Autophagy Delivers Viral Antigens for MHC Class II Presentation and is Regulated by Viral Infection

MHC class II molecules generally present peptides derived from exogenous antigens after endocytosis. However, biochemical studies have revealed that MHC class II ligands are frequently derived from intracellular proteins after endogenous processing. Endogenous MHC class II antigen presentation has been described for viral and model antigens and might represent an important mechanism to initiate CD4+ T cell responses to intracellular pathogens. We studied this unusual MHC class II presentation pathway using the Epstein- Barr virus nuclear antigen 1 (EBNA1) as a model antigen with relevance for human disease. We found that EBNA1 was degraded by lysosomal proteases and detected EBNA1 in double membrane structures by immuno-electron microscopy. Furthermore, inhibition of autophagy led to reduced stimulation of EBNA1-specific CD4+ T cells, suggesting that EBNA1 was delivered for MHC class II presentation by autophagy. This defines a new endogenous MHC class II processing pathway and EBNA1 is the first pathogen-derived antigen found to follow this pathway. To address the general relevance and the efficacy of this novel MHC class II pathway, we quantified autophagy in MHC class II-positive human cells and demonstrated constitutive autophagosome formation in epithelial, B and dendritic cells. The autophagosome marker Atg8/LC3 strongly overlapped with markers of MHC class II loading compartments (MIICs) by confocal and immuno-electron microscopy, suggesting that autophagosomes frequently fuse with MIICs. Furthermore, this pathway was of functional relevance, because targeting of influenza matrix protein 1 to autophagosomes via LC3 fusion led to strongly enhanced CD4+ T cell stimulation. This suggests that autophagy constitutively and efficiently delivers cytosolic antigens for MHC class II presentation and can be harnessed for improved helper T cell stimulation. In addition to its role in antigen presentation, autophagy might be an innate immune mechanism to restrict virus replication. We found that autophagosomes strongly accumulated in influenza A virus-infected lung epithelial cells, most likely because they do not fuse with lysosomes anymore. Infected cells contained unusually large autophagosomes filled with amorphous protein or nucleic acid, possibly of viral origin. Inhibition of autophagy led to an increase in influenza virus replication, suggesting that autophagy might be a mechanism to restrict or delay virus replication

Constructing an illusion of scientific uncertainty? Framing climate change in German and British print media

This article uses quantitative content analysis data from June 1, 2012 to May 31, 2013 to examine the salience and construction of scientific uncertainty about climate change in German and British press coverage using quantitative content analysis data from June 1, 2012 to May 31, 2013. The results show that uncertainty about climate change − against overwhelming consensus among climate scientists − is prominent in the press coverage of both countries. The findings indicate that it is important to distinguish whether scientific uncertainty can be found at the level of single articles, or at the level of the coverage as a whole. The study also reveals that uncertainty is constructed differently in German and British press coverage in terms of the media's framing of climate science and the types of actors who are involved in the construction of scientific uncertainty

18F-FET PET/CT in Advanced Head and Neck Squamous Cell Carcinoma: an Intra-individual Comparison with 18F-FDG PET/CT

Purpose: To assess the diagnostic value of O-2-fluoro-18(F)-ethyl-l-tyrosine (18F-FET) positron emission tomography/computed tomography (PET/CT) for patients with advanced head and neck squamous cell carcinoma compared with 18F-fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT at initial staging and following radiochemotherapy. Procedures: Thirteen patients were prospectively enrolled; each of them underwent an 18F-FDG PET/CT and 18F-FET PET/CT before treatment. Ten of those were scanned 10weeks after treatment. Results: Sensitivity, specificity, and accuracy for 18F-FDG PET/CT (primary and lymph node metastases) at initial staging were 89%, 50%, and 81%. For 18F-FET PET/CT the numbers were 70%, 90%, and 74%. Sensitivity, specificity, and accuracy for 18F-FDG PET/CT at follow-up were 71%, 65%, and 67%. For 18F-FET PET/CT the numbers were 29%, 100%, and 83%. Additionally, 18F-FDG PET/CT detected a higher number of second malignancies or distant metastases. Conclusions: 18F-FET is no substitute for 18F-FDG. Although it is more specific, too many malignant lesions are missed due to its lower sensitivit

