SUMOylation Is Required for Glycine-Induced Increases in AMPA Receptor Surface Expression (ChemLTP) in Hippocampal Neurons

yesMultiple pathways participate in the AMPA receptor trafficking that underlies long-term potentiation (LTP) of synaptic transmission. Here we demonstrate that protein SUMOylation is required for insertion of the GluA1 AMPAR subunit following transient glycine-evoked increase in AMPA receptor surface expression (ChemLTP) in dispersed neuronal cultures. ChemLTP increases co-localisation of SUMO-1 and the SUMO conjugating enzyme Ubc9 and with PSD95 consistent with the recruitment of SUMOylated proteins to dendritic spines. In addition, we show that ChemLTP increases dendritic levels of SUMO-1 and Ubc9 mRNA. Consistent with activity dependent translocation of these mRNAs to sites near synapses, levels of the mRNA binding and dendritic transport protein CPEB are also increased by ChemLTP. Importantly, reducing the extent of substrate protein SUMOylation by overexpressing the deSUMOylating enzyme SENP-1 or inhibiting SUMOylation by expressing dominant negative Ubc9 prevent the ChemLTP-induced increase in both AMPAR surface expression and dendritic SUMO-1 mRNA. Taken together these data demonstrate that SUMOylation of synaptic protein(s) involved in AMPA receptor trafficking is necessary for activity-dependent increases in AMPAR surface expression.Medical Research Council, the European Research Council and the Wellcome Trus

A Primal-Dual Interior-Point Method for Nonlinear Programming with Strong Global and Local Convergence Properties

A scheme---inspired from an old idea due to Mayne and Polak (Math. Prog.,vol.~11, 1976, pp.~67--80)---is proposed for extending to general smoothconstrained optimization problems a previously proposed feasibleinterior-point method for inequality constrained problems.It is shown that the primal-dual interior point framework allows for asignificantly more effective implementation of the Mayne-Polak idea thanthat discussed an analyzed by the originators in the contextof first order methods of feasible direction. Strong global and localconvergence results are proved under mild assumptions. In particular,the proposed algorithm does not suffer the Wachter-Biegler effect

Review article: MHD wave propagation near coronal null points of magnetic fields

We present a comprehensive review of MHD wave behaviour in the neighbourhood of coronal null points: locations where the magnetic field, and hence the local Alfven speed, is zero. The behaviour of all three MHD wave modes, i.e. the Alfven wave and the fast and slow magnetoacoustic waves, has been investigated in the neighbourhood of 2D, 2.5D and (to a certain extent) 3D magnetic null points, for a variety of assumptions, configurations and geometries. In general, it is found that the fast magnetoacoustic wave behaviour is dictated by the Alfven-speed profile. In a $\beta=0$ plasma, the fast wave is focused towards the null point by a refraction effect and all the wave energy, and thus current density, accumulates close to the null point. Thus, null points will be locations for preferential heating by fast waves. Independently, the Alfven wave is found to propagate along magnetic fieldlines and is confined to the fieldlines it is generated on. As the wave approaches the null point, it spreads out due to the diverging fieldlines. Eventually, the Alfven wave accumulates along the separatrices (in 2D) or along the spine or fan-plane (in 3D). Hence, Alfven wave energy will be preferentially dissipated at these locations. It is clear that the magnetic field plays a fundamental role in the propagation and properties of MHD waves in the neighbourhood of coronal null points. This topic is a fundamental plasma process and results so far have also lead to critical insights into reconnection, mode-coupling, quasi-periodic pulsations and phase-mixing.Comment: 34 pages, 5 figures, invited review in Space Science Reviews => Note this is a 2011 paper, not a 2010 pape

Nustar and Chandra Insight into the Nature of the 3-40 Kev Nuclear Emission in Ngc 253

