Use of computational fluid dynamics to compare upper airway pressures and airflow resistance in brachycephalic, mesocephalic, and dolichocephalic dogs

Brachycephalic dog breeds are prone to breathing difficulties because of their upper airway anatomy. Several surgical techniques exist to correct anatomical pathologies and common surgical approaches aim to correct functional abnormalities in the nares and/or the soft palate. However, further research is needed to improve clinical outcomes. This study evaluated air pressure and airflow resistance in the upper airways and trachea in nine sedated, sternally recumbent dogs of different skull types (dolichocephalic, n = 3; mesocephalic, n = 3; brachycephalic, n = 3). CT images were acquired from the nostrils to the caudal border of the lungs and geometrical reconstruction of the upper airway and trachea was performed. Analysis of computational fluid dynamics was performed using inspiratory flow adapted to bodyweight for each dog. Flow (L/min) and pressure (cmH2O) were computed for the entire upper airway and trachea. Resistance (cmH2O/L/min) was calculated using pressure differences between the nose, larynx, and trachea. In this pilot study, statistical comparisons were not performed. Pressure maps, airflow, and resistance were similar in dolichocephalic and mesocephalic breeds. Median pressure difference (3.76 cmH2O) and resistance (0.154 cmH2O/L/min) between the nose and larynx were numerically higher in brachycephalic dogs than in other breeds (0.45 cmH2O and 0.016 cmH2O/L/min, respectively). Median pressure difference (0.205 cmH2O) and resistance (0.009 cmH2O/L/min) between the larynx and trachea was numerically similar in all dogs, except for the English bulldog. The methodology used in this preliminary study to quantify airflow characteristics such as pressure and resistance could improve the understanding of brachycephalic obstruction airway syndrome

Structural Characterization of Rapid Thermal Oxidized Si\u3csub\u3e1−x−y\u3c/sub\u3eGe\u3csub\u3ex\u3c/sub\u3eC\u3csub\u3ey\u3c/sub\u3e Alloy Films Grown by Rapid Thermal Chemical Vapor Deposition

The structural properties of as-grown and rapid thermal oxidized Si1−x−yGexCy epitaxial layers have been examined using a combination of infrared, x-ray photoelectron, x-ray diffraction, secondary ion mass spectroscopy, and Raman spectroscopy techniques. Carbon incorporation into the Si1−x−yGexCy system can lead to compressive or tensile strain in the film. The structural properties of the oxidized Si1−x−yGexCy film depend on the type of strain (i.e., carbon concentration) of the as-prepared film. For compressive or fully compensated films, the oxidation process drastically reduces the carbon content so that the oxidized films closely resemble to Si1−xGex films. For tensile films, two broad regions, one with carbon content higher and the other lower than that required for full strain compensation, coexist in the oxidized films

Site-to-site interdomain communication may mediate different loss-of-function mechanisms in a cancer-associated NQO1 polymorphism

Disease associated genetic variations often cause intracellular enzyme inactivation, dysregulation and instability. However, allosteric communication of mutational effects to distant functional sites leading to loss-of-function remains poorly understood. We characterize here interdomain site-to-site communication by which a common cancer-associated single nucleotide polymorphism (c.C609T/p.P187S) reduces the activity and stability in vivo of NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 is a FAD-dependent, two-domain multifunctional stress protein acting as a Phase II enzyme, activating cancer pro-drugs and stabilizing p53 and p73a oncosuppressors. We show that p.P187S causes structural and dynamic changes communicated to functional sites far from the mutated site, affecting the FAD binding site located at the N-terminal domain (NTD) and accelerating proteasomal degradation through dynamic effects on the C-terminal domain (CTD). Structural protein:protein interaction studies reveal that the cancer-associated polymorphism does not abolish the interaction with p73a, indicating that oncosuppressor destabilization largely mirrors the low intracellular stability of p.P187S. In conclusion, we show how a single disease associated amino acid change may allosterically perturb several functional sites in an oligomeric and multidomain protein. These results have important implications for the understanding of loss-of-function genetic diseases and the identification of novel structural hot spots as targets for pharmacological intervention

