Multiband Superconductivity in KFe2As2: Evidence for one Isotropic and several Liliputian Energy Gaps

We report a detailed low-temperature thermodynamic investigation (heat capacity and magnetization) of the superconducting state of KFe2As2 for H || c axis. Our measurements reveal that the properties of KFe2As2 are dominated by a relatively large nodeless energy gap (Delta?0 = 1.9 kBTc) which excludes dx2-y2 symmetry. We prove the existence of several additional extremely small gaps (?Delta0 < 1.0 kBTc) that have a profound impact on the low-temperature and low-field behavior, similar to MgB2, CeCoIn5 and PrOs4Sb12. The zero-field heat capacity is analyzed in a realistic self-consistent 4-band BCS model which qualitatively reproduces the recent laser ARPES results of Okazaki et al. (Science 337 (2012) 1314). Our results show that extremely low-temperature measurements, i.e. T < 0.1 K, will be required in order to resolve the question of the existence of line nodes in this compound.Comment: 7 pages, 6 figure

Prioritisation of Adverse Drug Events Leading to Hospital Admission and Occurring during Hospitalisation: A RAND Survey

(1) Adverse drug events (ADEs) are a common cause of emergency department visits and occur frequently during hospitalisation. Instruments that facilitate the detection of the most relevant ADEs could lead to a more targeted and efficient use of limited resources in research and practice. (2) We conducted two consensus processes based on the RAND/UCLA appropriateness method, in order to prioritise ADEs leading to hospital admission (panel 1) and occurring during hospital stay (panel 2) for inclusion in future ADE measurement instruments. In each panel, the experts were asked to assess the overall importance of each ADE on a four-point Likert scale (1 = not important to 4 = very important). ADEs with a median rating of >= 3 without disagreement were defined as prioritised. (3) The 13 experts in panel 1 prioritised 38 out of 65 ADEs, while the 12 experts in panel 2 prioritised 34 out of 63 ADEs. The highest rated events were acute kidney injury and hypoglycaemia (both panels), as well as Stevens-Johnson syndrome in panel 1 and rhabdomyolysis in panel 2. (4) The survey led to a set of ADEs for which there was consensus that they were of particular importance as presentations of acute medication-related harm, thereby providing a focus for further medication safety research and clinical practice

Distinct pressure evolution of coupled nematic and magnetic orders in FeSe

We present a microscopic study of nematicity and magnetism in FeSe over a wide temperature and pressure range using high-energy x-ray diffraction and time-domain Mössbauer spectroscopy. The low-temperature magnetic hyperfine field increases monotonically up to ∼ 6 GPa. The orthorhombic distortion initially decreases under increasing pressure but is stabilized at intermediate pressures by cooperative coupling to the pressure-induced magnetic order. Close to the reported maximum of the superconducting critical temperature at p = 6.8 GPa , the orthorhombic distortion suddenly disappears and a new tetragonal magnetic phase occurs. The pressure and temperature evolution of the structural and magnetic order parameters suggests that they have distinct origins

Structure of a Natively-glycosylated HIV-1 Env Reveals a New Mode for VH1-2 Antibody Recognition of the CD4 Binding Site Relevant to Vaccine Design

