Momoko Kawana
Apr 7, 2020; 0:jlr.RA120000671v1-jlr.RA120000671
Research Articles

Ceramides are the predominant lipids in the stratum corneum (SC) and are crucial components for normal skin barrier function. Although the composition of various ceramide classes in the human SC has been reported, that in mice is still unknown, despite mice being widely used as animal models of skin barrier function. Here, we performed LC–MS/MS analyses using recently available ceramide class standards to measure 25 classes of free ceramides and 5 classes of protein-bound ceramides from the human and mouse SC. Phytosphingosine-type ceramides (P-ceramides) and 6-hydroxy sphingosine-type ceramides (H-ceramides), which both contain an additional hydroxyl group, were abundant in human SC (35% and 45% of total ceramides, respectively). In contrast, in mice, P-ceramides and H-ceramides were present at ~1% and undetectable levels, respectively, and sphingosine-type ceramides accounted for ~90%. In humans, ceramides containing α-hydroxy FA were abundant, whereas ceramides containing β-hydroxy FA (B-ceramides) or -hydroxy FA were abundant in mice. The hydroxylated β-carbon in B-ceramides was in the (R)-configuration. Genetic knockout of β-hydroxy acyl-CoA dehydratases in HAP1 cells increased B-ceramide levels, suggesting that β-hydroxy acyl-CoA, an FA-elongation cycle intermediate in the endoplasmic reticulum, is a substrate for B-ceramide synthesis. We anticipate that our methods and findings will help to elucidate the role of each ceramide class in skin barrier formation and in the pathogenesis of skin disorders.

Protein tyrosine kinases (PTKs) play key roles in cellular signal transduction, cell cycle regulation, cell division, and cell differentiation. Dysregulation of PTK-activated pathways, often by receptor overexpression, gene amplification, or genetic mutation, is a causal factor underlying numerous cancers. In this study, we have developed a parallel reaction monitoring (PRM)-based assay for quantitative profiling of 83 PTKs. The assay detects 308 proteotypic peptides from 54 receptor tyrosine kinases and 29 nonreceptor tyrosine kinases in a single run. Quantitative comparisons were based on the labeled reference peptide method. We implemented the assay in four cell models: 1) a comparison of proliferating versus epidermal growth factor (EGF)-stimulated A431 cells, 2) a comparison of SW480Null (mutant APC) and SW480APC (APC restored) colon tumor cell lines, and 3) a comparison of 10 colorectal cancer cell lines with different genomic abnormalities, and 4) lung cancer cell lines with either susceptibility (11-18) or acquired resistance (11-18R) to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. We observed distinct PTK expression changes that were induced by stimuli, genomic features or drug resistance, which were consistent with previous reports. However, most of the measured expression differences were novel observations. For example, acquired resistance to erlotinib in the 11-18 cell model was associated not only with previously reported upregulation of MET, but also with upregulation of FLK2 and downregulation of LYN and PTK7. Immunoblot analyses and shotgun proteomics data were highly consistent with PRM data. Multiplexed PRM assays provide a targeted, systems-level profiling approach to evaluate cancer-related proteotypes and adaptations. Data are available through Proteome eXchange Accession PXD002706.

This article has been withdrawn by the authors. This article did not comply with the editorial guidelines of MCP. Specifically, single peptide based protein identifications of 9-19% were included in the analysis and discussed in the results and conclusions. We wish to withdraw this article and resubmit a clarified, corrected manuscript for review.

Elevated levels of triglyceride-rich lipoproteins (TRLs), both fasting and postprandial, are associated with increased risk for atherosclerosis. However, guidelines for treatment are defined solely by fasting lipid levels, even though postprandial lipids may be more informative. In the postprandial state, circulating lipids consist of dietary fat transported from the intestine in chylomicrons (CMs; containing ApoB48) and fat transported from the liver in VLDL (containing ApoB100). Research into the roles of endogenous versus dietary fat has been hindered because of the difficulty in separating these particles by ultracentrifugation. CM fractions have considerable contamination from VLDL (purity, 10%). To separate CMs from VLDL, we produced polyclonal antibodies against ApoB100 and generated immunoaffinity columns. TRLs isolated by ultracentrifugation of plasma were applied to these columns, and highly purified CMs were collected (purity, 90–94%). Overall eight healthy unmedicated adult volunteers (BMI, 27.2 ± 1.4 kg/m²; fasting triacylglycerol, 102.6 ± 19.5 mg/dl) participated in a feeding study, which contained an oral stable-isotope tracer (1-¹³C acetate). We then used this technique on plasma samples freshly collected during an 8 h human feeding study from a subset of four subjects. We analyzed fractionated lipoproteins by Western blot, isolated and derivatized triacylglycerols, and calculated fractional de novo lipogenesis. The results demonstrated effective separation of postprandial lipoproteins and substantially improved purity compared with ultracentrifugation protocols, using the immunoaffinity method. This method can be used to better delineate the role of dietary sugar and fat on postprandial lipids in cardiovascular risk and explore the potential role of CM remnants in atherosclerosis.

