No abstract

The vanilloid receptor-1 (VR1) is a heat-gated ion channel that is responsible for the burning sensation elicited by capsaicin. A similar sensation is reported by patients with esophagitis when they consume alcoholic beverages or are administered alcohol by injection as a medical treatment. We report here that ethanol activates primary sensory neurons, resulting in neuropeptide release or plasma extravasation in the esophagus, spinal cord or skin. Sensory neurons from trigeminal or dorsal root ganglia as well as VR1-expressing HEK293 cells responded to ethanol in a concentration-dependent and capsazepine-sensitive fashion. Ethanol potentiated the response of VR1 to capsaicin, protons and heat and lowered the threshold for heat activation of VR1 from approximately 42 degrees C to approximately 34 degrees C. This provides a likely mechanistic explanation for the ethanol-induced sensory responses that occur at body temperature and for the sensitivity of inflamed tissues to ethanol, such as might be found in esophagitis, neuralgia or wounds.

The glycopeptide teicoplanin is used for the treatment of serious infections caused by Gram-positive pathogens. The tcp gene cluster, devoted to teicoplanin biosynthesis in the actinomycete Actinoplanes teichomyceticus, was isolated and characterized. From sequence analysis, the tcp cluster spans approximately 73 kb and includes 39 ORFs participating in teicoplanin biosynthesis, regulation, resistance and export. Of these, 34 ORFs find a match in at least one of the five glycopeptide gene clusters previously characterized. Putative roles could be assigned for most of the tcp genes. The two glycosyltransferases responsible for attaching amino sugars to amino acids 4 and 6 of the teicoplanin aglycon were overexpressed in Escherichia coli and characterized. They both recognize N-acetylglucosamine as the substrate. tGtfA can add a sugar residue in the presence or absence of N-acetylglucosamine at amino acid 4, while tGtfB can only glycosylate the teicoplanin aglycon.

Acute lymphoblastic leukemia (ALL) blasts undergo migration into layers of bone marrow fibroblasts (BMF) in vitro, utilizing the ␤1 integrins VLA-4 and VL-5 as adhesion molecules. However, it has been unclear as to whether this is a selective process mediated by specific chemoattractant molecules, or simply a reflection of the highly motile nature of early B cell precursors. We further characterized this process using a transwell culture system, in which the two chambers were separated by an 8 m diameter microporous membrane, through which leukemic cells could move. When a BMF layer was grown on the upper surface of the membrane there was an 84.1% reduction in transmigration of the human pre-B ALL cell line NALM-6 into the lower chamber, compared to control membrane with no BMF layer. Localization of leukemic cells under the BMF layer was confirmed ultrastructurally, suggesting the possibility that the migration of leukemic cells was directed by a chemotactic agent secreted by BMF. The involvement of the chemokine stromal cell-derived factor-1 (SDF-1) in this process was next investigated. BMF were shown to express m-RNA for SDF-1. Addition of SDF-1 at 100 ng/ml into the lower chamber increased transmigration of NALM-6 across the membrane by 2.2-fold, and also induced a 1.4-to 6.1-fold increase in movement of NALM-6 through a BMF layer into the lower chamber. The receptor for SDF-1, CXCR4, was demonstrated by flow cytometry on all 10 cases of precursor-B ALL analyzed, as well as on NALM-6, KM-3 and REH lines. An inhibitory antibody to CXCR4 was able to block the migration of NALM-6 cells into BMF monolayers grown on plastic by 51%, and in nine cases of ALL by 8-40%, as well as partially inhibit transmigration of leukemic cells through BMF layers along an SDF-1 concentration gradient. These results confirm that precursor-B ALL cells selectively localize within bone marrow stroma in vitro, and that this process is partially due to the stromal chemokine SDF-1 binding to its receptor CXCR4 on leukemic cells. SDF-1 may be important in influencing the localization of precursor-B ALL cells in marrow microenvironmental inches which regulate their survival and proliferation. Leukemia (2000) 14, 882-888.

In this paper we study the metastable behavior of one of the simplest disordered spin system, the random field Curie-Weiss model. We will show how the potential theoretic approach can be used to prove sharp estimates on capacities and metastable exit times also in the case when the distribution of the random field is continuous. Previous work was restricted to the case when the random field takes only finitely many values, which allowed the reduction to a finite dimensional problem using lumping techniques. Here we produce the first genuine sharp estimates in a context where entropy is important.

We study the condensation regime of the finite reversible inclusion process, i.e., the inclusion process on a finite graph $S$ with an underlying random walk that admits a reversible measure. We assume that the random walk kernel is irreducible and its reversible measure takes maximum value on a subset of vertices $S_\star\subset S$. We consider initial conditions corresponding to a single condensate that is localized on one of those vertices and study the metastable (or tunneling) dynamics. We find that, if the random walk restricted to $S_\star$ is irreducible, then there exists a single time-scale for the condensate motion. In this case we compute this typical time-scale and characterize the law of the (properly rescaled) limiting process. If the restriction of the random walk to $S_\star$ has several connected components, a metastability scenario with multiple time-scales emerges. We prove such a scenario, involving two additional time-scales, in a one-dimensional setting with two metastable states and nearest-neighbor jumps.Comment: 34 page

ABSTRACT. We establish metastability in the sense of Lebowitz and Penrose under practical and simple hypotheses for Markov chains on a finite configuration space in some asymptotic regime. By comparing restricted ensemble and quasi-stationary measures, and introducing soft measures as interpolation between the two, we prove asymptotic exponential exit law and, on a generally different time scale, asymptotic exponential transition law. By using potential-theoretic tools, and introducing "(κ, λ)-capacities", we give sharp estimates on relaxation time, as well as mean exit time and transition time. We also establish local thermalization on shorter time scales. (a) only one thermodynamic phase is present, (b) a system that starts in this state is likely to take a long time to get out, (c) once the system has gotten out, it is unlikely to return. We can think, for example, about freezing fog made of small droplets in which only one phase is present (liquid phase) that remains for a long time in such a state (until collision with ground or trees, forming then hard rime) and that once frozen will typically not return to liquid state before pressure or temperature have changed.To model such a state they considered in [4] a deterministic dynamics with equilibrium measure µ. First, they associated with the metastable phase a subset R of the configuration space, and described this metastable state by the restricted ensemble µ R = µ(·|R). Second, they proved that the escape rate from R of the system started in µ R is maximal at time t = 0, and that this initial escape rate is very small. Last, they used standard methods of equilibrium statistical mechanics to deal with (c). As an estimate of the returning probability to the metastable state they used the fraction of members of the equilibrium ensemble that have configurations in R and they noted ([4], Section 8):This amounts to assuming that a system whose dynamical state has just left R is no more likely to return to it than one whose dynamical state was never anywhere near R. The validity of this assumption, at least in the short run, is dubious, but at least it provides us with some indication of what to expect. In this paper we want to give a different model for the same phenomenology that overcomes the last difficulty. We will work with stochastic processes rather than deterministic dynamics, but the Lebowitz-Penrose modelization will be our guideline. We will try to recover this phenomenology under simple and practical hypotheses only. Since the study of metastability has been considerably enriched after the Lebowitz and Penrose work, we want also to incorporate in our modeling as much as possible of what was previously achieved. We will then make a brief and partial review of these achievements. Our goals and starting ideas will depend on this review but not our proofs, since we want to make this paper as self-contained as possible. Our model and results are presented in Section 2. Examples of applications are given in Section 7.

No abstract