Showing papers by "University of Mainz published in 2016"

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

Discrete Choice Methods with Simulation

Abstract: Discrete Choice Methods with Simulation by Kenneth Train has been available in the second edition since 2009. The book is published by Cambridge University Press and is also available for download ...

Precomputed Real-Time Texture Synthesis with Markovian Generative Adversarial Networks

Abstract: This paper proposes Markovian Generative Adversarial Networks (MGANs), a method for training generative networks for efficient texture synthesis. While deep neural network approaches have recently demonstrated remarkable results in terms of synthesis quality, they still come at considerable computational costs (minutes of run-time for low-res images). Our paper addresses this efficiency issue. Instead of a numerical deconvolution in previous work, we precompute a feed-forward, strided convolutional network that captures the feature statistics of Markovian patches and is able to directly generate outputs of arbitrary dimensions. Such network can directly decode brown noise to realistic texture, or photos to artistic paintings. With adversarial training, we obtain quality comparable to recent neural texture synthesis methods. As no optimization is required at generation time, our run-time performance (0.25 M pixel images at 25 Hz) surpasses previous neural texture synthesizers by a significant margin (at least 500 times faster). We apply this idea to texture synthesis, style transfer, and video stylization.

Observation of room-temperature magnetic skyrmions and their current-driven dynamics in ultrathin metallic ferromagnets

Abstract: Magnetic skyrmions are topologically protected spin textures that exhibit fascinating physical behaviours and large potential in highly energy-efficient spintronic device applications. The main obstacles so far are that skyrmions have been observed in only a few exotic materials and at low temperatures, and fast current-driven motion of individual skyrmions has not yet been achieved. Here, we report the observation of stable magnetic skyrmions at room temperature in ultrathin transition metal ferromagnets with magnetic transmission soft X-ray microscopy. We demonstrate the ability to generate stable skyrmion lattices and drive trains of individual skyrmions by short current pulses along a magnetic racetrack at speeds exceeding 100 m s(-1) as required for applications. Our findings provide experimental evidence of recent predictions and open the door to room-temperature skyrmion spintronics in robust thin-film heterostructures.

Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma

Abstract: BackgroundDaratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma. MethodsIn this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival. ResultsA prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period ...

Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy

Abstract: Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses. However, the systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encoded antigen by DC populations and macrophages in various lymphoid compartments. RNA-LPX triggers interferon-α (IFNα) release by plasmacytoid DCs and macrophages. Consequently, DC maturation in situ and inflammatory immune mechanisms reminiscent of those in the early systemic phase of viral infection are activated. We show that RNA-LPX encoding viral or mutant neo-antigens or endogenous self-antigens induce strong effector and memory T-cell responses, and mediate potent IFNα-dependent rejection of progressive tumours. A phase I dose-escalation trial testing RNA-LPX that encode shared tumour antigens is ongoing. In the first three melanoma patients treated at a low-dose level, IFNα and strong antigen-specific T-cell responses were induced, supporting the identified mode of action and potency. As any polypeptide-based antigen can be encoded as RNA, RNA-LPX represent a universally applicable vaccine class for systemic DC targeting and synchronized induction of both highly potent adaptive as well as type-I-IFN-mediated innate immune mechanisms for cancer immunotherapy.

