Skin Cell Proliferation Stimulated by Microneedles

A classical wound may be defined as a disruption of tissue integrity. Wounds, caused by trauma from accidents or surgery, that close via secondary intention rely on the biological phases of healing, i.e., hemostasis, inflammation, proliferation, and remodeling (HIPR). Depending on the wound type and severity, the inflammation phase begins immediately after injury and may last for an average of 7–14 days. Concurrent with the inflammation phase or slightly delayed, cell proliferation is stimulated followed by the activation of the remodeling (maturation) phase. The latter phase can last as long as 1 year or more, and the final healed state is represented by a scar tissue, a cross-linked collagen formation that usually aligns collagen fibers in a single direction. One may assume that skin microneedling that involves the use of dozens or as many as 200 needles that limit penetration to 1.5 mm over 1 cm2 of skin would cause trauma and bleeding followed by the classical HIPR. However, this is not the case or at least the HIPR phases are significantly curtailed and healing never ends in a scar formation. Conversely dermabrasion used in aesthetic medicine for improving skin quality is based on “ablation” (destruction or wounding of superficial skin layers), which requires several weeks for healing that involves formation of new skin layers. Such procedures provoke an acute inflammatory response. We believe that a less intense inflammatory response occurs following microneedle perforation of the skin. However, the mechanism of action of microneedling appears to be different. Here we review the potential mechanisms by which microneedling of the skin facilitates skin repair without scarring after the treatment of superficial burns, acne, hyperpigmentation, and the non-advancing periwound skin surrounding the chronic ulcerations of the integument

Thermomechanical material modelling based on a hybrid free energy density depending on pressure, isochoric deformation and temperature

AbstractIn order to represent temperature-dependent mechanical material properties in a thermomechanical consistent manner it is common practice to start with the definition of a model for the specific Helmholtz free energy. Its canonical independent variables are the Green strain tensor and the temperature. But to represent calorimetric material properties under isobaric conditions, for example the exothermal behaviour of a curing process or the dependence of the specific heat on the temperature history, the temperature and the pressure should be taken as independent variables. Thus, in the field of calorimetry the Gibbs free energy is usually used as thermodynamic potential whereas in continuum mechanics the Helmholtz free energy is normally applied. In order to simplify the representation of calorimetric phenomena in continuum mechanics a hybrid free energy density is introduced. Its canonical independent variables are the isochoric Green strain tensor, the pressure and the temperature. It is related to the Helmholtz free energy density by a Legendre transformation. In combination with the additive split of the stress power into the sum of isochoric and volumetric terms this approach leads to thermomechanical consistent constitutive models for large deformations. The article closes with applications of this approach to finite thermoelasticity, curing adhesives and the glass transition

Wormholes in String Theory

A wormhole is constructed by cutting and joining two spacetimes satisfying the low energy string equations with a dilaton field. In spacetimes described by the "string metric" the dilaton energy-momentum tensor need not satisfy the weak or dominant energy conditions. In the cases considered here the dilaton field violates these energy conditions and is the source of the exotic matter required to maintain the wormhole. There is also a surface stress-energy, that must be produced by additional matter, where the spacetimes are joined. It is shown that wormholes can be constructed for which this additional matter satisfies the weak and dominant energy conditions, so that it could be a form of "normal" matter. Charged dilaton wormholes with a coupling between the dilaton and the electromagnetic field that is more general than in string theory are also briefly discussed.Comment: 9 pages, LaTex, submitted to Phys. Rev.

The Human Fungal Pathogen Cryptococcus neoformans Escapes Macrophages by a Phagosome Emptying Mechanism That Is Inhibited by Arp2/3 Complex-Mediated Actin Polymerisation

The lysis of infected cells by disease-causing microorganisms is an efficient but risky strategy for disseminated infection, as it exposes the pathogen to the full repertoire of the host's immune system. Cryptococcus neoformans is a widespread fungal pathogen that causes a fatal meningitis in HIV and other immunocompromised patients. Following intracellular growth, cryptococci are able to escape their host cells by a non-lytic expulsive mechanism that may contribute to the invasion of the central nervous system. Non-lytic escape is also exhibited by some bacterial pathogens and is likely to facilitate long-term avoidance of the host immune system during latency. Here we show that phagosomes containing intracellular cryptococci undergo repeated cycles of actin polymerisation. These actin ‘flashes’ occur in both murine and human macrophages and are dependent on classical WASP-Arp2/3 complex mediated actin filament nucleation. Three dimensional confocal imaging time lapse revealed that such flashes are highly dynamic actin cages that form around the phagosome. Using fluorescent dextran as a phagosome membrane integrity probe, we find that the non-lytic expulsion of Cryptococcus occurs through fusion of the phagosome and plasma membranes and that, prior to expulsion, 95% of phagosomes become permeabilised, an event that is immediately followed by an actin flash. By using pharmacological agents to modulate both actin dynamics and upstream signalling events, we show that flash occurrence is inversely related to cryptococcal expulsion, suggesting that flashes may act to temporarily inhibit expulsion from infected phagocytes. In conclusion, our data reveal the existence of a novel actin-dependent process on phagosomes containing cryptococci that acts as a potential block to expulsion of Cryptococcus and may have significant implications for the dissemination of, and CNS invasion by, this organism.\ud \u