Severity: Medium Description: SAS Enterprise Case Management contains a cross-site scripting vulnerability in the CASE_ID parameter. Potential Impact:

Tau is a microtubule-associated protein that plays a major role in Alzheimer's disease (AD) and other tauopathies. Recent reports indicate that, in the presence of crowding agents, tau can undergo liquid–liquid phase separation (LLPS), forming highly dynamic liquid droplets. Here, using recombinantly expressed proteins, turbidimetry, fluorescence microscopy imaging, and fluorescence recovery after photobleaching (FRAP) assays, we show that the divalent transition metal zinc strongly promotes this process, shifting the equilibrium phase boundary to lower protein or crowding agent concentrations. We observed no tau LLPS-promoting effect for any other divalent transition metal ions tested, including Mn2+, Fe2+, Co2+, Ni2+, and Cu2+. We also demonstrate that multiple zinc-binding sites on tau are involved in the LLPS-promoting effect and provide insights into the mechanism of this process. Zinc concentration is highly elevated in AD brains, and this metal ion is believed to be an important player in the pathogenesis of this disease. Thus, the present findings bring a new dimension to understanding the relationship between zinc homeostasis and the pathogenic process in AD and related neurodegenerative disorders.

Mario Luca Morieri
Apr 1, 2020; 69:771-783
Genetics/Genomes/Proteomics/Metabolomics

Ralph A. DeFronzo
Apr 1, 2009; 58:773-795
Banting Lecture

VOLUME 295 (2020) PAGES 1898–1914Yichen Zhong's name was misspelled. The correct spelling is shown above.

The life cycle of malaria parasites in both their mammalian host and mosquito vector consists of multiple developmental stages that ensure proper replication and progeny survival. The transition between these stages is fueled by nutrients scavenged from the host and fed into specialized metabolic pathways of the parasite. One such pathway is used by Plasmodium falciparum, which causes the most severe form of human malaria, to synthesize its major phospholipids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. Much is known about the enzymes involved in the synthesis of these phospholipids, and recent advances in genetic engineering, single-cell RNA-Seq analyses, and drug screening have provided new perspectives on the importance of some of these enzymes in parasite development and sexual differentiation and have identified targets for the development of new antimalarial drugs. This Minireview focuses on two phospholipid biosynthesis enzymes of P. falciparum that catalyze phosphoethanolamine transmethylation (PfPMT) and phosphatidylserine decarboxylation (PfPSD) during the blood stages of the parasite. We also discuss our current understanding of the biochemical, structural, and biological functions of these enzymes and highlight efforts to use them as antimalarial drug targets.

Research Event

Event participants

Lord Tu'ivakano, Prime Minister of the Kingdom of Tonga

The same piece of evidence may reach you via a journalist, or via your doctor - but the way in which that evidence is communicated is changed by your relationship between that person. Julia Beluz from Vox and Victor Montori from the Mayo Clinic join us to discuss if it's possible to reconcile those competing points of view.

