Functions of several Cayley-Dickson variables and manifolds over them

Functions of several octonion variables are investigated and integral representation theorems for them are proved. With the help of them solutions of the ${\tilde {\partial}}$-equations are studied. More generally functions of several Cayley-Dickson variables are considered. Integral formulas of the Martinelli-Bochner, Leray, Koppelman type used in complex analysis here are proved in the new generalized form for functions of Cayley-Dickson variables instead of complex. Moreover, analogs of Stein manifolds over Cayley-Dickson graded algebras are defined and investigated

Genetically altered AMPA-type glutamate receptor kinetics in interneurons disrupt long-range synchrony of gamma oscillation

Gamma oscillations synchronized between distant neuronal populations may be critical for binding together brain regions devoted to common processing tasks. Network modeling predicts that such synchrony depends in part on the fast time course of excitatory postsynaptic potentials (EPSPs) in interneurons, and that even moderate slowing of this time course will disrupt synchrony. We generated mice with slowed interneuron EPSPs by gene targeting, in which the gene encoding the 67-kDa form of glutamic acid decarboxylase (GAD67) was altered to drive expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit GluR-B. GluR-B is a determinant of the relatively slow EPSPs in excitatory neurons and is normally expressed at low levels in γ-aminobutyric acid (GABA)ergic interneurons, but at high levels in the GAD-GluR-B mice. In both wild-type and GAD-GluR-B mice, tetanic stimuli evoked gamma oscillations that were indistinguishable in local field potential recordings. Remarkably, however, oscillation synchrony between spatially separated sites was severely disrupted in the mutant, in association with changes in interneuron firing patterns. The congruence between mouse and model suggests that the rapid time course of AMPA receptor-mediated EPSPs in interneurons might serve to allow gamma oscillations to synchronize over distance

Comparison and characterization of α-amylase inducers in Aspergillus nidulans based on nuclear localization of AmyR

AmyR, a fungal transcriptional activator responsible for induction of amylolytic genes in Aspergillus nidulans, localizes to the nucleus in response to the physiological inducer isomaltose. Maltose, kojibiose, and d-glucose were also found to trigger the nuclear localization of GFP-AmyR. Isomaltose- and kojibiose-triggered nuclear localization was not inhibited by the glucosidase inhibitor, castanospermine, while maltose-triggered localization was inhibited. Thus, maltose itself does not appear to be an direct inducer, but its degraded or transglycosylated product does. Non-metabolizable d-glucose analogues were also able to trigger the nuclear localization, implying that these sugars, except maltose, directly function as the inducers of AmyR nuclear entry. The inducing activity of d-glucose was 4 orders-of-magnitude weaker compared with isomaltose. Although d-glucose has the ability to induce α-amylase production, this activity would generally be masked by CreA-dependent carbon catabolite repression. Significant induction of α-amylase by d-glucose was observed in creA-defective A. nidulans

Vegetable, fruit and antioxidant nutrient consumption and subsequent risk of hepatocellular carcinoma: a prospective cohort study in Japan

In a population-based prospective study of 19 998 Japanese individuals, consumption of vegetables, green–yellow and green leafy vegetables was inversely associated with the risk of hepatocellular carcinoma (101 cases), with multivariable hazard ratios for the highest vs lowest tertile of 0.61 (95% confidence interval (CI)=0.36–1.03, Ptrend=0.07), 0.65 (95% CI=0.39–1.08, Ptrend=0.06) and 0.59 (95% CI=0.35–1.01, Ptrend=0.04), respectively

Contribution of proteasome-catalyzed peptide cis-splicing to viral targeting by CD8⁺ T cells in HIV-1 infection

Peptides generated by proteasome-catalyzed splicing of noncontiguous amino acid sequences have been shown to constitute a source of nontemplated human leukocyte antigen class I (HLA-I) epitopes, but their role in pathogen-specific immunity remains unknown. CD8⁺ T cells are key mediators of HIV type 1 (HIV-1) control, and identification of novel epitopes to enhance targeting of infected cells is a priority for prophylactic and therapeutic strategies. To explore the contribution of proteasome-catalyzed peptide splicing (PCPS) to HIV-1 epitope generation, we developed a broadly applicable mass spectrometry-based discovery workflow that we employed to identify spliced HLA-I–bound peptides on HIV-infected cells. We demonstrate that HIV-1–derived spliced peptides comprise a relatively minor component of the HLA-I–bound viral immunopeptidome. Although spliced HIV-1 peptides may elicit CD8⁺ T cell responses relatively infrequently during infection, CD8⁺ T cells primed by partially overlapping contiguous epitopes in HIV-infected individuals were able to cross-recognize spliced viral peptides, suggesting a potential role for PCPS in restricting HIV-1 escape pathways. Vaccine-mediated priming of responses to spliced HIV-1 epitopes could thus provide a novel means of exploiting epitope targets typically underutilized during natural infection