Cyclin-dependent kinase 5 mediates pleiotrophin-induced endothelial cell migration

Pleiotrophin (PTN) stimulates endothelial cell migration through binding to receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) and ανβ3 integrin. Screening for proteins that interact with RPTPβ/ζ and potentially regulate PTN signaling, through mass spectrometry analysis, identified cyclin-dependent kinase 5 (CDK5) activator p35 among the proteins displaying high sequence coverage. Interaction of p35 with the serine/threonine kinase CDK5 leads to CDK5 activation, known to be implicated in cell migration. Protein immunoprecipitation and proximity ligation assays verified p35-RPTPβ/ζ interaction and revealed the molecular association of CDK5 and RPTPβ/ζ. In endothelial cells, PTN activates CDK5 in an RPTPβ/ζ- and phosphoinositide 3-kinase (PI3K)-dependent manner. On the other hand, c-Src, ανβ3 and ERK1/2 do not mediate the PTN-induced CDK5 activation. Pharmacological and genetic inhibition of CDK5 abolished PTN-induced endothelial cell migration, suggesting that CDK5 mediates PTN stimulatory effect. A new pyrrolo[2,3-α]carbazole derivative previously identified as a CDK1 inhibitor, was found to suppress CDK5 activity and eliminate PTN stimulatory effect on cell migration, warranting its further evaluation as a new CDK5 inhibitor. Collectively, our data reveal that CDK5 is activated by PTN, in an RPTPβ/ζ-dependent manner, regulates PTN-induced cell migration and is an attractive target for the inhibition of PTN pro-angiogenic properties

Thermodynamics of Black Holes in Two (and Higher) Dimensions

A comprehensive treatment of black hole thermodynamics in two-dimensional dilaton gravity is presented. We derive an improved action for these theories and construct the Euclidean path integral. An essentially unique boundary counterterm renders the improved action finite on-shell, and its variational properties guarantee that the path integral has a well-defined semi-classical limit. We give a detailed discussion of the canonical ensemble described by the Euclidean partition function, and examine various issues related to stability. Numerous examples are provided, including black hole backgrounds that appear in two dimensional solutions of string theory. We show that the Exact String Black Hole is one of the rare cases that admits a consistent thermodynamics without the need for an external thermal reservoir. Our approach can also be applied to certain higher-dimensional black holes, such as Schwarzschild-AdS, Reissner-Nordstrom, and BTZ.Comment: 63 pages, 3 pdf figures, v2: added reference

Geometric Interpretation and Classification of Global Solutions in Generalized Dilaton Gravity

Two dimensional gravity with torsion is proved to be equivalent to special types of generalized 2d dilaton gravity. E.g. in one version, the dilaton field is shown to be expressible by the extra scalar curvature, constructed for an independent Lorentz connection corresponding to a nontrivial torsion. Elimination of that dilaton field yields an equivalent torsionless theory, nonpolynomial in curvature. These theories, although locally equivalent exhibit quite different global properties of the general solution. We discuss the example of a (torsionless) dilaton theory equivalent to the $R^2 + T^2$--model. Each global solution of this model is shown to split into a set of global solutions of generalized dilaton gravity. In contrast to the theory with torsion the equivalent dilaton one exhibits solutions which are asymptotically flat in special ranges of the parameters. In the simplest case of ordinary dilaton gravity we clarify the well known problem of removing the Schwarzschild singularity by a field redefinition.Comment: 21 pages, 6 Postscript figure

Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis

Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction of this process underlies many neurological diseases including ataxia and the most common pediatric brain tumor, medulloblastoma. To better define the pathways controlling the most abundant neuronal cells in the mammalian cerebellum, cerebellar granule cell progenitors (GCPs), we performed RNA-sequencing of GCPs exiting the cell cycle. Time-series modeling of GCP cell cycle exit identified downregulation of activity of the epigenetic reader protein Brd4. Brd4 binding to the Gli1 locus is controlled by Casein Kinase 1δ (CK1 δ)-dependent phosphorylation during GCP proliferation, and decreases during GCP cell cycle exit. Importantly, conditional deletion of Brd4 in vivo in the developing cerebellum induces cerebellar morphological deficits and ataxia. These studies define an essential role for Brd4 in cerebellar granule cell neurogenesis and are critical for designing clinical trials utilizing Brd4 inhibitors in neurological indications