Showing papers by "University of Mainz published in 2018"

Minimal information for studies of extracellular vesicles 2018 (MISEV2018) : a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

Dark Matter Search Results from a One Ton-Year Exposure of XENON1T.

Abstract: We report on a search for weakly interacting massive particles (WIMPs) using 278.8 days of data collected with the XENON1T experiment at LNGS. XENON1T utilizes a liquid xenon time projection chamber with a fiducial mass of (1.30±0.01) ton, resulting in a 1.0 ton yr exposure. The energy region of interest, [1.4,10.6] keVee ([4.9,40.9] keVnr), exhibits an ultralow electron recoil background rate of [82-3+5(syst)±3(stat)] events/(ton yr keVee). No significant excess over background is found, and a profile likelihood analysis parametrized in spatial and energy dimensions excludes new parameter space for the WIMP-nucleon spin-independent elastic scatter cross section for WIMP masses above 6 GeV/c2, with a minimum of 4.1×10-47 cm2 at 30 GeV/c2 and a 90% confidence level.

MODOMICS: a database of RNA modification pathways. 2017 update.

Abstract: MODOMICS is a database of RNA modifications that provides comprehensive information concerning the chemical structures of modified ribonucleosides, their biosynthetic pathways, the location of modified residues in RNA sequences, and RNA-modifying enzymes. In the current database version, we included the following new features and data: extended mass spectrometry and liquid chromatography data for modified nucleosides; links between human tRNA sequences and MINTbase - a framework for the interactive exploration of mitochondrial and nuclear tRNA fragments; new, machine-friendly system of unified abbreviations for modified nucleoside names; sets of modified tRNA sequences for two bacterial species, updated collection of mammalian tRNA modifications, 19 newly identified modified ribonucleosides and 66 functionally characterized proteins involved in RNA modification. Data from MODOMICS have been linked to the RNAcentral database of RNA sequences. MODOMICS is available at http://modomics.genesilico.pl.

Electrifying Organic Synthesis

Abstract: The direct synthetic organic use of electricity is currently experiencing a renaissance. More synthetically oriented laboratories working in this area are exploiting both novel and more traditional concepts, paving the way to broader applications of this niche technology. As only electrons serve as reagents, the generation of reagent waste is efficiently avoided. Moreover, stoichiometric reagents can be regenerated and allow a transformation to be conducted in an electrocatalytic fashion. However, the application of electroorganic transformations is more than minimizing the waste footprint, it rather gives rise to inherently safe processes, reduces the number of steps of many syntheses, allows for milder reaction conditions, provides alternative means to access desired structural entities, and creates intellectual property (IP) space. When the electricity originates from renewable resources, this surplus might be directly employed as a terminal oxidizing or reducing agent, providing an ultra-sustainable and therefore highly attractive technique. This Review surveys recent developments in electrochemical synthesis that will influence the future of this area.

Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial

Abstract: Summary Background Combined BRAF-MEK inhibitor therapy is the standard of care for BRAF V600 -mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAF V600 -mutant melanoma. Methods COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer [AJCC] stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAF V600E or BRAF V600K mutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and were treatment naive or had progressed on or after previous first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) via interactive response technology to receive either oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). The primary endpoint was progression-free survival by blinded independent central review for encorafenib plus binimetinib versus vemurafenib. Efficacy analyses were by intention-to-treat. Safety was analysed in patients who received at least one dose of study drug and one postbaseline safety assessment. The results of part 2 will be published separately. This study is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38. Findings Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8–16·9), median progression-free survival was 14·9 months (95% CI 11·0–18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6–8·2) in the vemurafenib group (hazard ratio [HR] 0·54, 95% CI 0·41–0·71; two-sided p Interpretation Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF -mutant melanoma. Funding Array BioPharma, Novartis.

Modern Electrochemical Aspects for the Synthesis of Value-Added Organic Products.

