Endothelial Nox4 NADPH oxidase enhances vasodilatation and reduces blood pressure in vivo

Objective- Increased reactive oxygen species (ROS) production is involved in the pathophysiology of endothelial dysfunction. NADPH oxidase-4 (Nox4) is a ROS-generating enzyme expressed in the endothelium, levels of which increase in pathological settings. Recent studies indicate that it generates predominantly hydrogen peroxide (H O ), but its role in vivo remains unclear. Methods and Results- We generated transgenic mice with endothelium-targeted Nox4 overexpression (Tg) to study the in vivo role of Nox4. Tg demonstrated significantly greater acetylcholine- or histamine-induced vasodilatation than wild-type littermates. This resulted from increased H O production and H O -induced hyperpolarization but not altered nitric oxide bioactivity. Tg had lower systemic blood pressure than wild-type littermates, which was normalized by antioxidants. Conclusion- Endothelial Nox4 exerts potentially beneficial effects on vasodilator function and blood pressure that are attributable to H O production. These effects contrast markedly with those reported for Nox1 and Nox2, which involve superoxide-mediated inactivation of nitric oxide. Our results suggest that therapeutic strategies to modulate ROS production in vascular disease may need to separately target individual Nox isoforms. © 2011 American Heart Association, Inc.

NADPH oxidase and heart failure

Reactive oxygen species play important roles in the pathophysiology of chronic heart failure secondary to chronic left ventricular hypertrophy or myocardial infarction. Reactive oxygen species influence several components of the phenotype of the failing heart, including contractile function, interstitial fibrosis, endothelial dysfunction and myocyte hypertrophy. Recent studies implicate the production of reactive oxygen species by a family of NADPH oxidases in these effects. NADPH oxidases are activated in an isoform-specific manner by many pathophysiological stimuli and exert distinct downstream effects. Understanding NADPH oxidase activation and regulation, and their downstream effectors, could help to develop novel therapeutic targets.

NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure

Markers of increased oxidative stress are known to be elevated following acute myocardial infarction and in the context of chronic left ventricular hypertrophy or heart failure, and their levels may correlate with the degree of contractile dysfunction or cardiac deficit. An obvious pathological mechanism that may account for this correlation is the potential deleterious effects of increased oxidative stress through the induction of cellular dysfunction, energetic deficit or cell death. However, reactive oxygen species have several much more subtle effects in the remodelling or failing heart that involve specific redox-regulated modulation of signalling pathways and gene expression. Such redox-sensitive regulation appears to play important roles in the development of several components of the phenotype of the failing heart, for example cardiomyocyte hypertrophy, interstitial fibrosis and chamber remodelling. In this article, we review the evidence supporting the involvement of reactive oxygen species and redox signalling pathways in the development of cardiac hypertrophy and heart failure, with a particular focus on the NADPH oxidase family of superoxide-generating enzymes which appear to be especially important in redox signalling.

Endothelial NADPH oxidase-2 promotes interstitial cardiac fibrosis and diastolic dysfunction through proinflammatory effects and endothelial-mesenchymal transition

OBJECTIVES: This study sought to investigate the effect of endothelial dysfunction on the development of cardiac hypertrophy and fibrosis. BACKGROUND: Endothelial dysfunction accompanies cardiac hypertrophy and fibrosis, but its contribution to these conditions is unclear. Increased nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX2) activation causes endothelial dysfunction. METHODS: Transgenic mice with endothelial-specific NOX2 overexpression (TG mice) and wild-type littermates received long-term angiotensin II (AngII) infusion (1.1 mg/kg/day, 2 weeks) to induce hypertrophy and fibrosis. RESULTS: TG mice had systolic hypertension and hypertrophy similar to those seen in wild-type mice but developed greater cardiac fibrosis and evidence of isolated left ventricular diastolic dysfunction (p < 0.05). TG myocardium had more inflammatory cells and VCAM-1-positive vessels than did wild-type myocardium after AngII treatment (both p < 0.05). TG microvascular endothelial cells (ECs) treated with AngII recruited 2-fold more leukocytes than did wild-type ECs in an in vitro adhesion assay (p < 0.05). However, inflammatory cell NOX2 per se was not essential for the profibrotic effects of AngII. TG showed a higher level of endothelial-mesenchymal transition (EMT) than did wild-type mice after AngII infusion. In cultured ECs treated with AngII, NOX2 enhanced EMT as assessed by the relative expression of fibroblast versus endothelial-specific markers. CONCLUSIONS: AngII-induced endothelial NOX2 activation has profound profibrotic effects in the heart in vivo that lead to a diastolic dysfunction phenotype. Endothelial NOX2 enhances EMT and has proinflammatory effects. This may be an important mechanism underlying cardiac fibrosis and diastolic dysfunction during increased renin-angiotensin activation.

