Functional mechanisms of the cellular prion protein (PrPC) associated anti-HIV-1 properties

The cellular prion protein PrP(C)/CD230 is a GPI-anchor protein highly expressed in cells from the nervous and immune systems and well conserved among vertebrates. In the last decade, several studies suggested that PrP(C) displays antiviral properties by restricting the replication of different viruses, and in particular retroviruses such as murine leukemia virus (MuLV) and the human immunodeficiency virus type 1 (HIV-1). In this context, we previously showed that PrP(C) displays important similarities with the HIV-1 nucleocapsid protein and found that PrP(C) expression in a human cell line strongly reduced HIV-1 expression and virus production. Using different PrP(C) mutants, we report here that the anti-HIV-1 properties are mostly associated with the amino-terminal 24-KRPKP-28 basic domain. In agreement with its reported RNA chaperone activity, we found that PrP(C) binds to the viral genomic RNA of HIV-1 and negatively affects its translation. Using a combination of biochemical and cell imaging strategies, we found that PrP(C) colocalizes with the virus assembly machinery at the plasma membrane and at the virological synapse in infected T cells. Depletion of PrP(C) in infected T cells and microglial cells favors HIV-1 replication, confirming its negative impact on the HIV-1 life cycle.     

Large-scale forest girdling shows that current photosynthesis drives soil respiration.

The respiratory activities of plant roots, of their mycorrhizal fungi and of the free-living microbial heterotrophs (decomposers) in soils are significant components of the global carbon balance, but their relative contributions remain uncertain. To separate mycorrhizal root respiration from heterotrophic respiration in aboreal pine forest, we conducted a large-scale tree-girdling experiment, comprising 9 plots each containing about 120 trees. Tree-girdling involves stripping the stem bark to the depth of the current xylem at breast height terminating the supply of current photosynthates to roots and their mycorrhizal fungi without physically disturbing the delicate root-microbe-soil system. Here we report that girdling reduced soil respiration within 1-2 months by about 54% relative to respiration on ungirdled control plots, and that decreases of up to 37% were detected within 5 days. These values clearly show that the flux of current assimilates to roots is a key driver of soil respiration; they are conservative estimates of root respiration, however, because girdling increased the use of starch reserves in the roots. Our results indicate that models of soil respiration should incorporate measures of photosynthesis and of seasonal patterns of photosynthate allocation to roots.     

Observation of a roton collective mode in a two-dimensional Fermi liquid

Understanding the dynamics of correlated many-body quantum systems is a challenge for modern physics. Owing to the simplicity of their Hamiltonians, (4)He (bosons) and (3)He (fermions) have served as model systems for strongly interacting quantum fluids, with substantial efforts devoted to their understanding. An important milestone was the direct observation of the collective phonon-roton mode in liquid (4)He by neutron scattering, verifying Landau's prediction and his fruitful concept of elementary excitations. In a Fermi system, collective density fluctuations (known as 'zero-sound' in (3)He, and 'plasmons' in charged systems) and incoherent particle-hole excitations are observed. At small wavevectors and energies, both types of excitation are described by Landau's theory of Fermi liquids. At higher wavevectors, the collective mode enters the particle-hole band, where it is strongly damped. The dynamics of Fermi liquids at high wavevectors was thus believed to be essentially incoherent. Here we report inelastic neutron scattering measurements of a monolayer of liquid (3)He, observing a roton-like excitation. We find that the collective density mode reappears as a well defined excitation at momentum transfers larger than twice the Fermi momentum. We thus observe unexpected collective behaviour of a Fermi many-body system in the regime beyond the scope of Landau's theory. A satisfactory interpretation of the measured spectra is obtained using a dynamic many-body theory.     

Toxicity of pyrazole and 4-methylpyrazole in mice and rats

Zusammenfassung Subchronische Gaben von Pyrazol, nicht dagegen von 4-Methylpyrazol, führen bei Ratten und Mäusen zu toxischen Läsionen.     