Neutrino Physics with JUNO

Abstract: The Jiangmen Underground Neutrino Observatory (JUNO), a 20 kton multi-purpose underground liquid scintillator detector, was proposed with the determination of the neutrino mass hierarchy (MH) as a primary physics goal. The excellent energy resolution and the large fiducial volume anticipated for the JUNO detector offer exciting opportunities for addressing many important topics in neutrino and astro-particle physics. In this document, we present the physics motivations and the anticipated performance of the JUNO detector for various proposed measurements. Following an introduction summarizing the current status and open issues in neutrino physics, we discuss how the detection of antineutrinos generated by a cluster of nuclear power plants allows the determination of the neutrino MH at a 3–4σ significance with six years of running of JUNO. The measurement of antineutrino spectrum with excellent energy resolution will also lead to the precise determination of the neutrino oscillation parameters ${\mathrm{sin}}^{2}{\theta }_{12}$, ${\rm{\Delta }}{m}_{21}^{2}$, and $| {\rm{\Delta }}{m}_{{ee}}^{2}| $ to an accuracy of better than 1%, which will play a crucial role in the future unitarity test of the MNSP matrix. The JUNO detector is capable of observing not only antineutrinos from the power plants, but also neutrinos/antineutrinos from terrestrial and extra-terrestrial sources, including supernova burst neutrinos, diffuse supernova neutrino background, geoneutrinos, atmospheric neutrinos, and solar neutrinos. As a result of JUNO's large size, excellent energy resolution, and vertex reconstruction capability, interesting new data on these topics can be collected. For example, a neutrino burst from a typical core-collapse supernova at a distance of 10 kpc would lead to ∼5000 inverse-beta-decay events and ∼2000 all-flavor neutrino–proton ES events in JUNO, which are of crucial importance for understanding the mechanism of supernova explosion and for exploring novel phenomena such as collective neutrino oscillations. Detection of neutrinos from all past core-collapse supernova explosions in the visible universe with JUNO would further provide valuable information on the cosmic star-formation rate and the average core-collapse neutrino energy spectrum. Antineutrinos originating from the radioactive decay of uranium and thorium in the Earth can be detected in JUNO with a rate of ∼400 events per year, significantly improving the statistics of existing geoneutrino event samples. Atmospheric neutrino events collected in JUNO can provide independent inputs for determining the MH and the octant of the ${\theta }_{23}$ mixing angle. Detection of the (7)Be and (8)B solar neutrino events at JUNO would shed new light on the solar metallicity problem and examine the transition region between the vacuum and matter dominated neutrino oscillations. Regarding light sterile neutrino topics, sterile neutrinos with ${10}^{-5}\,{{\rm{eV}}}^{2}\lt {\rm{\Delta }}{m}_{41}^{2}\lt {10}^{-2}\,{{\rm{eV}}}^{2}$ and a sufficiently large mixing angle ${\theta }_{14}$ could be identified through a precise measurement of the reactor antineutrino energy spectrum. Meanwhile, JUNO can also provide us excellent opportunities to test the eV-scale sterile neutrino hypothesis, using either the radioactive neutrino sources or a cyclotron-produced neutrino beam. The JUNO detector is also sensitive to several other beyondthe-standard-model physics. Examples include the search for proton decay via the $p\to {K}^{+}+\bar{ u }$ decay channel, search for neutrinos resulting from dark-matter annihilation in the Sun, search for violation of Lorentz invariance via the sidereal modulation of the reactor neutrino event rate, and search for the effects of non-standard interactions. The proposed construction of the JUNO detector will provide a unique facility to address many outstanding crucial questions in particle and astrophysics in a timely and cost-effective fashion. It holds the great potential for further advancing our quest to understanding the fundamental properties of neutrinos, one of the building blocks of our Universe.

The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy.

Abstract: Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease, though severe forms are rare. Management of GO is often suboptimal, largely because available treatments do not target pathogenic mechanisms of the disease. Treatment should rely on a thorough assessment of the activity and severity of GO and its impact on the patient's quality of life. Local measures (artificial tears, ointments and dark glasses) and control of risk factors for progression (smoking and thyroid dysfunction) are recommended for all patients. In mild GO, a watchful strategy is usually sufficient, but a 6-month course of selenium supplementation is effective in improving mild manifestations and preventing progression to more severe forms. High-dose glucocorticoids (GCs), preferably via the intravenous route, are the first line of treatment for moderate-to-severe and active GO. The optimal cumulative dose appears to be 4.5-5 g of methylprednisolone, but higher doses (up to 8 g) can be used for more severe forms. Shared decision-making is recommended for selecting second-line treatments, including a second course of intravenous GCs, oral GCs combined with orbital radiotherapy or cyclosporine, rituximab or watchful waiting. Rehabilitative treatment (orbital decompression surgery, squint surgery or eyelid surgery) is needed in the majority of patients when GO has been conservatively managed and inactivated by immunosuppressive treatment.

A single-atom heat engine

Abstract: Heat engines convert thermal energy into mechanical work and generally involve a large number of particles. We report the experimental realization of a single-atom heat engine. An ion is confined in a linear Paul trap with tapered geometry and driven thermally by coupling it alternately to hot and cold reservoirs. The output power of the engine is used to drive a harmonic oscillation. From direct measurements of the ion dynamics, we were able to determine the thermodynamic cycles for various temperature differences of the reservoirs. We then used these cycles to evaluate the power P and efficiency η of the engine, obtaining values up to P = 3.4 × 10(-22)joules per second and η = 0.28%, consistent with analytical estimations. Our results demonstrate that thermal machines can be reduced to the limit of single atoms.