Cypher: An Evolving Query Language for Property Graphs

International audienceThe Cypher property graph query language is an evolving language, originally designed and implemented as part of the Neo4j graph database, and it is currently used by several commercial database products and researchers. We describe Cypher 9, which is the first version of the language governed by the openCypher Implementers Group. We first introduce the language by example, and describe its uses in industry. We then provide a formal semantic definition of the core read-query features of Cypher, including its variant of the property graph data model, and its " ASCII Art " graph pattern matching mechanism for expressing subgraphs of interest to an application. We compare the features of Cypher to other property graph query languages, and describe extensions, at an advanced stage of development, which will form part of Cypher 10, turning the language into a compositional language which supports graph projections and multiple named graphs

A single evolutionarily divergent mutation determines the different FAD-binding affinities of human and rat NQO1 due to site-specific phosphorylation

The phosphomimetic mutation S82D in the cancer-associated, FAD-dependent human NADP(H):quinone oxidoreductase 1 (hNQO1) causes a decrease in flavin-adenine dinucleotide-binding affinity and intracellular stability. We test in this work whether the evolutionarily recent neutral mutation R80H in the vicinity of S82 may alter the strong functional effects of S82 phosphorylation through electrostatic interactions. We show using biophysical and bioinformatic analyses that the reverse mutation H80R prevents the effects of S82D phosphorylation on hNQO1 by modulating the local stability. Consistently, in rat NQO1 (rNQO1) which contains R80, the effects of phosphorylation were milder, resembling the behaviour found in hNQO1 when this residue was humanized in rNQO1 (by the R80H mutation). Thus, apparently neutral and evolutionarily divergent mutations may determine the functional response of mammalian orthologues towards phosphorylation. © 2021 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societie

Investigation of the Fundamental Reliability Unit for Cu Dual-Damascene Metallization

An investigation has been carried out to determine the fundamental reliability unit of copper dual-damascene metallization. Electromigration experiments have been carried out on straight via-to-via interconnects in the lower metal (M1) and the upper metal (M2), and in a simple interconnect tree structure consisting of straight via-to-via line with an extra via in the middle of the line (a "dotted-I"). Multiple failure mechanisms have been observed during electromigration testing of via-to-via Cu interconnects. The failure times of the M2 test structures are significantly longer than that of identical M1 structures. It is proposed that this asymmetry is the result of a difference in the location of void formation and growth, which is believed to be related to the ease of electromigration-induced void nucleation and growth at the Cu/Si₃N₄ interface. However, voids were also detected in the vias instead of in the Cu lines for some cases of early failure of the test lines. These early failures are suspected to be related to the integrity and reliability of the Cu via. Different magnitudes and directions of electrical current were applied independently in two segments of the interconnect tree structure. As with Al-based interconnects, the reliability of a segment in this tree strongly depends on the stress conditions of the connected segment. Beyond this, there are important differences in the results obtained under similar test conditions for Al-based and Cu-based interconnect trees. These differences are thought to be associated with variations in the architectural schemes of the two metallizations. The absence of a conducting electromigration-resistant overlayer in Cu technology allows smaller voids to cause failure in Cu compared to Al. Moreover, the Si₃N₄ overlayer that serves as an interlevel diffusion barrier provides sites for easy nucleation of voids and also provides a high diffusivity path for electromigration. The results reported here suggest that while segments are not the fundamental reliability unit for circuit-level reliability assessments for Al or Cu, vias, rather than trees, might be the appropriate fundamental units for the assessment of Cu reliability.Singapore-MIT Alliance (SMA

Structural basis of the pleiotropic and specific phenotypic consequences of missense mutations in the multifunctional NAD(P)H:quinone oxidoreductase 1 and their pharmacological rescue

