Towards a Graphical User Interface for Quantitative Analysis in Digital Musicology

We introduce the first prototype of a web application for digital musicology: BeyondTheNotes (working title). The goal of the tool is to support the in-depth analysis of individual pieces of music as well as the large scale analysis and comparison of summative features of multiple pieces of music. In contrast to existing tools, BeyondTheNotes is ready to use without installation, enables the upload and analysis of own material and offers different visualizations of musical metrics like chords, pitches, durations and key. We design the tool according to the User Centered Design Approach to improve the usability and address the specific needs of musicologists. We describe the results of the requirement analysis and discuss future steps

BeyondTheNotes: Ein Tool zur quantitativen Analyse in den digitalen Musikwissenschaften

Wir präsentieren den momentanen Entwicklungsstand des Web-Tools BeyondTheNotes. Es handelt sich um ein Tool zur quantitativen Analyse von Musikstücken, dass Funktionen sowohl für die Einzel- als auch die Analyse und den Vergleich von größeren Mengen an Musikstücken anbietet. Der Fokus liegt dabei auf der Visualisierungen verschiedener musikalischer Metriken. Für die Entwicklung des Tools wurden Methoden des User Centered Design genutzt um den Bedürfnissen von potentiellen Nutzern aus der Musikwissenschaft gerecht zu werden. Über eine Anforderungsanalyse bestehend aus Interviews und Fokusgruppen wurden Features herausgearbeitet, die besonders bedeutend für Musikwissenschaftler sind. Über das Tool kann eigenes Material analysiert werden oder in einem vorgefertigten Korpus gearbeitet werden. Das Tool akzeptiert alle gängigen Dateiformate symbolhaft repräsentierter Musik. Nutzer können sich unter anderem Visualisierungen über Akkorde, Tonumfänge, Tondauern, Pausen oder Tonarten anzeigen und herunterladen. Das Tool kann über GitHub heruntergeladen werden; es steht aber auch ein Online-Prototyp zur Verfügung

PAX3 haploinsufficiency in Maine Coon cats with dominant blue eyes and hearing loss resembling the human Waardenburg syndrome.

This study investigated the dominant blue eyes (DBE) trait linked to hearing impairment and variable white spotting in Maine Coon cats. Fifty-eight animals descending from two different DBE lineages, the Dutch and the Topaz lines, were sampled. They comprised 48 cats from the Dutch bloodline, including 9 green-eyed and 31 blue-eyed cats, with some individuals exhibiting signs of deafness, and 8 stillborn kittens. Samples from the Topaz lineage included ten blue-eyed animals. A brainstem auditory evoked potential test (BAER) revealed a reduced to absent response to auditory stimuli and absent physiological waveforms in all of the eight examined DBE animals. We sequenced the genome of two affected cats from the Dutch line and searched for variants in 19 candidate genes for the human Waardenburg syndrome and pigmentary disorders. This search yielded nine private protein-changing candidate variants in the genes PAX3, EDN3, KIT, OCA2, SLC24A5, HERC2 and TYRP1. The genotype-phenotype co-segregation was observed for the PAX3 variant within all animals from the Dutch lineage. The mutant allele was absent from 461 control genomes and 241 additionally genotyped green-eyed Maine Coons. We considered the PAX3 variant as the most plausible candidate -a heterozygous nonsense single basepair substitution in exon 6 of PAX3 (NC_051841.1: g.205,787,310G>A, XM_019838731.3:c.937C>T, XP_019694290.1:p.Gln313*), predicted to result in a premature stop codon. PAX3 variants cause auditory-pigmentary syndrome in humans, horses, and mice. Together with the comparative data from other species, our findings strongly suggest PAX3:c.937C>T (OMIA:001688-9685) as the most likely candidate variant for the DBE, deafness and minimal white spotting in the Maine Coon Dutch line. Finally, we propose the designation of DBERE (Rociri Elvis Dominant Blue Eyes) allele in the domestic cat

