Magnetic phase separation in ordered alloys

We present a lattice model to study the equilibrium phase diagram of ordered alloys with one magnetic component that exhibits a low temperature phase separation between paramagnetic and ferromagnetic phases. The model is constructed from the experimental facts observed in Cu$_{3-x}$AlMn$_{x}$ and it includes coupling between configurational and magnetic degrees of freedom which are appropriated for reproducing the low temperature miscibility gap. The essential ingredient for the occurrence of such a coexistence region is the development of ferromagnetic order induced by the long-range atomic order of the magnetic component. A comparative study of both mean-field and Monte Carlo solutions is presented. Moreover, the model may enable the study of the structure of the ferromagnetic domains embedded in the non-magnetic matrix. This is relevant in relation to phenomena such as magnetoresistance and paramagnetism.Comment: 12 pages, 11 figures, accepted in Phys. Rev.

Muscle injury and impaired function, and insulin resistance in Chromogranin A knockout mice

Chromogranin A (CgA) is widely expressed in endocrine and neuroendocrine tissues as well as in the central nervous system. We observed CgA expression (mRNA and protein) in the gastrocnemius (GAS) muscle and found that performance of CgA-deficient Chga-KO mice in treadmill exercise was impaired. Supplementation with CgA in Chga-KO mice restored exercise ability suggesting a novel role for endogenous CgA in skeletal muscle function. Chga-KO mice display (i) lack of exercise-induced stimulation of pAKT, pTBC1D1 and phospho-p38 kinase signaling, (ii) loss of GAS muscle mass, (iii) extensive formation of tubular aggregates (TA), (iv) disorganized cristae architecture in mitochondria, (v) increased expression of the inflammatory cytokines Tnfα, Il6 and Ifnɣ, and fibrosis. The impaired maximum running speed and endurance in the treadmill exercise in Chga-KO mice correlated with decreased glucose uptake and glycolysis, defects in glucose oxidation and decreased mitochondrial cytochrome C oxidase activity. The lack of adaptation to endurance training correlated with the lack of stimulation of p38MAPK that is known to mediate the response to tissue damage. Since CgA sorts proteins to the regulated secretory pathway, we speculate that lack of CgA could cause misfolding of membrane proteins inducing aggregation of sarcoplasmic reticulum (SR) membranes and formation of tubular aggregates that is observed in Chga-KO mice. In conclusion, CgA deficiency renders the muscle energy deficient, impairs performance in treadmill exercise and prevents regeneration after exercise-induced tissue damage

The Evolution of the Kinematics of Nebular Shells in Planetary Nebulae in the Milky Way Bulge

We study the line widths in the [\ion{O}{3}]$\lambda$5007 and H$\alpha$ lines for two groups of planetary nebulae in the Milky Way bulge based upon spectroscopy obtained at the Observatorio Astron\'omico Nacional in the Sierra San Pedro M\'artir (OAN-SPM) using the Manchester Echelle Spectrograph. The first sample includes objects early in their evolution, having high H$\beta$ luminosities, but [\ion{O}{3}]$\lambda 5007/\mathrm H\beta < 3$. The second sample comprises objects late in their evolution, with \ion{He}{2} $\lambda 4686/\mathrm H\beta > 0.5$. These planetary nebulae represent evolutionary phases preceeding and following those of the objects studied by Richer et al. (2008). Our sample of planetary nebulae with weak [\ion{O}{3}]$\lambda$5007 has a line width distribution similar to that of the expansion velocities of the envelopes of AGB stars, and shifted to systematically lower values as compared to the less evolved objects studied by Richer et al. (2008). The sample with strong \ion{He}{2} $\lambda 4686$ has a line width distribution indistinguishable from that of the more evolved objects from Richer et al. (2008), but a distribution in angular size that is systematically larger and so they are clearly more evolved. These data and those of Richer et al. (2008) form a homogeneous sample from a single Galactic population of planetary nebulae, from the earliest evolutionary stages until the cessation of nuclear burning in the central star. They confirm the long-standing predictions of hydrodynamical models of planetary nebulae, where the kinematics of the nebular shell are driven by the evolution of the central star.Comment: accepted for publication in the Astrophysical Journa

The Diversity of REcent and Ancient huMan (DREAM): a new microarray for genetic anthropology and genealogy, forensics, and personalized medicine

The human population displays wide variety in demographic history, ancestry, content of DNA derived from hominins or ancient populations, adaptation, traits, copy number variation (CNVs), drug response, and more. These polymorphisms are of broad interest to population geneticists, forensics investigators, and medical professionals. Historically, much of that knowledge was gained from population survey projects. While many commercial arrays exist for genome-wide single-nucleotide polymorphism (SNP) genotyping, their design specifications are limited and they do not allow a full exploration of biodiversity. We thereby aimed to design the Diversity of REcent and Ancient huMan (DREAM) - an all-inclusive microarray that would allow both identification of known associations and exploration of standing questions in genetic anthropology, forensics, and personalized medicine. DREAM includes probes to interrogate ancestry informative markers obtained from over 450 human populations, over 200 ancient genomes, and 10 archaic hominins. DREAM can identify 94% and 61% of all known Y and mitochondrial haplogroups, respectively and was vetted to avoid interrogation of clinically relevant markers. To demonstrate its capabilities, we compared its FST distributions with those of the 1000 Genomes Project and commercial arrays. Although all arrays yielded similarly shaped (inverse J) FST distributions, DREAM's autosomal and X-chromosomal distributions had the highest mean FST, attesting to its ability to discern subpopulations. DREAM performances are further illustrated in biogeographical, identical by descent (IBD), and CNV analyses. In summary, with approximately 800,000 markers spanning nearly 2,000 genes, DREAM is a useful tool for genetic anthropology, forensic, and personalized medicine studies

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Characterisation of a Wheat Breeders’ Array suitable for high throughput SNP genotyping of global accessions of hexaploid bread wheat (<i>Triticum aestivium</i>)

Targeted selection and inbreeding have resulted in a lack of genetic diversity in elite hexaploid bread wheat accessions. Reduced diversity can be a limiting factor in the breeding of high yielding varieties and crucially can mean reduced resilience in the face of changing climate and resource pressures. Recent technological advances have enabled the development of molecular markers for use in the assessment and utilization of genetic diversity in hexaploid wheat. Starting with a large collection of 819 571 previously characterized wheat markers, here we describe the identification of 35 143 single nucleotide polymorphism-based markers, which are highly suited to the genotyping of elite hexaploid wheat accessions. To assess their suitability, the markers have been validated using a commercial high-density Affymetrix Axiom® genotyping array (the Wheat Breeders' Array), in a high-throughput 384 microplate configuration, to characterize a diverse global collection of wheat accessions including landraces and elite lines derived from commercial breeding communities. We demonstrate that the Wheat Breeders' Array is also suitable for generating high-density genetic maps of previously uncharacterized populations and for characterizing novel genetic diversity produced by mutagenesis. To facilitate the use of the array by the wheat community, the markers, the associated sequence and the genotype information have been made available through the interactive web site 'CerealsDB'

System Dynamics Modeling as a Potentially Useful Tool in Analyzing Mitigation Strategies to Reduce Overdose Deaths Associated with Pharmaceutical Opioid Treatment of Chronic Pain

Objective. To illustrate a system-level, simulationbased approach for evaluating mitigation strategies to address the dramatic rise in abuse, addiction, and overdose deaths associated with the use of pharmaceutical opioid analgesics to treat chronic pain. Simulated Interventions. Making available drug formulations with increased tamper-resistance, prescriber education programs, and programs that reduce rates of medical user-related abuse and addiction. Simulated Outcome Measure. Number of overdose deaths of medical users of pharmaceutical opioid analgesics, including those who abuse or have become addicted. Methods. A demonstration system dynamics model is developed, tested, and used to evaluate the impact of candidate mitigation strategies on the outcome measures. Results. Tamper-resistant drug products will likely reduce overdose death rates but may not reduce overall deaths if there is increased prescribing. Prescriber education would likely reduce deaths through a reduction in patient access to pharmaceutical opioid analgesics. Conclusions. The system dynamics approach may have potential for opioid-related policy evaluation. However, metrics must be carefully selected, and trade-offs may be involved. For example, it may be difficult to limit negative outcomes associated with pharmaceutical opioids without adversely affecting chronic pain patients’ access to pharmaceutical treatment. Ultimately, a combination of metrics and value judgments will be needed to properly evaluate mitigation strategies. Keywords. Chronic Pain; Outcome Assessment; Opioids; Prescriptions; Mitigation Strategies; System Dynamic

Characterization of structures in biofilms formed by a Pseudomonas fluorescens isolated from soil

<p>Abstract</p> <p>Background</p> <p>Microbial biofilms represent an incompletely understood, but fundamental mode of bacterial growth. These sessile communities typically consist of stratified, morphologically-distinct layers of extracellular material, where numerous metabolic processes occur simultaneously in close proximity. Limited reports on environmental isolates have revealed highly ordered, three-dimensional organization of the extracellular matrix, which may hold important implications for biofilm physiology <it>in vivo</it>.</p> <p>Results</p> <p>A <it>Pseudomonas </it>spp. isolated from a natural soil environment produced flocculent, nonmucoidal biofilms <it>in vitro </it>with unique structural features. These mature biofilms were made up of numerous viable bacteria, even after extended culture, and contained up to 50% of proteins and accumulated 3% (by dry weight) calcium, suggesting an important role for the divalent metal in biofilm formation. Ultrastructurally, the mature biofilms contained structural motifs consisting of dense, fibrillary clusters, nanofibers, and ordered, honeycomb-like chambers enveloped in thin sheets.</p> <p>Conclusion</p> <p>Mature biofilms contained living bacteria and were structurally, chemically, and physiologically heterogeneous. The principal architectural elements observed by electron microscopy may represent useful morphological clues for identifying bacterial biofilms <it>in vivo</it>. The complexity and reproducibility of the structural motifs observed in bacterial biofilms appear to be the result of organized assembly, suggesting that this environmental isolate may possess ecological advantages in its natural habitat.</p