A bright, dust-obscured, millimetre-selected galaxy beyond the Bullet Cluster (1E0657−56)

This article has been accepted for publication in Monthly notices of the Royal Astronomical Society ©: 2008 G. W. Wilson et al. Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved.Deep 1.1 mm continuum observations of 1E0657−56 (the ‘Bullet Cluster’) taken with the millimeter-wavelength camera AzTEC on the 10-m Atacama Submillimeter Telescope Experiment (ASTE), have revealed an extremely bright (S1.1 mm= 15.9 mJy) unresolved source. This source, MMJ065837−5557.0, lies close to a maximum in the density of underlying mass distribution, towards the larger of the two interacting clusters as traced by the weak-lensing analysis of Clowe et al. Using optical–infrared (IR) colours, we argue that MMJ065837−5557.0 lies at a redshift of z= 2.7 ± 0.2. A lensing-derived mass model for the Bullet Cluster shows a critical line (caustic) of magnification within a few arcsec of the AzTEC source, sufficient to amplify the intrinsic millimetre-wavelength flux of the AzTEC galaxy by a factor of ≫20. After subtraction of the foreground cluster emission at 1.1 mm due to the Sunyaev-Zel'dovich effect, and correcting for the magnification, the rest-frame far-IR luminosity of MMJ065837−5557.0 is ≤1012L⊙, characteristic of a luminous infrared galaxy (LIRG). We explore various scenarios to explain the colours, morphologies and positional offsets between the potential optical and IR counterparts, and their relationship with MMJ065837−5557.0. Until higher resolution and more sensitive (sub)millimetre observations are available, the detection of background galaxies close to the caustics of massive lensing clusters offers the only opportunity to study this intrinsically faint millimetre-galaxy population

Live-Cell Microscopy Reveals Small Molecule Inhibitor Effects on MAPK Pathway Dynamics

Oncogenic mutations in the mitogen activated protein kinase (MAPK) pathway are prevalent in human tumors, making this pathway a target of drug development efforts. Recently, ATP-competitive Raf inhibitors were shown to cause MAPK pathway activation via Raf kinase priming in wild-type BRaf cells and tumors, highlighting the need for a thorough understanding of signaling in the context of small molecule kinase inhibitors. Here, we present critical improvements in cell-line engineering and image analysis coupled with automated image acquisition that allow for the simultaneous identification of cellular localization of multiple MAPK pathway components (KRas, CRaf, Mek1 and Erk2). We use these assays in a systematic study of the effect of small molecule inhibitors across the MAPK cascade either as single agents or in combination. Both Raf inhibitor priming as well as the release from negative feedback induced by Mek and Erk inhibitors cause translocation of CRaf to the plasma membrane via mechanisms that are additive in pathway activation. Analysis of Erk activation and sub-cellular localization upon inhibitor treatments reveals differential inhibition and activation with the Raf inhibitors AZD628 and GDC0879 respectively. Since both single agent and combination studies of Raf and Mek inhibitors are currently in the clinic, our assays provide valuable insight into their effects on MAPK signaling in live cells

