Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis

Introduction

The purpose of this study was to evaluate the effects of L-4F, an apolipoprotein A-1 mimetic peptide, alone or with pravastatin, in apoE^-/-Fas^-/-C57BL/6 mice that spontaneously develop immunoglobulin G (IgG) autoantibodies, glomerulonephritis, osteopenia, and atherosclerotic lesions on a normal chow diet.

Methods

Female mice, starting at eight to nine weeks of age, were treated for 27 weeks with 1) pravastatin, 2) L-4F, 3) L-4F plus pravastatin, or 4) vehicle control, followed by disease phenotype assessment.

Results

In preliminary studies, dysfunctional, proinflammatory high-density lipoproteins (piHDL) were decreased six hours after a single L-4F, but not scrambled L-4F, injection in eight- to nine-week old mice. After 35 weeks, L-4F-treated mice, in the absence/presence of pravastatin, had significantly smaller lymph nodes and glomerular tufts (P_{L, LP} < 0.05), lower serum levels of IgG antibodies to double stranded DNA (dsDNA) (P_L < 0.05) and oxidized phospholipids (oxPLs) (P_{L, LP} < 0.005), and elevated total and vertebral bone mineral density (P_{L, LP} < 0.01) compared to vehicle controls. Although all treatment groups presented larger aortic root lesions compared to vehicle controls, enlarged atheromas in combination treatment mice had significantly less infiltrated CD68⁺ macrophages (P_LP < 0.01), significantly increased mean α-actin stained area (P_LP < 0.05), and significantly lower levels of circulating markers for atherosclerosis progression, CCL19 (P_{L, LP} < 0.0005) and VCAM-1 (P_L < 0.0002).

Conclusions

L-4F treatment, alone or with pravastatin, significantly reduced IgG anti-dsDNA and IgG anti-oxPLs, proteinuria, glomerulonephritis, and osteopenia in a murine lupus model of accelerated atherosclerosis. Despite enlarged aortic lesions, increased smooth muscle content, decreased macrophage infiltration, and decreased pro-atherogenic chemokines in L-4F plus pravastatin treated mice suggest protective mechanisms not only on lupus-like disease, but also on potential plaque remodeling in a murine model of systemic lupus erythematosus (SLE) and accelerated atherosclerosis.     

Molecular architecture of the ribosome‐bound Hepatitis C Virus internal ribosomal entry site RNA

Internal ribosomal entry sites (IRESs) are structured cis‐acting RNAs that drive an alternative, cap‐independent translation initiation pathway. They are used by many viruses to hijack the translational machinery of the host cell. IRESs facilitate translation initiation by recruiting and actively manipulating the eukaryotic ribosome using only a subset of canonical initiation factor and IRES transacting factors. Here we present cryo‐EM reconstructions of the ribosome 80S‐ and 40S‐bound Hepatitis C Virus (HCV) IRES. The presence of four subpopulations for the 80S•HCV IRES complex reveals dynamic conformational modes of the complex. At a global resolution of 3.9 Å for the most stable complex, a derived atomic model reveals a complex fold of the IRES RNA and molecular details of its interaction with the ribosome. The comparison of obtained structures explains how a modular architecture facilitates mRNA loading and tRNA binding to the P‐site. This information provides the structural foundation for understanding the mechanism of HCV IRES RNA‐driven translation initiation.     

Density estimates of two endangered nocturnal lemur species from northern Madagascar: new results and a comparison of commonly used methods

Very little information is known of the recently described Microcebus tavaratra and Lepilemur milanoii in the Daraina region, a restricted area in far northern Madagascar. Since their forest habitat is highly fragmented and expected to undergo significant changes in the future, rapid surveys are essential to determine conservation priorities. Using both distance sampling and capture-recapture methods, we estimated population densities in two forest fragments. Our results are the first known density and population size estimates for both nocturnal species. In parallel, we compare density results from four different approaches, which are widely used to estimate lemur densities and population sizes throughout Madagascar. Four approaches (King, Kelker, Muller and Buckland) are based on transect surveys and distance sampling, and they differ from each other by the way the effective strip width is estimated. The fifth method relies on a capture-mark-recapture (CMR) approach. Overall, we found that the King method produced density estimates that were significantly higher than other methods, suggesting that it generates overestimates and hence overly optimistic estimates of population sizes in endangered species. The other three distance sampling methods provided similar estimates. These estimates were similar to those obtained with the CMR approach when enough recapture data were available. Given that Microcebus species are often trapped for genetic or behavioral studies, our results suggest that existing data can be used to provide estimates of population density for that species across Madagascar.     

