Heme oxygenase-1 derived carbon monoxide suppresses Aβ1-42 toxicity in astrocytes

Neurodegeneration in Alzheimer’s disease (AD) is extensively studied, and the involvement of astrocytes and other cell types in this process has been described. However, the responses of astrocytes themselves to amyloid peptides ((A; the widely accepted major toxic factor in AD) is less well understood. Here, we show that A(1-42) is toxic to primary cultures of astrocytes. Toxicity does not involve disruption of astrocyte Ca2+ homeostasis, but instead occurs via formation of the toxic reactive species, peroxynitrite. Thus, A(1-42) raises peroxynitrite levels in astrocytes, and A(1-42) toxicity can be inhibited by antioxidants, or by inhibition of nitric oxide (NO) formation (reactive oxygen species (ROS) and NO combine to form peroxynitrite), or by a scavenger of peroxynitrite. Increased ROS levels observed following A(1-42) application were derived from NADPH oxidase. Induction of heme oxygenase-1 (HO-1) protected astrocytes from A(1-42) toxicity, and this protective effect was mimicked by application of the carbon monoxide (CO) releasing molecule CORM-2, suggesting HO-1 protection was attributable to its formation of CO. CO suppressed the rise of NADPH oxidase-derived ROS caused by A(1-42). Under hypoxic conditions (0.5% O2, 48h) HO-1 was induced in astrocytes and A(1-42) toxicity was significantly reduced, an effect which was reversed by the specific HO-1 inhibitor, QC-15. Our data suggest that A(1-42) is toxic to astrocytes, but that induction of HO-1 affords protection against this toxicity due to formation of CO. HO-1 induction, or CO donors, would appear to present attractive possible approaches to provide protection of both neuronal and non-neuronal cell types from the degenerative effects of AD in the central nervous system

Purification of matrix Gla protein from a marine teleost fish, Argyrosomus regius: Calcified cartilage and not bone as the primary site of MGP accumulation in fish

Matrix Gla protein (MGP) belongs to the family of vitamin K-dependent, Gla-containing proteins, and in mammals, birds, and Xenopus, its mRNA was previously detected in extracts of bone, cartilage, and soft tissues (mainly heart and kidney), whereas the protein was found to accumulate mainly in bone. However, at that time, it was not evaluated if this accumulation originated from protein synthesized in cartilage or in bone cells because both coexist in skeletal structures of higher vertebrates and Xenopus. Later reports showed that MGP also accumulated in costal calcified cartilage as well as at sites of heart valves and arterial calcification. Interestingly, MGP was also found to accumulate in vertebra of shark, a cartilaginous fish. However, to date, no information is available on sites of MGP expression or accumulation in teleost fishes, the ancestors of terrestrial vertebrates, who have in their skeleton mineralized structures with both bone and calcified cartilage. To analyze MGP structure and function in bony fish, MGP was acid-extracted from the mineralized matrix of either bone tissue (vertebra) or calcified cartilage (branchial arches) from the bony fish, Argyrosomus regius,(1) separated from the mineral phase by dialysis, and purified by Sephacryl S-100 chromatography. No MGP was recovered from bone tissue, whereas a protein peak corresponding to the MGP position in this type of gel filtration was obtained from an extract of branchial arches, rich in calcified cartilage. MGP was identified by N-terminal amino acid sequence analysis, and the resulting protein sequence was used to design specific oligonucleotides suitable to amplify the corresponding DNA by a mixture of reverse transcription-polymerase chain reaction (RT-PCR) and 5'rapid amplification of cDNA (RACE)-PCR. In parallel, ArBGP (bone Gla protein, osteocalcin) was also identified in the same fish, and its complementary DNA cloned by an identical procedure. Tissue distribution/accumulation was analyzed by Northern blot, in situ hybridization, and immunohistochemistry. In mineralized tissues, the MGP gene was predominantly expressed in cartilage from branchial arches, with no expression detected in the different types of bone analyzed, whereas BGP mRNA was located in bone tissue as expected. Accordingly, the MGP protein was found to accumulate, by immunohistochemical analysis, mainly in the extracellular matrix of calcified cartilage. In soft tissues, MGP mRNA was mainly expressed in heart but in situ hybridization, indicated that cells expressing the MGP gene were located in the bulbus arteriosus and aortic wall, rich in smooth muscle and endothelial cells, whereas no expression was detected in the striated muscle myocardial fibers of the ventricle. These results show that in marine teleost fish, as in mammals, the MGP gene is expressed in cartilage, heart, and kidney tissues, but in contrast with results obtained in Xenopus and higher vertebrates, the protein does not accumulate in vertebra of non-osteocytic teleost fish, but only in calcified cartilage. In addition, our results also indicate that the presence of MGP mRNA in heart tissue is due, at least in fish, to the expression of the MGP gene in only two specific cell types, smooth muscle and endothelial cells, whereas no expression was found in the striated muscle fibers of the ventricle. In light of these results and recent information on expression of MGP gene in these same cell types in mammalian aorta, it is likely that the levels of MGP mRNA previously detected in Xenopus, birds, and mammalian heart tissue may be restricted toregions rich in smoot Our results also emphasize the need to re-evaluate which cell types are involved in MGP gene expression in other soft tissues and bring further evidence that fish are a valuable model system to study MGP gene expression and regulation.NIAMS NIH HHS [AR25921]info:eu-repo/semantics/publishedVersio

Development of an IS change reason - IS change type combination matrix

Firms change their information systems (IS) for various reasons, ranging from compliance with government regulations to the development of new capabilities. When making these changes a firm can choose between four different IS change types: IS introduction, IS extension, IS replacement, and IS merger. This paper proposes that change reasons and change types are interrelated, and that certain reason-type combinations are more likely than others to result in a successful IS change. To identify these combinations, an IS change reason–IS change type matrix is developed. While the matrix is created from prior IS research, we conducted a focus group study of IS professionals to further explore and refine the matrix. The findings from the focus group study reveal that some IS change reason–IS change type combinations are more appropriate than others to carry out the IS change project successfully. We also present three examples of IS change projects to illustrate the use and value of the matrix in practice

Heme oxygenase-1 derived carbon monoxide suppresses Aβ1-42 toxicity in astrocytes

Neurodegeneration in Alzheimer’s disease (AD) is extensively studied, and the involvement of astrocytes and other cell types in this process has been described. However, the responses of astrocytes themselves to amyloid β peptides ((Aβ; the widely accepted major toxic factor in AD) is less well understood. Here, we show that Aβ(1-42) is toxic to primary cultures of astrocytes. Toxicity does not involve disruption of astrocyte Ca2+ homeostasis, but instead occurs via formation of the toxic reactive species, peroxynitrite. Thus, Aβ(1-42) raises peroxynitrite levels in astrocytes, and Aβ(1-42) toxicity can be inhibited by antioxidants, or by inhibition of nitric oxide (NO) formation (reactive oxygen species (ROS) and NO combine to form peroxynitrite), or by a scavenger of peroxynitrite. Increased ROS levels observed following Aβ(1-42) application were derived from NADPH oxidase. Induction of heme oxygenase-1 (HO-1) protected astrocytes from Aβ(1-42) toxicity, and this protective effect was mimicked by application of the carbon monoxide (CO) releasing molecule CORM-2, suggesting HO-1 protection was attributable to its formation of CO. CO suppressed the rise of NADPH oxidase-derived ROS caused by Aβ(1-42). Under hypoxic conditions (0.5% O2, 48h) HO-1 was induced in astrocytes and Aβ(1-42) toxicity was significantly reduced, an effect which was reversed by the specific HO-1 inhibitor, QC-15. Our data suggest that Aβ(1-42) is toxic to astrocytes, but that induction of HO-1 affords protection against this toxicity due to formation of CO. HO-1 induction, or CO donors, would appear to present attractive possible approaches to provide protection of both neuronal and non-neuronal cell types from the degenerative effects of AD in the central nervous system

Microtubule sliding activity of a kinesin-8 promotes spindle assembly and spindle length control

Molecular motors play critical roles in the formation of mitotic spindles, either through controlling the stability of individual microtubules, or by cross-linking and sliding microtubule arrays. Kinesin-8 motors are best known for their regulatory roles in controlling microtubule dynamics. They contain microtubule-destabilizing activities, and restrict spindle length in a wide variety of cell types and organisms. Here, we report for the first time on an anti-parallel microtubule-sliding activity of the budding yeast kinesin-8, Kip3. The in vivo importance of this sliding activity was established through the identification of complementary Kip3 mutants that separate the sliding activity and microtubule destabilizing activity. In conjunction with kinesin-5/Cin8, the sliding activity of Kip3 promotes bipolar spindle assembly and the maintenance of genome stability. We propose a “slide-disassemble” model where Kip3’s sliding and destabilizing activity balance during pre-anaphase. This facilitates normal spindle assembly. However, Kip3’s destabilizing activity dominates in late anaphase, inhibiting spindle elongation and ultimately promoting spindle disassembly

Aquatic Macroinvertebrate Biodiversity Associated with Artificial Agricultural Drainage Ditches

Agricultural drainage channels and ditches are ubiquitous features in the lowland agricultural landscapes, built primarily to facilitate land drainage, irrigate agricultural crops and alleviate flood risk. Most drainage ditches are considered artificial waterbodies and are not typically included in routine monitoring programmes, and as a result the faunal and floral communities they support are poorly quantified. This paper characterizes the aquatic macroinvertebrate diversity (alpha, beta and gamma) of agricultural drainage ditches managed by an internal drainage board in Lincolnshire, UK. The drainage ditches support very diverse macroinvertebrate communities at both the site (alpha diversity) and landscape scale (gamma diversity) with the main arterial drainage ditches supporting greater numbers of taxa when compared to smaller ditches. Examination of the between site community heterogeneity (beta diversity) indicated that differences among ditches were high spatially and temporally. The results illustrate that both main arterial and side ditches make a unique contribution to aquatic biodiversity of the agricultural landscape. Given the need to maintain drainage ditches to support agriculture and flood defence measures, we advocate the application of principles from ‘reconciliation ecology’ to inform the future management and conservation of drainage ditches

Exchange rate volatility and capital inflows: role of financial development

There is vast literature examining the impact of exchange rate volatility on various macroeconomic aggregates such as economic growth, trade flows, domestic investment, and more recently capital flows. However, these studies have ignored the role of financial development while examining the impact of exchange rate volatility on capital flows. This study aims to analyze the impact of exchange rate volatility on capital inflows towards developing countries by incorporating the role of financial development over the time period 1980–2013. In this regard, the behavior of two types of capital flows is examined: physical capital inflows measured as foreign direct investment, and financial inflows quantified through remittance inflows. The empirical investigation comprises the direct as well as indirect effect of exchange rate volatility on capital inflows. The study employs dynamic system GMM estimation technique to empirically estimate the effect of exchange rate volatility on capital inflows. The empirical results of the study identify that exchange rate volatility dampens both physical and financial inflows towards developing countries. The indirect impact of exchange rate volatility through financial development, however, turns out positive and statistically significant. This finding reflects that financial development helps in reduc- ing the harmful impact of exchange rate volatility on capital inflows. Hence, the study concludes that a developed financial system is an important channel through which developing countries may improve capital inflows in the long run.info:eu-repo/semantics/publishedVersio

Air pollution mixture complexity and its effect on PM2.5-related mortality: A multicountry time-series study in 264 cities

Background: Fine particulate matter (PM2.5) occurs within a mixture of other pollutant gases that interact and impact its composition and toxicity. To characterize the local toxicity of PM2.5, it is useful to have an index that accounts for the whole pollutant mix, including gaseous pollutants. We consider a recently proposed pollutant mixture complexity index (PMCI) to evaluate to which extent it relates to PM2.5 toxicity. Methods: The PMCI is constructed as an index spanning seven different pollutants, relative to the PM2.5 levels. We consider a standard two-stage analysis using data from 264 cities in the Northern Hemisphere. The first stage estimates the city-specific relative risks between daily PM2.5 and all-cause mortality, which are then pooled into a second-stage meta-regression model with which we estimate the effect modification from the PMCI. Results: We estimate a relative excess risk of 1.0042 (95% confidence interval: 1.0023, 1.0061) for an interquartile range increase (from 1.09 to 1.95) of the PMCI. The PMCI predicts a substantial part of within-country relative risk heterogeneity with much less between-country heterogeneity explained. The Akaike information criterion and Bayesian information criterion of the main model are lower than those of alternative meta-regression models considering the oxidative capacity of PM2.5 or its composition. Conclusions: The PMCI represents an efficient and simple predictor of local PM2.5-related mortality, providing evidence that PM2.5 toxicity depends on the surrounding gaseous pollutant mix. With the advent of remote sensing for pollutants, the PMCI can provide a useful index to track air quality

Developmentally regulated GTP binding protein 1 (DRG1) controls microtubule dynamics

The mitotic spindle, essential for segregating the sister chromatids into the two evolving daughter cells, is composed of highly dynamic cytoskeletal filaments, the microtubules. The dynamics of microtubules are regulated by numerous microtubule associated proteins. We identify here Developmentally regulated GTP binding protein 1 (DRG1) as a microtubule binding protein with diverse microtubule-associated functions. In vitro, DRG1 can diffuse on microtubules, promote their polymerization, drive microtubule formation into bundles, and stabilize microtubules. HeLa cells with reduced DRG1 levels show delayed progression from prophase to anaphase because spindle formation is slowed down. To perform its microtubule-associated functions, DRG1, although being a GTPase, does not require GTP hydrolysis. However, all domains are required as truncated versions show none of the mentioned activities besides microtubule binding