The ADMA/DDAH Pathway Regulates VEGF-Mediated Angiogenesis

Objectives— Asymmetrical dimethylarginine (ADMA) is a nitric oxide synthase (NOS) inhibitor and cardiovascular risk factor associated with angiogenic disorders. Enzymes metabolising ADMA, dimethylarginine dimethylaminohydrolases (DDAH) promote angiogenesis, but the mechanisms are not clear. We hypothesized that ADMA/DDAH modifies endothelial responses to vascular endothelial growth factor (VEGF) by affecting activity of Rho GTPases, regulators of actin polymerization, and focal adhesion dynamics. Methods and Results— The effects of ADMA on VEGF-induced endothelial cell motility, focal adhesion turnover, and angiogenesis were studied in human umbilical vein endothelial cells (HUVECs) and DDAH I heterozygous knockout mice. ADMA inhibited VEGF-induced chemotaxis in vitro and angiogenesis in vitro and in vivo in an NO-dependent way. ADMA effects were prevented by overexpression of DDAH but were not associated with decreased proliferation, increased apoptosis, or changes in VEGFR-2 activity or expression. ADMA inhibited endothelial cell polarization, protrusion formation, and decreased focal adhesion dynamics, resulting from Rac1 inhibition after decrease in phosphorylation of vasodilator stimulated phosphoprotein (VASP). Constitutively active Rac1, and to a lesser extent dominant negative RhoA, abrogated ADMA effects in vitro and in vivo. Conclusion— The ADMA/DDAH pathway regulates VEGF-induced angiogenesis in an NO- and Rac1-dependent manner

Explicit Evidence Systems with Common Knowledge

Justification logics are epistemic logics that explicitly include justifications for the agents' knowledge. We develop a multi-agent justification logic with evidence terms for individual agents as well as for common knowledge. We define a Kripke-style semantics that is similar to Fitting's semantics for the Logic of Proofs LP. We show the soundness, completeness, and finite model property of our multi-agent justification logic with respect to this Kripke-style semantics. We demonstrate that our logic is a conservative extension of Yavorskaya's minimal bimodal explicit evidence logic, which is a two-agent version of LP. We discuss the relationship of our logic to the multi-agent modal logic S4 with common knowledge. Finally, we give a brief analysis of the coordinated attack problem in the newly developed language of our logic

Voltage rectification by a SQUID ratchet

We argue that the phase across an asymmetric dc SQUID threaded by a magnetic flux can experience an effective ratchet (periodic and asymmetric) potential. Under an external ac current, a rocking ratchet mechanism operates whereby one sign of the time derivative of the phase is favored. We show that there exists a range of parameters in which a fixed sign (and, in a narrower range, even a fixed value) of the average voltage across the ring occurs, regardless of the sign of the external current dc component.Comment: 4 pages, 4 EPS figures, uses psfig.sty. Revised version, to appear in Physical Review Letters (26 August 1996

Structural Evolution of a Composite Middle to Lower Crustal Section: The Sierra de Pie de Palo, Northwest Argentina

The Sierra de Pie de Palo of northwest Argentina preserves middle to lower crustal metamorphic rocks that were penetratively deformed during Ordovician accretion of the Precordillera terrane to the Gondwana margin. New structural, petrologic, and geochronologic data from a 40 km structural transect reveals that the Sierra de Pie de Palo preserves a middle to lower crustal ductile thrust complex consisting of individual structural units and not an intact ophiolite and cover sequence. Top-to-the-west thrusting occurred intermittently on discrete ductile shear zones from ∼515 to ∼417 Ma and generally propagated toward the foreland with progressive deformation. Ordovician crustal shortening and peak metamorphic temperatures in the central portion of the Sierra de Pie de Palo were synchronous with retro-arc shortening and magmatic flare-up within the Famatina arc. Accretion of the Precordillera terrane resulted in the end of arc flare-up and the onset of synconvergent extension by ∼439 Ma. Continued synextensional to postextensional convergence was accommodated along progressively lower grade shear zones following terrane accretion and the establishment of a new plate margin west of the Precordillera terrane. The results support models of Cordilleran orogens that link voluminous arc magmatism to periods of regional shortening. The deformation, metamorphic, and magmatic history within the Sierra de Pie de Palo is consistent with models placing the region adjacent to the Famatina margin in the middle Cambrian and not as basement to the Precordillera terrane

