The HERMES high-resolution spectrograph project aims at exploiting the specific potential of small but flexible telescopes in observational astrophysics. The optimised optical design of the spectrograph is based on the well-proven concept of white-pupil beam folding for high-resolution spectroscopy. In this contribution we present the complete project, including the spectrograph design and procurement details, the telescope adaptor and calibration unit, the detector system, as well as the optimised data-reduction pipeline. We present a detailed performance analysis to show that the spectrograph performs as specified both in optical quality and in total efficiency. With a spectral resolution of 85 000 (63 000 for the low-resolution fibre), a spectral coverage from 377 to 900 nm in a single exposure and a peak efficiency of 28%, HERMES proves to be an ideal instrument for building up time series of high-quality data of variable (stellar) phenomena.

We describe the construction of GROND, a 7-channel imager, primarily designed for rapid observations of gamma-ray burst afterglows. It allows simultaneous imaging in the Sloan g ′ r ′ i ′ z ′ and near-infrared JHK bands. GROND was commissioned at the MPI/ESO 2.2 m telescope at La Silla (Chile) in April 2007, and first results of its performance and calibration are presented.

Myocardial fibrosis refers to a variety of quantitative and qualitative changes in the interstitial myocardial collagen network that occur in response to cardiac ischaemic insults, systemic diseases, drugs, or any other harmful stimulus affecting the circulatory system or the heart itself. Myocardial fibrosis alters the architecture of the myocardium, facilitating the development of cardiac dysfunction, also inducing arrhythmias, influencing the clinical course and outcome of heart failure patients. Focusing on myocardial fibrosis may potentially improve patient care through the targeted diagnosis and treatment of emerging fibrotic pathways. The European Commission funded the FIBROTARGETS consortium as a multinational academic and industrial consortium with the primary aim of performing a systematic and collaborative search of targets of myocardial fibrosis, and then translating these mechanisms into individualized diagnostic tools and specific therapeutic pharmacological options for heart failure. This review focuses on those methodological and technological aspects considered and developed by the consortium to facilitate the transfer of the new mechanistic knowledge on myocardial fibrosis into potential biomedical applications.

Therapeutic gene silencing promises significant progress in pharmacotherapy, including considerable expansion of the druggable target space and the possibility for treating orphan diseases. Technological hurdles have complicated the efficient use of therapeutic oligonucleotides, and siRNA agents suffer particularly from insufficient pharmacokinetic properties and poor cellular uptake. Intense development and evolution of delivery systems have resulted in efficient uptake predominantly in liver tissue, in which practically all nanoparticulate and liposomal delivery systems show the highest accumulation. The most efficacious strategies include liposomes and bioconjugations with N-acetylgalactosamine. Both are in early clinical evaluation stages for treatment of liver-associated diseases. Approaches for achieving knockdown in other tissues and tumors have been proven to be more complicated. Selective targeting to tumors may be enabled through careful modulation of physical properties, such as particle size, or by taking advantage of specific targeting ligands. Significant barriers stand between sufficient accumulation in other organs, including endothelial barriers, cellular membranes, and the endosome. The brain, which is shielded by the blood-brain barrier, is of particular interest to facilitate efficient oligonucleotide therapy of neurological diseases. Transcytosis of the blood-brain barrier through receptor-specific docking is investigated to increase accumulation in the central nervous system. In this review, the current clinical status of siRNA therapeutics is summarized, as well as innovative and promising preclinical concepts employing tissue- and tumor-targeted ligands. The requirements and the respective advantages and drawbacks of bioconjugates and ligand-decorated lipid or polymeric particles are discussed.

The discovery of miRNAs as important regulatory agents for gene expression has expanded the therapeutic opportunities for oligonucleotides. In contrast to siRNA, miRNA-targeted therapy is able to influence not only a single gene, but entire cellular pathways or processes. It is possible to supplement downregulated or non-functional miRNAs by synthetic oligonucleotides, as well as alleviating effects caused by overexpression of malignant miRNAs through artificial antagonists, either oligonucleotides or small molecules. Chemical oligonucleotide modifications together with an efficient delivery system seem to be mandatory for successful therapeutic application. While miRNA-based therapy benefits from the decades of research spent on other therapeutic oligonucleotides, there are some specific challenges associated with miRNA therapy, mainly caused by the short target sequence. The current status and recent progress of miRNA-targeted therapeutics is described and future challenges and potential applications in treatment of cancer and viral infections are discussed.

