Brca1 inactivation induces p27Kip1-dependent cell cycle arrest and delayed development in the mouse mammary gland

One common characteristic of breast cancers arising in carriers of the predisposition gene BRCA1 is a loss of expression of the CDK inhibitor p27(Kip1) (p27), suggesting that p27 interacts epistatically with BRCA1. To investigate this relationship, we examined expression of p27 in mice expressing a dominant negative allele of Brca1 (MMTV-trBr) in the mammary gland. While these mice rarely develop tumors, they showed a 50% increase in p27 protein and a delay in mammary gland development associated with reduced proliferation. In contrast, on a p27 heterozygote background, MMTV-trBrca1 mice showed an increase in S phase cells, and normal mammary development. p27 was the only protein in the cyclin cyclin-dependent kinase network to show altered expression, suggesting that it may be a central mediator of cell cycle arrest in response to loss of function of BRCA1. Furthermore, in human mammary epithelial MCF7 cells expressing BRCA1-specific RNAi and in the BRCA1-deficient human tumor cell line HCC1937, p27 is elevated at the mRNA level compared to cells expressing wild-type BRCA1. We hypothesize that disruption of BRCA1 induces an increase in p27 that inhibits proliferation. Accordingly, reduction in p27 expression leads to enhancement of cellular proliferation in the absence of BRCA1.

Pax9 and Jagged1 act downstream of Gli3 in vertabrate limb development

From early in limb development the transcription factor Gli3 acts to define boundaries of gene expression along the anterior-posterior (AP) axis, establishing asymmetric patterns required to provide positional information. As limb development proceeds, posterior mesenchyme expression of Sonic hedgehog (Shh) regulates Gli3 transcription and post-translational processing to specify digit number and identity. The molecular cascades dependent on Gli3 at later stages of limb development, which link early patterning events with final digit morphogenesis, remain poorly characterised. By analysing the transcriptional consequences of loss of Gli3 in the anterior margin of the E11.5 and E12.5 limb bud in the polydactylous mouse mutant extra-toes (Gli3(Xt/Xt)), we have identified a number of known and novel transcripts dependent on Gli3 in the limb. In particular, we demonstrated that the genes encoding the paired box transcription factor Pax9, the Notch ligand Jagged1 and the cell surface receptor Cdo are dependent on Gli3 for correct expression in the anterior limb mesenchyme. Analysis of expression in compound Shh;Gli3 mutant mouse embryos and in both in vitro and in vivo Shh signaling assays, further defined the importance of Shh regulated processing of Gli3 in controlling gene expression. In particular Pax9 regulation by Shh and Gli3 was shown to be context dependent, with major differences between the limb and somite revealed by Shh bead implantation experiments in the chick. Jagged1 was shown to be induced by Shh in the chick limb and in a C3H10T1/2 cell based signaling assay, with Shh;Gli3 mutant analysis indicating that expression is dependent on Gli3 derepression. Our data have also revealed that perturbation of early patterning events within the Gli3(Xt/Xt), limb culminates in a specific delay of anterior chondrogenesis which is subsequently realised as extra digits. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Development of a non-intrusive heat transfer coefficient gauge and its application to high pressure die casting Effect of the process parameters

A heat transfer coefficient gauge has been built, obeying particular rules in order to ensure the relevance and accuracy of the collected information. The gauge body is made out of the same materials as the die casting die (H13). It is equipped with six thermocouples located at different depths in the body and with a sapphire light pipe. The light pipe is linked to an optic fibre, which is connected to a monochromatic pyrometer. Thermocouples and pyrometer measurements are recorded with a data logger. A high pressure die casting die was instrumented with one such gauge. A set of 150 castings was done and the data recorded. During the casting, some process parameters have been modified such as piston velocity, intensification pressure, delay before switch to the intensification stage, temperature of the alloy, etc.... The data was treated with an inverse method in order to transform temperature measurements into heat flux density and heat transfer coefficient plots. The piston velocity and the initial temperature of the die seem to be the process parameters that have the greatest influence on the heat transfer. (c) 2005 Elsevier B.V. All rights reserved.

