Rad/Rem/Gem/Kir (RGK) GTPases potently inhibit Ca V 1 and Ca V 2 (Ca V 1-2) channels, a paradigm of ion channel regulation by monomeric G-proteins with significant physiological ramifications and potential biotechnology applications. The mechanism(s) underlying how RGK proteins inhibit I Ca is unknown, and it is unclear how key structural and regulatory properties of these GTPases (such as the role of GTP binding to the nucleotide binding domain (NBD), and the C-terminus which contains a membrane-targeting motif) feature in this effect. Here, we show that Rem inhibits Ca V 1.2 channels by three independent mechanisms that rely on distinct configurations of the GTPase: (1) a reduction in surface density of channels is accomplished by enhancing dynamin-dependent endocytosis, (2)

A search for neutral heavy leptons (NHLs) has been performed using an instrumented decay channel at the NuTeV (E-815) experiment at Fermilab. The decay channel was composed of helium bags interspersed with drift chambers, and was used in conjunction with the NuTeV neutrino detector to search for NHL decays. The data were examined for NHLs decaying into muonic final states (µµν, µeν, µπ, and µρ); no evidence has been found for NHLs in the 0.25 -2.0 GeV mass range. This analysis places limits on the mixing of NHLs with standard light neutrinos at a level up to an order of magnitude more restrictive than previous search limits in this mass range.PACS numbers: 13.15.+g,13.35.Hb,14.60.Pq 1 Various extensions [1,2] to the Standard Model predict neutral heavy leptons (NHLs) which can mix with the standard light neutrinos. In these extensions, the NHLs are weak isosinglets that do not couple directly to the Z and W bosons, but can decay via mixing with the Standard Model neutrinos. Figure 1 shows one possible set of tree-level diagrams for NHL production and decay. The NuTeV (E815) neutrino experiment at Fermilab has made a sensitive search for these NHLs by combining the capabilities of a high intensity neutrino source with an instrumented decay region.In these extended models [1], the NHL lifetime depends on the mixing parameter |U | 2 and the mass of the NHL. They are expected to decay (e.g. Fig. 1b) into a neutrino and two charged leptons, into a lepton and two quarks, or into three neutrinos.NHLs may be created in the NuTeV beamline by the decays of secondary mesons produced by the Tevatron proton beam. During the 1996-1997 fixed-target run at Fermilab, NuTeV received 2.54 × 10 18 800 GeV protons on a beryllium oxide production target with the detector configured for this search. A sign-selected quadrupole train focused secondary π and K mesons down a beamline 7.8 mrad from the primary proton beam direction. 1.13 × 10 18 protons were received with the magnets set to focus positive mesons, and 1.41 × 10 18 protons with negative meson focusing. The mesons could decay into NHLs as shown in Fig. 1a. The production of secondary pions and kaons was simulated using the parameterization in [3]; the Decay Turtle program [4] simulated the propagation of charged particles through the beamline.NHLs may also be produced by prompt decays of charmed mesons produced by incident protons on the BeO target and proton dumps. These processes were simulated using a Monte Carlo program based on measured production cross sections [5]. The effects of decay phase space, NHL polarization, and helicity suppression [6] were included in the simulation of the production and decays. For NHLs of mass 1.45 GeV from D meson decay, the average momentum was ∼100 GeV; for the 0.35 GeV NHLs coming mainly from K decay, the average momentum was ∼140 GeV.This analysis reports the results of a search for NHLs with masses between 0.25 to 2.0 GeV, which decay with a muon in the final state. The primary NHL decay modes of this type are µeν, µµν, µπ, and µρ. In...

Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) form a light-sensitive system separate from rods and cones. Direct light stimulation of ipRGCs can regulate many nonimageforming visual functions such as photoentrainment of circadian rhythms and pupil responses, and can intensify migraine headache in adults. In mice, ipRGCs are light responsive as early as the day of birth. In contrast, their eyelids do not open until 12-13 d after birth (P12-13), and light signaling from rods and cones does not begin until approximately P10. No physiological or behavioral function is established for ipRGCs in neonates before the onset of rod and cone signaling. Here we report that mouse pups as young as P6 will completely turn away from a light. Light-induced responses of ipRGCs could be readily recorded in retinas of pups younger than P9, and we found no evidence for rod-and cone-mediated visual signaling to the RGCs of these younger mice. These results confirm that negative phototaxis is evident before the onset of rod-and cone-mediated visual signaling, and well before the onset of image-forming vision. Negative phototaxis was absent in mice lacking melanopsin. We conclude that light activation of melanopsin ipRGCs is necessary and sufficient for negative phototaxis. These results strongly suggest that light activation of ipRGCs may regulate physiological functions such as sleep/wake cycles in preterm and neonatal infants.

Megavoltage cone beam computed tomography (MVCBCT) is routinely used for visualizing anatomical structures and implanted fiducials for patient positioning in radiotherapy. MVCBCT using a 6 MV treatment beam with high atomic number (Z) target and flattening filter in the beamline, as done conventionally, has lower image quality than can be achieved with a MV beam due to heavy filtration of the low-energy bremsstrahlung. The unflattened beam of a low Z target has an abundance of diagnostic energy photons, detected with modern flat panel detectors with much higher efficiency given the same dose to the patient. This principle guided the development of a new megavoltage imaging beamline (IBL) for a commercial radiotherapy linear accelerator. A carbon target was placed in one of the electron primary scattering foil slots on the target-foil slide. A PROM on a function controller board was programed to put the carbon target in place for MVCBCT. A low accelerating potential of 4.2 MV was used for the IBL to restrict leakage of primary electrons through the target such that dose from x rays dominated the signal in the monitor chamber and the patient surface dose. Results from phantom and cadaver images demonstrated that the IBL had much improved image quality over the treatment beam. For similar imaging dose, the IBL improved the contrast-to-noise ratio by as much as a factor of 3 in soft tissue over that of the treatment beam. The IBL increased the spatial resolution by about a factor of 2, allowing the visualization of finer anatomical details. Images of the cadaver contained useful information with doses as low as 1 cGy. The IBL may be installed on certain models of linear accelerators without mechanical modification and results in significant improvement in the image quality with the same dose, or images of the same quality with less than one-third of the dose.

The as-yet unidentified E. coli metabolite colibactin induces DNA damage in eukaryotic cells and promotes tumorigenesis. Its wide distribution in pathogenic and probiotic strains has raised great interest in its structure and biosynthesis. Here we show that colibactin formation involves a rare aminomalonyl unit used as a building block.