Immune correlates of aging in outdoor-housed captive rhesus macaques (<Emphasis Type="Italic">Macaca mulatta</Emphasis>)

Background

Questions remain about whether inflammation is a cause, consequence, or coincidence of aging. The purpose of this study was to define baseline immunological characteristics from blood to develop a model in rhesus macaques that could be used to address the relationship between inflammation and aging. Hematology, flow cytometry, clinical chemistry, and multiplex cytokine/chemokine analyses were performed on a group of 101 outdoor-housed captive rhesus macaques ranging from 2 to 24 years of age, approximately equivalent to 8 to 77 years of age in humans.

Results

These results extend earlier reports correlating changes in lymphocyte subpopulations and cytokines/chemokines with increasing age. There were significant declines in numbers of white blood cells (WBC) overall, as well as lymphocytes, monocytes, and polymorphonuclear cells with increasing age. Among lymphocytes, there were no significant declines in NK cells and T cells, whereas B cell numbers exhibited significant declines with age. Within the T cell populations, there were significant declines in numbers of CD4+ naïve T cells and CD8+ naïve T cells. Conversely, numbers of CD4+CD8+ effector memory and CD8+effector memory T cells increased with age. New multiplex analyses revealed that concentrations of a panel of ten circulating cytokines/chemokines, IFNγ, IL1b, IL6, IL12, IL15, TNFα, MCP1, MIP1α, IL1ra, and IL4, each significantly correlated with age and also exhibited concordant pairwise correlations with every other factor within this group. To also control for outlier values, mean rank values of each of these cytokine concentrations in relation to age of each animal and these also correlated with age.

Conclusions

A panel of ten cytokines/chemokines were identified that correlated with aging and also with each other. This will permit selection of animals exhibiting relatively higher and lower inflammation status as a model to test mechanisms of inflammation status in aging with susceptibility to infections and vaccine efficacy.

     

Human proximity and habitat fragmentation are key drivers of the rangewide bonobo distribution

Habitat loss and hunting threaten bonobos (Pan paniscus), Endangered (IUCN) great apes endemic to lowland rainforests of the Democratic Republic of Congo. Conservation planning requires a current, data-driven, rangewide map of probable bonobo distribution and an understanding of key attributes of areas used by bonobos. We present a rangewide suitability model for bonobos based on a maximum entropy algorithm in which data associated with locations of bonobo nests helped predict suitable conditions across the species’ entire range. We systematically evaluated available biotic and abiotic factors, including a bonobo-specific forest fragmentation layer (forest edge density), and produced a final model revealing the importance of simple threat-based factors in a data poor environment. We confronted the issue of survey bias in presence-only models and devised a novel evaluation approach applicable to other taxa by comparing models built with data from geographically distinct sub-regions that had higher survey effort. The model’s classification accuracy was high (AUC = 0.82). Distance from agriculture and forest edge density best predicted bonobo occurrence with bonobo nests more likely to occur farther from agriculture and in areas of lower edge density. These results suggest that bonobos either avoid areas of higher human activity, fragmented forests, or both, and that humans reduce the effective habitat of bonobos. The model results contribute to an increased understanding of threats to bonobo populations, as well as help identify priority areas for future surveys and determine core bonobo protection areas.     

Higher order structure of short collagen model peptides attached to dendrimers and linear polymers

Collagen, which is used as a biomaterial, is the most abundant protein in mammals. We have previously reported that a dendrimer modified with collagen model peptides, (Gly‐Pro‐Pro)₅, formed a collagen‐like triple‐helical structure, showing thermal reversibility. In this study, various collagen‐mimic dendrimers of different generations and at different binding ratios were synthesized, to investigate the relationship between the peptide clustering effect and the higher order structure formation. The formation of the higher order structure was influenced by the binding ratios of the peptide to the dendrimer, but was not influenced by the dendrimer generation. A spacer, placed between the dendrimer terminal group and the peptide, negatively contributed to the formation of the higher order structure. The collagen model peptides were also attached to poly(allylamine) (PAA) and poly‐L ‐lysine (poly(Lys)) to compare them with the collagen‐mimic dendrimers. The PAA‐based collagen‐mimic compound, bearing more collagen model peptides than the dendrimer, exhibited a thermally stable higher order structure. In contrast, this was not observed for the collagen‐mimic polymers based on poly(Lys). Therefore, dendrimers and vinyl polymers act as a scaffold for collagen model peptides and subsequently induce higher order structures. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 640–648, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com     

