A FimH inhibitor prevents acute bladder infection and treats chronic cystitis caused by multidrug-resistant uropathogenic Escherichia coli ST131

Background. Escherichia coli O25b:H4-ST131 represents a predominant clone of multidrug-resistant uropathogens currently circulating worldwide in hospitals and the community. Urinary tract infections (UTIs) caused by E. coli ST131 are typically associated with limited treatment options and are often recurrent. Methods. Using established mouse models of acute and chronic UTI, we mapped the pathogenic trajectory of the reference E. coli ST131 UTI isolate, strain EC958. Results. We demonstrated that E. coli EC958 can invade bladder epithelial cells and form intracellular bacterial communities early during acute UTI. Moreover, E. coli EC958 persisted in the bladder and established chronic UTI. Prophylactic antibiotic administration failed to prevent E. coli EC958–mediated UTI. However, 1 oral dose of a small-molecular-weight compound that inhibits FimH, the type 1 fimbriae adhesin, significantly reduced bacterial colonization of the bladder and prevented acute UTI. Treatment of chronically infected mice with the same FimH inhibitor lowered their bladder bacterial burden by >1000-fold. Conclusions. In this study, we provide novel insight into the pathogenic mechanisms used by the globally disseminated E. coli ST131 clone during acute and chronic UTI and establish the potential of FimH inhibitors as an alternative treatment against multidrug-resistant E. coli.

A pseudo-marginal sequential Monte Carlo algorithm for random effects models in Bayesian sequential design

A computationally efficient sequential Monte Carlo algorithm is proposed for the sequential design of experiments for the collection of block data described by mixed effects models. The difficulty in applying a sequential Monte Carlo algorithm in such settings is the need to evaluate the observed data likelihood, which is typically intractable for all but linear Gaussian models. To overcome this difficulty, we propose to unbiasedly estimate the likelihood, and perform inference and make decisions based on an exact-approximate algorithm. Two estimates are proposed: using Quasi Monte Carlo methods and using the Laplace approximation with importance sampling. Both of these approaches can be computationally expensive, so we propose exploiting parallel computational architectures to ensure designs can be derived in a timely manner. We also extend our approach to allow for model uncertainty. This research is motivated by important pharmacological studies related to the treatment of critically ill patients.

Incorporating human-factors in car-following models : a review of recent developments and research needs

Over the past decades there has been a considerable development in the modeling of car-following (CF) behavior as a result of research undertaken by both traffic engineers and traffic psychologists. While traffic engineers seek to understand the behavior of a traffic stream, traffic psychologists seek to describe the human abilities and errors involved in the driving process. This paper provides a comprehensive review of these two research streams. It is necessary to consider human-factors in {CF} modeling for a more realistic representation of {CF} behavior in complex driving situations (for example, in traffic breakdowns, crash-prone situations, and adverse weather conditions) to improve traffic safety and to better understand widely-reported puzzling traffic flow phenomena, such as capacity drop, stop-and-go oscillations, and traffic hysteresis. While there are some excellent reviews of {CF} models available in the literature, none of these specifically focuses on the human factors in these models. This paper addresses this gap by reviewing the available literature with a specific focus on the latest advances in car-following models from both the engineering and human behavior points of view. In so doing, it analyses the benefits and limitations of various models and highlights future research needs in the area.

Theorizing the use of multiple conceptual models in combination

Conceptual modelling continues to be an important means for graphically capturing the requirements of an information system. Observations of modelling practice suggest that modellers often use multiple conceptual models in combination, because they articulate different aspects of real-world domains. Yet, the available empirical as well as theoretical research in this area has largely studied the use of single models, or single modelling grammars. We develop a Theory of Combined Ontological Coverage by extending an existing theory of ontological expressiveness of conceptual modelling grammars. Our new theory posits that multiple conceptual models are used to increase the maximum coverage of the real-world domain being modelled, whilst trying to minimize the ontological overlap between the models. We illustrate how the theory can be applied to analyse sets of conceptual models. We develop three propositions of the theory about evaluations of model combinations in terms of users’ selection, understandability and usefulness of conceptual models.

