Complex actions in two-dimensional topology change

We investigate topology change in (1+1) dimensions by analyzing the scalar-curvature action $1/2 \int R dV$ at the points of metric-degeneration that (with minor exceptions) any nontrivial Lorentzian cobordism necessarily possesses. In two dimensions any cobordism can be built up as a combination of only two elementary types, the ``yarmulke'' and the ``trousers.'' For each of these elementary cobordisms, we consider a family of Morse-theory inspired Lorentzian metrics that vanish smoothly at a single point, resulting in a conical-type singularity there. In the yarmulke case, the distinguished point is analogous to a cosmological initial (or final) singularity, with the spacetime as a whole being obtained from one causal region of Misner space by adjoining a single point. In the trousers case, the distinguished point is a ``crotch singularity'' that signals a change in the spacetime topology (this being also the fundamental vertex of string theory, if one makes that interpretation). We regularize the metrics by adding a small imaginary part whose sign is fixed to be positive by the condition that it lead to a convergent scalar field path integral on the regularized spacetime. As the regulator is removed, the scalar density $1/2 \sqrt{-g} R$ approaches a delta-function whose strength is complex: for the yarmulke family the strength is $\beta -2\pi i$, where $\beta$ is the rapidity parameter of the associated Misner space; for the trousers family it is simply $+2\pi i$. This implies that in the path integral over spacetime metrics for Einstein gravity in three or more spacetime dimensions, topology change via a crotch singularity is exponentially suppressed, whereas appearance or disappearance of a universe via a yarmulke singularity is exponentially enhanced.Comment: 34 pages, REVTeX v3.0. (Presentational reorganization; core results unchanged.

Thermodynamics of (3+1)-dimensional black holes with toroidal or higher genus horizons

We examine counterparts of the Reissner-Nordstrom-anti-de Sitter black hole spacetimes in which the two-sphere has been replaced by a surface Sigma of constant negative or zero curvature. When horizons exist, the spacetimes are black holes with an asymptotically locally anti-de Sitter infinity, but the infinity topology differs from that in the asymptotically Minkowski case, and the horizon topology is not S^2. Maximal analytic extensions of the solutions are given. The local Hawking temperature is found. When Sigma is closed, we derive the first law of thermodynamics using a Brown-York type quasilocal energy at a finite boundary, and we identify the entropy as one quarter of the horizon area, independent of the horizon topology. The heat capacities with constant charge and constant electrostatic potential are shown to be positive definite. With the boundary pushed to infinity, we consider thermodynamical ensembles that fix the renormalized temperature and either the charge or the electrostatic potential at infinity. Both ensembles turn out to be thermodynamically stable, and dominated by a unique classical solution.Comment: 25 pages, REVTeX v3.1, contains 5 LaTeX figures. (Typos corrected, references and minor comments added. To be published in Phys. Rev. D.

Convex hulls of random walks, hyperplane arrangements, and Weyl chambers

We give an explicit formula for the probability that the convex hull of an n-step random walk in Rd does not contain the origin, under the assumption that the distribution of increments of the walk is centrally symmetric and puts no mass on affine hyperplanes. This extends the formula by Sparre Andersen (Skand Aktuarietidskr 32:27–36, 1949) for the probability that such random walk in dimension one stays positive. Our result is distribution-free, that is, the probability does not depend on the distribution of increments. This probabilistic problem is shown to be equivalent to either of the two geometric ones: (1) Find the number of Weyl chambers of type Bn intersected by a generic linear subspace of Rn of codimension d; (2) Find the conic intrinsic volumes of a Weyl chamber of type Bn. We solve the first geometric problem using the theory of hyperplane arrangements. A by-product of our method is a new simple proof of the general formula by Klivans and Swartz (Discrete Comput Geom 46(3):417–426, 2011) relating the coefficients of the characteristic polynomial of a linear hyperplane arrangement to the conic intrinsic volumes of the chambers constituting its complement. We obtain analogous distribution-free results for Weyl chambers of type An−1 (yielding the probability of absorption of the origin by the convex hull of a generic random walk bridge), type Dn, and direct products of Weyl chambers (yielding the absorption probability for the joint convex hull of several random walks or bridges). The simplest case of products of the form B1 ×···× B1 recovers the Wendel formula (Math Scand 11:109–111, 1962) for the probability that the convex hull of an i.i.d. multidimensional sample chosen from a centrally symmetric distribution does not contain the origin. We also give an asymptotic analysis of the obtained absorption probabilities as n → ∞, in both cases of fixed and increasing dimension d

