The ribosome as novel target for small regulatory RNAs

Small non-protein-coding RNA (ncRNA) molecules have been recognized recently as major contributors to regulatory networks in controlling gene expression in a highly efficient manner. While the list of validated ncRNAs that regulate crucial cellular processes grows steadily, not a single ncRNA has been identified that directly interacts and regulates the ribosome during protein biosynthesis (with the notable exceptions of 7SL RNA and tmRNA). All of the recently discovered regulatory ncRNAs that act on translation (e.g. microRNAs, siRNAs or antisense RNAs) target the mRNA rather than the ribosome. This is unexpected, given the central position the ribosome plays during gene expression. Furthermore it is strongly assumed that the primordial translation system in the ‘RNA world’ most likely received direct regulatory input from ncRNA-like cofactors. The fundamental question that we would like to ask is: Does the ‘RNA world still communicate’ with the ribosome? To address this question, we have analyzed the small ncRNA interactomes of ribosomes of organisms from all three domains of life. Deep-sequencing and subsequent bioinformatic analyses revealed thousands of putative ribosome-associated ncRNAs.1,2 For a subset of these ncRNA candidates we have gathered experimental evidence that they are expressed in a stress-dependent manner and indeed directly target the ribosome. We show that some of these ribosome-bound small ncRNAs are capable of fine tuning protein synthesis in vitro and in vivo. Our data therefore reveal the ribosome as a novel target for small regulatory ncRNAs in all domains of life and suggest the existence of a so far largely unexplored mechanism of translation regulation.

Pion emission from the T2K replica target: method, results and application

The T2K long-baseline neutrino oscillation experiment in Japan needs precise predictions of the initial neutrino flux. The highest precision can be reached based on detailed measurements of hadron emission from the same target as used by T2K exposed to a proton beam of the same kinetic energy of 30 GeV. The corresponding data were recorded in 2007-2010 by the NA61/SHINE experiment at the CERN SPS using a replica of the T2K graphite target. In this paper details of the experiment, data taking, data analysis method and results from the 2007 pilot run are presented. Furthermore, the application of the NA61/SHINE measurements to the predictions of the T2K initial neutrino flux is described and discussed.

The quiet eye without a target: The primacy of visual information processing

Motor-performance-enhancing effects of long final fixations before movement initiation – a phenomenon called Quiet Eye (QE) – have repeatedly been demonstrated. Drawing on the information-processing framework, it is assumed that the QE supports information processing revealed by the close link between QE duration and task demands concerning, in particular, response selection and movement parameterisation. However, the question remains whether the suggested mechanism also holds for processes referring to stimulus identification. Thus, in a series of two experiments, performance in a targeting task was tested as a function of experimentally manipulated visual processing demands as well as experimentally manipulated QE durations. The results support the suggested link because a performance-enhancing QE effect was found under increased visual processing demands only: Whereas QE duration did not affect performance as long as positional information was preserved (Experiment 1), in the full vs. no target visibility comparison, QE efficiency turned out to depend on information processing time as soon as the interval falls below a certain threshold (Experiment 2). Thus, the results rather contradict alternative, e.g., posture-based explanations of QE effects and support the assumption that the crucial mechanism behind the QE phenomenon is rooted in the cognitive domain.

tRNA-derived fragments target the small ribosomal subunit to fine-tune translation

Post-transcriptional cleavage of RNA molecules to generate smaller fragments is a widespread mechanism that enlarges the structural and functional complexity of cellular RNomes. In particular, fragments deriving from both precursor and mature tRNAs represent one of the rapidly growing classes of post-transcriptional RNA pieces. Importantly, these tRNA-derived fragments (tRFs) possess distinct expression patterns, abundance, cellular localizations, or biological roles compared with their parental tRNA molecules (1). Here we present evidence that tRFs from the archaeon Haloferax volcanii directly bind to ribosomes. In a previous genomic screen for ribosome-associated small RNAs we have identified a 26 residue long fragment originating from the 5’ part of valine tRNA (Val-tRF) to be by far the most abundant tRF in H. volcanii (2). The Val-tRF is processed in a stress- dependent manner and was found to primarily target the small ribosomal subunit in vitro and in vivo. Translational activity was markedly reduced in the presence of Val-tRF, while control RNA fragments of similar length did not show inhibition of protein biosynthesis. Crosslinking experiments and subsequent primer extension analyses revealed the Val-tRF interaction site to surround the mRNA path in the 30S subunit. In support of this, binding experiments demonstrated that Val-tRF does compete with mRNAs for ribosome binding. Therefore this tRF represents a ribosome-bound non-protein-coding RNA (ncRNA) capable of regulating gene expression in H. volcanii under environmental stress conditions probably by fine-tuning the rate of protein production (1). (1) Gebetsberger J. and Polacek N. (2013), RNA Biol. 10:1798-1808 (2) Gebetsberger J. et. al. (2012), Archaea, Article ID 260909