Franz M Matschinsky
Feb 1, 1996; 45:223-241
Banting Lecture 1995

Eve Van Cauter
Mar 1, 1992; 41:368-377
Original Article

Ralph A. DeFronzo
Apr 1, 2009; 58:773-795
Banting Lecture

JW Baynes
Jan 1, 1999; 48:1-9
Articles

This study aims to model genetic, immunologic, metabolomics, and proteomic biomarkers for development of islet autoimmunity (IA) and progression to type 1 diabetes in a prospective high-risk cohort. We studied 67 children: 42 who developed IA (20 of 42 progressed to diabetes) and 25 control subjects matched for sex and age. Biomarkers were assessed at four time points: earliest available sample, just prior to IA, just after IA, and just prior to diabetes onset. Predictors of IA and progression to diabetes were identified across disparate sources using an integrative machine learning algorithm and optimization-based feature selection. Our integrative approach was predictive of IA (area under the receiver operating characteristic curve [AUC] 0.91) and progression to diabetes (AUC 0.92) based on standard cross-validation (CV). Among the strongest predictors of IA were change in serum ascorbate, 3-methyl-oxobutyrate, and the PTPN22 (rs2476601) polymorphism. Serum glucose, ADP fibrinogen, and mannose were among the strongest predictors of progression to diabetes. This proof-of-principle analysis is the first study to integrate large, diverse biomarker data sets into a limited number of features, highlighting differences in pathways leading to IA from those predicting progression to diabetes. Integrated models, if validated in independent populations, could provide novel clues concerning the pathways leading to IA and type 1 diabetes.

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34–0.72), whereas no benefit was observed for other genotypes (P_interaction = 3.7 x 10^–4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11—a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.

Glucagon-like peptide 1 (GLP-1) mimetics are effective drugs for treatment of type 2 diabetes, and there is consequently extensive interest in increasing endogenous GLP-1 secretion and L-cell abundance. Here we identify G-protein–coupled bile acid receptor 1 (GPBAR1) as a selective regulator of intestinal L-cell differentiation. Lithocholic acid and the synthetic GPBAR1 agonist, L3740, selectively increased L-cell density in mouse and human intestinal organoids and elevated GLP-1 secretory capacity. L3740 induced expression of Gcg and transcription factors Ngn3 and NeuroD1. L3740 also increased the L-cell number and GLP-1 levels and improved glucose tolerance in vivo. Further mechanistic examination revealed that the effect of L3740 on L cells required intact GLP-1 receptor and serotonin 5-hydroxytryptamine receptor 4 (5-HT4) signaling. Importantly, serotonin signaling through 5-HT4 mimicked the effects of L3740, acting downstream of GLP-1. Thus, GPBAR1 agonists and other powerful GLP-1 secretagogues facilitate L-cell differentiation through a paracrine GLP-1–dependent and serotonin-mediated mechanism.

Clinical studies have suggested that changes in peripheral nerve microcirculation may contribute to nerve damage in diabetic polyneuropathy (DN). High-sensitivity troponin T (hsTNT) assays have been recently shown to provide predictive values for both cardiac and peripheral microangiopathy in type 2 diabetes (T2D). This study investigated the association of sciatic nerve structural damage in 3 Tesla (3T) magnetic resonance neurography (MRN) with hsTNT and N-terminal pro-brain natriuretic peptide serum levels in patients with T2D. MRN at 3T was performed in 51 patients with T2D (23 without DN, 28 with DN) and 10 control subjects without diabetes. The sciatic nerve’s fractional anisotropy (FA), a marker of structural nerve integrity, was correlated with clinical, electrophysiological, and serological data. In patients with T2D, hsTNT showed a negative correlation with the sciatic nerve’s FA (r = –0.52, P < 0.001), with a closer correlation in DN patients (r = –0.66, P < 0.001). hsTNT further correlated positively with the neuropathy disability score (r = 0.39, P = 0.005). Negative correlations were found with sural nerve conduction velocities (NCVs) (r = –0.65, P < 0.001) and tibial NCVs (r = –0.44, P = 0.002) and amplitudes (r = –0.53, P < 0.001). This study is the first to show that hsTNT is a potential indicator for structural nerve damage in T2D. Our results indirectly support the hypothesis that microangiopathy contributes to structural nerve damage in T2D.