Casimir-Polder forces: A non-perturbative approach

Within the frame of macroscopic QED in linear, causal media, we study the radiation force of Casimir-Polder type acting on an atom which is positioned near dispersing and absorbing magnetodielectric bodies and initially prepared in an arbitrary electronic state. It is shown that minimal and multipolar coupling lead to essentially the same lowest-order perturbative result for the force acting on an atom in an energy eigenstate. To go beyond perturbation theory, the calculations are based on the exact center-of-mass equation of motion. For a nondriven atom in the weak-coupling regime, the force as a function of time is a superposition of force components that are related to the electronic density-matrix elements at a chosen time. Even the force component associated with the ground state is not derivable from a potential in the ususal way, because of the position dependence of the atomic polarizability. Further, when the atom is initially prepared in a coherent superposition of energy eigenstates, then temporally oscillating force components are observed, which are due to the interaction of the atom with both electric and magnetic fields.Comment: 23 pages, 3 figures, additional misprints correcte

Crustal Shortening, Exhumation, and Strain Localization in a Collisonal Orogen: the Bajo Pequeno Shear Zone, Sierra de Pie de Palo, Argentina

The Bajo Pequeño Shear Zone (BPSZ) is a lower-crustal shear zone that records shortening and exhumation associated with the establishment of a new plate boundary, and its placement in a regional structural context suggests that local- to regional-scale strain localization occurred with progressive deformation. A kilometer-scale field and analytical cross section through the ~80 m thick BPSZ and its adjacent rocks indicates an early Devonian (405–400 Ma) phase of deformation on the western margin of Gondwanan continental crust. The earliest stages of the BPSZ, recorded by metamorphic and microstructural data, involved thrusting of a hotter orthogneiss over a relatively cool pelitic unit, which resulted in footwall garnet growth and reset footwall white mica 40Ar/39Ar ages in proximity to the shear zone. Later stages of BPSZ activity, as recorded by additional microstructures and quartz c-axis opening angles, were characterized by strain localization to the center of the shear zone coincident with cooling and exhumation. These and other data suggest that significant regional tectonism persisted in the Famatinian orogenic system for 60–70 million years after one microplate collision (the Precordillera) but ceased 5–10 million years prior to another (Chilenia). A survey of other synchronous structures shows that strain was accommodated on progressively narrower structures with time, indicating a regional pattern of strain localization and broad thermal relaxation as the Precordillera collision evolved

Current Issues in Terrestrial Solar Radiation Instrumentation for Energy, Climate and Space Applications Preprint prepared for New RAD '99

Reductions of uncertainty in terrestrial solar radiation measurements are needed to validate the Earth's radiation balance derived from satellite data. Characterization of solar energy resources for renewable technologies requires greater time and spatial resolution for economical technology deployment. Solar radiation measurement research at the National Renewable Energy Laboratory addresses calibrations, operational characteristics, and corrections for terrestrial solar radiation measurements. We describe progress in measurements of broadband diffuse-sky radiation, and characterization of field instrument thermal offsets and spectral irradiance. The need and prospects for absolute references for diffuse and long-wave terrestrial solar radiation measurements are discussed. Reductions in uncertainty of broadband irradiance measurements from tens of watts per square meter to a few (one to two) watts per square meter are reported, which reduce time and labor to quantify and identify trends in artificial optical radiation sources, terrestrial solar radiation, and the Earth's radiation budget

Does mass drug administration for the integrated treatment of neglected tropical diseases really work? Assessing evidence for the control of schistosomiasis and soil-transmitted helminths in Uganda

This paper was one of four papers commissioned to review the role of social sciences in NTD control by TDR, the Special Programme for Research and Training on Tropical Diseases, which is executed by WHO and co-sponsored by UNICEF, UNDP, the World Bank and WHO.This article has been made available through the Brunel Open Access Publishing Fund.Background: Less is known about mass drug administration [MDA] for neglected tropical diseases [NTDs] than is suggested by those so vigorously promoting expansion of the approach. This paper fills an important gap: it draws upon local level research to examine the roll out of treatment for two NTDs, schistosomiasis and soil-transmitted helminths, in Uganda. Methods: Ethnographic research was undertaken over a period of four years between 2005-2009 in north-west and south-east Uganda. In addition to participant observation, survey data recording self-reported take-up of drugs for schistosomiasis, soil-transmitted helminths and, where relevant, lymphatic filariasis and onchocerciasis was collected from a random sample of at least 10% of households at study locations. Data recording the take-up of drugs in Ministry of Health registers for NTDs were analysed in the light of these ethnographic and social survey data. Results: The comparative analysis of the take-up of drugs among adults revealed that although most long term residents have been offered treatment at least once since 2004, the actual take up of drugs for schistosomiasis and soil-transmitted helminths varies considerably from one district to another and often also within districts. The specific reasons why MDA succeeds in some locations and falters in others relates to local dynamics. Issues such as population movement across borders, changing food supply, relations between drug distributors and targeted groups, rumours and conspiracy theories about the 'real' purpose of treatment, subjective experiences of side effects from treatment, alternative understandings of affliction, responses to social control measures and historical experiences of public health control measures, can all make a huge difference. The paper highlights the need to adapt MDA to local circumstances. It also points to specific generalisable issues, notably with respect to health education, drug distribution and more effective use of existing public health legislation. Conclusion: While it has been an achievement to have offered free drugs to so many adults, current standard practices of monitoring, evaluation and delivery of MDA for NTDs are inconsistent and inadequate. Efforts to integrate programmes have exacerbated the difficulties. Improved assessment of what is really happening on the ground will be an essential step in achieving long-term overall reduction of the NTD burden for impoverished communities.This article is available through the Brunel Open Access Publishing Fund

