessive lipid accumulation leads to cellular dysfunction. Distinct from mouse beta cells, LDs are prominent in human beta cells, however, the regulation of LD mobilization (lipolysis) in human beta cells remains unclear. We found that glucose increases lipolysis in non-diabetic human islets, but not in type 2 diabetic (T2D) islets, indicating dysregulation of lipolysis in T2D islets. Silencing adipose triglyceride lipase (ATGL) in human pseudoislets (shATGL) increased triglycerides, and the number and size of LDs indicating that ATGL is the principal lipase in human beta cells. In shATGL pseudoislets, biphasic glucose-stimulated insulin secretion (GSIS) and insulin secretion to IBMX and KCl were all reduced without altering oxygen consumption rate compared with scramble control. Like human islets, INS1 cells showed visible LDs, glucose responsive lipolysis, and impairment of GSIS after ATGL silencing. ATGL deficient INS1 cells and human pseudoislets showed reduced Stx1a, a key SNARE component. Proteasomal degradation of Stx1a was accelerated likely through reduced palmitoylation in ATGL deficient INS1 cells. Therefore, ATGL is responsible for LD mobilization in human beta cells and supports insulin secretion by stabilizing Stx1a. The dysregulated lipolysis may contribute to LD accumulation and beta cell dysfunction in T2D islets.

Lipid droplets (LDs) are frequently increased when excessive lipid accumulation leads to cellular dysfunction. Distinct from mouse beta cells, LDs are prominent in human beta cells, however, the regulation of LD mobilization (lipolysis) in human beta cells remains unclear. We found that glucose increases lipolysis in non-diabetic human islets, but not in type 2 diabetic (T2D) islets, indicating dysregulation of lipolysis in T2D islets. Silencing adipose triglyceride lipase (ATGL) in human pseudoislets (shATGL) increased triglycerides, and the number and size of LDs indicating that ATGL is the principal lipase in human beta cells. In shATGL pseudoislets, biphasic glucose-stimulated insulin secretion (GSIS) and insulin secretion to IBMX and KCl were all reduced without altering oxygen consumption rate compared with scramble control. Like human islets, INS1 cells showed visible LDs, glucose responsive lipolysis, and impairment of GSIS after ATGL silencing. ATGL deficient INS1 cells and human pseudoislets showed reduced Stx1a, a key SNARE component. Proteasomal degradation of Stx1a was accelerated likely through reduced palmitoylation in ATGL deficient INS1 cells. Therefore, ATGL is responsible for LD mobilization in human beta cells and supports insulin secretion by stabilizing Stx1a. The dysregulated lipolysis may contribute to LD accumulation and beta cell dysfunction in T2D islets.

At EBM live recently, we ran a workshop with researchers, patients and clinicians to talk about patient rights in research - should patients be setting the full research agenda? Should they be full participants and authors? Helen Macdonald, BMJ’s UK research editor and co-host of our talk evidence podcast sat down to Paul Wicks, researcher and...

Charles M. Alexander
May 1, 2003; 52:1210-1214
Complications

Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children’s plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and -aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D.

The COVID-19 pandemic around the world has taken the world by storm, touching the lives of every human being on Earth. The global nature of the crisis has united us as human beings and tragedy and deaths in any country by COVID-19 worry us all....

Branched esters of palmitic acid and hydroxystearic acid (PAHSA) are anti-inflammatory and antidiabetic lipokines that connect glucose and lipid metabolism. We aimed to characterize involvement of the 5-PAHSA regioisomer in the adaptive metabolic response of white adipose tissue (WAT) to cold exposure (CE) in mice, exploring the cross talk between glucose utilization and lipid metabolism. CE promoted local production of 5- and 9-PAHSAs in WAT. Metabolic labeling of de novo lipogenesis (DNL) using ²H₂O revealed that 5-PAHSA potentiated the effects of CE and stimulated triacylglycerol (TAG)/fatty acid (FA) cycling in WAT through impacting lipogenesis and lipolysis. Adipocyte lipolytic products were altered by 5-PAHSA through selective FA re-esterification. The impaired lipolysis in global adipose triglyceride lipase (ATGL) knockout mice reduced free PAHSA levels and uncovered a metabolite reservoir of TAG-bound PAHSAs (TAG estolides) in WAT. Utilization of ¹³C isotope tracers and dynamic metabolomics documented that 5-PAHSA primes adipocytes for glucose metabolism in a different way from insulin, promoting DNL and impeding TAG synthesis. In summary, our data reveal new cellular and physiological mechanisms underlying the beneficial effects of 5-PAHSA and its relation to insulin action in adipocytes and independently confirm a PAHSA metabolite reservoir linked to ATGL-mediated lipolysis.

OBJECTIVE

To compare medical resource use, costs, and health utilities for 14,752 patients with type 2 diabetes who were randomized to once-weekly exenatide (EQW) or placebo in addition to usual diabetes care in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).

Following a ruling in federal court two days prior, the Department of Health and Human Services announced Jan. 25 that the Health Insurance Portability and Accountability Act Privacy Rule fee limitations do not apply to requests to transmit copies of records to third-parties.

Ogden, Utah — The Office for Civil Rights announced March 3 that it had reached a settlement with Dr. Steven A. Porter’s medical practice to settle a potential violation of the Health Insurance Portability and Accountability Act security rule.

As part of its ongoing efforts to support dentists during the COVID-19 pandemic, the ADA is offering members two free e-books the week of April 8-14: “Managing Finances: Best Practices” and “The ADA Practical Guide to HIPAA Training.”

The American Dental Association is seeking qualified individuals to join a canvass committee to consider approval of the 2020 revision of the Systemized Nomenclature of Dentistry.

In the face of economic challenges, the ADA has released two online guides relating to third-party payment programs available at ADA.org/virus that are intended to help smooth the path of reopening practices: Handling Contract Negotiations and Handling Eligibility Verification

The two astronauts who are to begin a new era of human spaceflight from U.S. soil this month said Friday they hope to inspire generations of Americans.

The COVID-19 coronavirus pandemic is causing a number of societal changes that are new to nearly all of us, with governments around the world locking down cities and countries in an attempt to slow the spread of the virus. This situation is pushing some people together, but pulling others apart—and we’ve never seen anything quite like it in the modern era. Countless media articles have been written about the ways in which this is affecting people’s sex lives and relationships; however, most of them are purely speculative. This led some of my colleagues at the Kinsey Institute and I to wonder what’s really happening—and we’ve designed a study to help us better understand how emergency situations like this affect people’s sexual and romantic lives, which may help us to better plan and prepare for similar events in the future.

School districts are competing against each other for purchases of digital devices as remote learning expands to schools across the country.

The assistant principal wrote a children's book featuring Pepe the Frog, a cartoon character that has been adopted by the alt-right.

Students at Bellevue Elementary in Syracuse, N.Y., spend an extra 70 minutes at school each day, and their principal says the extended school day has improved their academic performance.

The Tennessee department of education is proposing unsually comprehensive legislation that will require all current and new K-3 teachers, and those who train them, to know evidence-based reading instruction.

Frank DeAngelis, who was the principal of Columbine High School from 1996-2014, talks about the steps he took to heal students and staff in the wake of the school shooting.

Knowing the shift to remote learning would be tough for teachers, school and district administrators have scrambled to assemble as many kinds of supports as they can.

All of Hawaii's public schools were closed down last week in anticipation of a powerful hurricane.

Now Newark, New Jersey, is exploding, thanks to the attempts at intimidation by Governor Christie's hand-picked superintendent of schools, Cami Anderson.

Utah's state board members said last week that they support its state's test participation law which conflicts with the Every Student Succeeds Act.

Bethany Hill, the principal at Central Elementary School in Cabot, Ark., shuns a formal office in favor of roving around classrooms, hallways, the playground, and the cafeteria, where she can be as close as possible to teachers and students all day.

In this seventh installment on the growth in dual-language learning, two experts from Delaware explore how state education leaders can build capacity to support both students and educators.

Valencia : M. Alufre, 1886.

London : Taylor and Walton, 1841.

Idaho became the first state in the country to prohibit transgender girls from participating in girls' school sports after Gov. Brad Little, a Republican, signed the "Fairness in Women's Sports Act" into law Tuesday.

A Paris : Chez Iean Dhourry, au bout du Pont-Neuf, près les Augustins, à l'Image S. Iean, M. DC. LXI. [1661]

Paris (28 et 29 rue St. Sulpice) : Maison Bouasse-Lebel, Imp. Edit. et ancienne Maison Basset reunies, [1851?]

[19--?]

In three days of rock climbing, orienteering, and other challenging outdoor experiences, principals get to examine their own—and others’—strengths and weaknesses as leaders.

