MMPBSA decomposition of the binding energy throughout a molecular dynamics simulation of Amyloid-Beta (Aß10-35) aggregation

Recent experiments with amyloid-beta (Aß) peptides indicate that the formation of toxic oligomers may be an important contribution to the onset of Alzheimer's disease. The toxicity of Aß oligomers depend on their structure, which is governed by assembly dynamics. However, a detailed knowledge of the structure of at the atomic level has not been achieved yet due to limitations of current experimental techniques. In this study, replica exchange molecular dynamics simulations are used to identify the expected diversity of dimer conformations of Aß10-35 monomers. The most representative dimer conformation has been used to track the dimer formation process between both monomers. The process has been characterized by means of the evolution of the decomposition of the binding free energy, which provides an energetic profile of the interaction. Dimers undergo a process of reorganization driven basically by inter-chain hydrophobic and hydrophilic interactions and also solvation/desolvation processes.

Beta-oxidation in fatty acid degradation and beyond.

The degradation of fatty acids in plants occurs primarily in the peroxisomes through the beta-oxidation cycle. Enzymes that are involved in various aspects of beta-oxidation have been identified recently and shown to act biochemically on a diversity of fatty acids and derivatives. Analysis of several mutants has revealed essential roles for beta-oxidation in the breakdown of reserve triacylglycerols, seed development, seed germination and post-germinative growth before the establishment of photosynthesis. Beta-oxidation has also a considerable importance during the vegetative and reproductive growth phases, and plays a role in plant responses to stress, particularly in the synthesis of jasmonic acid.

Signal transduction by the cloned glucagon-like peptide-1 receptor: comparison with signaling by the endogenous receptors of beta cell lines.

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone that potentiates glucose-induced insulin secretion by pancreatic beta cells. The mechanisms of interaction between GLP-1 and glucose signaling pathways are not well understood. Here we studied the coupling of the cloned GLP-1 receptor, expressed in fibroblasts or in COS cells, to intracellular second messengers and compared this signaling with that of the endogenous receptor expressed in insulinoma cell lines. Binding of GLP-1 to the cloned receptor stimulated formation of cAMP with the same dose dependence and similar kinetics, compared with the endogenous receptor of insulinoma cells. Compared with forskolin-induced cAMP accumulation, that induced by GLP-1 proceeded with the same initial kinetics but rapidly reached a plateau, suggesting fast desensitization of the receptor. Coupling to the phospholipase C pathway was assessed by measuring inositol phosphate production and variations in the intracellular calcium concentration. No GLP-1-induced production of inositol phosphates could be measured in the different cell types studied. A rise in the intracellular calcium concentration was nevertheless observed in transfected COS cells but was much smaller than that observed in response to norepinephrine in cells also expressing the alpha 1B-adrenergic receptor. Importantly, no such increase in the intracellular calcium concentration could be observed in transfected fibroblasts or insulinoma cells, which, however, responded well to thrombin or carbachol, respectively. Together, our data show that interaction between GLP-1 and glucose signaling pathways in beta cells may be mediated uniquely by an increase in the intracellular cAMP concentration, with the consequent activation of protein kinase A and phosphorylation of elements of the glucose-sensing apparatus or of the insulin granule exocytic machinery.

Measuring gait using a ground laser range sensor

This paper describes a mesurement system designed to register the displacement of the legs using a two-dimensional laser range sensor with a scanning plane parallel to the ground and extract gait parameters. In the proposed methodology, the position of the legs is estimated by fitting two circles with the laser points that define their contour and the gait parameters are extracted applying a step-line model to the estimated displacement of the legs to reduce uncertainty in the determination of the stand and swing phase of the gait. Results obtained in a range up to 8 m shows that the systematic error in the location of one static leg is lower than 10 mm with and standard deviation lower than 8 mm; this deviation increases to 11 mm in the case of a moving leg. The proposed measurement system has been applied to estimate the gait parameters of six volunteers in a preliminary walking experiment.

Measuring oscillating walking paths with a LIDAR

This work describes the analysis of different walking paths registered using a Light Detection And Ranging (LIDAR) laser range sensor in order to measure oscillating trajectories during unsupervised walking. The estimate of the gait and trajectory parameters were obtained with a terrestrial LIDAR placed 100 mm above the ground with the scanning plane parallel to the floor to measure the trajectory of the legs without attaching any markers or modifying the floor. Three different large walking experiments were performed to test the proposed measurement system with straight and oscillating trajectories. The main advantages of the proposed system are the possibility to measure several steps and obtain average gait parameters and the minimum infrastructure required. This measurement system enables the development of new ambulatory applications based on the analysis of the gait and the trajectory during a walk.

Um panorama atual da química e da farmacologia de naftoquinonas, com ênfase na beta-lapachona e derivados

Naphthoquinones have been extensively studied due to their activity as topoisomerase inhibitors. These enzymes are critical to DNA replication in cells. In addition, naphthoquinones have been shown to induce what are known as "reactive oxygen species" that can cause damage to cells. beta-Lapachone is a very important pyranaphthoquinone obtained from the heartwood of the lapacho tree, Tabebuia avellanedae Lorentz ex. Griseb. (Bignoniaceae), and other Tabebuia trees native to Central and South America and chemically from lapachol. beta-Lapachone has a diversity of useful biological activities against various cancer cell lines such as human ovarian and prostate tumors and, at lower doses is a radiosensitizer of several human cancer cell lines. It gives rise to a variety of effects in vitro including the inhibition or activation of topoisomerase I an II in a distinct manner from that of other topoisomerase inhibitors. This review intend to discuss some details of the mechanisms of quinone-induced cell damage and death, and we also summarize results of the literature indicating that b-Lapachone may take part in quinone-elicited apoptosis despite the fact that its mechanism of action in vivo and its targets are still unknown.

Identification of clonally rearranged T-cell receptor beta chain genes in HTLV-I carriers as a potential instrument for early detection of neoplasia

We analyzed the genetic recombination pattern of the T-cell receptor beta-chain gene (TCR-beta) in order to identify clonal expansion of T-lymphocytes in 17 human T-lymphotropic virus type I (HTLV-I)-positive healthy carriers, 7 of them with abnormal features in the peripheral blood lymphocytes. Monoclonal or oligoclonal expansion of T-cells was detected in 5 of 7 HTLV-I-positive patients with abnormal lymphocytes and unconfirmed diagnosis by using PCR amplification of segments of TCR-beta gene, in a set of reactions that target 102 different variable (V) segments, covering all members of the 24 V families available in the gene bank, including the more recently identified segments of the Vbeta-5 and Vbeta-8 family and the two diversity beta segments. Southern blots, the gold standard method to detect T-lymphocyte clonality, were negative for all of these 7 patients, what highlights the low sensitivity of this method that requires a large amount of very high quality DNA. To evaluate the performance of PCR in the detection of clonality we also analyzed 18 leukemia patients, all of whom tested positive. Clonal expansion was not detected in any of the negative controls or healthy carriers without abnormal lymphocytes. In conclusion, PCR amplification of segments of rearranged TCR-beta is reliable and highly suitable for the detection of small populations of clonal T-cells in asymptomatic HTLV-I carriers who present abnormal peripheral blood lymphocytes providing an additional instrument for following up these patients with potentially higher risk of leukemia.

Habitat selection of three rodents in a frequently burned boreal environment : productivity and habitat diversity

How does fire affect the plant and animal community of the boreal forest? This study attempted to examine the changes in plant composition and productivity, and small mammal demography brought about by fire in the northern boreal environment at Chick Lake, N.W.T. (65053fN, 128°14,W). Two 5*6 ha plots measuring 375m x 150m were selected for study during the summers of 1973 and 197^. One had been unburned for 120 years, the other was part of a fire which burned in the spring of 1969. Grids of 15m x 15m were established in each plot and meter square quadrats taken at each of the 250 grid intersections in order to determine plant composition and density. Aerial primary production was assessed by clipping and drying 80 samples of terminal new production for each species under investigation. Small mammal populations were sampled by placing a Sherman live trap at each grid intersection for ten days in every month. The two plots were similar in plant species composition which suggested that most regrowth in the burned area was from rootstocks which survived the fire. The plant data were submitted to a cluster analysis that revealed nine separate species associations, six of which occured in the burned area and eight of which occured in the control. These were subsequently treated as habitats for purposes of comparison with small mammal distributions. The burned area showed a greater productivity in flowers and fruits although total productivity in the control area was higher due to a large contribution from the non-vascular component. Maximum aerial productivity as dry wieght was measured at 157.1 g/m and 207.8 g/m for the burn and control respectively. Microtus pennsylvanicus and Clethrionomys rutilus were the two most common small mammals encountered; Microtus xanthognathus, Synaptomys borealis, and Phenacomys intermedius also occured in the area. Populations of M. pennsylvanicus and C. rutilus were high during the summer of 1973; however, M. pennsylvanicus was rare on the control but abundant on the burn, while C. rutilus was rare on the burn but abundant in the control. During the summer of 197^ populations declined, with the result that few voles of any species were caught in the burn while equal numbers of the two species were caught in the control. During the summer of 1973 M. pennsylvanicus showed a positive association to the most productive habitat type in the burn which was avoided by C. rutilus. In the control £• rutilus showed a similar positive association to the most productive habitat type which was avoided by M. pennsylvanicus. In all cases for the high population year of 1973# the two species never overlapped in habitat preference. When populations declined in 197^f "both species showed a strong association for the most productive habitat in the control. This would suggest that during a high population year, an abundant species can exclude competitors from a chosen habitat, but that this dominance decreases as population levels decrease. It is possible that M. pennsylvanicus is a more efficient competitor in a recently burned environment, while C. rutilus assumes this role once non-vascular regrowth becomes extensive.