Reduced complexity on-line estimation of hidden Markov model parameters

In this paper we propose and study low complexity algorithms for on-line estimation of hidden Markov model (HMM) parameters. The estimates approach the true model parameters as the measurement noise approaches zero, but otherwise give improved estimates, albeit with bias. On a nite data set in the high noise case, the bias may not be signi cantly more severe than for a higher complexity asymptotically optimal scheme. Our algorithms require O(N3) calculations per time instant, where N is the number of states. Previous algorithms based on earlier hidden Markov model signal processing methods, including the expectation-maximumisation (EM) algorithm require O(N4) calculations per time instant.

MIMO and SISO identification of radiation force terms for models of marine structures in waves

This paper presents a discussion on the use of MIMO and SISO techniques for identification of the radiation force terms in models for surface vessels. We compare and discuss two techniques recently proposed in literature for this application: time domain identification and frequency domain identification. We compare the methods in terms of estimates model order, accuracy of the fit, use of the available information, and ease of use and implementation.

Principles of goal-directed spatial robot navigation in biomimetic models

Mobile robots and animals alike must effectively navigate their environments in order to achieve their goals. For animals goal-directed navigation facilitates finding food, seeking shelter or migration; similarly robots perform goal-directed navigation to find a charging station, get out of the rain or guide a person to a destination. This similarity in tasks extends to the environment as well; increasingly, mobile robots are operating in the same underwater, ground and aerial environments that animals do. Yet despite these similarities, goal-directed navigation research in robotics and biology has proceeded largely in parallel, linked only by a small amount of interdisciplinary research spanning both areas. Most state-of-the-art robotic navigation systems employ a range of sensors, world representations and navigation algorithms that seem far removed from what we know of how animals navigate; their navigation systems are shaped by key principles of navigation in ‘real-world’ environments including dealing with uncertainty in sensing, landmark observation and world modelling. By contrast, biomimetic animal navigation models produce plausible animal navigation behaviour in a range of laboratory experimental navigation paradigms, typically without addressing many of these robotic navigation principles. In this paper, we attempt to link robotics and biology by reviewing the current state of the art in conventional and biomimetic goal-directed navigation models, focusing on the key principles of goal-oriented robotic navigation and the extent to which these principles have been adapted by biomimetic navigation models and why.

Computation of Mathematical Models for Complex Industrial Processes

Designed for undergraduate and postgraduate students, academic researchers and industrial practitioners, this book provides comprehensive case studies on numerical computing of industrial processes and step-by-step procedures for conducting industrial computing. It assumes minimal knowledge in numerical computing and computer programming, making it easy to read, understand and follow. Topics discussed include fundamentals of industrial computing, finite difference methods, the Wavelet-Collocation Method, the Wavelet-Galerkin Method, High Resolution Methods, and comparative studies of various methods. These are discussed using examples of carefully selected models from real processes of industrial significance. The step-by-step procedures in all these case studies can be easily applied to other industrial processes without a need for major changes and thus provide readers with useful frameworks for the applications of engineering computing in fundamental research problems and practical development scenarios.

Fourier active appearance models

Gaining invariance to camera and illumination variations has been a well investigated topic in Active Appearance Model (AAM) fitting literature. The major problem lies in the inability of the appearance parameters of the AAM to generalize to unseen conditions. An attractive approach for gaining invariance is to fit an AAM to a multiple filter response (e.g. Gabor) representation of the input image. Naively applying this concept with a traditional AAM is computationally prohibitive, especially as the number of filter responses increase. In this paper, we present a computationally efficient AAM fitting algorithm based on the Lucas-Kanade (LK) algorithm posed in the Fourier domain that affords invariance to both expression and illumination. We refer to this as a Fourier AAM (FAAM), and show that this method gives substantial improvement in person specific AAM fitting performance over traditional AAM fitting methods.

Gray matter deficits, mismatch negativity, and outcomes in schizophrenia

Reduced mismatch negativity (MMN) in response to auditory change is a well-established finding in schizophrenia and has been shown to be correlated with impaired daily functioning, rather than with hallmark signs and symptoms of the disorder. In this study, we investigated (1) whether the relationship between reduced MMN and impaired daily functioning is mediated by cortical volume loss in temporal and frontal brain regions in schizophrenia and (2) whether this relationship varies with the type of auditory deviant generating MMN. MMN in response to duration, frequency, and intensity deviants was recorded from 18 schizophrenia subjects and 18 pairwise age- and gender-matched healthy subjects. Patients’ levels of global functioning were rated on the Social and Occupational Functioning Assessment Scale. High-resolution structural magnetic resonance scans were acquired to generate average cerebral cortex and temporal lobe models using cortical pattern matching. This technique allows accurate statistical comparison and averaging of cortical measures across subjects, despite wide variations in gyral patterns. MMN amplitude was reduced in schizophrenia patients and correlated with their impaired day-to-day function level. Only in patients, bilateral gray matter reduction in Heschl’s gyrus, as well as motor and executive regions of the frontal cortex, correlated with reduced MMN amplitude in response to frequency deviants, while reduced gray matter in right Heschl’s gyrus also correlated with reduced MMN to duration deviants. Our findings further support the importance of MMN reduction in schizophrenia by linking frontotemporal cerebral gray matter pathology to an automatically generated event-related potential index of daily functioning.

The current state of play in human neural stem cell models : what we have learnt from the rodent

Rodent (mouse and rat) models have been crucial in developing our understanding of human neurogenesis and neural stem cell (NSC) biology. The study of neurogenesis in rodents has allowed us to begin to understand adult human neurogenesis and in particular, protocols established for isolation and in vitro propagation of rodent NSCs have successfully been applied to the expansion of human NSCs. Furthermore, rodent models have played a central role in studying NSC function in vivo and in the development of NSC transplantation strategies for cell therapy applications. Rodents and humans share many similarities in the process of neurogenesis and NSC biology however distinct species differences are important considerations for the development of more efficient human NSC therapeutic applications. Here we review the important contributions rodent studies have had to our understanding of human neurogenesis and to the development of in vitro and in vivo NSC research. Species differences will be discussed to identify key areas in need of further development for human NSC therapy applications.

Tissue-engineered 3D tumor angiogenesis models : potential technologies for anti-cancer drug discovery

Angiogenesis is indispensable for solid tumor expansion, and thus it has become a major target of cancer research and anti-cancer therapies. Deciphering the arcane actions of various cell populations during tumor angiogenesis requires sophisticated research models, which could capture the dynamics and complexity of the process. There is a continuous need for improvement of existing research models, which engages interdisciplinary approaches of tissue engineering with life sciences. Tireless efforts to develop a new model to study tumor angiogenesis result in innovative solutions, which bring us one step closer to decipher the dubious nature of cancer. This review aims to overview the recent developments, current limitations and future challenges in three-dimensional tissue-engineered models for the study of tumor angiogenesis and for the purpose of elucidating novel targets aimed at anti-cancer drug discovery.

Use of contract models to improve environmental outcomes in transport infrastructure construction

The type of contract model may have a significant influence on achieving project objectives, including environmental and climate change goals. This research investigates non-standard contract models impacting greenhouse gas emissions (GHG) in transport infrastructure construction in Australia. The research is based on the analysis of two case studies: an Early Contractor Involvement (ECI) contract and a Design and Construct (D&C) contract with GHG reduction requirements embedded in the contractor selection. Main findings support the use of ECIs for better integrating decisions made during the planning phase with the construction activities, and improve environmental outcomes while achieving financial and time savings. Key words: greenhouse gases reduction; road construction; contracting; ECI; D&C

Old mastheads and new media : newspapers striving to adapt in Australia and South-east Asia

As a key element in their response to new media forcing transformations in mass media and media use, newspapers have deployed various strategies to not only establish online and mobile products, and develop healthy business plans, but to set out to be dominant portals. Their response to change was the subject of an early investigation by one of the present authors (Keshvani 2000). That was part of a set of short studies inquiring into what impact new software applications and digital convergence might have on journalism practice (Tickle and Keshvani 2000), and also looking for demonstrations of the way that innovations, technologies and protocols then under development might produce a “wireless, streamlined electronic news production process (Tickle and Keshvani 2001).” The newspaper study compared the online products of The Age in Melbourne and the Straits Times in Singapore. It provided an audit of the Singapore and Australia Information and Communications Technology (ICT) climate concentrating on the state of development of carrier networks, as a determining factor in the potential strength of the two services with their respective markets. In the outcome, contrary to initial expectations, the early cable roll-out and extensive ‘wiring’ of the city in Singapore had not produced a level of uptake of Internet services as strong as that achieved in Melbourne by more ad hoc and varied strategies. By interpretation, while news websites and online content were at an early stage of development everywhere, and much the same as one another, no determining structural imbalance existed to separate these leading media participants in Australia and South-east Asia. The present research revisits that situation, by again studying the online editions of the two large newspapers in the original study, and one other, The Courier Mail, (recognising the diversification of types of product in this field, by including it as a representative of Newscorp, now a major participant). The inquiry works through the principle of comparison. It is an exercise in qualitative, empirical research that establishes a comparison between the situation in 2000 as described in the earlier work, and the situation in 2014, after a decade of intense development in digital technology affecting the media industries. It is in that sense a follow-up study on the earlier work, although this time giving emphasis to content and style of the actual products as experienced by their users. It compares the online and print editions of each of these three newspapers; then the three mastheads as print and online entities, among themselves; and finally it compares one against the other two, as representing a South-east Asian model and Australian models. This exercise is accompanied by a review of literature on the developments in ICT affecting media production and media organisations, to establish the changed context. The new study of the online editions is conducted as a systematic appraisal of the first level, or principal screens, of the three publications, over the course of six days (10-15.2.14 inclusive). For this, categories for analysis were made, through conducting a preliminary examination of the products over three days in the week before. That process identified significant elements of media production, such as: variegated sourcing of materials; randomness in the presentation of items; differential production values among media platforms considered, whether text, video or stills images; the occasional repurposing and repackaging of top news stories of the day and the presence of standard news values – once again drawn out of the trial ‘bundle’ of journalistic items. Reduced in this way the online artefacts become comparable with the companion print editions from the same days. The categories devised and then used in the appraisal of the online products have been adapted to print, to give the closest match of sets of variables. This device, to study the two sets of publications on like standards -- essentially production values and news values—has enabled the comparisons to be made. This comparing of the online and print editions of each of the three publications was set up as up the first step in the investigation. In recognition of the nature of the artefacts, as ones that carry very diverse information by subject and level of depth, and involve heavy creative investment in the formulation and presentation of the information; the assessment also includes an open section for interpreting and commenting on main points of comparison. This takes the form of a field for text, for the insertion of notes, in the table employed for summarising the features of each product, for each day. When the sets of comparisons as outlined above are noted, the process then becomes interpretative, guided by the notion of change. In the context of changing media technology and publication processes, what substantive alterations have taken place, in the overall effort of news organisations in the print and online fields since 2001; and in their print and online products separately? Have they diverged or continued along similar lines? The remaining task is to begin to make inferences from that. Will the examination of findings enforce the proposition that a review of the earlier study, and a forensic review of new models, does provide evidence of the character and content of change --especially change in journalistic products and practice? Will it permit an authoritative description on of the essentials of such change in products and practice? Will it permit generalisation, and provide a reliable base for discussion of the implications of change, and future prospects? Preliminary observations suggest a more dynamic and diversified product has been developed in Singapore, well themed, obviously sustained by public commitment and habituation to diversified online and mobile media services. The Australian products suggest a concentrated corporate and journalistic effort and deployment of resources, with a strong market focus, but less settled and ordered, and showing signs of limitations imposed by the delay in establishing a uniform, large broadband network. The scope of the study is limited. It is intended to test, and take advantage of the original study as evidentiary material from the early days of newspaper companies’ experimentation with online formats. Both are small studies. The key opportunity for discovery lies in the ‘time capsule’ factor; the availability of well-gathered and processed information on major newspaper company production, at the threshold of a transformational decade of change in their industry. The comparison stands to identify key changes. It should also be useful as a reference for further inquiries of the same kind that might be made, and for monitoring of the situation in regard to newspaper portals on line, into the future.

Reduced motor facilitation during action observation in schizophrenia : a mirror neuron deficit?

Impairments in social cognitive functioning are well documented in schizophrenia, however the neural basis of these deficits is unclear. A recent explanatory model of social cognition centers upon the activity of mirror neurons, which are cortical brain cells that become active during both the performance and observation of behavior. Here, we test for the first time whether mirror neuron functioning is reduced in schizophrenia. Fifteen individuals with schizophrenia or schizoaffective disorder and fifteen healthy controls completed a transcranial magnetic stimulation (TMS) experiment designed to assess mirror neuron activation. While patients demonstrated no abnormalities in cortical excitability, motor facilitation during action observation, putatively reflecting mirror neuron activity, was reduced in schizophrenia. Dysfunction within the mirror neuron system may contribute to the pathophysiology of schizophrenia.