A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X.

BackgroundActivated factor X (FXa) is a vitamin K-dependent serine protease that plays a pivotal role in blood coagulation by converting prothrombin to thrombin. There are no reports of humans with complete deficiency of FX, and knockout of murine F10 is embryonic or perinatal lethal.ObjectiveWe sought to generate a viable mouse model of FX deficiency.MethodsWe used a socket-targeting construct to generate F10-knockout mice by eliminating F10 exon 8 (knockout allele termed F10(tm1Ccmt), abbreviated as '-'; wild-type '+'), and a plug-targeting construct to generate mice expressing a FX variant with normal antigen levels but low levels of FX activity [4-9% normal in humans carrying the defect, Pro343-->Ser, termed FX Friuli (mutant allele termed F10(tm2Ccmt), abbreviated as F)].ResultsF10 knockout mice exhibited embryonic or perinatal lethality. In contrast, homozygous Friuli mice [F10 (F/F)] had FX activity levels of approximately 5.5% (sufficient to rescue both embryonic and perinatal lethality), but developed age-dependent iron deposition and cardiac fibrosis. Interestingly, F10 (-/F) mice with FX activity levels of 1-3% also showed complete rescue of lethality. Further study of this model provides evidence supporting a role of maternal FX transfer in the embryonic survival.ConclusionsWe demonstrate that, while complete absence of FX is incompatible with murine survival, minimal FX activity as low as 1-3% is sufficient to rescue the lethal phenotype. This viable low-FX mouse model will facilitate the development of FX-directed therapies as well as investigation of the FX role in embryonic development

All work and no pay: consequences of unpaid work experience in the creative industries

This research note evaluates the benefits and pitfalls of unpaid work as an entry route into employment in the creative industries and investigates the consequences of this practice for those who already work in the sector. Based on a qualitative study of perspectives of stakeholders in unpaid work, this article argues that the social capital thesis, often used as a rationale for unpaid work, inadequately explains the practice of unpaid work experience, primarily because it does not take cognisance of the consequences of this practice for other people working in the sector. The study also highlights methodological issues that need to be considered in the future. As well as the importance of a plurality of stakeholder perspectives, the study emphasizes the need to consider the perspectives of those who are excluded from unpaid work and those who are potentially displaced by it

A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X

Background:Activated factor X (FXa) is a vitamin K-dependent serine protease that plays a pivotal role in blood coagulation by converting prothrombin to thrombin. There are no reports of humans with complete deficiency of FX, and knockout of murine F10 is embryonic or perinatal lethal. Objective:We sought to generate a viable mouse model of FX deficiency. Methods:We used a socket-targeting construct to generate F10-knockout mice by eliminating F10 exon 8 (knockout allele termed F10tm1Ccmt, abbreviated as ‘−’; wild-type ‘+’), and a plug-targeting construct to generate mice expressing a FX variant with normal antigen levels but low levels of FX activity [4–9% normal in humans carrying the defect, Pro343→Ser, termed FX Friuli (mutant allele termed F10tm2Ccmt, abbreviated as F)]. Results:F10 knockout mice exhibited embryonic or perinatal lethality. In contrast, homozygous Friuli mice [F10 (F/F)] had FX activity levels of ∼5.5% (sufficient to rescue both embryonic and perinatal lethality), but developed age-dependent iron deposition and cardiac fibrosis. Interestingly, F10 (−/F) mice with FX activity levels of 1–3% also showed complete rescue of lethality. Further study of this model provides evidence supporting a role of maternal FX transfer in the embryonic survival. Conclusions:We demonstrate that, while complete absence of FX is incompatible with murine survival, minimal FX activity as low as 1–3% is sufficient to rescue the lethal phenotype. This viable low-FX mouse model will facilitate the development of FX-directed therapies as well as investigation of the FX role in embryonic development

Declination dependence of the cosmic-ray flux at extreme energies

We study the large-scale distribution of the arrival directions of the highest energy cosmic rays observed by various experiments. Despite clearly insufficient statistics, we find a deficit of cosmic rays at energies higher than 10^{20} eV from a large part of the sky around the celestial North Pole. We speculate on possible explanations of this feature.Comment: 5 pages, 4 figures; v2: 11 pages, 4 figures, title changed (to avoid confusion with the Southern hemisphere), analysis extended, more data included, results unchanged; to be published in JCA

Greening the state for a sustainable political economy

The intensifying global ecological crisis is, by any measure, among the defining political economy issues of our epoch. Questions concerning the state have recently returned to prominence in the field of environmental politics, offering a productive meeting point for research addressing environmental politics and that addressing the political economy of state transformation. The papers in this section all approach the question of the state and its relationship to ecological crisis from a political-economic perspective, foregrounding its relationship to the broader political-economic model in which it is situated. This short article introduces the four contributions to the special section and situates them amidst the broader contemporary research literature

‘Talent-spotting’ or ‘social magic’? Inequality, cultural sorting and constructions of the ideal graduate in elite professions