Abstract: The use of electricity instead of stoichiometric amounts of oxidizers or reducing agents in synthesis is very appealing for economic and ecological reasons, and represents a major driving force for research efforts in this area. To use electron transfer at the electrode for a successful transformation in organic synthesis, the intermediate radical (cation/anion) has to be stabilized. Its combination with other approaches in organic chemistry or concepts of contemporary synthesis allows the establishment of powerful synthetic methods. The aim in the 21st Century will be to use as little fossil carbon as possible and, for this reason, the use of renewable sources is becoming increasingly important. The direct conversion of renewables, which have previously mainly been incinerated, is of increasing interest. This Review surveys many of the recent seminal important developments which will determine the future of this dynamic emerging field.

Personalized vaccines for cancer immunotherapy.

Abstract: Cancer is characterized by an accumulation of genetic alterations. Somatic mutations can generate cancer-specific neoepitopes that are recognized by autologous T cells as foreign and constitute ideal cancer vaccine targets. Every tumor has its own unique composition of mutations, with only a small fraction shared between patients. Technological advances in genomics, data science, and cancer immunotherapy now enable the rapid mapping of the mutations within a genome, rational selection of vaccine targets, and on-demand production of a therapy customized to a patient's individual tumor. First-in-human clinical trials of personalized cancer vaccines have shown the feasibility, safety, and immunotherapeutic activity of targeting individual tumor mutation signatures. With vaccination development being promoted by emerging innovations of the digital age, vaccinating a patient with individual tumor mutations may become the first truly personalized treatment for cancer.

Heterogeneous electro-Fenton and photoelectro-Fenton processes: A critical review of fundamental principles and application for water/wastewater treatment

Abstract: This exhaustive review focuses on the fundamental principles and applications of heterogeneous electrochemical wastewater treatment based on Fenton’s chemistry reaction. The elementary equations involved in formation of hydroxyl radical in homogeneous electro-Fenton (EF) and photo electro-Fenton (PEF) processes was presented and the advantages of using insoluble solids as heterogeneous catalyst rather than soluble iron salts (heterogeneous electro-Fenton process) (Hetero-EF) was enumerated. Some of the required features of good heterogeneous catalysts were discussed, followed by the mechanisms of catalytic activation of H2O2 to reactive oxygen species (ROS) especially hydroxyl radical ( OH) by heterogeneous catalyst in Hetero-EF system. Extensive discussion on the two configuration of Hetero-EF system vis-a-vis added solid catalysts and functionalized cathodic materials were provided along with summaries of some relevant studies that are available in literature. The solid catalysts and the functionalized cathodic materials that have been utilized in Hetero-EF wastewater treatment were grouped into different classes and brief discussion on their synthesis route were given. Besides, the use of solid catalysts and iron-functionalized cathodic materials in bioelectrochemical system (BES) especially bioelectro-Fenton technology (BEF) using microbial fuel cells (MFCs) with concurrent electricity generation for Hetero-EF treatment of biorefractory organic pollutants was discussed. In the final part, emphasis was made on the challenges and future prospects of the Hetero-EF for wastewater treatment.

Electrochemical Arylation Reaction.

Abstract: Arylated products are found in various fields of chemistry and represent essential entities for many applications. Therefore, the formation of this structural feature represents a central issue of contemporary organic synthesis. By the action of electricity the necessity of leaving groups, metal catalysts, stoichiometric oxidizers, or reducing agents can be omitted in part or even completely. The replacement of conventional reagents by sustainable electricity not only will be environmentally benign but also allows significant short cuts in electrochemical synthesis. In addition, this methodology can be considered as inherently safe. The current survey is organized in cathodic and anodic conversions as well as by the number of leaving groups being involved. In some electroconversions the reagents used are regenerated at the electrode, whereas in other electrotransformations free radical sequences are exploited to afford a highly sustainable process. The electrochemical formation of the aryl–substrate bond ...