Adaptation changes in dynamic postural control and contingent negative variation during repeated transient forward translation in the elderly

Background

Adaptation changes in postural control and contingent negative variation (CNV) for the elderly were investigated during repeated forward floor translation.

Methods

Fifteen healthy elderly persons, living in the suburban area of Kanazawa City, Japan, underwent backward postural disturbance by a forward-floor translation (S2) 2 s after an auditory warning signal (S1). A set with 20 trials was repeated until a negative peak of late CNV was recognized in the 600-ms period before S2, and the last set was defined as the final set. Electroencephalograms, center of foot pressure in the anteroposterior direction (CoPap), and electromyograms of postural muscles were analyzed.

Results

CoPap displacement generated by the floor translation was significantly decreased until the twelfth trial in the first set, and mean CoPap displacement was smaller in the second and final sets than in the first set. The mean displacement was significantly smaller in the final set than the previous set. A late CNV with a negative peak was not recognized in the first and second sets. However, most subjects (13/15) showed a negative peak by the fourth set, when the late CNV started to increase negatively from about 1,000 ms after S1 and peaked at about 300 ms before S2. At about 160 ms before the CNV peak, the CoPap forward shift started. The increase in timing of the gastrocnemius activity related to the CoPap shift was significantly correlated with the CNV peak timing (r = 0.64). After S2, peak amplitudes of the anterior postural muscles were significantly decreased in the final set compared to the first set.

Conclusions

It was demonstrated that even for the elderly, with so many repetitions of postural disturbance, a late CNV with a negative peak was recognized, leading to accurate postural preparation. This suggests the improvement of frontal lobe function (e.g., anticipatory attention and motor preparation) in the elderly.     

Nanoparticles Containing Curcumin Useful for Suppressing Macrophages In Vivo in Mice

To explore a novel method using liposomes to suppress macrophages, we screened food constituents through cell culture assays. Curcumin was one of the strongest compounds exhibiting suppressive effects on macrophages. We subsequently tried various methods to prepare liposomal curcumin, and eventually succeeded in preparing liposomes with sufficient amounts of curcumin to suppress macrophages by incorporating a complex of curcumin and bovine serum albumin. The diameter of the resultant nanoparticles, the liposomes containing curcumin, ranged from 60 to 100 nm. Flow cytometric analyses revealed that after intraperitoneal administration of the liposomes containing curcumin into mice, these were incorporated mainly by macrophages positive for F4/80, CD36, and CD11b antigens. Peritoneal cells prepared from mice injected in vivo with the liposomes containing curcumin apparently decreased interleukin-6-producing activities. Major changes in body weight and survival rates in the mice were not observed after administrating the liposomes containing curcumin. These results indicate that the liposomes containing curcumin are safe and useful for the selective suppression of macrophages in vivo in mice.     

CXCR4-derived synthetic peptides inducing anti-HIV-1 antibodies

Despite almost 30 years since the identification of the human immunodeficiency virus type I (HIV-1), development of effective AIDS vaccines has been hindered by the high mutability of HIV-1. The HIV-1 co-receptors CCR5 and CXCR4 are genetically stable, but viral proteins may mutate rapidly during the course of infection. CXCR4 is a seven transmembrane G protein-coupled receptor, possessing an N-terminal region (NT) and three extracellular loops (ECL1-3). Previous studies have shown that the CXCR4-ED-derived peptides inhibit the entry of HIV-1 by interacting with gp120, an HIV-1 envelope glycoprotein. In the present study, antigenicity of CXCR4-derived peptides has been investigated and the anti-HIV-1 effects of induced antisera have been assessed. It was found that CXCR4-ED-derived antigen molecules immunize mice, showing that the linear peptides have higher antigenicity than the cyclic peptides. The L1- and L2-induced antisera inhibited the HIV-1 entry significantly, while anti-N1 antibodies have no inhibitory activity. This study produced promising examples for the design of AIDS vaccines which target the human protein and can overcome mutability of HIV-1.     