Graduate outcomes – including rates of employment and earnings – are marked by persistent inequalities related to social class, as well as gender, ethnicity and institution. Despite national policy agendas related to social mobility and ‘fair access to the professions’, high-status occupations are disproportionately composed of those from socially privileged backgrounds, and evidence suggests that in recent decades many professions have become less socially representative. This article makes an original contribution to sociological studies of inequalities in graduate transitions and elite reproduction through a distinct focus on the ‘pre-hiring’ practices of graduate employers. It does this through a critical analysis of the graduate recruitment material of two popular graduate employers. It shows how, despite espousing commitments to diversity and inclusion, constructions of the ‘ideal’ graduate privilege individuals who can mobilise and embody certain valued capitals. Using Bourdieusian concepts of ‘social magic’ and ‘institutional habitus’, the article argues that more attention must be paid to how graduate employers’ practices constitute tacit processes of social exclusion and thus militate against the achievement of more equitable graduate outcomes and fair access to the ‘top jobs

Ultra-High Energy Cosmic Ray Nuclei from Individual Magnetized Sources

We investigate the dependence of composition, spectrum and angular distributions of ultra-high energy cosmic rays above 10^19 eV from individual sources on their magnetization. We find that, especially for sources within a few megaparsecs from the observer, observable spectra and composition are severely modified if the source is surrounded by fields of ~ 10^-7 Gauss on scales of a few megaparsecs. Low energy particles diffuse over larger distances during their energy loss time. This leads to considerable hardening of the spectrum up to the energy where the loss distance becomes comparable to the source distance. Magnetized sources thus have very important consequences for observations, even if cosmic rays arrive within a few degrees from the source direction. At the same time, details in spectra and chemical composition may be intrinsically unpredictable because they depend on the unknown magnetic field structure. If primaries are predominantly nuclei of atomic mass A accelerated up to a maximum energy E_max with spectra not much softer than E^-2, secondary protons from photo-disintegration can produce a conspicuous peak in the spectrum at energy ~ E_max/A. A related feature appears in the average mass dependence on energy.Comment: 15 pages, 16 ps figures, published version with minor changes, see http://stacks.iop.org/1475-7516/2004/i=08/a=01

First Results from Pan-STARRS1: Faint, High Proper Motion White Dwarfs in the Medium-Deep Fields

The Pan-STARRS1 survey has obtained multi-epoch imaging in five bands (Pan-STARRS1 gps, rps, ips, zps, and yps) on twelve "Medium Deep Fields", each of which spans a 3.3 degree circle. For the period between Apr 2009 and Apr 2011 these fields were observed 50-200 times. Using a reduced proper motion diagram, we have extracted a list of 47 white dwarf (WD) candidates whose Pan-STARRS1 astrometry indicates a non-zero proper motion at the 6-sigma level, with a typical 1-sigma proper motion uncertainty of 10 mas/yr. We also used astrometry from SDSS (when available) and USNO-B to assess our proper motion fits. None of the WD candidates exhibits evidence of statistically significant parallaxes, with a typical 1-sigma uncertainty of 8 mas. Twelve of these candidates are known WDs, including the high proper motion (1.7"/yr) WD LHS 291. We confirm three more objects as WDs through optical spectroscopy. Based on the Pan-STARRS1 colors, ten of the stars are likely to be cool WDs with 4170 K Teff 5000 K and cooling ages <9 Gyr. We classify these objects as likely thick disk WDs based on their kinematics. Our current sample represents only a small fraction of the Pan-STARRS1 data. With continued coverage from the Medium Deep Field Survey and the 3pi survey, Pan-STARRS1 should find many more high proper motion WDs that are part of the old thick disk and halo.Comment: 33 pages, 8 figures, submitted to Ap

Binding of SGTA to Rpn13 selectively modulates protein quality control

YesRpn13 is an intrinsic ubiquitin receptor of the 26S proteasome regulatory subunit that facilitates substrate capture prior to degradation. Here we show that the C-terminal region of Rpn13 binds to the tetratricopeptide repeat (TPR) domain of SGTA, a cytosolic factor implicated in the quality control of mislocalised membrane proteins (MLPs). The overexpression of SGTA results in a substantial increase in steady-state MLP levels, consistent with an effect on proteasomal degradation. However, this effect is strongly dependent upon the interaction of SGTA with the proteasomal component Rpn13. Hence, overexpression of the SGTA-binding region of Rpn13 or point mutations within the SGTA TPR domain both inhibit SGTA binding to the proteasome and substantially reduce MLP levels. These findings suggest that SGTA can regulate the access of MLPs to the proteolytic core of the proteasome, implying that a protein quality control cycle that involves SGTA and the BAG6 complex can operate at the 19S regulatory particle. We speculate that the binding of SGTA to Rpn13 enables specific polypeptides to escape proteasomal degradation and/or selectively modulates substrate degradation.BBSRC [grant number: BB/L006510/1] and the Wellcome Trust [grant number: 092107/Z/10/Z]. K.K. was supported by the UPStream network [EU, FP7, ITN project 290257

Application of short time energy analysis in monitoring the stability of arc sound signal

This paper employed the short time energy of arc sound signals to online quantitatively describe the stability of arc sound signal. At first the signal can be preprocessed by wavelet packet filtering and then detailed information of the short time energy of the signal was obtained using hamming window. After statistical analyzed the short time energy the energy distribution possibility and cumulative distribution function of the signal can be collected. Then a proposed stability evaluation criterion was employed to quantitatively describe the stability of arc sound signal. Relative experimental data showed that more stable signal corresponded lager value of the criterion. The proposed method which combined the short time energy and statistical analysis was supported by many actual experiments. This contribution can benefit the quantitative evaluation of the arc welding process and instructed the future parameters optimization to obtain welding products with high quality. (C) 2017 Elsevier Ltd. All rights reserved