NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis

Cardiac failure occurs when the heart fails to adapt to chronic stresses. Reactive oxygen species (ROS)-dependent signaling is implicated in cardiac stress responses but the role of different ROS sources remains unclear. Here, we report that NADPH oxidase-4 (Nox4) facilitates cardiac adaptation to chronic stress. Unlike other Nox proteins, Nox4 activity is regulated mainly by its expression level which increased in cardiomyocytes during stresses such as pressure overload or hypoxia. To investigate the functional role of Nox4 during the cardiac response to stress, we generated mice with a genetic deletion of Nox4 or a cardiomyocyte-targeted overexpression of Nox4. Basal cardiac function was normal in both models but Nox4-null animals developed exaggerated contractile dysfunction, hypertrophy and cardiac dilatation during exposure to chronic overload whereas Nox4-transgenic mice were protected. Investigation of mechanisms underlying this protective effect revealed a significant Nox4-dependent preservation of myocardial capillary density after pressure overload. Nox4 enhanced stress-induced activation of cardiomyocyte Hif1 and the release of VEGF, resulting in an increased paracrine angiogenic activity. These data indicate that cardiomyocyte Nox4 is a novel inducible regulator of myocardial angiogenesis, a key determinant of cardiac adaptation to overload stress. Our results also have wider relevance to the use of non-specific antioxidant approaches in cardiac disease and may provide an explanation for the failure of such strategies in many settings.

Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology.

Aims/hypothesis
Methylglyoxal (MG) is an important precursor for AGEs. Normally, MG is detoxified by the glyoxalase (GLO) enzyme system (including component enzymes GLO1 and GLO2). Enhanced glycolytic metabolism in many cells during diabetes may overpower detoxification capacity and lead to AGE-related pathology. Using a transgenic rat model that overexpresses GLO1, we investigated if this enzyme can inhibit retinal AGE formation and prevent key lesions of diabetic retinopathy.
Methods
Transgenic rats were developed by overexpression of full length GLO1. Diabetes was induced in wild-type (WT) and GLO1 rats and the animals were killed after 12 or 24 weeks of hyperglycaemia. N e-(Carboxyethyl)lysine (CEL), N e-(carboxymethyl)lysine (CML) and MG-derived-hydroimidazalone-1 (MG-H1) were determined by immunohistochemistry and by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MSMS). Müller glia dysfunction was determined by glial fibrillary acidic protein (GFAP) immunoreactivity and by spatial localisation of the potassium channel Kir4.1. Acellular capillaries were quantified in retinal flat mounts.
Results
GLO1 overexpression prevented CEL and MG-H1 accumulation in the diabetic retina when compared with WT diabetic counterparts (p?<?0.01). Diabetes-related increases in Müller glial GFAP levels and loss of Kir4.1 at the vascular end-feet were significantly prevented by GLO1 overexpression (p?<?0.05) at both 12- and 24-week time points. GLO1 diabetic animals showed fewer acellular capillaries than WT diabetic animals (p?<?0.001) at 24 weeks’ diabetes.
Conclusions/interpretation
Detoxification of MG reduces AGE adduct accumulation, which, in turn, can prevent formation of key retinal neuroglial and vascular lesions as diabetes progresses. MG-derived AGEs play an important role in diabetic retinopathy.

Protection of cattle against a natural infection of Fasciola hepatica by vaccination with recombinant cathepsin L1 (rFhCL1)

The liver fluke, Fasciola hepatica causes liver fluke disease, or fasciolosis, in ruminants such as cattle and sheep. An effective vaccine against the helminth parasite is essential to reduce our reliance on anthelmintics, particularly in light of frequent reports of resistance to some frontline drugs. In our study, Friesian cattle (13 per group) were vaccinated with recombinant F. hepatica cathepsin L1 protease (rFhCL1) formulated in mineral-oil based adjuvants, Montanide (TM) ISA 70VG and ISA 206VG. Following vaccination the animals were exposed to fluke-contaminated pastures for 13 weeks. At slaughter, there was a significant reduction in fluke burden of 48.2% in the cattle in both vaccinated groups, relative to the control non-vaccinated group, at p

Enhancing MPLS QoS routing algorithms by using the network protection degree paradigm

