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Interphase boundary plays a dominant role in the mechanical properties of dual-phase titanium alloys, and therefore mechanistic understandings of the effect of phase boundary on the plasticity is significant to tailor the microstructure for desired performance. In this study, compression tests were conducted on the Ti-6Al-4V micro-pillars with a dual-phase lamellar structure and designated crystallographic orientation of pillars and the number of interphase boundaries in the pillars were achieved by elaborate processing, to reveal the interphase boundary and its quantity on the dislocation behavior and critical resolved shear stress (CRSS) of the alloy. Transmission electron microscopy was employed to characterize the dislocations and their interplay with interphase boundaries during compression. It is found that in the pillars oriented for prismatic 〈a 3 〉 slip, which represents the hard mode for dislocation transmission through the α/β phase boundary, the strain distribution in the pillars was significantly delocalized by introducing interphase boundaries. More dislocation slip bands are generated owing to the strengthening effect from the interphase boundaries during compression, which results in a more homogeneous strain distribution. Moreover, quantitative analyses of the contribution of interphase boundaries on the CRSS were performed, and the interphase strength for prismatic 〈a 3 〉 slip was experimentally determined to be ∼ 50 MPa. The effect of pillar size on the CRSS value was also assessed. Although the CRSS of the pillars increases when their size decreases, the size dependency becomes much less pronounced when more interphase boundaries are introduced into the pillars. The underlying mechanisms for these phenomena were discussed based on the experimental results and finite element modeling. These results provide some new insights into the plasticity and strengthening mechanism of Ti-6Al-4V alloy, which are also applicable to other dual-phase titanium alloys. [Display omitted] [ABSTRACT FROM AUTHOR]

Cardiovascular disease is a leading cause of morbidity, mortality, and healthcare expenditure worldwide. Importantly, there is interindividual variation in response to cardiovascular medications, leading to variable efficacy and adverse events. Therefore a rapid, selective, sensitive and reproducible multi-analyte HPLC-MS/MS assay for the quantification in human plasma of atorvastatin, its major metabolites 2-hydroxyatorvastatin, atorvastatin lactone and 2-hydroxyatorvastatin lactone, plus bisoprolol and clopidogrel-carboxylic acid has been developed, fully validated, and applied to a large patient study. Fifty microliter plasma samples were extracted with a simple protein precipitation procedure involving acetonitrile with acetic acid (0.1%, v/v ). Chromatographic separation was via a 2.7 μm Halo C18 (50 × 2.1 mm ID, 90 Å) column and gradient elution at a flow rate of 500 μL/min consisting of a mobile phase of water (A) and acetonitrile (B), each containing 0.1% formic acid ( v/v ), over a 6.0 min run time. The six analytes and their corresponding six deuterated internal standards underwent positive ion electrospray ionisation and were detected with multiple reaction monitoring. The developed method was fully validated with acceptable selectivity, carryover, dilution integrity, and within-run and between-run accuracy and precision. Mean extraction recovery for the analytes was 92.7–108.5%, and internal standard-normalised matrix effects had acceptable precision (coefficients of variation 2.2–12.3%). Moreover, all analytes were stable under the tested conditions. Atorvastatin lactone to acid interconversion was assessed and recommendations for its minimisation are made. The validated assay was successfully applied to analyse 1279 samples from 1024 patients recruited to a cardiovascular secondary prevention prospective study. [ABSTRACT FROM AUTHOR]

We assessed auditory sensitivity to three classes of temporal-envelope statistics (modulation depth, modulation rate, and comodulation) that are important for the perception of ‘sound textures’. The textures were generated by a probabilistic model that prescribes the temporal statistics of a selected number of modulation envelopes, superimposed onto noise carriers. Discrimination thresholds were measured for normal-hearing (NH) listeners and users of a MED-EL pulsar cochlear implant (CI), for separate manipulations of the average rate and modulation depth of the envelope in each frequency band of the stimulus, and of the co-modulation between bands. Normal-hearing (NH) listeners' discrimination of envelope rate was similar for baseline modulation rates of 5 and 34 Hz, and much poorer than previously reported for sinusoidally amplitude-modulated sounds. In contrast, discrimination of model parameters that controlled modulation depth was poorer at the lower baseline rate, consistent with the idea that, at the lower rate, subjects get fewer ‘looks’ at the relevant information when comparing stimuli differing in modulation depth. NH listeners could discriminate differences in co-modulation across bands; a multidimensional scaling study revealed that this was likely due to genuine across-frequency processing, rather than within-channel cues. CI users' discrimination performance was worse overall than for NH listeners, but showed a similar dependence on stimulus parameters. [ABSTRACT FROM AUTHOR]

