Revealing the secrets of neuronal circuits with recombinant rabies virus technology

An understanding of how the brain processes information requires knowledge of the architecture of its underlying neuronal circuits, as well as insights into the relationship between architecture and physiological function. A range of sophisticated tools is needed to acquire this knowledge, and recombinant rabies virus (RABV) is becoming an increasingly important part of this essential toolbox. RABV has been recognized for years for its properties as a synapse-specific trans-neuronal tracer. A novel genetically modified variant now enables the investigation of specific monosynaptic connections. This technology, in combination with other genetic, physiological, optical, and computational tools, has enormous potential for the visualization of neuronal circuits, and for monitoring and manipulating their activity. Here we will summarize the latest developments in this fast moving field and provide a perspective for the use of this technology for the dissection of neuronal circuit structure and function in the normal and diseased brain

Z-petawatt driven ion beam radiography development.

Laser-driven proton radiography provides electromagnetic field mapping with high spatiotemporal resolution, and has been applied to many laser-driven High Energy Density Physics (HEDP) experiments. Our report addresses key questions about the feasibility of ion radiography at the Z-Accelerator (%E2%80%9CZ%E2%80%9D), concerning laser configuration, hardware, and radiation background. Charged particle tracking revealed that radiography at Z requires GeV scale protons, which is out of reach for existing and near-future laser systems. However, it might be possible to perform proton deflectometry to detect magnetic flux compression in the fringe field region of a magnetized liner inertial fusion experiment. Experiments with the Z-Petawatt laser to enhance proton yield and energy showed an unexpected scaling with target thickness. Full-scale, 3D radiation-hydrodynamics simulations, coupled to fully explicit and kinetic 2D particle-in-cell simulations running for over 10 ps, explain the scaling by a complex interplay of laser prepulse, preplasma, and ps-scale temporal rising edge of the laser

Insights Into Patient Variability During Ivacaftor-Lumacaftor Therapy in Cystic Fibrosis

Background: The advent of cystic fibrosis transmembrane conductance regulator protein (CFTR) modulators like ivacaftor have revolutionised the treatment of cystic fibrosis (CF). However, due to the plethora of variances in disease manifestations in CF, there are inherent challenges in unified responses under CFTR modulator treatment arising from variability in patient outcomes. The pharmacokinetic (PK) data available for ivacaftor-lumacaftor cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drug combination is limited. Methods: Secondary objectives were to identify (1) patient characteristics and (2) the interactions between ivacaftor-lumacaftor responsible for interindividual variability (IIV). Results: Peak plasma concentrations (Cmax) of ivacaftor - lumacaftor were >10 fold lower than expected compared to label information. The one-way ANOVA indicated that the patient site had an effect on Cmax values of ivacaftor metabolites ivacaftor-M1, ivacaftor-M6, and lumacaftor (p < 0.001, p < 0.001, and p < 0.001, respectively). The Spearman’s rho test indicated that patient weight and age have an effect on the Cmax of lumacaftor (p = 0.003 and p < 0.001, respectively) and ivacaftor metabolite M1 (p = 0.020 and p < 0.001, respectively). Age (p < 0.001) was found to effect on Cmax of ivacaftor M6 and on Tmax of ivacaftor M1 (p = 0.026). A large impact of patient characteristics on the IIV of PK parameters Cmax and Tmax, was observed among the CF patients. Conclusion: Understanding the many sources of variability can help reduce this individual patient variability and ensure consistent patient outcomes

The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.

Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies

Z-petawatt driven ion beam radiography development.

Laser-driven proton radiography provides electromagnetic field mapping with high spatiotemporal resolution, and has been applied to many laser-driven High Energy Density Physics (HEDP) experiments. Our report addresses key questions about the feasibility of ion radiography at the Z-Accelerator (%E2%80%9CZ%E2%80%9D), concerning laser configuration, hardware, and radiation background. Charged particle tracking revealed that radiography at Z requires GeV scale protons, which is out of reach for existing and near-future laser systems. However, it might be possible to perform proton deflectometry to detect magnetic flux compression in the fringe field region of a magnetized liner inertial fusion experiment. Experiments with the Z-Petawatt laser to enhance proton yield and energy showed an unexpected scaling with target thickness. Full-scale, 3D radiation-hydrodynamics simulations, coupled to fully explicit and kinetic 2D particle-in-cell simulations running for over 10 ps, explain the scaling by a complex interplay of laser prepulse, preplasma, and ps-scale temporal rising edge of the laser

Distinct Roles of Different Homer1 Isoforms in Behaviors and Associated Prefrontal Cortex Function

Homer1 mutant mice exhibit behavioral and neurochemical abnormalities that are consistent with an animal model of schizophrenia. Because the Homer1 gene encodes both immediate early gene (IEG) and constitutively expressed (CC) gene products, we used the local infusion of adeno-associated viral vectors carrying different Homer1 transcriptional variants into the prefrontal cortex (PFC) to distinguish between the roles for IEG and CC Homer1 isoforms in the “schizophrenia-like” phenotype of Homer1 mutant mice. PFC overexpression of the IEG Homer1 isoform Homer1a reversed the genotypic differences in behavioral adaptation to repeated stress, whereas overexpression of the constitutively expressed Homer1 isoform Homer1c reversed the genotypic differences in sensorimotor and cognitive processing, as well as cocaine behavioral sensitivity. Homer1a overexpression did not influence PFC basal glutamate content but blunted the glutamate response to cocaine in wild-type mice. In contrast, Homer1c overexpression reversed the genotypic difference in PFC basal glutamate content and enhanced cocaine-induced elevations in glutamate. These data demonstrate active and distinct roles for Homer1a and Homer1c isoforms in the PFC in the mediation of behavior, in the maintenance of basal extracellular glutamate, and in the regulation of PFC glutamate release relevant to schizophrenia and stimulant abuse comorbidity

The Muonium Atom as a Probe of Physics beyond the Standard Model

The observed interactions between particles are not fully explained in the successful theoretical description of the standard model to date. Due to the close confinement of the bound state muonium ($M = \mu^+ e^-$) can be used as an ideal probe of quantum electrodynamics and weak interaction and also for a search for additional interactions between leptons. Of special interest is the lepton number violating process of sponteanous conversion of muonium to antimuonium.Comment: 15 pages,6 figure

Surface relaxation and ferromagnetism of Rh(001)

The significant discrepancy between first-principles calculations and experimental analyses for the relaxation of the (001) surface of rhodium has been a puzzle for some years. In this paper we present density functional theory calculations using the local-density approximation and the generalized gradient approximation of the exchange-correlation functional. We investigate the thermal expansion of the surface and the possibility of surface magnetism. The results throw light on several, hitherto overlooked, aspects of metal surfaces. We find, that, when the free energy is considered, density-functional theory provides results in good agreement with experiments.Comment: 6 pages, 4 figures, submitted to Phys. Rev. Lett. (April 28, 1996

Imaging the water snow-line during a protostellar outburst

A snow-line is the region of a protoplanetary disk at which a major volatile, such as water or carbon monoxide, reaches its condensation temperature. Snow-lines play a crucial role in disk evolution by promoting the rapid growth of ice-covered grains^1, 2, 3, 4, 5, 6. Signatures of the carbon monoxide snow-line (at temperatures of around 20 kelvin) have recently been imaged in the disks surrounding the pre-main-sequence stars TW Hydra^7, 8, 9 and HD163296 (refs 3, 10), at distances of about 30 astronomical units (au) from the star. But the water snow-line of a protoplanetary disk (at temperatures of more than 100 kelvin) has not hitherto been seen, as it generally lies very close to the star (less than 5 au away for solar-type stars^11). Water-ice is important because it regulates the efficiency of dust and planetesimal coagulation5, and the formation of comets, ice giants and the cores of gas giants^12. Here we report images at 0.03-arcsec resolution (12 au) of the protoplanetary disk around V883 Ori, a protostar of 1.3 solar masses that is undergoing an outburst in luminosity arising from a temporary increase in the accretion rate^13. We find an intensity break corresponding to an abrupt change in the optical depth at about 42 au, where the elevated disk temperature approaches the condensation point of water, from which we conclude that the outburst has moved the water snow-line. The spectral behaviour across the snow-line confirms recent model predictions^14: dust fragmentation and the inhibition of grain growth at higher temperatures results in soaring grain number densities and optical depths. As most planetary systems are expected to experience outbursts caused by accretion during their formation^15, 16, our results imply that highly dynamical water snow-lines must be considered when developing models of disk evolution and planet formation