Effect of metanotal secretion ingestion on oviposition in a tree cricket, Truljalia hibinonis (Orthoptera: Gryllidae)

The female Truljalia hibinonis ingests metanotal secretions of the male during copulation. The effect of ingestion on oviposition behavior was compared between three female groups: females that copulated once with an intact male (a male that had not been manipulated; M group); females that copulated once with a male from which most of the metanotal secretion had been removed (NO group); and females that copulated once with an intact male followed by being artificially supplied with metanotal secretion three times (MS group). There were no obvious differences in female fecundity across the three groups. However, within the MS group, intake of an optimal amount of metanotal secretion increased the number of eggs laid. This effect appeared quickly after ingestion and was most effective on the first bout (eggs laid during the first few days after copulation) after ingestion of the metanotal secretion. In contrast, the number of eggs laid had a negative correlation with the amount of metanotal secretion ingested when the amount exceeded the optimal in this experimental arrangement.     

An attenuated LC16m8 smallpox vaccine: analysis of full-genome sequence and induction of immune protection

The potential threat of smallpox bioterrorism has made urgent the development of lower-virulence vaccinia virus vaccines. An attenuated LC16m8 (m8) vaccine was developed in 1975 from the Lister strain used in the World Health Organization smallpox eradication program but was not used against endemic smallpox. Today, no vaccines can be tested with variola virus for efficacy in humans, and the mechanisms of immune protection against the major intracellular mature virion (IMV) and minor extracellular enveloped virion (EEV) populations of poxviruses are poorly understood. Here, we determined the full-genome sequences of the m8, parental LC16mO (mO), and grandparental Lister (LO) strains and analyzed their evolutionary relationships. Sequence data and PCR analysis indicated that m8 was a progeny of LO and that m8 preserved almost all of the open reading frames of vaccinia virus except for the disrupted EEV envelope gene B5R. In accordance with this genomic background, m8 induced 100% protection against a highly pathogenic vaccinia WR virus in mice by a single vaccination, despite the lack of anti-B5R and anti-EEV antibodies. The immunogenicity and priming efficacy with the m8 vaccine consisting mainly of IMV were as high as those with the intact-EEV parental mO and grandparental LO vaccines. Thus, mice vaccinated with 10(7) PFU of m8 produced low levels of anti-B5R antibodies after WR challenge, probably because of quick clearance of B5R-expressing WR EEV by strong immunity induced by the vaccination. These results suggest that priming with m8 IMV provides efficient protection despite undetectable levels of immunity against EEV.     

Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet

Autophagy is an evolutionarily conserved machinery for bulk degradation of cytoplasmic components. Here, we report upregulation of autophagosome formation in pancreatic beta cells in diabetic db/db and in nondiabetic high-fat-fed C57BL/6 mice. Free fatty acids (FFAs), which can cause peripheral insulin resistance associated with diabetes, induced autophagy in beta cells. Genetic ablation of atg7 in beta cells resulted in degeneration of islets and impaired glucose tolerance with reduced insulin secretion. While high-fat diet stimulated beta cell autophagy in control mice, it induced profound deterioration of glucose tolerance in autophagy-deficient mutants, partly because of the lack of compensatory increase in beta cell mass. These findings suggest that basal autophagy is important for maintenance of normal islet architecture and function. The results also identified a unique role for inductive autophagy as an adaptive response of beta cells in the presence of insulin resistance induced by high-fat diet.