Evolution of functional diversity in the cupin superfamily

The cupin superfamily of proteins is among the most functionally diverse of any described to date. It was named on the basis of the conserved beta-barrel fold ('cupa' is the Latin term for a small barrel), and comprises both enzymatic and non-enzymatic members, which have either one or two cupin domains. Within the conserved tertiary structure, the variety of biochemical function is provided by minor variation of the residues in the active site and the identity of the bound metal ion. This review discusses the advantages of this particular scaffold and provides an evolutionary analysis of 18 different subclasses within the cupin superfamily.

Phylogeny and the hierarchical organization of plant diversity

R. H. Whittaker's idea that plant diversity can be divided into a hierarchy of spatial components from alpha at the within-habitat scale through beta for the turnover of species between habitats to gamma along regional gradients implies the underlying existence of alpha, beta, and gamma niches. We explore the hypothesis that the evolution of a, (3, and gamma niches is also hierarchical, with traits that define the a niche being labile, while those defining a and 7 niches are conservative. At the a level we find support for the hypothesis in the lack of close significant phylogenetic relationship between meadow species that have similar a niches. In a second test, a niche overlap based on a variety of traits is compared between congeners and noncongeners in several communities; here, too, there is no evidence of a correlation between a niche and phylogeny. To test whether beta and gamma niches evolve conservatively, we reconstructed the evolution of relevant traits on evolutionary trees for 14 different clades. Tests against null models revealed a number of instances, including some in island radiations, in which habitat (beta niche) and elevational maximum (an aspect of the gamma niche) showed evolutionary conservatism.

Measuring societal awareness of the rural agrarian landscape: indicators and scale issues

The work presented in this report is part of the effort to define the landscape state and diversity indicator in the frame of COM (2006) 508 “Development of agri-environmental indicators for monitoring the integration of environmental concerns into the common agricultural policy”. The Communication classifies the indicators according to their level of development, which, for the landscape indicator is “in need of substantial improvements in order to become fully operational”. For this reason a full re-definition of the indicator has been carried out, following the initial proposal presented in the frame of the IRENA operation (“Indicator Reporting on the Integration of Environmental Concerns into Agricultural Policy”). The new proposal for the landscape state and diversity indicator is structured in three components: the first concerns the degree of naturalness, the second landscape structure, the third the societal appreciation of the rural landscape. While the first two components rely on a strong bulk of existing literature, the development of the methodology has made evident the need for further analysis of the third component, which is based on a newly proposed top-down approach. This report presents an in-depth analysis of such component of the indicator, and the effort to include a social dimension in large scale landscape assessment.

Measuring significant variability characteristics: An assessment of three UK renewables

The variability of renewable energy is widely recognised as a challenge for integrating high levels of renewable generation into electricity systems. However, to explore its implications effectively, variability itself should first be clearly understood. This is particularly true for national electricity systems with high planned penetration of renewables and limited interconnection such as the UK. Variability cannot be considered as a distinct resource property with a single measurable parameter, but is a multi-faceted concept best described by a range of distinct characteristics. This paper identifies relevant characteristics of variability, and considers their implications for energy research. This is done through analysis of wind, solar and tidal current resources, with a primary focus on the Bristol Channel region in the UK. The relationship with electricity demand is considered, alongside the potential benefits of resource diversity. Analysis is presented in terms of persistence, distribution, frequency and correlation between supply and demand. Marked differences are seen between the behaviours of the individual resources, and these give rise to a range of different implications for system integration. Wind shows strong persistence and a useful seasonal pattern, but also a high spread in energy levels at timescales beyond one or two days. The solar resource is most closely correlated with electricity demand, but is undermined by night-time zero values and an even greater spread of monthly energy delivered than wind. In contrast, the tidal resource exhibits very low persistence, but also much greater consistency in energy values assessed across monthly time scales. Whilst this paper focuses primarily on the behaviour of resources, it is noted that discrete variability characteristics can be related to different system impacts. Persistence and predictability are relevant for system balancing, whereas statistical distribution is more relevant when exploring issues of asset utilisation and energy curtailment. Areas of further research are also identified, including the need to assess the value of predictability in relation to other characteristics.

The diversity of diversity: further methodological considerations on the use of the concept in cultural economics

The implications of diversity still raise confusion in the cultural debate. We address them from both a formal and conceptual viewpoints, putting in check the validity of some arguments. We conclude that: measuring diversity demands key decisions and careful statistical procedures; ignorance on optimal diversity levels and on ways to generate them is widespread in the cultural field; there is no support for cultural diversity as something associated to fair economic and political systems; restriction to sheer economics requires the establishment of links between diversity and measurable properties – something rather incipient. Diversity, as a social choice, should be distinguished from it as an economic value.

Tumor Necrosis Factor alpha and Interleukin-1 beta Modulate Calcium and Nitric Oxide Signaling in Mechanically Stimulated Osteocytes

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