The contrasting genetic patterns of two sympatric flying fox species from the Comoros and the implications for conservation

Pteropus livingstonii and Pteropus seychellensis comorensis are endemic fruit bat species that are among the most threatened animals in the Comoros archipelago. Both species are pollinators and seed dispersers of native and cultivated plants and are thus of crucial importance for the regeneration of natural forests as well as for cultivated plantations. However, these species are subject to strong anthropogenic pressures and face one of the highest rates of natural habitat loss reported worldwide. Yet little is known about the population genetic structure of these two species, making it difficult to define relevant conservation strategies. In this study, we investigated for the two flying fox species (1) the level of genetic diversity within islands, as well as across the archipelago and (2) the genetic structure between the two islands (Anjouan and Mohéli) for P. livingstonii and between the four islands of the archipelago (Anjouan, Mohéli, Grande Comore and Mayotte) for P. s. comorensis using mitochondrial and microsatellite markers. The results revealed contrasting patterns of genetic structure, with P. s. comorensis showing low genetic structure between islands, whereas P. livingstonii exhibited high levels of inter-island genetic differentiation. Overall, the genetic analyses showed low genetic diversity for both species. These contrasting genetic patterns may be the result of different dispersal patterns and the populations’ evolutionary histories. Our findings lead us to suggest that in terms of conservation strategy, the two populations of P. livingstonii (on Anjouan and Mohéli islands) should be considered as two separate management units. We recommend focusing conservation efforts on the Anjouan population, which is the largest, exhibits the highest genetic diversity, and suffers the greatest anthropogenic pressure. As for P. s. comorensis, its four populations could be considered as a single unit for conservation management purposes. For this species, we recommend protecting roosting trees to reduce population disturbance.     

Hormone-regulated expression and distribution of versican in mouse uterine tissues

Background  

Remodeling of the extracellular matrix is one of the most striking features observed in the uterus during the estrous cycle and after hormone replacement. Versican (VER) is a hyaluronan-binding proteoglycan that undergoes RNA alternative splicing, generating four distinct isoforms. This study analyzed the synthesis and distribution of VER in mouse uterine tissues during the estrous cycle, in ovariectomized (OVX) animals and after 17beta-estradiol (E2) and medroxyprogesterone (MPA) treatments, either alone or in combination.     

A habitat suitability analysis at multi-spatial scale of two sympatric flying fox species reveals the urgent need for conservation action

In this study we used a multi-spatial scale approach to investigate habitat suitability, roosting characteristics, and ecological niche in two flying fox species on the Comoros Islands—Pteropus livingstonii and Pteropus seychellensis comorensis. At a broad scale, we assessed the ecological niche and habitat suitability for both species using the Species Distribution Modeling method based on the recent ensembles of small models (ESM) approach. At a fine scale, Ecological Niche Factor Analysis (ENFA) was applied to assess habitat selection by each species. Direct observation was used at each roost to estimate the total number of individuals and to identify the roost characteristics. At both broad and fine scales, the analyses highlighted clear niche partitioning by the two species. We found that P. livingstonii has a very limited distribution, restricted to steep, high-elevation slopes of the islands’ remaining natural forests, and the patterns were the same for roosting, foraging sites and the entire habitat. By contrast, P. s. comorensis has a relatively large geographic range that extends over low-elevation farmlands and villages and it was negatively correlated to natural forest across the entire area and all roosting sites, but its foraging areas were positively correlated to natural forest and high elevation areas. Both species selected large, tall trees for roosting. The total number of individuals in the studied area was estimated to be 1243 P. livingstonii and 11,898 P. s. comorensis. The results of our study demonstrated that these two species use different habitat types and ensure different ecosystem services in pollination and seed dispersion and thus are both critical for maintaining overall ecosystem dynamics. However, the currently high level of hunting pressure and roost disturbance makes them vulnerable to extinction. To ensure the viability of both species, conservation measures need to be taken by the Comoros government.     

<Emphasis Type="Italic">Chlamydomonas reinhardtii</Emphasis> chloroplasts express an orally immunogenic protein targeting the p210 epitope implicated in atherosclerosis immunotherapies

Key message

An algae-based vaccine model against atherosclerosis was developed with positive findings in terms of antigen yield and immunogenicity in mouse.

Abstract

Several immunotherapies against atherosclerosis have been evaluated at the preclinical level thus far, with some of them currently under evaluation in clinical trials. In particular, the p210 epitope from ApoB100 is known to elicit atheroprotective responses. Considering that Chlamydomonas reinhardtii is an attractive host for the production and delivery of subunit vaccines, in this study a chimeric protein consisting of the B subunit of the cholera toxin and the p210 epitope from ApoB100 (CTB:p210) has been expressed in C. reinhardtii chloroplast as an attempt to establish an oral vaccine candidate against atherosclerosis. The Chlamydomonas-made CTB:p210 protein was successfully expressed at levels of up to 60 µg per g of fresh weight biomass. The antigenic activity of the CTB and the p210 moiety was preserved in the CTB:p210 chimera. Moreover the algae-made CTB:p210 showed an immunogenic activity, when orally administered to BALB/c mice, as evidenced the presence of anti-p210 serum antibodies in mice treated with the algae-derived CTB:p210. The antibody response lasts for at least 80 days after the last boost. This experimental model is proposed as a convenient tool in the development of low cost atherosclerosis vaccines of easy compliance and friendly delivery. Further studies will determine the therapeutic potential of this algae-made vaccine in atherosclerosis animal models.