First development of a polyurethane keratoprosthesis and its Australian connection: An unbeknown episode in the history of artificial cornea

This paper is aimed at establishing a particular chronological priority issue in the convoluted history of artificial cornea. According to existing records, the first keratoprosthesis made from polyurethane was developed by Caldwell and Jacob-Labarre in the late 1980s. This paper demonstrates that in fact the first polyurethane keratoprosthesis was proposed and designed in 1985 by Lawrence Hirst, an Australian ophthalmologist then working in St Louis, USA. The first prototype was manufactured in January 1986 by Thermedics Inc according to Dr Hirst's instructions from Tecoflex, a transparent polyurethane developed by the same company. This keratoprosthesis, which also had a porous skirt, was inserted intralamellarly in a monkey cornea and followed up clinically for about 3 months. There were no significant postoperative complications, and the histology of the explant indicated proper biointegration of the prosthetic skirt within the host stromal tissue. Because of a delay in the manufacture of further prototypes and to Dr Hirst's decision to return to Australia, the project was eventually abandoned. As no report was published on this development, the present paper is entirely based on original documents held in Dr Hirst's archives.

Minimising cold damage during reproductive development among temperate rice genotypes. I. Avoiding low temperature with the use of appropriate sowing time and photoperiod-sensitive varieties

Multiple-sown field trials in 4 consecutive years in the Riverina region of south-eastern Australia provided 24 different combinations of temperature and day length, which enabled the development of crop phenology models. A crop model was developed for 7 cultivars from diverse origins to identify if photoperiod sensitivity is involved in determining phenological development, and if that is advantageous in avoiding low-temperature damage. Cultivars that were mildly photoperiod-sensitive were identified from sowing to flowering and from panicle initiation to flowering. The crop models were run for 47 years of temperature data to quantify the risk of encountering low temperature during the critical young microspore stage for 5 different sowing dates. Cultivars that were mildly photoperiod-sensitive, such as Amaroo, had a reduced likelihood of encountering low temperature for a wider range of sowing dates compared with photoperiod-insensitive cultivars. The benefits of increased photoperiod sensitivity include greater sowing flexibility and reduced water use as growth duration is shortened when sowing is delayed. Determining the optimal sowing date also requires other considerations, e. g. the risk of cold damage at other sensitive stages such as flowering and the response of yield to a delay in flowering under non-limiting conditions. It was concluded that appropriate sowing time and the use of photoperiod-sensitive cultivars can be advantageous in the Riverina region in avoiding low temperature damage during reproductive development.

An investigation of the factor-analytic approach to the determination of abilities involved in psychomotor learning

This research began with an attempt to solve a practical problem, namely, the prediction of the rate at which an operator will learn a task. From a review of the literature, communications with researchers in this area and the study of psychomotor learning in factories it was concluded that a more fundamental approach was required which included the development of a task taxonomy. This latter objective had been researched for over twenty years by E. A. Fleishman and his approach was adopted. Three studies were carried out to develop and extend Fleishman's approach to the industrial area. However, the results of these studies were not in accord with FIeishman's conclusions and suggested that a critical re-assessment was required of the arguments, methods and procedures used by Fleishman and his co-workers. It was concluded that Fleishman's findings were to some extent an artifact of the approximate methods and procedures which he used in the original factor analyses and that using the more modern computerised factor analytic methods a reliable ability taxonomy could be developed to describe the abilities involved in the learning of psychomotor tasks. The implications for a changing-task or changing-subject model were drawn and it was concluded that a changing task and subject model needs to be developed.

Strategic development of transport systems: a study of the physical constraints on planning processes

Investment in transport infrastructure can be highly sensitive to uncertainty. The scale and lead time of strategic transport programmes are such that they require continuing policy support and accurate forecasting. Delay, cost escalation and abandonment of projects often result if these conditions are not present. In Part One the physical characteristics of infrastructure are identified as a major constraint on planning processes. The extent to which strategies and techniques acknowledge these constraints is examined. A simple simulation model is developed to evaluate the effects on system development of variations in the scale and lead time of investments. In Part Two, two case studies of strategic infrastructure investment are analysed. The absence of a policy consensus for airport location was an important factor in the delayed resolution of the Third London Airport issue. In London itself, the traffic and environmental effects of major highway investment ultimately resulted in the abandonment of plans to construct urban motorways. In both cases, the infrastructure implications of alternative strategies are reviewed with reference to the problems of uncertainty. In conclusion, the scale of infrastructure investment is considered the most important of the constraints on the processes of transport planning. Adequate appraisal of such constraints may best be achieved by evaluation more closely aligned to policy objectives.