A genome-wide association study of metabolic traits in human urine

We present a genome-wide association study of metabolic traits in human urine, designed to investigate the detoxification capacity of the human body. Using NMR spectroscopy, we tested for associations between 59 metabolites in urine from 862 male participants in the population-based SHIP study. We replicated the results using 1,039 additional samples of the same study, including a 5-year follow-up, and 992 samples from the independent KORA study. We report five loci with joint P values of association from 3.2 × 10(-19) to 2.1 × 10(-182). Variants at three of these loci have previously been linked with important clinical outcomes: SLC7A9 is a risk locus for chronic kidney disease, NAT2 for coronary artery disease and genotype-dependent response to drug toxicity, and SLC6A20 for iminoglycinuria. Moreover, we identify rs37369 in AGXT2 as the genetic basis of hyper-β-aminoisobutyric aciduria.     

PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling

The secreted protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipid (LDL) receptor family members LDLR, very low density lipoprotein receptor (VLDLR) and apolipoprotein receptor 2 (ApoER2), and promotes their degradation in intracellular acidic compartments. In the liver, LDLR is a major controller of blood LDL levels, whereas VLDLR and ApoER2 in the brain mediate Reelin signaling, a critical pathway for proper development of the nervous system. Expression level of PCSK9 in the brain is highest in the cerebellum during perinatal development, but is also increased in the adult brain after ischemia. The mechanism of PCSK9 function and its involvement in neuronal apoptosis is poorly understood. We show here that RNAi-mediated knockdown of PCSK9 significantly reduced the death of potassium-deprived cerebellar granule neurons (CGN), as shown by reduced levels of nuclear phosphorylated c-Jun and activated caspase-3, as well as condensed apoptotic nuclei. ApoER2 protein levels were increased in PCSK9 RNAi cells. Knockdown of ApoER2 but not of VLDLR was sufficient to reverse the protection provided by PCSK9 RNAi, suggesting that proapoptotic signaling of PCSK9 is mediated by altered ApoER2 function. Pharmacological inhibition of signaling pathways associated with lipoprotein receptors suggested that PCSK9 regulates neuronal apoptosis independently of NMDA receptor function but in concert with ERK and JNK signaling pathways. PCSK9 RNAi also reduced staurosporine-induced CGN apoptosis and axonal degeneration in the nerve growth factor-deprived dorsal root ganglion neurons. We conclude that PCSK9 potentiates neuronal apoptosis via modulation of ApoER2 levels and related anti-apoptotic signaling pathways.     

A low level of extragalactic background light as revealed by gamma-rays from blazars

The diffuse extragalactic background light consists of the sum of the starlight emitted by galaxies through the history of the Universe, and it could also have an important contribution from the 'first stars', which may have formed before galaxy formation began. Direct measurements are difficult and not yet conclusive, owing to the large uncertainties caused by the bright foreground emission associated with zodiacal light. An alternative approach is to study the absorption features imprinted on the gamma-ray spectra of distant extragalactic objects by interactions of those photons with the background light photons. Here we report the discovery of gamma-ray emission from the blazars H 2356 - 309 and 1ES 1101 - 232, at redshifts z = 0.165 and z = 0.186, respectively. Their unexpectedly hard spectra provide an upper limit on the background light at optical/near-infrared wavelengths that appears to be very close to the lower limit given by the integrated light of resolved galaxies. The background flux at these wavelengths accordingly seems to be strongly dominated by the direct starlight from galaxies, thus excluding a large contribution from other sources-in particular from the first stars formed. This result also indicates that intergalactic space is more transparent to gamma-rays than previously thought.     

In situ multi-satellite detection of coherent vortices as a manifestation of Alfvénic turbulence

Turbulence in fluids and plasmas is a ubiquitous phenomenon driven by a variety of sources-currents, sheared flows, gradients in density and temperature, and so on. Turbulence involves fluctuations of physical properties on many different scales, which interact nonlinearly to produce self-organized structures in the form of vortices. Vortex motion in fluids and magnetized plasmas is typically governed by nonlinear equations, examples of which include the Navier-Stokes equation, the Charney-Hasegawa-Mima equations and their numerous generalizations. These nonlinear equations admit solutions in the form of different types of vortices that are frequently observed in a variety of contexts: in atmospheres, in oceans and planetary systems, in the heliosphere, in the Earth's ionosphere and magnetosphere, and in laboratory plasma experiments. Here we report the discovery by the Cluster satellites of a distinct class of vortex motion-short-scale drift-kinetic Alfvén (DKA) vortices-in the Earth's magnetospheric cusp region. As is the case for the larger Kelvin-Helmholtz vortices observed previously, these dynamic structures should provide a channel for transporting plasma particles and energy through the magnetospheric boundary layers.