Investigation of structural requirements of anticancer activity at the paclitaxel/tubulin binding site using CoMFA and CoMSIA

CoMFA and CoMSIA analysis were utilized in this investigation to define the important interacting regions in paclitaxel/tubulin binding site and to develop selective paclitaxel-like active compounds. The starting geometry of paclitaxel analogs was taken from the crystal structure of docetaxel. A total of 28 derivatives of paclitaxel were divided into two groups—a training set comprising of 19 compounds and a test set comprising of nine compounds. They were constructed and geometrically optimized using SYBYL v6.6. CoMFA studies provided a good predictability (q2 = 0.699, r2 = 0.991, PC = 6, S.E.E. = 0.343 and F = 185.910). They showed the steric and electrostatic properties as the major interacting forces whilst the lipophilic property contribution was a minor factor for recognition forces of the binding site. These results were in agreement with the experimental data of the binding activities of these compounds. Five fields in CoMSIA analysis (steric, electrostatic, hydrophobic, hydrogen-bond acceptor and donor properties) were considered contributors in the ligand–receptor interactions. The results obtained from the CoMSIA studies were: q2 = 0.535, r2 = 0.983, PC = 5, S.E.E. = 0.452 and F = 127.884. The data obtained from both CoMFA and CoMSIA studies were interpreted with respect to the paclitaxel/tubulin binding site. This intuitively suggested where the most significant anchoring points for binding affinity are located. This information could be used for the development of new compounds having paclitaxel-like activity with new chemical entities to overcome the existing pharmaceutical barriers and the economical problem associated with the synthesis of the paclitaxel analogs. These will boost the wide use of this useful class of compounds, i.e. in brain tumors as the most of the present active compounds have poor blood–brain barrier crossing ratios and also, various tubulin isotypes has shown resistance to taxanes and other antimitotic agents.

Plant biology: Coding in non-coding RNAs

The discovery of peptides encoded by what were thought to be non-coding – or 'junk' – regions of precursors to microRNA sequences reveals a new layer of gene regulation. These sequences may not be junk, after all.

Investigating the impact of project definition clarity on project performance: Structural equation modeling study

Having a clear project definition is crucial for successful construction projects. It affects design quality, project communication between stakeholders and final project performance in terms of cost, schedule and quality. This study examines the relationship between project definition and final project performance through a structural equation model comprising 4 latent constructs and 6 path hypotheses using data from a questionnaire survey of 120 general contractors in the Malaysian construction industry. The results show that in the study population, all three items impact the project performance, but the link between design quality and project performance is indirect. Instead, the clarity of project definition affects project performance indirectly through design quality and project communication and design quality affects project performance indirectly through project communication. The primary contribution is to provide quantitative confirmation of the more general statements made in the literature from around the world and therefore adds to and consolidates existing knowledge. Practical implications derived from the finding are also proposed for various project stakeholders. Furthermore, as lack of the clarity of project definition is a very common occurrence in construction projects globally, these findings have important ramifications for all construction projects in expanding and clarifying existing knowledge on what is needed for the successful delivery of construction projects.

The structural basis of DNA binding by the single-stranded DNA-binding protein from Sulfolobus solfataricus

Canonical single-stranded DNA-binding proteins (SSBs) from the oligosaccharide/oligonucleotide-binding (OB) domain family are present in all known organisms and are critical for DNA replication, recombination and repair. The SSB from the hyperthermophilic crenarchaeote Sulfolobus solfataricus (SsoSSB) has a ‘simple’ domain organization consisting of a single DNA-binding OB fold coupled to a flexible C-terminal tail, in contrast with other SSBs in this family that incorporate up to four OB domains. Despite the large differences in the domain organization within the SSB family, the structure of the OB domain is remarkably similar all cellular life forms. However, there are significant differences in the molecular mechanism of ssDNA binding. We have determined the structure of the SsoSSB OB domain bound to ssDNA by NMR spectroscopy. We reveal that ssDNA recognition is modulated by base-stacking of three key aromatic residues, in contrast with the OB domains of human RPA and the recently discovered human homologue of SsoSSB, hSSB1. We also demonstrate that SsoSSB binds ssDNA with a footprint of five bases and with a defined binding polarity. These data elucidate the structural basis of DNA binding and shed light on the molecular mechanism by which these ‘simple’ SSBs interact with ssDNA.

Common psychotic symptoms can be explained by the theory of ecological perception

The symptoms of psychiatric illness are diverse, as are the causes of the illnesses that cause them. Yet, regardless of the heterogeneity of cause and presentation, a great deal of symptoms can be explained by the failure of a single perceptual function – the reprocessing of ecological perception. It is a central tenet of the ecological theory of perception that we perceive opportunities to act. It has also been found that perception automatically causes actions and thoughts to occur unless this primary action pathway is inhibited. Inhibition allows perceptions to be reprocessed into more appropriate alternative actions and thoughts. Reprocessing of this kind takes place over the entire frontal lobe and it renders action optional. Choice about what action to take (if any) is the basis for the feeling of autonomy and ultimately for the sense-of-self. When thoughts and actions occur automatically (without choice) they appear to originate outside of the self, thereby providing prima facie evidence for some of the bizarre delusions that define schizophrenia such as delusional misidentification, delusions of control and Cotard’s delusion. Automatic actions and thoughts are triggered by residual stimulation whenever reprocessing is insufficient to balance automatic excitatory cues (for whatever reason). These may not be noticed if they are neutral and therefore unimportant whereas actions and thoughts with a positive bias are desirable. Responses to negative stimulus, on the other hand, are always unwelcome, because the actions that are triggered will carry the negative bias. Automatic thoughts may include spontaneous positive feelings of love and joy, but automatic negative thoughts and visualisations are experienced as hallucinations. Not only do these feel like they emerge from elsewhere but they carry a negative bias (they are most commonly critical, rude and are irrationally paranoid). Automatic positive actions may include laughter and smiling and these are welcome. Automatic behaviours that carry a negative bias, however, are unwelcome and like hallucinations, occur without a sense of choice. These include crying, stereotypies, perseveration, ataxia, utilization and imitation behaviours and catatonia.

Structural optimization approach for specially shaped composite tank in spacecrafts

This study proposes an optimized approach of designing in which a model specially shaped composite tank for spacecrafts is built by applying finite element analysis. The composite layers are preliminarily designed by combining quasi-network design method with numerical simulation, which determines the ratio between the angle and the thickness of layers as the initial value of the optimized design. By adopting an adaptive simulated annealing algorithm, the angles and the numbers of layers at each angle are optimized to minimize the weight of structure. Based on this, the stacking sequence of composite layers is formulated according to the number of layers in the optimized structure by applying the enumeration method and combining the general design parameters. Numerical simulation is finally adopted to calculate the buckling limit of tanks in different designing methods. This study takes a composite tank with a cone-shaped cylinder body as example, in which ellipsoid head section and outer wall plate are selected as the object to validate this method. The result shows that the quasi-network design method can improve the design quality of composite material layer in tanks with complex preliminarily loading conditions. The adaptive simulated annealing algorithm can reduce the initial design weight by 30%, which effectively probes the global optimal solution and optimizes the weight of structure. It can be therefore proved that, this optimization method is capable of designing and optimizing specially shaped composite tanks with complex loading conditions.

