Specific functions of synaptically localized potassium channels in synaptic transmission at the neocortical GABAergic fast-spiking cell synapse

Potassium (K+) channel subunits of the Kv3 subfamily (Kv3.1-Kv3.4) display a positively shifted voltage dependence of activation and fast activation/deactivation kinetics when compared with other voltage-gated K+ channels, features that confer on Kv3 channels the ability to accelerate the repolarization of the action potential (AP) efficiently and specifically. In the cortex, the Kv3.1 and Kv3.2 proteins are expressed prominently in a subset of GABAergic interneurons known as fast-spiking (FS) cells and in fact are a significant determinant of the fast-spiking discharge pattern. However, in addition to expression at FS cell somata, Kv3.1 and Kv3.2 proteins also are expressed prominently at FS cell terminals, suggesting roles for Kv3 channels in neurotransmitter release. We investigated the effect of 1.0 mM tetraethylammonium (TEA; which blocks Kv3 channels) on inhibitory synaptic currents recorded in layer II/III neocortical pyramidal cells. Spike-evoked GABA release by FS cells was enhanced nearly twofold by 1.0 mM TEA, with a decrease in the paired pulse ratio (PPR), effects not reproduced by blockade of the non-Kv3 subfamily K+ channels also blocked by low concentrations of TEA. Moreover, in Kv3.1/Kv3.2 double knock-out (DKO) mice, the large effects of TEA were absent, spike-evoked GABA release was larger, and the PPR was lower than in wild-type mice. Together, these results suggest specific roles for Kv3 channels at FS cell terminals that are distinct from those of Kv1 and large-conductance Ca2+-activated K+ channels (also present at the FS cell synapse). We propose that at FS cell terminals synaptically localized Kv3 channels keep APs brief, limiting Ca2+ influx and hence release probability, thereby influencing synaptic depression at a synapse designed for sustained high-frequency synaptic transmission

Sensitivity of Present and Future Surface Temperatures to Precipitation Characteristics

A model simulation study shows that different diurnal cycles of precipitation are consistent with radically different present and future climate characteristics. In projected future climate scenarios, divergence in the time of day and type of precipitation had very divergent impacts on the radiation balance and consequently on surface temperatures. The relationship between the diurnal cycle of precipitation versus the present and future climate was examined using the GISS-MM5 (Goddard Institute for Space Studies Mesoscale Model 5) regional climate modeling system with 2 alternative moist convection schemes. June-August (JJA) mean surface temperatures of the 1990s, 2050s, and 2080s were simulated over the eastern US on a double nested 108/36 km domain, with the 36 km domain centered over the eastern US. In the 1990s, one model version simulated maxima in (convective) precipitation during the early morning, while the second model simulated the hour of precipitation maxima with considerable spatial variability (in better agreement with observations). In the futuristic climate scenarios, differences in the time of day of precipitation had very important impacts on the radiation balance at the surface. One version gave more precipitation at night and fewer clouds during the day, promoting higher surface temperatures. The alternative version created more precipitation during the day, consistent with diminished absorption of solar radiation at the surface and consequently lower surface temperatures. The results demonstrate the importance of improving cumulus parameterizations in regional mesoscale and global climate models and suggest that such improvements would lead to greater confidence in model projections of climate change

Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies

Background: Bevacizumab is frequently combined with 5-fluorouracil-based chemotherapy for patients with metastatic colorectal cancer (mCRC). The relative benefit of bevacizumab in older patients has not been widely studied and is of interest. Patients and methods: This retrospective analysis used data from three first-line randomized controlled studies and one second-line randomized controlled study of bevacizumab plus chemotherapy in medically fit (Eastern Cooperative Oncology Group performance status 0 or 1) patients with mCRC. Overall survival (OS) and on-treatment progression-free survival (PFS) were assessed in patients aged greater than 65, greater than or equal to 65, and greater than or equal to 70 years. Results were compared using unstratified hazard ratios (HRs). Grade 3-5 adverse events were also assessed. Results: Bevacizumab statistically significantly improved PFS [HR 0.58; 95% confidence interval (CI) 0.49-0.68] and OS (HR 0.85; 95% CI 0.74-0.97) in patients aged greater than or equal to 65 years; patients aged greater than or equal to 70 years had similar improvements. Benefits were consistent across the studies, irrespective of setting, bevacizumab dose, or chemotherapy regimen. Increases in thromboembolic events were observed in patients aged greater than or equal to 65 and greater than or equal to 70 years in the bevacizumab group compared with the control group, mainly as a result of increases in arterial thromboembolic events. No other substantial age-related increases in grade 3-5 adverse events were observed. Conclusions: In medically fit older patients, bevacizumab provides similar PFS and OS benefits as in younger patients

Computing radiation from Kerr black holes: Generalization of the Sasaki-Nakamura equation

As shown by Teukolsky, the master equation governing the propagation of weak radiation in a black hole spacetime can be separated into four ordinary differential equations, one for each spacetime coordinate. (``Weak'' means the radiation's amplitude is small enough that its own gravitation may be neglected.) Unfortunately, it is difficult to accurately compute solutions to the separated radial equation (the Teukolsky equation), particularly in a numerical implementation. The fundamental reason for this is that the Teukolsky equation's potentials are long ranged. For non-spinning black holes, one can get around this difficulty by applying transformations which relate the Teukolsky solution to solutions of the Regge-Wheeler equation, which has a short-ranged potential. A particularly attractive generalization of this approach to spinning black holes for gravitational radiation (spin weight s = -2) was given by Sasaki and Nakamura. In this paper, I generalize Sasaki and Nakamura's results to encompass radiation fields of arbitrary integer spin weight, and give results directly applicable to scalar (s = 0) and electromagnetic (s = -1) radiation. These results may be of interest for studies of astrophysical radiation processes near black holes, and of programs to compute radiation reaction forces in curved spacetime.Comment: 10 pages, no figures, to appear in Phys. Rev. D. Present version updates the references, fixes some typos, and corrects some of the Introductory tex

