IFN alpha activates dormant haematopoietic stem cells in vivo

Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs) with long-term self-renewal capacity. After injury these cells are induced to proliferate to quickly reestablish homeostasis(1). The signalling molecules promoting the exit of HSCs out of the dormant stage remain largely unknown. Here we show that in response to treatment of mice with interferon-alpha (IFN alpha), HSCs efficiently exit G(0) and enter an active cell cycle. HSCs respond to IFN alpha treatment by the increased phosphorylation of STAT1 and PKB/Akt (also known as AKT1), the expression of IFN alpha target genes, and the upregulation of stem cell antigen-1 (Sca-1, also known as LY6A). HSCs lacking the IFN alpha/beta receptor (IFNAR)(2), STAT1 (ref. 3) or Sca-1 (ref. 4) are insensitive to IFN alpha stimulation, demonstrating that STAT1 and Sca-1 mediate IFN alpha-induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-fluoro-uracil(1,5), HSCs pre-treated (primed) with IFN alpha and thus induced to proliferate are efficiently eliminated by 5-fluoro-uracil exposure in vivo. Conversely, HSCs chronically activated by IFN alpha are functionally compromised and are rapidly out-competed by non-activatable Ifnar(-/-) cells in competitive repopulation assays. Whereas chronic activation of the IFN alpha pathway in HSCs impairs their function, acute IFN alpha treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFN alpha on leukaemic cells(6,7), and raise the possibility for new applications of type I interferons to target cancer stem cells(8).

Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity.

Myc activity is emerging as a key element in acquisition and maintenance of stem cell properties. We have previously shown that c-Myc deficiency results in accumulation of defective hematopoietic stem cells (HSCs) due to niche-dependent differentiation defects. Here we report that immature HSCs coexpress c-myc and N-myc mRNA at similar levels. Although conditional deletion of N-myc in the bone marrow does not affect hematopoiesis, combined deficiency of c-Myc and N-Myc (dKO) results in pancytopenia and rapid lethality. Interestingly, proliferation of HSCs depends on both myc genes during homeostasis, but is c-Myc/N-Myc independent during bone marrow repair after injury. Strikingly, while most dKO hematopoietic cells undergo apoptosis, only self-renewing HSCs accumulate the cytotoxic molecule Granzyme B, normally employed by the innate immune system, thereby revealing an unexpected mechanism of stem cell apoptosis. Collectively, Myc activity (c-Myc and N-Myc) controls crucial aspects of HSC function including proliferation, differentiation, and survival.

An AdS/QCD model from tachyon condensation: II

A simple holographic model is presented and analyzed that describes chiral symmetry breaking and the physics of the meson sector in QCD. This is a bottom-up model that incorporates string theory ingredients like tachyon condensation which is expected to be the main manifestation of chiral symmetry breaking in the holographic context. As a model for glue the Kuperstein-Sonnenschein background is used. The structure of the flavor vacuum is analyzed in the quenched approximation. Chiral symmetry breaking is shown at zero temperature. Above the deconfinement transition chiral symmetry is restored. A complete holographic renormalization is performed and the chiral condensate is calculated for different quark masses both at zero and non-zero temperatures. The 0++, 0¿+, 1++, 1¿¿ meson trajectories are analyzed and their masses and decay constants are computed. The asymptotic trajectories are linear. The model has one phenomenological parameter beyond those of QCD that affects the 1++, 0¿+ sectors. Fitting this parameter we obtain very good agreement with data. The model improves in several ways the popular hard-wall and soft wall bottom-up models.

Los conceptos de espacio y tiempo en la teoría de la relatividad

Algunos filósofos no han vacilado en afirmar que la teoria de la relatividad era el relativismo aplicado a la Física. Para probar su apreciación han aducido algunas expresiones de EINSTEIN -de otros físicosno nos ocuparemos aquí-, que pueden inducir a confusión: así, por ejemplo, la afirmación de que no se puede hablar de la trayectoria deun móvil, de que en la realidad no es válida la ley de composición de ve locidades, etc. Con su acostumbrada brillantez ha dicho ORTEGA YGASSET frases como la siguiente: "Para la física de EINSTEIN, nuestro conocimiento es absoluto, la realidad es la relativa".Para ver si aquellas aprensiones son justificadas y, sobre todo, para ver si se puede admitir lo filosófico que hay en la teoría de la relatividad,vamos a someter a ésta a una dura prueba: a ser examinada por la filosofía que mejor ha sabido armonizar, a nuestro parecer, lo sensible y loideal: la filosofía escolástica, que al no apoyarse en teorías científicas, sino en la observación cierta de las cosas, podemos considerarla comoadecuado instrumento de trabajo. Entre los filósofos escolásticos nos ha parecido muy digno de tenerse en cuenta SUAREZ. El llega, efectivamente,al campo escolástico en una época de intenso renacimiento. Las grandes aportaciones medievales son sometidas por él a una aguda críticay sin integrarse en ninguna escuela, tiene la suficiente libertad de espíritu para seguir sus propios derroteros. Además, en este problema, nose aparta SUAREZ en lo esencial del sentir común de los filósofos escolásticos.

