Neurogenic subventricular zone stem/progenitor cells are notch1-dependent in their active but not quiescent state.

The adult mammalian forebrain contains neural stem/progenitor cells (NSCs) that generate neurons throughout life. As in other somatic stem cell systems, NSCs are proposed to be predominantly quiescent and proliferate only sporadically to produce more committed progeny. However, quiescence has recently been shown not to be an essential criterion for stem cells. It is not known whether NSCs show differences in molecular dependence based on their proliferation state. The subventricular zone (SVZ) of the adult mouse brain has a remarkable capacity for repair by activation of NSCs. The molecular interplay controlling adult NSCs during neurogenesis or regeneration is not clear but resolving these interactions is critical in order to understand brain homeostasis and repair. Using conditional genetics and fate mapping, we show that Notch signaling is essential for neurogenesis in the SVZ. By mosaic analysis, we uncovered a surprising difference in Notch dependence between active neurogenic and regenerative NSCs. While both active and regenerative NSCs depend upon canonical Notch signaling, Notch1-deletion results in a selective loss of active NSCs (aNSCs). In sharp contrast, quiescent NSCs (qNSCs) remain after Notch1 ablation until induced during regeneration or aging, whereupon they become Notch1-dependent and fail to fully reinstate neurogenesis. Our results suggest that Notch1 is a key component of the adult SVZ niche, promoting maintenance of aNSCs, and that this function is compensated in qNSCs. Therefore, we confirm the importance of Notch signaling for maintaining NSCs and neurogenesis in the adult SVZ and reveal that NSCs display a selective reliance on Notch1 that may be dictated by mitotic state.

Pressure-dependent scaling scenarios in experiments of spontaneous imbibition

The scaling properties of the rough liquid-air interface formed in the spontaneous imbibition of a viscous liquid by a model porous medium are found to be very sensitive to the magnitude of the pressure difference applied at the liquid inlet. Interface fluctuations change from obeying intrinsic anomalous scaling at large negative pressure differences, to being super-rough with the same dynamic exponent z¿3 at less negative pressure differences, to finally obeying ordinary Family-Vicsek scaling with z¿2 at large positive pressure differences. This rich scenario reflects the relative importance on different length scales of capillary and permeability disorder, and the role of surface tension and viscous pressure in damping interface fluctuations.

Time-dependent couplings and crossover length scales in nonequilibrium surface roughening

We show that time-dependent couplings may lead to nontrivial scaling properties of the surface fluctuations of the asymptotic regime in nonequilibrium kinetic roughening models. Three typical situations are studied. In the case of a crossover between two different rough regimes, the time-dependent coupling may result in anomalous scaling for scales above the crossover length. In a different setting, for a crossover from a rough to either a flat or damping regime, the time-dependent crossover length may conspire to produce a rough surface, although the most relevant term tends to flatten the surface. In addition, our analysis sheds light into an existing debate in the problem of spontaneous imbibition, where time-dependent couplings naturally arise in theoretical models and experiments.

Reentrant transition induced by multiplictative noise in the Time Dependent Ginzburg-Landau model

An effect of multiplicative noise in the time-dependent Ginzburg-Landau model is reported, namely, that noise at a relatively low intensity induces a phase transition towards an ordered state, whereas strong noise plays a destructive role, driving the system back to its disordered state through a reentrant phase transition. The phase diagram is calculated analytically using a mean-field theory and a more sophisticated approach and is compared with the results from extensive numerical simulations.

