Mapping the early steps in the pH-induced conformational conversion of the prion protein

Under certain conditions, the prion protein (PrP) undergoes a conformational change from the normal cellular isoform, PrPC, to PrPSc, an infectious isoform capable of causing neurodegenerative diseases in many mammals. Conversion can be triggered by low pH, and in vivo this appears to take place in an endocytic pathway and/or caveolae-like domains. It has thus far been impossible to characterize the conformational change at high resolution by experimental methods. Therefore, to investigate the effect of acidic pH on PrP conformation, we have performed 10-ns molecular dynamics simulations of PrPC in water at neutral and low pH. The core of the protein is well maintained at neutral pH. At low pH, however, the protein is more dynamic, and the sheet-like structure increases both by lengthening of the native β-sheet and by addition of a portion of the N terminus to widen the sheet by another two strands. The side chain of Met-129, a polymorphic codon in humans associated with variant Creutzfeldt–Jakob disease, pulls the N terminus into the sheet. Neutralization of Asp-178 at low pH removes interactions that inhibit conversion, which is consistent with the Asp-178–Asn mutation causing human prion diseases.

Components of verbal working memory: Evidence from neuroimaging

We review research on the neural bases of verbal working memory, focusing on human neuroimaging studies. We first consider experiments that indicate that verbal working memory is composed of multiple components. One component involves the subvocal rehearsal of phonological information and is neurally implemented by left-hemisphere speech areas, including Broca’s area, the premotor area, and the supplementary motor area. Other components of verbal working memory may be devoted to pure storage and to executive processing of the contents of memory. These studies rest on a subtraction logic, in which two tasks are imaged, differing only in that one task presumably has an extra process, and the difference image is taken to reflect that process. We then review studies that show that the previous results can be obtained with experimental methods other than subtraction. We focus on the method of parametric variation, in which a parameter that presumably reflects a single process is varied. In the last section, we consider the distinction between working memory tasks that require only storage of information vs. those that require that the stored items be processed in some way. These experiments provide some support for the hypothesis that, when a task requires processing the contents of working memory, the dorsolateral prefrontal cortex is disproportionately activated.

John Winthrop's proposal respecting electrical globes and jars, ca. 1758

In this proposal, John Winthrop explains the need to replace damaged "electric globes" used in the College's collection of scientific apparatus. He states that Benjamin Franklin, at the time residing in London, was willing to seek replacement globes for the College's collection. Winthrop then proceeds to assert that the College should acquire "square bottles, of a moderate size, fitted in a wooden box, like what they call case bottles for spirits" instead of the large jars included in the scientific apparatus, because those jars cracked frequently.

Enhancements to passive warning devices at railroad-highway grade crossings.

Texas Department of Transportation, Austin

Investigation of some of the problems of vehicle rear lighting. Appendices A and B.

Bolt, Beranek and Newman, Inc., Van Nuys, Calif.

Motor vehicle rear lighting and signalling. Final report.

National Highway Safety Bureau, Washington, D.C.

Design Expressions and Dynamic Evaluation of CFST Bridges Subjected to Seismic Hazards

Thesis (Ph.D.)--University of Washington, 2016-06

User dyads in software testing: bypassing the need for expert observers

This paper arises out of a research study into the online help facilities provided in popular software applications such as word processors. Its particular focus is on experimental methods of evaluating the effectiveness and usability of those facilities. Focus groups, questionnaires, and online surveys had already been used in other phases of the study, but it was judged that these approaches would be unsuitable for measuring effectiveness and usability because they are susceptible to respondents' subjectivity. Direct observation of people working on set word-processing tasks was ruled out initially because of a lack of trained observers; it would have taken too long for the investigator to observe a large enough sample by himself. Automatic recording of users' actions was also rejected, as it would have demanded equipment and/or software that was not available and seemed too expensive to acquire. The approach and techniques described here were an attempt to overcome these difficulties by using observers drawn from the same population of students that provided the test subjects; as a by-product, this may also have enhanced the acceptability (and hence possibly the validity) of the experiments by reducing the exam pressure perceived by participants.

Modelling cell lifespan and proliferation: is likelihood to die or to divide independent of age?