The August 6, 2012 Te Maari, New Zealand eruption produced a very small ash-dominated plume (~ 230,000 m 3 , 8–10 km high) that was rapidly and widely dispersed, covering 1600 km 2 within an hour. This paper documents for the August 6, 2012 Te Maari eruption the upper level (troposphere) plume movement based on ash-detection algorithms applied to IR satellite imagery. It also presents the distribution of airborne ash and wind-influenced ashfall as determined by NAME-III aerial dispersion modelling using observed particle characteristics and grain size distribution measurements (that are also presented) and compares the ashfall with observations. The upper level (troposphere) ash movement was also evaluated from ash-detection algorithms, applied to infra-red satellite imagery and the resulting distributions were compared to those forecast by the numerical dispersion models. Forecasts of upper level ash-dispersion patterns explained the satellite imagery observations well, predicting the correct altitudes when using plausible ash size distributions and release levels. Patterns in proximal ashfall could only be partly explained by aerial dispersal of large particles released at low altitudes in the eruption column. The extreme distal (100–150 km away) observed ashfall distributions also cannot be fully explained by NAME-III when using: reasonably prescribed initial particle size distributions, eruption column height, eruption timing, well forecast winds, and dry sedimentation processes. Aggregation and ice nucleation effects (observed in deposits) were not included in the ash dispersion model, but appear as a plausible mechanism to account for the observed fraction of wind dispersed ash particles < 30 μm deposited but not captured by the models. [ABSTRACT FROM AUTHOR]

Abstract: Multi-product biopharmaceutical facilities need flexible process configurations that can adapt to products with diverse characteristics and impurity loads so as to avoid bottlenecks and delays, whilst meeting final product specifications and cost targets. In order to aid the design of such facilities, this work presents a meta-heuristic optimisation approach using genetic algorithms where different levels of decision are addressed (facility, product sequence and unit operation) and multiple process and business criteria are used to evaluate each alternative generated. This is applied to a case study on the production of therapeutic monoclonal antibodies (mAbs), with a focus on the optimal purification sequences and chromatography column sizing strategies to cope with different facility configurations of upstream and downstream trains and different product impurity loads. The industrial case study provides novel insights that allow the identification of the most cost-effective purification sequences and column sizing strategies that meet demand and purity targets for each product in the facility. Emphasis is placed also on providing methods to visualise the trade-offs in the set of optimal solutions with similar cost values so as to enhance the decision making process. [Copyright &y& Elsevier]

Abstract: Previous studies have shown that individual TCRs are able to effectively recognize multiple peptide/MHC complexes that have varying degrees of structural diversity. These TCR cross-reactivities have usually been demonstrated by using peptides that have different amino acid sequences. To further examine the extent to which TCRs can accommodate structurally diverse ligands, we analyzed human TCR cross-reactivity to eight structurally distinct haptens that are coupled to the HLA-A2-binding Tax peptide with a lysine substitution at position 5 (Tax-5K, LLFG[K-hapten]PVYV). The results demonstrate that 71% percent of the haptenated-peptide-induced CTL lines could cross-react on at least one other hapten. We compared the effects of HLA-A2 mutants with substitutions at known TCR contact sites for recognition by hapten-cross-reactive CTL. Recognition of the A2 mutants was remarkably similar whether they were presenting the immunizing or the cross-reactive peptide, indicating that similar amino acid contacts are made by the TCR during recognition of both complexes. Thus, hapten cross-reactivity is apparently accomplished without major adjustments to the interaction between the TCR and the surface of the HLA-A2 molecule. Collectively, these results suggest that TCRs possess the molecular flexibility to accommodate very structurally diverse ligands while retaining conserved interactions with the surface of the MHC molecule. [Copyright &y& Elsevier]

SummaryWe and colleagues have suggested that deletions of mitochondrial DNA may be useful as a biomarker of ultraviolet radiation exposure in skin. In this study using a southwestern approach involving monoclonal antibodies against thymine dimers we provide direct evidence for the presence of ultraviolet-induced damage in mitochondrial DNA purified from any nuclear DNA contamination. Previous studies have been limited, as they have focused on the frequency of a single mitochondrial DNA deletion. Therefore we have addressed the question of the spectrum of mitochondrial DNA deletions in skin and whether this can be used as an index of overall DNA damage. We have used a long polymerase chain reaction technique to determine the mitochondrial DNA deletion spectrum of almost the entire mitochondrial genome in 71 split skin samples in relation to sun exposure. There was a significant increase in the number of deletions with increasing ultraviolet exposure in the epidermis (Kruskal–Wallis test, p = 0.0015) but not the dermis (p = 0.6376). The findings in the epidermis are not confounded by any age-dependent increases in mitochondrial DNA deletions also detected by the long polymerase chain reaction technique. The large spectrum of deletions identified in our study highlights the ubiquitous nature and the high mutational load of mitochondrial DNA associated with ultraviolet exposure and chronologic aging. Compared with the detection of single deletions using competitive polymerase chain reaction, we show that long polymerase chain reaction is a sensitive technique and may therefore provide a more comprehensive, although not quantitative, index of overall mitochondrial DNA damage in skin. [ABSTRACT FROM AUTHOR]

