The effects of Cstb duplication on APP/amyloid-β pathology and cathepsin B activity in a mouse model

People with Down syndrome (DS), caused by trisomy of chromosome 21 have a greatly increased risk of developing Alzheimer's disease (AD). This is in part because of triplication of a chromosome 21 gene, APP. This gene encodes amyloid precursor protein, which is cleaved to form amyloid-β that accumulates in the brains of people who have AD. Recent experimental results demonstrate that a gene or genes on chromosome 21, other than APP, when triplicated significantly accelerate amyloid-β pathology in a transgenic mouse model of amyloid-β deposition. Multiple lines of evidence indicate that cysteine cathepsin activity influences APP cleavage and amyloid-β accumulation. Located on human chromosome 21 (Hsa21) is an endogenous inhibitor of cathepsin proteases, CYSTATIN B (CSTB) which is proposed to regulate cysteine cathepsin activity in vivo. Here we determined if three copies of the mouse gene Cstb is sufficient to modulate amyloid-β accumulation and cathepsin activity in a transgenic APP mouse model. Duplication of Cstb resulted in an increase in transcriptional and translational levels of Cstb in the mouse cortex but had no effect on the deposition of insoluble amyloid-β plaques or the levels of soluble or insoluble amyloid-β42, amyloid-β40, or amyloid-β38 in 6-month old mice. In addition, the increased CSTB did not alter the activity of cathepsin B enzyme in the cortex of 3-month or 6-month old mice. These results indicate that the single-gene duplication of Cstb is insufficient to elicit a disease-modifying phenotype in the dupCstb x tgAPP mice, underscoring the complexity of the genetic basis of AD-DS and the importance of multiple gene interactions in disease

T1, diffusion tensor, and quantitative magnetization transfer imaging of the hippocampus in an Alzheimer's disease mouse model

Alzheimer's disease (AD) pathology causes microstructural changes in the brain. These changes, if quantified with magnetic resonance imaging (MRI), could be studied for use as an early biomarker for AD. The aim of our study was to determine if T1 relaxation, diffusion tensor imaging (DTI), and quantitative magnetization transfer imaging (qMTI) metrics could reveal changes within the hippocampus and surrounding white matter structures in ex vivo transgenic mouse brains overexpressing human amyloid precursor protein with the Swedish mutation. Delineation of hippocampal cell layers using DTI color maps allows more detailed analysis of T1-weighted imaging, DTI, and qMTI metrics, compared with segmentation of gross anatomy based on relaxation images, and with analysis of DTI or qMTI metrics alone. These alterations are observed in the absence of robust intracellular Aβ accumulation or plaque deposition as revealed by histology. This work demonstrates that multiparametric quantitative MRI methods are useful for characterizing changes within the hippocampal substructures and surrounding white matter tracts of mouse models of AD

Arenavirus budding resulting from viral-protein-associated cell membrane curvature

Viral replication occurs within cells, with release (and onward infection) primarily achieved through two alternative mechanisms: lysis, in which virions emerge as the infected cell dies and bursts open; or budding, in which virions emerge gradually from a still living cell by appropriating a small part of the cell membrane. Virus budding is a poorly understood process that challenges current models of vesicle formation. Here, a plausible mechanism for arenavirus budding is presented, building on recent evidence that viral proteins embed in the inner lipid layer of the cell membrane. Experimental results confirm that viral protein is associated with increased membrane curvature, whereas a mathematical model is used to show that localized increases in curvature alone are sufficient to generate viral buds. The magnitude of the protein-induced curvature is calculated from the size of the amphipathic region hypothetically removed from the inner membrane as a result of translation, with a change in membrane stiffness estimated from observed differences in virion deformation as a result of protein depletion. Numerical results are based on experimental data and estimates for three arenaviruses, but the mechanisms described are more broadly applicable. The hypothesized mechanism is shown to be sufficient to generate spontaneous budding that matches well both qualitatively and quantitatively with experimental observations

Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP

Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration

Ethical Issues in Engineering Models: An Operations Researcher’s Reflections

This article starts with an overview of the author’s personal involvement—as an Operations Research consultant—in several engineering case-studies that may raise ethical questions; e.g., case-studies on nuclear waste, water management, sustainable ecology, military tactics, and animal welfare. All these case studies employ computer simulation models. In general, models are meant to solve practical problems, which may have ethical implications for the various stakeholders; namely, the modelers, the clients, and the public at large. The article further presents an overview of codes of ethics in a variety of disciples. It discusses the role of mathematical models, focusing on the validation of these models’ assumptions. Documentation of these model assumptions needs special attention. Some ethical norms and values may be quantified through the model’s multiple performance measures, which might be optimized. The uncertainty about the validity of the model leads to risk or uncertainty analysis and to a search for robust models. Ethical questions may be pressing in military models, including war games. However, computer games and the related experimental economics may also provide a special tool to study ethical issues. Finally, the article briefly discusses whistleblowing. Its many references to publications and websites enable further study of ethical issues in modeling

Confrontational scavenging as a possible source for language and cooperation

The emergence of language and the high degree of cooperation found among humans seems to require more than a straightforward enhancement of primate traits. Some triggering episode unique to human ancestors was likely necessary. Here it is argued that confrontational scavenging was such an episode. Arguments for and against an established confrontational scavenging niche are discussed, as well as the probable effects of such a niche on language and co-operation. Finally, several possible directions for future research are suggested

On the use of parataxonomy in biodiversity monitoring: a case study on wild flora

International audienceMonitoring programs that assess species-richness and turnover are now regarded as essential to document biodiversity loss worldwide. Implementation of such programs is impeded by a general decrease in the number of skilled naturalists. Here we studied how morphotypes, instead of species, might be used by unskilled participants (referred to as “volunteers”) to survey common plant communities. Our main questions were: (1) Can morphotypes be used as a robust estimator of species-richness (alpha-diversity) and assemblage turnover (Beta-diversity)? and (2) What is the robustness (reproducibility and repeatability) of such methods? Double inventories were performed on 150 plots in arable Weld margins, one by a non-expert using morphotypes, the other by a taxonomist using species. To test the robustness of morphotype identiWcation among participants, 20 additional plots were surveyed by eight volunteers using the same protocol. We showed that (1) the number of morphotypes identiWed by unskilled volunteers in a plot was always strongly correlated with species-richness. (2) Morphotypes were sensitive to diVerences among habitats but were less accurate than species to detect these diVerences. (3) Morphotype identiWcation varied signiWcantly within and between volunteers. Due to this lack of repeatability and reproducibility, parataxonomy cannot be considered a good surrogate for taxonomy. Nevertheless, assuming that morphotypes are identiWed with standardized methods, and that results are used only to evaluate gross species-richness but not species turnover, parataxonomy might be a valuable tool for rapid biodiversity assessment of common wild flora

Syntenic relationships between cucumber (Cucumis sativus L.) and melon (C. melo L.) chromosomes as revealed by comparative genetic mapping

<p>Abstract</p> <p>Background</p> <p>Cucumber, <it>Cucumis sativus </it>L. (2n = 2 × = 14) and melon, <it>C. melo </it>L. (2n = 2 × = 24) are two important vegetable species in the genus <it>Cucumis </it>(family Cucurbitaceae). Both species have an Asian origin that diverged approximately nine million years ago. Cucumber is believed to have evolved from melon through chromosome fusion, but the details of this process are largely unknown. In this study, comparative genetic mapping between cucumber and melon was conducted to examine syntenic relationships of their chromosomes.</p> <p>Results</p> <p>Using two melon mapping populations, 154 and 127 cucumber SSR markers were added onto previously reported F₂- and RIL-based genetic maps, respectively. A consensus melon linkage map was developed through map integration, which contained 401 co-dominant markers in 12 linkage groups including 199 markers derived from the cucumber genome. Syntenic relationships between melon and cucumber chromosomes were inferred based on associations between markers on the consensus melon map and cucumber draft genome scaffolds. It was determined that cucumber Chromosome 7 was syntenic to melon Chromosome I. Cucumber Chromosomes 2 and 6 each contained genomic regions that were syntenic with melon chromosomes III+V+XI and III+VIII+XI, respectively. Likewise, cucumber Chromosomes 1, 3, 4, and 5 each was syntenic with genomic regions of two melon chromosomes previously designated as II+XII, IV+VI, VII+VIII, and IX+X, respectively. However, the marker orders in several syntenic blocks on these consensus linkage maps were not co-linear suggesting that more complicated structural changes beyond simple chromosome fusion events have occurred during the evolution of cucumber.</p> <p>Conclusions</p> <p>Comparative mapping conducted herein supported the hypothesis that cucumber chromosomes may be the result of chromosome fusion from a 24-chromosome progenitor species. Except for a possible inversion, cucumber Chromosome 7 has largely remained intact in the past nine million years since its divergence from melon. Meanwhile, many structural changes may have occurred during the evolution of the remaining six cucumber chromosomes. Further characterization of the genomic nature of <it>Cucumis </it>species closely related to cucumber and melon might provide a better understanding of the evolutionary history leading to modern cucumber.</p

External ballistics of Pleistocene hand-thrown spears: experimental performance data and implications for human evolution

The appearance of weaponry - technology designed to kill - is a critical but poorly established threshold in human evolution. It is an important behavioural marker representing evolutionary changes in ecology, cognition, language and social behaviours. While the earliest weapons are often considered to be hand-held and consequently short-ranged, the subsequent appearance of distance weapons is a crucial development. Projectiles are seen as an improvement over contact weapons, and are considered by some to have originated only with our own species in the Middle Stone Age and Upper Palaeolithic. Despite the importance of distance weapons in the emergence of full behavioral modernity, systematic experimentation using trained throwers to evaluate the ballistics of thrown spears during fight and at impact is lacking. This paper addresses this by presenting results from a trial of trained javelin athletes, providing new estimates for key performance parameters. Overlaps in distances and impact energies between hand-thrown spears and spearthrowers are evidenced, and skill emerges as a signifcant factor in successful use. The results show that distance hunting was likely within the repertoire of hunting strategies of Neanderthals, and the resulting behavioural flexibility closely mirrors that of our own specie