Azulene-based compounds for targeting orexin receptors

A library of 70 000 synthetically accessible azulene-based compounds was virtually screened at the OX2 receptor. Based on the results, a series of azulene derivatives was synthesized and the binding to and activation of both orexin receptor subtypes were assessed. Two most promising binders were determined to have inhibition constants in the 3-9 mu M range and two other compounds showed weak OX2 receptor agonism. Furthermore, three compounds exhibited a concentration-dependent potentiation of the response to orexin-A at the OX1 but not the OX2 receptors. Altogether this data opens new approaches for further development of antagonists, agonists, and potentiators of orexin response based on the azulene scaffold. (C) 2018 Elsevier Masson SAS. All rights reserved.Peer reviewe

Status of COLDDIAG: A Cold Vacuum Chamber for Diagnostics

One of the still open issues for the development of superconducting insertion devices is the understanding of the beam heat load. With the aim of measuring the beam heat load to a cold bore and the hope to gain a deeper understanding in the beam heat load mechanisms, a cold vacuum chamber for diagnostics is under construction. The following diagnostics will be implemented: i) retarding field analyzers to measure the electron energy and flux, ii) temperature sensors to measure the total heat load, iii) pressure gauges, iv) and mass spectrometers to measure the gas content. The inner vacuum chamber will be removable in order to test different geometries and materials. This will allow the installation of the cryostat in different synchrotron light sources. COLDDIAG will be built to fit in a short straight section at ANKA. A first installation at the synchrotron light source Diamond is foreseen in June 2011. Here we describe the technical design report of this device and the planned measurements with beam.Comment: Presented at First International Particle Accelerator Conference, IPAC'10, Kyoto, Japan, from 23 to 28 May 201

Genetic parameters for cow-specific digestibility predicted by near infrared reflectance spectroscopy

Digestibility traits included in this study were dry matter digestibility (DMD, g/kg), which was calculated based on the indigestible neutral detergent fibre (iNDF, g/kg of dry matter) content in faeces (iNDFf) and in diet (iNDFd), and iNDFf predicted directly from faecal samples by near infrared reflectance spectroscopy (NIRS). The data set was collected at three research herds in Finland and one in Norway including in total 931 records from 328 lactating Nordic Red Cattle and Holstein cows. Observations were associated with different accuracy, due to the differences in sampling protocols used for collecting faecal samples. Heritability estimates varied between different sampling protocols and ranged from 0.14 ± 0.06 to 0.51 ± 0.24 for DMD and from 0.13 ± 0.05 to 0.48 ± 0.18 for iNDFf. Estimated genetic standard deviations were 10.5 g/kg and 6.2 g/kg dry matter for DMD and iNDFf, respectively. Results of our study indicated that recording only the iNDF content in the faeces is sufficient to determine genetic variation in cows’ ability to digest feed. The coefficient of genetic variation for DMD was rather small (1.7%), but could be utilized if it is supported by a positive analysis of benefits over costs.Peer reviewe

Genomic Consequences of Fragmentation in the Endangered Fennoscandian Arctic Fox (Vulpes lagopus)

Accelerating climate change is causing severe habitat fragmentation in the Arctic, threatening the persistence of many cold-adapted species. The Scandinavian arctic fox (V. lagopus) is highly fragmented, with a once continuous, circumpolar distribution, it struggled to recover from a demographic bottleneck in the late 19th century. The future persistence of the entire Scandinavian population is highly dependent on the northernmost Fennoscandian subpopulations (Scandinavia and the Kola Peninsula), to provide a link to the viable Siberian population. By analyzing 43 arctic fox genomes, we quantified genomic variation and inbreeding in these populations. Signatures of genome erosion increased from Siberia to northern Sweden indicating a stepping-stone model of connectivity. In northern Fennoscandia, runs of homozygosity (ROH) were on average ~1.47-fold longer than ROH found in Siberia, stretching almost entire scaffolds. Moreover, consistent with recent inbreeding, northern Fennoscandia harbored more homozygous deleterious mutations, whereas Siberia had more in heterozygous state. This study underlines the value of documenting genome erosion following population fragmentation to identify areas requiring conservation priority. With the increasing fragmentation and isolation of Arctic habitats due to global warming, understanding the genomic and demographic consequences is vital for maintaining evolutionary potential and preventing local extinctions. inbreeding; runs of homozygosity; bottleneck; fragmentation; mutational load; conservatio