IP based networks still do not have the required degree of reliability required by new multimedia services, achieving such reliability will be crucial in the success or failure of the new Internet generation. Most of existing schemes for QoS routing do not take into consideration parameters concerning the quality of the protection, such as packet loss or restoration time. In this paper, we define a new paradigm to develop new protection strategies for building reliable MPLS networks, based on what we have called the network protection degree (NPD). This NPD consists of an a priori evaluation, the failure sensibility degree (FSD), which provides the failure probability and an a posteriori evaluation, the failure impact degree (FID), to determine the impact on the network in case of failure. Having mathematical formulated these components, we point out the most relevant components. Experimental results demonstrate the benefits of the utilization of the NPD, when used to enhance some current QoS routing algorithms to offer a certain degree of protection

Optimal protection of stabilised dry live bacteria from bile toxicity in oral dosage forms by bile acid adsorbent resins

We previously found that dried live bacteria of a vaccine strain can be temporarily sensitive to bile acids and suggested that Bile Adsorbing Resins (BAR) can be used in oral vaccine tablets to protect dried bacteria from intestinal bile. Here, we report a quantitative analysis of the ability of BAR to exclude the dye bromophenol blue from penetrating into matrix tablets and also sections of hard capsule shells. Based on this quantitative analysis, we made a fully optimised formulation, comprising 25% w/w of cholestyramine in Vcaps™ HPMC capsules. This gave effectively 100% protection of viability from 4% bile, with 4200-fold more live bacteria recovered from this formulation compared to unprotected dry bacteria. From the image analysis, we found that the filler material or compaction force used had no measurable effect on dye exclusion but did affect the rate of tablet hydration. Increasing the mass fraction of BAR gave more exclusion of dye up to 25% w/w, after which a plateau was reached and no further dye exclusion was seen. More effective dye exclusion was seen with smaller particle sizes (i.e. cholestyramine) and when the BAR was thoroughly dried and disaggregated. Similar results were found when imaging dye penetration into capsule sections or tablets. The predictions of the dye penetration study were tested using capsules filled with dried attenuated Salmonella vaccine plus different BAR types, and the expected protection from bile was found, validating the imaging study. Surprisingly, depending on the capsule shell material, some protection was given by the capsule alone without adding BAR, with Vcaps™ HPMC capsules providing up to 174-fold protection against 1% bile; faster releasing Vcaps Plus™ HPMC capsules and Coni Snap™ gelatin capsules gave less protection.

Motion of the dayside polar cap boundary during substorm cycles: II. Generation of poleward-moving events and polar cap patches by pulses in the magnetopause reconnection rate

Using data from the EISCAT (European Incoherent Scatter) VHF and CUTLASS (Co-operative UK Twin- Located Auroral Sounding System) HF radars, we study the formation of ionospheric polar cap patches and their relationship to the magnetopause reconnection pulses identified in the companion paper by Lockwood et al. (2005). It is shown that the poleward-moving, high-concentration plasma patches observed in the ionosphere by EISCAT on 23 November 1999, as reported by Davies et al. (2002), were often associated with corresponding reconnection rate pulses. However, not all such pulses generated a patch and only within a limited MLT range (11:00–12:00 MLT) did a patch result from a reconnection pulse. Three proposed mechanisms for the production of patches, and of the concentration minima that separate them, are analysed and evaluated: (1) concentration enhancement within the patches by cusp/cleft precipitation; (2) plasma depletion in the minima between the patches by fast plasma flows; and (3) intermittent injection of photoionisation-enhanced plasma into the polar cap. We devise a test to distinguish between the effects of these mechanisms. Some of the events repeat too frequently to apply the test. Others have sufficiently long repeat periods and mechanism (3) is shown to be the only explanation of three of the longer-lived patches seen on this day. However, effect (2) also appears to contribute to some events. We conclude that plasma concentration gradients on the edges of the larger patches arise mainly from local time variations in the subauroral plasma, via the mechanism proposed by Lockwood et al. (2000).

