Structural, Biophysical, and Functional Studies of TREM2 In Neurodegenerative Disease

Alzheimer\u27s disease (AD) and other neurodegenerative diseases present a large and growing challenge to global health. The immune system, particularly the innate immune system, is increasingly recognized as having a major role in these pathologies. The innate immune system is responsible to contain disease and promote healing. However, immune misregulation exacerbates disease. The innate immunomodulatory receptor Triggering receptor expressed on myeloid cells-2 (TREM2) is expressed on myeloid cells such as dendritic cells, macrophages, and in the brain, on microglia. TREM2 is a single-pass transmembrane receptor with an extracellular Ig domain that mediates ligand binding. This protein regulates inflammation in vitro and is required in vivo to sustain the microglia response during neurodegenerative diseases. Additionally, genetic studies have identified rare coding variants that increase risk for AD and separate variants that cause the severe, early fatal dementia known as Nasu-Hakola Disease (NHD). Combined, these animal and genetic studies have described a crucial role for TREM2 and identified variants that contribute disease risk. However, a full understanding of TREM2 function has been lacking due to a dearth of information regarding its structure and ligands. The goal of this study was to determine the TREM2 structure and understand how the disease variants alter structure and function. The TREM2 Ig domain was expressed, purified, and crystallized using a novel mammalian expression system. The TREM2 crystal structure and subsequent biophysical and functional assays revealed that NHD variants reduce protein stability and cause protein misfolding while the AD variants have minimal structural changes and instead impact ligand binding. TREM2 bound cell-surface sulfated proteoglycans on mammalian cells. AD-risk variants decreased binding while another variant, which is possibly protective, increased binding. These variants mapped a functional ligand-binding surface on the TREM2 protein. Functionally, chemical inhibition of nascent proteoglycan sulfation impaired TREM2 signaling, suggesting a ligand that acts in cis to position TREM2 for signaling. Additionally, TREM2 interacts with the soluble lipoprotein apolipoprotein E (ApoE) and with amyloid beta (Aβ) peptides. Intriguingly, AD-risk variants impair both of these interactions, suggesting a physiological relevance during AD. These experiments offer the first structural and mechanistic studies of TREM2 function and will engender targeted molecular therapies to restore or enhance TREM2 function during neurodegenerative disease

Impulsive noise removal from color images with morphological filtering

This paper deals with impulse noise removal from color images. The proposed noise removal algorithm employs a novel approach with morphological filtering for color image denoising; that is, detection of corrupted pixels and removal of the detected noise by means of morphological filtering. With the help of computer simulation we show that the proposed algorithm can effectively remove impulse noise. The performance of the proposed algorithm is compared in terms of image restoration metrics and processing speed with that of common successful algorithms.Comment: The 6th international conference on analysis of images, social networks, and texts (AIST 2017), 27-29 July, 2017, Moscow, Russi

Damage accumulation in multilayer thin films on gamma titanium aluminides

The present paper involves comprehensive investigations towards an understanding on how aggressive environments, high service temperatures and long dwell times affect damage growth and lifetime reduction of different components of automotive combustion engines and aero-engines made out of gamma titanium aluminides with protective coatings. The outcome of this paper is related to the practical recommendations on how damage growth at high temperatures in multilayer thin films on gamma titanium aluminides under thermal cyclic conditions and multiaxial stress state may be controlled in order to reduce environmental degradation, optimize the protective coating and extend lifetime of a component for automotive, energy and aerospace applications.Настоящая статья включает в себя всеобъемлющие исследования, направленные на понимание того, как агрессивные среды, высокие температуры и время цикла нагружения влияют на рост повреждаемости и сокращение долговечности различных компонентов автомобильных двигателей внутреннего сгорания и авиационных двигателей, изготовленных из гамма алюминидов титана с защитными покрытиями. В результате этих исследований установлено, как рост поврежденности при высоких температурах в многослойных тонких пленках на основе гамма алюминидов титана в условиях теплового циклического нагружения и многоосного напряженного состояния можно контролировать с целью снижения деградации под влиянием окружающей среды, оптимизации защитного покрытия и увеличения срока службы элементов конструкций для автомобильной, энергетической и аэрокосмической промышленности

