91 research outputs found
SOCS3 Is Essential in the Regulation of Fetal Liver Erythropoiesis
AbstractSOCS3 (CIS3/JAB2) is an SH2-containing protein that binds to the activation loop of Janus kinases, inhibiting kinase activity, and thereby suppressing cytokine signaling. During embryonic development, SOCS3 is highly expressed in erythroid lineage cells and is Epo independent. Transgene-mediated expression blocks fetal erythropoiesis, resulting in embryonic lethality. SOCS3 deletion results in an embryonic lethality at 12â16 days associated with marked erythrocytosis. Moreover, the in vitro proliferative capacity of progenitors is greatly increased. SOCS3-deficient fetal liver stem cells can reconstitute hematopoiesis in lethally irradiated adults, indicating that its absence does not disturb bone marrow erythropoiesis. Reconstitution of lymphoid lineages in JAK3-deficient mice also occurs normally. The results demonstrate that SOCS3 is critical in negatively regulating fetal liver hematopoiesis
Ars2 Links the Nuclear Cap-Binding Complex to RNA Interference and Cell Proliferation
SummaryHere we identify a component of the nuclear RNA cap-binding complex (CBC), Ars2, that is important for miRNA biogenesis and critical for cell proliferation. Unlike other components of the CBC, Ars2 expression is linked to the proliferative state of the cell. Deletion of Ars2 is developmentally lethal, and deletion in adult mice led to bone marrow failure whereas parenchymal organs composed of nonproliferating cells were unaffected. Depletion of Ars2 or CBP80 from proliferating cells impaired miRNA-mediated repression and led to alterations in primary miRNA processing in the nucleus. Ars2 depletion also reduced the levels of several miRNAs, including miR-21, let-7, and miR-155, that are implicated in cellular transformation. These findings provide evidence for a role for Ars2 in RNA interference regulation during cell proliferation
Approximate Ginzburg-Landau solution for the regular flux-line lattice. Circular cell method
A variational model is proposed to describe the magnetic properties of
type-II superconductors in the entire field range between and
for any values of the Ginzburg-Landau parameter . The
hexagonal unit cell of the triangular flux-line lattice is replaced by a circle
of the same area, and the periodic solutions to the Ginzburg-Landau equations
within this cell are approximated by rotationally symmetric solutions. The
Ginzburg-Landau equations are solved by a trial function for the order
parameter. The calculated spatial distributions of the order parameter and the
magnetic field are compared with the corresponding distributions obtained by
numerical solution of the Ginzburg-Landau equations. The comparison reveals
good agreement with an accuracy of a few percent for all values
exceeding . The model can be extended to anisotropic
superconductors when the vortices are directed along one of the principal axes.
The reversible magnetization curve is calculated and an analytical formula for
the magnetization is proposed. At low fields, the theory reduces to the London
approach at , provided that the exact value of is used.
At high fields, our model reproduces the main features of the well-known
Abrikosov theory. The magnetic field dependences of the reversible
magnetization found numerically and by our variational method practically
coincide. The model also refines the limits of some approximations which have
been widely used. The calculated magnetization curves are in a good agreement
with experimental data on high-T superconductors.Comment: 8 pages, RevTex, 6 figures, submitted to Phys. Rev.
New horizons in geriatric medicine education and training: the need for pan-European education and training standards
The ageing population ought to be celebrated as evidence for the efficacy of modern medicine, but the challenge that this demographic shift presents for 21st century healthcare systems, with increasing numbers of people living with multi-morbidity and frailty, cannot be ignored. There is therefore a need to ensure that all healthcare professionals grasp the basic principles of care of older people. In this paper, we make a case for the development of pan-European education and training standards for the field of geriatric medicine. Firstly, the challenges which face the implementation and delivery of geriatric medicine in a systematic way across Europe are described â these include, but are not limited to; variance in geriatric medicine practice across Europe, insecurity of the specialty in some countries and significant heterogeneity in geriatric medicine training programs across Europe. The opportunities for geriatric medicine are then presented and we consider how engendering core geriatric medicine competencies amongst nongeriatricians has potential to bridge existing gaps in service provision across Europe. Finally, we consider how work can proceed to teach sufficient numbers of doctors and health professionals in the core knowledge, skills and attitudes required to do this. To safeguard the future of the specialty across Europe, we contend that there is a need to strive towards harmonisation of post-graduate geriatric medicine training across Europe, through the establishment of pan-European education and training standards in the specialty
The Flux-Line Lattice in Superconductors
Magnetic flux can penetrate a type-II superconductor in form of Abrikosov
vortices. These tend to arrange in a triangular flux-line lattice (FLL) which
is more or less perturbed by material inhomogeneities that pin the flux lines,
and in high- supercon- ductors (HTSC's) also by thermal fluctuations. Many
properties of the FLL are well described by the phenomenological
Ginzburg-Landau theory or by the electromagnetic London theory, which treats
the vortex core as a singularity. In Nb alloys and HTSC's the FLL is very soft
mainly because of the large magnetic penetration depth: The shear modulus of
the FLL is thus small and the tilt modulus is dispersive and becomes very small
for short distortion wavelength. This softness of the FLL is enhanced further
by the pronounced anisotropy and layered structure of HTSC's, which strongly
increases the penetration depth for currents along the c-axis of these uniaxial
crystals and may even cause a decoupling of two-dimensional vortex lattices in
the Cu-O layers. Thermal fluctuations and softening may melt the FLL and cause
thermally activated depinning of the flux lines or of the 2D pancake vortices
in the layers. Various phase transitions are predicted for the FLL in layered
HTSC's. The linear and nonlinear magnetic response of HTSC's gives rise to
interesting effects which strongly depend on the geometry of the experiment.Comment: Review paper for Rep.Prog.Phys., 124 narrow pages. The 30 figures do
not exist as postscript file
Global respiratory syncytial virusârelated infant community deaths
Background
Respiratory syncytial virus (RSV) is a leading cause of pediatric death, with >99% of mortality occurring in low- and lower middle-income countries. At least half of RSV-related deaths are estimated to occur in the community, but clinical characteristics of this group of children remain poorly characterized.