Semiautomatic Cochleostomy Target and Insertion Trajectory Planning for Minimally Invasive Cochlear Implantation

A major component of minimally invasive cochlear implantation is atraumatic scala tympani (ST) placement of the electrode array. This work reports on a semiautomatic planning paradigm that uses anatomical landmarks and cochlear surface models for cochleostomy target and insertion trajectory computation. The method was validated in a human whole head cadaver model (n = 10 ears). Cochleostomy targets were generated from an automated script and used for consecutive planning of a direct cochlear access (DCA) drill trajectory from the mastoid surface to the inner ear. An image-guided robotic system was used to perform both, DCA and cochleostomy drilling. Nine of 10 implanted specimens showed complete ST placement. One case of scala vestibuli insertion occurred due to a registration/drilling error of 0.79 mm. The presented approach indicates that a safe cochleostomy target and insertion trajectory can be planned using conventional clinical imaging modalities, which lack sufficient resolution to identify the basilar membrane.

The geography of large-scale land acquisitions: Analysing socio-ecological patterns of target contexts in the global South

This paper analyses local geographical contexts targeted by transnational large-scale land acquisitions (>200 ha per deal) in order to understand how emerging patterns of socio-ecological characteristics can be related to processes of large-scale foreign investment in land. Using a sample of 139 land deals georeferenced with high spatial accuracy, we first analyse their target contexts in terms of land cover, population density, accessibility, and indicators for agricultural potential. Three distinct patterns emerge from the analysis: densely populated and easily accessible croplands (35% of land deals); remote forestlands with lower population densities (34% of land deals); and moderately populated and moderately accessible shrub- or grasslands (26% of land deals). These patterns are consistent with processes described in the relevant case study literature, and they each involve distinct types of stakeholders and associated competition over land. We then repeat the often-cited analysis that postulates a link between land investments and target countries with abundant so-called “idle” or “marginal” lands as measured by yield gap and available suitable but uncultivated land; our methods differ from the earlier approach, however, in that we examine local context (10-km radius) rather than countries as a whole. The results show that earlier findings are disputable in terms of concepts, methods, and contents. Further, we reflect on methodologies for exploring linkages between socioecological patterns and land investment processes. Improving and enhancing large datasets of georeferenced land deals is an important next step; at the same time, careful choice of the spatial scale of analysis is crucial for ensuring compatibility between the spatial accuracy of land deal locations and the resolution of available geospatial data layers. Finally, we argue that new approaches and methods must be developed to empirically link socio-ecological patterns in target contexts to key determinants of land investment processes. This would help to improve the validity and the reach of our findings as an input for evidence-informed policy debates.

Loss of appetite in acutely ill medical inpatients: physiological response or therapeutic target?

Loss of appetite and ensuing weight loss is a key feature of severe illnesses. Protein-energy malnutrition (PEM) contributes significantly to the adverse outcome of these conditions. Pharmacological interventions to target appetite stimulation have little efficacy but considerable side effects. Therefore nutritional therapy appears to be the logical step to combat inadequate nutrition. However, clinical trial data demonstrating benefits are sparse and there is no current established standard algorithm for use of nutritional support in malnourished, acutely ill medical inpatients. Recent high-quality evidence from critical care demonstrating harmful effects when parenteral nutritional support is used indiscriminately has led to speculation that loss of appetite in the acute phase of illness is indeed an adaptive, protective response that improves cell recycling (autophagy) and detoxification. Outside critical care, there is an important gap in high quality clinical trial data shedding further light on these important issues. The selection, timing, and doses of nutrition should be evaluated as carefully as with any other therapeutic intervention, with the aim of maximising efficacy and minimising adverse effects and costs. In light of the current controversy, a reappraisal of how nutritional support should be used in acutely ill medical inpatients outside critical care is urgently required. The aim of this review is to discuss current pathophysiological concepts of PEM and to review the current evidence for the efficacy of nutritional support regarding patient outcomes when used in an acutely ill medical patient population outside critical care.