Rockville, Maryland : National Institute on Drug Abuse, 1979.

Heiko Werner, Hajo Holzmann, Pierre Vandekerkhove.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 1816--1871.

Abstract:
We investigate a flexible two-component semiparametric mixture of regressions model, in which one of the conditional component distributions of the response given the covariate is unknown but assumed symmetric about a location parameter, while the other is specified up to a scale parameter. The location and scale parameters together with the proportion are allowed to depend nonparametrically on covariates. After settling identifiability, we provide local M-estimators for these parameters which converge in the sup-norm at the optimal rates over Hölder-smoothness classes. We also introduce an adaptive version of the estimators based on the Lepski-method. Sup-norm bounds show that the local M-estimator properly estimates the functions globally, and are the first step in the construction of useful inferential tools such as confidence bands. In our analysis we develop general results about rates of convergence in the sup-norm as well as adaptive estimation of local M-estimators which might be of some independent interest, and which can also be applied in various other settings. We investigate the finite-sample behaviour of our method in a simulation study, and give an illustration to a real data set from bioinformatics.

Ben Jones, Andreas Artemiou, Bing Li.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 1--23.

Abstract:
We give a probabilistic analysis of a phenomenon in statistics which, until recently, has not received a convincing explanation. This phenomenon is that the leading principal components tend to possess more predictive power for a response variable than lower-ranking ones despite the procedure being unsupervised. Our result, in its most general form, shows that the phenomenon goes far beyond the context of linear regression and classical principal components — if an arbitrary distribution for the predictor $X$ and an arbitrary conditional distribution for $Yvert X$ are chosen then any measureable function $g(Y)$, subject to a mild condition, tends to be more correlated with the higher-ranking kernel principal components than with the lower-ranking ones. The “arbitrariness” is formulated in terms of unitary invariance then the tendency is explicitly quantified by exploring how unitary invariance relates to the Cauchy distribution. The most general results, for technical reasons, are shown for the case where the kernel space is finite dimensional. The occurency of this tendency in real world databases is also investigated to show that our results are consistent with observation.

Benjamin Colling, Ingrid Van Keilegom.

Source: Electronic Journal of Statistics, Volume 14, Number 1, 769--800.

Abstract:
Consider the following semiparametric transformation model $Lambda_{ heta }(Y)=m(X)+varepsilon $, where $X$ is a $d$-dimensional covariate, $Y$ is a univariate response variable and $varepsilon $ is an error term with zero mean and independent of $X$. We assume that $m$ is an unknown regression function and that ${Lambda _{ heta }: heta inTheta }$ is a parametric family of strictly increasing functions. Our goal is to develop two new estimators of the transformation parameter $ heta $. The main idea of these two estimators is to minimize, with respect to $ heta $, the $L_{2}$-distance between the transformation $Lambda _{ heta }$ and one of its fully nonparametric estimators. We consider in particular the nonparametric estimator based on the least-absolute deviation loss constructed in Colling and Van Keilegom (2019). We establish the consistency and the asymptotic normality of the two proposed estimators of $ heta $. We also carry out a simulation study to illustrate and compare the performance of our new parametric estimators to that of the profile likelihood estimator constructed in Linton et al. (2008).

Principal component analysis (PCA) is a well-established tool in machine learning and data processing. The principal axes in PCA were shown to be equivalent to the maximum marginal likelihood estimator of the factor loading matrix in a latent factor model for the observed data, assuming that the latent factors are independently distributed as standard normal distributions. However, the independence assumption may be unrealistic for many scenarios such as modeling multiple time series, spatial processes, and functional data, where the outcomes are correlated. In this paper, we introduce the generalized probabilistic principal component analysis (GPPCA) to study the latent factor model for multiple correlated outcomes, where each factor is modeled by a Gaussian process. Our method generalizes the previous probabilistic formulation of PCA (PPCA) by providing the closed-form maximum marginal likelihood estimator of the factor loadings and other parameters. Based on the explicit expression of the precision matrix in the marginal likelihood that we derived, the number of the computational operations is linear to the number of output variables. Furthermore, we also provide the closed-form expression of the marginal likelihood when other covariates are included in the mean structure. We highlight the advantage of GPPCA in terms of the practical relevance, estimation accuracy and computational convenience. Numerical studies of simulated and real data confirm the excellent finite-sample performance of the proposed approach.