SentiBooks: Enhancing Audiobooks via Affective Computing and Smart Light Bulbs

We present SentiBooks, a smartphone application to enhance the audiobook listening experience via affective computing and smart light bulbs. Users can connect to Philips Hue Light Bulbs with a smartphone app while listening to an audiobook. The app analyzes the emotional expression of the narrator of the audiobook using speech emotion recognition and adjusts the colors of the lighting settings according to the expression of the narrator in 10-seconds intervals. By transitioning between colors that are connected to the specific emotion that is currently dominant in the reading, the overall audiobook experience is intensified

Biochemical analysis of novel NAA10 variants suggests distinct pathogenic mechanisms involving impaired protein N-terminal acetylation

NAA10 is the catalytic subunit of the N-terminal acetyltransferase complex, NatA, which is responsible for N-terminal acetylation of nearly half the human proteome. Since 2011, at least 21 different NAA10 missense variants have been reported as pathogenic in humans. The clinical features associated with this X-linked condition vary, but commonly described features include developmental delay, intellectual disability, cardiac anomalies, brain abnormalities, facial dysmorphism and/or visual impairment. Here, we present eight individuals from five families with five different de novo or inherited NAA10 variants. In order to determine their pathogenicity, we have performed biochemical characterisation of the four novel variants c.16G>C p.(A6P), c.235C>T p.(R79C), c.386A>C p.(Q129P) and c.469G>A p.(E157K). Additionally, we clinically describe one new case with a previously identified pathogenic variant, c.384T>G p.(F128L). Our study provides important insight into how different NAA10 missense variants impact distinct biochemical functions of NAA10 involving the ability of NAA10 to perform N-terminal acetylation. These investigations may partially explain the phenotypic variability in affected individuals and emphasise the complexity of the cellular pathways downstream of NAA10.publishedVersio

New insights into the intracellular distribution pattern of cationic amphiphilic drugs

Cationic amphiphilic drugs (CADs) comprise a wide variety of different substance classes such as antidepressants, antipsychotics, and antiarrhythmics. It is well recognized that CADs accumulate in certain intracellular compartments leading to specific morphological changes of cells. So far, no adequate technique exists allowing for ultrastructural analysis of CAD in intact cells. Azidobupramine, a recently described multifunctional antidepressant analogue, allows for the first time to perform high-resolution studies of CADs on distribution pattern and morphological changes in intact cells. We showed here that the intracellular distribution pattern of azidobupramine strongly depends on drug concentration and exposure time. The mitochondrial compartment (mDsRed) and the late endolysosomal compartment (CD63-GFP) were the preferred localization sites at low to intermediate concentrations (i.e. 1 mu M, 5 mu M). In contrast, the autophagosomal compartment (LC3-GFP) can only be reached at high concentrations (10 mu M) and long exposure times (72 hrs). At the morphological level, LC3-clustering became only prominent at high concentrations (10 mu M), while changes in CD63 pattern already occurred at intermediate concentrations (5 mu M). To our knowledge, this is the first study that establishes a link between intracellular CAD distribution pattern and morphological changes. Therewith, our results allow for gaining deeper understanding of intracellular effects of CADs

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Peer reviewedPublisher PD

Cancer risk among insulin users : comparing analogues with human insulin in the CARING five-country cohort study