Faith and protection: the construction of hope by parents of children with leukemia and their oncologists

Background. Oncologists are criticized for fostering unrealistic hope in patients and families, but criticisms reflect a perspective that is oversimplified and “expert” guidance that is ambiguous or impractical. Our aim was to understand how pediatric oncologists manage parents' hope in practice and to evaluate how they address parents' needs. Methods. Participants were 53 parents and 12 oncologists whom they consulted across six U.K. centers. We audio recorded consultations approximately 1–2, 6, and 12 months after diagnosis. Parents were interviewed after each consultation to elicit their perspectives on the consultation and clinical relationship. Transcripts of consultations and interviews were analyzed qualitatively. Results. Parents needed hope in order to function effectively in the face of despair, and all wanted the oncologists to help them be hopeful. Most parents focused hope on the short term. They therefore needed oncologists to be authoritative in taking responsibility for the child's long-term survival while cushioning parents from information about longer-term uncertainties and being positive in providing information about short-term progress. A few parents who could not fully trust their oncologist were unable to hope. Conclusion. Oncologists' pivotal role in sustaining hope was one that parents gave them. Most parents' “faith” in the oncologist allowed them to set aside, rather than deny, their fears about survival while investing their hopes in short-term milestones. Oncologists' behavior generally matched parents' needs, contradicting common criticisms of oncologists. Nevertheless, oncologists need to identify and address the difficulty that some parents have in fully trusting the oncologist and, consequently, being hopeful.

Biogeochemical cycles and biodiversity as key drivers of ecosystem services provided by soils

Soils play a pivotal role in major global biogeochemical cycles (carbon, nutrient and water), while hosting the largest diversity of organisms on land. Because of this, soils deliver fundamental ecosystem services, and management to change a soil process in support of one ecosystem service can either provide co-benefits to other services or can result in trade-offs. In this critical review, we report the state-of-the-art understanding concerning the biogeochemical cycles and biodiversity in soil, and relate these to the provisioning, regulating, supporting and cultural ecosystem services which they underpin. We then outline key knowledge gaps and research challenges, before providing recommendations for management activities to support the continued delivery of ecosystem services from soils. We conclude that although there are knowledge gaps that require further research, enough is known to start improving soils globally. The main challenge is in finding ways to share knowledge with soil managers and policy-makers, so that best-practice management can be implemented. A key element of this knowledge sharing must be in raising awareness of the multiple ecosystem services underpinned by soils, and the natural capital they provide. The International Year of Soils in 2015 presents the perfect opportunity to begin a step-change in how we harness scientific knowledge to bring about more sustainable use of soils for a secure global society.

Biogeochemical cycles and biodiversity as key drivers of ecosystem services provided by soils

Soils play a pivotal role in major global biogeochemical cycles (carbon, nutrient, and water), while hosting the largest diversity of organisms on land. Because of this, soils deliver fundamental ecosystem services, and management to change a soil process in support of one ecosystem service can either provide co-benefits to other services or result in trade-offs. In this critical review, we report the state-of-the-art understanding concerning the biogeochemical cycles and biodiversity in soil, and relate these to the provisioning, regulating, supporting, and cultural ecosystem services which they underpin. We then outline key knowledge gaps and research challenges, before providing recommendations for management activities to support the continued delivery of ecosystem services from soils. We conclude that, although soils are complex, there are still knowledge gaps, and fundamental research is still needed to better understand the relationships between different facets of soils and the array of ecosystem services they underpin, enough is known to implement best practices now. There is a tendency among soil scientists to dwell on the complexity and knowledge gaps rather than to focus on what we do know and how this knowledge can be put to use to improve the delivery of ecosystem services. A significant challenge is to find effective ways to share knowledge with soil managers and policy makers so that best management can be implemented. A key element of this knowledge exchange must be to raise awareness of the ecosystems services underpinned by soils and thus the natural capital they provide. We know enough to start moving in the right direction while we conduct research to fill in our knowledge gaps. The lasting legacy of the International Year of Soils in 2015 should be for soil scientists to work together with policy makers and land managers to put soils at the centre of environmental policy making and land management decisions.

