A New Type of Metal Recognition by Human T Cells: Contact Residues for Peptide-independent Bridging of T Cell Receptor and Major Histocompatibility Complex by Nickel

In spite of high frequencies of metal allergies, the structural basis for major histocompatibility complex (MHC)-restricted metal recognition is among the unanswered questions in the field of T cell activation. For the human T cell clone SE9, we have identified potential Ni contact sites in the T cell receptor (TCR) and the restricting human histocompatibility leukocyte antigen (HLA)-DR structure. The specificity of this HLA-DR–promiscuous VA22/VB17+ TCR is primarily harbored in its α chain. Ni reactivity is neither dependent on protein processing in antigen-presenting cells nor affected by the nature of HLA-DR–associated peptides. However, SE9 activation by Ni crucially depends on Tyr29 in CDR1α, an N-nucleotide–encoded Tyr94 in CDR3α, and a conserved His81 in the HLA-DR β chain. These data indicate that labile, nonactivating complexes between the SE9 TCR and most HLA-DR/peptide conjugates might supply sterically optimized coordination sites for Ni ions, three of which were identified in this study. In such complexes Ni may effectively bridge the TCR α chain to His81 of most DR molecules. Thus, in analogy to superantigens, Ni may directly link TCR and MHC in a peptide-independent manner. However, unlike superantigens, Ni requires idiotypic, i.e., CDR3α-determined TCR amino acids. This new type of TCR–MHC linkage might explain the high frequency of Ni-reactive T cells in the human population

Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice

Genetic studies link adenosine triphosphate-binding cassette transporter C6 (ABCC6) mutations to pseudoxanthoma elasticum (PXE). ABCC6 sequence variations are correlated with altered HDL cholesterol levels and an elevated risk of coronary artery diseases. However, the role of ABCC6 in cholesterol homeostasis is not widely known. Here, we report reduced serum cholesterol and phytosterol levels in Abcc6-deficient mice, indicating an impaired sterol absorption. Ratios of cholesterol precursors to cholesterol were increased, confirmed by upregulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) expression, suggesting activation of cholesterol biosynthesis in Abcc6-/- mice. We found that cholesterol depletion was accompanied by a substantial decrease in HDL cholesterol mediated by lowered ApoA-I and ApoA-II protein levels and not by inhibited lecithin-cholesterol transferase activity. Additionally, higher proprotein convertase subtilisin/kexin type 9 (Pcsk9) serum levels in Abcc6-/- mice and PXE patients and elevated ApoB level in knockout mice were observed, suggesting a potentially altered very low-density lipoprotein synthesis. Our results underline the role of Abcc6 in cholesterol homeostasis and indicate impaired cholesterol metabolism as an important pathomechanism involved in PXE manifestation

A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling

J. Kaprio, A. Palotie, A. Raevuori-Helkamaa ja S. Ripatti ovat työryhmän Eating Disorders Working Group of the Psychiatric Genomics Consortium jäseniä. Erratum in: Sci Rep. 2017 Aug 21;7(1):8379, doi: 10.1038/s41598-017-06409-3We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 x 10(-7); OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.Peer reviewe

Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages. Methods Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (≥65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0–100 based on the 2·5th and 97·5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion target—1 billion more people benefiting from UHC by 2023—we estimated additional population equivalents with UHC effective coverage from 2018 to 2023. Findings Globally, performance on the UHC effective coverage index improved from 45·8 (95% uncertainty interval 44·2–47·5) in 1990 to 60·3 (58·7–61·9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2·6% [1·9–3·3] per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010–2019 relative to 1990–2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0·79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach $1398 pooled health spending per capita (US$ adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388·9 million (358·6–421·3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3·1 billion (3·0–3·2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968·1 million [903·5–1040·3]) residing in south Asia. Interpretation The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all people—the ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how close—or how far—all populations are in benefiting from UHC

Associations between Attention-Deficit/Hyperactivity Disorder and various eating disorders: A Swedish nationwide population study using multiple genetically informative approaches

Background Although attention-deficit hyperactivity/impulsivity disorder (ADHD) and eating disorders (EDs) frequently co-occur, little is known about the shared etiology. In this study we comprehensively investigated the genetic association between ADHD and various EDs, including anorexia nervosa (AN) and other EDs (OED, including bulimia nervosa [BN]). Methods We applied different genetically informative designs to register-based information of a Swedish nationwide population (N=3,550,118). We first examined the familial co-aggregation of clinically diagnosed ADHD and EDs across multiple types of relatives. We then applied quantitative genetic modeling in full-sisters and maternal half-sisters to estimate the genetic correlations between ADHD and EDs. We further tested the associations between ADHD polygenic risk scores (PRS) and ED symptoms, and between AN PRS and ADHD symptoms, in a genotyped population-based sample (N=13,472). Results Increased risk of all types of EDs was found in individuals with ADHD (any ED: OR [95% CI]=3.97 [3.81-4.14], AN: 2.68 [2.15-2.86], OED: 4.66 [4.47-4.87], BN: 5.01 [4.63-5.41]) and their relatives compared to individuals without ADHD and their relatives. The magnitude of the associations reduced as the degree of relatedness decreased, suggesting shared familial liability between ADHD and EDs. Quantitative genetic models revealed stronger genetic correlation of ADHD with OED (0.37 [0.31-0.42]) than with AN (0.14 [0.05-0.22]). ADHD PRS correlated positively with ED symptom measures overall and sub-scales “drive for thinness” and “body dissatisfaction”, despite small effect sizes. Conclusions We observed stronger genetic association with ADHD for non-AN EDs than AN, highlighting specific genetic correlation beyond a general genetic factor across psychiatric disorders

Years of persecution, years of extermination: Saul Friedländer and the future of Holocaust studies

This volume provides an in-depth discussion of Saul Friedlanders landmark two-volume history of the Holocaust, Nazi Germany and the Jews. It brings together a range of internationally acclaimed historians to address the manifold conceptual and historiographical issues raised in Friedlanders monumental work. It includes a major essay by Friedlander himself on the challenges of producing an integrated history of the Holocaust. The aim of this book is not simply to evaluate Friedlanders work on its own merits, but rather to use his text as a means of exploring the contours and future of Holocaust historiography. The central concern is to situate his work within the broader terrain of Holocaust studies and European history, as well as to explore the ways in which his book opens up new directions in the knowledge, study and understanding of the Shoah in particular and twentieth century genocide in general