2018 European Thyroid Association Guideline for the Management of Graves' Hyperthyroidism

Abstract: Graves' disease (GD) is a systemic autoimmune disorder characterized by the infiltration of thyroid antigen-specific T cells into thyroid-stimulating hormone receptor (TSH-R)-expressing tissues. Stimulatory autoantibodies (Ab) in GD activate the TSH-R leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. Diagnosis of GD is straightforward in a patient with biochemically confirmed thyrotoxicosis, positive TSH-R-Ab, a hypervascular and hypoechoic thyroid gland (ultrasound), and associated orbitopathy. In GD, measurement of TSH-R-Ab is recommended for an accurate diagnosis/differential diagnosis, prior to stopping antithyroid drug (ATD) treatment and during pregnancy. Graves' hyperthyroidism is treated by decreasing thyroid hormone synthesis with the use of ATD, or by reducing the amount of thyroid tissue with radioactive iodine (RAI) treatment or total thyroidectomy. Patients with newly diagnosed Graves' hyperthyroidism are usually medically treated for 12-18 months with methimazole (MMI) as the preferred drug. In children with GD, a 24- to 36-month course of MMI is recommended. Patients with persistently high TSH-R-Ab at 12-18 months can continue MMI treatment, repeating the TSH-R-Ab measurement after an additional 12 months, or opt for therapy with RAI or thyroidectomy. Women treated with MMI should be switched to propylthiouracil when planning pregnancy and during the first trimester of pregnancy. If a patient relapses after completing a course of ATD, definitive treatment is recommended; however, continued long-term low-dose MMI can be considered. Thyroidectomy should be performed by an experienced high-volume thyroid surgeon. RAI is contraindicated in Graves' patients with active/severe orbitopathy, and steroid prophylaxis is warranted in Graves' patients with mild/active orbitopathy receiving RAI.

Topological antiferromagnetic spintronics

Abstract: The recent demonstrations of electrical manipulation and detection of antiferromagnetic spins have opened up a new chapter in the story of spintronics. Here, we review the emerging research field that is exploring the links between antiferromagnetic spintronics and topological structures in real and momentum space. Active topics include proposals to realize Majorana fermions in antiferromagnetic topological superconductors, to control topological protection and Dirac points by manipulating antiferromagnetic order parameters, and to exploit the anomalous and topological Hall effects of zero-net-moment antiferromagnets. We explain the basic concepts behind these proposals, and discuss potential applications of topological antiferromagnetic spintronics.

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Abstract: Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10-13) and African ancestries (rs2066702; P = 2.2 × 10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

Perspective: Magnetic skyrmions—Overview of recent progress in an active research field

Abstract: Within a decade, the field of magnetic skyrmionics has developed from a niche prediction to a huge and active research field. Not only do magnetic skyrmions—magnetic whirls with a unique topology—reveal fundamentally new physics, but they have also risen to prominence as up-and-coming candidates for next-generation high-density efficient information encoding. Within a few years, it has been possible to efficiently create, manipulate, and destroy nanometer-size skyrmions in device-compatible materials at room-temperature by all electrical means. Despite the incredibly rapid progress, several challenges still remain to obtain fully functional and competitive skyrmion devices, as discussed in this perspective article with a focus on recent results.

Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial

Abstract: Summary Background Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAF V600 -mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival. Methods COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF V600E or BRAF V600K mutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38. Findings Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9–37·5). Median overall survival was 33·6 months (95% CI 24·4–39·2) with encorafenib plus binimetinib and 16·9 months (14·0–24·5) with vemurafenib (hazard ratio 0·61 [95% CI 0·47–0·79]; two-sided p Interpretation The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAF V600 -mutant melanoma. Funding Array BioPharma, Novartis.

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Abstract: Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein-protein or DNA-protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases.

Writing and reading antiferromagnetic Mn2Au by Néel spin-orbit torques and large anisotropic magnetoresistance.

Abstract: Using antiferromagnets as active elements in spintronics requires the ability to manipulate and read-out the Neel vector orientation. Here we demonstrate for Mn2Au, a good conductor with a high ordering temperature suitable for applications, reproducible switching using current pulse generated bulk spin-orbit torques and read-out by magnetoresistance measurements. Reversible and consistent changes of the longitudinal resistance and planar Hall voltage of star-patterned epitaxial Mn2Au(001) thin films were generated by pulse current densities of ≃107 A/cm2. The symmetry of the torques agrees with theoretical predictions and a large read-out magnetoresistance effect of more than ≃6% is reproduced by ab initio transport calculations.