"Suddenly I get into the zone": Examining discontinuities and nonlinear changes in flow experiences at work

Work-related flow is defined as a sudden and enjoyable merging of action and awareness that represents a peak experience in the daily lives of workers. Employees" perceptions of challenge and skill and their subjective experiences in terms of enjoyment, interest and absorption were measured using the experience sampling method, yielding a total of 6981 observations from a sample of 60 employees. Linear and nonlinear approaches were applied in order to model both continuous and sudden changes. According to the R2, AICc and BIC indexes, the nonlinear dynamical systems model (i.e. cusp catastrophe model) fit the data better than the linear and logistic regression models. Likewise, the cusp catastrophe model appears to be especially powerful for modelling those cases of high levels of flow. Overall, flow represents a nonequilibrium condition that combines continuous and abrupt changes across time. Research and intervention efforts concerned with this process should focus on the variable of challenge, which, according to our study, appears to play a key role in the abrupt changes observed in work-related flow.

Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.

Bone marrow hematopoietic stem cells (HSCs) are crucial to maintain lifelong production of all blood cells. Although HSCs divide infrequently, it is thought that the entire HSC pool turns over every few weeks, suggesting that HSCs regularly enter and exit cell cycle. Here, we combine flow cytometry with label-retaining assays (BrdU and histone H2B-GFP) to identify a population of dormant mouse HSCs (d-HSCs) within the lin(-)Sca1+cKit+CD150+CD48(-)CD34(-) population. Computational modeling suggests that d-HSCs divide about every 145 days, or five times per lifetime. d-HSCs harbor the vast majority of multilineage long-term self-renewal activity. While they form a silent reservoir of the most potent HSCs during homeostasis, they are efficiently activated to self-renew in response to bone marrow injury or G-CSF stimulation. After re-establishment of homeostasis, activated HSCs return to dormancy, suggesting that HSCs are not stochastically entering the cell cycle but reversibly switch from dormancy to self-renewal under conditions of hematopoietic stress.

Quantum Hall Phases of two-component bosons

The recent production of synthetic magnetic fields acting on electroneutral particles, such as atoms or photons, has boosted interest in the quantum Hall physics of bosons. Adding pseudospin 1/2 to the bosons greatly enriches the scenario, as it allows them to form an interacting integer quantum Hall (IQH) phase with no fermionic counterpart. Here we show that, for a small two-component Bose gas on a disk, the complete strongly correlated regime, extending from the integer phase at filling factor ν = 2 to the Halperin phase at filling factor ν = 2 / 3, is well described by composite fermionization of the bosons. Moreover we study the edge excitations of the IQH state, which, in agreement with expectations from topological field theory, are found to consist of forward-moving charge excitations and backward-moving spin excitations. Finally, we demonstrate how pair-correlation functions allow one to experimentally distinguish the IQH state from competing states, such as non-Abelian spin singlet (NASS) states.

Kinetic equations for difussion in the presence of entropic barriers

We use the mesoscopic nonequilibrium thermodynamics theory to derive the general kinetic equation of a system in the presence of potential barriers. The result is applied to a description of the evolution of systems whose dynamics is influenced by entropic barriers. We analyze in detail the case of diffusion in a domain of irregular geometry in which the presence of the boundaries induces an entropy barrier when approaching the exact dynamics by a coarsening of the description. The corresponding kinetic equation, named the Fick-Jacobs equation, is obtained, and its validity is generalized through the formulation of a scaling law for the diffusion coefficient which depends on the shape of the boundaries. The method we propose can be useful to analyze the dynamics of systems at the nanoscale where the presence of entropy barriers is a common feature.

A Thermokinetic approach to radiative heat transfer at the nanoscale

Radiative heat exchange at the nanoscale presents a challenge for several areas due to its scope and nature. Here, we provide a thermokinetic description of microscale radiative energy transfer including phonon-photon coupling manifested through a non-Debye relaxation behavior. We show that a lognormal-like distribution of modes of relaxation accounts for this non-Debye relaxation behavior leading to the thermal conductance. We also discuss the validity of the fluctuation-dissipation theorem. The general expression for the thermal conductance we obtain fits existing experimental results with remarkable accuracy. Accordingly, our approach offers an overall explanation of radiative energy transfer through micrometric gaps regardless of geometrical configurations and distances.

Higher-dimensional rotating charged black holes

Using the blackfold approach, we study new classes of higher-dimensional rotating black holes with electric charges and string dipoles, in theories of gravity coupled to a 2-form or 3-form field strength and to a dilaton with arbitrary coupling. The method allows to describe not only black holes with large angular momenta, but also other regimes that include charged black holes near extremality with slow rotation. We construct explicit examples of electric rotating black holes of dilatonic and non-dilatonic Einstein-Maxwell theory, with horizons of spherical and non-spherical topology. We also find new families of solutions with string dipoles, including a new class of prolate black rings. Whenever there are exact solutions that we can compare to, their properties in the appropriate regime are reproduced precisely by our solutions. The analysis of blackfolds with string charges requires the formulation of the dynamics of anisotropic fluids with conserved string-number currents, which is new, and is carried out in detail for perfect fluids. Finally, our results indicate new instabilities of near-extremal, slowly rotating charged black holes, and motivate conjectures about topological constraints on dipole hair.

Nonperturbative semiclassical stability of de Sitter spacetime for small metric deviations

We consider the linearized semiclassical Einstein equations for small deviations around de Sitter spacetime including the vacuum polarization effects of conformal fields. Employing the method of order reduction, we find the exact solutions for general metric perturbations (of scalar, vector and tensor type). Our exact (nonperturbative) solutions show clearly that in this case de Sitter is stable with respect to small metric deviations and a late-time attractor. Furthermore, they also reveal a breakdown of perturbative solutions for a sufficiently long evolution inside the horizon. Our results are valid for any conformal theory, even self-interacting ones with arbitrarily strong coupling.