Inventing life: Intellectual property and the new biology

In 2009, the National Research Council of the National Academies released a report on A New Biology for the 21st Century. The council preferred the term ‘New Biology’ to capture the convergence and integration of the various disciplines of biology. The National Research Council stressed: ‘The essence of the New Biology, as defined by the committee, is integration—re-integration of the many sub-disciplines of biology, and the integration into biology of physicists, chemists, computer scientists, engineers, and mathematicians to create a research community with the capacity to tackle a broad range of scientific and societal problems.’ They define the ‘New Biology’ as ‘integrating life science research with physical science, engineering, computational science, and mathematics’. The National Research Council reflected: 'Biology is at a point of inflection. Years of research have generated detailed information about the components of the complex systems that characterize life––genes, cells, organisms, ecosystems––and this knowledge has begun to fuse into greater understanding of how all those components work together as systems. Powerful tools are allowing biologists to probe complex systems in ever greater detail, from molecular events in individual cells to global biogeochemical cycles. Integration within biology and increasingly fruitful collaboration with physical, earth, and computational scientists, mathematicians, and engineers are making it possible to predict and control the activities of biological systems in ever greater detail.' The National Research Council contended that the New Biology could address a number of pressing challenges. First, it stressed that the New Biology could ‘generate food plants to adapt and grow sustainably in changing environments’. Second, the New Biology could ‘understand and sustain ecosystem function and biodiversity in the face of rapid change’. Third, the New Biology could ‘expand sustainable alternatives to fossil fuels’. Moreover, it was hoped that the New Biology could lead to a better understanding of individual health: ‘The New Biology can accelerate fundamental understanding of the systems that underlie health and the development of the tools and technologies that will in turn lead to more efficient approaches to developing therapeutics and enabling individualized, predictive medicine.’ Biological research has certainly been changing direction in response to changing societal problems. Over the last decade, increasing awareness of the impacts of climate change and dwindling supplies of fossil fuels can be seen to have generated investment in fields such as biofuels, climate-ready crops and storage of agricultural genetic resources. In considering biotechnology’s role in the twenty-first century, biological future-predictor Carlson’s firm Biodesic states: ‘The problems the world faces today – ecosystem responses to global warming, geriatric care in the developed world or infectious diseases in the developing world, the efficient production of more goods using less energy and fewer raw materials – all depend on understanding and then applying biology as a technology.’ This collection considers the roles of intellectual property law in regulating emerging technologies in the biological sciences. Stephen Hilgartner comments that patent law plays a significant part in social negotiations about the shape of emerging technological systems or artefacts: 'Emerging technology – especially in such hotbeds of change as the life sciences, information technology, biomedicine, and nanotechnology – became a site of contention where competing groups pursued incompatible normative visions. Indeed, as people recognized that questions about the shape of technological systems were nothing less than questions about the future shape of societies, science and technology achieved central significance in contemporary democracies. In this context, states face ongoing difficulties trying to mediate these tensions and establish mechanisms for addressing problems of representation and participation in the sociopolitical process that shapes emerging technology.' The introduction to the collection will provide a thumbnail, comparative overview of recent developments in intellectual property and biotechnology – as a foundation to the collection. Section I of this introduction considers recent developments in United States patent law, policy and practice with respect to biotechnology – in particular, highlighting the Myriad Genetics dispute and the decision of the Supreme Court of the United States in Bilski v. Kappos. Section II considers the cross-currents in Canadian jurisprudence in intellectual property and biotechnology. Section III surveys developments in the European Union – and the interpretation of the European Biotechnology Directive. Section IV focuses upon Australia and New Zealand, and considers the policy responses to the controversy of Genetic Technologies Limited’s patents in respect of non-coding DNA and genomic mapping. Section V outlines the parts of the collection and the contents of the chapters.

Climate-ready crops: Intellectual property, agriculture, and climate change

In The Climate Change Review, Ross Garnaut emphasised that ‘Climate change and climate change mitigation will bring about major structural change in the agriculture, forestry and other land use sectors’. He provides this overview of the effects of climate change on food demand and supply: ‘Domestic food production in many developing countries will be at immediate risk of reductions in agricultural productivity due to crop failure, livestock loss, severe weather events and new patterns of pests and diseases.’ He observes that ‘Changes to local climate and water availability will be key determinants of where agricultural production occurs and what is produced.’ Gert Würtenberger has commented that modern plant breeding is particularly concerned with addressing larger issues about nutrition, food security and climate change: ‘Modern plant breeding has an increasing importance with regard to the continuously growing demand for plants for nutritional and feeding purposes as well as with regard to renewal energy sources and the challenges caused by climate changes.’ Moreover, he notes that there is a wide array of scientific and technological means of breeding new plant varieties: ‘Apart from classical breeding, technologies have an important role in the development of plants that satisfy the various requirements that industrial and agricultural challenges expect to be fulfilled.’ He comments: ‘Plant variety rights, as well as patents which protect such results, are of increasingly high importance to the breeders and enterprises involved in plant development programmes.’ There has been larger interest in the intersections between sustainable agriculture, environmental protection and food security. The debate over agricultural intellectual property is a polarised one, particularly between plant breeders, agricultural biotechnology companies and a range of environmentalist groups. Susan Sell comments that there are complex intellectual property battles surrounding agriculture: 'Seeds are at the centre of a complex political dynamic between stakeholders. Access to seeds concerns the balance between private rights and public obligations, private ownership and the public domain, and commercial versus humanitarian objectives.' Part I of this chapter considers debates in respect of plant breeders’ rights, food security and climate change in relation to the UPOV Convention 1991. Part II explores efforts by agricultural biotechnology companies to patent climate-ready crops. Part III considers the report of the Special Rapporteur for Food, Olivier De Schutter. It looks at a variety of options to encourage access to plant varieties with climate adaptive or mitigating properties.

Structural identification of a laboratory-based steel through truss cantilevered bridge with suspended span using a layered genetic algorithm with patternsearch step (GAPS)

Structural identification (St-Id) can be considered as the process of updating a finite element (FE) model of a structural system to match the measured response of the structure. This paper presents the St-Id of a laboratory-based steel through-truss cantilevered bridge with suspended span. There are a total of 600 degrees of freedom (DOFs) in the superstructure plus additional DOFs in the substructure. The St-Id of the bridge model used the modal parameters from a preliminary modal test in the objective function of a global optimisation technique using a layered genetic algorithm with patternsearch step (GAPS). Each layer of the St-Id process involved grouping of the structural parameters into a number of updating parameters and running parallel optimisations. The number of updating parameters was increased at each layer of the process. In order to accelerate the optimisation and ensure improved diversity within the population, a patternsearch step was applied to the fittest individuals at the end of each generation of the GA. The GAPS process was able to replicate the mode shapes for the first two lateral sway modes and the first vertical bending mode to a high degree of accuracy and, to a lesser degree, the mode shape of the first lateral bending mode. The mode shape and frequency of the torsional mode did not match very well. The frequencies of the first lateral bending mode, the first longitudinal mode and the first vertical mode matched very well. The frequency of the first sway mode was lower and that of the second sway mode was higher than the true values, indicating a possible problem with the FE model. Improvements to the model and the St-Id process will be presented at the upcoming conference and compared to the results presented in this paper. These improvements will include the use of multiple FE models in a multi-layered, multi-solution, GAPS St-Id approach.

Functional and structural of the erector spinae muscle during isometric lumbar extension

Study Design Cross-sectional study. Objectives To compare erector spinae (ES) muscle fatigue between chronic non-specific lower back pain (CNLBP) sufferers and healthy subjects from a biomechanical perspective during fatiguing isometric lumbar extensions. Background Paraspinal muscle maximal contraction and fatigue are used as a functional predictor for disabilities. The simplest method to determine muscle fatigue is by evaluating the evolution during specific contractions, such as isometric contractions. There are no studies that evaluate the evolution of the ES muscle during fatiguing isometric lumbar extensions and analyse functional and architectural variables. Methods In a pre-calibrated system, participants performed a maximal isometric extension of the lumbar spine for 5 and 30 seconds. Functional variables (torque and muscle activation) and architecture (pennation angle and muscle thickness) were measured using a load cell, surface electromyography and ultrasound, respectively. The results were normalised and a reliability study of the ultrasound measurement was made. Results: The ultrasound measurements were highly reliable, with Cronbach’s alpha values ranging from 0.951 0.981. All measured variables shown significant differences before and after fatiguing isometric lumbar extension. Conclusion During a lumbar isometric extension test, architecture and functional variables of the ES muscle could be analised using ultrasound, surface EMG and load cell. In adition, during an endurance test, ES muscle suffers an acute effect on architectural and functional variables.

A new registration method based on Log-Euclidean tensor metrics and its application to genetic studies

In structural brain MRI, group differences or changes in brain structures can be detected using Tensor-Based Morphometry (TBM). This method consists of two steps: (1) a non-linear registration step, that aligns all of the images to a common template, and (2) a subsequent statistical analysis. The numerous registration methods that have recently been developed differ in their detection sensitivity when used for TBM, and detection power is paramount in epidemological studies or drug trials. We therefore developed a new fluid registration method that computes the mappings and performs statistics on them in a consistent way, providing a bridge between TBM registration and statistics. We used the Log-Euclidean framework to define a new regularizer that is a fluid extension of the Riemannian elasticity, which assures diffeomorphic transformations. This regularizer constrains the symmetrized Jacobian matrix, also called the deformation tensor. We applied our method to an MRI dataset from 40 fraternal and identical twins, to revealed voxelwise measures of average volumetric differences in brain structure for subjects with different degrees of genetic resemblance.