A mechanistic perspective on plastically flexible coordination polymers

Mechanical flexibility in single crystals of covalently bound materials is a fascinating and poorly understood phenomenon. We present here the first example of a plastically flexible one‐dimensional (1D) coordination polymer. The compound [Zn(μ‐Cl)2(3,5‐dichloropyridine)2]n is flexible over two crystallographic faces. Remarkably, the single crystal remains intact when bent to 180°. A combination of microscopy, diffraction, and spectroscopic studies have been used to probe the structural response of the crystal lattice to mechanical bending. Deformation of the covalent polymer chains does not appear to be responsible for the observed macroscopic bending. Instead, our results suggest that mechanical bending occurs by displacement of the coordination polymer chains. Based on experimental and theoretical evidence, we propose a new model for mechanical flexibility in 1D coordination polymers. Moreover, our calculations propose a cause of the different mechanical properties of this compound and a structurally similar elastic material

Augmented Reality in der Lehrerinnen- und Lehrerbildung beim Arbeiten mit Modellen in den Naturwissenschaften

Bisherige Projekte zu Augmented Reality in der Bildung versprechen u.a. Motivationssteigerung und bessere Lernleistungen. Die hier beschriebene hochschulübergreifende Entwicklung einer Augmented-Reality-Lernumgebung zum elektrischen Stromkreis befasst sich mit der Kombination von physikdidaktischem Denken in Modellen und der digitalen Repräsentation solcher Modellierungen im Realexperiment. Der Einsatz in der Lehrpersonenbildung zielt auf die Förderung von technologiebezogenem fachdidaktischem Wissen (TPACK) ab, das die angehenden Lehrpersonen befähigen soll, die neuen Möglichkeiten digitaler Technologien lernförderlich in den Unterricht zu integrieren

Accumulation of Four Electrons on a Terphenyl (Bis)disulfide

The activation of N2, CO2 or H2O to energy-rich products relies on multi-electron transfer reactions, and consequently it seems desirable to understand the basics of light-driven accumulation of multiple redox equivalents. Most of the previously reported molecular acceptors merely allow the storage of up to two electrons. We report on a terphenyl compound including two disulfide bridges, which undergoes four-electron reduction in two separate electrochemical steps, aided by a combination of potential compression and inversion. Under visible-light irradiation using the organic super-electron donor tetrakis(dimethylamino)ethylene, a cascade of light-induced reaction steps is observed, leading to the cleavage of both disulfide bonds. Whereas one of them undergoes extrusion of sulfur to result in a thiophene, the other disulfide is converted to a dithiolate. These insights seem relevant to enhance the current fundamental understanding of photochemical energy storage

Racial Disparities in Blood Pressure Control and Treatment Differences in a Medicaid Population, North Carolina, 2005-2006

Introduction: Racial disparities in prevalence and control of high blood pressure are well-documented. We studied blood pressure control and interventions received during the course of a year in a sample of black and white Medicaid recipients with high blood pressure and examined patient, provider, and treatment characteristics as potential explanatory factors for racial disparities in blood pressure control. Methods: We retrospectively reviewed the charts of 2,078 black and 1,436 white North Carolina Medicaid recipients who had high blood pressure managed in primary care practices from July 2005 through June 2006. Documented provider responses to high blood pressure during office visits during the prior year were reviewed. Results: Blacks were less likely than whites to have blood pressure at goal (43.6% compared with 50.9%, P = .001). Blacks above goal were more likely than whites above goal to have been prescribed 4 or more antihypertensive drug classes (24.7% compared with 13.4%, P < .001); to have had medication adjusted during the prior year (46.7% compared with 40.4%, P = .02); and to have a documented provider response to high blood pressure during office visits (35.7% compared with 30.0% of visits, P = .02). Many blacks (28.0%) and whites (34.3%) with blood pressure above goal had fewer than 2 antihypertensive drug classes prescribed. Conclusion: In this population with Medicaid coverage and access to primary care, blacks were less likely than whites to have their blood pressure controlled. Blacks received more frequent intervention and had greater use of combination antihypertensive therapy. Care patterns observed in the usual management of high blood pressure were not sufficient to achieve treatment goals or eliminate disparities