Despite proven efficacy of pharmacotherapies targeting primarily global neurohormonal dysregulation, heart failure (HF) is a growing pandemic with increasing burden. Treatments mechanistically focusing at the cardiomyocyte level are lacking. MicroRNAs (miRNA) are transcriptional regulators and essential drivers of disease progression. We previously demonstrated that miR-132 is both necessary and sufficient to drive the pathological cardiomyocytes growth, a hallmark of adverse cardiac remodelling. Therefore, miR-132 may serve as a target for HF therapy. Here we report further mechanistic insight of the mode of action and translational evidence for an optimized, synthetic locked nucleic acid antisense oligonucleotide inhibitor (antimiR-132). We reveal the compound's therapeutic efficacy in various models, including a clinically highly relevant pig model of HF. We demonstrate favourable pharmacokinetics, safety, tolerability, dose-dependent PK/PD relationships and high clinical potential for the antimiR-132 treatment scheme.

The CARMENES radial velocity (RV) survey is observing 324 M dwarfs to search for any orbiting planets. In this paper, we present the survey sample by publishing one CARMENES spectrum for each M dwarf. These spectra cover the wavelength range 520-1710 nm at a resolution of at least R > 80, 000, and we measure its RV, Hα emission, and projected rotation velocity. We present an atlas of high-resolution M-dwarf spectra and compare the spectra to atmospheric models. To quantify the RV precision that can be achieved in low-mass stars over the CARMENES wavelength range, we analyze our empirical information on the RV precision from more than 6500 observations. We compare our high-resolution M-dwarf spectra to atmospheric models where we determine the spectroscopic RV information content, Q, and signal-to-noise ratio. We find that for all M-type dwarfs, the highest RV precision can be reached in the wavelength range 700-900 nm. Observations at longer wavelengths are equally precise only at the very latest spectral types (M8 and M9). We demonstrate that in this spectroscopic range, the large amount of absorption features compensates for the intrinsic faintness of an M7 star. To reach an RV precision of 1 m s −1 in very low mass M dwarfs at longer wavelengths likely requires the use of a 10 m class telescope. For spectral types M6 and earlier, the combination of a red visual and a near-infrared spectrograph is ideal to search for low-mass planets and to distinguish between planets and stellar variability. At a 4 m class telescope, an instrument like CARMENES has the potential to push the RV precision well below the typical jitter level of 3-4 m s −1 .

Insufficient pharmacokinetic properties and poor cellular uptake are the main hurdles for successful therapeutic development of oligonucleotide agents. The covalent attachment of various ligands designed to influence the biodistribution and cellular uptake or for targeting specific tissues is an attractive possibility to advance therapeutic applications and to expand development options. In contrast to advanced formulations, which often consist of multiple reagents and are sensitive to a variety of preparation conditions, oligonucleotide conjugates are defined molecules, enabling structure-based analytics and quality control techniques. This review gives an overview of current developments of oligonucleotide conjugates for therapeutic applications. Attached ligands comprise peptides, proteins, carbohydrates, aptamers and small molecules, including cholesterol, tocopherol and folic acid. Important linkage types and conjugation methods are summarized. The distinct ligands directly influence biochemical parameters, uptake machanisms and pharmacokinetic properties.Although oligonucleotides have been regarded as a new class of drugs for more than three decades, their therapeutic applications have so far failed to fully live up to the expectations [1,2]. Today, there are many different subclasses, which are mainly divided by different mechanisms of biological actions, and include antisense [3], splice-switching oligonucleotides [4,5], siRNA [6], miRNA [7], aptamers [8] and immunostimulatory oligonucleotides [9]. Structural differences are minimal, and consequently all nucleic acidbased drugs generally suffer from poor pharmacokinetics [10], the lack of cell membrane permeation [11], and often insufficient stability and sometimes relevant off-target effects [12]. Those properties are generally caused by their hydrophilicity, multiple anionic charges and ready interaction with degrading enzymes. Decades of therapeutic development have brought advances in enzymatic stability through chemical derivatization [3], and a multitude of distinct liposomal or polymeric delivery systems for improving their pharmacokinetic behavior [13]. Until 2012, one antisense agent (fomivirsen) and one aptamer (pegaptanib) had won market approval. Both are restricted to local application, circumventing the major problems. Mipomersen (Kynamro® [CA, USA]), an antisense agent targeted at apoB-100 for treatment of homozygous familial hypercholesterolemia [14][15][16], has been approved by the US FDA in January 2013, and could mark a major breakthrough for this type of biological therapeutic. Mipomersen, like other phosphorothioate drugs, accumulates in the liver, the site of apoB production. Clinical safety profiling showed a risk of hepatotoxic effects, including elevation of liver enzymes alanine aminotransferase and aspartate aminotransferase, and hepatic steatosis [17]. As a consequence, the FDA is requiring a risk evaluation and mitigation strategy program for mipomersen, including an enhanced