JAK2V617F homozygosity arises commonly and recurrently in PV and ET, but PV is characterized by expansion of a dominant homozygous subclone

Subclones homozygous for JAK2V617F are more common in polycythemia vera (PV) than essential thrombocythemia (ET), but their prevalence and significance remain unclear. The JAK2 mutation status of 6495 BFU-E, grown in low erythropoietin conditions, was determined in 77 patients with PV or ET. Homozygous-mutant colonies were common in patients with JAK2V617F-positive PV and were surprisingly prevalent in JAK2V617F-positive ET and JAK2 exon 12-mutated PV. Using microsatellite PCR to map loss-of-heterozygosity breakpoints within individual colonies, we demonstrate that recurrent acquisition of JAK2V617F homozygosity occurs frequently in both PV and ET. PV was distinguished from ET by expansion of a dominant homozygous subclone, the selective advantage of which is likely to reflect additional genetic or epigenetic lesions. Our results suggest a model in which development of a dominant JAK2V617F-homzygous subclone drives erythrocytosis in many PV patients, with alternative mechanisms operating in those with small or undetectable homozygous-mutant clones.

A carefully curated collection: female figures as sites of inscription in Gautier’s Émaux et Camées

This article examines the ways in which female figures function as additional sites for poetic inscription in Gautier's Émaux et Camées. Although considerable attention has already been paid to the numerous and varied objects catalogued in the collection and, indeed, to the notion of the poems themselves as objects, the present study aims to expand upon such interpretations of the work by focusing on three texts, "Le Poëme de la femme", "Étude de mains : Impéria" and "La fellah". In these poems, female figures who, while they may at first be granted some agency (and be represented going about the business of daily, if highly stylized, life), are finally immobilized within the verse as their bodies, and particularly their pristine skin, ultimately function as an additional paper-like surface for the poet, permitting their assimilation into Gautier's diminutive private collection.

Description and search labor for information retrieval

Selection power is taken as the fundamental value for information retrieval systems. Selection power is regarded as produced by selection labor, which itself separates historically into description and search labor. As forms of mental labor, description and search labor participate in the conditions for labor and for mental labor. Concepts and distinctions applicable to physical and mental labor are indicated, introducing the necessity of labor for survival, the idea of technology as a human construction, and the possibility of the transfer of human labor to technology. Distinctions specific to mental labor, particular between semantic and syntactic labor, are introduced. Description labor is exemplified by cataloging, classification, and database description, can be more formally understood as the labor involved in the transformation of objects for description into searchable descriptions, and is also understood to include interpretation. The costs of description labor are discussed. Search labor is conceived as the labor expended in searching systems. For both description and search labor, there has been a progressive reduction in direct human labor, with its syntactic aspects transferred to technology, effectively compelled by the high relative costs of direct human labor compared to machine processes.

Mixing of dielectronic and multiply-excited states in electron-ion recombination: a study of Au24+

It has been suggested (Gribakin et al 1999 Aust. J. Phys. 52 443–57, Flambaum et al 2002 Phys. Rev. A 66 012713) that strongly enhanced low-energy electron recombination observed in Au25+ (Hoffknecht et al 1998 J. Phys. B: At. Mol. Opt. Phys. 31 2415–28) is mediated by complex multiply excited states, while simple dielectronic excitations play the role of doorway states for the electron capture process. We present the results of an extensive study of con?guration mixing between doubly excited (doorway) states and multiply excited states which account for the large electron recombination rate on Au25+ . A detailed analysis of spectral statistics and statistics of eigenstate components shows that the dielectronic doorway states are virtually ‘dissolved’ in complicated chaotic multiply excited eigenstates. This work provides a justi?cation for the use of statistical theory to calculate the recombination rates of Au25+ and similar complex multiply charged ions. We also investigate approaches which allow one to study complex chaotic many-body eigenstates and criteria of strong con?guration mixing, without diagonalizing large Hamiltonian matrices.

N-terminally modified glucagon-like peptide-1(7-36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo

Glucagon-like peptide-1 (7-36)amide (tGLP-1) is inactivated by dipeptidyl peptidase (DPP) IV by removal of the NH2-terminal dipeptide His(7)-Ala(8). We examined the degradation of NH2-terminally modified His(7)-glucitol tGLP-1 and its insulin-releasing and antihyperglycaemic activity in vivo, tGLP-1 was degraded by purified DPP IV after 4 h (43% intact) and after 12 hi 89% was converted to GLP-1(9-36)amide. In contrast > 99% of His(7)-glucitol tGLP-1 remained intact at 12 h. His(7)-glucitol tGLP-1 was similarly resistant to plasma degradation in vitro. His7-glucitol tGLP-1 showed greater resistance to degradation in vivo (92% intact) compared to tGLP-1 (27% intact) 10 min after i.p. administration to Wistar rats. Glucose homeostasis was examined following i.p. injection of both peptides (12 nmol/kg) together with glucose (18 mmol/kg). Plasma glucose concentrations were significantly reduced and insulin concentrations elevated following peptides administration compared with glucose alone. The area under the curve (AUC) for glucose for controls (AUC 691 +/- 35 mM/min) was significantly lower after administration of tGLP-1 and His7-glucitol tGLP-1 (36 and 49% less; AUC; 440 +/- 40 and 353 +/- 31 mM/min, respectively; P

The genus Pikea (Dumontiaceae, Rhodophyta) in England and the North Pacific: Comparative morphological, life history, and molecular studies

A Pikea species attributed to Pikea californica Harvey has been established in England since at least 1967. Previously, this species was believed to occur only in Japan and Pacific North America. Comparative morphological studies on field-collected material and cultured isolates from England, California, and Japan and analysis of organellar DNA restriction fragment length polymorphisms, detected using labeled organellar DNA as a non-radioactive probe, showed that English Pikea is conspecific with P. californica from California. Both populations consist of dioecious gametophytes with heteromorphic life histories involving crustose tetrasporophytes; 96% of organellar DNA bands were shared between interoceanic samples. A second dioecious species of Pikea, P. pinnata Setchell In Collins, Holden et Setchell, grows sympatrically with P. californica near San Francisco but can be distinguished by softer texture, more regular branching pattern, and elongate cystocarpic axes. Pikea pinnata and P. californica samples shared 49-50% of organellar DNA bands, consistent with their being distinct species. Herbarium specimens of P. robusta Abbott resemble P. pinnata in some morphological features but axes are much wider; P. robusta may represent a further, strictly subtidal species but fertile material is unknown. Pikea thalli from Japan, previously attributed to P. californica and described here as Pikea yoshizakii sp. nov., are monoecious and show a strikingly different type of life history. After fertilization, gonimoblast filaments grow outward through the cortex and form tetrasporangial nemathecia; released tetraspores develop directly into erect thalli. Tetrasporoblastic life histories are characteristic of certain members of the Phyllophoraceae but were previously unknown in the Dumontiaceae. Japanese P. yoshizakii shared 55 and 56% of organellar DNA bands with P. californica and P. pinnata, respectively phylogenetic analysis indicated equally distant relationships to both species. Pikea yoshizakii or a closely similar species with the same life history occurs in southern California and Mexico.

Age-dependent accumulation of N epsilon-(carboxymethyl)lysine and N epsilon-(carboxymethyl)hydroxylysine in human skin collagen

N epsilon-(Carboxymethyl)lysine (CML) is formed on oxidative cleavage of carbohydrate adducts to lysine residues in glycated proteins in vitro [Ahmed et al. (1988) J. Biol. Chem. 263, 8816-8821; Dunn et al. (1990) Biochemistry 29, 10964-10970]. We have shown that, in human lens proteins in vivo, the concentration of fructose-lysine (FL), the Amadori adduct of glucose to lysine, is constant with age, while the concentration of the oxidation product, CML, increases significantly with age [Dunn et al. (1989) Biochemistry 28, 9464-9468]. In this work we extend our studies to the analysis of human skin collagen. The extent of glycation of insoluble skin collagen was greater than that of lens proteins (4-6 mmol of FL/mol of lysine in collagen versus 1-2 mmol of FL/mol of lysine in lens proteins), consistent with the lower concentration of glucose in lens, compared to plasma. In contrast to lens, there was a slight but significant age-dependent increase in glycation of skin collagen, 33% between ages 20 and 80. As in lens protein, CML, present at only trace levels in neonatal collagen, increased significantly with age, although the amount of CML in collagen at 80 years of age, approximately 1.5 mmol of CML/mol of lysine, was less than that found in lens protein, approximately 7 mmol of CML/mol of lysine. The concentration of N epsilon-(carboxymethyl)hydroxylysine (CMhL), the product of oxidation of glycated hydroxylysine, also increased with age in collagen, in parallel with the increase in CML, from trace levels at infancy to approximately 5 mmol of CMhL/mol of hydroxylysine at age 80.(ABSTRACT TRUNCATED AT 250 WORDS)

The NOTCH signaling pathway in normal and malignant blood cell production

The NOTCH pathway is an evolutionarily conserved signalling network, which is fundamental in regulating developmental processes in invertebrates and vertebrates (Gazave et al. in BMC Evol Biol 9:249, 2009). It regulates self-renewal (Butler et al. in Cell Stem Cell 6:251–264, 2010), differentiation (Auderset et al. in Curr Top Microbiol Immunol 360:115–134, 2012), proliferation (VanDussen et al. in Development 139:488–497, 2012) and apoptosis (Cao et al. in APMIS 120:441–450, 2012) of diverse cell types at various stages of their development. NOTCH signalling governs cell-cell interactions and the outcome of such responses is highly context specific. This makes it impossible to generalize about NOTCH functions as it stimulates survival and differentiation of certain cell types, whereas inhibiting these processes in others (Meier-Stiegen et al. in PLoS One 5:e11481, 2010). NOTCH was first identified in 1914 in Drosophila and was named after the indentations (notches) present in the wings of the mutant flies (Bigas et al. in Int J Dev Biol 54:1175–1188, 2010). Homologs of NOTCH in vertebrates were initially identified in Xenopus (Coffman et al. in Science 249:1438–1441, 1990) and in humans NOTCH was first identified in T-Acute Lymphoblastic Leukaemia (T-ALL) (Ellisen et al. in Cell 66:649–61, 1991). NOTCH signalling is integral in neurogenesis (Mead and Yutzey in Dev Dyn 241:376–389, 2012), myogenesis (Schuster-Gossler et al. in Proc Natl Acad Sci U S A 104:537–542, 2007), haematopoiesis (Bigas et al. in Int J Dev Biol 54:1175–1188, 2010), oogenesis (Xu and Gridley in Genet Res Int 2012:648207, 2012), differentiation of intestinal cells (Okamoto et al. in Am J Physiol Gastrointest Liver Physiol 296:G23–35, 2009) and pancreatic cells (Apelqvist et al. in Nature 400:877–881, 1999). The current review will focus on NOTCH signalling in normal and malignant blood cell production or haematopoiesis.

ELM-induced transient tungsten melting in the JET divertor

The original goals of the JET ITER-like wall included the study of the impact of an all W divertor on plasma operation (Coenen et al 2013 Nucl. Fusion 53 073043) and fuel retention (Brezinsek et al 2013 Nucl. Fusion 53 083023). ITER has recently decided to install a full-tungsten (W) divertor from the start of operations. One of the key inputs required in support of this decision was the study of the possibility of W melting and melt splashing during transients. Damage of this type can lead to modifications of surface topology which could lead to higher disruption frequency or compromise subsequent plasma operation. Although every effort will be made to avoid leading edges, ITER plasma stored energies are sufficient that transients can drive shallow melting on the top surfaces of components. JET is able to produce ELMs large enough to allow access to transient melting in a regime of relevance to ITER.

Transient W melt experiments were performed in JET using a dedicated divertor module and a sequence of I-P = 3.0 MA/B-T = 2.9 T H-mode pulses with an input power of P-IN = 23 MW, a stored energy of similar to 6 MJ and regular type I ELMs at Delta W-ELM = 0.3 MJ and f(ELM) similar to 30 Hz. By moving the outer strike point onto a dedicated leading edge in the W divertor the base temperature was raised within similar to 1 s to a level allowing transient, ELM-driven melting during the subsequent 0.5 s. Such ELMs (delta W similar to 300 kJ per ELM) are comparable to mitigated ELMs expected in ITER (Pitts et al 2011 J. Nucl. Mater. 415 (Suppl.) S957-64).