Aims/hypothesis The aim of this work was to investigate the relationship between use of certain insulins and risk for cancer, when addressing the limitations and biases involved in previous studies. Methods National Health Registries from Denmark (1996-2010), Finland (1996-2011), Norway (2005-2010) and Sweden (2007-2012) and the UK Clinical Practice Research Datalink database (1987-2013) were used to conduct a cohort study on new insulin users (N = 327,112). By using a common data model and semi-aggregate approach, we pooled individual-level records from five cohorts and applied Poisson regression models. For each of ten cancer sites studied, we estimated the rate ratios (RRs) by duration (6 years) of cumulative exposure to insulin glargine or insulin detemir relative to that of human insulin. Results A total of 21,390 cancer cases occurred during a mean follow-up of 4.6 years. No trend with cumulative treatment time for insulin glargine relative to human insulin was observed in risk for any of the ten studied cancer types. Of the 136 associations tested in the main analysis, only a few increased and decreased risks were found: among women, a higher risk was observed for colorectal (RR 1.54, 95% CI 1.06, 2.25) and endometrial cancer (RR 1.78, 95% CI 1.07, 2.94) for 6 years (RR 0.22, 95% CI 0.05, 0.92). Comparisons of insulin detemir with human insulin also showed no consistent differences. Conclusions/interpretation The present multi-country study found no evidence of consistent differences in risk for ten cancers for insulin glargine or insulin detemir use compared with human insulin, at follow-up exceeding 5 years.Peer reviewe

Filling two needs with one deed: a combinatory mucosal vaccine against influenza A virus and respiratory syncytial virus

Influenza A Virus (IAV) and Respiratory Syncytial Virus (RSV) are both responsible for millions of severe respiratory tract infections every year worldwide. Effective vaccines able to prevent transmission and severe disease, are important measures to reduce the burden for the global health system. Despite the strong systemic immune responses induced upon current parental immunizations, this vaccination strategy fails to promote a robust mucosal immune response. Here, we investigated the immunogenicity and efficacy of a mucosal adenoviral vector vaccine to tackle both pathogens simultaneously at their entry site. For this purpose, BALB/c mice were immunized intranasally with adenoviral vectors (Ad) encoding the influenza-derived proteins, hemagglutinin (HA) and nucleoprotein (NP), in combination with an Ad encoding for the RSV fusion (F) protein. The mucosal combinatory vaccine induced neutralizing antibodies as well as local IgA responses against both viruses. Moreover, the vaccine elicited pulmonary CD8+ and CD4+ tissue resident memory T cells (TRM) against the immunodominant epitopes of RSV-F and IAV-NP. Furthermore, the addition of Ad-TGFβ or Ad-CCL17 as mucosal adjuvant enhanced the formation of functional CD8+ TRM responses against the conserved IAV-NP. Consequently, the combinatory vaccine not only provided protection against subsequent infections with RSV, but also against heterosubtypic challenges with pH1N1 or H3N2 strains. In conclusion, we present here a potent combinatory vaccine for mucosal applications, which provides protection against two of the most relevant respiratory viruses

Geographical Distribution and Genetic Diversity of Bank Vole Hepaciviruses in Europe

The development of new diagnostic methods resulted in the discovery of novel hepaciviruses in wild populations of the bank vole (Myodes glareolus, syn. Clethrionomys glareolus). The naturally infected voles demonstrate signs of hepatitis similar to those induced by hepatitis C virus (HCV) in humans. The aim of the present research was to investigate the geographical distribution of bank vole-associated hepaciviruses (BvHVs) and their genetic diversity in Europe. Real-time reverse transcription polymerase chain reaction (RT-qPCR) screening revealed BvHV RNA in 442 out of 1838 (24.0%) bank voles from nine European countries and in one of seven northern red-backed voles (Myodes rutilus, syn. Clethrionomys rutilus). BvHV RNA was not found in any other small mammal species (n = 23) tested here. Phylogenetic and isolation-by-distance analyses confirmed the occurrence of both BvHV species (Hepacivirus F and Hepacivirus J) and their sympatric occurrence at several trapping sites in two countries. The broad geographical distribution of BvHVs across Europe was associated with their presence in bank voles of different evolutionary lineages. The extensive geographical distribution and high levels of genetic diversity of BvHVs, as well as the high population fluctuations of bank voles and occasional commensalism in some parts of Europe warrant future studies on the zoonotic potential of BvHVs.Peer reviewe