EPA,not DHA,prevents fibrosis in pressure overload-induced heart failure: potential role of free fatty acid receptor 4

Heart failure with preserved ejection fraction (HFpEF) is half of all HF, but standard HF therapies are ineffective. Diastolic dysfunction, often secondary to interstitial fibrosis, is common in HFpEF. Previously, we found that supra-physiologic levels of ω3-PUFAs produced by 12 weeks of ω3-dietary supplementation prevented fibrosis and contractile dysfunction following pressure overload [transverse aortic constriction (TAC)], a model that resembles aspects of remodeling in HFpEF. This raised several questions regarding ω3-concentration-dependent cardioprotection, the specific role of EPA and DHA, and the relationship between prevention of fibrosis and contractile dysfunction. To achieve more clinically relevant ω3-levels and test individual ω3-PUFAs, we shortened the ω3-diet regimen and used EPA- and DHA-specific diets to examine remodeling following TAC. The shorter diet regimen produced ω3-PUFA levels closer to Western clinics. Further, EPA, but not DHA, prevented fibrosis following TAC. However, neither ω3-PUFA prevented contractile dysfunction, perhaps due to reduced uptake of ω3-PUFA. Interestingly, EPA did not accumulate in cardiac fibroblasts. However, FFA receptor 4, a G protein-coupled receptor for ω3-PUFAs, was sufficient and required to block transforming growth factor β1-fibrotic signaling in cultured cardiac fibroblasts, suggesting a novel mechanism for EPA. In summary, EPA-mediated prevention of fibrosis could represent a novel therapy for HFpEF.     

Studies on ulcerative dermal necrosis of salmonids

Fourteen fresh run salmon Satmo salar L. with early extant lesions of ulcerative dermal necrosis (UDN) were kept in separate tanks and treated with zinc free malachite green. Ten of the fish were held at 10° C and 4 at 2° C. The treatment precluded infection with Saprolegnia fungus and allowed natural resolution of the lesions. There was a marked difference in rate of healing between warm and cold water conditions.
Histological examination of healing lesions at different stages showed that there was a primary invasion of cuboidal epithelium over the collagen scar followed by a phase of disorganized proliferation which eventually organized itself into normal epithelium. Melanocytes were very obvious in the dermis of healing lesions.     

The self determinants recognized by human virus-immune T cells can be distinguished from the serologically defined HLA antigens

The self specificity of human influenza virus-immune cytotoxic T cells has been analyzed in order to clarify the relationship between the self antigens that they recognize and the serologically defined HLA-A and -B antigens. Virus-immune effectors from HLA-A2-positive donors were tested on panels of virus-infected target cells from donors who were either HLA-mismatched or matched only for HLA-A2. Virus-immune T cells from 11 out of 11 A2-positive donors lysed all A2-matched virus-infected target cells (and no HLA-mismatched targets), except that each of these effector cells consistently failed to lyse virus-infected target cells from one A2-positive donor (designated M7). Although the A2 specificity of donor M7 could also be distinguished from the A2 antigen of other donors by alloimmune cytotoxic T cells, no differences in the A2 antigen of donor M7 could be defined by extensive serologic analyses. These results indicate that there is a strong but incomplete association between a self antigen recognized by virus-immune T cells and the serologically defined HLA-A2 specificity.     

Nitrogen isotopic fractionation and 18O exchange in relation to the mechanism of denitrification of nitrite by Pseudomonas stutzeri

Two types of mechanisms for the enzymatic reduction of NO2- to N2O have been proposed. In one, two NO2- ions are reduced in parallel, with the nitrogen-nitrogen bond formed from reduced intermediates. In the second, the two NO2- ions enter the reaction sequentially, with the nitrogen of at least one of the two having a valence of 3+ when the nitrogen-nitrogen bond is formed. Our objective was to distinguish between these two types of mechanism. Toward that end, the exchange of 18O from H2O to NO2- and the overall nitrogen isotopic fractionation factor (beta obs) were measured. The rate of exchange of oxygen from H2O to NO2-, resulting from a protonation-dehydration step preceding reductive events in both mechanisms, was less than 10% of the rate of denitrification at both low and high [NO2-]. The value of beta obs was 1.010 +/- 0.001 and 1.020 +/- 0.001 at low and high [NO2-], respectively. Expressions for beta obs, as a function of the measured rate of entry of oxygen from H2O into NO2-, were derived for both types of mechanism. The measured dependence of beta obs on substrate concentration, as constrained by the 18O exchange data, is inconsistent with the first type of mechanism, but consistent with the second type. Thus, by combining nitrogen isotopic fractionation and 18O exchange data, we rule out any mechanism in Pseudomonas stutzeri in which NO2- ions are reduced in parallel, with the nitrogen-nitrogen bond being formed from reduced intermediates.