Lewis X antigen mediates adhesion of human breast carcinoma cells to activated endothelium. Possible involvement of the endothelial scavenger receptor C-Type lectin

Lewis x (Lex, CD15), also known as SSEA-1 (stage specific embryonic antigen-1), is a trisaccharide with the structure Galβ(1–4)Fucα(1–3)GlcNAc, which is expressed on glycoconjugates in human polymorphonuclear granulocytes and various tumors such as colon and breast carcinoma. We have investigated the role of Lex in the adhesion of MCF-7 human breast cancer cells and PMN to human umbilical endothelial cells (HUVEC) and the effects of two different anti-Lex mAbs (FC-2.15 and MCS-1) on this adhesion. We also analyzed the cytolysis of Lex+-cells induced by anti-Lex mAbs and complement when cells were adhered to the endothelium, and the effect of these antibodies on HUVEC. The results indicate that MCF-7 cells can bind to HUVEC, and that MCS-1 but not FC-2.15 mAb inhibit this interaction. Both mAbs can efficiently lyse MCF-7 cells bound to HUVEC in the presence of complement without damaging endothelial cells. We also found a Lex-dependent PMN interaction with HUVEC. Although both anti-Lex mAbs lysed PMN in suspension and adhered to HUVEC, PMN aggregation was only induced by mAb FC-2.15. Blotting studies revealed that the endothelial scavenger receptor C-type lectin (SRCL), which binds Lex-trisaccharide, interacts with specific glycoproteins of Mr␣∼␣28 kD and 10 kD from MCF-7 cells. The interaction between Lex+-cancer cells and vascular endothelium is a potential target for cancer treatment.Fil: Elola, Maria Teresa. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Capurro, Mariana Isabel. University of Toronto; CanadáFil: Barrio, Maria Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación, Docencia y Prevención del Cáncer; ArgentinaFil: Coombs, Peter J.. Imperial College London; Reino UnidoFil: Taylor, Maureen E.. Imperial College London; Reino UnidoFil: Drickamer, Kurt. Imperial College London; Reino UnidoFil: Mordoh, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación, Docencia y Prevención del Cáncer; Argentin

Decrease in shunt volume in patients with cryptogenic stroke and patent foramen ovale

<p>Abstract</p> <p>Background</p> <p>In patients with patent foramen ovale (PFO) there is evidence supporting the hypothesis of a change in right-to-left shunt (RLS) over time. Proven, this could have implications for the care of patients with PFO and a history of stroke. The following study addressed this hypothesis in a cohort of patients with stroke and PFO.</p> <p>Methods</p> <p>The RLS volume assessed during hospitalisation for stroke (index event/T0) was compared with the RLS volume on follow-up (T1) (median time between T0 and T1 was 10 months). In 102 patients with a history of stroke and PFO the RLS volume was re-assessed on follow-up using contrast-enhanced transcranial Doppler/duplex (ce-TCD) ultrasound. A change in RLS volume was defined as a difference of ≥20 microembolic signals (MES) or no evidence of RLS during ce-TCD ultrasound on follow-up.</p> <p>Results</p> <p>There was evidence of a marked reduction in RLS volume in 31/102 patients; in 14/31 patients a PFO was no longer detectable. An index event classified as cryptogenic stroke (P < 0.001; OD = 39.2, 95% confidence interval 6.0 to 258.2) and the time interval to the follow-up visit (P = 0.03) were independently associated with a change in RLS volume over time.</p> <p>Conclusions</p> <p>RLS volume across a PFO decreases over time, especially in patients with cryptogenic stroke. These may determine the development of new strategies for the management in the secondary stroke prevention.</p