We aimed to assess the value of ¹¹C-choline PET in patients with primary hyperparathyroidism and negative or discordant results on ^99mTc-sestamibi imaging and neck ultrasound. Methods: Eighty-seven such patients were assessed and subsequently underwent parathyroidectomy. PET/CT image data were analyzed semiquantitatively using SUV_max and SUV ratios (target to contralateral thyroid gland and carotid artery). A positive PET/CT result was defined as focal uptake significantly higher than regular thyroid tissue. Ectopic foci were also considered positive. Inconclusive PET/CT cases were defined as a lesion with uptake equal to normal thyroid tissue. If no prominent or ectopic uptake was detectable, the PET/CT result was considered negative. Results: When dichotomizing the ¹¹C-choline PET/CT imaging results by defining lesions with both positive and inconclusive uptake as positive, we found 84 of 92 lesions (91.3%) to have true-positive uptake whereas 8 lesions (8.7%) had false-positive uptake. One lesion showed false-negative uptake; the sensitivity was 98.8%. The corresponding positive predictive value for lesions was 91.3%. The mean SUV_max was 6.15 ± 4.92 in 72 lesions with positive uptake (70 patients) and 2.96 ± 2.32 in 20 lesions with inconclusive uptake (18 patients). Conclusion: These results in a large group of patients indicate that ¹¹C-choline PET/CT is a promising tool for parathyroid adenoma localization when ultrasound and ^99mTc-sestamibi imaging yield negative or discordant results.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, definitive treatment usually requiring surgical removal of the offending parathyroid glands. To perform focused surgical approaches, it is necessary to localize all hyperfunctioning glands. The aim of the study was to compare the efficiency of established conventional scintigraphic imaging modalities with emerging ¹⁸F-fluorocholine PET/CT imaging in preoperative localization of hyperfunctioning parathyroid glands in a larger series of PHPT patients. Methods: In total, 103 patients with PHPT were imaged preoperatively with ¹⁸F-fluorocholine PET/CT and conventional scintigraphic imaging methods, consisting of ^99mTc-sestamibi SPECT/CT, ^99mTc-sestamibi/pertechnetate subtraction imaging, and ^99mTc-sestamibi dual-phase imaging. The results of histologic analysis, as well as intact parathyroid hormone and serum calcium values obtained 1 d after surgery and on follow-up, served as the standard of truth for evaluation of imaging results. Results: Diagnostic performance of ¹⁸F-fluorocholine PET/CT surpassed conventional scintigraphic methods (separately or combined), with calculated sensitivity of 92% for PET/CT and 39%–56% for conventional imaging (65% for conventional methods combined) in the entire patient group. Subgroup analysis, differentiating single and multiple hyperfunctioning parathyroid glands, showed PET/CT to be most valuable in the group with multiple hyperfunctioning glands, with sensitivity of 88%, whereas conventional imaging was significantly inferior, with sensitivity of 22%–34% (44% combined). Conclusion: ¹⁸F-fluorocholine PET/CT is a diagnostic modality superior to conventional imaging methods in patients with PHPT, allowing for accurate preoperative localization.

Convocamos un seminario en línea (webinar) en español en la ocasión del lanzamiento del informe, Creatividad dentro de la crisis: opciones legales para inmigrantes venezolanos en América Latina, que describe donde se han radicado los migrantes venezolanos; las medidas que han utilizado los gobiernos latinoamericanos para regularizar el estatus legal de los migrantes venezolanos; y los esfuerzos por integrar a los recién llegados en sus nuevas comunidades de residencia.

Discussion at launch of this MPI-IOM Issue in Brief, Human Rights, Climate Change, Environmental Degradation and Migration: A New Paradigm, which focuses on the vulnerability of environmental migrants and how the international legal framework can better ensure their protection, particularly in the Asia-Pacific region.

This issue brief addresses the rights of migrants whose movement is induced by environmental degradation or climate change, particularly in the highly vulnerable Asia-Pacific region. The brief evaluates the current international legal framework, identifies gaps in the framework and its implementation, and reviews options available to the international community.

This MPI event, in partnership with the International Organization for Migration (IOM), discusses the critical issue of climate-related displacement in the Asia-Pacific region, focusing on the vulnerability of environmental migrants and how the international legal framework can better ensure their protection.

Edward A. Chow
Jul 1, 2012; 30:130-133
Diabetes Advocacy

Angelo Avogaro
May 1, 2011; 34:S285-S290
Hypertension

Khalid A. Jadoon
Oct 1, 2016; 39:1777-1786
Emerging Technologies and Therapeutics

Presentación del reporte que refleja el contenido de encuentros del grupo de estudio sobre la migración México-Estados Unidos convocado por El Colegio de México y el Migration Policy Institute (MPI).