Thrombosis in paroxysmal nocturnal hemoglobinuria at a glance: a clinical review.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder, with its primary clinical manifestations being hemolytic anemia, marrow failure and thrombophilia. Chronic hemolysis, failures of the fibrinolytic system, increased leukocyte-derived tissue factor levels in plasma, procoagulant microparticles generated through complement-mediated damage of platelets and venous endothelium are related to the acquired hypercoagulable state. Visceral thrombosis (including hepatic veins and mesenteric veins), cerebrovascular events and pulmonary embolism predict a poor outcome. Thrombosis is also associated with significant morbidity during pregnancy. Depending on the sites of thrombosis, a score-based probability to predict outcome can be assigned. Abdominal vein thromboses account for the majority of morbidity and mortality related to thrombosis, and time-dependent trends suggest that mortality rates tend to decline, with the advent of evolution of therapeutic and diagnostic strategies. In contrast, mortality rates from cerebrovascular events display no significant decline. Prompt diagnosis requires both clinical suspicion and sophisticated imaging techniques, along with multidisciplinary therapeutic intervention. In the eculizumab era, a significant reduction of thrombotic events was observed during therapy, and long-term follow up is needed to establish any benefit in rates and pattern of this complication. However, up to now, only bone marrow transplantation permanently abolishes the coagulation defect.

Condition-dependent expression of melanin-based coloration in the Eurasian kestrel.

Melanin is the most common pigment in animal integuments and is responsible for some of the most striking ornaments. A central tenet of sexual selection theory states that melanin-based traits can signal absolute individual quality in any environment only if their expression is condition-dependent. Significant costs imposed by an ornament would ensure that only the highest quality individuals display the most exaggerated forms of the signal. Firm evidence that melanin-based traits can be condition-dependent is still rare in birds. In an experimental test of this central assumption, we report condition-dependent expression of a melanin-based trait in the Eurasian kestrel (Falco tinnunculus). We manipulated nestling body condition by reducing or increasing the number of nestlings soon after hatching. A few days before fledging, we measured the width of sub-terminal black bands on the tail feathers. Compared to nestlings from enlarged broods, individuals raised in reduced broods were in better condition and thereby developed larger sub-terminal bands. Furthermore, in 2 years, first-born nestlings also developed larger sub-terminal bands than their younger siblings that are in poorer condition. This demonstrates that expression of melanin-based traits can be condition-dependent.

Relativistic mean-field interaction with density-dependent meson-nucleon vertices based on microscopical calculations

Although ab initio calculations of relativistic Brueckner theory lead to large scalar isovector fields in nuclear matter, at present, successful versions of covariant density functional theory neglect the interactions in this channel. A new high-precision density functional DD-MEδ is presented which includes four mesons, σ, ω, δ, and ρ, with density-dependent meson-nucleon couplings. It is based to a large extent on microscopic ab initiocalculations in nuclear matter. Only four of its parameters are determined by adjusting to binding energies and charge radii of finite nuclei. The other parameters, in particular the density dependence of the meson-nucleon vertices, are adjusted to nonrelativistic and relativistic Brueckner calculations of symmetric and asymmetric nuclear matter. The isovector effective mass mp*−mn* derived from relativistic Brueckner theory is used to determine the coupling strength of the δ meson and its density dependence.

Involvement of gap junctional intercellular communication in the pathophysiology of inflammation

SUMMARY Inflammation has evolved as a mechanism to defend the body against invading microorganisms and to respond to injury. It requires the coordinated response of a large number of cell types from the whole organism in a time- and space-dependent fashion. This coordination involves several cell-cell communication mechanisms. Exchange of humoral mediators such as cytokines is a major one. Moreover, direct contact between cells happens and plays a primordial role, for example when macrophages present antigens to lymphocytes. Contact between endothelial cells and leucocytes occurs when the latter cross the blood vessel barrier and transmigrate to the inflammatory site. A particular way by which cells communicate with each other in the course of inflammation, which at this time starts to gain attention, is the intercellular communication mediated by gap junctions. Gap junctions are channels providing a direct pathway (i.e. without transit through the extracellular space) for the diffusion of small molecules between adjacent cells. This process is known as gap junctional intercellular communication (GJIC). The general aim of this thesis was to study a possible involvement of GJIC in the pathophysiology of inflammation. A first part of the work was dedicated to study the implication of GJIC in the modification of vascular endothelial function by inflammation. In a second part, we were interested in the possible role of GJIC in the transmigration of neutrophil polymorphonuclear leucocytes through the endothelium. The main positive finding of this work is that acute inflammation preferentially modulates the expression of connexin 40 (Cx40), a gap junction protein specifically expressed in vascular endothelium. The modulation could be towards overexpression (aortic endothelium of septic rats) or towards downregulation (acutely inflamed mouse lung). We put a lot of efforts in search of possible functions of these modulations, in two directions: a potential protective role of Cx40 increased expression against sepsis-induced endothelial dysfunction, and a facilitating role of Cx40 decreased expression in neutrophil transmigration. To pursue both directions, it seemed logical to study the impact of Cx40 deletion using knock-out mice. Concerning the potential protective role of Cx40 overexpression we encountered a roadblock as we observed, in the aorta, a Cx40 downregulation in wild type mouse whereas Cx40 was upregulated in the rat. Regarding the second direction and using an in vivo approach, we observed that pulmonary neutrophil transmigration was not affected by the genetic deletion of Cx40. In spite of their negative nature, these results are the very first ones regarding the potential implication of GJIC concerning leucocyte transmigration in vivo. Because this process involves such tight cell-cell physical contacts, the hypothesis for a role of GJIC remains attractive.