Histoplasma capsulatum Heat-Shock 60 Orchestrates the Adaptation of the Fungus to Temperature Stress

Heat shock proteins (Hsps) are among the most widely distributed and evolutionary conserved proteins. Hsps are essential regulators of diverse constitutive metabolic processes and are markedly upregulated during stress. A 62 kDa Hsp (Hsp60) of Histoplasma capsulatum (Hc) is an immunodominant antigen and the major surface ligand to CR3 receptors on macrophages. However little is known about the function of this protein within the fungus. We characterized Hc Hsp60-protein interactions under different temperature to gain insights of its additional functions oncell wall dynamism, heat stress and pathogenesis. We conducted co-immunoprecipitations with antibodies to Hc Hsp60 using cytoplasmic and cell wall extracts. Interacting proteins were identified by shotgun proteomics. For the cell wall, 84 common interactions were identified among the 3 growth conditions, including proteins involved in heat-shock response, sugar and amino acid/protein metabolism and cell signaling. Unique interactions were found at each temperature [30°C (81 proteins), 37°C (14) and 37/40°C (47)]. There were fewer unique interactions in cytoplasm [30°C (6), 37°C (25) and 37/40°C (39)] and four common interactions, including additional Hsps and other known virulence factors. These results show the complexity of Hsp60 function and provide insights into Hc biology, which may lead to new avenues for the management of histoplasmosis

A Comparative Computer Simulation of Dendritic Morphology

Computational modeling of neuronal morphology is a powerful tool for understanding developmental processes and structure-function relationships. We present a multifaceted approach based on stochastic sampling of morphological measures from digital reconstructions of real cells. We examined how dendritic elongation, branching, and taper are controlled by three morphometric determinants: Branch Order, Radius, and Path Distance from the soma. Virtual dendrites were simulated starting from 3,715 neuronal trees reconstructed in 16 different laboratories, including morphological classes as diverse as spinal motoneurons and dentate granule cells. Several emergent morphometrics were used to compare real and virtual trees. Relating model parameters to Branch Order best constrained the number of terminations for most morphological classes, except pyramidal cell apical trees, which were better described by a dependence on Path Distance. In contrast, bifurcation asymmetry was best constrained by Radius for apical, but Path Distance for basal trees. All determinants showed similar performance in capturing total surface area, while surface area asymmetry was best determined by Path Distance. Grouping by other characteristics, such as size, asymmetry, arborizations, or animal species, showed smaller differences than observed between apical and basal, pointing to the biological importance of this separation. Hybrid models using combinations of the determinants confirmed these trends and allowed a detailed characterization of morphological relations. The differential findings between morphological groups suggest different underlying developmental mechanisms. By comparing the effects of several morphometric determinants on the simulation of different neuronal classes, this approach sheds light on possible growth mechanism variations responsible for the observed neuronal diversity

Deletion of the BDNF Truncated Receptor TrkB.T1 Delays Disease Onset in a Mouse Model of Amyotrophic Lateral Sclerosis

