Identification of a target antigen in human anti-tubular basement membrane nephritis

Identification of a target antigen in human anti-tubular basement membrane nephritis. Sera from two patients with primary anti-tubular–basement–membrane–mediated tubulointerstitial nephritis, one a renal allograft recipient and the other with spontaneous anti-tubular–basement–membrane disease, were analyzed for the specificity of their autoantibodies. Both sera had circulating antibodies that reacted by ELISA with extracts of tubular basement membrane from several species, but failed to react significantly with extracts of glomerular basement membrane. Reactive antigen was solubilized with 6 M guanidine-HCl, 6 M urea, with reduction and alkylation, and with sodium dodecylsulfate. Digestion of the basement membrane with collagenase released relatively small quantities of antigen from the membrane, and trypsin and pepsin destroyed its antigenicity. The antigenic activity was characterized with respect to its size distribution by gel filtration and by immuno-overlay analysis of protein blots. Collectively, the results indicate that the major reactivity of both sera is directed towards a Mr 58,000 component that is unique to the tubular basement membrane. Minor reactivities toward high molecular weight components common to both glomerular and tubular basement membranes were detected by immuno-overlay analysis. This study identifies an antigen that is involved in human anti-tubular–basement–membrane–mediated tubulointerstitial nephritis, and demonstrates an advantage of the use of denaturing extraction over proteolytic methods to prepare the antigen

The transprecision computing paradigm: Concept, design, and applications

Guaranteed numerical precision of each elementary step in a complex computation has been the mainstay of traditional computing systems for many years. This era, fueled by Moore’s law and the constant exponential improvement in computing efficiency, is at its twilight: from tiny nodes of the Internet-of-Things, to large HPC computing centers, subpicoJoule/operation energy efficiency is essential for practical realizations. To overcome the power wall, a shift from traditional computing paradigms is now mandatory. In this paper we present the driving motivations, roadmap, and expected impact of the European project OPRECOMP. OPRECOMP aims to (i) develop the first complete transprecision computing framework, (ii) apply it to a wide range of hardware platforms, from the sub-milliWatt up to the MegaWatt range, and (iii) demonstrate impact in a wide range of computational domains, spanning IoT, Big Data Analytics, Deep Learning, and HPC simulations. By combining together into a seamless design transprecision advances in devices, circuits, software tools, and algorithms, we expect to achieve major energy efficiency improvements, even when there is no freedom to relax end-to-end application quality of results. Indeed, OPRECOMP aims at demolishing the ultraconservative “precise” computing abstraction, replacing it with a more flexible and efficient one, namely transprecision computing

Direct m6A recognition by IMP1 underlays an alternative model of target selection for non-canonical methyl-readers

m6A methylation provides an essential layer of regulation in organismal development, and is aberrant in a range of cancers and neuro-pathologies. The information encoded by m6A methylation is integrated into existing RNA regulatory networks by RNA binding proteins that recognise methylated sites, the m6A readers. m6A readers include a well-characterised class of dedicated proteins, the YTH proteins, as well as a broader group of multi-functional regulators where recognition of m6A is only partially understood. Molecular insight in this recognition is essential to build a mechanistic understanding of global m6A regulation. In this study, we show that the reader IMP1 recognises the m6A using a dedicated hydrophobic platform that assembles on the methyl moiety, creating a stable high-affinity interaction. This recognition is conserved across evolution and independent from the underlying sequence context but is layered upon the strong sequence specificity of IMP1 for GGAC RNA. This leads us to propose a concept for m6A regulation where methylation plays a context-dependent role in the recognition of selected IMP1 targets that is dependent on the cellular concentration of available IMP1, differing from that observed for the YTH proteins

A new PET prototype for proton therapy: comparison of data and Monte Carlo simulations

Ion beam therapy is a valuable method for the treatment of deep-seated and radio-resistant tumors thanks to the favorable depth-dose distribution characterized by the Bragg peak. Hadrontherapy facilities take advantage of the specific ion range, resulting in a highly conformal dose in the target volume, while the dose in critical organs is reduced as compared to photon therapy. The necessity to monitor the delivery precision, i.e. the ion range, is unquestionable, thus different approaches have been investigated, such as the detection of prompt photons or annihilation photons of positron emitter nuclei created during the therapeutic treatment. Based on the measurement of the induced β+ activity, our group has developed various in-beam PET prototypes: the one under test is composed by two planar detector heads, each one consisting of four modules with a total active area of 10 × 10 cm2. A single detector module is made of a LYSO crystal matrix coupled to a position sensitive photomultiplier and is read-out by dedicated frontend electronics. A preliminary data taking was performed at the Italian National Centre for Oncological Hadron Therapy (CNAO, Pavia), using proton beams in the energy range of 93–112 MeV impinging on a plastic phantom. The measured activity profiles are presented and compared with the simulated ones based on the Monte Carlo FLUKA package

The emergence of Exercise Addiction, Body Dysmorphic Disorder, and other image-related psychopathological correlates in fitness settings: A cross sectional study.

INTRODUCTION: In a society that perpetuates the strive for a perfect appearance, a fit body has become synonymous with success, but simultaneously hard to achieve. This represents a fertile ground for the development of Exercise Addiction (EA) alongside other disorders, such as Body Dysmorphic Disorder (BDD). This study aims to explore the diffusion of EA in fitness settings in the United Kingdom, Italy, Netherlands, Hungary and the previously unexplored association with appearance anxiety, BDD, self-esteem and the use of fitness supplements. METHODS: A large cross-sectional sample (N = 1711) was surveyed in fitness settings using the Exercise Addiction Inventory (EAI), Appearance Anxiety Inventory (AAI) and Rosenberg's Self Esteem Scale (RSE) in addition to questions surrounding the use of fitness supplements. RESULTS: Compulsive exercise, appearance anxiety and low self-esteem were present in this sample according to the psychometric measures used (EAI, AAI, RSE). 11.7% scored over the cut off for EA, with alarming peaks in the Netherlands (20.9%) and the United Kingdom (16.1%). 38.5% were found at risk of BDD, mainly female (47.2%). 39.8% used fitness enhancing supplements without medical consultation (95.5%). This cohort of supplement users scored higher in both EAI and AAI. The logistic regression model revealed a strong association between the consumption of sport products and the level of EA across the sample with an odds ratio (OR) of 3.03. Other co-variable factors among female were appearance anxiety (AAI; OR 1.59) and to a lesser extent self-esteem (RSE) (OR 1.08). CONCLUSIONS: This study identified a high risk of EA, appearance anxiety and BDD amongst a cohort of gym users internationally. The previously-unexplored association between these disorders and the unsupervised use of a variety of fitness products, including illicit drugs, highlights the need for informed and integrated responses targeting such vulnerable individuals

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London