Enhanced process verification through re-engineering the manufacturing procedure

In today’s modern manufacturing industry there is an increasing need to improve internal processes to meet diverse client needs. Process re-engineering is an important activity that is well understood by industry but its rate of application within small to medium size enterprises (SME) is less developed. Business pressures shift the focus of SMEs toward winning new projects and contracts rather than developing long-term, sustainable manufacturing processes. Variations in manufacturing processes are inevitable, but the amount of non-conformity often exceeds the acceptable levels. This paper is focused on the re-engineering of the manufacturing and verification procedure for discrete parts production with the aim of enhancing process control and product verification. The ideologies of the ‘Push’ and ‘Pull’ approaches to manufacturing are useful in the context of process re-engineering for data improvement. Currently information is pulled from the market and prominent customers, and manufacturing companies always try to make the right product, by following customer procedures that attempt to verify against specifications. This approach can result in significant quality control challenges. The aim of this paper is to highlight the importance of process re-engineering in product verification in SMEs. Leadership, culture, ownership and process management are among the main attributes required for the successful deployment of process re-engineering. This paper presents the findings from a case study showcasing the application of a modified re-engingeering method for the manufacturing and verification process. The findings from the case study indicate there are several advantages to implementing the re-engineering method outlined in this paper.

Implementation of a machine tool performance measurement and diagnostic system and its impact on parts verification

Five axis machine tools are increasing and becoming more popular as customers demand more complex machined parts. In high value manufacturing, the importance of machine tools in producing high accuracy products is essential. High accuracy manufacturing requires producing parts in a repeatable manner and precision in compliance to the defined design specifications. The performance of the machine tools is often affected by geometrical errors due to a variety of causes including incorrect tool offsets, errors in the centres of rotation and thermal growth. As a consequence, it can be difficult to produce highly accurate parts consistently. It is, therefore, essential to ensure that machine tools are verified in terms of their geometric and positioning accuracy. When machine tools are verified in terms of their accuracy, the resulting numerical values of positional accuracy and process capability can be used to define design for verification rules and algorithms so that machined parts can be easily produced without scrap and little or no after process measurement. In this paper the benefits of machine tool verification are listed and a case study is used to demonstrate the implementation of robust machine tool performance measurement and diagnostics using a ballbar system.

Manufacturing process challenges when machining superalloys

The implementation of advanced manufacturing systems with high process capability is an essential requirement for the high value manufacturing industries. To ensure high process capability, industry needs to deal with the requirement for tight tolerances and the unavoidable variations in materials, and manufacturing and inspection processes. In the case of machining superalloys, such variations result in the need to change the machine parameters for producing different batches of materials from different suppliers. This is required in order to get the process under control and reduce waste and defects, leading to better competitiveness. This papers discuss the variability in materials and the corresponding process requirements when machining superalloys, and highlights the impact of metrology in achieving manufacturing process improvement.

The effects of material variations in high value manufacturing industries

It has never been easy for manufacturing companies to understand their confidence level in terms of how accurate and to what degree of flexibility parts can be made. This brings uncertainty in finding the most suitable manufacturing method as well as in controlling their product and process verification systems. The aim of this research is to develop a system for capturing the company’s knowledge and expertise and then reflect it into an MRP (Manufacturing Resource Planning) system. A key activity here is measuring manufacturing and machining capabilities to a reasonable confidence level. For this purpose an in-line control measurement system is introduced to the company. Using SPC (Statistical Process Control) not only helps to predict the trend in manufacturing of parts but also minimises the human error in measurement. Gauge R&R (Repeatability and Reproducibility) study identifies problems in measurement systems. Measurement is like any other process in terms of variability. Reducing this variation via an automated machine probing system helps to avoid defects in future products.Developments in aerospace, nuclear, oil and gas industries demand materials with high performance and high temperature resistance under corrosive and oxidising environments. Superalloys were developed in the latter half of the 20th century as high strength materials for such purposes. For the same characteristics superalloys are considered as difficult-to-cut alloys when it comes to formation and machining. Furthermore due to the sensitivity of superalloy applications, in many cases they should be manufactured with tight tolerances. In addition superalloys, specifically Nickel based, have unique features such as low thermal conductivity due to having a high amount of Nickel in their material composition. This causes a high surface temperature on the work-piece at the machining stage which leads to deformation in the final product.Like every process, the material variations have a significant impact on machining quality. The main cause of variations can originate from chemical composition and mechanical hardness. The non-uniform distribution of metal elements is a major source of variation in metallurgical structures. Different heat treatment standards are designed for processing the material to the desired hardness levels based on application. In order to take corrective actions, a study on the material aspects of superalloys has been conducted. In this study samples from different batches of material have been analysed. This involved material preparation for microscopy analysis, and the effect of chemical compositions on hardness (before and after heat treatment). Some of the results are discussed and presented in this paper.

