Reliable Witnesses: Integrating Multimedia, Distributed Electronic Textual Editions into Library Collections

The Reliable Witnesses project addresses current vulnerabilities of distributed electronic textual editions and integrates such projects into library collections through workflows for acquisition, description, and preservation. Electronic editions of unique manuscript materials represent an important part of our cultural heritage, providing access to materials otherwise inaccessible to most users, serving as incubators for cutting-edge scholarship, and providing a platform for technological innovation. However, e-text projects frequently employ infrastructures from a variety of resources, and such innovative, distributed designs can result in projects that are not easily integrated into library collections, which consist primarily of traditional print and subscription digital resources. The Reliable Witnesses project will result in local best practices for meeting these challenges as well as a generalized life-cycle model that other institutions can adapt to their needs

Exploring regulatory networks of miR-96 in the developing inner ear.

Mutations in the microRNA Mir96 cause deafness in mice and humans. In the diminuendo mouse, which carries a single base pair change in the seed region of miR-96, the sensory hair cells crucial for hearing fail to develop fully and retain immature characteristics, suggesting that miR-96 is important for coordinating hair cell maturation. Our previous transcriptional analyses show that many genes are misregulated in the diminuendo inner ear and we report here further misregulated genes. We have chosen three complementary approaches to explore potential networks controlled by miR-96 using these transcriptional data. Firstly, we used regulatory interactions manually curated from the literature to construct a regulatory network incorporating our transcriptional data. Secondly, we built a protein-protein interaction network using the InnateDB database. Thirdly, gene set enrichment analysis was used to identify gene sets in which the misregulated genes are enriched. We have identified several candidates for mediating some of the expression changes caused by the diminuendo mutation, including Fos, Myc, Trp53 and Nr3c1, and confirmed our prediction that Fos is downregulated in diminuendo homozygotes. Understanding the pathways regulated by miR-96 could lead to potential therapeutic targets for treating hearing loss due to perturbation of any component of the network

Evaluating complex interventions in end of life care: the MORECare statement on good practice generated by a synthesis of transparent expert consultations and systematic reviews.

BACKGROUND: Despite being a core business of medicine, end of life care (EoLC) is neglected. It is hampered by research that is difficult to conduct with no common standards. We aimed to develop evidence-based guidance on the best methods for the design and conduct of research on EoLC to further knowledge in the field. METHODS: The Methods Of Researching End of life Care (MORECare) project built on the Medical Research Council guidance on the development and evaluation of complex circumstances. We conducted systematic literature reviews, transparent expert consultations (TEC) involving consensus methods of nominal group and online voting, and stakeholder workshops to identify challenges and best practice in EoLC research, including: participation recruitment, ethics, attrition, integration of mixed methods, complex outcomes and economic evaluation. We synthesised all findings to develop a guidance statement on the best methods to research EoLC. RESULTS: We integrated data from three systematic reviews and five TECs with 133 online responses. We recommend research designs extending beyond randomised trials and encompassing mixed methods. Patients and families value participation in research, and consumer or patient collaboration in developing studies can resolve some ethical concerns. It is ethically desirable to offer patients and families the opportunity to participate in research. Outcome measures should be short, responsive to change and ideally used for both clinical practice and research. Attrition should be anticipated in studies and may affirm inclusion of the relevant population, but careful reporting is necessitated using a new classification. Eventual implementation requires consideration at all stages of the project. CONCLUSIONS: The MORECare statement provides 36 best practice solutions for research evaluating services and treatments in EoLC to improve study quality and set the standard for future research. The statement may be used alongside existing statements and provides a first step in setting common, much needed standards for evaluative research in EoLC. These are relevant to those undertaking research, trainee researchers, research funders, ethical committees and editors.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

OSBPL2 encodes a protein of inner and outer hair cell stereocilia and is mutated in autosomal dominant hearing loss (DFNA67)

Background: Early-onset hearing loss is mostly of genetic origin. The complexity of the hearing process is reflected by its extensive genetic heterogeneity, with probably many causative genes remaining to be identified. Here, we aimed at identifying the genetic basis for autosomal dominant non-syndromic hearing loss (ADNSHL) in a large German family. Methods: A panel of 66 known deafness genes was analyzed for mutations by next-generation sequencing (NGS) in the index patient. We then conducted genome-wide linkage analysis, and whole-exome sequencing was carried out with samples of two patients. Expression of Osbpl2 in the mouse cochlea was determined by immunohistochemistry. Because Osbpl2 has been proposed as a target of miR-96, we investigated homozygous Mir96 mutant mice for its upregulation. Results: Onset of hearing loss in the investigated ADNSHL family is in childhood, initially affecting the high frequencies and progressing to profound deafness in adulthood. However, there is considerable intrafamilial variability. We mapped a novel ADNSHL locus, DFNA67, to chromosome 20q13.2-q13.33, and subsequently identified a co-segregating heterozygous frameshift mutation, c.141-142delTG (p.Arg50Alafs∗103), in OSBPL2, encoding a protein known to interact with the DFNA1 protein, DIAPH1. In mice, Osbpl2 was prominently expressed in stereocilia of cochlear outer and inner hair cells. We found no significant Osbpl2 upregulation at the mRNA level in homozygous Mir96 mutant mice. Conclusion: The function of OSBPL2 in the hearing process remains to be determined. Our study and the recent description of another frameshift mutation in a Chinese ADNSHL family identify OSBPL2 as a novel gene for progressive deafness.</p