Level of blood pressure above goal and clinical inertia in a Medicaid population

Failure to adjust hypertension therapy despite elevated blood pressure (BP) levels is an important contributor to lack of BP control. One possible explanation is that small elevations above goal BP are not concerning to clinicians. BP levels farther above goal, however, should be more likely to prompt clinical action. We reviewed one year’s worth of primary care records of 3,742 North Carolina Medicaid recipients 21 years and older with hypertension (a total of 15,516 office visits) to examine variations in hypertension management stratified by level of BP above goal and the association of BP level above goal with documented anti-hypertensive medication change. Among the 53% of patients not at goal BP, 42% were within 10/5 mm Hg of goal; 11% had a BP ≥40/20 mm Hg above goal. Higher level of BP above goal was independently associated with anti-hypertensive medication change. Compared to visits at which BP was <10/5 mm Hg above goal, the adjusted odds of medication change were 7.9 (95% CI 6.2-10.2) times greater at visits when patients’ BP was ≥ 40/20 mm Hg above goal. However, even when BP was above goal at this level, treatment change occurred only 46% (95% CI 40.2-51.8) of the time

Type 2 diabetes mellitus and medications for type 2 diabetes mellitus are associated with risk for and mortality from cancer in a German primary care cohort

There is growing evidence that patients with type 2 diabetes mellitus have increased cancer risk. We examined the association between diabetes, cancer, and cancer-related mortality and hypothesized that insulin sensitizers lower cancer-related mortality. Participants in the Diabetes Cardiovascular Risk and Evaluation: Targets and Essential Data for Commitment of Treatment study, a nationwide cross-sectional and prospective epidemiological study, were recruited from German primary care practices. In the cross-sectional study, subjects with type 2 diabetes mellitus had a higher prevalence of malignancies (66/1308, 5.1%) compared to nondiabetic subjects (185/6211, 3.0%) (odds ratio, 1.64; 95% confidence interval, 1.12-2.41) before and after adjustment for age, sex, hemoglobin A1c, smoking status, and body mass index. Patients on metformin had a lower prevalence of malignancies, comparable with that among nondiabetic patients, whereas those on any other oral combination treatment had a 2-fold higher risk for malignancies even after adjusting for possible confounders; inclusion of metformin in these regimens decreased the prevalence of malignancies. In the prospective analyses, diabetic patients in general and diabetic patients treated with insulin (either as monotherapy or in combination with other treatments) had a 2- and 4-fold, respectively, higher mortality rate than nondiabetic patients, even after adjustment for potential confounders (incidence of cancer deaths in patients with type 2 diabetes mellitus [2.6%] vs the incidence of cancer deaths in patients without type 2 diabetes mellitus [1.2%]). Our results suggest that diabetes and medications for diabetes, with the exception of the insulin sensitizer metformin, increase cancer risk and mortality

Prevention and Treatment of Childhood Obesity: Care Received by a State Medicaid Population

Based on chart review for a representative cluster sample of North Carolina Medicaid enrollees aged 3 to 5 years (n = 1951) and 13 to 16 years (n = 1922) years, this study describes prevalence, practice patterns, and comorbidities related to overweight/obese immediately prior to 2007 Expert Recommendations. In total, 16% of children in both age groups were overweight, and 20% (ages 3–5 years) and 25% (ages 13–16 years) were obese. For 3- to 5-year-olds, body mass index percentile was infrequently recorded (22%) or plotted on growth charts (24%), and weight status category was rarely documented (10%). Results were similar for adolescents (21%, 20%, and 12%, respectively). In both groups, documentation of counseling in nutrition or physical activity was rare (16% for ages 3–5 years; 7% for ages 13–16 years). In adolescents, approximately 20% received recommended laboratory screening and overweight/obesity was significantly associated with chart-documented asthma, back pain, prediabetes, gastroesophageal reflux disease, hypertension, and sleep apnea. Whether improvements in documentation of care followed these new guidelines deserves further research