Brain Derived Neurotrophic Factor (BDNF) exerts strong pro-survival effects on developing and injured motoneurons. However, in clinical trials, BDNF has failed to benefit patients with amyotrophic lateral sclerosis (ALS). To date, the cause of this failure remains unclear. Motoneurons express the TrkB kinase receptor but also high levels of the truncated TrkB.T1 receptor isoform. Thus, we investigated whether the presence of this receptor may affect the response of diseased motoneurons to endogenous BDNF. We deleted TrkB.T1 in the hSOD1G93A ALS mouse model and evaluated the impact of this mutation on motoneuron death, muscle weakness and disease progression. We found that TrkB.T1 deletion significantly slowed the onset of motor neuron degeneration. Moreover, it delayed the development of muscle weakness by 33 days. Although the life span of the animals was not affected we observed an overall improvement in the neurological score at the late stage of the disease. To investigate the effectiveness of strategies aimed at bypassing the TrkB.T1 limit to BDNF signaling we treated SOD1 mutant mice with the adenosine A2A receptor agonist CGS21680, which can activate motoneuron TrkB receptor signaling independent of neurotrophins. We found that CGS21680 treatment slowed the onset of motor neuron degeneration and muscle weakness similarly to TrkB.T1 removal. Together, our data provide evidence that endogenous TrkB.T1 limits motoneuron responsiveness to BDNF in vivo and suggest that new strategies such as Trk receptor transactivation may be used for therapeutic intervention in ALS or other neurodegenerative disorders

Developmental Patterns of Doublecortin Expression and White Matter Neuron Density in the Postnatal Primate Prefrontal Cortex and Schizophrenia

Postnatal neurogenesis occurs in the subventricular zone and dentate gyrus, and evidence suggests that new neurons may be present in additional regions of the mature primate brain, including the prefrontal cortex (PFC). Addition of new neurons to the PFC implies local generation of neurons or migration from areas such as the subventricular zone. We examined the putative contribution of new, migrating neurons to postnatal cortical development by determining the density of neurons in white matter subjacent to the cortex and measuring expression of doublecortin (DCX), a microtubule-associated protein involved in neuronal migration, in humans and rhesus macaques. We found a striking decline in DCX expression (human and macaque) and density of white matter neurons (humans) during infancy, consistent with the arrival of new neurons in the early postnatal cortex. Considering the expansion of the brain during this time, the decline in white matter neuron density does not necessarily indicate reduced total numbers of white matter neurons in early postnatal life. Furthermore, numerous cells in the white matter and deep grey matter were positive for the migration-associated glycoprotein polysialiated-neuronal cell adhesion molecule and GAD65/67, suggesting that immature migrating neurons in the adult may be GABAergic. We also examined DCX mRNA in the PFC of adult schizophrenia patients (n = 37) and matched controls (n = 37) and did not find any difference in DCX mRNA expression. However, we report a negative correlation between DCX mRNA expression and white matter neuron density in adult schizophrenia patients, in contrast to a positive correlation in human development where DCX mRNA and white matter neuron density are higher earlier in life. Accumulation of neurons in the white matter in schizophrenia would be congruent with a negative correlation between DCX mRNA and white matter neuron density and support the hypothesis of a migration deficit in schizophrenia

Biological Function and Molecular Mapping of M Antigen in Yeast Phase of Histoplasma capsulatum

Histoplasmosis, due to the intracellular fungus Histoplasma capsulatum, can be diagnosed by demonstrating the presence of antibodies specific to the immunodominant M antigen. However, the role of this protein in the pathogenesis of histoplasmosis has not been elucidated. We sought to structurally and immunologically characterize the protein, determine yeast cell surface expression, and confirm catalase activity. A 3D-rendering of the M antigen by homology modeling revealed that the structures and domains closely resemble characterized fungal catalases. We generated monoclonal antibodies (mAbs) to the protein and determined that the M antigen is present on the yeast cell surface and in cell wall/cell membrane preparations. Similarly, we found that the majority of catalase activity was in extracts containing fungal surface antigens and that the M antigen is not significantly secreted by live yeast cells. The mAbs also identified unique epitopes on the M antigen. The localization of the M antigen to the cell surface of H. capsulatum yeast and the characterization of the protein's major epitopes have important implications since it demonstrates that although the protein may participate in protecting the fungus against oxidative stress it is also accessible to host immune cells and antibody