The vascular-disrupting agent combretastatin impairs splitting and sprouting forms of physiological angiogenesis

Vascular-disrupting agents like combretastatin (CA-4-P), used to attenuate tumor blood flow in vivo, exert anti-mitotic and anti-migratory effects on endothelial cells in vitro. We tested whether anti-vascular or anti-angiogenic effects of CA-4-P are evident with physiological angiogenesis in skeletal muscle (EDL) due to sustained hyperemia (intraluminal splitting) and chronic muscle overload (abluminal sprouting).

Cannabinoid receptor trafficking in peripheral cells is dynamically regulated by a binary biochemical switch

The cannabinoid G protein-coupled receptors (GPCRs) CB₁ and CB₂ are expressed in different peripheral cells. Localization of GPCRs in the cell membrane determines signaling via G protein pathways. Here we show that unlike in transfected cells, CB receptors in cell lines and primary human cells are not internalized upon agonist interaction, but move between cytoplasm and cell membranes by ligand-independent trafficking mechanisms. Even though CB receptors are expressed in many cells of peripheral origin they are not always localized in the cell membrane and in most cancer cell lines the ratios between CB₁ and CB₂ receptor gene and surface expression vary significantly. In contrast, CB receptor cell surface expression in HL60 cells is subject to significant oscillations and CB₂ receptors form oligomers and heterodimers with CB₁ receptors, showing synchronized surface expression, localization and trafficking. We show that hydrogen peroxide and other nonspecific protein tyrosine phosphatase inhibitors (TPIs) such as phenylarsine oxide trigger both CB₂ receptor internalization and externalization, depending on receptor localization. Phorbol ester-mediated internalization of CB receptors can be inhibited via this switch. In primary human immune cells hydrogen peroxide and other TPIs lead to a robust internalization of CB receptors in monocytes and an externalization in T cells. This study describes, for the first time, the dynamic nature of CB receptor trafficking in the context of a biochemical switch, which may have implications for studies on the cell-type specific effects of cannabinoids and our understanding of the regulation of CB receptor cell surface expression.

Verifying Harder's Conjecture for Classical and Siegel Modular Forms

A conjecture by Harder shows a surprising congruence between the coefficients of “classical” modular forms and the Hecke eigenvalues of corresponding Siegel modular forms, contigent upon “large primes” dividing the critical values of the given classical modular form. Harder’s Conjecture has already been verified for one-dimensional spaces of classical and Siegel modular forms (along with some two-dimensional cases), and for primes p 37. We verify the conjecture for higher-dimensional spaces, and up to a comparable prime p.

Plato's Doctrine Of Forms: Modern Misunderstandings

Among the philosophical ideas of Plato, perhaps the most famous is his doctrine of forms. This doctrine has faced harsh criticism due, in large part, to the interpretations of this position by modern philosophers such as René Descartes, John Locke, and Immanuel Kant. For example, Plato has been interpreted as presenting a ¿two-worlds¿ approach to form and thing and as advancing a rationalist approach to epistemology. His forms have often been interpreted as ideas and as perfect copies of the things of the visible world. In this thesis, I argue that these, along with other interpretations of Plato presented by the moderns, are based on misunderstandings of Plato¿s overall philosophy. In so doing, I attempt to show that the doctrine of forms cannot be directly interpreted into the language of Cartesian, Lockean, and Kantian metaphysics and epistemology, and thus should not be prematurely dismissed because of these modern Platonic interpretations. By analyzing the Platonic dialogues beside the writings of the modern philosophers, I conclude that three of the most prominent modern philosophers, as representatives of their respective philosophical frameworks, have fundamentally misunderstood the nature of Plato¿s famous doctrine of forms. This could have significant implications for the future of metaphysics and epistemology by providing an interpretation of Plato which adds to, instead of contradicts, the developments of modern philosophy.

Zeros of Weakly Holomorphic Modular Forms of Levels 2 and 3

Let M-k(#)(N) be the space of weakly holomorphic modular forms for Gamma(0)(N) that are holomorphic at all cusps except possibly at infinity. We study a canonical basis for M-k(#)(2) and M-k(#)(3) and prove that almost all modular forms in this basis have the property that the majority of their zeros in a fundamental domain lie on a lower boundary arc of the fundamental domain.

