A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Information professionals and copyright literacy: a multinational study

Purpose: The purpose of this paper is to present findings from a multinational survey on copyright literacy of specialists from libraries and other cultural institutions. Design/methodology/approach: This paper is based on a multinational survey of copyright literacy competencies of Library and Information Science (LIS) professionals and those who work in the cultural heritage sector (archives and museums), conducted in 13 countries, namely Bulgaria (BG), Croatia (CR), Finland (FI), France (FR), Hungary (HU), Lithuania (LT), Mexico (MX), Norway (NO), Portugal (PT), Romania (RO), Turkey (TR), UK and USA in the period July 2013-March 2015. An online survey instrument was developed in order to collect data from professionals regarding their familiarity with, knowledge and awareness of, and opinions on copyright-related issues. Findings: Findings of this study highlight gaps in existing knowledge of copyright, and information about the level of copyright literacy of LIS and cultural sector professionals. Also attitudes toward copyright learning content in academic education and continuing professional development training programs are investigated. Originality/value: This study aimed to address a gap in the literature by encompassing specialists from the cultural institutions in an international comparative context. The paper offers guidance for further understanding of copyright in a wider framework of digital and information literacy; and for the implementation of copyright policy, and the establishment of copyright advisor positions in cultural institutions. The recommendations support a revision of academic and continuing education programs learning curriculum and methods

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Diseño de un Generador de Impulsos de Alta Tensión de Hasta 20kv Para Ensayo, Diagnostico y Detección de Fallas en Conductores Eléctricos Subterraneos de BT y MT

Trabajo de suficiencia profesionalEn la actualidad una gran cantidad de sistemas de distribución de energía eléctrica a nivel mundial operan mediante cables subterráneos. Incluso la transmisión de energía en alta tensión por medio de cables ha incrementado en los últimos años. Esto se debe a que los cables subterráneos tienen mucha menor propensión que las líneas aéreas a sufrir fallas ocasionadas por efectos ambientales tales como nieve, hielo, lluvia, descargas atmosféricas, contaminación, etc. Adicionalmente, la reducción del uso de líneas aéreas y postes mejora la visibilidad y el aspecto de las ciudades. Un problema de particular importancia en la operación de cables subterráneos es la localización oportuna y precisa de fallas, de tal forma que pueda reducirse el tiempo fuera de operación y el área de excavación para realizar las reparaciones correspondientes, así como evitar riesgos de seguridad en el caso de redes subterráneas ubicadas en zonas urbanas

Box plots for <i>AGPAT6</i> expression by QTL genotype.

<p>Box plots showing expression of the <i>AGPAT6</i> gene in lactating mammary tissue quantified by RNA sequencing and quantitative PCR in conjunction with ARS-BFGL-NGS-57448 g.36155097C&gt;T genotype. Log₂ transformed fragments per kilobase of exon model per million mapped (FPKM) values derived by RNA sequencing are indicated on the left-hand Y-axis, log₂ transformed relative expression values derived by quantitative PCR are on the right-hand axis. Genotype groups for the ARS-BFGL-NGS-57448 SNP are on the x-axis, p-values for association are P = 8.97×10⁻⁷ for RNA sequence data and P = 1.20×10⁻³ for quantitative PCR data.</p

Analysis of <i>AGPAT6</i> candidate causative variants.

<p>Manhattan plot showing association of variants with milk fat percentage in Friesian-Jersey crossbreed animals in the chromosome 27 1 Mbp interval of interest (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085757#pone-0085757-g004" target="_blank">Figure 4A</a>). The X-axis shows Mbp position on chromosome 27, the Y-axis shows –log₁₀ p-values of marker association. Illumina BovineHD panel SNPs are indicated by blue dots. Custom-genotyped <i>AGPAT6</i> variants are indicated by red (highly associated), green (associated), and yellow (un-associated) dots, with significance of other markers demarcated by the dashed blue line. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085757#pone-0085757-g004" target="_blank">Figure 4B</a> shows the distribution of F1 sire variants across the <i>AGPAT6</i> gene. The black variant track shows all variants targeted for genotyping from analysis of whole genome sequence data, the blue variant track shows genotyped variants that passed quality filtering criteria prior to association analysis. The red and green variant track shows significantly associated variants as displayed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085757#pone-0085757-g004" target="_blank">Figure 4A</a>. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085757#pone-0085757-g004" target="_blank">Figure 4C</a> shows the distribution of highly associated variants with genome evolutionary rate profiling (GERP) conservation scores calculated from multiple genome alignments of 35 eutherian mammals. Site-wise scores are indicated by the light purple bar graph, with positive scores indicating conservation. Evolutionarily constrained elements are indicated by dark purple blocks, calculated from the same 35-way alignments. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085757#pone-0085757-g004" target="_blank">Figure 4D</a> shows exploded views for each variant, with individual GERP scores indicated. For indel variants, the most and least conserved scores for the corresponding sequence are shown. An interspecies regional alignment for the g.36198118GGC(4_5) VNTR polymorphism is also shown.</p