Methods
The RSV Global Online Mortality Database (RSV GOLD), a global registry of under-5 children who have died with RSV-related illness, describes clinical characteristics of children dying of RSV through global data sharing. RSV GOLD acts as a collaborative platform for global deaths, including community mortality studies described in this supplement. We aimed to compare the age distribution of infant deaths <6 months occurring in the community with in-hospital.
Results
We studied 829 RSV-related deaths <1 year of age from 38 developing countries, including 166 community deaths from 12 countries. There were 629 deaths that occurred <6 months, of which 156 (25%) occurred in the community. Among infants who died before 6 months of age, median age at death in the community (1.5 months; IQR: 0.8â3.3) was lower than in-hospital (2.4 months; IQR: 1.5â4.0; Pâ
<â
.0001). The proportion of neonatal deaths was higher in the community (29%, 46/156) than in-hospital (12%, 57/473, Pâ
<â
0.0001).
Conclusions
We observed that children in the community die at a younger age. We expect that maternal vaccination or immunoprophylaxis against RSV will have a larger impact on RSV-related mortality in the community than in-hospital. This case series of RSV-related community deaths, made possible through global data sharing, allowed us to assess the potential impact of future RSV vaccines
Determination of the transphosphorylation sites of Jak2 kinase.
Janus kinases are the key enzymes involved in the initial transmission of signals in response to type I and II cytokines. Activation of the signal begins with the transphosphorylation of Jak kinases. Substrates that give rise to downstream events are recruited to the receptor complex in part by interactions with phosphorylated tyrosines. The identity of many of the phosphotyrosines responsible for recruitment has been elucidated as being receptor-based tyrosines. The ability of Jaks to recruit substrates through their own phosphotyrosines has been demonstrated for tyrosines in the kinase activation loop. Recent studies demonstrate that other tyrosines have implications in regulatory roles of Jak kinase activity. In this study, baculovirus-produced Jak2 was utilized to demonstrate that transphosphorylation of Jak kinases occurs on multiple residues throughout the protein. We demonstrate that among the tyrosines phosphorylated, those in the kinase domain occur as expected, but many other sites are also phosphorylated. The tyrosines conserved in the Jak family are the object of this study, although many of them are phosphorylated, many are not. This result suggests that conservation of tyrosines is perhaps as important in maintaining structure of the Jak family. Additionally, non-Jak family conserved tyrosines are phosphorylated suggesting that the individual Jaks ability to phosphorylated specific tyrosines may influence signals emitting from activated Jaks
Jak2 FERM Domain Interaction with the Erythropoietin Receptor Regulates Jak2 Kinase Activityâż
Janus kinases are essential for signal transduction by a variety of cytokine receptors and when inappropriately activated can cause hematopoietic disorders and oncogenesis. Consequently, it can be predicted that the interaction of the kinases with receptors and the events required for activation are highly controlled. In a screen to identify phosphorylation events regulating Jak2 activity in EpoR signaling, we identified a mutant (Jak2-Y613E) which has the property of being constitutively activated, as well as an inactivating mutation (Y766E). Although no evidence was obtained to indicate that either site is phosphorylated in signaling, the consequences of the Y613E mutation are similar to those observed with recently described activating mutations in Jak2 (Jak2-V617F and Jak2-L611S). However, unlike the V617F or L611S mutant, the Y613E mutant requires the presence of the receptor but not Epo stimulation for activation and downstream signaling. The properties of the Jak2-Y613E mutant suggest that under normal conditions, Jak2 that is not associated with a receptor is locked into an inactive state and receptor binding through the FERM domain relieves steric constraints, allowing the potential to be activated with receptor engagement
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