Development of brain structural connectivity between ages 12 and 30: A 4-Tesla diffusion imaging study in 439 adolescents and adults

Understanding how the brain matures in healthy individuals is critical for evaluating deviations from normal development in psychiatric and neurodevelopmental disorders. The brain's anatomical networks are profoundly re-modeled between childhood and adulthood, and diffusion tractography offers unprecedented power to reconstruct these networks and neural pathways in vivo. Here we tracked changes in structural connectivity and network efficiency in 439 right-handed individuals aged 12 to 30 (211 female/126 male adults, mean age=23.6, SD=2.19; 31 female/24 male 12 year olds, mean age=12.3, SD=0.18; and 25 female/22 male 16 year olds, mean age=16.2, SD=0.37). All participants were scanned with high angular resolution diffusion imaging (HARDI) at 4 T. After we performed whole brain tractography, 70 cortical gyral-based regions of interest were extracted from each participant's co-registered anatomical scans. The proportion of fiber connections between all pairs of cortical regions, or nodes, was found to create symmetric fiber density matrices, reflecting the structural brain network. From those 70 × 70 matrices we computed graph theory metrics characterizing structural connectivity. Several key global and nodal metrics changed across development, showing increased network integration, with some connections pruned and others strengthened. The increases and decreases in fiber density, however, were not distributed proportionally across the brain. The frontal cortex had a disproportionate number of decreases in fiber density while the temporal cortex had a disproportionate number of increases in fiber density. This large-scale analysis of the developing structural connectome offers a foundation to develop statistical criteria for aberrant brain connectivity as the human brain matures.

Test-retest reliability of graph theory measures of structural brain connectivity

The human connectome has recently become a popular research topic in neuroscience, and many new algorithms have been applied to analyze brain networks. In particular, network topology measures from graph theory have been adapted to analyze network efficiency and 'small-world' properties. While there has been a surge in the number of papers examining connectivity through graph theory, questions remain about its test-retest reliability (TRT). In particular, the reproducibility of structural connectivity measures has not been assessed. We examined the TRT of global connectivity measures generated from graph theory analyses of 17 young adults who underwent two high-angular resolution diffusion (HARDI) scans approximately 3 months apart. Of the measures assessed, modularity had the highest TRT, and it was stable across a range of sparsities (a thresholding parameter used to define which network edges are retained). These reliability measures underline the need to develop network descriptors that are robust to acquisition parameters.

Reducing structural variation to determine the genetics of white matter integrity across hemispheres - a dti study of 100 twins

Studies of cerebral asymmetry can open doors to understanding the functional specialization of each brain hemisphere, and how this is altered in disease. Here we examined hemispheric asymmetries in fiber architecture using diffusion tensor imaging (DTI) in 100 subjects, using high-dimensional fluid warping to disentangle shape differences from measures sensitive to myelination. Confounding effects of purely structural asymmetries were reduced by using co-registered structural images to fluidly warp 3D maps of fiber characteristics (fractional and geodesic anisotropy) to a structurally symmetric minimal deformation template (MDT). We performed a quantitative genetic analysis on 100 subjects to determine whether the sources of the remaining signal asymmetries were primarily genetic or environmental. A twin design was used to identify the heritable features of fiber asymmetry in various regions of interest, to further assist in the discovery of genes influencing brain micro-architecture and brain lateralization. Genetic influences and left/right asymmetries were detected in the fiber architecture of the frontal lobes, with minor differences depending on the choice of registration template.

Multiple stages classification of Alzheimer’s disease based on structural brain networks using generalized low rank approximations (GLRAM)

To classify each stage for a progressing disease such as Alzheimer’s disease is a key issue for the disease prevention and treatment. In this study, we derived structural brain networks from diffusion-weighted MRI using whole-brain tractography since there is growing interest in relating connectivity measures to clinical, cognitive, and genetic data. Relatively little work has usedmachine learning to make inferences about variations in brain networks in the progression of the Alzheimer’s disease. Here we developed a framework to utilize generalized low rank approximations of matrices (GLRAM) and modified linear discrimination analysis for unsupervised feature learning and classification of connectivity matrices. We apply the methods to brain networks derived from DWI scans of 41 people with Alzheimer’s disease, 73 people with EMCI, 38 people with LMCI, 47 elderly healthy controls and 221 young healthy controls. Our results show that this new framework can significantly improve classification accuracy when combining multiple datasets; this suggests the value of using data beyond the classification task at hand to model variations in brain connectivity.