Reverse undercompressive shock structures in driven thin film flow

We show experimental evidence of a new structure involving an undercompressive and reverse undercompressive shock for draining films driven by a surface tension gradient against gravity. The reverse undercompressive shock is unstable to transverse perturbations while the leading undercompressive shock is stable. Depending on the pinch-off film thickness, as controlled by the meniscus, either a trailing rarefaction wave or a compressive shock separates from the reverse undercompressive shock

Zero-bias anomalies of point contact resistance due to adiabatic electron renormalization of dynamical defects

We study effect of the adiabatic electron renormalization on the parameters of the dynamical defects in the ballistic metallic point contact. The upper energy states of the ``dressed'' defect are shown to give a smaller contribution to a resistance of the contact than the lower energy ones. This holds both for the "classical" renormalization related to defect coupling with average local electron density and for the "mesoscopic" renormalization caused by the mesoscopic fluctuations of electronic density the dynamical defects are coupled with. In the case of mesoscopic renormalization one may treat the dynamical defect as coupled with Friedel oscillations originated by the other defects, both static and mobile. Such coupling lifts the energy degeneracy of the states of the dynamical defects giving different mesoscopic contribution to resistance, and provides a new model for the fluctuator as for the object originated by the electronic mesoscopic disorder rather than by the structural one. The correlation between the defect energy and the defect contribution to the resistance leads to zero-temperature and zero-bias anomalies of the point contact resistance. A comparison of these anomalies with those predicted by the Two Channel Kondo Model (TCKM) is made. It is shown, that although the proposed model is based on a completely different from TCKM physical background, it leads to a zero-bias anomalies of the point contact resistance, which are qualitatively similar to TCKM predictions.Comment: 6 pages, to be published in Phys. Rev.

A Clinical Decision Support System for the Diagnosis, Fracture Risks and Treatment of Osteoporosis

Expanding medical knowledge increases the potential risk of medical errors in clinical practice. We present, OPAD, a clinical decision support system in the field of the medical care of osteoporosis. We utilize clinical information from international guidelines and experts in the field of osteoporosis. Physicians are provided with user interface to insert standard patient data, from which OPAD provides instant diagnostic comments, 10-year risk of fragility fracture, treatment options for the given case, and when to offer a follow-up DXA-evaluation. Thus, the medical decision making is standardized according to the best expert knowledge at any given time. OPAD was evaluated in a set of 308 randomly selected individuals. OPAD’s ten-year fracture risk computation is nearly identical to FRAX (r = 0.988). In 58% of cases OPAD recommended DXA evaluation at the present time. Following a DXA measurement in all individuals, 71% of those that were recommended to have DXA at the present time received recommendation for further investigation or specific treatment by the OPAD. In only 5.9% of individuals in which DXA was not recommended, the result of the BMD measurement changed the recommendations given by OPAD

A Quantitative Study of the Mechanisms behind Thymic Atrophy in Gαi2-Deficient Mice during Colitis Development

Mice deficient for the G protein subunit Gαi2 spontaneously develop colitis, a chronic inflammatory disease associated with dysregulated T cell responses. We and others have previously demonstrated a thymic involution in these mice and an aberrant thymocyte dynamics. The Gαi2−/− mice have a dramatically reduced fraction of double positive thymocytes and an increased fraction of single positive (SP) thymocytes. In this study, we quantify a number of critical parameters in order to narrow down the underlying mechanisms that cause the dynamical changes of the thymocyte development in the Gαi2−/− mice. Our data suggest that the increased fraction of SP thymocytes results only from a decreased number of DP thymocytes, since the number of SP thymocytes in the Gαi2−/− mice is comparable to the control littermates. By measuring the frequency of T cell receptor excision circles (TRECs) in the thymocytes, we demonstrate that the number of cell divisions the Gαi2−/− SP thymocytes undergo is comparable to SP thymocytes from control littermates. In addition, our data show that the mature SP CD4+ and CD8+ thymocytes divide to the same extent before they egress from the thymus. By estimating the number of peripheral TREC+ T lymphocytes and their death rate, we could calculate the daily egression of thymocytes. Gαi2−/− mice with no/mild and moderate colitis were found to have a slower export rate in comparison to the control littermates. The quantitative measurements in this study suggest a number of dynamical changes in the thymocyte development during the progression of colitis

