The PrPC Cl fragment derived from the ovine A(136)R(154)R(171) PRNP allele is highly abundant in sheep brain and inhibits fibrillisation of full-length PrPC protein in vitro

AbstractExpression of the cellular prion protein (PrPC) is crucial for the development of prion diseases. Resistance to prion diseases can result from reduced availability of the prion protein or from amino acid changes in the prion protein sequence. We propose here that increased production of a natural PrP α-cleavage fragment, C1, is also associated with resistance to disease. We show, in brain tissue, that ARR homozygous sheep, associated with resistance to disease, produced PrPC comprised of 25% more C1 fragment than PrPC from the disease-susceptible ARQ homozygous and highly susceptible VRQ homozygous animals. Only the C1 fragment derived from the ARR allele inhibits in-vitro fibrillisation of other allelic PrPC variants. We propose that the increased α-cleavage of ovine ARR PrPC contributes to a dominant negative effect of this polymorphism on disease susceptibility. Furthermore, the significant reduction in PrPC β-cleavage product C2 in sheep of the ARR/ARR genotype compared to ARQ/ARQ and VRQ/VRQ genotypes, may add to the complexity of genetic determinants of prion disease susceptibility

Enhancement of Magneto-Optic Effects via Large Atomic Coherence

We utilize the generation of large atomic coherence to enhance the resonant nonlinear magneto-optic effect by several orders of magnitude, thereby eliminating power broadening and improving the fundamental signal-to-noise ratio. A proof-of-principle experiment is carried out in a dense vapor of Rb atoms. Detailed numerical calculations are in good agreement with the experimental results. Applications such as optical magnetometry or the search for violations of parity and time reversal symmetry are feasible

The potential of neglected and underutilized species for improving diets and nutrition

The paper highlights the novel and ingenious approaches Brazil, Kenya, Sri Lanka and Turkey used to prioritize a rich diversity of NUS for healthier diets and improved nutrition, and how this knowledge was used to mainstream these plant species into production and consumption systems. The paper concludes with some perspectives on the way forward for NUS and the community working on them in meeting the challenges of malnutrition and environmental sustainability in the 2030 sustainable development context

Status of the GAMMA-400 Project

The preliminary design of the new space gamma-ray telescope GAMMA-400 for the energy range 100 MeV - 3 TeV is presented. The angular resolution of the instrument, 1-2{\deg} at E{\gamma} ~100 MeV and ~0.01^{\circ} at E{\gamma} > 100 GeV, its energy resolution ~1% at E{\gamma} > 100 GeV, and the proton rejection factor ~10E6 are optimized to address a broad range of science topics, such as search for signatures of dark matter, studies of Galactic and extragalactic gamma-ray sources, Galactic and extragalactic diffuse emission, gamma-ray bursts, as well as high-precision measurements of spectra of cosmic-ray electrons, positrons, and nuclei.Comment: 6 pages, 1 figure, 1 table, submitted to Advances in Space Researc

The uses and abuses of power: teaching school leadership through children's literature

There are relatively few studies of how representations of teachers, schools and educational administrators in popular films and television might be, and are, used in leadership preparation. This paper seeks to add to this small body of work; it reports on an exploratory study of the representation of headteachers in contemporary children's fiction. Thirty-one texts are analysed to ascertain key themes and the major characterisations. The paper draws on children's literature scholars to argue that both the historical school story and its contemporary counterpart focus heavily on the power of the head to control the micro-world of the school. Because these fictional accounts deal with issues of power and justice more openly than many mainstream educational administration texts, this makes them particularly useful in the preparation of potential school leaders

Improved tree height estimation of secondary forests in the Brazilian Amazon

This paper presents a novel approach for estimating the height of individual trees in secondary forests at two study sites: Manaus (central Amazon) and Santarém (eastern Amazon) in the Brazilian Amazon region. The approach consists of adjusting tree height-diameter at breast height (H:DBH) models in each study site by ecological species groups: pioneers, early secondary, and late secondary. Overall, the DBH and corresponding height (H) of 1,178 individual trees were measured during two field campaigns: August 2014 in Manaus and September 2015 in Santarém. We tested the five most commonly used log-linear and nonlinear H:DBH models, as determined by the available literature. The hyperbolic model: H = a.DBH/(b+DBH) was found to present the best fit when evaluated using validation data. Significant differences in the fitted parameters were found between pioneer and secondary species from Manaus and Santarém by F-test, meaning that site-specific and also ecological-group H:DBH models should be used to more accurately predict H as a function of DBH. This novel approach provides specific equations to estimate height of secondary forest trees for particular sites and ecological species groups. The presented set of equations will allow better biomass and carbon stock estimates in secondary forests of the Brazilian Amazon

Models of KPTN-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models.Kptn−/− mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants.Molecular and structural analysis of Kptn−/− mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1.By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.Genetics of disease, diagnosis and treatmen

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe