Prevalence and management of iron overload in pyruvate kinase deficiency: report from the Pyruvate Kinase Deficiency Natural History Study

Pyruvate kinase (PK) deficiency is the most common red cell glycolytic enzyme defect causing hereditary non-spherocytic hemolytic anemia. Current treatments are mainly supportive and include red cell transfusions and splenectomy.11 Regular red cell transfusions are known to result in iron overload; however, the prevalence and spectrum of transfusion-independent iron overload in the overall PK deficient population has not been well defined. This analysis describes the prevalence and clinical characteristics of iron overload in patients enrolled in the PK Deficiency Natural History Study (NHS) with a focus on those patients who are not regularly transfused.

Reframing the future: the role of reflexivity in governance networks in sustainability transitions

Contains fulltext : 183569.pdf (Publisher’s version ) (Open Access)30 november 201

How does our motor system determine its learning rate?

Motor learning is driven by movement errors. The speed of learning can be quantified by the learning rate, which is the proportion of an error that is corrected for in the planning of the next movement. Previous studies have shown that the learning rate depends on the reliability of the error signal and on the uncertainty of the motor system’s own state. These dependences are in agreement with the predictions of the Kalman filter, which is a state estimator that can be used to determine the optimal learning rate for each movement such that the expected movement error is minimized. Here we test whether not only the average behaviour is optimal, as the previous studies showed, but if the learning rate is chosen optimally in every individual movement. Subjects made repeated movements to visual targets with their unseen hand. They received visual feedback about their endpoint error immediately after each movement. The reliability of these error-signals was varied across three conditions. The results are inconsistent with the predictions of the Kalman filter because correction for large errors in the beginning of a series of movements to a fixed target was not as fast as predicted and the learning rates for the extent and the direction of the movements did not differ in the way predicted by the Kalman filter. Instead, a simpler model that uses the same learning rate for all movements with the same error-signal reliability can explain the data. We conclude that our brain does not apply state estimation to determine the optimal planning correction for every individual movement, but it employs a simpler strategy of using a fixed learning rate for all movements with the same level of error-signal reliability

Дослідження підходів до оцінки стану конкурентоспроможності підприємств

Мета статті – наведення підходів до оцінки стану конкурентоспроможності підприємств

The Origin of the Bifurcation in the Sagittarius Stream

The latest Sloan Digital Sky Survey data reveal a prominent bifurcation in the distribution of debris of the Sagittarius dwarf spheroidal (Sgr) beginning at a right ascension of roughly 190 degrees. Two branches of the stream (A and B) persist at roughly the same heliocentric distance over at least 50 degrees of arc. There is also evidence for a more distant structure (C) well behind the A branch. This paper provides the first explanation for the bifurcation. It is caused by the projection of the young leading (A) and old trailing (B) tidal arms of the Sgr, whilst the old leading arm (C) lies well behind A. This explanation is only possible if the halo is close to spherical, as the angular difference between the branches is a measure of the precession of the orbital plane.Comment: ApJ, in pres

A dynamical and kinematical model of the Galactic stellar halo and possible implications for galaxy formation scenarios

We re-analyse the kinematics of the system of blue horizontal branch field (BHBF) stars in the Galactic halo (in particular the outer halo), fitting the kinematics with the model of radial and tangential velocity dispersions in the halo as a function of galactocentric distance r proposed by Sommer-Larsen, Flynn & Christensen (1994), using a much larger sample (almost 700) of BHBF stars. The basic result is that the character of the stellar halo velocity ellipsoid changes markedly from radial anisotropy at the sun to tangential anisotropy in the outer parts of the Galactic halo (r greater than approx 20 kpc). Specifically, the radial component of the stellar halo's velocity ellipsoid decreases fairly rapidly beyond the solar circle, from approx 140 +/- 10 km/s at the sun, to an asymptotic value of 89 +/- 19 km/s at large r. The rapid decrease in the radial velocity dispersion is matched by an increase in the tangential velocity dispersion, with increasing r. Our results may indicate that the Galaxy formed hierarchically (partly or fully) through merging of smaller subsystems - the 'bottom-up' galaxy formation scenario, which for quite a while has been favoured by most theorists and recently also has been given some observational credibility by HST observations of a potential group of small galaxies, at high redshift, possibly in the process of merging to a larger galaxy (Pascarelle et al 1996).Comment: Latex, 16 pages. 2 postscript figures. Submitted to the Astrophysical Journal. also available at http://astro.utu.fi/~cflynn/outerhalo.htm

Abundances of metal-weak thick-disc candidates

High resolution spectra of 5 candidate metal-weak thick-disc stars suggested by Beers & Sommer-Larsen (1995) are analyzed to determine their chemical abundances. The low abundance of all the objects has been confirmed with metallicity reaching [Fe/H]=-2.9. However, for three objects, the astrometric data from the Hipparcos catalogue suggests they are true halo members. The remaining two, for which proper-motion data are not available, may have disc-like kinematics. It is therefore clear that it is useful to address properties of putative metal-weak thick-disc stars only if they possess full kinematic data. For CS 22894-19 the abundance pattern similar to those of typical halo stars is found, suggesting that chemical composition is not a useful discriminant between thick-disc and halo stars. CS 29529-12 is found to be C enhanced with [C/Fe]=+1.0; other chemical peculiarities involve the s process elements: [Sr/Fe]=-0.65 and [Ba/Fe]=+0.62, leading to a high [Ba/Sr] considerably larger than what is found in more metal-rich carbon-rich stars, but similar to LP 706-7 and LP 625-44 discussed by Norris et al (1997a). Hipparcos data have been used to calculate the space velocities of 25 candidate metal-weak thick-disc stars, thus allowing us to identify 3 bona fide members, which support the existence of a metal-poor tail of the thick-disc, at variance with a claim to the contrary by Ryan & Lambert (1995).Comment: to be published in MNRA

An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients

Background: Breast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-likeCGH classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents

Oxidized and Aggregated Recombinant Human Interferon Beta is Immunogenic in Human Interferon Beta Transgenic Mice

PurposeTo study the effect of oxidation on the structure of recombinant human interferon beta-1a (rhIFNβ-1a) and its immunogenicity in wild-type and immune-tolerant transgenic mice.MethodsUntreated rhIFNβ-1a was degraded by metal-catalyzed oxidation, H2O2-mediated oxidation, and guanidine-mediated unfolding/refolding. Four rhIFNβ-1a preparations with different levels of oxidation and aggregation were injected intraperitoneally in mice 15× during 3 weeks. Both binding and neutralizing antibodies were measured.ResultsAll rhIFNβ-1a preparations contained substantial amounts of aggregates. Metal-catalyzed oxidized rhIFNβ-1a contained high levels of covalent aggregates as compared with untreated rhIFNβ-1a. H2O2-treated rhIFNβ-1a showed an increase in oligomer and unrecovered protein content by HP-SEC; RP-HPLC revealed protein oxidation. Guanidine-treated rhIFNβ-1a mostly consisted of dimers and oligomers and some non-covalent aggregates smaller in size than those in untreated rhIFNβ-1a. All degraded samples showed alterations in tertiary protein structure. Wild-type mice showed equally high antibody responses against all preparations. Transgenic mice were discriminative, showing elevated antibody responses against both metal-catalyzed oxidized and H2O2-treated rhIFNβ-1a as compared to untreated and guanidine-treated rhIFNβ-1a.ConclusionsOxidation-mediated aggregation increased the immunogenicity of rhIFNβ-1a in transgenic mice, whereas aggregated preparations devoid of measurable oxidation levels were hardly immunogenic