Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction

Macrophagic myofasciitis (MMF) is an emerging condition, characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients mainly complain of arthromyalgias, chronic fatigue, and cognitive difficulties. We designed a comprehensive battery of neuropsychological tests to prospectively delineate MMF-associated cognitive dysfunction (MACD). Compared to control patients with arthritis and chronic pain, MMF patients had pronounced and specific cognitive impairment. MACD mainly affected (i) both visual and verbal memory; (ii) executive functions, including attention, working memory, and planning; and (iii) left ear extinction at dichotic listening test. Cognitive deficits did not correlate with pain, fatigue, depression, or disease duration. Pathophysiological mechanisms underlying MACD remain to be determined. In conclusion, long-term persistence of vaccine-derived aluminum hydroxide within the body assessed by MMF is associated with cognitive dysfunction, not solely due to chronic pain, fatigue and depression.     

Trophic niche overlap between sympatric harbour seals (Phoca vitulina) and grey seals (Halichoerus grypus) at the southern limit of their European range (Eastern English Channel)

Sympatric harbour (Phoca vitulina) and grey seals (Halichoerus grypus) are increasingly considered potential competitors, especially since recent local declines in harbour seal numbers while grey seal numbers remained stable or increased at their European core distributions. A better understanding of the interactions between these species is critical for conservation efforts. This study aimed to identify the trophic niche overlap between harbour and grey seals at the southern limit of their European range, in the Baie de Somme (BDS, Eastern English Channel, France), where numbers of resident harbour seals and visiting grey seals are increasing exponentially. Dietary overlap was identified from scat contents using hierarchical clustering. Isotopic niche overlap was quantified using δ¹³C and δ¹⁵N isotopic values from whiskers of 18 individuals, by estimating isotopic standard ellipses with a novel hierarchical model developed in a Bayesian framework to consider both intraindividual variability and interindividual variability. Foraging areas of these individuals were identified from telemetry data. The three independent approaches provided converging results, revealing a high trophic niche overlap due to consumption of benthic flatfish. Two diet clusters were dominated by either small or large benthic flatfish; these comprised 85.5% [CI95%: 80.3%–90.2%] of harbour seal scats and 46.8% [35.1%–58.4%] of grey seal scats. The narrower isotopic niche of harbour seals was nested within that of grey seals (58.2% [22.7%–100%] overlap). Grey seals with isotopic values similar to harbour seals foraged in coastal waters close to the BDS alike harbour seals did, suggesting the niche overlap may be due to individual grey seal strategies. Our findings therefore provide the basis for potential competition between both species (foraging on benthic flatfish close to the BDS). We suggest that a continued increase in seal numbers and/or a decrease in flatfish supply in this area could cause/amplify competitive interactions and have deleterious effects on harbour seal colonies.     

Flexible parametric modeling of survival from age at death data: A mixed linear regression framework

Many long-lived vertebrate species are under threat in the Anthropocene, but their conservation is hampered by a lack of demographic information to assess population long-term viability. When longitudinal studies (e.g., Capture-Mark-Recapture design) are not feasible, the only available data may be cross-sectional, for example, stranding for marine mammals. Survival analysis deals with age at death (i.e., time to event) data and allows to estimate survivorship and hazard rates assuming that the cross-sectional sample is representative. Accommodating a bathtub-shaped hazard, as expected in wild populations, was historically difficult and required specific models. We identified a simple linear regression model with individual frailty that can fit a bathtub-shaped hazard, take into account covariates, allow goodness-of-fit assessments and give accurate estimates of survivorship in realistic settings. We first conducted a Monte Carlo study and simulated age at death data to assess the accuracy of estimates with respect to sample size. Secondly, we applied this framework on a handful of case studies from published studies on marine mammals, a group with many threatened and data-deficient species. We found that our framework is flexible and accurate to estimate survivorship with a sample size of 300 . This approach is promising for obtaining important demographic information on data-poor species.     

Improved synthesis of a protected 11-oxoestrone

An improved synthesis of 11-oxoestrone-3-acetate-17-ethyleneketal is reported. Adjustments are proposed for the oxidation of estrone by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone into 9(11)-dehydroestrone. A complete hydroboration-oxidation of the resulting ketal, by means of borane-methylsulfide complex, gives the corresponding 11-hydroxy derivative. This latter compound is then acetylated for successful oxidation with pyridinium chlorochromate on alumina. The overall yield is 30%.     

A lipidomic and metabolomic serum signature from nonhuman primates exposed to ionizing radiation

Introduction

Due to dangers associated with potential accidents from nuclear energy and terrorist threats, there is a need for high-throughput biodosimetry to rapidly assess individual doses of radiation exposure. Lipidomics and metabolomics are becoming common tools for determining global signatures after disease or other physical insult and provide a “snapshot” of potential cellular damage.

Objectives

The current study assesses changes in the nonhuman primate (NHP) serum lipidome and metabolome 7 days following exposure to ionizing radiation (IR).

Methods

Serum sample lipids and metabolites were extracted using a biphasic liquid–liquid extraction and analyzed by ultra performance liquid chromatography quadrupole time-of-flight mass spectrometry. Global radiation signatures were acquired in data-independent mode.

Results

Radiation exposure caused significant perturbations in lipid metabolism, affecting all major lipid species, including free fatty acids, glycerolipids, glycerophospholipids and esterified sterols. In particular, we observed a significant increase in the levels of polyunsaturated fatty acids (PUFA)-containing lipids in the serum of NHPs exposed to 10 Gy radiation, suggesting a primary role played by PUFAs in the physiological response to IR. Metabolomics profiling indicated an increase in the levels of amino acids, carnitine, and purine metabolites in the serum of NHPs exposed to 10 Gy radiation, suggesting perturbations to protein digestion/absorption, biological oxidations, and fatty acid β-oxidation.

Conclusions

This is the first report to determine changes in the global NHP serum lipidome and metabolome following radiation exposure and provides information for developing metabolomic biomarker panels in human-based biodosimetry.

     

Looking at the unseen: combining animal bio‐logging and stable isotopes to reveal a shift in the ecological niche of a deep diving predator

Understanding how marine top predators exploit their environment is a central topic in marine ecology. Among all methodologies used to investigate this part of ecology, electronic devices are very useful to track animals' movements and foraging habitats, but they do not provide any dietary information. Stable isotopes provide information on trophic levels but remain imprecise to identify small spatial‐scale habitats. In this study, we combined the two approaches to obtain a synoptic view of the foraging behaviour variability of southern elephant seals Mirounga leonina. Our results suggested marked differences in distribution, diving behaviour, foraging habitats, trophic levels, and dietary habits of elephant seals according to their sex and age. Thus, we characterized main foraging habitats over the Kerguelen‐Heard Plateau and the Antarctic shelf for juvenile males, while females foraged mainly in oceanic waters of the Polar Frontal Zone and the Antarctic Zone. In addition, we highlighted the ontogeny of niche partitioning in this sexually dimorphic species. While females did not exhibit a major dietary shift in relation to their age and their breeding status, a different picture emerged for males. Young males had a trophic level identical to that of all females. However, at 3–4 yr of age, males showed a progressive increase in trophic level. The inter‐annual combination of bio‐logging and stable isotopes could provide a powerful tool to investigate possible shifts in ecological niche between years according to environmental changes.     

Population trends of female Elephant Seals breeding on the Courbet Peninsula, ?les Kerguelen

Southern Elephant Seals are upper marine predators of the Southern Ocean. As such, their population dynamics and fluctuations reflect environment conditions. Their worldwide populations crashed during the second half of the twentieth century for reasons not yet completely elucidated. Here, we studied the largest population of Southern Elephant Seals within the South Indian Ocean that are breeding on ?les Kerguelen. In a previous analysis, Guinet et al. in Antarct Sci 11:193–197, 1999) suggested that the decline on ?les Kerguelen might be over, as observed elsewhere. Using 10 years of additional data, we updated this analysis using state-of-the-art statistical methods to account for most uncertainties associated with count data. We showed that the population of female Southern Elephant Seals breeding on ?les Kerguelen has been stable over the past 20 years. Despite concomitant global changes within the Southern Ocean, we did not find any evidence of a phenological shift in peak haul-out date of breeding females between the 1970s and the 2000s.     

Endosomal proteolysis of internalized insulin at the C-terminal region of the B chain by cathepsin D.

The endosomal compartment of hepatic parenchymal cells contains an acidic endopeptidase, endosomal acidic insulinase, which hydrolyzes internalized insulin and generates the major primary end product A(1--21)-B(1--24) insulin resulting from a major cleavage at residues Phe(B24)-Phe(B25). This study addresses the nature of the relevant endopeptidase activity in rat liver that is responsible for most receptor-mediated insulin degradation in vivo. The endosomal activity was shown to be aspartic acid protease cathepsin D (CD), based on biochemical similarities to purified CD in 1) the rate and site of substrate cleavage, 2) pH optimum, 3) sensitivity to pepstatin A, and 4) binding to pepstatin A-agarose. The identity of the protease was immunologically confirmed by removal of greater than 90% of the insulin-degrading activity associated with an endosomal lysate using polyclonal antibodies to CD. Moreover, the elution profile of the endosomal acidic insulinase activity on a gel-filtration TSK-GEL G3000 SW(XL) high performance liquid chromatography column corresponded exactly with the elution profile of the immunoreactive 45-kDa mature form of endosomal CD. Using nondenaturating immunoprecipitation and immunoblotting procedures, other endosomal aspartic acid proteases such as cathepsin E and beta-site amyloid precursor protein-cleaving enzyme (BACE) were ruled out as candidate enzymes for the endosomal degradation of internalized insulin. Immunofluorescence studies showed a largely vesicular staining pattern for internalized insulin in rat hepatocytes that colocalized partially with CD. In vivo pepstatin A treatment was without any observable effect on the insulin receptor content of endosomes but augmented the phosphotyrosine content of the endosomal insulin receptor after insulin injection. These results suggest that CD is the endosomal acidic insulinase activity which catalyzes the rate-limiting step of the in vivo cleavage at the Phe(B24)-Phe(B25) bond, generating the inactive A(1--21)-B(1--24) insulin intermediate.