Neanderthal admixture in current human populations

In the present body of work two primary subjects have been addressed, both individually and in their correspondence, namely (1) the potential for Neanderthals to have contributed to the Modern Human population, and (2) the genetic diversity of one of the most prehistorically impactful human popuations, the Armenians. The first subject is addressed by assessing 1000 mutations in 384 current humans, particularly for those mutations which appear to derive from the Neanderthal lineage. Additionally, the validity of the Neanderthal sequences themselves is evaluated through alignment analysis of fragementary DNA derived from the Vindija Cave sample. Armenian genetic diversity is analyzed through the autosomal short tandem repeats, y-chromsome single nucleotide polymorphisms, and y-chromosome short tandem repeats. The diversity found indicates that Armenians are a diverse group which has been genetically influenced by the various migrations and invasions which have entered their historic lands. Further, we find evidence that Armenians may be closely associated with the peopling of Europe.

A 34-month sediment trap experiment at the Cape Verde Ocean Observatory (CVOO, December 2009 - October 2012)

Anticyclonic mesoscale eddies (ACME) have been proposed as a mechanism by which new nutrients are episodically delivered into the euphotic zone, thereby enhancing new production as well as shifting phytoplankton community structure. In this paper, we report on a 34-month sediment trap experiment at the Cape Verde Ocean Observatory (CVOO; ca. 18°N, 24°E; December 2009-October 2012), occasionally influenced by ACME passages. The typically oligotrophic, weakly seasonal particle flux pattern at the CVOO is strongly modified by the appearance of a highly productive and low oxygen ACME. Out of four recorded diatom flux maxima at CVOO, three were associated with the passage of ACMEs. The recorded diatom maxima events support the view that local ACME dynamics promotes upward nutrient supply into the euphotic zone leading to a rapid response of diatoms. This response is clearly reflected by the flux seasonality: between 40% and 60% of the total annual diatom flux at the CVOO site was intercepted in a relatively short time interval (<60 days). A highly diverse diatom community characterized the diatom fluxes throughout. Along with the ACME passages, small species of the genus Nitzschia, and Thalassionema nitzschioides var. parva dominated and delivered a major portion of the opal and organic carbon into deeper waters at site CVOO. Several pelagic, warm-water background species became dominant during intervals with low nutrient availability in the euphotic zone. Results of our interannual time-series suggest that ACMEs impact on total diatom production and the species-specific composition of the assemblage north of the Cave Verde Islands, and can strengthen the biological pump in open-ocean, oligotrophic subtropical regions of the world ocean. Our observations are useful for testing biogeochemical ocean models and will also help in improving the knowledge of processes and mechanisms behind interannual time-series of bulk components and microorganisms in pelagic and hemipelagic ocean areas.

Petrologia das fraturas associadas a feições típicas de dissolução hipogênica na Formação Salitre, Bacia de Irecê, Bahia, Brasil