Wbp2 is required for normal glutamatergic synapses in the cochlea and is crucial for hearing

WBP2 encodes the WW domain-binding protein 2 that acts as a transcriptional coactivator for estrogen receptor a (ESR1) and progesterone receptor (PGR). We reported that the loss of Wbp2 expression leads to progressive high-frequency hearing loss in mouse, as well as in two deaf children, each carrying two different variants in the WBP2 gene. The earliest abnormality we detect in Wbp2-deficient mice is a primary defect at inner hair cell afferent synapses. This study defines a new gene involved in the molecular pathway linking hearing impairment to hormonal signalling and provides new therapeutic targets

Foot pressure distribution during walking in young and old adults

BACKGROUND: Measurement of foot pressure distribution (FPD) is clinically useful for evaluation of foot and gait pathologies. The effects of healthy aging on FPD during walking are not well known. This study evaluated FPD during normal walking in healthy young and elderly subjects. METHODS: We studied 9 young (30 ± 5.2 years), and 6 elderly subjects (68.7 ± 4.8 years). FPD was measured during normal walking speed using shoe insoles with 99 capacitive sensors. Measured parameters included gait phase characteristics, mean and maximum pressure and force, and relative load. Time-series measurements of each variable for all sensors were grouped into 9 anatomical masks. RESULTS: Elderly subjects had lower normalized maximum pressure for the medial and lateral calcaneal masks, and for all medial masks combined. In the medial calcaneus mask, the elderly group also had a lower absolute maximum and lower mean and normalized mean pressures and forces, compared to young subjects. Elderly subjects had lower maximum force and normalized maximum force and lower mean force and normalized mean forces in the medial masks as well. CONCLUSION: FPD differences between the young and elderly groups were confined to the calcaneus and hallux regions and to the medial side of the foot. In elderly subjects, weight bearing on the lateral side of the foot during heel touch and toe-off phases may affect stability during walking

Mouse screen reveals multiple new genes underlying mouse and human hearing loss.

Adult-onset hearing loss is very common, but we know little about the underlying molecular pathogenesis impeding the development of therapies. We took a genetic approach to identify new molecules involved in hearing loss by screening a large cohort of newly generated mouse mutants using a sensitive electrophysiological test, the auditory brainstem response (ABR). We review here the findings from this screen. Thirty-eight unexpected genes associated with raised thresholds were detected from our unbiased sample of 1,211 genes tested, suggesting extreme genetic heterogeneity. A wide range of auditory pathophysiologies was found, and some mutant lines showed normal development followed by deterioration of responses, revealing new molecular pathways involved in progressive hearing loss. Several of the genes were associated with the range of hearing thresholds in the human population and one, SPNS2, was involved in childhood deafness. The new pathways required for maintenance of hearing discovered by this screen present new therapeutic opportunities

The WiggleZ Dark Energy Survey: the transition to large-scale cosmic homogeneity

We have made the largest-volume measurement to date of the transition to large-scale homogeneity in the distribution of galaxies. We use the WiggleZ survey, a spectroscopic survey of over 200,000 blue galaxies in a cosmic volume of ~1 (Gpc/h)^3. A new method of defining the 'homogeneity scale' is presented, which is more robust than methods previously used in the literature, and which can be easily compared between different surveys. Due to the large cosmic depth of WiggleZ (up to z=1) we are able to make the first measurement of the transition to homogeneity over a range of cosmic epochs. The mean number of galaxies N(<r) in spheres of comoving radius r is proportional to r^3 within 1%, or equivalently the fractal dimension of the sample is within 1% of D_2=3, at radii larger than 71 \pm 8 Mpc/h at z~0.2, 70 \pm 5 Mpc/h at z~0.4, 81 \pm 5 Mpc/h at z~0.6, and 75 \pm 4 Mpc/h at z~0.8. We demonstrate the robustness of our results against selection function effects, using a LCDM N-body simulation and a suite of inhomogeneous fractal distributions. The results are in excellent agreement with both the LCDM N-body simulation and an analytical LCDM prediction. We can exclude a fractal distribution with fractal dimension below D_2=2.97 on scales from ~80 Mpc/h up to the largest scales probed by our measurement, ~300 Mpc/h, at 99.99% confidence.Comment: 21 pages, 16 figures, accepted for publication in MNRA