Frequency-dependent attenuation as a potential indicator of oil saturation

At seismic frequencies, wave-induced fluid flow is a major cause of P-wave attenuation in partially saturated porous rocks. Attenuation is of great importance for the oil industry in the interpretation of seismic field data. Here, the effects on P-wave attenuation resulting from changes in oil saturation are studied for media with coexisting water, oil, and gas. For that, creep experiments are numerically simulated by solving Biot's equations for consolidation of poroelastic media with the finite-element method. The experiments yield time-dependent stress?strain relations that are used to calculate the complex P-wave modulus from which frequency-dependent P-wave attenuation is determined. The models are layered media with periodically alternating triplets of layers. Models consisting of triplets of layers having randomly varying layer thicknesses are also considered. The layers in each triplet are fully saturated with water, oil, and gas. The layer saturated with water has lower porosity and permeability than the layers saturated with oil and gas. These models represent hydrocarbon reservoirs in which water is the wetting fluid preferentially saturating regions of lower porosity. The results from the numerical experiments showed that increasing oil saturation, connected to a decrease in gas saturation, resulted in a significant increase of attenuation at low frequencies (lower than 2 Hz). Furthermore, replacing the oil with water resulted in a distinguishable behavior of the frequency-dependent attenuation. These results imply that, according to the physical mechanism of wave-induced fluid flow, frequency-dependent attenuation in media saturated with water, oil, and gas is a potential indicator of oil saturation.

Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma.

5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-gamma(+/-) mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-gamma expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a peroxisome-proliferator response element-driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-gamma as a target of 5-ASA underlying antiinflammatory effects in the colon.

Hamiltonian formalism for path-dependent Lagrangians

A presymplectic structure for path-dependent Lagrangian systems is set up such that, when applied to ordinary Lagrangians, it yields the familiar Legendre transformation. It is then applied to derive a Hamiltonian formalism and the conserved quantities for those predictive invariant systems whose solutions also satisfy a Fokker-type action principle.

Bystander-Activated Memory CD8 T Cells Control Early Pathogen Load in an Innate-like, NKG2D-Dependent Manner.

During an infection the antigen-nonspecific memory CD8 T cell compartment is not simply an inert pool of cells, but becomes activated and cytotoxic. It is unknown how these cells contribute to the clearance of an infection. We measured the strength of T cell receptor (TCR) signals that bystander-activated, cytotoxic CD8 T cells (BA-CTLs) receive in vivo and found evidence of limited TCR signaling. Given this marginal contribution of the TCR, we asked how BA-CTLs identify infected target cells. We show that target cells express NKG2D ligands following bacterial infection and demonstrate that BA-CTLs directly eliminate these target cells in an innate-like, NKG2D-dependent manner. Selective inhibition of BA-CTL-mediated killing led to a significant defect in pathogen clearance. Together, these data suggest an innate role for memory CD8 T cells in the early immune response before the onset of a de novo generated, antigen-specific CD8 T cell response.