The multifunctional nature of human flavoproteins is critically linked to their ability to populate multiple conformational states. Ligand binding, post-translational modifications and disease-associated mutations can reshape this functional landscape, although the structure-function relationships of these effects are not well understood. Herein, we characterized the structural and functional consequences of two mutations (the cancer-associated P187S and the phosphomimetic S82D) on different ligation states which are relevant to flavin binding, intracellular stability and catalysis of the disease-associated NQO1 flavoprotein. We found that these mutations affected the stability locally and their effects propagated differently through the protein structure depending both on the nature of the mutation and the ligand bound, showing directional preference from the mutated site and leading to specific phenotypic manifestations in different functional traits (FAD binding, catalysis and inhibition, intracellular stability and pharmacological response to ligands). Our study thus supports that pleitropic effects of disease-causing mutations and phosphorylation events on human flavoproteins may be caused by long-range structural propagation of stability effects to different functional sites that depend on the ligation-state and site-specific perturbations. Our approach can be of general application to investigate these pleiotropic effects at the flavoproteome scale in the absence of high-resolution structural models. © 202

Physical and biological processes at the Subtropical Convergence in the South-west Indian Ocean

A detailed hydrographic and biological survey was conducted in the region of the Subtropical Convergence in the Indian sector of the Southern Ocean in April 2007. Hydrographic data revealed that the subsurface expression of the Subtropical Convergence (at 200 m), marked by the 10°C isotherm, appeared to meander considerably between 41°S and 42°15’S. Total surface chlorophyll- a concentration was low and ranged from 0.03 to 0.42 µg l–1 and was always dominated by the pico- ( 0.05). The zooplankton community was dominated, numerically and by biomass, by mesozooplankton comprising mainly copepods of the genera, Oithona,Paraeuchaeta, Pleuromamma, Calanus and Clausocalanus. An exception was recorded at those stations in the region of the front where the tunicate, Salpa thompsoni, dominated the total zooplankton biomass

PM speciation and sources in Mexico during the MILAGRO-2006 Campaign

International audienceLevels of PM10, PM2.5 and PM1 and chemical speciation of PM10 and PM2.5 were measured during the MILAGRO campaign (1st to 31st March 2006, but extended in some cases until 6th April) at four urban, one suburban, two rural background and two rural sites, with different degree of industrial influence, in the Mexico City Metropolitan Area (MCMA) and adjacent regions. PM10 and PM2.5 daily levels varied between 50?56?g/m3 and 24?46?g/m3 at the urban sites, 22?35?g/m3 and 13?25?g/m3 at the rural sites, and 75?g/m3 and 31?g/m3 at the industrial hotspot, lower than those recorded at some Asian mega-cities and similar to those recorded at other Latin American cities. At the urban sites, hourly PM2.5 and PM1 concentrations showed a marked impact of road traffic emissions (at rush hours), with levels of coarse PM remaining elevated during daytime. At the suburban and rural sites different PM daily patterns were registered according to the influence of the pollution plume from MCMA, and also of local soil resuspension. The speciation studies showed that mineral matter accounted for 25?27% of bulk PM10 at the urban sites and a higher proportion (up to 43%) at the suburban and rural sites. This pattern is repeated in PM2.5, with 15% at urban and 28% at suburban and rural sites. Carbonaceous compounds accounted for a significant proportion at the urban and industrial sites (32?46% in PM10, and 51?55% in PM2.5), markedly reduced at the suburban and rural sites (16?23% in PM10, and 30% in PM2.5). The secondary inorganic aerosols accounted for 10?20% of bulk PM10 at urban, suburban, rural and industrial sites, with a higher proportion (40%) at the industrial background site. A relatively high proportion of nitrate in rural sites was present in the coarse fraction. Typically anthropogenic elements (As, Cr, Zn, Cu, Pb, Sn, Sb, Ba, among others) showed considerably high levels at the urban sites; however levels of particulate Hg and crustal trace elements (Rb, Ti, La, Sc, Ga) were generally higher at the suburban site. Principal component analysis identified three major common factors: crustal, regional background and road traffic. Moreover, some specific factors were obtained for each site