We present results from three nearly simultaneous Nuclear Spectroscopic Telescope Array (NuSTAR) and Chandra monitoring observations between 2012 September 2 and 2012 November 16 of the local star-forming galaxy NGC 253. The 3-40 kiloelectron volt intensity of the inner approximately 20 arcsec (approximately 400 parsec) nuclear region, as measured by NuSTAR, varied by a factor of approximately 2 across the three monitoring observations. The Chandra data reveal that the nuclear region contains three bright X-ray sources, including a luminous (L (sub 2-10 kiloelectron volt) approximately few 10 (exp 39) erg per s) point source located approximately 1 arcsec from the dynamical center of the galaxy (within the sigma 3 positional uncertainty of the dynamical center); this source drives the overall variability of the nuclear region at energies greater than or approximately equal to 3 kiloelectron volts. We make use of the variability to measure the spectra of this single hard X-ray source when it was in bright states. The spectra are well described by an absorbed (power-law model spectral fit value, N(sub H), approximately equal to 1.6 x 10 (exp 23) per square centimeter) broken power-law model with spectral slopes and break energies that are typical of ultraluminous X-ray sources (ULXs), but not active galactic nuclei (AGNs). A previous Chandra observation in 2003 showed a hard X-ray point source of similar luminosity to the 2012 source that was also near the dynamical center (Phi is approximately equal to 0.4 arcsec); however, this source was offset from the 2012 source position by approximately 1 arcsec. We show that the probability of the 2003 and 2012 hard X-ray sources being unrelated is much greater than 99.99% based on the Chandra spatial localizations. Interestingly, the Chandra spectrum of the 2003 source (3-8 kiloelectron volts) is shallower in slope than that of the 2012 hard X-ray source. Its proximity to the dynamical center and harder Chandra spectrum indicate that the 2003 source is a better AGN candidate than any of the sources detected in our 2012 campaign; however, we were unable to rule out a ULX nature for this source. Future NuSTAR and Chandra monitoring would be well equipped to break the degeneracy between the AGN and ULX nature of the 2003 source, if again caught in a high state

Dual control of fault intersections on stop-start rupture in the 2016 Central Italy seismic sequence

Large continental earthquakes necessarily involve failure of multiple faults or segments. But these same critically-stressed systems sometimes fail in drawn-out sequences of smaller earthquakes over days or years instead. These two modes of failure have vastly different implications for seismic hazard and it is not known why fault systems sometimes fail in one mode or the other, or what controls the termination and reinitiation of slip in protracted seismic sequences. A paucity of modern observations of seismic sequences has hampered our understanding to-date, but a series of three Mw>6 earthquakes from August to November 2016 in Central Italy represents a uniquely well-observed example. Here we exploit a wealth of geodetic, seismological and field data to understand the spatio-temporal evolution of the sequence. Our results suggest that pre-existing fault structures controlled the extent and termination of rupture in each event in the sequence, and that fluid diffusion, channelled along these same structures, may have also determined the timing of rupture reinitiation. This dual control of subsurface structure on the stop-start rupture in seismic sequences may be common; future efforts should focus on investigating its prevalence

Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia

RATIONALE: Antimicrobial resistance challenges therapy of pneumonia. Enhancing macrophage microbicidal responses would combat this problem but is limited by our understanding of how alveolar macrophages (AM) kill bacteria. OBJECTIVES: To define the role and mechanism of AM apoptosis-associated bacterial killing in the lung. METHODS: We generated a unique CD68.hMcl-1 transgenic mouse with macrophage-specific over-expression of the human anti-apoptotic Mcl-1 protein, a factor upregulated in AM from patients at increased risk of community-acquired pneumonia, to address the requirement for apoptosis-associated killing. MEASUREMENTS AND MAIN RESULTS: Wild-type and transgenic macrophages demonstrated comparable ingestion and initial phagolysosomal killing of bacteria. Continued ingestion (for > 12 h) overwhelmed initial killing and a second late-phase microbicidal response killed viable bacteria in wild-type macrophages, but this response was blunted in CD68.hMcl-1 transgenic macrophages. The late-phase of bacterial killing required both caspase-induced generation of mitochondrial reactive oxygen species (mROS) and nitric oxide (NO), whose peak generation coincided with the late-phase of killing. The CD68.hMcl-1 transgene prevented mROS but not NO generation. Apoptosis-associated killing enhanced pulmonary clearance of Streptococcus pneumoniae and Haemophilus influenzae in wild-type but not CD68.hMcl-1 transgenic mice. Bacterial clearance was enhanced in vivo in CD68.hMcl-1 transgenic mice by reconstitution of apoptosis with BH3 mimetics or clodronate-encapsulated liposomes. Apoptosis-associated killing was not activated during Staphylococcus aureus lung infection. CONCLUSIONS: Mcl-1 upregulation prevents macrophage apoptosis-associated killing and establishes that apoptosis-associated killing is required to allow AM to clear ingested bacteria. Engagement of macrophage apoptosis should be investigated as a novel host-based antimicrobial strategy

Meta-analysis identifies seven susceptibility loci involved in the atopic March

Eczema often precedes the development of asthma in a disease course called the a 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified