Parity and total, ischemic heart disease and stroke mortality. The Adventist Health Study, 1976–1988

In a prospective study with information about life style and reproductive factors, we assessed the relationship between parity and total, ischemic heart disease, and stroke mortality. The large majority of the 19,688 California Seventh-day Adventist women included did not smoke or drink alcohol, 31 percent never ate meat and physical activity was relatively high. Cox proportional hazard analysis was conducted with parity as the main independent variable and with adjustment for a number of other possible confounders. During follow-up from 1976 through 1988, there were 3,122 deaths; 782 deaths from ischemic heart disease and 367 deaths due to stroke. There were no relationships between parity and total mortality (P-value for overall effect of parity = 0.32). Grand multiparous women (>4 children) had somewhat increased ischemic heart disease mortality (MRR = 1.45, 95% CI: 1.15, 1.84) before adjustment for educational level. After adjustment for educational level and marital status, there were no relationship with mortality from ischemic heart disease (P = 0.29) or stroke (P = 0.72). In parous women, there were, after adjustment for age at first delivery, some suggestions of an increased total mortality in women with one child. For ischemic heart disease and stroke mortality, no associations were found. Stratified and adjusted analyses confirmed these results. Thus, we found no consistent relationships between parity and total, ischemic heart disease or stroke mortality. However, a longer follow-up would have been helpful and the conclusions may be somewhat influenced by the lifestyle of the women included

Terminal Investment: Individual Reproduction of Ant Queens Increases with Age

The pattern of age-specific fecundity is a key component of the life history of organisms and shapes their ecology and evolution. In numerous animals, including humans, reproductive performance decreases with age. Here, we demonstrate that some social insect queens exhibit the opposite pattern. Egg laying rates of Cardiocondyla obscurior ant queens increased with age until death, even when the number of workers caring for them was kept constant. Cardiocondyla, and probably also other ants, therefore resemble the few select organisms with similar age-specific reproductive investment, such as corals, sturgeons, or box turtles (e.g., [1]), but they differ in being more short-lived and lacking individual, though not social, indeterminate growth. Furthermore, in contrast to most other organisms, in which average life span declines with increasing reproductive effort, queens with high egg laying rates survived as long as less fecund queens

Brief Exposure to Sensory Cues Elicits Stimulus-Nonspecific General Sensitization in an Insect

The effect of repeated exposure to sensory stimuli, with or without reward is well known to induce stimulus-specific modifications of behaviour, described as different forms of learning. In recent studies we showed that a brief single pre-exposure to the female-produced sex pheromone or even a predator sound can increase the behavioural and central nervous responses to this pheromone in males of the noctuid moth Spodoptera littoralis. To investigate if this increase in sensitivity might be restricted to the pheromone system or is a form of general sensitization, we studied here if a brief pre-exposure to stimuli of different modalities can reciprocally change behavioural and physiological responses to olfactory and gustatory stimuli. Olfactory and gustatory pre-exposure and subsequent behavioural tests were carried out to reveal possible intra- and cross-modal effects. Attraction to pheromone, monitored with a locomotion compensator, increased after exposure to olfactory and gustatory stimuli. Behavioural responses to sucrose, investigated using the proboscis extension reflex, increased equally after pre-exposure to olfactory and gustatory cues. Pheromone-specific neurons in the brain and antennal gustatory neurons did, however, not change their sensitivity after sucrose exposure. The observed intra- and reciprocal cross-modal effects of pre-exposure may represent a new form of stimulus-nonspecific general sensitization originating from modifications at higher sensory processing levels

The relationship between fertility and lifespan in humans

Evolutionary theories of aging predict a trade-off between fertility and lifespan, where increased lifespan comes at the cost of reduced fertility. Support for this prediction has been obtained from various sources. However, which genes underlie this relationship is unknown. To assess it, we first analyzed the association of fertility with age at menarche and menopause, and with mortality in 3,575 married female participants of the Rotterdam Study. In addition, we conducted a candidate gene study where 1,664 single nucleotide polymorphisms (SNPs) in 25 candidate genes were analyzed in relation to number of children as a measure of fertility. SNPs that associated with fertility were analyzed for association with mortality. We observed no associations between fertility and age at menarche (p = 0.38) and menopause (p = 0.07). In contrast, fertility was associated with mortality. Women with two to three children had significantly lower mortality (hazard ratio (HR), 0.82; 95% confidence interval (95% CI), 0.69–0.97) compared to women with no children. No such benefit was observed for women with four or more children, who had a similar mortality risk (HR, 0.93; 95% CI, 0.76–1.13) as women with no children. The analysis of candidate genes revealed four genes that influence fertility after correction for multiple testing: CGB/LHB gene cluster (p = 0.0036), FSHR (p = 0.023), FST (p = 0.023), and INHBA (p = 0.021). However, none of the independent SNPs in these genes predicted mortality. In conclusion, women who bear two to three children live longer than those who bear none or many children, but this relationship was not mediated by the candidate genes analyzed in this study

In Vivo Generation of Neurotoxic Prion Protein: Role for Hsp70 in Accumulation of Misfolded Isoforms

Prion diseases are incurable neurodegenerative disorders in which the normal cellular prion protein (PrPC) converts into a misfolded isoform (PrPSc) with unique biochemical and structural properties that correlate with disease. In humans, prion disorders, such as Creutzfeldt-Jakob disease, present typically with a sporadic origin, where unknown mechanisms lead to the spontaneous misfolding and deposition of wild type PrP. To shed light on how wild-type PrP undergoes conformational changes and which are the cellular components involved in this process, we analyzed the dynamics of wild-type PrP from hamster in transgenic flies. In young flies, PrP demonstrates properties of the benign PrPC; in older flies, PrP misfolds, acquires biochemical and structural properties of PrPSc, and induces spongiform degeneration of brain neurons. Aged flies accumulate insoluble PrP that resists high concentrations of denaturing agents and contains PrPSc-specific conformational epitopes. In contrast to PrPSc from mammals, PrP is proteinase-sensitive in flies. Thus, wild-type PrP rapidly converts in vivo into a neurotoxic, protease-sensitive isoform distinct from prototypical PrPSc. Next, we investigated the role of molecular chaperones in PrP misfolding in vivo. Remarkably, Hsp70 prevents the accumulation of PrPSc-like conformers and protects against PrP-dependent neurodegeneration. This protective activity involves the direct interaction between Hsp70 and PrP, which may occur in active membrane microdomains such as lipid rafts, where we detected Hsp70. These results highlight the ability of wild-type PrP to spontaneously convert in vivo into a protease-sensitive isoform that is neurotoxic, supporting the idea that protease-resistant PrPSc is not required for pathology. Moreover, we identify a new role for Hsp70 in the accumulation of misfolded PrP. Overall, we provide new insight into the mechanisms of spontaneous accumulation of neurotoxic PrP and uncover the potential therapeutic role of Hsp70 in treating these devastating disorders

Transcriptional responses underlying the hormetic and detrimental effects of the plant secondary metabolite gossypol on the generalist herbivore Helicoverpa armigera

<p>Abstract</p> <p>Background</p> <p>Hormesis is a biphasic biological response characterized by the stimulatory effect at relatively low amounts of chemical compounds which are otherwise detrimental at higher concentrations. A hormetic response in larval growth rates has been observed in cotton-feeding insects in response to increasing concentrations of gossypol, a toxic metabolite found in the pigment glands of some plants in the family Malvaceae. We investigated the developmental effect of gossypol in the cotton bollworm, <it>Helicoverpa armigera</it>, an important heliothine pest species, by exposing larvae to different doses of this metabolite in their diet. In addition, we sought to determine the underlying transcriptional responses to different gossypol doses.</p> <p>Results</p> <p>Larval weight gain, pupal weight and larval development time were measured in feeding experiments and a hormetic response was seen for the first two characters. On the basis of net larval weight gain responses to gossypol, three concentrations (0%, 0.016% and 0.16%) were selected for transcript profiling in the gut and the rest of the body in a two-color double reference design microarray experiment. Hormesis could be observed at the transcript level, since at the low gossypol dose, genes involved in energy acquisition such as β-fructofuranosidases were up-regulated in the gut, and genes involved in cell adhesion were down-regulated in the body. Genes with products predicted to be integral to the membrane or associated with the proteasome core complex were significantly affected by the detrimental dose treatment in the body. Oxidoreductase activity-related genes were observed to be significantly altered in both tissues at the highest gossypol dose.</p> <p>Conclusions</p> <p>This study represents the first transcriptional profiling approach investigating the effects of different concentrations of gossypol in a lepidopteran species. <it>H. armigera</it>'s transcriptional response to gossypol feeding is tissue- and dose-dependent and involves diverse detoxifying mechanisms not only to alleviate direct effects of gossypol but also indirect damage such as pH disturbance and oxygen radical formation. Genes discovered through this transcriptional approach may be additional candidates for understanding gossypol detoxification and coping with gossypol-induced stress. In a generalist herbivore that has evolved transcriptionally-regulated responses to a variety of different plant compounds, hormesis may be due to a lower induction threshold of growth-promoting, stress-coping responses and a higher induction threshold of detoxification pathways that are costly and cause collateral damage to the cell.</p