Although significant material losses in terms of ejections into the plasma were not observed, there is indirect evidence that some small droplets (similar to 80 mu m) were released. Almost 1 mm (similar to 6 mm(3)) of W was moved by similar to 150 ELMs within 7 subsequent discharges. The impact on the main plasma parameters was minor and no disruptions occurred. The W-melt gradually moved along the leading edge towards the high-field side, driven by j x B forces. The evaporation rate determined from spectroscopy is 100 times less than expected from steady state melting and is thus consistent only with transient melting during the individual ELMs. Analysis of IR data and spectroscopy together with modelling using the MEMOS code Bazylev et al 2009 J. Nucl. Mater. 390-391 810-13 point to transient melting as the main process. 3D MEMOS simulations on the consequences of multiple ELMs on damage of tungsten castellated armour have been performed.

These experiments provide the first experimental evidence for the absence of significant melt splashing at transient events resembling mitigated ELMs on ITER and establish a key experimental benchmark for the MEMOS code.

IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes

Insulin signaling to the glomerular podocyte is important for normal kidney function and is implicated in the pathogenesis of diabetic nephropathy (DN). This study determined the role of the insulin receptor substrate 2 (IRS2) in this system. Conditionally immortalized murine podocytes were generated from wild-type (WT) and insulin receptor substrate 2-deficient mice (Irs2−/−). Insulin signaling, glucose transport, cellular motility and cytoskeleton rearrangement were then analyzed. Within the glomerulus IRS2 is enriched in the podocyte and is preferentially phosphorylated by insulin in comparison to IRS1. Irs2−/− podocytes are significantly insulin resistant in respect to AKT signaling, insulin-stimulated GLUT4-mediated glucose uptake, filamentous actin (F-actin) cytoskeleton remodeling and cell motility. Mechanistically, we discovered that Irs2 deficiency causes insulin resistance through up-regulation of the phosphatase and tensin homolog (PTEN). Importantly, suppressing PTEN in Irs2−/− podocytes rescued insulin sensitivity. In conclusion, this study has identified for the first time IRS2 as a critical molecule for sensitizing the podocyte to insulin actions through its ability to modulate PTEN expression. This finding reveals two potential molecular targets in the podocyte for modulating insulin sensitivity and treating DN.

Number comparison and number ordering as predictors of arithmetic performance in adults: Exploring the link between the two skills, and investigating the question of domain-specificity.

Recent evidence has highlighted the important role that number ordering skills play in arithmetic abilities (e.g., Lyons & Beilock, 2011). In fact, Lyons et al. (2014) demonstrated that although at the start of formal mathematics education number comparison skills are the best predictors of arithmetic performance, from around the age of 10, number ordering skills become the strongest numerical predictors of arithmetic abilities. In the current study we demonstrated that number comparison and ordering skills were both significantly related to arithmetic performance in adults, and the effect size was greater in the case of ordering skills. Additionally, we found that the effect of number comparison skills on arithmetic performance was partially mediated by number ordering skills. Moreover, performance on comparison and ordering tasks involving the months of the year was also strongly correlated with arithmetic skills, and participants displayed similar (canonical or reverse) distance effects on the comparison and ordering tasks involving months as when the tasks included numbers. This suggests that the processes responsible for the link between comparison and ordering skills and arithmetic performance are not specific to the domain of numbers. Finally, a factor analysis indicated that performance on comparison and ordering tasks loaded on a factor which included performance on a number line task and self-reported spatial thinking styles. These results substantially extend previous research on the role of order processing abilities in mental arithmetic.

Inhibition and fibril formation and toxicity of a fragment of alpha-synuclein by an N-methylated peptide analogue

Alpha-synuclein has been linked to amyloidogenesis in Parkinson's disease and other neurodegenerative disorders. We have previously shown that a peptide comprising residues 68-78 of alpha-synuclein is the minimum fragment that, like alpha-synuclein itself, forms amyloid fibrils and exhibits toxicity towards cells in culture. Hughes et al. [J. Biol. Chem. 275 (2000) 25109] showed that an N-methylated derivative of Abeta(25-35) inhibited the formation of fibrils by Abeta(25-35) and reduced its toxicity. We have now extended this concept to an amyloidogenic alpha-synuclein-based peptide. Alpha-synuclein(68-78), N-methylated at G1y73, was compared to non-methylated peptide. Whereas alpha-synuclein(68-78) formed fibrils and was toxic to cells, the N-methylated analogue had neither of these properties. Moreover, an equimolar mixture of the non-methylated and methylated peptides formed very few fibrils and toxicity was markedly reduced.

Philadelphia-Negative Classical Myeloproliferative Neoplasms: Critical Concepts and Management Recommendations From European LeukemiaNet

We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first-and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation-related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years.