Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway

Numerous studies have now shown that the amyloid beta-protein (Abeta), the principal component of cerebral plaques in Alzheimer disease, rapidly and potently inhibits certain forms of synaptic plasticity. The amyloid (or Abeta) hypothesis proposes that the continuous disruption of normal synaptic physiology by Abeta contributes to the development of Alzheimer disease. However, there is little consensus about how Abeta mediates this inhibition at the molecular level. Using mouse primary hippocampal neurons, we observed that a brief treatment with cell-derived, soluble, human Abeta disrupted the activation of three kinases (Erk/MAPK, CaMKII, and the phosphatidylinositol 3-kinase-activated protein Akt/protein kinase B) that are required for long term potentiation, whereas two other kinases (protein kinase A and protein kinase C) were stimulated normally. An antagonist of the insulin receptor family of tyrosine kinases was found to mimic the pattern of Abeta-mediated kinase inhibition. We then found that soluble Abeta binds to the insulin receptor and interferes with its insulin-induced autophosphorylation. Taken together, these data demonstrate that physiologically relevant levels of naturally secreted Abeta interfere with insulin receptor function in hippocampal neurons and prevent the rapid activation of specific kinases required for long term potentiation.     

"Skittish" Abca2 knockout mice display tremor, hyperactivity, and abnormal myelin ultrastructure in the central nervous system

The ATP-binding cassette transporter 2 (ABCA2) is an endolysosomal protein most highly expressed in the central and peripheral nervous system tissues and macrophages. Previous studies indicated its role in cholesterol/steroid (estramustine, estradiol, and progesterone) trafficking/sequestration, oxidative stress response, and Alzheimer's disease. Developmental studies have shown its expression during macrophage and oligodendrocyte differentiation, processes requiring membrane growth. To determine the in vivo function(s) of this transporter, we generated a knockout mouse from a gene-targeted disruption of the murine ABCA2 gene. Knockout males and females are viable and fertile. However, a non-Mendelian inheritance pattern was shown among male progeny of heterozygous crosses. Compared to wild-type and heterozygous littermates, knockout mice displayed a tremor without ataxia, hyperactivity, and reduced body weight; the latter two phenotypes were more marked in females than in males. This sexual disparity suggests a role for ABCA2 in hormone-dependent neurological and/or developmental pathways. Myelin sheath thickness in the spinal cords of knockout mice was greatly increased compared to that in wild-type mice, while a significant reduction in myelin membrane periodicity (compaction) was observed in both spinal cords and cerebra of knockout mice. Loss of ABCA2 function in vivo resulted in abnormal myelin compaction in spinal cord and cerebrum, an ultrastructural defect that we propose to be the cause of the phenotypic tremor.     

Rate-limiting steps and role of active site Lys443 in the mechanism of carbapenam synthetase

Carbapenam synthetase (hereafter named CPS) catalyzes the formation of the beta-lactam ring in the biosynthetic pathway to (5R)-carbapen-2-em-3-carboxylate, the simplest of the carbapenem antibiotics. Kinetic studies showed remarkable tolerance to substrate stereochemistry in the turnover rate but did not distinguish between chemistry and a nonchemical step such as product release or conformational change as being rate-determining. Also, X-ray structural studies and modest sequence homology to beta-lactam synthetase, an enzyme that catalyzes the formation of a monocyclic beta-lactam ring in a similar ATP/Mg2+-dependent reaction, implicate K443 as an essential residue for substrate binding and intermediate stabilization. In these experiments, we use pH-rate profiles, deuterium solvent isotope effects, and solvent viscosity measurements to examine the rate-limiting step in this complex overall process of substrate adenylation and intramolecular ring formation. Mutagenesis and chemical rescue demonstrate that K443 is the general acid visible in the pH-rate profile of the wild-type CPS-catalyzed reaction. On the basis of these results, we propose a mechanism in which the rate-limiting step is beta-lactam ring formation coupled to a protein conformational change and underscore the role of K443 throughout the reaction.     

Profiling phylogenetic informativeness

The resolution of four controversial topics in phylogenetic experimental design hinges upon the informativeness of characters about the historical relationships among taxa. These controversies regard the power of different classes of phylogenetic character, the relative utility of increased taxonomic versus character sampling, the differentiation between lack of phylogenetic signal and a historical rapid radiation, and the design of taxonomically broad phylogenetic studies optimized by taxonomically sparse genome-scale data. Quantification of the informativeness of characters for resolution of phylogenetic hypotheses during specified historical epochs is key to the resolution of these controversies. Here, such a measure of phylogenetic informativeness is formulated. The optimal rate of evolution of a character to resolve a dated four-taxon polytomy is derived. By scaling the asymptotic informativeness of a character evolving at a nonoptimal rate by the derived asymptotic optimum, and by normalizing so that net phylogenetic informativeness is equivalent for all rates when integrated across all of history, an informativeness profile across history is derived. Calculation of the informativeness per base pair allows estimation of the cost-effectiveness of character sampling. Calculation of the informativeness per million years allows comparison across historical radiations of the utility of a gene for the inference of rapid adaptive radiation. The theory is applied to profile the phylogenetic informativeness of the genes BRCA1, RAG1, GHR, and c-myc from a muroid rodent sequence data set. Bounded integrations of the phylogenetic profile of these genes over four epochs comprising the diversifications of the muroid rodents, the mammals, the lobe-limbed vertebrates, and the early metazoans demonstrate the differential power of these genes to resolve the branching order among ancestral lineages. This measure of phylogenetic informativeness yields a new kind of information for evaluation of phylogenetic experiments. It conveys the utility of the addition of characters a phylogenetic study and it provides a basis for deciding whether appropriate phylogenetic power has been applied to a polytomy that is proposed to be a rapid radiation. Moreover, it provides a quantitative measure of the capacity of a gene to resolve soft polytomies.     

Scale dependency of diversity components estimated from primary biodiversity data and distribution maps

Different sources of information about biodiversity may lead to unrealistic or biased estimation of its components, with different patterns according to the scale of analysis. In this study, we analyse patterns of species richness at the local (average alpha) and regional (gamma) scales, and the relationship between them (Whittaker's beta), in central Mexico, using as a source of data for the species' distributions: (1) museum specimen occurrence data for birds, and (2) distribution maps based on ecological niche models developed and refined by experts. We performed analyses at five spatial resolutions (1/32°−1/2°). Scale changes (grain and extent) affected significantly the estimates of average alpha, gamma, and beta. Use of raw occurrence data vs. distribution maps yielded contrasting results, with raw data underestimating alpha and overestimating beta, as functions of area. As regards species–area relationships, our results suggest a natural decomposition of factors into an area-invariant component (related to alpha), and an area dependent factor (related to beta). Most of our results are maintained in a null model that randomizes occurrences without changing observed range-size distributions. From this result we argue that average alpha and Whittaker's beta capture little information about the spatial covariation of species distribution patterns.     

S-glutathionylation: indicator of cell stress and regulator of the unfolded protein response

The specific posttranslational modification of protein cysteine residues by the addition of the tripeptide glutathione is termed S-glutathionylation. This process is promoted by oxidative and nitrosative stress but also occurs in unstressed cells. Altered levels of S-glutathionylation in some proteins have been associated with numerous pathologies, many of which have been linked to redox stress in the endoplasmic reticulum (ER). Proper protein folding is dependent upon controlled redox conditions within the ER, and it seems that ER conditions can in turn affect rates of S-glutathionylation. This article seeks to bring together the ways through which these processes are interrelated and considers the implications of these interrelationships upon therapeutic approaches to disease.     

Atlas of Mexican Triatominae (Reduviidae: Hemiptera) and vector transmission of Chagas disease

Chagas disease is one of the most important yet neglected parasitic diseases in Mexico and is transmitted by Triatominae. Nineteen of the 31 Mexican triatomine species have been consistently found to invade human houses and all have been found to be naturally infected with Trypanosoma cruzi. The present paper aims to produce a state-of-knowledge atlas of Mexican triatomines and analyse their geographic associations with T. cruzi, human demographics and landscape modification. Ecological niche models (ENMs) were constructed for the 19 species with more than 10 records in North America, as well as for T. cruzi. The 2010 Mexican national census and the 2007 National Forestry Inventory were used to analyse overlap patterns with ENMs. Niche breadth was greatest in species from the semiarid Nearctic Region, whereas species richness was associated with topographic heterogeneity in the Neotropical Region, particularly along the Pacific Coast. Three species, Triatoma longipennis, Triatoma mexicana and Triatoma barberi, overlapped with the greatest numbers of human communities, but these communities had the lowest rural/urban population ratios. Triatomine vectors have urbanised in most regions, demonstrating a high tolerance to human-modified habitats and broadened historical ranges, exposing more than 88% of the Mexican population and leaving few areas in Mexico without the potential for T. cruzi transmission.     

Effects of general,specific and combined warm-up on explosive muscular performance

The purpose of this study was to compare the acute effects of general, specific and combined warm-up (WU) on explosive performance. Healthy male (n = 10) subjects participated in six WU protocols in a crossover randomized study design. Protocols were: passive rest (PR; 15 min of passive rest), running (Run; 5 min of running at 70% of maximum heart rate), stretching (STR; 5 min of static stretching exercise), jumping [Jump; 5 min of jumping exercises – 3x8 countermovement jumps (CMJ) and 3x8 drop jumps from 60 cm (DJ60)], and combined (COM; protocols Run+STR+Jump combined). Immediately before and after each WU, subjects were assessed for explosive concentric-only (i.e. squat jump – SJ), slow stretch-shortening cycle (i.e. CMJ), fast stretch-shortening cycle (i.e. DJ60) and contact time (CT) muscle performance. PR significantly reduced SJ performance (p =0.007). Run increased SJ (p =0.0001) and CMJ (p =0.002). STR increased CMJ (p =0.048). Specific WU (i.e. Jump) increased SJ (p =0.001), CMJ (p =0.028) and DJ60 (p =0.006) performance. COM increased CMJ performance (p =0.006). Jump was superior in SJ performance vs. PR (p =0.001). Jump reduced (p =0.03) CT in DJ60. In conclusion, general, specific and combined WU increase slow stretch-shortening cycle (SSC) muscle performance, but only specific WU increases fast SSC muscle performance. Therefore, to increase fast SSC performance, specific fast SSC muscle actions must be included during the WU.