Contingency, contiguity, and development: The ontogeny of contingency learning in northern bobwhite (Colinus virginianus) chicks

The purpose of this study was to investigate the ontogeny of auditory learning via operant contingency in Northern bobwhite (Colinus virginianus ) hatchlings and possible interaction between attention, orienting and learning during early development. Chicks received individual 5 min training sessions in which they received a playback of a bobwhite maternal call at a single delay following each vocalization they emitted. Playback was either from a single randomly chosen speaker or switched back and forth semi-randomly between two speakers during training. Chicks were tested 24 hrs later in a simultaneous choice test between the familiar and an unfamiliar maternal call. It was found that day-old chicks showed a significant time-specific decrement in auditory learning when trained with delays in the range of 470–910 ms between their vocalizations and call playback only when training involved two speakers. Two-day-old birds showed an even more sustained disruption of learning than day-old chicks, whereas three-day-old chicks showed a pattern of intermittent interference with their learning when trained at such delays. A similar but less severe decrement in auditory learning was found when chicks were provided with motor training in which playback was contingent upon chicks entering and exiting one of two colored squares placed on the floor of the arena. Chicks provided with playback of the call at randomly chosen delays each time they vocalized exhibited large fluctuations in their responsivity to the auditory stimulus as a function of delay—fluctuations which were correlated significantly with measures of chick learning, particularly at two-days-of-age. When playback was limited to a single location chicks no longer showed a time-specific disruption of their learning of the auditory stimulus. Sequential analyses revealed several patterns suggesting that an attentional process similar or analogous to attentional blink may have contributed both to the observed fluctuations in chick responsivity to the auditory stimulus as a function of delay and to the time-specific learning deficit shown by chicks provided with two-speaker training. The study highlights that learning can be substantially modulated by processes of orienting and attention and has a number of important implications for research within cognitive neuroscience, animal behavior and learning.

Understanding the Effect of Protein Tyrosine Phosphatase Receptor Type 0 on Mammalian Sensory Development: Behavioral Studies on PTPRO Knockout Mice

Nerve development, which includes axon outgrowth and guidance, is regulated by many protein families, including receptor protein tyrosine phosphatases (RPTP's).Protein tyrosine phosphatase receptor type 0 (PTPRO) is a type III RPTP that is important for axon growth and guidance, as observed in chicks and flies. In order to examine the effects ofPTPRO on mammalian development, standard behavioral tests were used to compare mice lacking the gene for PTPRO (ROKO mice) to wild-type (WT) mice. The ROKO mice showed a significant delay in reacting to a thermal noxious stimulus, hotplate analgesia, when compared to the WT mice suggesting deficient nociceptive function. In a rotarod test for proprioceptive function the ROKO mice exhibited a significant decrease in the amount of time spent on the rotating rod than did the WT mice. Additional proprioception tests were performed including the climb, step reflex, beam, and mesh walk tests. In the climb and step (place) test, the ROKO group had a significantly lower accuracy in performing the tests than did the WT mice. Thus, mice lacking the PTPRO gene showed behavioral deficiencies that reflect impairment in sensory function, specifically for nociception and proprioception.

Design and development of a one-degree-of-freedom force-reflecting manual controller prototype for teleoperation

The present research is carried out from the viewpoint of primarily space applications where human lives may be in danger if they are to work under these conditions. This work proposes to develop a one-degree-of-freedom (1-DOF) force-reflecting manual controller (FRMC) prototype for teleoperation, and address the effects of time delays commonly found in space applications where the control is accomplished via the earth-based control stations. To test the FRMC, a mobile robot (PPRK) and a slider-bar were developed and integrated to the 1-DOF FRMC. The software developed in Visual Basic is able to telecontrol any platform that uses an SV203 controller through the internet and it allows the remote system to send feedback information which may be in the form of visual or force signals. Time delay experiments were conducted on the platform and the effects of time delay on the FRMC system operation have been studied and delineated.

Delay-sensitive service request scheduling for cloud computing

Cloud computing realizes the long-held dream of converting computing capability into a type of utility. It has the potential to fundamentally change the landscape of the IT industry and our way of life. However, as cloud computing expanding substantially in both scale and scope, ensuring its sustainable growth is a critical problem. Service providers have long been suffering from high operational costs. Especially the costs associated with the skyrocketing power consumption of large data centers. In the meantime, while efficient power/energy utilization is indispensable for the sustainable growth of cloud computing, service providers must also satisfy a user's quality of service (QoS) requirements. This problem becomes even more challenging considering the increasingly stringent power/energy and QoS constraints, as well as other factors such as the highly dynamic, heterogeneous, and distributed nature of the computing infrastructures, etc. ^ In this dissertation, we study the problem of delay-sensitive cloud service scheduling for the sustainable development of cloud computing. We first focus our research on the development of scheduling methods for delay-sensitive cloud services on a single server with the goal of maximizing a service provider's profit. We then extend our study to scheduling cloud services in distributed environments. In particular, we develop a queue-based model and derive efficient request dispatching and processing decisions in a multi-electricity-market environment to improve the profits for service providers. We next study a problem of multi-tier service scheduling. By carefully assigning sub deadlines to the service tiers, our approach can significantly improve resource usage efficiencies with statistically guaranteed QoS. Finally, we study the power conscious resource provision problem for service requests with different QoS requirements. By properly sharing computing resources among different requests, our method statistically guarantees all QoS requirements with a minimized number of powered-on servers and thus the power consumptions. The significance of our research is that it is one part of the integrated effort from both industry and academia to ensure the sustainable growth of cloud computing as it continues to evolve and change our society profoundly.^

Development of a triage tool for neurodevelopmental risk in children aged 30 months

Peer reviewed

Development of a triage tool for neurodevelopmental risk in children aged 30 months

Peer reviewed

Development of a triage tool for neurodevelopmental risk in children aged 30 months

Peer reviewed

Delay-Sensitive Service Request Scheduling for Cloud Computing

Cloud computing realizes the long-held dream of converting computing capability into a type of utility. It has the potential to fundamentally change the landscape of the IT industry and our way of life. However, as cloud computing expanding substantially in both scale and scope, ensuring its sustainable growth is a critical problem. Service providers have long been suffering from high operational costs. Especially the costs associated with the skyrocketing power consumption of large data centers. In the meantime, while efficient power/energy utilization is indispensable for the sustainable growth of cloud computing, service providers must also satisfy a user's quality of service (QoS) requirements. This problem becomes even more challenging considering the increasingly stringent power/energy and QoS constraints, as well as other factors such as the highly dynamic, heterogeneous, and distributed nature of the computing infrastructures, etc. In this dissertation, we study the problem of delay-sensitive cloud service scheduling for the sustainable development of cloud computing. We first focus our research on the development of scheduling methods for delay-sensitive cloud services on a single server with the goal of maximizing a service provider's profit. We then extend our study to scheduling cloud services in distributed environments. In particular, we develop a queue-based model and derive efficient request dispatching and processing decisions in a multi-electricity-market environment to improve the profits for service providers. We next study a problem of multi-tier service scheduling. By carefully assigning sub deadlines to the service tiers, our approach can significantly improve resource usage efficiencies with statistically guaranteed QoS. Finally, we study the power conscious resource provision problem for service requests with different QoS requirements. By properly sharing computing resources among different requests, our method statistically guarantees all QoS requirements with a minimized number of powered-on servers and thus the power consumptions. The significance of our research is that it is one part of the integrated effort from both industry and academia to ensure the sustainable growth of cloud computing as it continues to evolve and change our society profoundly.