Hydration of the Sulfuric Acid−Methylamine Complex and Implications for Aerosol Formation

The binary H2SO4−H2O nucleation is one of the most important pathways by which aerosols form in the atmosphere, and the presence of ternary species like amines increases aerosol formation rates. In this study, we focus on the hydration of a ternary system of sulfuric acid (H2SO4), methylamine (NH2CH3), and up to six waters to evaluate its implications for aerosol formation. By combining molecular dynamics (MD) sampling with high-level ab initio calculations, we determine the thermodynamics of forming H2SO4(NH2CH3)(H2O)n, where n = 0−6. Because it is a strong acid−base system, H2SO4−NH2CH3 quickly forms a tightly bound HSO4−−NH3CH3+ complex that condenses water more readily than H2SO4 alone. The electronic binding energy of H2SO4−NH2CH3 is −21.8 kcal mol−1 compared with −16.8 kcal mol−1 for H2SO4−NH3 and −12.8 kcal mol−1 for H2SO4−H2O. Adding one to two water molecules to the H2SO4−NH2CH3 complex is more favorable than adding to H2SO4 alone, yet there is no systematic difference for n ≥ 3. However, the average number of water molecules around H2SO4−NH2CH3 is consistently higher than that of H2SO4, and it is fairly independent of temperature and relative humidity.

Hydration of the Sulfuric Acid-Methylamine Complex and Implications for Aerosol Formation

The binary H2SO4-H2O nucleation is one of the most important pathways by which aerosols form in the atmosphere, and the presence of ternary species like amines increases aerosol formation rates. In this study, we focus on the hydration of a ternary system of sulfuric acid (H2SO4), methylamine (NH2CH3), and up to six waters to evaluate its implications for aerosol formation. By combining molecular dynamics (MD) sampling with high-level ab initio calculations, we determine the thermodynamics of forming H2SO4(NH2CH3)(H2O)n, where n = 0-6. Because it is a strong acid-base system, H2SO4-NH2CH3 quickly forms a tightly bound HSO4(-)-NH3CH3(+) complex that condenses water more readily than H2SO4 alone. The electronic binding energy of H2SO4-NH2CH3 is -21.8 kcal mol(-1) compared with -16.8 kcal mol(-1) for H2SO4-NH3 and -12.8 kcal mol(-1) for H2SO4-H2O. Adding one to two water molecules to the H2SO4-NH2CH3 complex is more favorable than adding to H2SO4 alone, yet there is no systematic difference for n ≥ 3. However, the average number of water molecules around H2SO4-NH2CH3 is consistently higher than that of H2SO4, and it is fairly independent of temperature and relative humidity.

The Institutional Framework around Successful Art Forms in Communist Czechoslovakia

Mr. Michl posed the question of how the institutional framework that the former communist regime set up around art production contributed to the success of Czech applied arts. In his theoretical review of the question he discussed the reasons for the lack of success of socialist industrial design as opposed to what he terms pre-industrial arts (such as art glass), and also for the current lack of interest into art institutions of the past regime. His findings in the second, historical section of his work were based largely on interviews with artists and other insiders, as an initial attempt to use questionnaires was unsuccessful. His original assumption that the institutional framework was imposed on artists against their will in fact proved mistaken, as it turned out to have been proposed by the artists themselves. The basic blueprint for communist art institutions was the Memorandum document published on behalf of Czechoslovak visual artists in March 1947, i.e. before the communist coup of February 1948. Thus, while the communist state provided a beneficial institutional framework for artists' work, it was the artists themselves who designed this framework. Mr. Michl concludes that the text of the memorandum appealed to the general left-wing and anti-market sentiments of the immediate post-war period and by this and by later working through the administrative channels of the new state, the artists succeeded in gaining all of their demands over the next 15 years. The one exception was artistic freedom, although this they came to enjoy, if only by default and for a short time, during the ideological thaw of the 1960s. Mr. Michl also examined the art-related legislative framework in detail and looked at the main features of key art institutions in the field, such as the Czech Fund for Visual Arts and the 1960s art export enterprise Art Centrum, which opened the doors into foreign markets for artists.

K(L) --> pi0 e+ e- and K(L) --> pi0 mu+ mu-: A binary star on the stage of flavor physics

A systematic analysis of New Physics impacts on the rare decays KL→π0ell+ell- is performed. Thanks to their different sensitivities to flavor-changing local effective interactions, these two modes could provide valuable information on the nature of the possible New Physics at play. In particular, a combined measurement of both modes could disentangle scalar/pseudoscalar from vector or axial-vector contributions. For the latter, model-independent bounds are derived. Finally, the KL→π0μ+μ- forward-backward CP-asymmetry is considered, and shown to give interesting complementary information.