Background: Structural studies of broadly neutralizing antibodies (bNAbs) bound to Env trimers have revealed mechanisms by which bNAbs targeting various epitopes penetrate the glycan shield to either accommodate or include N-glycans in their epitopes. Although accessibility to the conserved host receptor (CD4) binding site (CD4bs) is restricted by surrounding glycans, VRC01-class bNAbs mimic CD4 binding to share a common mode of gp120 binding and glycan accommodation using a VH1-2*02- derived variable heavy (VH) domain. While attractive candidates for immunogen design, features of VRC01-class bNAbs such as a high degree of somatic hypermutation (SHM) and a short (5-residue) light chain (LC) complementarity determining region 3 (CDRL3) (found in only 1% of human LCs) suggest they might be difficult to elicit through vaccination. However, we recently isolated a VH1-2*02-derived CD4bs bNAb, named IOMA, that includes a normal-length (8 residues) CDRL3. Methods: We used X-ray crystallography to solve the first structure of a fully- and natively-glycosylated Env trimer in complex with IOMA, and the V3-loop-directed bNAb 10-1074. Results: Our structure revealed antibody-vulnerable glycan holes and roles of complex-type N-glycans on Env that are relevant to vaccine design, while also demonstrating that IOMA is a new class of CD4-mimetic bNAb that contains features of both VH1-2/VRC01-class and VH1-46/8ANC131-class bNAbs. Conclusions: Analysis of the native glycan shield on HIV-1 Env allows the first full description of the interplay between heterogeneous untrimmed high-mannose and complex-type N-glycans within the CD4bs, V3-loop, and other epitopes on Env. In addition, the structural characterization of IOMA revealed an alternative pathway from VRC01-class bNAbs relevant to vaccine design, which could more readily lead to an effective vaccine response due to higher frequencies of normal-length CDRL3s compared with the rare 5-residue CDRL3s required for VRC01-class bNAbs, and a lower need for SHMs

Structure of a Natively-glycosylated HIV-1 Env Reveals a New Mode for VH1-2 Antibody Recognition of the CD4 Binding Site Relevant to Vaccine Design

Background: Structural studies of broadly neutralizing antibodies (bNAbs) bound to Env trimers have revealed mechanisms by which bNAbs targeting various epitopes penetrate the glycan shield to either accommodate or include N-glycans in their epitopes. Although accessibility to the conserved host receptor (CD4) binding site (CD4bs) is restricted by surrounding glycans, VRC01-class bNAbs mimic CD4 binding to share a common mode of gp120 binding and glycan accommodation using a VH1-2*02- derived variable heavy (VH) domain. While attractive candidates for immunogen design, features of VRC01-class bNAbs such as a high degree of somatic hypermutation (SHM) and a short (5-residue) light chain (LC) complementarity determining region 3 (CDRL3) (found in only 1% of human LCs) suggest they might be difficult to elicit through vaccination. However, we recently isolated a VH1-2*02-derived CD4bs bNAb, named IOMA, that includes a normal-length (8 residues) CDRL3. Methods: We used X-ray crystallography to solve the first structure of a fully- and natively-glycosylated Env trimer in complex with IOMA, and the V3-loop-directed bNAb 10-1074. Results: Our structure revealed antibody-vulnerable glycan holes and roles of complex-type N-glycans on Env that are relevant to vaccine design, while also demonstrating that IOMA is a new class of CD4-mimetic bNAb that contains features of both VH1-2/VRC01-class and VH1-46/8ANC131-class bNAbs. Conclusions: Analysis of the native glycan shield on HIV-1 Env allows the first full description of the interplay between heterogeneous untrimmed high-mannose and complex-type N-glycans within the CD4bs, V3-loop, and other epitopes on Env. In addition, the structural characterization of IOMA revealed an alternative pathway from VRC01-class bNAbs relevant to vaccine design, which could more readily lead to an effective vaccine response due to higher frequencies of normal-length CDRL3s compared with the rare 5-residue CDRL3s required for VRC01-class bNAbs, and a lower need for SHMs

Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice

A subset of individuals infected with HIV-1 develops broadly neutralizing antibodies (bNAbs) that can prevent infection, but it has not yet been possible to elicit these antibodies by immunization. To systematically explore how immunization might be tailored to produce them, we generated mice expressing the predicted germline or mature heavy chains of a potent bNAb to the CD4 binding site (CD4bs) on the HIV-1 envelope glycoprotein (Env). Immunogens specifically designed to activate B cells bearing germline antibodies are required to initiate immune responses, but they do not elicit bNAbs. In contrast, native-like Env trimers fail to activate B cells expressing germline antibodies but elicit bNAbs by selecting for a restricted group of light chains bearing specific somatic mutations that enhance neutralizing activity. The data suggest that vaccination to elicit anti-HIV-1 antibodies will require immunization with a succession of related immunogens