The multiple directions of antiferromagnetic spintronics

Abstract: New developments in spintronics based on antiferromagnetic materials show promise for improved fundamental understanding and applications in technology.

Tunable long-distance spin transport in a crystalline antiferromagnetic iron oxide

Abstract: Spintronics relies on the transport of spins, the intrinsic angular momentum of electrons, as an alternative to the transport of electron charge as in conventional electronics. The long-term goal of spintronics research is to develop spin-based, low-dissipation computing-technology devices. Recently, long-distance transport of a spin current was demonstrated across ferromagnetic insulators1. However, antiferromagnetically ordered materials, the most common class of magnetic materials, have several crucial advantages over ferromagnetic systems for spintronics applications2: antiferromagnets have no net magnetic moment, making them stable and impervious to external fields, and can be operated at terahertz-scale frequencies3. Although the properties of antiferromagnets are desirable for spin transport4–7, indirect observations of such transport indicate that spin transmission through antiferromagnets is limited to only a few nanometres8–10. Here we demonstrate long-distance propagation of spin currents through a single crystal of the antiferromagnetic insulator haematite (α-Fe2O3)11, the most common antiferromagnetic iron oxide, by exploiting the spin Hall effect for spin injection. We control the flow of spin current across a haematite–platinum interface—at which spins accumulate, generating the spin current—by tuning the antiferromagnetic resonance frequency using an external magnetic field12. We find that this simple antiferromagnetic insulator conveys spin information parallel to the antiferromagnetic Neel order over distances of more than tens of micrometres. This mechanism transports spins as efficiently as the most promising complex ferromagnets1. Our results pave the way to electrically tunable, ultrafast, low-power, antiferromagnetic-insulator-based spin-logic devices6,13 that operate without magnetic fields at room temperature.

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis:

Abstract: Background:Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years There is a need for a reference tool compiling current data to aid professionals in trea

Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m6A machinery component Wtap/Fl(2)d.

Abstract: N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes, playing crucial roles in multiple biological processes. m6A is catalyzed by the activity of methyltransferase-like 3 (Mettl3), which depends on additional proteins whose precise functions remain poorly understood. Here we identified Zc3h13 (zinc finger CCCH domain-containing protein 13)/Flacc [Fl(2)d-associated complex component] as a novel interactor of m6A methyltransferase complex components in Drosophila and mice. Like other components of this complex, Flacc controls m6A levels and is involved in sex determination in Drosophila We demonstrate that Flacc promotes m6A deposition by bridging Fl(2)d to the mRNA-binding factor Nito. Altogether, our work advances the molecular understanding of conservation and regulation of the m6A machinery.

Search for dark matter and other new phenomena in events with an energetic jet and large missing transverse momentum using the ATLAS detector

Abstract: Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses proton-proton collision data corresponding to an integrated luminosity of 36.1 fb−1 at a centre-of-mass energy of 13 TeV collected in 2015 and 2016 with the ATLAS detector at the Large Hadron Collider. Events are required to have at least one jet with a transverse momentum above 250 GeV and no leptons (e or μ). Several signal regions are considered with increasing requirements on the missing transverse momentum above 250 GeV. Good agreement is observed between the number of events in data and Standard Model predictions. The results are translated into exclusion limits in models with pair-produced weakly interacting dark-matter candidates, large extra spatial dimensions, and supersymmetric particles in several compressed scenarios.

The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update

Abstract: Hereditary Angioedema (HAE) is a rare and disabling disease. Early diagnosis and appropriate therapy are essential. This update and revision of the global guideline for HAE provides up-to-date consensus recommendations for the management of HAE. In the development of this update and revision of the guideline, an international expert panel reviewed the existing evidence and developed 20 recommendations that were discussed, finalized and consented during the guideline consensus conference in June 2016 in Vienna. The final version of this update and revision of the guideline incorporates the contributions of a board of expert reviewers and the endorsing societies. The goal of this guideline update and revision is to provide clinicians and their patients with guidance that will assist them in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2). The key clinical questions covered by these recommendations are: (1) How should HAE-1/2 be defined and classified?, (2) How should HAE-1/2 be diagnosed?, (3) Should HAE-1/2 patients receive prophylactic and/or on-demand treatment and what treatment options should be used?, (4) Should HAE-1/2 management be different for special HAE-1/2 patient groups such as pregnant/lactating women or children?, and (5) Should HAE-1/2 management incorporate self-administration of therapies and patient support measures?

Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.

Abstract: This Consensus Statement was organized by the European Network of Human Congenital Imprinting Disorders (EUCIDnet) with financial support from European Cooperation in Science and Technology (COST; BM1208) Newlife the Charity for Disabled Children, the European Society of Pediatric Endocrinology (ESPE) and the Societe Francaise de lutte contre les Cancers et leucemies de l'enfant et de l'adolescent (SFCE) provided funding for the consensus meeting The European Society of Pediatric Nephrology (ESPN) provided support for the meeting Individual authors would like to thank the following funders for research support: Alex's Lemonade Stand Foundation (JMK); Bundesministerium fur Bildung und Forschung (BMBF) (number 01GM1513C) (DP); Child Growth Foundation (KT-B); European Union FP7 Innovative Training Network (ITN) Ingenium N 290123 (YLeB, AR, IN, ERM); FIS (grant PI15/01481) (PL, JT); Fondation de Recherche Medicale (YLeB); Margaret Q Landenberger Foundation (JMK); MIUR PRIN 2015 JHLY35 (AR, GBF, SRu); MOH Grants to Istituto Auxologico Italiano (grant: RC 08C502_2015) (SRu); US National Institutes of Health (grant K08CA193915) (JMK); UK National Institute for Health Research (NIHR) Rare Diseases Translational Research Collaboration (ACF); St Baldrick's Scholar Award (JMK); The Estonian Research Council (grant PUT355) (KO); Universite P et M Curie, Institut National de la Sante Et de la Recherche Medicale (YLB); Telethon-Italia GGP15131 and AIRC IG18671 (AR); Wellcome Trust (MDK); European Research Council (ERM); and NIHR Senior Investigator Award (ERM) The University of Cambridge has received salary support in respect of ERM from the National Health Service (NHS) in the East of England through the Clinical Academic Reserve The views expressed are those of the authors and not necessarily those of the NHS or UK Department of Health No funding was received from pharmaceutical companies

Precision and accuracy of single-molecule FRET measurements—a multi-laboratory benchmark study

Abstract: Single-molecule Forster resonance energy transfer (smFRET) is increasingly being used to determine distances, structures, and dynamics of biomolecules in vitro and in vivo. However, generalized protocols and FRET standards to ensure the reproducibility and accuracy of measurements of FRET efficiencies are currently lacking. Here we report the results of a comparative blind study in which 20 labs determined the FRET efficiencies (E) of several dye-labeled DNA duplexes. Using a unified, straightforward method, we obtained FRET efficiencies with s.d. between ±0.02 and ±0.05. We suggest experimental and computational procedures for converting FRET efficiencies into accurate distances, and discuss potential uncertainties in the experiment and the modeling. Our quantitative assessment of the reproducibility of intensity-based smFRET measurements and a unified correction procedure represents an important step toward the validation of distance networks, with the ultimate aim of achieving reliable structural models of biomolecular systems by smFRET-based hybrid methods.

Substantial convection and precipitation enhancements by ultrafine aerosol particles

Abstract: Aerosol-cloud interactions remain the largest uncertainty in climate projections. Ultrafine aerosol particles smaller than 50 nanometers (UAP<50) can be abundant in the troposphere but are conventionally considered too small to affect cloud formation. Observational evidence and numerical simulations of deep convective clouds (DCCs) over the Amazon show that DCCs forming in a low-aerosol environment can develop very large vapor supersaturation because fast droplet coalescence reduces integrated droplet surface area and subsequent condensation. UAP<50 from pollution plumes that are ingested into such clouds can be activated to form additional cloud droplets on which excess supersaturation condenses and forms additional cloud water and latent heating, thus intensifying convective strength. This mechanism suggests a strong anthropogenic invigoration of DCCs in previously pristine regions of the world.