The recognition of karst reservoirs in carbonate rocks has become increasingly common. However, most karst features are small to be recognized in seismic sections or larger than expected to be investigated with borehole data. One way forward has been the study of analogue outcrops and caves. The present study investigates lithofacies and karst processes, which lead to the generation of the largest system of caves in South America. The study area is located in the Neoproterozoic Una Group in central-eastern Brazil. This province comprises several systems of carbonate caves (Karmann and Sanchéz, 1979), which include the Toca da Boa Vista and Barriguda caves, considered the largest caves in South America (Auler and Smart, 2003). These caves were formed mainly in dolomites of the Salitre Formation, which was deposited in a shallow marine environment in an epicontinental sea (Medeiros and Pereira, 1994). The Salitre Formation in the cave area comprises laminated mud/wakestones, intraclastic grainstones, oncolitic grainstones, oolitic grainstones, microbial laminites, colunar stromatolites, trombolites and fine siliciclastic rocks (marls, shales, and siltites). A thin layer and chert nodules also occur at the top of the carbonate unit. Phosphate deposits are also found. Our preliminary data indicate that folds and associated joints control the main karstification event at the end of the Brasiliano orogeny (740-540 Ma). We recognized five lithofacies in the cave system: (1) Bottom layers of grainstone with cross bedding comprise the main unit affected by speleogenesis, (2) thin grainstone layers with thin siltite layers, (3) microbial laminites layers, (4) layers of columnar stromatolites, and a (5) top layer of siltite. Levels (1) to (3) are affected by intense fracturing, whereas levels (4) and (5) seal the caves and have little fracturing. Chert, calcite and gipsite veins cut across the carbonate units and play a major role in diagenesis. Our preliminary study indicate that hypogenic spelogenesis is the main process of karst development and contributed significantly to the generation of secondary porosity and permeability in the carbonate units.

2003 Habitat Maps derived from Grey Nurse Shark (GNS) Project of Wolf Rock, Double Island Point, Queensland, Australia

Surveying habitats critical to the survival of grey nurse sharks in South-East Queensland has mapped critical habitats, gathered species inventories and developed protocols for ecological monitoring of critical habitats in southern Queensland. This information has assisted stakeholders with habitat definition and effective management. In 2002 members of UniDive applied successfully for World Wide Fund for Nature, Threatened Species Network funds to map the critical Grey Nurse Shark Habitats in south east Queensland. UniDive members used the funding to survey, from the boats of local dive operators, Wolf Rock at Double Island Point, Gotham, Cherub's Cave, Henderson's Rock and China Wall at North Moreton and Flat Rock at Point Look Out during 2002 and 2003. These sites are situated along the south east Queensland coast and are known to be key Grey Nurse Shark aggregation sites. During the project UniDive members were trained in mapping and survey techniques that include identification of fish, invertebrates and substrate types. Training was conducted by experts from the University of Queensland (Centre of Marine Studies, Biophysical Remote Sensing) and the Queensland Parks and Wildlife Service who are also UniDive members. The monitoring methods (see methods) are based upon results of the UniDive Coastcare project from 2002, the international established Reef Check program and research conducted by Biophysical Remote Sensing and the Centre of Marine Studies. Habitats were mapped using a combination of towed GPS photo transects, aerial photography, bathymetry surveys and expert knowledge. This data provides georeferenced information regarding the major features of each of Sites mapped including Wolf Rock

(Table 1) Age determination on monospecies planktonic foraminifera of sediment core AN25-934

Reconstruction of regional climate and the Okhotsk Sea (OS) environment for the Last Glacial Maximum (LGM), deglaciation and Holocene were performed on the basis of high-resolution records of ice rafted debris (IRD), CaCO3, opal, total organic carbon (TOC), biogenic Ba (Ba_bio) and redox sensitive element (Mn, Mo) content, and diatom and pollen results of four cores that form a north-southern transect. Age models of the studied cores were earlier established by AMS 14C data, oxygen - isotope chronostratigraphy and tephrochronology. According to received results, since 25 ka the regional climate and OS environmental conditions have changed synchronously with LGM condition, cold Heinrich event 1, Bølling -Allerød (BA) warming, Younger Dryas (YD) cooling and Pre-Boreal (PB) warming recorded in the Greenland ice core, North Atlantic sediment, and China cave stalagmites. Calculation of IRD MAR in sediment of north-south transect cores indicate an increase of sea ice formation several times in the glacial OS as compared to the Late Holocene. Accompanying ice formation, increased brine rejection and the larger potential density of surface water at the north shelf due to a drop of glacial East Asia summer monsoon precipitation and Amur River run off, led to strong enhancement of the role of the OS in glacial North Pacific Intermediate Water (NPIW) formation. The remarkable increase in OS productivity during BA and PB warming was probably related with significant reorganisation of the North Pacific deep water ventilation and nutrient input into the NPIW and OS Intermediate Water (OSIW). Seven Holocene OS millennial cold events based on the elevated values of the detrended IRD stack record over the IRD broad trend in the sediments of the studied cores have occurred synchronously with cold events recorded in the North Atlantic, Greenland ice cores and China cave stalagmites after 9 ka. Diatom production in the OS were mostly controlled by sea ice cover changes and surface water stratification induced by sea-ice melting; therefore significant opal accumulation in sediments of this basin begin from 4-6 ka ago simultaneously with a remarkable decrease of sea ice cover.

