New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

The best of both:a study of the feasibility of integrating scale of design and production for sustainable products

Contemporary design assumes and employs a highly diverse range of materials, skills and technologies to create new products for production. A close consideration of the relationships and characteristics of this multifaceted design and production system can help designers better understand the social and environmental implications of current practices, and help move us in constructive and positive directions for change. Academic researchers are able to take the long view on such change, they can analyse the existing situation and suggest beneficial possibilities for the future. This discussion takes such a view by bringing together design research, systems thinking and product design explorations. From this, we have developed a fresh approach that we have termed ‘integrated scales of design and production for sustainability’ (ISDPS). This integrated approach was first proposed by Walker in 2000. Since then the concept has been developed and elaborated upon (Dogan and Walker, Restoring Local Scale: Rethinking the Company Structures for Sustainable Product Design. Sustainable Innovation Conference 3, October 26–27, Stockholm, Sweden). This present discussion focuses on the feasibility and implications of sustainability of the ISDPS concept

¹³C-Carbamylation as a mechanistic probe for the inhibition of class D β-lactamases by avibactam and halide ions

The class D (OXA) serine β-lactamases are a major cause of resistance to β-lactam antibiotics. The class D enzymes are unique amongst β-lactamases because they have a carbamylated lysine that acts as a general acid/base in catalysis. Previous crystallographic studies led to the proposal that β-lactamase inhibitor avibactam targets OXA enzymes in part by promoting decarbamylation. Similarly, halide ions are proposed to inhibit OXA enzymes via decarbamylation. NMR analyses, in which the carbamylated lysines of OXA-10, -23 and -48 were 13C-labelled, indicate that reaction with avibactam does not ablate lysine carbamylation in solution. While halide ions did not decarbamylate the 13C-labelled OXA enzymes in the absence of substrate or inhibitor, avibactam-treated OXA enzymes were susceptible to decarbamylation mediated by halide ions, suggesting halide ions may inhibit OXA enzymes by promoting decarbamylation of acyl-enzyme complex. Crystal structures of the OXA-10 avibactam complex were obtained with bromide, iodide, and sodium ions bound between Trp-154 and Lys-70. Structures were also obtained wherein bromide and iodide ions occupy the position expected for the ‘hydrolytic water’ molecule. In contrast with some solution studies, Lys-70 was decarbamylated in these structures. These results reveal clear differences between crystallographic and solution studies on the interaction of class D β-lactamases with avibactam and halides, and demonstrate the utility of 13C-NMR for studying lysine carbamylation in solution

Differential Cross Sections for Neutron Elastic and Inelastic Scattering on

Measurements of neutron elastic and inelastic scattering from 23Na have been performed for sixteen incident neutron energies above 1.5 MeV with the 7-MV University of Kentucky Accelerator using the 3H(p,n) reaction as the neutron source. These measurements were complemented by γ-ray excitation functions using the (n,n'γ) reaction. The time-of-flight technique is employed for background reduction in both neutron and γ- ray measurements and for determining the energy of the scattered neutrons. Cross section determinations support fuel cycle and structural materials research and development. Previous reaction model evaluations [1] relied primarily on total cross sections and four (n,n0) and (n,n1) angular distributions in the En = 5 to 9 MeV range. The inclusion of more inelastic channels at lower neutron energies provides additional information on direct couplings between elastic and inelastic scattering as a function of angular momentum transfer. Reaction model calculations examining direct collective and statistical properties were performed

Differential Cross Sections for Neutron Elastic and Inelastic Scattering on 23

Measurements of neutron elastic and inelastic scattering from 23Na have been performed for sixteen incident neutron energies above 1.5 MeV with the 7-MV University of Kentucky Accelerator using the 3H(p,n) reaction as the neutron source. These measurements were complemented by γ-ray excitation functions using the (n,n'γ) reaction. The time-of-flight technique is employed for background reduction in both neutron and γ- ray measurements and for determining the energy of the scattered neutrons. Cross section determinations support fuel cycle and structural materials research and development. Previous reaction model evaluations [1] relied primarily on total cross sections and four (n,n0) and (n,n1) angular distributions in the En = 5 to 9 MeV range. The inclusion of more inelastic channels at lower neutron energies provides additional information on direct couplings between elastic and inelastic scattering as a function of angular momentum transfer. Reaction model calculations examining direct collective and statistical properties were performed