Efficient metallic spintronic emitters of ultrabroadband terahertz radiation

Abstract: Ultrashort pulses covering the 1–30 THz range are generated from a W/CoFeB/Pt trilayer and originate from photoinduced spin currents, the inverse spin Hall effect and a broadband Fabry–Perot resonance. The resultant peak fields are several 100 kV cm–1.

Physics reach of the XENON1T dark matter experiment

Abstract: The XENON1T experiment is currently in the commissioning phase at the Laboratori Nazionali del Gran Sasso, Italy. In this article we study the experiment's expected sensitivity to the spin-independent WIMP-nucleon interaction cross section, based on Monte Carlo predictions of the electronic and nuclear recoil backgrounds. The total electronic recoil background in 1 tonne fiducial volume and (1, 12) keV electronic recoil equivalent energy region, before applying any selection to discriminate between electronic and nuclear recoils, is (1.80 ± 0.15) · 10(−)(4) (kg·day·keV)(−)(1), mainly due to the decay of (222)Rn daughters inside the xenon target. The nuclear recoil background in the corresponding nuclear recoil equivalent energy region (4, 50) keV, is composed of (0.6 ± 0.1) (t·y)(−)(1) from radiogenic neutrons, (1.8 ± 0.3) · 10(−)(2) (t·y)(−)(1) from coherent scattering of neutrinos, and less than 0.01 (t·y)(−)(1) from muon-induced neutrons. The sensitivity of XENON1T is calculated with the Profile Likelihood Ratio method, after converting the deposited energy of electronic and nuclear recoils into the scintillation and ionization signals seen in the detector. We take into account the systematic uncertainties on the photon and electron emission model, and on the estimation of the backgrounds, treated as nuisance parameters. The main contribution comes from the relative scintillation efficiency Script L(eff), which affects both the signal from WIMPs and the nuclear recoil backgrounds. After a 2 y measurement in 1 t fiducial volume, the sensitivity reaches a minimum cross section of 1.6 · 10(−)(47) cm(2) at m(χ) = 50 GeV/c(2).

DARWIN: towards the ultimate dark matter detector

Abstract: DARk matter WImp search with liquid xenoN (DARWIN(2)) will be an experiment for the direct detection of dark matter using a multi-ton liquid xenon time projection chamber at its core. Its primary g ...

Supramolecular Polymers in Aqueous Media

Abstract: This review discusses one-dimensional supramolecular polymers that form in aqueous media. First, naturally occurring supramolecular polymers are described, in particular, amyloid fibrils, actin filaments, and microtubules. Their structural, thermodynamic, kinetic, and nanomechanical properties are highlighted, as well as their importance for the advancement of biologically inspired supramolecular polymer materials. Second, five classes of synthetic supramolecular polymers are described: systems based on (1) hydrogen-bond motifs, (2) large π-conjugated surfaces, (3) host–guest interactions, (4) peptides, and (5) DNA. We focus on recent studies that address key challenges in the field, providing mechanistic understanding, rational polymer design, important functionality, robustness, or unusual thermodynamic and kinetic properties.

Combining Markov Random Fields and Convolutional Neural Networks for Image Synthesis

Abstract: This paper studies a combination of generative Markov random field (MRF) models and discriminatively trained deep convolutional neural networks (dCNNs) for synthesizing 2D images. The generative MRF acts on higher-levels of a dCNN feature pyramid, controling the image layout at an abstract level. We apply the method to both photographic and non-photo-realistic (artwork) synthesis tasks. The MRF regularizer prevents over-excitation artifacts and reduces implausible feature mixtures common to previous dCNN inversion approaches, permitting synthezing photographic content with increased visual plausibility. Unlike standard MRF-based texture synthesis, the combined system can both match and adapt local features with considerable variability, yielding results far out of reach of classic generative MRF methods.