Geometry-dependent critical currents in superconducting nanocircuits

In this paper we calculate the critical currents in thin superconducting strips with sharp right-angle turns, 180-degree turnarounds, and more complicated geometries, where all the line widths are much smaller than the Pearl length $\Lambda = 2 \lambda^2/d$. We define the critical current as the current that reduces the Gibbs free-energy barrier to zero. We show that current crowding, which occurs whenever the current rounds a sharp turn, tends to reduce the critical current, but we also show that when the radius of curvature is less than the coherence length this effect is partially compensated by a radius-of-curvature effect. We propose several patterns with rounded corners to avoid critical-current reduction due to current crowding. These results are relevant to superconducting nanowire single-photon detectors, where they suggest a means of improving the bias conditions and reducing dark counts. These results also have relevance to normal-metal nanocircuits, as these patterns can reduce the electrical resistance, electromigration, and hot spots caused by nonuniform heating.Comment: 29 pages, 24 figure

A reduced model for shock and detonation waves. II. The reactive case

We present a mesoscopic model for reactive shock waves, which extends a previous model proposed in [G. Stoltz, Europhys. Lett. 76 (2006), 849]. A complex molecule (or a group of molecules) is replaced by a single mesoparticle, evolving according to some Dissipative Particle Dynamics. Chemical reactions can be handled in a mean way by considering an additional variable per particle describing a rate of reaction. The evolution of this rate is governed by the kinetics of a reversible exothermic reaction. Numerical results give profiles in qualitative agreement with all-atom studies

Benchmark creep tests for thermal barrier coatings

The topic of this paper involves a number of benchmark creep tests and reference solutions that give the possibility to verify the finite element analysis of stress redistribution in thermal barrier coatings related to commercial software packages. The numerical results have been compared in the benchmark tests with the results obtained by other methods and by other authors. The results of creep studies revealed the magnitudes of the local stresses that correlate with the residual stresses determined in the thermally grown oxide by the luminescence spectroscopy method. The creep properties of Ni-based superalloy substrate have strong influence on the stress state and subsequent failure of EB-PVD thermal barrier coatings. The obtained numerical results demonstrate that the future EB-PVD thermal barrier coatings should be developed simultaneously with the Ni-based superalloy substrate, because the effectiveness of coating is influenced by the composition and properties of the substrate.Тема цієї статті включає в себе ряд тестів на повзучість та еталонні рішення, які дають можливість перевірити аналіз методом скінченних елементів перерозподілу напружень в теплозахисних покриттях, пов'язаний з комерційними пакетами програмного забезпечення. Чисельні результати були порівняні у тестах з результатами, отриманими іншими методами та іншими авторами. Результати досліджень повзучості показали величини локальних напружень, які корелюють із залишковими напруженнями, визначеними в термічно вирощеному оксиді методом люмінесцентної спектроскопії. Повзучість нікелевих жароміцних сплавів підкладки має сильний вплив на напружений стан і подальше руйнування EB-PVD теплозахисних покриттів. Отримані чисельні результати показують, що майбутні EB-PVD теплозахисні покриття повинні бути розроблені одночасно з нікелевою підкладкою, оскільки ефективність покриття залежить від складу і властивостей підкладки

Public sector nurses in Swaziland: can the downturn be reversed?