Ethnosciences - A step towards the integration of scientific and non-scientific forms of knowledge in the management of natural resources for the future

Integration of indigenous knowledge and ethnoscientific approaches into contemporary frameworks for conservation and sustainable management of natural resources will become increasingly important in policies on an international and national level. We set the scene on how this can be done by exploring the key conditions and dimensions of a dialogue between ‘ontologies’ and the roles, which ethnosciences could play in this process. First, the roles which ethnosciences in the context of sustainable development were analysed, placing emphasis on the implications arising when western sciences aspire to relate to indigenous forms of knowledge. Secondly, the contributions of ethnosciences to such an ‘inter-ontological dialogue’ were explored, based on an ethnoecological study of the encounter of sciences and indigenous knowledge in the Andes of Bolivia, and reviewed experiences from mangrove systems in Kenya, India and Sri Lanka, and from case-studies in other ecosystems world-wide.

Differential gene and protein expression in abluminal sprouting and intraluminal splitting forms of angiogenesis

In adult skeletal muscle, abluminal sprouting or longitudinal splitting of capillaries can be initiated separately by muscle overload and elevated microcirculation shear stress respectively. In the present study, gene and protein expression patterns associated with the different forms of angiogenesis were examined using a targeted gene array (Superarray), validated by quantitative RT (reverse transcription)-PCR and immunoblots. Sprouting angiogenesis induced large changes in expression levels in genes associated with extracellular matrix remodelling, such as MMP-2 (matrix metalloproteinase-2), TIMP (tissue inhibitor of metalloproteinases), SPARC (secreted protein, acidic and rich in cysteine) and thrombospondin. Changes in neuropilin, midkine and restin levels, which may underpin changes in endothelial morphology, were seen during splitting angiogenesis. Up-regulation of VEGF (vascular endothelial growth factor), Flk-1, angiopoietin-2 and PECAM-1 (platelet/endothelial cell adhesion molecule-1) was seen in both forms of angiogenesis, representing a common angiogenic response of endothelial cells. In conclusion, the present study demonstrates that general angiogenic signals from growth factors can be influenced by the local microenvironment resulting in differing forms of capillary growth to produce a co-ordinated expansion of the vascular bed.

Intracavity Generation of Radially Polarized CO2 Laser Beams Based on a Simple Binary Dielectric Diffraction Grating

We present experimental results on the intracavity generation of radially polarized light by incorporation of a polarization-selective mirror in a CO2 -laser resonator. The selectivity is achieved with a simple binary dielectric diffraction grating etched in the backsurface of the mirror substrate. Very high polarization selectivity was achieved, and good agreement of simulation and experimental results is shown. The overall radial polarization purity of the generated laser beam was found to be higher than 90% .

A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints

Publication bias and related bias in meta-analysis is often examined by visually checking for asymmetry in funnel plots of treatment effect against its standard error. Formal statistical tests of funnel plot asymmetry have been proposed, but when applied to binary outcome data these can give false-positive rates that are higher than the nominal level in some situations (large treatment effects, or few events per trial, or all trials of similar sizes). We develop a modified linear regression test for funnel plot asymmetry based on the efficient score and its variance, Fisher's information. The performance of this test is compared to the other proposed tests in simulation analyses based on the characteristics of published controlled trials. When there is little or no between-trial heterogeneity, this modified test has a false-positive rate close to the nominal level while maintaining similar power to the original linear regression test ('Egger' test). When the degree of between-trial heterogeneity is large, none of the tests that have been proposed has uniformly good properties.

A Faster Circular Binary Segmentation Algorithm for the Analysis of Array CGH Data

Motivation: Array CGH technologies enable the simultaneous measurement of DNA copy number for thousands of sites on a genome. We developed the circular binary segmentation (CBS) algorithm to divide the genome into regions of equal copy number (Olshen {\it et~al}, 2004). The algorithm tests for change-points using a maximal $t$-statistic with a permutation reference distribution to obtain the corresponding $p$-value. The number of computations required for the maximal test statistic is $O(N^2),$ where $N$ is the number of markers. This makes the full permutation approach computationally prohibitive for the newer arrays that contain tens of thousands markers and highlights the need for a faster. algorithm. Results: We present a hybrid approach to obtain the $p$-value of the test statistic in linear time. We also introduce a rule for stopping early when there is strong evidence for the presence of a change. We show through simulations that the hybrid approach provides a substantial gain in speed with only a negligible loss in accuracy and that the stopping rule further increases speed. We also present the analysis of array CGH data from a breast cancer cell line to show the impact of the new approaches on the analysis of real data. Availability: An R (R Development Core Team, 2006) version of the CBS algorithm has been implemented in the ``DNAcopy'' package of the Bioconductor project (Gentleman {\it et~al}, 2004). The proposed hybrid method for the $p$-value is available in version 1.2.1 or higher and the stopping rule for declaring a change early is available in version 1.5.1 or higher.