The J-elongated conformation of β2-glycoprotein I predominates in solution: implications for our understanding of antiphospholipid syndrome

β2-Glycoprotein I (β2GPI) is an abundant plasma protein displaying phospholipid-binding properties. Because it binds phospholipids, it is a target of antiphospholipid antibodies (aPLs) in antiphospholipid syndrome (APS), a life-threatening autoimmune thrombotic disease. Indeed, aPLs prefer membrane-bound β2GPI to that in solution. β2GPI exists in two almost equally populated redox states: oxidized, in which all the disulfide bonds are formed, and reduced, in which one or more disulfide bonds are broken. Furthermore, β2GPI can adopt multiple conformations (i.e. J-elongated, S-twisted, and O-circular). While strong evidence indicates that the J-form is the structure bound to aPLs, which conformation exists and predominates in solution remains controversial, and so is the conformational pathway leading to the bound state. Here, we report that human recombinant β2GPI purified under native conditions is oxidized. Moreover, under physiological pH and salt concentrations, this oxidized form adopts a J-elongated, flexible conformation, not circular or twisted, in which the N-terminal domain I (DI) and the C-terminal domain V (DV) are exposed to the solvent. Consistent with this model, binding kinetics and mutagenesis experiments revealed that in solution the J-form interacts with negatively charged liposomes and with MBB2, a monoclonal anti-DI antibody that recapitulates most of the features of pathogenic aPLs. We conclude that the preferential binding of aPLs to phospholipid-bound β2GPI arises from the ability of its preexisting J-form to accumulate on the membranes, thereby offering an ideal environment for aPL binding. We propose that targeting the J-form of β2GPI provides a strategy to block pathogenic aPLs in APS

The global burden of adolescent and young adult cancer in 2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15–39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods: Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15–39 years to define adolescents and young adults. Findings: There were 1·19 million (95% UI 1·11–1·28) incident cancer cases and 396 000 (370 000–425 000) deaths due to cancer among people aged 15–39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59·6 [54·5–65·7] per 100 000 person-years) and high-middle SDI countries (53·2 [48·8–57·9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14·2 [12·9–15·6] per 100 000 person-years) and middle SDI (13·6 [12·6–14·8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23·5 million (21·9–25·2) DALYs to the global burden of disease, of which 2·7% (1·9–3·6) came from YLDs and 97·3% (96·4–98·1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation: Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Funding: Bill & Melinda Gates Foundation, American Lebanese Syrian Associated Charities, St Baldrick's Foundation, and the National Cancer Institute

A question of confidence. Is tourism as vulnerable to civil unrest as we think? A comparative analysis of the impact of Arab Spring on total reserves and tourism

This paper uses monthly data to compare how international tourism receipts and the overall economy responded to the Arab Spring Total Reserves were used as an indicator of the economy overall, because they reflect confidence in the economy through such factors as Foreign Direct Investment and the effects of capital flight. To examine the response, interrupted time series was employed, using the outbreak of Arab Spring as the key interruption. To separate the impact of Arab Spring from other events, two treated and two untreated cases were selected. The results show that tourist spending recovered faster than the overall economy

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

The J-elongated conformation of b2-glycoprotein I predominates in solution: implications for our understanding of antiphospholipid syndrome

b2-Glycoprotein I (b2GPI) is an abundant plasma protein displaying phospholipid-binding properties. Because it binds phospholipids, it is a target of antiphospholipid antibodies (aPLs) in antiphospholipid syndrome (APS), a life-threatening autoimmune thrombotic disease. Indeed, aPLs prefer membrane-bound b2GPI to that in solution. b2GPI exists in two almost equally populated redox states: oxidized, in which all the disulfide bonds are formed, and reduced, in which one or more disulfide bonds are broken. Furthermore, b2GPI can adopt multiple conformations (i.e. J-elongated, S-twisted, and O-circular). While strong evidence indicates that the J-form is the structure bound to aPLs, which conformation exists and predominates in solution remains controversial, and so is the conformational pathway leading to the bound state. Here, we report that human recombinant b2GPI purified under native conditions is oxidized. Moreover, under physiological pH and salt concentrations, this oxidized form adopts a J-elongated, flexible conformation, not circular or twisted, in which the N-terminal domain I (DI) and the C-terminal domain V (DV) are exposed to the solvent. Consistent with this model, binding kinetics and mutagenesis experiments revealed that in solution the J-form interacts with negatively charged liposomes and with MBB2, a monoclonal anti-DI antibody that recapitulates most of the features of pathogenic aPLs. We conclude that the preferential binding of aPLs to phospholipid-bound b2GPI arises from the ability of its preexisting J-form to accumulate on the membranes, thereby offering an ideal environment for aPL binding. We propose that targeting the J-form of b2GPI provides a strategy to block pathogenic aPLs in APS

Optical properties of bulk and thin-film SrTiO\u3csub\u3e3\u3c/sub\u3e on Si and Pt

We have studied the optical properties (complex dielectric function) of bulk SrTiO3 and thin films on Si and Pt using spectroscopic ellipsometry over a very broad spectral range, starting at 0.03 eV [using Fourier transform infrared (FTIR) ellipsometry] to 8.7 eV. In the bulk crystals, we analyze the interband transitions in the spectra to determine the critical-point parameters. To interpret these transitions, we performed band structure calculations based on ab initio pseudopotentials within the local-density approximation. The dielectric function was also calculated within this framework and compared with our ellipsometry data. In the FTIR ellipsometry data, we notice a strong lattice absorption peak due to oxygen-related vibrations. Two longitudinal optic (LO) phonons were also identified. In SrTiO3 films on Si, the refractive index below the band gap decreases with decreasing thickness because of the increasing influence of the amorphous interfacial layer between the SrTiO3 film and the Si substrate. There is also a decrease in amplitude and an increase in broadening of the critical points with decreasing thickness. In SrTiO3 films on Pt, there is a strong correlation between the crystallinity and texture of the films (mostly aligned with the Pt pseudosubstrate) and the magnitude of the refractive index, the Urbach tail below the bulk band edge, and the critical-point parameters. FTIR reflectance measurements of SrTiO3 on Pt (reflection–absorption spectroscopy) show absorption peaks at the LO phonon energies, a typical manifestation of the Berreman effect for thin insulating films on a metal. The Urbach tail in our ellipsomety data and the broadening of the optical phonons in SrTiO3 on Pt are most likely caused by oxygen vacancy clusters

Why might medical student empathy change throughout medical school? Protocol for a systematic review and thematic synthesis of qualitative studies

INTRODUCTION: Several studies suggest that medical student empathy declines throughout medical school. However, no studies have systematically investigated why. The objective of our proposed review is to conduct a systematic review and thematic synthesis of qualitative studies investigating the reasons empathy may change throughout medical school. METHODS AND ANALYSIS: This systematic review protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We have searched MEDLINE, Scopus, CINAHL, ERIC and APA PsycINFO for relevant studies. We will also search reference lists of included studies and contact experts to identify additional studies. We will include any qualitative study investigating the reasons why empathy changes throughout medical school. We will use the Joanna Briggs Institute tool to evaluate the risk of bias in the included studies. We will use thematic analysis to synthesise our results. For all included studies, we will summarise the main characteristics including the number of participants, medical school year, country and gender. In our discussion, we will summarise the limitations of the evidence (including the risk of bias and inconsistency), and provide a general interpretation of the results and important implications. ETHICS AND DISSEMINATION: This study will not require ethical approval since no original data will be collected. The results of this review will be published through peer-reviewed publications and conference presentations. Additionally, this review will inform changes to the enhanced empathy curriculum at the Leicester Medical School