In cell lifespan studies the exponential nature of cell survival curves is often interpreted as showing the rate of death is independent of the age of the cells within the population. Here we present an alternative model where cells that die are replaced and the age and lifespan of the population pool is monitored until a, steady state is reached. In our model newly generated individual cells are given a determined lifespan drawn from a number of known distributions including the lognormal, which is frequently found in nature. For lognormal lifespans the analytic steady-state survival curve obtained can be well-fit by a single or double exponential, depending on the mean and standard deviation. Thus, experimental evidence for exponential lifespans of one and/or two populations cannot be taken as definitive evidence for time and age independence of cell survival. A related model for a dividing population in steady state is also developed. We propose that the common adoption of age-independent, constant rates of change in biological modelling may be responsible for significant errors, both of interpretation and of mathematical deduction. We suggest that additional mathematical and experimental methods must be used to resolve the relationship between time and behavioural changes by cells that are predominantly unsynchronized.

Evaluation of parameters effective in FRP shear strengthening of RC beams using FE method

Shear strengthening is required when an RC beam is found deficient in shear, or when its shear capacity falls below its flexural capacity after flexural strengthening. A recent technique for the shear strengthening of RC beams is to provide additional FRP web reinforcement, commonly in the form of bonded external FRP strips/sheets. Over the last few years, several experimental studies have been conducted on this new strengthening technique, which has established its effectiveness. While experimental methods of investigation are extremely useful in obtaining information about the composite behaviour of FRP and reinforced concrete, the use of numerical models such as the one presented in this paper helps in developing a good understanding of the behaviour at lower costs. In the study presented in this paper, ANSYS finite element program is used to examine the response of beams strengthened in shear by FRPs. The FE model is calibrated against test results performed at the University of Kentucky. Once validated, the model is used to examine the influence of fibre orientation, compressive strength of concrete, area of tensile and compressive reinforcements, and amount and distance between stirrups on the strength and ductility of FRP strengthened beam.

Spring Phenology of Butterflies : The role of seasonal variation in life-cycle regulation

Animals and plants in temperate regions must adapt their life cycle to pronounced seasonal variation. The research effort that has gone into studying these cyclical life history events, or phenological traits, has increased greatly in recent decades. As phenological traits are often correlated to temperature, they are relevant to study in terms of understanding the effect of short term environmental variation as well as long term climate change. Because of this, changes in phenology are the most obvious and among the most commonly reported responses to climate change. Moreover, phenological traits are important for fitness as they determine the biotic and abiotic environment an individual encounters. Fine-tuning of phenology allows for synchronisation at a local scale to mates, food resources and appropriate weather conditions. On a between-population scale, variation in phenology may reflect regional variation in climate. Such differences can not only give insights to life cycle adaptation, but also to how populations may respond to environmental change through time. This applies both on an ecological scale through phenotypic plasticity as well as an evolutionary scale through genetic adaptation. In this thesis I have used statistical and experimental methods to investigate both the larger geographical patterns as well as mechanisms of fine-tuning of phenology of several butterfly species. The main focus, however, is on the orange tip butterfly, Anthocharis cardamines, in Sweden and the United Kingdom. I show a contrasting effect of spring temperature and winter condition on spring phenology for three out of the five studied butterfly species. For A. cardamines there are population differences in traits responding to these environmental factors between and within Sweden and the UK that suggest adaptation to local environmental conditions. All populations show a strong negative plastic relationship between spring temperature and spring phenology, while the opposite is true for winter cold duration. Spring phenology is shifted earlier with increasing cold duration. The environmental variables show correlations, for example, during a warm year a short winter delays phenology while a warm spring speeds phenology up. Correlations between the environmental variables also occur through space, as the locations that have long winters also have cold springs. The combined effects of these two environmental variables cause a complex geographical pattern of phenology across the UK and Sweden. When predicting phenology with future climate change or interpreting larger geographical patterns one must therefore have a good enough understanding of how the phenology is controlled and take the relevant environmental factors in to account. In terms of the effect of phenological change, it should be discussed with regards to change in life cycle timing among interacting species. For example, the phenology of the host plants is important for A. cardamines fitness, and it is also the main determining factor for oviposition. In summary, this thesis shows that the broad geographical pattern of phenology of the butterflies is formed by counteracting environmental variables, but that there also are significant population differences that enable fine-tuning of phenology according to the seasonal progression and variation at the local scale.

Studies on the thermal decomposition behaviour, kinetics and electrical conductivity of the non-isothermal decomposition of pyridine mono carboxylic acids and some of their transition metal complexes

The thesis is divided into four chapters. They are: introduction, experimental, results and discussion about the free ligands and results and discussion about the complexes. The First Chapter, the introductory chapter, is a general introduction to the study of solid state reactions. The Second Chapter is devoted to the materials and experimental methods that have been used for carrying out tile experiments. TIle Third Chapter is concerned with the characterisations of free ligands (Picolinic acid, nicotinic acid, and isonicotinic acid) by using elemental analysis, IR spectra, X-ray diffraction, and mass spectra. Additionally, the thermal behaviour of free ligands in air has been studied by means of thermogravimetry (TG), derivative thermogravimetry (DTG), and differential scanning calorimetry (DSC) measurements. The behaviour of thermal decomposition of the three free ligands was not identical Finally, a computer program has been used for kinetic evaluation of non-isothermal differential scanning calorimetry data according to a composite and single heating rate methods in comparison with the methods due to Ozawa and Kissinger methods. The most probable reaction mechanism for the free ligands was the Avrami-Erofeev equation (A) that described the solid-state nucleation-growth mechanism. The activation parameters of the decomposition reaction for free ligands were calculated and the results of different methods of data analysis were compared and discussed. The Fourth Chapter, the final chapter, deals with the preparation of cobalt, nickel, and copper with mono-pyridine carboxylic acids in aqueous solution. The prepared complexes have been characterised by analyses, IR spectra, X-ray diffraction, magnetic moments, and electronic spectra. The stoichiometry of these compounds was ML2x(H20), (where M = metal ion, L = organic ligand and x = water molecule). The environments of cobalt, nickel, and copper nicotinates and the environments of cobalt and nickel picolinates were octahedral, whereas the environment of copper picolinate [Cu(PA)2] was tetragonal. However, the environments of cobalt, nickel, and copper isonicotinates were polymeric octahedral structures. The morphological changes that occurred throughout the decomposition were followed by SEM observation. TG, DTG, and DSC measurements have studied the thermal behaviour of the prepared complexes in air. During the degradation processes of the hydrated complexes, the crystallisation water molecules were lost in one or two steps. This was also followed by loss of organic ligands and the metal oxides remained. Comparison between the DTG temperatures of the first and second steps of the dehydration suggested that the water of crystallisation was more strongly bonded with anion in Ni(II) complexes than in the complexes of Co(II) and Cu(II). The intermediate products of decomposition were not identified. The most probable reaction mechanism for the prepared complexes was also Avrami-Erofeev equation (A) characteristic of solid-state nucleation-growth mechanism. The tempemture dependence of conductivity using direct current was determined for cobalt, nickel, Cl.nd copper isonicotinates. An activation energy (ΔΕ), the activation energy (ΔΕ ) were calculated.The ternperature and frequency dependence of conductivity, the frequency dependence of dielectric constant, and the dielectric loss for nickel isonicotinate were determined by using altemating current. The value of s paralneter and the value of'density of state [N(Ef)] were calculated. Keyword Thermal decomposition, kinetic, electrical conduclion, pyridine rnono~ carboxylic acid, cOlnplex, transition metal compJex.

Phase equilibrium studies at moderate pressures

The theory of vapour-liquid equilibria is reviewed, as is the present status or prediction methods in this field. After discussion of the experimental methods available, development of a recirculating equilibrium still based on a previously successful design (the modified Raal, Code and Best still of O'Donnell and Jenkins) is described. This novel still is designed to work at pressures up to 35 bar and for the measurement of both isothermal and isobaric vapour-liquid equilibrium data. The equilibrium still was first commissioned by measuring the saturated vapour pressures of pure ethanol and cyclohexane in the temperature range 77-124°C and 80-142°C respectively. The data obtained were compared with available literature experimental values and with values derived from an extended form of the Antoine equation for which parameters were given in the literature. Commissioning continued with the study of the phase behaviour of mixtures of the two pure components as such mixtures are strongly non-ideal, showing azeotopic behaviour. Existing data did not exist above one atmosphere pressure. Isothermal measurements were made at 83.29°C and 106.54°C, whilst isobaric measurements were made at pressures of 1 bar, 3 bar and 5 bar respectively. The experimental vapour-liquid equilibrium data obtained are assessed by a standard literature method incorporating a themodynamic consistency test that minimises the errors in all the measured variables. This assessment showed that reasonable x-P-T data-sets had been measured, from which y-values could be deduced, but that the experimental y-values indicated the need for improvements in the design of the still. The final discussion sets out the improvements required and outlines how they might be attained.