Durante su primera visita oficial a Washington, DC, la Secretaria de Gobierno Olga Sánchez Cordero presento un discurso público sobre la nueva política migratoria de México en el Instituto de Políticas Migratorias.

Dado el incremento de los flujos migratorios provenientes de Centroamérica, el pasado mes de junio de 2019, los Estados Unidos y México acordaron tomar una serie de medidas para reducir los flujos irregulares. Sin embargo, será muy difícil mantener estos esfuerzos de corto plazo, debido a una debilidad institucional crónica y a estructuras de política pública poco planificadas en ambos países. Este comentario ofrece cinco recomendaciones a ambos países considerando soluciones de mediano y largo plazo para disuadir la migración irregular y, al mismo tiempo, garantizar que aquellos que busquen protección tengan un proceso justo.

The deadline for dental offices to install amalgam separators remains intact but the Environmental Protection Agency announced March 26 that it will be initiating “a new temporary enforcement discretion policy” during the COVID-19 pandemic.

The virus responsible for chronic bee paralysis is spreading rapidly among honey bee colonies in Britain, according to a new study.

Social psychologist William B. Swann once had a group of married people evaluate their spouses even as their spouses evaluated them. People with high self-esteem, the psychologist found, felt closer to their partners when they received positive evaluations. People with low self-esteem, however, felt...

The United States is awash in gloom. Overwhelming majorities of Americans say they are dissatisfied with the country's economic direction, and the intensity of unhappiness is greater than it has been in 15 years, according to a recent Washington Post-ABC News poll. The answer, pundits, politicians...

La migración entre México y Estados Unidos ha cambiado dramáticamente en los últimos años, pero las políticas y la retórica política en ambos países no se han actualizado a este contexto a la misma velocidad. Este reporte explora esta nueva realidad migratoria y cómo los dos gobiernos podrían trabajar juntos para abordar los desafíos de políticas públicas que tienen en común.

Marking the release of an MPI brief that articulates a new adult education program model, this webinar features a discussion among immigration and legal services, adult education, and digital learning experts. The webinar includes a discussion of strategies to implement the English Plus Integration model, which would maintain a central focus on English language acquisition while also building skills necessary for successful immigrant integration.

To successfully integrate, immigrants and refugees need a variety of skills and knowledge—from English proficiency to understanding how school systems and local services work. Yet the adult education programs in place to support them have narrowed in scope. This policy brief proposes a new instructional model, English Plus Integration, to help states more comprehensively meet the diverse needs of their adult immigrant learners.

Taking stock of weaknesses in the WIOA-driven design of most adult basic education programming, MPI analysts draw on research from the integration, adult education, and postsecondary success fields in arguing for the adoption of an “English Plus Integration” (EPI) adult education program model, and discuss strategies for implementation. 

WASHINGTON – A pesar de que los gobiernos de América Latina y el Caribe han tomado medidas generosas e innovadoras para lidiar con el desplazamiento forzado desde Venezuela y más recientemente desde Nicaragua, la cálida bienvenida se ha enfriado en algunos lugares a medida que el número de entradas, la presión sobre los servicios públicos y la preocupación del público aumenta.

Spring has definitely in the air well and truly. Loving the produce, country aromas, and appearance as I cycle through the country side. I love asparagus... this local stuff growing by a great friend and awesome farmer. Side dishes are often overlooked but are a very important part to a great meal.

This recipe features on Foodie Tuesday, a weekly segment on 774 Drive with Raf Epstein, 3.30PM, shared by Dan Hunter, chef and owner of Otways' restaurant Brae.

A simple summer seafood dish!

This recipe features on Foodie Tuesday, a weekly segment on 774 Drive with Raf Epstein, 3.30PM

Aunque colombianos encontraron un refugio cálido en Ecuador después de ser desplazados de su país por una guerra civil que duro décadas, la vida se ha vuelto más difícil para ellos en los últimos años, en parte como resultado del flujo de venezolanos que buscan seguridad. Este artículo se basa en encuestas de migrantes en Quito, comparando y contrastando las experiencias de colombianos y venezolanos, y evaluando sus percepciones de discriminación, victimización y esperanzas para el futuro.

OBJECTIVE

To determine the effect of fitness on the association between BMI and mortality among patients with diabetes.

Edward A. Chow
Jul 1, 2012; 30:130-133
Diabetes Advocacy