Strong quenching of chlorophyll fluorescence in the desiccated state in three poikilohydric and homoiochlorophyllous moss species indicates photo-oxidative protection on highly light-exposed rocks of a tropical inselberg

The three poikilophydric and homoiochlorophyllous moss species Campylopus savannarum (C. Muell.) Mitt., Racocarpus fontinaloides (C. Muell.) Par. and Ptychomitrium vaginatum Besch. grow on sun-exposed rocks of a tropical inselberg in Brazil subject to regular drying and wetting cycles. Effective photo-oxidative protection in the light-adapted desiccated state in all three species is achieved by a reduction of ground chlorophyll fluorescence, F, to almost zero. Upon rewatering, the kinetics of the recovery of F in air dry cushions to higher values is very fast in the first 5min, but more than 80min are needed until an equilibrium is reached gradually. The kinetics were not different between the three species. The three moss species, have a distinct niche occupation and form a characteristic zonation around soil vegetation islands on the rock outcrops, where C. savannarum and R. fontinaloides form an inner and outer belt, respectively, around vegetation islands and P vaginatum occurs as small isolated cushions on bare rock. However, they were not distinguished by the reduction of F in the dry state and the rewetting recovery kinetics and only slightly different in their photosynthetic capacity. Stable isotope ratios (delta C-13, delta N-15) indicate that liquid films of water limiting diffusion of CO2 are important in determining carbon acquisition and suggest that limitation of CO2 fixation by water films must be more pronounced over time in P vaginatum than in the latter species. This is determined by both the micro site occupied and the form of the moss cushions. (c) 2007 Elsevier GmbH. All rights reserved.

Poly(lactic acid-glycolic acid) nanoparticles markedly improve immunological protection provided by peptide P10 against murine paracoccidioidomycosis

Background and purpose: The present study reports on the preparation and testing of a sustained delivery system for the immunomodulatory peptide P10 aimed at reducing the in vivo degradation of the peptide and the amount required to elicit a protective immune response against paracoccidioidomycosis. Experimental approach: BALB/c mice were infected with the yeast Paracoccidioides brasiliensis to mimic the chronic form of paracoccidioidomycosis. The animals were treated daily with sulfamethoxazole/trimethoprim alone or combined with peptide P10, either emulsified in Freund`s adjuvant or entrapped in poly(lactic acid-glycolic acid) (PLGA) nanoparticles at different concentrations (1 mu g, 5 mu g, 10 mu g, 20 mu g or 40 mu g center dot 50 mu L-1). Therapeutic efficacy was assessed as fungal burden in tissues and the immune response by quantitative determination of cytokines. Key results: Animals given combined chemotherapy and P10 nanotherapy presented a marked reduction of fungal load in the lungs, compared with the non-treated animals. After 30 days of treatment, P10 entrapped within PLGA (1 mu g center dot 50 mu L-1) was more effective than `free` P10 emulsified in Freund`s adjuvant (20 mu g center dot 50 mu L-1), as an adjuvant to chemotherapy. After treatment for 90 days, the higher doses of P10 entrapped within PLGA (5 or 10 mu g center dot 50 mu L-1) were most effective. Treatment with P10 emulsified in Freund`s adjuvant (20 mu g center dot 50 mu L-1) or P10 entrapped within PLGA (1 mu g center dot 50 mu L-1) were accompanied by high levels of interferon-gamma in lung. Conclusions and implications: Combination of sulfamethoxazole/trimethoprim with the P10 peptide entrapped within PLGA demonstrated increased therapeutic efficacy against paracoccidioidomycosis. P10 incorporation into PLGA nanoparticles dramatically reduced the peptide amount necessary to elicit a protective effect.

Determination of Thermal and Blue Light Photochemical Hazard Protection needed by Automatic Welding filters

Recent developments in biological research, has shown that the initial maximum permissible exposure (MPE) limits for protection of workers from risks associated with artificial optical radiations were more stringent than needed. Using the most recent MPE limits for artificial optical radiation this piece of work was focused on the investigation of the level of visible light attenuation needed by automatic welding filters in case of switching failure. Results from the comparison of different exposure standards were employed in investigating the need of Vis/IR and blue light transmittance requirement for automatic welding filters. Real and arbitrary spectra were taken into consideration for the worst and best case scenarios of artificial optical radiations. An excel worksheet developed during the execution of this project took into consideration the exposure from different light sources and the precision of the spectrometer used in measuring the transmittances of a welding filter. The worksheet was developed and tested with known product properties to investigate the validity of its formulation. The conclusion drawn from this project was that attenuation in the light state will be needed for products with the darkest state shade 11 or higher. Also shown is that current welding filter protects the eye well enough even in the case of switching failure.