A Supercooled Spin Liquid State in the Frustrated Pyrochlore Dy2Ti2O7

A "supercooled" liquid develops when a fluid does not crystallize upon cooling below its ordering temperature. Instead, the microscopic relaxation times diverge so rapidly that, upon further cooling, equilibration eventually becomes impossible and glass formation occurs. Classic supercooled liquids exhibit specific identifiers including microscopic relaxation times diverging on a Vogel-Tammann-Fulcher (VTF) trajectory, a Havriliak-Negami (HN) form for the dielectric function, and a general Kohlrausch-Williams-Watts (KWW) form for time-domain relaxation. Recently, the pyrochlore Dy2Ti2O7 has become of interest because its frustrated magnetic interactions may, in theory, lead to highly exotic magnetic fluids. However, its true magnetic state at low temperatures has proven very difficult to identify unambiguously. Here we introduce high-precision, boundary-free magnetization transport techniques based upon toroidal geometries and gain a fundamentally new understanding of the time- and frequency-dependent magnetization dynamics of Dy2Ti2O7. We demonstrate a virtually universal HN form for the magnetic susceptibility, a general KWW form for the real-time magnetic relaxation, and a divergence of the microscopic magnetic relaxation rates with precisely the VTF trajectory. Low temperature Dy2Ti2O7 therefore exhibits the characteristics of a supercooled magnetic liquid; the consequent implication is that this translationally invariant lattice of strongly correlated spins is evolving towards an unprecedented magnetic glass state, perhaps due to many-body localization of spin.Comment: Version 2 updates: added legend for data in Figures 4A and 4B; corrected equation reference in caption for Figure 4

Modelling and model assessment of grid based Multi-Energy Systems

Two main strategies should be implemented to decarbonise the energy sector: substituting fossil fuels with renewable energies, and increasing system efficiency. Both strategies pose challenges for today's energy systems and their operators, because renewable energy is mainly decentralized, not always predictable, and introduces a degree of volatility into grids. Multi-energy systems, which incorporate multiple energy sectors, allow flexibility options to be used across energy carriers and thus further increase system flexibility. In addition, these multi-energy systems can also improve the overall energy efficiency. They enable cascaded energy use and allow for seasonal storage between different energy carriers. A comprehensive system modelling framework should consider all profound interactions between relevant system control variables. The aim of this proposed paper is to show the correlation between major aspects of grid based MES and how they can be combined in a system modelling framework

Photocathode Behavior During High Current Running in the Cornell ERL Photoinjector

The Cornell University Energy Recovery Linac (ERL) photoinjector has recently demonstrated operation at 20 mA for approximately 8 hours, utilizing a multialkali photocathode deposited on a Si substrate. We describe the recipe for photocathode deposition, and will detail the parameters of the run. Post-run analysis of the photocathode indicates the presence of significant damage to the substrate, perhaps due to ion back-bombardment from the residual beamline gas. While the exact cause of the substrate damage remains unknown, we describe multiple surface characterization techniques (X-ray fluorescence spectroscopy, X-ray diffraction, atomic force and scanning electron microscopy) used to study the interesting morphological and crystallographic features of the photocathode surface after its use for high current beam production. Finally, we present a simple model of crystal damage due to ion back-bombardment, which agrees qualitatively with the distribution of damage on the substrate surface.Comment: 20 pages, 15 figure

Effect of Process Parameters and High-Temperature Preheating on Residual Stress and Relative Density of Ti6Al4V Processed by Selective Laser Melting

The aim of this study is to observe the effect of process parameters on residual stresses and relative density of Ti6Al4V samples produced by Selective Laser Melting. The investigated parameters were hatch laser power, hatch laser velocity, border laser velocity, high-temperature preheating and time delay. Residual stresses were evaluated by the bridge curvature method and relative density by the optical method. The effect of the observed process parameters was estimated by the design of experiment and surface response methods. It was found that for an effective residual stress reduction, the high preheating temperature was the most significant parameter. High preheating temperature also increased the relative density but caused changes in the chemical composition of Ti6Al4V unmelted powder. Chemical analysis proved that after one build job with high preheating temperature, oxygen and hydrogen content exceeded the ASTM B348 limits for Grade 5 titanium

Vedolizumab use after failure of TNF- antagonists in children and adolescents with inflammatory bowel disease