(Table 1) Age determination of sediment core AAS-62/2

Variations in the Indian summer monsoon (ISM) intensity during the last 16.7?ka have been studied using organic carbon (Corg), d15N of sedimentary organic matter, CaCO3, sediment texture, d18OC, and Mg/Ca-derived sea surface temperature, d18O of sea water and sea surface salinity, in a 14C-dated sediment core from the eastern Arabian Sea. The d18O in water and planktonic foraminifera shells off the central west coast of India may be controlled by the ISM intensity as this area receives high precipitation and land runoff. Also, the Corg and CaCO3 contents of sediments and d15N of sedimentary organic matter may be linked to ISM-induced productivity and denitrification. The results of the present study reveal that between 16 and 15.2 ka BP, the ISM was weak with minor fluctuations and started intensifying around 15.2 ka BP, at the onset of the Bølling-Ållerød (B-A) event. The B-A event is characterized by higher water column denitrification rates comparable to the present day. The ISM signatures observed in the d18OC record of B-A event compare well with those from Timta cave of the western Himalayas and also the Asian summer monsoon signatures from the Hulu caves in China and warming signatures in Greenland Ice Sheet Project 2 (GISP2) suggesting atmospheric teleconnections through Intertropical Convergence Zone. The boundary between the Younger Dryas and the Holocene is discernible with small episodes of abrupt events of increased ISM intensity. This decrease in d18OC values at ~11.8 ka BP is contemporary with June solar insolation maximum at 30° north and the increase in methane in the GISP2 ice core supporting episodes of warmer climate and increase in ISM intensity. The ISM seems to have been most stable between 7 and 5.6 ka BP. The core exhibits periodicity of 500 years that is comparable to the Atlantic water formation and the Chinese monsoon.

Pollen profile and age determination for sediment core M72/5_619-1 (22-GC3)

Sediments from the Black Sea, a region historically dominated by forests and steppe landscapes, are a valuable source of detailed information on the changes in regional terrestrial and aquatic environments at decadal to millennial scales. Here we present multi-proxy environmental records (pollen, dinoflagellate cysts, Ca, Ti and oxygen isotope data) from the uppermost 305 cm of the core 22-GC3 (42°13.53' N, 36°29.55' E) collected from a water depth of 838 m in the southern part of the Black Sea in 2007. The records span the last ~ 18 kyr (all ages are given in cal kyr BP). The pollen data reveal the dominance of the Artemisia-steppe in the region, suggesting rather dry/cold environments ~ 18-14.5 kyr BP. Warming/humidity increase during melt-water pulses (~ 16.1-14.5 kyr BP), indicated by d18O records from the 22-GC3 core sediment and from the Sofular Cave stalagmite, is expressed in more negative d13C values from the Sofular Cave, usually interpreted as the spreading of C3 plants. The records representing the interstadial complex (~ 14.5-12.9 kyr BP) show an increase in temperature and moisture, indicated by forest development, increased primary productivity and reduced surface run-off, whereas the switch from primary terrigenous to primary authigenic Ca origin occurs ~ 500 yr later. The Younger Dryas cooling is clearly demonstrated by more negative d13C values from the Sofular Cave and a reduction of pines. The early Holocene (11.7-8.5 kyr BP) interval reveals relatively dry conditions compared to the mostly moist and warm middle Holocene (8.5-5 kyr BP), which is characterized by the establishment of the species-rich warm mixed and temperate deciduous forests in the low elevation belt, temperate deciduous beech-hornbeam forests in the middle and cool conifer forest in upper mountain belt. The border between the early and middle Holocene in the vegetation records coincides with the opening of the Mediterranean corridor at ~ 8.3 kyr BP, as indicated by a marked change in the dinocyst assemblages and in the sediment lithology. Changes in the pollen assemblages indicate a reduction in forest cover after ~ 5 kyr BP, which was likely caused by increased anthropogenic pressure on the regional vegetation.