Cooling and societal change during the Late Antique Little Ice Age from 536 to around 660 AD

Abstract: Societal upheaval occurred across Eurasia in the sixth and seventh centuries. Tree-ring reconstructions suggest a period of pronounced cooling during this time associated with several volcanic eruptions. Climatic changes during the first half of the Common Era have been suggested to play a role in societal reorganizations in Europe1,2 and Asia3,4. In particular, the sixth century coincides with rising and falling civilizations1,2,3,4,5,6, pandemics7,8, human migration and political turmoil8,9,10,11,12,13. Our understanding of the magnitude and spatial extent as well as the possible causes and concurrences of climate change during this period is, however, still limited. Here we use tree-ring chronologies from the Russian Altai and European Alps to reconstruct summer temperatures over the past two millennia. We find an unprecedented, long-lasting and spatially synchronized cooling following a cluster of large volcanic eruptions in 536, 540 and 547 AD (ref. 14), which was probably sustained by ocean and sea-ice feedbacks15,16, as well as a solar minimum17. We thus identify the interval from 536 to about 660 AD as the Late Antique Little Ice Age. Spanning most of the Northern Hemisphere, we suggest that this cold phase be considered as an additional environmental factor contributing to the establishment of the Justinian plague7,8, transformation of the eastern Roman Empire and collapse of the Sasanian Empire1,2,5, movements out of the Asian steppe and Arabian Peninsula8,11,12, spread of Slavic-speaking peoples9,10 and political upheavals in China13.

Polymerization of Ethylene Oxide, Propylene Oxide, and Other Alkylene Oxides: Synthesis, Novel Polymer Architectures, and Bioconjugation.

Abstract: The review summarizes current trends and developments in the polymerization of alkylene oxides in the last two decades since 1995, with a particular focus on the most important epoxide monomers ethylene oxide (EO), propylene oxide (PO), and butylene oxide (BO). Classical synthetic pathways, i.e., anionic polymerization, coordination polymerization, and cationic polymerization of epoxides (oxiranes), are briefly reviewed. The main focus of the review lies on more recent and in some cases metal-free methods for epoxide polymerization, i.e., the activated monomer strategy, the use of organocatalysts, such as N-heterocyclic carbenes (NHCs) and N-heterocyclic olefins (NHOs) as well as phosphazene bases. In addition, the commercially relevant double-metal cyanide (DMC) catalyst systems are discussed. Besides the synthetic progress, new types of multifunctional linear PEG (mf-PEG) and PPO structures accessible by copolymerization of EO or PO with functional epoxide comonomers are presented as well as complex bra...

An essential role for the IL-2 receptor in Treg cell function

Abstract: Regulatory T cells (Treg cells), which have abundant expression of the interleukin 2 receptor (IL-2R), are reliant on IL-2 produced by activated T cells. This feature indicates a key role for a simple network based on the consumption of IL-2 by Treg cells in their suppressor function. However, congenital deficiency in IL-2R results in reduced expression of the Treg cell lineage-specification factor Foxp3, which has confounded experimental efforts to understand the role of IL-2R expression and signaling in the suppressor function of Treg cells. Using genetic gain- and loss-of-function approaches, we found that capture of IL-2 was dispensable for the control of CD4+ T cells but was important for limiting the activation of CD8+ T cells, and that IL-2R-dependent activation of the transcription factor STAT5 had an essential role in the suppressor function of Treg cells separable from signaling via the T cell antigen receptor.

Activity–composition relations for the calculation of partial melting equilibria in metabasic rocks

Abstract: A set of thermodynamic models is presented that, for the first time, allows partial melting equilibria to be calculated for metabasic rocks. The models consist of new activity–composition relations combined with end-member thermodynamic properties from the Holland & Powell dataset, version 6. They allow for forward modelling in the system Na (Formula presented.) O–CaO–K (Formula presented.) O–FeO–MgO–Al (Formula presented.) O (Formula presented.) –SiO (Formula presented.) –H (Formula presented.) O–TiO (Formula presented.) –Fe (Formula presented.) O (Formula presented.). In particular, new activity–composition relations are presented for silicate melt of broadly trondhjemitic–tonalitic composition, and for augitic clinopyroxene with Si–Al mixing on the tetrahedral sites, while existing activity–composition relations for hornblende are extended to include K (Formula presented.) O and TiO (Formula presented.). Calibration of the activity–composition relations was carried out with the aim of reproducing major experimental phase-in/phase-out boundaries that define the amphibolite–granulite transition, across a range of bulk compositions, at ≤13 kbar.