BACKGROUND: Vedolizumab is safe and effective in adult patients with Crohn's disease (CD) and ulcerative colitis (UC); however, data in children with inflammatory bowel disease (IBD) are scarce. Therefore, we evaluated vedolizumab use in a cohort of Austrian paediatric patients with IBD. METHODS: Twelve patients (7 female; 7 CD; 5 UC), aged 8-17 years (median, 15 years), with severe IBD who received vedolizumab after tumour necrosis factor antagonist treatment were retrospectively analysed. Clinical activity scores, relevant laboratory parameters, and auxological measures were obtained at infusion visits. RESULTS: In the CD group, 1/7 patient discontinued therapy due to a severe systemic allergic reaction; 1/7 and 2/7 patients achieved complete and partial response, respectively, at week 14; and 3/7 patients discontinued therapy due to a primary non-response or loss of response. In the UC group, complete clinical remission was achieved at weeks 2, 6, and 14 in 2/5, 1/5 and 1/5 patients respectively; partial response was observed in one patient at week 2. CD activity scores did not significantly change from baseline to week 38 (median 47.5 vs. 40 points, p=1,0), while median UC activity scores changed from 70 to 5 points (p<0,001). Substantial weight gain and increased albumin and haemoglobin levels were observed in both groups. CONCLUSION: These results demonstrate that vedolizumab can be an effective treatment for individual paediatric patients with IBD who are unresponsive, intolerant, or experience a loss of efficacy in other therapies. However, vedolizumab appears to be more effective in paediatric UC than in paediatric CD.(VLID)286504

Cancer immunotherapy is accompanied by distinct metabolic patterns in primary and secondary lymphoid organs observed by non-invasive in vivo18F-FDG-PET

Purpose: Cancer immunotherapy depends on a systemic immune response, but the basic underlying mechanisms are still largely unknown. Despite the very successful and widespread use of checkpoint inhibitors in the clinic, the majority of cancer patients do not benefit from this type of treatment. In this translational study, we investigated whether noninvasive in vivo positron emission tomography (PET) imaging using 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) is capable of detecting immunotherapy-associated metabolic changes in the primary and secondary lymphoid organs and whether this detection enables the prediction of a successful anti-cancer immune response. Methods: RIP1-Tag2 mice with progressed endogenous insular cell carcinomas underwent a combined cancer immunotherapy consisting of CD4+ T cells plus monoclonal antibodies (mAbs) against programmed death ligand-1 (PD-L1) and lymphocyte activation gene-3 (LAG-3) or a sham treatment after radiation-mediated immune cell depletion. A second cohort of RIP1-Tag2 mice underwent exclusive checkpoint inhibitor therapy (CIT) using anti-PD-L1/LAG-3 mAbs or sham treatment without initial immune cell depletion to mimic the clinical situation. All mice were monitored by 18F-FDG-PET combined with anatomical magnetic resonance imaging (MRI). In addition, we retrospectively analyzed PET / computed tomography (CT) scans (PET/CT) regarding 18F-FDG uptake of CIT-treated metastatic melanoma patients in the spleen (n=23) and bone marrow (BM; n=20) as well as blood parameters (n=17-21). Results: RIP1-Tag2 mice with advanced insular cell carcinomas treated with combination immunotherapy exhibited significantly increased 18F-FDG uptake in the spleen compared to sham-treated mice. Histopathology of the spleens from treated mice revealed atrophy of the white pulp with fewer germinal centers and an expanded red pulp with hyperplasia of neutrophils than those of sham-treated mice. Immunohistochemistry and flow cytometry analyses of the spleens revealed a lower number of T cells and a higher number of neutrophils compared to those in the spleens of sham-treated mice. Flow cytometry of the BM showed enhanced activation of T cells following the treatment schemes that included checkpoint inhibitors. The ratio of 18F-FDG uptake at baseline to the uptake at follow-up in the spleens of exclusively CIT-treated RIP1-Tag2 mice was significantly enhanced, but the ratio was not enhanced in the spleens of the sham-treated littermates. Flow cytometry analysis confirmed a reduced number of T cells in the spleens of exclusively CIT-treated mice compared to that of sham-treated mice. A retrospective analysis of clinical 18F-FDG-PET/CT scans revealed enhanced 18F-FDG uptake in the spleens of some successfully CIT-treated patients with metastatic melanoma, but there were no significant differences between responders and non-responders. The analysis of the BM in clinical 18F-FDG-PET/CT scans with a computational segmentation tool revealed significantly higher baseline 18F-FDG uptake in patients who responded to CIT than in non-responders, and this relationship was independent of bone metastasis, even in the baseline scan. Conclusions: Thus, we are presenting the first translational study of solid tumors focusing on the metabolic patterns of primary and secondary lymphoid organs induced by the systemic immune response after CIT. We demonstrate that the widely available 18F-FDG-PET modality is an applicable translational tool that has high potential to stratify patients at an early time point

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in &gt;100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P &lt; 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.