Enabling the Digital Democratic Revival:A Research Program for Digital Democracy

This white paper outlines a long-term scientific vision for the development of digital-democracy technology. We contend that if digital democracy is to meet the ambition of enabling a participatory renewal in our societies, then a comprehensive multi-methods research effort is required that could, over the years, support its development in a democratically principled, empirically and computationally informed way. The paper is co-authored by an international and interdisciplinary team of researchers and arose from the Lorentz Center Workshop on "Algorithmic Technology for Democracy'' (Leiden, October 2022)

Enabling the Digital Democratic Revival:A Research Program for Digital Democracy

This white paper outlines a long-term scientific vision for the development of digital-democracy technology. We contend that if digital democracy is to meet the ambition of enabling a participatory renewal in our societies, then a comprehensive multi-methods research effort is required that could, over the years, support its development in a democratically principled, empirically and computationally informed way. The paper is co-authored by an international and interdisciplinary team of researchers and arose from the Lorentz Center Workshop on "Algorithmic Technology for Democracy'' (Leiden, October 2022)

Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site

HIV-1 vaccine design is informed by structural studies elucidating mechanisms by which broadly neutralizing antibodies (bNAbs) recognize and/or accommodate N-glycans on the trimeric envelope glycoprotein (Env). Variability in high-mannose and complex-type Env glycoforms leads to heterogeneity that usually precludes visualization of the native glycan shield. We present 3.5-Å- and 3.9-Å-resolution crystal structures of the HIV-1 Env trimer with fully processed and native glycosylation, revealing a glycan shield of high-mannose and complex-type N-glycans, which we used to define complete epitopes of two bNAbs. Env trimer was complexed with 10-1074 (against the V3-loop) and IOMA, a new CD4-binding site (CD4bs) antibody. Although IOMA derives from VH1-2*02, the germline gene of CD4bs-targeting VRC01-class bNAbs, its light chain lacks the short CDRL3 that defines VRC01-class bNAbs. Thus IOMA resembles 8ANC131-class/VH1-46-derived CD4bs bNAbs, which have normal-length CDRL3s. The existence of bNAbs that combine features of VRC01-class and 8ANC131-class antibodies has implications for immunization strategies targeting VRC01-like bNAbs

Substantial variation across geographic regions in the obesity prevalence among 6–8 years old Hungarian children (COSI Hungary 2016)

Abstract Background There have been previous representative nutritional status surveys conducted in Hungary, but this is the first one that examines overweight and obesity prevalence according to the level of urbanization and in different geographic regions among 6–8-year-old children. We also assessed whether these variations were different by sex. Methods This survey was part of the fourth data collection round of World Health Organization (WHO) Childhood Obesity Surveillance Initiative which took place during the academic year 2016/2017. The representative sample was determined by two-stage cluster sampling. A total of 5332 children (48.4% boys; age 7.54 ± 0.64 years) were measured from all seven geographic regions including urban (at least 500 inhabitants per square kilometer; n = 1598), semi-urban (100 to 500 inhabitants per square kilometer; n = 1932) and rural (less than 100 inhabitants per square kilometer; n = 1802) areas. Results Using the WHO reference, prevalence of overweight and obesity within the whole sample were 14.2, and 12.7%, respectively. According to the International Obesity Task Force (IOTF) reference, rates were 12.6 and 8.6%. Northern Hungary and Southern Transdanubia were the regions with the highest obesity prevalence of 11.0 and 12.0%, while Central Hungary was the one with the lowest obesity rate (6.1%). The prevalence of overweight and obesity tended to be higher in rural areas (13.0 and 9.8%) than in urban areas (11.9 and 7.0%). Concerning differences in sex, girls had higher obesity risk in rural areas (OR = 2.0) but boys did not. Odds ratios were 2.0–3.4 in different regions for obesity compared to Central Hungary, but only among boys. Conclusions Overweight and obesity are emerging problems in Hungary. Remarkable differences were observed in the prevalence of obesity by geographic regions. These variations can only be partly explained by geographic characteristics. Trial registration Study protocol was approved by the Scientific and Research Ethics Committee of the Medical Research Council (61158–2/2016/EKU)