Drosophila Carrying Pex3 or Pex16 Mutations Are Models of Zellweger Syndrome That Reflect Its Symptoms Associated with the Absence of Peroxisomes

The peroxisome biogenesis disorders (PBDs) are currently difficult-to-treat multiple-organ dysfunction disorders that result from the defective biogenesis of peroxisomes. Genes encoding Peroxins, which are required for peroxisome biogenesis or functions, are known causative genes of PBDs. The human peroxin genes PEX3 or PEX16 are required for peroxisomal membrane protein targeting, and their mutations cause Zellweger syndrome, a class of PBDs. Lack of understanding about the pathogenesis of Zellweger syndrome has hindered the development of effective treatments. Here, we developed potential Drosophila models for Zellweger syndrome, in which the Drosophila pex3 or pex16 gene was disrupted. As found in Zellweger syndrome patients, peroxisomes were not observed in the homozygous Drosophila pex3 mutant, which was larval lethal. However, the pex16 homozygote lacking its maternal contribution was viable and still maintained a small number of peroxisome-like granules, even though PEX16 is essential for the biosynthesis of peroxisomes in humans. These results suggest that the requirements for pex3 and pex16 in peroxisome biosynthesis in Drosophila are different, and the role of PEX16 orthologs may have diverged between mammals and Drosophila. The phenotypes of our Zellweger syndrome model flies, such as larval lethality in pex3, and reduced size, shortened longevity, locomotion defects, and abnormal lipid metabolisms in pex16, were reminiscent of symptoms of this disorder, although the Drosophila pex16 mutant does not recapitulate the infant death of Zellweger syndrome. Furthermore, pex16 mutants showed male-specific sterility that resulted from the arrest of spermatocyte maturation. pex16 expressed in somatic cyst cells but not germline cells had an essential role in the maturation of male germline cells, suggesting that peroxisome-dependent signals in somatic cyst cells could contribute to the progression of male germ-cell maturation. These potential Drosophila models for Zellweger syndrome should contribute to our understanding of its pathology

Local spatial structure of forest biomass and its consequences for remote sensing of carbon stocks

Advances in forest carbon mapping have the potential to greatly reduce uncertainties in the global carbon budget and to facilitate effective emissions mitigation strategies such as REDD+. Though broad scale mapping is based primarily on remote sensing data, the accuracy of resulting forest carbon stock estimates depends critically on the quality of field measurements and calibration procedures. The mismatch in spatial scales between field inventory plots and larger pixels of current and planned remote sensing products for forest biomass mapping is of particular concern, as it has the potential to introduce errors, especially if forest biomass shows strong local spatial variation. Here, we used 30 large (8–50 ha) globally distributed permanent forest plots to quantify the spatial variability in aboveground biomass (AGB) at spatial grains ranging from 5 to 250m (0.025–6.25 ha), and we evaluate the implications of this variability for calibrating remote sensing products using simulated remote sensing footprints. We found that the spatial sampling error in AGB is large for standard plot sizes, averaging 46.3% for 0.1 ha subplots and 16.6% for 1 ha subplots. Topographically heterogeneous sites showed positive spatial autocorrelation in AGB at scales of 100m and above; at smaller scales, most study sites showed negative or nonexistent spatial autocorrelation in AGB. We further show that when field calibration plots are smaller than the remote sensing pixels, the high local spatial variability in AGB leads to a substantial “dilution” bias in calibration parameters, a bias that cannot be removed with current statistical methods. Overall, our results suggest that topography should be explicitly accounted for in future sampling strategies and that much care must be taken in designing calibration schemes if remote sensing of forest carbon is to achieve its promise