17 research outputs found
A small ribosome-associated ncRNA globally inhibits translation by restricting ribosome dynamics
Ribosome-associated non-coding RNAs (rancRNAs) have been recognized as an emerging class of regulatory molecules capable of fine-tuning translation in all domains of life. RancRNAs are ideally suited for allowing a swift response to changing environments and are therefore considered pivotal during the first wave of stress adaptation. Previously, we identified an mRNA-derived 18 nucleotides long rancRNA (rancRNA_18) in Saccharomyces cerevisiae that rapidly downregulates protein synthesis during hyperosmotic stress. However, the molecular mechanism of action remained enigmatic. Here, we combine biochemical, genetic, transcriptome-wide and structural evidence, thus revealing rancRNA_18 as global translation inhibitor by targeting the E-site region of the large ribosomal subunit. Ribosomes carrying rancRNA_18 possess decreased affinity for A-site tRNA and impaired structural dynamics. Cumulatively, these discoveries reveal the mode of action of a rancRNA involved in modulating protein biosynthesis at a thus far unequalled precision
Lessons Learned from a Decade of Providing Interactive, On-Demand High Performance Computing to Scientists and Engineers
For decades, the use of HPC systems was limited to those in the physical
sciences who had mastered their domain in conjunction with a deep understanding
of HPC architectures and algorithms. During these same decades, consumer
computing device advances produced tablets and smartphones that allow millions
of children to interactively develop and share code projects across the globe.
As the HPC community faces the challenges associated with guiding researchers
from disciplines using high productivity interactive tools to effective use of
HPC systems, it seems appropriate to revisit the assumptions surrounding the
necessary skills required for access to large computational systems. For over a
decade, MIT Lincoln Laboratory has been supporting interactive, on-demand high
performance computing by seamlessly integrating familiar high productivity
tools to provide users with an increased number of design turns, rapid
prototyping capability, and faster time to insight. In this paper, we discuss
the lessons learned while supporting interactive, on-demand high performance
computing from the perspectives of the users and the team supporting the users
and the system. Building on these lessons, we present an overview of current
needs and the technical solutions we are building to lower the barrier to entry
for new users from the humanities, social, and biological sciences.Comment: 15 pages, 3 figures, First Workshop on Interactive High Performance
Computing (WIHPC) 2018 held in conjunction with ISC High Performance 2018 in
Frankfurt, German
Interactive Supercomputing on 40,000 Cores for Machine Learning and Data Analysis
Interactive massively parallel computations are critical for machine learning
and data analysis. These computations are a staple of the MIT Lincoln
Laboratory Supercomputing Center (LLSC) and has required the LLSC to develop
unique interactive supercomputing capabilities. Scaling interactive machine
learning frameworks, such as TensorFlow, and data analysis environments, such
as MATLAB/Octave, to tens of thousands of cores presents many technical
challenges - in particular, rapidly dispatching many tasks through a scheduler,
such as Slurm, and starting many instances of applications with thousands of
dependencies. Careful tuning of launches and prepositioning of applications
overcome these challenges and allow the launching of thousands of tasks in
seconds on a 40,000-core supercomputer. Specifically, this work demonstrates
launching 32,000 TensorFlow processes in 4 seconds and launching 262,000 Octave
processes in 40 seconds. These capabilities allow researchers to rapidly
explore novel machine learning architecture and data analysis algorithms.Comment: 6 pages, 7 figures, IEEE High Performance Extreme Computing
Conference 201
rRNA expansion segment 27Lb modulates the factor recruitment capacity of the yeast ribosome and shapes the proteome.