A microstructural characterisation and computational modelling framework for simulating the coupled thermal-mechanical cycles with two different initial parent microstructures, and their impact upon the emerging microstructure features including β grain size and phase volume fractions during electron beam welding (EBW) of Ti-6Al-4 V (Ti64) alloy is presented. Ti64 plates (measuring 5.5 mm in thickness) with different thermal processing have been electron beam welded using differing process parameter sets. These experimental welds have been fully characterised to provide information on the effect that a prior heat treatment has upon the microstructural evolution caused by the EB welding. Microstructure characterisation was investigated using both light microscopy and scanning electron microscopy. The results from this microstructure characterisation have been used to identity physically-based parameters required for microstructure predictions. [ABSTRACT FROM AUTHOR]

• This study uniquely investigates ex cult-members' experiences of a creative therapy workshop. • Flow states were measured in creative therapy activities and explored with participants. • Multimodal arts within a pluralistic therapeutic framework enabled Flow and goal attainment. • Therapeutic arts can support individuals surviving, transcending and healing from cultic abuse. • Research recruitment and novel methods can trigger ex-cult members' suspicion and resistance. Creative arts can play an important role for cult survivors in surviving, transcending and healing from their past realities. Flow – an empowering state of mind-body integration and skilful, intuitive action while engaged in a challenging yet enjoyable task (Csikszentmihalyi, 1997) – may be an important mechanism in arts therapies and may be especially impactful as an experience for cult survivors. Research reporting on arts therapies for cult survivors, Flow in cult survivors and Flow in arts therapies is currently severely lacking. This study reports on a multimodal creative psychological therapy, Arts for the Blues, piloted as a workshop with a small group of cult survivors. Results obtained from three participants show that they experienced Flow in their creative activities and increased attainment in a self-selected personal goal. Interviews with two participants reveal important considerations for working with cult survivors, the healing power of the arts, the attainment of Flow states in the process, and the impact of the Arts for the Blues approach. This study is the first of its kind to trial art therapies with ex cult-members, or to document participants' views on Flow states during an arts therapy approach. Although limited by a small sample size, further research is warranted. [ABSTRACT FROM AUTHOR]

A fluid dynamics approach to modelling of fusion welding in titanium alloys is proposed. The model considers the temporal and spatial evolution of liquid metal/gas interface to capture the transient physical effects during the heat source–material interaction of a fusion welding process. Melting and vaporisation have been considered through simulation of all interfacial phenomena such as surface tension, Marangoni force and recoil pressure. The evolution of the metallic (solid and liquid) and gaseous phases which are induced by the process enables the formation of the keyhole, keyhole dynamics, and the fully developed weld pool geometry. This enables the likelihood of fluid flow-induced porosity to be predicted. These features are all a function of process parameters and formulated as time-dependent phenomena. The proposed modelling framework can be utilised as a simulation tool to further develop understanding of defect formation such as weld-induced porosity for a particular fusion welding application. The modelling results are qualitatively compared with available experimental information. [ABSTRACT FROM AUTHOR]

The development of atrial flutter and fibrillation (AFL/AF) in patients with pre-capillary pulmonary hypertension has been associated with an increased risk of morbidity and mortality. Rate and rhythm control strategies have not been directly compared. Eighty-four patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) with new-onset AFL/AF were identified in the ASPIRE registry. First, baseline characteristics and rates of sinus rhythm (SR) restoration of 3 arrhythmia management strategies (rate control, medical rhythm control and DC cardioversion, DCCV) in an early (2009–13) and later (2014–19) cohort were compared. Longer-term outcomes in patients who achieved SR versus those who did not were then explored. Sixty (71%) patients had AFL and 24 (29%) AF. Eighteen (22%) patients underwent rate control, 22 (26%) medical rhythm control and 44 (52%) DCCV. SR was restored in 33% treated by rate control, 59% medical rhythm control and 95% DCCV (p < 0.001). Restoration of SR was associated with greater improvement in functional class (FC) and Incremental Shuttle Walk Distance (p both <0.05). It also independently predicted superior survival (3-year survival 62% vs 23% in those remaining in AFL/AF, p < 0.0001). In addition, FC III/IV independently predicted higher mortality (HR 2.86, p = 0.007). Right atrial area independently predicted AFL/AF recurrence (OR 1.08, p = 0.01). DCCV was generally well tolerated with no immediate major complications. Restoration of SR is associated with superior functional improvement and survival in PAH/CTEPH compared with rate control. DCCV is generally safe and is more effective than medical therapy at achieving SR. • Atrial arrhythmias increase morbidity and mortality in pulmonary hypertension • Restoration of sinus rhythm leads to improved functional status and survival • DC cardioversion is a safe and effective initial strategy to achieve rhythm control [ABSTRACT FROM AUTHOR]

Relative stability of therapeutic antibody candidates is currently evaluated primarily through their response to thermal degradation, yet this technique is not always predictive of stability in manufacture, shipping, and storage. A rotating disk shear device is proposed that produces defined shear conditions at a known solid-liquid interface to measure stability in this environment. Five variants of Ig G1 and Ig G4 antibodies were created using combinations of two discrete triple amino acid sequence mutations denoted TM and YTE. Antibodies were ranked for stability based on shear device output (protein decay coefficient, PDC), and compared with accelerated thermal stability data and the melting temperature of the CH2 domain ( Tm1) from differential scanning calorimetry to investigate technique complimentarity. Results suggest that the techniques are orthogonal, with thermal methods based on intramolecular interaction and shear device stability based on localized unfolding revealing less stable regions that drive aggregation. Molecular modeling shows the modifications' effects on the antibody structures and indicates a possible role for Fc conformation and Fab- Fc docking in determining suspended protein stability. The data introduce the PDC value as an orthogonal stability indicator, complementary to traditional thermal methods, allowing lead antibody selection based on a more full understanding of process stability. © 2013 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:437-444, 2014 [ABSTRACT FROM AUTHOR]

• Time-series ML pipeline for predicting process performance in biologics manufacturing. • Distinguish poor-, moderate, and high-performing processes in first half of operation. • Identify "grey zones" of performance where decision should be delayed until later. • Automation for bioprocess QbD compliance to ensure reproducibility in manufacturing. Despite the availability of large amount of data in bioprocess databases, little has been done for its retrospective analysis for process improvement. Historic bioprocess data is multivariate time-series, and due to its inherent nature, is incompatible with a variety of statistical methods employed in data analysis resulting in the lack of a tailored methodology. We present here an integrative framework of knowledge discovery tailored for handling historical bioprocess datasets. The pipeline successfully predicts process performance at harvest from an early time point, and robustly identifies the most relevant process parameters to model process performance. We present the utility of this pipeline on biologics manufacturing data from upstream bioprocess development for antibody production by mammalian cells. The proposed multi-model system that employs machine learning can predict performance at harvest after two weeks of operation with satisfactory accuracy employing data generated as early as on the sixth day of the culture. [ABSTRACT FROM AUTHOR]

We have examined the use of mitochondrial DNA (mtDNA) as a molecular marker to study the relation between chronologic aging and photoageing in human skin. Using a 3‐primer quantitative polymerase chain reaction method we have studied changes in the ratio of the 4977 bp deleted to wild‐type mtDNA in relation to sun exposure and chronologic age of human skin. Based on previous studies, samples showing greater than 1% deleted mtDNA were classed as abnormal. There was a significant increase in the incidence of high levels (i.e., >1%) of the 4977 bp deleted mtDNA in sun‐exposed sites (27%, 27 of 100) compared with sun‐protected sites (1.1%, one of 90) (Fisher’s exact test, p < 0.0001). There appeared to be no relation between the frequency of the mtDNA deletion and age. Analysis of split skin samples showed that most deletions (93%, n = 27) were confined to the dermal rather than the epidermal component, and in keeping with this deletions were found in three of six primary cultures of fibroblasts from sun‐exposed sites. Deletions were not seen in the epidermal component of several epidermal tumors nor were deletions seen in fibroblasts cultured from an individual with Werner’s syndrome. We propose that deletions or mutations of mitochondrial DNA may be useful as a marker of cumulative ultraviolet radiation exposure. [ABSTRACT FROM AUTHOR]

The study aims to estimate design wind speeds and associated directional multipliers, also lee-zone multipliers for New Zealand through the analysis of historical wind data recorded at meteorological stations and also utilising a high-resolution convection-resolving numerical weather prediction model (New Zealand Convective-Scale Model (NZCSM)) analyses. New Zealand's historical wind data have not been analysed in the past two decades for design wind-load purposes. In addition, no attempt has been made to thoroughly homogenise the mean and gust wind speed data recorded prior to the 1990s and to convert them to equivalent Automatic Weather Stations (AWS) records. Furthermore, lee zones, areas affected by the wind speed-up due to the presence of mountains, can significantly influence the design wind loads, thus, it is crucial to estimate the spatial extent and magnitude of the lee multiplier accurately. In this study, the wind data were initially subjected to a robust homogenisation algorithm and then, they were separated into synoptic and non-synoptic events to gain a better understanding of New Zealand's gust climatology and sources of extreme events. It was demonstrated that synoptic events dominate the design wind speeds at most locations in New Zealand. For extreme value analysis, three different extreme value distributions were used, namely Type I (using Gumbel, Gringorten and BLUE fitting methods), Type III (using maximum likelihood and probability weighted moments methods), and Peaks-Over-Threshold (POT) approach. In addition, the predictions of NZCSM along with historical wind speeds were used to identify the lee zones, which confirms existing zones and provides evidence to support introducing new zones, and obtain estimates of the lee-multipliers. Substantial changes have been proposed for the next version of the Australian/New Zealand wind-loading standard (AS/NZS 1170.2) based on the results of this study. The changes include adding a new wind region to New Zealand, refinements of wind zone boundaries, revising all regional wind speeds and directional multipliers, and modifying the lee-zone regions and multipliers. • Estimation of New Zealand design wind speeds, directional and lee multipliers. • Homogenisation of historical wind data using a robust algorithm. • Analyses of historical wind data records and predictions of the NZCSM. • Changes are recommended for the next version of AS/NZS1170.2. [ABSTRACT FROM AUTHOR]