Search for Millicharged Particles at SLAC

Particles with electric charge q < 10^(-3)e and masses in the range 1--100 MeV/c^2 are not excluded by present experiments. An experiment uniquely suited to the production and detection of such "millicharged" particles has been carried out at SLAC. This experiment is sensitive to the infrequent excitation and ionization of matter expected from the passage of such a particle. Analysis of the data rules out a region of mass and charge, establishing, for example, a 95%-confidence upper limit on electric charge of 4.1X10^(-5)e for millicharged particles of mass 1 MeV/c^2 and 5.8X10^(-4)e for mass 100 MeV/c^2.Comment: 4 pages, REVTeX, multicol, 3 figures. Minor typo corrected. Submitted to Physical Review Letter

Radiative multipole moments of integer-spin fields in curved spacetime

Radiative multipole moments of scalar, electromagnetic, and linearized gravitational fields in Schwarzschild spacetime are computed to third order in v in a weak-field, slow-motion approximation, where v is a characteristic velocity associated with the motion of the source. To zeroth order in v, a radiative moment of order l is given by the corresponding source moment differentiated l times with respect to retarded time. At second order in v, additional terms appear inside the spatial integrals. These are near-zone corrections which depend on the detailed behavior of the source. At third order in v, the correction terms occur outside the spatial integrals, so that they do not depend on the detailed behavior of the source. These are wave-propagation corrections which are heuristically understood as arising from the scattering of the radiation by the spacetime curvature surrounding the source. Our calculations show that the wave-propagation corrections take a universal form which is independent of multipole order and field type. We also show that in general relativity, temporal and spatial curvatures contribute equally to the wave-propagation corrections.Comment: 34 pages, ReVTe

What we talk about when we talk about "global mindset": managerial cognition in multinational corporations

Recent developments in the global economy and in multinational corporations have placed significant emphasis on the cognitive orientations of managers, giving rise to a number of concepts such as “global mindset” that are presumed to be associated with the effective management of multinational corporations (MNCs). This paper reviews the literature on global mindset and clarifies some of the conceptual confusion surrounding the construct. We identify common themes across writers, suggesting that the majority of studies fall into one of three research perspectives: cultural, strategic, and multidimensional. We also identify two constructs from the social sciences that underlie the perspectives found in the literature: cosmopolitanism and cognitive complexity and use these two constructs to develop an integrative theoretical framework of global mindset. We then provide a critical assessment of the field of global mindset and suggest directions for future theoretical and empirical research

Cluster Lenses

Clusters of galaxies are the most recently assembled, massive, bound structures in the Universe. As predicted by General Relativity, given their masses, clusters strongly deform space-time in their vicinity. Clusters act as some of the most powerful gravitational lenses in the Universe. Light rays traversing through clusters from distant sources are hence deflected, and the resulting images of these distant objects therefore appear distorted and magnified. Lensing by clusters occurs in two regimes, each with unique observational signatures. The strong lensing regime is characterized by effects readily seen by eye, namely, the production of giant arcs, multiple-images, and arclets. The weak lensing regime is characterized by small deformations in the shapes of background galaxies only detectable statistically. Cluster lenses have been exploited successfully to address several important current questions in cosmology: (i) the study of the lens(es) - understanding cluster mass distributions and issues pertaining to cluster formation and evolution, as well as constraining the nature of dark matter; (ii) the study of the lensed objects - probing the properties of the background lensed galaxy population - which is statistically at higher redshifts and of lower intrinsic luminosity thus enabling the probing of galaxy formation at the earliest times right up to the Dark Ages; and (iii) the study of the geometry of the Universe - as the strength of lensing depends on the ratios of angular diameter distances between the lens, source and observer, lens deflections are sensitive to the value of cosmological parameters and offer a powerful geometric tool to probe Dark Energy. In this review, we present the basics of cluster lensing and provide a current status report of the field.Comment: About 120 pages - Published in Open Access at: http://www.springerlink.com/content/j183018170485723/ . arXiv admin note: text overlap with arXiv:astro-ph/0504478 and arXiv:1003.3674 by other author

Evidence for a Minimal Eukaryotic Phosphoproteome?

BACKGROUND: Reversible phosphorylation catalysed by kinases is probably the most important regulatory mechanism in eukaryotes. METHODOLOGY/PRINCIPAL FINDINGS: We studied the in vitro phosphorylation of peptide arrays exhibiting the majority of PhosphoBase-deposited protein sequences, by factors in cell lysates from representatives of various branches of the eukaryotic species. We derived a set of substrates from the PhosphoBase whose phosphorylation by cellular extracts is common to the divergent members of different kingdoms and thus may be considered a minimal eukaryotic phosphoproteome. The protein kinases (or kinome) responsible for phosphorylation of these substrates are involved in a variety of processes such as transcription, translation, and cytoskeletal reorganisation. CONCLUSIONS/SIGNIFICANCE: These results indicate that the divergence in eukaryotic kinases is not reflected at the level of substrate phosphorylation, revealing the presence of a limited common substrate space for kinases in eukaryotes and suggests the presence of a set of kinase substrates and regulatory mechanisms in an ancestral eukaryote that has since remained constant in eukaryotic life