Studies of the effects of molecular encounters on N.M.R. spin-lattice relaxation times

This thesis is concerned with investigations of the effects of molecular encounters on nuclear magnetic resonance spin-lattice relaxation times, with particular reference to mesitylene in mixtures with cyclohexane and TMS. The purpose of the work was to establish the best theoretical description of T1 and assess whether a recently identified mechanism (buffeting), that influences n.m.r. chemical shifts, governs Tl also. A set of experimental conditions are presented that allow reliable measurements of Tl and the N. O. E. for 1H and 13C using both C. W. and F.T. n.m.r. spectroscopy. Literature data for benzene, cyclohexane and chlorobenzene diluted by CC14 and CS2 are used to show that the Hill theory affords the best estimation of their correlation times but appears to be mass dependent. Evaluation of the T1 of the mesitylene protons indicates that a combined Hill-Bloembergen-Purcell-Pound model gives an accurate estimation of T1; subsequently this was shown to be due to cancellation of errors in the calculated intra and intemolecular components. Three experimental methods for the separation of the intra and intermolecular relaxation times are described. The relaxation times of the 13C proton satellite of neat bezene, 1,4 dioxane and mesitylene were measured. Theoretical analyses of the data allow the calculation of Tl intra. Studies of intermolecular NOE's were found to afford a general method of separating observed T1's into their intra and intermolecular components. The aryl 1H and corresponding 13C T1 values and the NOE for the ring carbon of mesitylene in CC14 and C6H12-TMS have been used in combination to determine T1intra and T1inter. The Hill and B.P.P. models are shown to predict similarly inaccurate values for T1linter. A buffeting contribution to T1inter is proposed which when applied to the BPP model and to the Gutowsky-Woessner expression for T1inter gives an inaccuracy of 12% and 6% respectively with respect to theexperimentally based T1inter.

Structural behaviour of glass reinforced plastics

The aim of this research is to promote the use of G.R.P. as a structural material. In the past, the use of G.R.P. has been confined to non-load carrying applications. Such uses are still rapidly increasing but in addition significant changes have been made during the last decade in the development of semi-structural and now even fully structural applications. Glass-reinforced plastic is characterized by a high strength but a relatively low modulus of elasticity. For this reasona G.R.P. structure can expect to show large deformations as a result of which the individual structural members will fail under load due to a loss of stability rather than approaching the ultimate strength of the material. For this reason the selection of the geometrical shapes of G.R.P. structural elements is considered to be an important factor in designing G.R.P. structures. The first chapter of this thesis deals with a general review of the theoretical and experimental methods used to describe the structural properties of G.R.P. The research programme includes five stages dealing with the structural behaviour of G.R.P. The first stage (Chapter 2) begins with selecting and designing an optimum box beam cross-section which gives the maximum flexural and torsional rigidity. The second stage of investigation (Chapter 3) deals with beam to beam connections. A joint was designed and manufactured with different types of fasteners used to connect two beam units. A suitable fastener was selected and the research extended to cover the behaviour of long span beams using multiple joints. The third part of the investigation includes a study of the behaviour of box beams subjected to combined bending, shear and torsion. A special torque rig was developed to perform the tests. Creep deformation of 6 m span G.R.P. was investigated as the fourth stage under a range of loading conditions. As a result of the phenomenon of post buckling behaviour exhibited in the compression flange during testing of box beams during earlier stages of the investigation it was decided to consider this phenomenon in more detail in the final stage of the investigation. G.R.P. plates with different fibre orientation were subjected to uniaxial compression and tested up to failure. In all stages of the investigation theoretical predictions and experimental results were compared and generally good correlation between theory and experimental data was observed.