• A novel small-scale perfusion bioreactor system for animal/human cells with working volumes <250 mL was developed. • Densities maintained at ≥80 × 106HEK293 cells/mL at 10pL/cell/day cell specific perfusion rate using enriched feed medium. • HEK293 cell expressing Erythropoietin cultured in high cell density perfusion process more than 75 days. Process intensification in mammalian cell culture-based recombinant protein production has been achieved by high cell density perfusion exceeding 108 cells/mL in the recent years. As the majority of therapeutic proteins are produced in Chinese Hamster Ovary (CHO) cells, intensified perfusion processes have been mainly developed for this type of host cell line. However, the use of CHO cells can result in non-human posttranslational modifications of the protein of interest, which may be disadvantageous compared with human cell lines. In this study, we developed a high cell density perfusion process of Human Embryonic Kidney (HEK293) cells producing recombinant human Erythropoietin (rhEPO). Firstly, a small-scale perfusion system from commercial bench-top screening bioreactors was developed for <250 mL working volume. Then, after the first trial runs with CHO cells, the system was modified for HEK293 cells (more sensitive than CHO cells) to achieve a higher oxygen transfer under mild aeration and agitation conditions. Steady states for medium (20 × 106 cells/mL) and high cell densities (80 × 106 cells/mL), normal process temperature (37 °C) and mild hypothermia (33 °C) as well as different cell specific perfusion rates (CSPR) from 10 to 60 pL/cell/day were applied to study the performance of the culture. The volumetric productivity was maximized for the high cell density steady state but decreased when an extremely low CSPR of 10 pL/cell/day was applied. The shift from high to low CSPR strongly reduced the nutrient uptake rates. The results from our study show that human cell lines, such as HEK293 can be used for intensified perfusion processes. [ABSTRACT FROM AUTHOR]

• Residual cathepsin D was identified as the primary cause of fragmentation for in-process mAbs by a combination of proteomic LC-MS and protease inhibitor screen. • A streamlined targeted LC-MS method was developed to quantify residual cathepsin D. • Cathepsin D is co-purified with investigated mAbs under platform purification process and alternative wash strategy at Protein A step can remove cathepsin D effectively. Monoclonal antibody (mAb) fragmentation is a well-known degradation pathway that results in product loss and can significantly impact product quality, efficacy, or even cause immunogenic reactions, thus potentially endangering patients' health. It is recognised that residual proteases present among host cell proteins (HCPs) such as those expressed by Chinese Hamster Ovary (CHO) can induce fragmentation, and failure of their complete removal during downstream processing could cause fragmentation during mAb production and in the final drug product. We identified, using a protease inhibitor screen, an aspartic protease that contributes to proteolytic fragmentation of partially purified mAbs in multiple projects. Subsequent LC–MS analysis indicated that cathepsin D, a typical aspartic protease, was responsible for the observed fragmentation of in-process samples. To address the issue, an alternative chromatography wash was implemented at the capture step and has been demonstrated to be an effective and scalable solution to mitigate the residual cathepsin D associated fragmentation risk. Furthermore, a near real time targeted mass spectrometry method has been developed to proactively monitor the presence of cathepsin D during upstream and downstream process. Our approach demonstrated an emerging HCP mitigation strategy through integrated upstream and downstream involvement and holds great promise for a range of future applications. [ABSTRACT FROM AUTHOR]

• High throughput scale-down chromatography workflow with decision-support. • Augmentation of design of experiments with the fractionation diagram method. • Automated and systematic high-throughput raw data manipulation. • Resin selection using empirical correlations through design of experiments. • Creation of windows of operation under uncertainty using empirical correlations. Chromatography remains the workhorse in antibody purification; however process development and characterisation still require significant resources. The high number of operating parameters involved requires extensive experimentation, traditionally performed at small- and pilot-scale, leading to demands in terms of materials and time that can be a challenge. The main objective of this research was the establishment of a novel High Throughput Process Development (HTPD) workflow combining scale-down chromatography experimentation with advanced decision-support techniques in order to minimise the consumption of resources and accelerate the development timeframe. Additionally, the HTPD workflow provides a framework to rapidly manipulate large datasets in an automated fashion. The central component of the HTPD workflow is the systematic integration of a microscale chromatography experimentation strategy with an advanced chromatogram evaluation method, design of experiments (DoE) and multivariate data analysis. The outputs of this are leveraged into the screening and optimisation components of the workflow. For the screening component, a decision-support tool was developed combining different multi-criteria decision-making techniques to enable a fair comparison of a number of CEX resin candidates and determine those that demonstrate superior purification performance. This provided a rational methodology for screening chromatography resins and process parameters. For the optimisation component, the workflow leverages insights provided through screening experimentation to guide subsequent DoE experiments so as to tune significant process parameters for the selected resin. The resulting empirical correlations are linked to a stochastic modelling technique so as to predict the optimal and most robust chromatographic process parameters to achieve the desired performance criteria. [ABSTRACT FROM AUTHOR]

A multi-phase, multi-component mean-field model has been developed for simulating the intermetallic precipitation kinetics in Inconel 718. The aim of this work is to develop predictive capability to aid in process optimisation and explore precipitation kinetics during additive manufacturing (AM). The model has been calibrated to available experimental data, and then applied to predict precipitation kinetics during typical solid solution treatment and aging operations, and during AM. It is shown that a Computer Coupling of Phase Diagrams and Thermochemistry (CALPHAD) based modelling approach provides a unified particle growth rate which can capture the growth, coarsening and dissolution of γ ′ , γ * and δ precipitates under relevant heat treatment conditions. To apply the model to AM, finite element simulations of a simple rectangular build have been carried out, using a property switching method to simulate the material deposition. The component level simulation provides the thermal fields to calculate precipitation kinetics during deposition, also allowing for the examination of the heat affected zone in the substrate. The modelling approach can capture the repeated nucleation and dissolution of precipitates that occurs during AM. The model shows good agreement with experimental data when applied to predicting precipitation kinetics during heat treatment. [ABSTRACT FROM AUTHOR]

This paper describes a method of predicting constant flow filtration capacities using constant pressure datasets collected during the purification of several monoclonal antibodies through depth filtration. The method required characterisation of the fouling mechanism occurring in constant pressure filtration processes by evaluating the best fit of each of the classic and combined theoretical fouling models. The optimised coefficients of the various models were correlated with the corresponding capacities achieved during constant flow operation at the specific pressures performed during constant pressure operation for each centrate. Of the classic and combined fouling models investigated, the Cake-Adsorption fouling model was found to best describe the fouling mechanisms observed for each centrate at the various different pressures investigated. A linear regression model was generated with these coefficients and was shown to predict accurately the capacities at constant flow operation at each pressure. This model was subsequently validated using an additional centrate and accurately predicted the constant flow capacities at three different pressures (0.69, 1.03 and 1.38 bar). The model used the optimised Cake-Adsorption model coefficients that best described the flux decline during constant pressure operation. The proposed method of predicting depth filtration performance proved to be faster than the traditional approach whilst requiring significantly less material, making it particularly attractive for early process development activities. [ABSTRACT FROM AUTHOR]

High energy-density beam welding, such as electron beam or laser welding, has found a number of industrial applications for clean, high-integrity welds. The deeply penetrating nature of the joints is enabled by the formation of metal vapour which creates a narrow fusion zone known as a “keyhole”. However the formation of the keyhole and the associated keyhole dynamics, when using a moving laser heat source, requires further research as they are not fully understood. Porosity, which is one of a number of process induced phenomena related to the thermal fluid dynamics, can form during beam welding processes. The presence of porosity within a welded structure, inherited from the fusion welding operation, degrades the mechanical properties of components during service such as fatigue life. In this study, a physics-based model for keyhole welding including heat transfer, fluid flow and interfacial interactions has been used to simulate keyhole and porosity formation during laser welding of Ti-6Al-4V titanium alloy. The modelling suggests that keyhole formation and the time taken to achieve keyhole penetration can be predicted, and it is important to consider the thermal fluid flow at the melting front as this dictates the evolution of the fusion zone. Processing induced porosity is significant when the fusion zone is only partially penetrating through the thickness of the material. The modelling results are compared with high speed camera imaging and measurements of porosity from welded samples using X-ray computed tomography, radiography and optical micrographs. These are used to provide a better understanding of the relationship between process parameters, component microstructure and weld integrity. [ABSTRACT FROM AUTHOR]

In this paper, an integrated computational materials science approach for selective laser melting (SLM) at the mesoscale is presented. A particle dropping model was developed to simulate the representative powder-bed particle distribution of a measured titanium alloy powder. Thermal fluid flow and resulting microstructural evolution of a set of laser scanned single tracks with different powder layer thicknesses and scanning speeds during SLM were also studied using both computational and experimental approaches. The simulated powder particle distribution was found to be consistent with experimental measurement. The thermal fluid flow model predicts that single laser scanned tracks become increasingly irregular-shaped with increased powder layer thickness and increased laser scanning speed. These findings were reinforced by scanning electron microscopy analysis. The more dispersed dissipation of the localised heat for thicker powder layers is understood to cause increased melting and evaporation. This can lead to increased Marangoni force and recoil pressure which in turn destabilises the melt flow. The use of an argon atmosphere speeds up the solidification process when compared with air but does not affect the morphology of single tracks significantly. The predicted microstructure was consistent with the electron backscattered diffraction data. The microstructure-based modelling methodology considering the representative powder size distribution provides a good predictive capability for the laser-powder interaction behaviour, surface structure and porosity development. [ABSTRACT FROM AUTHOR]

Background: Anal cancer is a human papillomavirus (HPV)-mediated neoplasia of the anal squamous epithelium. Anal cancer is much more common among women, particularly those with a previous high-grade gynaecological neoplasia.Methods: Cross-sectional study of women with a previous HPV-mediated gynaecological neoplasia in Tasmania, Australia. Women presenting for follow-up gynaecological care had anal swab samples taken for anal cytology by Hologic Liquid ThinPrep, followed by HPV genotyping. Women with abnormal anal cytology were invited for high-resolution anoscopy. Potential risk factors, including post-toilet wiping behaviours, were queried by questionnaire while clinical covariates were extracted from medical records. Covariates of anal outcomes evaluated by log-binomial and log-multinomial regression.Results: From 163 women enrolled in the study, 65 (39.9%) had abnormal cytology, with 46 (28.2%) being high-grade. Of the 50 women with abnormal anal cytology having high-resolution anoscopy, 32 (64.0%) had abnormal histology with 13 (26.0%) being high-grade. Of the 123 women tested for HR-HPV DNA, 48 (39.0%) had HR-HPV detected, the most common genotypes being 16 and 51 (14/123, 11.4% for both). In addition to some known anal cancer risk factors, we found front-to-back wiping was associated with significantly increased (Prevalence ratio (PR) range: 1.99-3.60) prevalence of cytological and histological abnormality and HR-HPV carriage/co-carriage, while dabbing post-toilet was significantly associated with decreased prevalences (PR range: 0.50-0.62).Conclusions: Post-toilet wiping behaviours were significantly associated with the prevalence of anal cytological, histological and HR-HPV carriage outcomes. This suggests a biologically plausible mechanism for HR-HPV introduction and the higher frequencies of anal neoplasia in women. [ABSTRACT FROM AUTHOR]

Foot-and-mouth disease virus (FMDV) spreads by direct contact between animals, by animal products (milk, meat and semen), by mechanical transfer on people or fomites and by the airborne route, with the relative importance of each mechanism depending on the particular outbreak characteristics. Atmospheric dispersion models have been developed to assess airborne spread of FMDV in a number of countries, including the UK, Denmark, Australia, New Zealand, USA and Canada. These models were compared at a Workshop hosted by the Institute for Animal Health/Met Office in 2008. Each modeller was provided with data relating to the 1967 outbreak of FMD in Hampshire, UK, and asked to predict the spread of FMDV by the airborne route. A number of key issues emerged from the Workshop and subsequent modelling work: (1) in general all models predicted similar directions for livestock at risk, with much of the remaining differences strongly related to differences in the meteorological data used; (2) determination of an accurate sequence of events on the infected premises is highly important, especially if the meteorological conditions vary substantially during the virus emission period; (3) differences in assumptions made about virus release, environmental fate and susceptibility to airborne infection can substantially modify the size and location of the downwind risk area. All of the atmospheric dispersion models compared at the Workshop can be used to assess windborne spread of FMDV and provide scientific advice to those responsible for making control and eradication decisions in the event of an outbreak of disease. [ABSTRACT FROM AUTHOR]

Mutational studies of T cell receptor (TCR) contact residues on the surface of the human class I major histocompatibility complex (MHC) molecule HLA-A2 have identified a "functional hot spot" that comprises Arg65 and Lys66 and is involved in recognition by most peptide-specific HLA-A2-restricted TCRs. Although there is a significant amount of functional data on the effects of mutations at these positions, there is comparatively little biochemical information that could illuminate their mode of action. Here, we have used a combination of fluorescence anisotropy, functional assays, and Biacore binding experiments to examine the effects of mutations at these positions on the peptide-MHC interaction and TCR recognition. The results indicate that mutations at both position 65 and position 66 influence peptide binding by HLA-A2 to various extents. In particular, mutations at position 66 result in significantly increased peptide dissociation rates. However, these effects are independent of their effects on TCR recognition, and the Arg65-Lys66 region thus represents a true "hot spot" for TCR recognition. We also made the observation that in vitro T cell reactivity does not scale with the half-life of the peptide-MHC complex, as is often assumed. Finally, position 66 is implicated in the "dual recognition" of both peptide and TCR, emphasizing the multiple roles of the class I MHC peptide-binding domain. [ABSTRACT FROM AUTHOR]

• Chromatography is an essential purification technology for therapeutic proteins. • Advances in PAT and process modelling provide opportunities to enhance control. • The current shortfalls in chromatography control systems are outlined. • Novel control strategies in development are discussed and compared. • A future vision of chromatography control is presented. Recent advances in process analytical technologies and modelling techniques present opportunities to improve industrial chromatography control strategies to enhance process robustness, increase productivity and move towards real-time release testing. This paper provides a critical overview of batch and continuous industrial chromatography control systems for therapeutic protein purification. Firstly, the limitations of conventional industrial fractionation control strategies using in-line UV spectroscopy and on-line HPLC are outlined. Following this, an evaluation of monitoring and control techniques showing promise within research, process development and manufacturing is provided. These novel control strategies combine rapid in-line data capture (e.g. NIR, MALS and variable pathlength UV) with enhanced process understanding obtained from mechanistic and empirical modelling techniques. Finally, a summary of the future states of industrial chromatography control systems is proposed, including strategies to control buffer formulation, product fractionation, column switching and column fouling. The implementation of these control systems improves process capabilities to fulfil product quality criteria as processes are scaled, transferred and operated, thus fast tracking the delivery of new medicines to market. [ABSTRACT FROM AUTHOR]

The identification of an association between variants in the human melanocortin 1 receptor (MC1R ) gene and red hair and fair skin, as well as the relation between variants of this gene and coat color in animals, suggests that the MC1R is an integral control point in the normal pigmentation phenotype. In order to further define the contribution of MC1R variants to pigmentation in a normal population, we have looked for alterations in this gene in series of individuals from a general Irish population, in whom there is a preponderance of individuals with fair skin type. Seventy‐five per cent contained a variant in the MC1R gene, with 30% containing two variants. The Arg151Cys, Arg160Trp, and Asp294His variants were significantly associated with red hair (p = 0.0015, p < 0.001, and p < 0.005, respectively). Importantly, no individuals harboring two of these three variants did not have red hair, although some red‐haired individuals only showed one alteration. The same three variants were also over‐represented in individuals with light skin type as assessed using a modified Fitzpatrick scale. Despite these associations many subjects with dark hair/darker skin type harbored MC1R variants, but there was no evidence of any particular association of variants with the darker phenotype. The Asp294His variant was similarly associated with red hair in a Dutch population, but was infrequent in red‐headed subjects from Sweden. The Asp294His variant was also significantly associated with nonmelanoma skin cancer in a U.K. population. The results show that the Arg151Cys, Arg160Trp, and Asp294His variants are of key significance in determining the pigmentary phenotype and response to ultraviolet radiation, and suggest that in many cases the red‐haired component and in some cases fair skin type are inherited as a Mendelian recessive. [ABSTRACT FROM AUTHOR]

• A longitudinal survey of 233 Australian coal miners was conducted. • Participants' age was a significant negative predictor of reported risk-taking. • Poor safety norms at mine sites were a significant positive predictor. • Reverse causal paths were nonsignificant in the longitudinal analysis. The present study undertook an exploratory investigation of the causes of risk-taking among Australian coal miners. A range of safety culture and climate variables were measured in a survey of open-cut and underground coal miners from New South Wales and Queensland. A repeat survey of 233 of these miners was conducted an average of 10 months after the initial survey. Participants' age and perceived safety norms at their mine site were significant longitudinal predictors of reported frequency of risk-taking. These findings suggest that young miners and miners who perceive it to be normal for miners at their mine site to ignore safety procedures are more likely to report taking safety risks in the future. Suggestions for safety interventions are considered. [ABSTRACT FROM AUTHOR]

The aim of the research described in this paper is to reduce the vulnerability of New Zealand's built infrastructure to wind damage through provision of improved wind speed prediction procedures for wind flow over complex terrain that could ultimately be incorporated into the AS/NZS 1170.2 loading standard. This paper presents results from a specific experiment which compares measured wind speedups (neutral atmosphere) over the rugged Belmont Hill region with wind speedups estimated from AS/NZS 1170.2 by two organisations, and from six other international wind-loading standards, through Computational Fluid Dynamics (Gerris and WAsP) modelling, and through wind-tunnel modelling. It was found that computer modelling with the large-eddy simulation CFD code Gerris and wind-tunnel measurements, agree remarkably well with the observations and differentiate considerably better between areas exposed or sheltered by the local terrain features compared to applying the CFD code WAsP (4.1), or applying the AS/NZS 1170.2 wind-loading standard. Furthermore, it was found that the AS/NZS1170.2 predictions differed significantly when carried out by different organisations. The wind speedup prediction methods from the six other international standards all use similar approaches and thus the predictions from all of them were quite similar, and did not agree particularly well with the field measurements. • Multiple method speedup comparison: Full-scale, Wind Tunnel, CFD LES and CFD WAsP. • Full-scale wind speedup measurements over complex terrain. • Large Collaboration: University of Auckland, NIWA, GNS Science, WPS-Opus. • Detailed analysis of wind speedup results and comparison with many wind standards. • Useful data for developing improved wind speedup algorithms for wind standards. [ABSTRACT FROM AUTHOR]