Evidence for ground-state electron capture of 40^{40}K

Potassium-40 is a widespread isotope whose radioactivity impacts estimated geological ages spanning billions of years, nuclear structure theory, and subatomic rare-event searches - including those for dark matter and neutrinoless double-beta decay. The decays of this long-lived isotope must be precisely known for its use as a geochronometer, and to account for its presence in low-background experiments. There are several known decay modes for $^{40}$K, but a predicted electron-capture decay directly to the ground state of argon-40 has never been observed, while theoretical predictions span an order of magnitude. The KDK Collaboration reports on the first observation of this rare decay, obtained using a novel combination of a low-threshold X-ray detector surrounded by a tonne-scale, high-efficiency $\gamma$-ray tagger at Oak Ridge National Laboratory. A blinded analysis reveals a distinctly nonzero ratio of intensities of ground-state electron-captures ($I_{\text{EC}^0}$) over excited-state ones ($I_{\text{EC}^*}$) of $I_{\text{EC}^0} / I_{\text{EC}^*}=0.0095\stackrel{\text{stat}}{\pm}0.0022\stackrel{\text{sys}}{\pm}0.0010$ (68% CL), with the null hypothesis rejected at 4$\sigma$ [Stukel et al., DOI:10.1103/PhysRevLett.131.052503]. This unambiguous signal yields a branching ratio of $I_{\text{EC}^0}=0.098\%\stackrel{\text{stat}}{\pm}0.023\%\stackrel{\text{sys}}{\pm}0.010$, roughly half of the commonly used prediction. This first observation of a third-forbidden unique electron capture improves understanding of low-energy backgrounds in dark-matter searches and has implications for nuclear-structure calculations. A shell-model based theoretical estimate for the $0\nu\beta\beta$ decay half-life of calcium-48 is increased by a factor of $7^{+3}_{-2}$. Our nonzero measurement shifts geochronological ages by up to a percent; implications are illustrated for Earth and solar system chronologies.Comment: This is a companion submission to Stukel et al (KDK collaboration) "Rare $^{40}$K decay with implications for fundamental physics and geochronology" [arXiv:2211.10319; DOI: 10.1103/PhysRevLett.131.052503]. As such, both texts share some figures and portions of text. This version updates the text following its review and production proces

Viral FLICE Inhibitory Protein of Rhesus Monkey Rhadinovirus Inhibits Apoptosis by Enhancing Autophagosome Formation

Rhesus monkey rhadinovirus (RRV) is a gamma-2 herpesvirus closely related to human herpesvirus 8 (HHV8). RRV encodes viral FLICE inhibitory protein (vFLIP), which has death effector domains. Little is known about RRV vFLIP. This study intended to examine its function in apoptosis. Here we found that RRV vFLIP inhibits apoptosis induced by tumor necrosis factor-α (TNF-α) and cycloheximide. In HeLa cells with vFLIP expression, the cleavage of poly [ADP-ribose] polymerase 1 (PARP-1) and activities of caspase 3, 7, and 9 were much lower than those in controls. Cell viability of HeLa cells with vFLIP expression was significantly higher than control cells after apoptosis induction. However, RRV vFLIP appears unable to induce NF-κB signaling when tested in NF-κB reporter assay. RRV vFLIP was able to enhance cell survival under starved conditions or apoptosis induction. At early time points after apoptosis induction, autophagosome formation was enhanced and LC3-II level was elevated in cells with vFLIP and, when autophagy was blocked with chemical inhibitors, these cells underwent apoptosis. Moreover, RRV latent infection of BJAB B-lymphoblastoid cells protects the cells against apoptosis by enhancing autophagy to maintain cell survival. Knockdown of vFLIP expression in the RRV-infected BJAB cells with siRNA abolished the protection against apoptosis. These results indicate that vFLIP protects cells against apoptosis by enhancing autophagosome formation to extend cell survival. The finding of vFLIP’s inhibition of apoptosis via the autophagy pathway provides insights of vFLIP in RRV pathogenesis