The LHC test string: first operational experience

CERN operates the first version of the LHC Test String which consists of one quadrupole and three 10-m twin aperture dipole magnets. An experimental programme aiming at the validation of the LHC systems started in February 1995. During this programme the string has been powered 100 times 35 of which at 12.4 kA or above. The experiments have yielded a number of results some of which, like quench recovery for cryogenics, have modified the design of subsystems of LHC. Others, like controlled helium leaks in the cold bore and quench propagation bewteen magnets, have given a better understanding on the evolution of the phenomena inside a string of superconducting magnets cooled at superfluid helium temperatures. Following the experimental programme, the string will be powered up and powered down in one hour cycles as a fatigue test of the structure thus simulating 20 years of operation of LHC

Generation of angiostatin-like fragments from plasminogen by prostate-specific antigen

Angiostatin, a potent inhibitor of angiogenesis, tumour growth and metastasis, is a biologically active fragment of plasminogen, containing the kringle domains 1–4. It is generated from plasminogen by limited proteolysis. We show that prostate-specific antigen (PSA), a serine proteinase secreted by human prostate and human prostate cancer cells, is able to convert Lys-plasminogen to biologically active angiostatin-like fragments, containing kringles 1–4, by limited proteolysis of peptide bond Glu439–Ala440 in vitro. In an in vitro morphogenesis assay, the purified angiostatin-like fragments inhibited proliferation and tubular formation of human umbilical vein endothelial cells with the same efficacy as angiostatin. This finding might help to understand growth characteristics of prostate cancer, which usually has low microvessel density and slow proliferation. © 1999 Cancer Research Campaig

Greenhouse gas emissions of realistic dietary choices in Denmark: the carbon footprint and nutritional value of dairy products

Background: Dairy products are important in a healthy diet due to their high nutritional value; they are, however, associated with relatively large greenhouse gas emissions (GHGE) per kg product. When discussing the need to reduce the GHGE caused by the food system, it is crucial to consider the nutritional value of alternative food choices. Objective: The objective of this study was to elucidate the role of dairy products in overall nutrition and to clarify the effects of dietary choices on GHGE, and to combine nutritional value and GHGE data. Methods: We created eight dietary scenarios with different quantity of dairy products using data from the Danish National Dietary Survey (1995–2006). Nutrient composition and GHGE data for 71 highly consumed foods were used to estimate GHGE and nutritional status for each dietary scenario. An index was used to estimate nutrient density in relation to nutritional recommendation and climate impact for solid food items; high index values were those with the highest nutrient density scores in relation to the GHGE. Results: The high-dairy scenario resulted in 27% higher protein, 13% higher vitamin D; 55% higher calcium; 48% higher riboflavin; and 18% higher selenium than the non-dairy scenario. There was a significant correlation between changes in calcium and changes in vitamin D, selenium, and riboflavin content (P=0.0001) throughout all of the diets. The estimated GHGE for the dietary scenario with average-dairy consumption was 4,631 g CO2e/day. Conclusions: When optimizing a diet with regard to sustainability, it is crucial to account for the nutritional value and not solely focus on impact per kg product. Excluding dairy products from the diet does not necessarily mitigate climate change but in contrast may have nutritional consequences

Design Strategies for ARX with Provable Bounds: SPARX and LAX

We present, for the first time, a general strategy for designing ARX symmetric-key primitives with provable resistance against single-trail differential and linear cryptanalysis. The latter has been a long standing open problem in the area of ARX design. The Wide-Trail design Strategy (WTS), that is at the basis of many S-box based ciphers, including the AES, is not suitable for ARX designs due to the lack of S-boxes in the latter. In this paper we address the mentioned limitation by proposing the Long-Trail design Strategy (LTS) -- a dual of the WTS that is applicable (but not limited) to ARX constructions. In contrast to the WTS, that prescribes the use of small and efficient S-boxes at the expense of heavy linear layers with strong mixing properties, the LTS advocates the use of large (ARX-based) S-Boxes together with sparse linear layers. With the help of the so-called long-trail argument, a designer can bound the maximum differential and linear probabilities for any number of rounds of a cipher built according to the LTS. To illustrate the effectiveness of the new strategy, we propose Sparx -- a family of ARX-based block ciphers designed according to the LTS. Sparx has 32-bit ARX-based S-boxes and has provable bounds against differential and linear cryptanalysis. In addition, Sparx is very efficient on a number of embedded platforms. Its optimized software implementation ranks in the top-6 of the most software-efficient ciphers along with Simon, Speck, Chaskey, LEA and RECTANGLE. As a second contribution we propose another strategy for designing ARX ciphers with provable properties, that is completely independent of the LTS. It is motivated by a challenge proposed earlier by Wallen and uses the differential properties of modular addition to minimize the maximum differential probability across multiple rounds of a cipher. A new primitive, called LAX is designed following those principles. LAX partly solves the Wallen challenge