OBSERVATION and CHARACTERIZATION of A COSMIC MUON NEUTRINO FLUX from the NORTHERN HEMISPHERE USING SIX YEARS of ICECUBE DATA

Abstract: The IceCube Collaboration has previously discovered a high-energy astrophysical neutrino flux using neutrino events with interaction vertices contained within the instrumented volume of the IceCube detector. We present a complementary measurement using charged current muon neutrino events where the interaction vertex can be outside this volume. As a consequence of the large muon range the effective area is significantly larger but the field of view is restricted to the Northern Hemisphere. IceCube data from 2009 through 2015 have been analyzed using a likelihood approach based on the reconstructed muon energy and zenith angle. At the highest neutrino energies between 194 TeV and 7.8 PeV a significant astrophysical contribution is observed, excluding a purely atmospheric origin of these events at 5.6s significance. The data are well described by an isotropic, unbroken power-law flux with a normalization at 100 TeV neutrino energy of (0.90 -0.27 +0.30) × 10-18 Gev-1 cm-2 s-1 sr-1and a hard spectral index of γ = 2.13 ± 0.13. The observed spectrum is harder in comparison to previous IceCube analyses with lower energy thresholds which may indicate a break in the astrophysical neutrino spectrum of unknown origin. The highest-energy event observed has a reconstructed muon energy of (4.5 ± 1.2) PeV which implies a probability of less than 0.005% for this event to be of atmospheric origin. Analyzing the arrival directions of all events with reconstructed muon energies above 200 TeV no correlation with known γ-ray sources was found. Using the high statistics of atmospheric neutrinos we report the current best constraints on a prompt atmospheric muon neutrino flux originating from charmed meson decays which is below 1.06 in units of the flux normalization of the model in Enberg et al.

Minimal Leptoquark Explanation for the R D ( * ) , R K , and ( g − 2 ) μ Anomalies

Abstract: We show that by adding a single new scalar particle to the standard model, a TeV-scale leptoquark with the quantum numbers of a right-handed down quark, one can explain in a natural way three of the most striking anomalies of particle physics: the violation of lepton universality in B[over ¯]→K[over ¯]l^{+}l^{-} decays, the enhanced B[over ¯]→D^{(*)}τν[over ¯] decay rates, and the anomalous magnetic moment of the muon. Constraints from other precision measurements in the flavor sector can be satisfied without fine-tuning. Our model predicts enhanced B[over ¯]→K[over ¯]^{(*)}νν[over ¯] decay rates and a new-physics contribution to B_{s}-B[over ¯]_{s} mixing close to the current central fit value.

Combining Markov Random Fields and Convolutional Neural Networks for Image Synthesis

Abstract: This paper studies a combination of generative Markov random field (MRF) models and discriminatively trained deep convolutional neural networks (dCNNs) for synthesizing 2D images. The generative MRF acts on higher-levels of a dCNN feature pyramid, controling the image layout at an abstract level. We apply the method to both photographic and non-photo-realistic (artwork) synthesis tasks. The MRF regularizer prevents over-excitation artifacts and reduces implausible feature mixtures common to previous dCNN inversion approaches, permitting synthezing photographic content with increased visual plausibility. Unlike standard MRF-based texture synthesis, the combined system can both match and adapt local features with considerable variability, yielding results far out of reach of classic generative MRF methods.

Muon reconstruction performance of the ATLAS detector in proton–proton collision data at √ s =13 TeV

Abstract: This article documents the performance of the ATLAS muon identification and reconstruction using the first LHC dataset recorded at s√ = 13 TeV in 2015. Using a large sample of J/ψ→μμ and Z→μμ decays from 3.2 fb−1 of pp collision data, measurements of the reconstruction efficiency, as well as of the momentum scale and resolution, are presented and compared to Monte Carlo simulations. The reconstruction efficiency is measured to be close to 99% over most of the covered phase space (|η| 2.2, the pT resolution for muons from Z→μμ decays is 2.9% while the precision of the momentum scale for low-pT muons from J/ψ→μμ decays is about 0.2%.

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

m 6 A modulates neuronal functions and sex determination in Drosophila

Abstract: N6-methyladenosine RNA (m6A) is a prevalent messenger RNA modification in vertebrates. Although its functions in the regulation of post-transcriptional gene expression are beginning to be unveiled, the precise roles of m6A during development of complex organisms remain unclear. Here we carry out a comprehensive molecular and physiological characterization of the individual components of the methyltransferase complex, as well as of the YTH domain-containing nuclear reader protein in Drosophila melanogaster. We identify the member of the split ends protein family, Spenito, as a novel bona fide subunit of the methyltransferase complex. We further demonstrate important roles of this complex in neuronal functions and sex determination, and implicate the nuclear YT521-B protein as a main m6A effector in these processes. Altogether, our work substantially extends our knowledge of m6A biology, demonstrating the crucial functions of this modification in fundamental processes within the context of the whole animal.