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesA meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.Swedish Research Council Knut and Alice Wallenberg Foundation AFA Foundation Swedish Brain Foundatio

Chagasic Thymic Atrophy Does Not Affect Negative Selection but Results in the Export of Activated CD4+CD8+ T Cells in Severe Forms of Human Disease

Extrathymic CD4+CD8+ double-positive (DP) T cells are increased in some pathophysiological conditions, including infectious diseases. In the murine model of Chagas disease, it has been shown that the protozoan parasite Trypanosoma cruzi is able to target the thymus and induce alterations of the thymic microenvironment and the lymphoid compartment. In the acute phase, this results in a severe atrophy of the organ and early release of DP cells into the periphery. To date, the effect of the changes promoted by the parasite infection on thymic central tolerance has remained elusive. Herein we show that the intrathymic key elements that are necessary to promote the negative selection of thymocytes undergoing maturation during the thymopoiesis remains functional during the acute chagasic thymic atrophy. Intrathymic expression of the autoimmune regulator factor (Aire) and tissue-restricted antigen (TRA) genes is normal. In addition, the expression of the proapoptotic Bim protein in thymocytes was not changed, revealing that the parasite infection-induced thymus atrophy has no effect on these marker genes necessary to promote clonal deletion of T cells. In a chicken egg ovalbumin (OVA)-specific T-cell receptor (TCR) transgenic system, the administration of OVA peptide into infected mice with thymic atrophy promoted OVA-specific thymocyte apoptosis, further indicating normal negative selection process during the infection. Yet, although the intrathymic checkpoints necessary for thymic negative selection are present in the acute phase of Chagas disease, we found that the DP cells released into the periphery acquire an activated phenotype similar to what is described for activated effector or memory single-positive T cells. Most interestingly, we also demonstrate that increased percentages of peripheral blood subset of DP cells exhibiting an activated HLA-DR+ phenotype are associated with severe cardiac forms of human chronic Chagas disease. These cells may contribute to the immunopathological events seen in the Chagas disease

A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

Efst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinnIL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.Netherlands Asthma Foundation University Medical Center Groningen Ministry of Health and Environmental Hygiene of Netherlands Netherlands Asthma Stichting Astma Bestrijding BBMRI European Respiratory Society private and public research funds AstraZeneca ALK-Abello, Denmar

ANCA-associated vasculitis.

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA (EGPA), are defined according to clinical features. However, genetic and other clinical findings suggest that these clinical syndromes may be better classified as PR3-positive AAV (PR3-AAV), MPO-positive AAV (MPO-AAV) and, for EGPA, by the presence or absence of ANCA (ANCA+ or ANCA-, respectively). Although any tissue can be involved in AAV, the upper and lower respiratory tract and kidneys are most commonly and severely affected. AAVs have a complex and unique pathogenesis, with evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation, recruitment and injury, with effector T cells also involved. Without therapy, prognosis is poor but treatments, typically immunosuppressants, have improved survival, albeit with considerable morbidity from glucocorticoids and other immunosuppressive medications. Current challenges include improving the measures of disease activity and risk of relapse, uncertainty about optimal therapy duration and a need for targeted therapies with fewer adverse effects. Meeting these challenges requires a more detailed knowledge of the fundamental biology of AAV as well as cooperative international research and clinical trials with meaningful input from patients

Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset

Funding Information: Funding The study was funded by NORDFORSK (grant agreement no. 90825, project NORA), the Swedish Research Council (2018-02803), the Swedish innovation Agency (Vinnova), Innovationsfonden and The Research Council of Norway, Region Stockholm-Karolinska Institutet and Region Västerbotten (ALF), the Danish Rheumatism Association (R194-A6956), the Swedish Brain Foundation, Nils and Bibbi Jensens Foundation, the Knut and Alice Wallenberg Foundation, Margaretha af Ugglas Foundation, the South-Eastern Heath Region of Norway, the Health Research Fund of Central Denmark Region, Region of Southern Denmark, the A.P. Moller Foundation for the Advancement of Medical Science, the Colitis-Crohn Foreningen, the Novo Nordisk Foundation (NNF15OC0016932), Aase og Ejnar Danielsens Fond, Beckett-Fonden, Augustinus Fonden, Knud and Edith Eriksens Mindefond, Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis’ Legat, the Psoriasis Forskningsfonden, the University of Aarhus, the Danish Rheumatism Association (R194-A6956, A1923, A3037 and A3570 – www. gigtforeningen.dk), Region of Southern Denmark’s PhD Fund, 12/7725 (www.regionsyddanmark.dk) and the Department of Rheumatology, Frederiksberg Hospital (www.frederiksberghospital. dk). MoBa Genetics has been funded by the Research Council of Norway (#229624, #223273), South East and Western Norway Health Authorities, ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Novo Nordisk Foundation and the University of Bergen. KB and SB acknowledge the Novo Nordisk Foundation (grant NNF14CC0001). Funding Information: competing financial interests as employees. OAA is a consultant to HealthLytix. The following coauthors report the following but unrelated to the current report: Karolinska Institutet, with JA as principal investigator, has entered into agreements with the following entities, mainly but not exclusively for safety monitoring of rheumatology immunomodulators: Abbvie, BMS, Eli Lilly, Janssen, MSD, Pfizer, Roche, Samsung Bioepis and Sanofi, unrelated to the present study. SB has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S and managing board memberships in Proscion A/S and Intomics A/S. BG has received research grants from AbbVie, Bristol Myers-Squibb and Pfizer; OH has received research grants from AbbVie, Novartis and Pfizer, DVJ has received speaker and consultation fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB, AGL has received speaking and/or consulting fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB; and CT has received consulting fees from Roche, speaker fees from Abbvie, Bristol Myers-Squibb, Nordic Drugs, Pfizer and Roche, and an unrestricted grant from Bristol Myers-Squibb. Publisher Copyright: © Funding Information: Funding The study was funded by NORDFORSK (grant agreement no. 90825, project NORA), the Swedish Research Council (2018-02803), the Swedish innovation Agency (Vinnova), Innovationsfonden and The Research Council of Norway, Region Stockholm-Karolinska Institutet and Region Västerbotten (ALF), the Danish Rheumatism Association (R194-A6956), the Swedish Brain Foundation, Nils and Bibbi Jensens Foundation, the Knut and Alice Wallenberg Foundation, Margaretha af Ugglas Foundation, the South-Eastern Heath Region of Norway, the Health Research Fund of Central Denmark Region, Region of Southern Denmark, the A.P. Moller Foundation for the Advancement of Medical Science, the Colitis-Crohn Foreningen, the Novo Nordisk Foundation (NNF15OC0016932), Aase og Ejnar Danielsens Fond, Beckett-Fonden, Augustinus Fonden, Knud and Edith Eriksens Mindefond, Laege Sofus Carl Emil Friis and Hustru Olga Doris Friis’ Legat, the Psoriasis Forskningsfonden, the University of Aarhus, the Danish Rheumatism Association (R194-A6956, A1923, A3037 and A3570 – www. gigtforeningen.dk), Region of Southern Denmark’s PhD Fund, 12/7725 (www.regionsyddanmark.dk) and the Department of Rheumatology, Frederiksberg Hospital (www.frederiksberghospital. dk). MoBa Genetics has been funded by the Research Council of Norway (#229624, #223273), South East and Western Norway Health Authorities, ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Novo Nordisk Foundation and the University of Bergen. KB and SB acknowledge the Novo Nordisk Foundation (grant NNF14CC0001). Funding Information: competing financial interests as employees. OAA is a consultant to HealthLytix. The following coauthors report the following but unrelated to the current report: Karolinska Institutet, with JA as principal investigator, has entered into agreements with the following entities, mainly but not exclusively for safety monitoring of rheumatology immunomodulators: Abbvie, BMS, Eli Lilly, Janssen, MSD, Pfizer, Roche, Samsung Bioepis and Sanofi, unrelated to the present study. SB has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S and managing board memberships in Proscion A/S and Intomics A/S. BG has received research grants from AbbVie, Bristol Myers-Squibb and Pfizer; OH has received research grants from AbbVie, Novartis and Pfizer, DVJ has received speaker and consultation fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB, AGL has received speaking and/or consulting fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB; and CT has received consulting fees from Roche, speaker fees from Abbvie, Bristol Myers-Squibb, Nordic Drugs, Pfizer and Roche, and an unrestricted grant from Bristol Myers-Squibb. Publisher Copyright: ©Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ∼1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-Alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10-9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10-160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10-11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10-9-10-27) and decreased plasma levels of interferon-Alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.Peer reviewe