Fine-tuned regulation of protein biosynthesis is crucial for cellular fitness and became even more vital when cellular and organismal complexity increased during the course of evolution. In order to cope with this augmented demand for translation control, eukaryal ribosomes have gained extensions both at the ribosomal protein and rRNA levels. Here we analyze the functional role of ES27L, an rRNA expansion segment in the large ribosomal subunit of Saccharomyces cerevisiae. Deletion of the b-arm of this expansion segment, called ES27Lb, did not hamper growth during optimal conditions, thus demonstrating that this 25S rRNA segment is not inherently crucial for ribosome functioning. However, reductive stress results in retarded growth and rendered unique protein sets prone to aggregation. Lack of ES27Lb negatively affects ribosome-association of known co-translational N-terminal processing enzymes which in turn contributes to the observed protein aggregation. Likely as a compensatory response to these challenges, the truncated ribosomes showed re-adjusted translation of specific sets of mRNAs and thus fine-tune the translatome in order to re-establish proteostasis. Our study gives comprehensive insight into how a highly conserved eukaryal rRNA expansion segment defines ribosomal integrity, co-translational protein maturation events and consequently cellular fitness
The Comorbidity of Psychotic Symptoms and Posttraumatic Stress Disorder: Evidence for a Specifier in DSM-5
A tRNA-derived fragment competes with mRNA for ribosome binding and regulates translation during stress
Posttranscriptional processing of RNA molecules is a common strategy to enlarge the structural and functional repertoire of RNomes observed in all three domains of life. Fragmentation of RNA molecules of basically all functional classes has been reported to yield smaller non-protein coding RNAs (ncRNAs) that typically possess different roles compared to their parental transcripts. Here we show that a valine tRNA-derived fragment (Val-tRF) that is produced under certain stress conditions in the halophilic archaeon Haloferax volcanii is capable of binding to the small ribosomal subunit. As a consequence of Val-tRF binding messenger RNA is displaced from the initiation complex which results in global translation attenuation in vivo and in vitro. The fact that the archaeal Val-tRF also inhibits eukaryal as well as bacterial protein biosynthesis implies a functionally conserved mode of action. While tRFs and tRNA halves have been amply identified in recent RNA-seq project, Val-tRF described herein represents one of the first functionally characterized tRNA processing products to date
Validation of the FACETS-OF-PPC as an Outcome Measure for Children with Severe Neurological Impairment and Their Families—A Multicenter Prospective Longitudinal Study
Outcome measurement in pediatric palliative care (PPC) is receiving increasing attention. The FACETS-OF-PPC, a multidimensional outcome measure for children with severe neurological impairment, has been developed and partly validated. This study aimed to conclude the validity of the German version of the FACETS-OF-PPC. A multicenter prospective study with two points of measurement has been conducted, employing confirmatory factor analyses, reliability analyses, and analyses to evaluate the tool’s sensitivity to change. Overall, 25 inpatient and outpatient teams throughout Germany recruited N = 227 parents of affected children and N = 238 professional caregivers. Participants filled out the FACETS-OF-PPC on the admission of a child to a palliative care service and at discharge from inpatient settings or two months after admission to outpatient services. The analyses revealed the questionnaire needing further adaption. Now, 17 of the original 34 items contribute to the construction of the questionnaire scales. The other items remain part of the questionnaire and may be evaluated descriptively. Furthermore, the FACETS-OF-PPC has moderate to appropriate internal consistency and is sensitive to change. Creating an outcome measure with good psychometric properties for the vulnerable population of children with severe neurological impairment appears extremely difficult. Considering these challenges, the FACETS-OF-PPC demonstrates adequate psychometric properties
Not4-dependent translational repression is important for cellular protein homeostasis in yeast
Translation of aberrant or problematic mRNAs can cause ribosome stalling which leads to the production of truncated or defective proteins. Therefore, cells evolved cotranslational quality control mechanisms that eliminate these transcripts and target arrested nascent polypeptides for proteasomal degradation. Here we show that Not4, which is part of the multifunctional Ccr4-Not complex in yeast, associates with polysomes and contributes to the negative regulation of protein synthesis. Not4 is involved in translational repression of transcripts that cause transient ribosome stalling. The absence of Not4 affected global translational repression upon nutrient withdrawal, enhanced the expression of arrested nascent polypeptides and caused constitutive protein folding stress and aggregation. Similar defects were observed in cells with impaired mRNA decapping protein function and in cells lacking the mRNA decapping activator and translational repressor Dhh1. The results suggest a role for Not4 together with components of the decapping machinery in the regulation of protein expression on the mRNA level and emphasize the importance of translational repression for the maintenance of proteome integrity