Global and local controlson continental margin stratigraphy

Integrated Ocean Drilling Program (IODP) Expedition 317 was devoted to understanding the relative importance of global sea level (eustasy) versus local tectonic and sedimentary processes in controlling continental margin sedimentary cycles. The expedition recovered sediments from the Eocene to recent period, with a particular focus on the sequence stratigraphy of the late Miocene to recent, when global sea level change was dominated by glacioeustasy. Drilling in the Canterbury Basin, on the eastern margin of the South Island of New Zealand, takes advantage of high rates of Neogene sediment supply, which preserves a high-frequency (0.1–0.5 m.y.) record of depositional cyclicity. The Canterbury Basin provides an opportunity to study the complex interactions between processes responsible for the preserved stratigraphic record of sequences because of the proximity of an uplifting mountain chain, the Southern Alps, and strong ocean currents. Currents have locally built large, elongate sediment drifts within the prograding Neogene section. Expedition 317 did not drill into one of these elongate drifts, but currents are inferred to have strongly influenced deposition across the basin, including in locations lacking prominent mounded drifts. Upper Miocene to recent sedimentary sequences were cored in a transect of three sites on the continental shelf (landward to basinward, Sites U1353, U1354, and U1351) and one on the continental slope (Site U1352). The transect provides a stratigraphic record of depositional cycles across the shallow-water environment most directly affected by relative sea level change. Lithologic boundaries, provisionally correlative with seismic sequence boundaries, have been identified in cores from each site and provide insights into the origins of seismically resolvable sequences. This record will be used to estimate the timing and amplitude of global sea level change and to document the sedimentary processes that operate during sequence formation. Sites U1353 and U1354 provide significant, double-cored, high-recovery sections through the Holocene and late Quaternary for high-resolution study of recent glacial cycles in a continental shelf setting. Continental slope Site U1352 represents a complete section from modern slope terrigenous sediment to hard Eocene limestone, with all the associated lithologic, biostratigraphic, physical, geochemical, and microbiological transitions. The site also provides a record of ocean circulation and fronts during the last ~35 m.y. The early Oligocene (~30 Ma) Marshall Paraconformity was the deepest drilling target of Expedition 317 and is hypothesized to represent intensified current erosion or nondeposition associated with the initiation of thermohaline circulation following the separation of Australian and Antarctica. Expedition 317 set a number of scientific ocean drilling records: (1) deepest hole drilled in a single expedition and second deepest hole in the history of scientific ocean drilling (Hole U1352C, 1927 m); (2) deepest hole and second deepest hole drilled by the R/V JOIDES Resolution on a continental shelf (Hole U1351B, 1030 m; Hole U1353B, 614 m); (3) shallowest water depth for a site drilled by the JOIDES Resolution for scientific purposes (Site U1353, 84.7 m water depth); and (4) deepest sample taken by scientific ocean drilling for microbiological studies (1925 m, Site U1352). Expedition 317 supplements previous drilling of sedimentary sequences for sequence stratigraphic and sea level objectives, particularly drilling on the New Jersey margin (Ocean Drilling Program [ODP] Legs 150, 150X, 174A, and 174AX and IODP Expedition 313) and in the Bahamas (ODP Leg 166), but includes an expanded Pliocene section. Completion of at least one transect across a geographically and tectonically distinct siliciclastic margin was the necessary next step in deciphering continental margin stratigraphy. Expedition 317 also complements ODP Leg 181, which focused on drift development in more distal parts of the Eastern New Zealand Oceanic Sedimentary System (ENZOSS).Integrated Ocean Drilling Program Management InternationalPublished2.2. Laboratorio di paleomagnetismorestricte

CNF1 Improves Astrocytic Ability to Support Neuronal Growth and Differentiation In vitro

Modulation of cerebral Rho GTPases activity in mice brain by intracerebral administration of Cytotoxic Necrotizing Factor 1 (CNF1) leads to enhanced neurotransmission and synaptic plasticity and improves learning and memory. To gain more insight into the interactions between CNF1 and neuronal cells, we used primary neuronal and astrocytic cultures from rat embryonic brain to study CNF1 effects on neuronal differentiation, focusing on dendritic tree growth and synapse formation, which are strictly modulated by Rho GTPases. CNF1 profoundly remodeled the cytoskeleton of hippocampal and cortical neurons, which showed philopodia-like, actin-positive projections, thickened and poorly branched dendrites, and a decrease in synapse number. CNF1 removal, however, restored dendritic tree development and synapse formation, suggesting that the toxin can reversibly block neuronal differentiation. On differentiated neurons, CNF1 had a similar effacing effect on synapses. Therefore, a direct interaction with CNF1 is apparently deleterious for neurons. Since astrocytes play a pivotal role in neuronal differentiation and synaptic regulation, we wondered if the beneficial in vivo effect could be mediated by astrocytes. Primary astrocytes from embryonic cortex were treated with CNF1 for 48 hours and used as a substrate for growing hippocampal neurons. Such neurons showed an increased development of neurites, in respect to age-matched controls, with a wider dendritic tree and a richer content in synapses. In CNF1-exposed astrocytes, the production of interleukin 1β, known to reduce dendrite development and complexity in neuronal cultures, was decreased. These results demonstrate that astrocytes, under the influence of CNF1, increase their supporting activity on neuronal growth and differentiation, possibly related to the diminished levels of interleukin 1β. These observations suggest that the enhanced synaptic plasticity and improved learning and memory described in CNF1-injected mice are probably mediated by astrocytes

Full characterization of GPCR monomer–dimer dynamic equilibrium by single molecule imaging

A single-molecule tracking technique coupled with mathematical modeling was developed for fully determining the dynamic monomer–dimer equilibrium of molecules in or on the plasma membrane, which will provide a framework for understanding signal transduction pathways initiated and regulated by dynamic dimers of membrane-localized receptors