BACKGROUND: The lack of human resources for health (HRH) is increasingly being recognized as a major bottleneck to scaling up antiretroviral treatment (ART), particularly in sub-Saharan Africa, whose societies and health systems are hardest hit by HIV/AIDS. In this case study of Swaziland, we describe the current HRH situation in the public sector. We identify major factors that contribute to the crisis, describe policy initiatives to tackle it and base on these a number of projections for the future. Finally, we suggest some areas for further research that may contribute to tackling the HRH crisis in Swaziland. METHODS: We visited Swaziland twice within 18 months in order to capture the HRH situation as well as the responses to it in 2004 and in 2005. Using semi-structured interviews with key informants and group interviews, we obtained qualitative and quantitative data on the HRH situation in the public and mission health sectors. We complemented this with an analysis of primary documents and a review of the available relevant reports and studies. RESULTS: The public health sector in Swaziland faces a serious shortage of health workers: 44% of posts for physicians, 19% of posts for nurses and 17% of nursing assistant posts were unfilled in 2004. We identified emigration and attrition due to HIV/AIDS as major factors depleting the health workforce. The annual training output of only 80 new nurses is not sufficient to compensate for these losses, and based on the situation in 2004 we estimated that the nursing workforce in the public sector would have been reduced by more than 40% by 2010. In 2005 we found that new initiatives by the Swazi government, such as the scale-up of ART, the introduction of retention measures to decrease emigration and the influx of foreign nurses could have the potential to improve the situation. A combination of such measures, together with the planned increase in the training capacity of the country's nursing schools, could even reverse the trend of a diminishing health workforce. CONCLUSION: Emigration and attrition due to HIV/AIDS are undermining the health workforce in the public sector of Swaziland. Short-term and long-term measures for overcoming this HRH crisis have been initiated by the Swazi government and must be further supported and increased. Scaling up antiretroviral treatment (ART) and making it accessible and acceptable for the health workforce is of paramount importance for halting the attrition due to HIV/AIDS. To this end, we also recommend exploring ways to make ART delivery less labour-intensive. The production of nurses and nursing assistants must be urgently increased. Although the migration of HRH is a global issue requiring solutions at various levels, innovative in-country strategies for retaining staff must be further explored in order to stem as much as possible the emigration from Swaziland

Field and current distributions and ac losses in superconducting strips

In this paper I discuss analytic and numerical calculations of the magnetic-field and sheet-current distributions in superconducting strips of width 2a and arbitrary thickness 2b at the center when the cross section is an ellipse, a rectangle, and a shape intermediate between these limits. Using critical-state theory, I use several methods to determine the functional dependence of the ac transport-current losses upon F = I/Ic, where I is the peak alternating current and Ic is the critical current, and I discuss how this dependence can be affected by the cross-sectional shape, aspect ratio, and a flux-density-dependent critical current density Jc(B).Comment: 13 pages, 11 figure

Impact of proton pump inhibitor treatment on gastrointestinal bleeding associated with non-steroidal anti-inflammatory drug use among post-myocardial infarction patients taking antithrombotics: nationwide study

Study question What is the effect of proton pump inhibitors (PPIs) on the risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with non-steroidal anti-inflammatory drugs (NSAIDs)? Methods This was a nationwide cohort study based on linked administrative registry data from all hospitals in Denmark between 1997 and 2011. The study included patients aged 30 years and over admitted with a first myocardial infarction who survived at least 30 days after discharge. The association between PPIs and risk of gastrointestinal bleeding according to NSAID plus antithrombotic therapy was estimated using adjusted time dependent Cox regression models. Study answer and limitations The use of PPIs was independently associated with decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with NSAIDs. Of 82 955 post-myocardial infarction patients (mean age 67.4 years, 64% (n=53 070) men), all of whom were taking single or dual antithrombotic therapy, 42.5% (n=35 233) filled at least one prescription for NSAIDs and 45.5% (n=37 771) received PPIs. Over a mean follow-up of 5.1 years, 3229 gastrointestinal bleeds occurred. The crude incidence rates of bleeding (events/100 person years) on NSAID plus antithrombotic therapy were 1.8 for patients taking PPIs and 2.1 for those not taking PPIs. The adjusted risk of bleeding was lower with PPI use (hazard ratio 0.72, 95% confidence interval 0.54 to 0.95) regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used. The main limitation of the study is its observational non-randomised design. The results suggest that PPI treatment probably has a beneficial effect regardless of underlying gastrointestinal risk and that when NSAIDs cannot be avoided in post-myocardial infarction patients, physicians might prescribe a PPI as well. The study does not clarify whether PPIs might be safely omitted in specific subgroups of patients with a low risk of gastrointestinal bleeding. What this study adds In post-myocardial infarction patients, bleeding complications have been associated with both antithrombotic and NSAID treatment. Concurrent use of PPIs was independently associated with a decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and NSAID, regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used. Funding, competing interests, data sharing AMSO has received a grant from the Danish Council of Independent Research (grant 12-132760). GHG is supported by an unrestricted research scholarship from the Novo Nordisk Foundation