Impact of an 11-week Nordic Pole Walking Program on the Overall Feelings of Health, Wellbeing and Motivation in Older Adults

Nordic Pole Walking (NPW), the act of walking with poles, is an activity that promotes health and wellness for individuals of all ages and fitness levels. For older adults, this activity can be part of a healthy lifestyle while assisting with balance and encouraging correct gait for those who require additional support. The Sheridan Centre for Elder Research, in partnership with Nordixx Canada, offered an 11-week Nordic Pole Walking program (20 hours) to evaluate its impact on the overall feelings of health, well-being and motivation in older adults. A total of sixteen people participated (14 female, 2 male), and each participant completed a comprehensive battery of surveys and standardized evaluations of health, physical activity levels and motivation. Results showed that participants enjoyed the ‘walk and talk’ component and reported improved fitness levels and eagerness to continue Nordic Pole Walking after the project ended

Learning the shape of protein micro-environments with a holographic convolutional neural network

Proteins play a central role in biology from immune recognition to brain activity. While major advances in machine learning have improved our ability to predict protein structure from sequence, determining protein function from structure remains a major challenge. Here, we introduce Holographic Convolutional Neural Network (H-CNN) for proteins, which is a physically motivated machine learning approach to model amino acid preferences in protein structures. H-CNN reflects physical interactions in a protein structure and recapitulates the functional information stored in evolutionary data. H-CNN accurately predicts the impact of mutations on protein function, including stability and binding of protein complexes. Our interpretable computational model for protein structure-function maps could guide design of novel proteins with desired function

Pinacol as a new green reducing agent: molybdenum-catalyzed chemoselective reduction of sulfoxides and nitroaromatics

Pinacol is disclosed as a new chemoselective and environmentally benign reducing agent for sulfoxides and nitroaromatics assisted by readily available dichlorodioxomolybdenum(VI) complexes as catalysts. A wide range of substrates including those bearing challenging functional groups has been efficiently and selectively reduced with acetone and water being the only by-products of these reactionsMinisterio de Ciencia e Innovacion (MICINN) and FEDER (CTQ2010-15358 and CTQ2009-09949/BQU) and Junta de Castilla y Leon (BU021 A09 and GR-172) for financial support. P.G.-G. and M.A.F.-R. thank MICINN for "Juan de la Cierva" and "Ramon y Cajal" contractsThis is the peer reviewed version of the following article:García, N., García-García, P., Fernández-Rodríguez, M. A., Rubio, R., Pedrosa, M. R., Arnáiz, F. J. and Sanz, R. (2012), Pinacol as a New Green Reducing Agent: Molybdenum- Catalyzed Chemoselective Reduction of Sulfoxides and Nitroaromatics. Adv. Synth. Catal., 354: 321–327. doi: 10.1002/adsc.201100877 , which has been published in final form at 10.1002/adsc.201100877. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archivin

Digital technology and governance in transition: The case of the British Library

Comment on the organizational consequences of the new information and communications technologies (ICTs) is pervaded by a powerful imagery of disaggregation and a tendency for ?virtual? forms of production to be seen as synonymous with the ?end? of bureaucracy. This paper questions the underlying assumptions of the ?virtual organization?, highlighting the historically enduring, diversified character of the bureaucratic form. The paper then presents case study findings on the web-based access to information resources now being provided by the British Library (BL). The case study evidence produces two main findings. First, radically decentralised virtual forms of service delivery are heavily dependent on new forms of capacity-building and information aggregation. Second, digital technology is embedded in an inherently contested and contradictory context of institutional change. Current developments in the management and control of digital rights are consistent with the commodification of the public sphere. However, the evidence also suggests that scholarly access to information resources is being significantly influenced by the ?information society? objectives of the BL and other institutional players within the network of UK research libraries

A Genome Wide Association Scan of Bovine Tuberculosis Susceptibility in Holstein-Friesian Dairy Cattle

peer-reviewedBackground: Bovine tuberculosis is a significant veterinary and financial problem in many parts of the world. Although many factors influence infection and progression of the disease, there is a host genetic component and dissection of this may enlighten on the wider biology of host response to tuberculosis. However, a binary phenotype of presence/absence of infection presents a noisy signal for genomewide association study. Methodology/Principal Findings: We calculated a composite phenotype of genetic merit for TB susceptibility based on disease incidence in daughters of elite sires used for artificial insemination in the Irish dairy herd. This robust measure was compared with 44,426 SNP genotypes in the most informative 307 subjects in a genome wide association analysis. Three SNPs in a 65 kb genomic region on BTA 22 were associated (i.e. p,1025, peaking at position 59588069, p = 4.0261026) with tuberculosis susceptibility. Conclusions/Significance: A genomic region on BTA 22 was suggestively associated with tuberculosis susceptibility; it contains the taurine transporter gene SLC6A6, or TauT, which is known to function in the immune system but has not previously been investigated for its role in tuberculosis infection

Patterns of democracy: Coalition governance and majoritarian modification in the United Kingdom, 2010–2015

The UK is often regarded as the archetype of Westminster democracy and as the empirical antithesis of the power-sharing coalitions of Western Europe. Yet, in recent years a different account has emerged that focuses on the subtler institutional dynamics which limit the executive. It is to this body of scholarship that this article responds, locating the recent chapter of coalition government within the wider context of the UK’s democratic evolution. To do so, the article draws Lijphart’s two-dimensional typology of democracies, developing a refined framework that enables systematic comparison over time. The article demonstrates that between over the course of the 2010-15 Parliament, the UK underwent another period of majoritarian modification, driven by factors including the long-term influence of the constitutional forces unleashed under Labour and the short-term impact of coalition management. The article makes several important contributions, salient in the UK and beyond. Theoretically, it offers a critical rejoinder to debates regarding the relationship between institutional design and democratic performance. Methodologically, it demonstrates that the tools of large-scale comparison can be effectively scaled-down to facilitate withincase analysis. Empirically, it provides a series of conclusions regarding the tenability of the UK’s extant democratic architecture under the weight of pressures to which it continues to be subject

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches