Exploring listening-related fatigue in children with and without hearing loss using self-report and parent-proxy measures

Children with hearing loss appear to experience greater fatigue than children with normal hearing (CNH). Listening-related fatigue is often associated with an increase in effortful listening or difficulty in listening situations. This has been observed in children with bilateral hearing loss (CBHL) and, more recently, in children with unilateral hearing loss (CUHL). Available tools for measuring fatigue in children include general fatigue questionnaires such as the child self-report and parent-proxy versions of the PedsQLTM-Multidimensional Fatigue Scale (MFS) and the PROMIS Fatigue Scale. Recently, the Vanderbilt Fatigue Scale (VFS-C: child self-report; VFS-P: parent-proxy report) was introduced with a specific focus on listening-related fatigue. The aims of this study were to compare fatigue levels experienced by CNH, CUHL and CBHL using both generic and listening-specific fatigue measures and compare outcomes from the child self-report and parent-proxy reports. Eighty children aged 6–16 years (32 CNH, 19 CUHL, 29 CBHL), and ninety-nine parents/guardians (39 parents to CNH, 23 parents to CUHL, 37 parents to CBHL), completed the above fatigue questionnaires online. Kruskal-Wallis H tests were performed to compare fatigue levels between the CNH, CUHL and CBHL. To determine the agreement between parent-proxy and child self-report measures, Bland-Altman 95% limits of agreement were performed. All child self-report fatigue measures indicated that CBHL experience greater fatigue than CNH. Only the listening-specific tool (VFS-C) was sufficiently able to show greater fatigue in CUHL than in CNH. Similarly, all parent-proxy measures of fatigue indicated that CBHL experience significantly greater fatigue than CNH. The VFS-P and the PROMIS Fatigue Parent-Proxy also showed greater fatigue in CUHL than in CNH. Agreement between the parent-proxy and child self-report measures were found within the PedsQL-MFS and the PROMIS Fatigue Scale. Our results suggest that CBHL experience greater levels of daily-life fatigue compared to CNH. CUHL also appear to experience more fatigue than CNH, and listening-specific measures of fatigue may be better able to detect this effect. Further research is needed to understand the bases of fatigue in these populations and to clarify whether fatigue experienced by CBHL and CUHL is comparable in nature and degree

Creating a health informatics data resource for hearing health research

Background: The National Institute of Health and Social Care Research (NIHR) Health Informatics Collaborative (HIC) for Hearing Health has been established in the UK to curate routinely collected hearing health data to address research questions. This study defines priority research areas, outlines its aims, governance structure and demonstrates how hearing health data have been integrated into a common data model using pure tone audiometry (PTA) as a case study. Methods: After identifying key research aims in hearing health, the governance structure for the NIHR HIC for Hearing Health is described. The Observational Medical Outcomes Partnership (OMOP) was chosen as our common data model to provide a case study example. Results: The NIHR HIC Hearing Health theme have developed a data architecture outlying the flow of data from all of the various siloed electronic patient record systems to allow the effective linkage of data from electronic patient record systems to research systems. Using PTAs as an example, OMOPification of hearing health data successfully collated a rich breadth of datapoints across multiple centres. Conclusion: This study identified priority research areas where routinely collected hearing health data could be useful. It demonstrates integration and standardisation of such data into a common data model from multiple centres. By describing the process of data sharing across the HIC, we hope to invite more centres to contribute and utilise data to address research questions in hearing health. This national initiative has the power to transform UK hearing research and hearing care using routinely collected clinical data

RTN3 Is a Novel Cold-Induced Protein and Mediates Neuroprotective Effects of RBM3.

Cooling and hypothermia are profoundly neuroprotective, mediated, at least in part, by the cold shock protein, RBM3. However, the neuroprotective effector proteins induced by RBM3 and the mechanisms by which mRNAs encoding cold shock proteins escape cooling-induced translational repression are unknown. Here, we show that cooling induces reprogramming of the translatome, including the upregulation of a new cold shock protein, RTN3, a reticulon protein implicated in synapse formation. We report that this has two mechanistic components. Thus, RTN3 both evades cooling-induced translational elongation repression and is also bound by RBM3, which drives the increased expression of RTN3. In mice, knockdown of RTN3 expression eliminated cooling-induced neuroprotection. However, lentivirally mediated RTN3 overexpression prevented synaptic loss and cognitive deficits in a mouse model of neurodegeneration, downstream and independently of RBM3. We conclude that RTN3 expression is a mediator of RBM3-induced neuroprotection, controlled by novel mechanisms of escape from translational inhibition on cooling

SIR AUSTIN BRADFORD HILL

CD40L/interleukin-4 (IL-4) stimulation occurs in vivo in the tumor microenvironment and induces global translation to varying degrees in individuals with chronic lymphocytic leukemia (CLL) in vitro. However, the implications of CD40L/IL-4 for the translation of specific genes is not known. To determine the most highly translationally regulated genes in response to CD40L/IL-4, we carried out ribosome profiling, a next-generation sequencing method. Significant differences in the translational efficiency of DNA damage response genes, specifically ataxia‐telangiectasia–mutated kinase (ATM) and the MRE11/RAD50/NBN (MRN) complex, were observed between patients, suggesting different patterns of translational regulation. We confirmed associations between CD40L/IL-4 response and baseline ATM levels, induction of ATM, and phosphorylation of the ATM targets, p53 and H2AX. X-irradiation was used to demonstrate that CD40L/IL-4 stimulation tended to improve DNA damage repair. Baseline ATM levels, independent of the presence of 11q deletion, correlated with overall survival (OS). Overall, we suggest that there are individual differences in translation of specific genes, including ATM, in response to CD40L/IL-4 and that these interpatient differences might be clinically important

The pathogenesis of mesothelioma is driven by a dysregulated translatome.

Funder: Department of HealthMalignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no 'druggable' driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease

RNA-binding residues in sequence space: Conservation and interaction patterns

No description supplie

A ligand-centric analysis of the diversity and evolution of protein-ligand relationships in E.coli

As enzymes evolve and diverge from common ancestor sequences, they often keep their overall reaction chemistry but specialize in the binding of different cognate ligands. This study borrows methods for the computational assessment of 2D similarity of small molecules from the field of chemoinformatics, to examine the extent of structure conservation of cognate ligands binding to similar proteins. Proteins from 87 structural superfamilies from Escherichia coli form the core dataset, which is extended using homologues with functional assignments from any organism. We find that correlation of the substrate similarity with protein similarity (measured by either sequence-based or structure-based scores) can only be clearly established for very similar proteins. At low sequence identities, the superfamily to which a protein belongs can give helpful clues to its function, and more importantly, the confidence attached to such clues is superfamily-dependent. Our data indicate that only a few superfamilies show great substrate diversity, and that most exhibit conservation of at least part of the structural scaffold of the substrate

SCOPEC: a database of protein catalytic domains

MOTIVATION: Domains are the units of protein structure, function and evolution. It is therefore essential to utilize knowledge of domains when studying the evolution of function, or when assigning function to genome sequence data. For this purpose, we have developed a database of catalytic domains, SCOPEC, by combining structural domain information from SCOP, full-length sequence information from Swiss-Prot, and verified functional information from the Enzyme Classification (EC) database. Two major problems need to be overcome to create a database of domain-function relationships; (1) for sequences, EC numbers are typically assigned to whole sequences rather than the functional unit, and (2) The Protein Data Bank (PDB) structures elucidated from a larger multi-domain protein will often have EC annotation although the relevant catalytic domain may lie elsewhere. RESULTS: SCOPEC entries have high quality enzyme assignments; having passed both computational and manual checks. SCOPEC currently contains entries for 75% of all EC annotations in the PDB. Overall, EC number is fairly well conserved within a superfamily, even when the proteins are distantly related. Initial analysis is encouraging; suggesting that there is a 50:50 chance of conserved function in distant homologues first detected by a third iteration PSI-BLAST search. Therefore, we envisage that a knowledge-based approach to function assignment using the domain-EC relationships in SCOPEC will gain a marked improvement over this base line. AVAILABILITY: The SCOPEC database is a valuable resource in the analysis and prediction of protein structure and function. It can be obtained or queried at our website http://www.enzome.co