ROCK2/rasHa cooperation induce malignant conversion via p53 loss, elevated NF-κβ and tenascin C-associated rigidity but p21 inhibits ROCK2/NF-κβ-mediated progression

To study ROCK2 activation in carcinogenesis, mice expressing 4-hydroxytamoxifen (4HT)- activated ROCK2 [K14.ROCKer] were crossed to mice expressing epidermal activated ras Ha [HK1.ras1205]. At 8 weeks, 4HT-treated K14.ROCKer-HK1.ras1205 cohorts exhibited papillomas similar to HK1.ras1205 controls; however, K14.ROCKer-HK1.ras1205 histotypes comprised a mixed papilloma/well-differentiated squamous cell carcinoma [wdSCC], exhibiting p53 loss, increased proliferation, and novel NF-κβ expression. By 12 weeks, K14.ROCKer-HK1.ras1205 wdSCCs exhibited increased NF-κβ and novel tenascin C, indicative of elevated rigidity; yet despite continued ROCK2 activities /p-Mypt1 inactivation, progression to SCC required loss of compensatory p21 expression. K14.ROCKer -HK1.ras1205 papillomatogenesis also required a wound-promotion stimulus, confirmed by breeding K14.ROCKer into promotion-insensitive HK1.ras1276 mice, suggesting a permissive K14.ROCKer-HK1.ras1205 papilloma context [wound-promoted/NF-κβ+ve/p53-ve/p21+ve] preceded K14.ROCKer-mediated [p-Mypt1/tenascin C/rigidity] malignant conversion. Malignancy depended on ROCKer/p-Mypt1 expression, as cessation of 4HT-treatment induced disorganised tissue architecture and p21-associated differentiation in wdSCCs; yet tenascin C retention in connective tissue ECM suggests the rigidity laid down for conversion persists. Novel papilloma outgrowths appeared expressing intense, basal-layer p21 which confined endogenous ROCK2/p-Mypt1/NF-κβ to supra-basal layers, and was paralleled by restored basal-layer p53. In later SCCs, 4HT-cessation became irrelevant as endogenous ROCK2 expression increased, driving progression via p21 loss, elevated NF-κβ expression and tenascin C-associated rigidity; with p-Mypt1 inactivation/actinomyosin-mediated contractility to facilitate invasion. However, p21-associated inhibition of early-stage malignant progression and the intense expression in papilloma outgrowths, identifies a novel, significant antagonism between p21 and ras Ha/ROCK2/NF-κβ signalling in skin 3 carcinogenesis. Collectively these data show that ROCK2 activation induces malignancy in rasHa-initiated/promoted papillomas in the context of p53 loss and novel NF-κβ expression;whilst increased tissue rigidity and cell motility/contractility help mediate tumour progression

KnowSe: Fostering user interaction context awareness

The CSCW area has recognized the concept of awareness as a critical issue to focus on (Schmidt et al., 2002) since “users who work together require adequate information about their environment” (Gross and Prinz, 2003). The environment of an individual encompasses her connections with other people, as well as with digital resources and actions (tasks or processes). If connections are not clear or hidden to the individual or to the group, the cost is a lack of awareness in the organization (McArthur and Bruza, 2003), which not only leads to inefficient cooperation but can even prevent it from being started. Unveiling the relations between persons, topics, tasks and processes to computer workers facilitates cooperative work by increasing the awareness of the personal social networks and the role of an individual in the organization, a project, or a group. These connections can be created and modeled manually but a better approach is to develop semi-automatic or even automatic tools to create and share them (McArthur and Bruza, 2003). Based on emails, McArthur and Bruza (2003) have computed such kind of connections, and suggest using more global corpora as well as taking into account dynamic ones

Detecting real user tasks by training on laboratory contextual attention metadata

Detecting the current task of a user is essential for providing her with contextualized and personalized support, and using Contextual Attention Metadata (CAM) can help doing so. Some recent approaches propose to perform automatic user task detection by means of task classifiers using such metadata. In this paper, we show that good results can be achieved by training such classifiers offline on CAM gathered in laboratory settings. We also isolate a combination of metadata features that present a significantly better discriminative power than classical ones

Exploiting the user interaction context for automatic task detection

Detecting the task a user is performing on her computer desktop is important for providing her with contextualized and personalized support. Some recent approaches propose to perform automatic user task detection by means of classifiers using captured user context data. In this paper we improve on that by using an ontology-based user interaction context model that can be automatically populated by (i) capturing simple user interaction events on the computer desktop and (ii) applying rule-based and information extraction mechanisms. We present evaluation results from a large user study we have carried out in a knowledge-intensive business environment, showing that our ontology-based approach provides new contextual features yielding good task detection performance. We also argue that good results can be achieved by training task classifiers `online' on user context data gathered in laboratory settings. Finally, we isolate a combination of contextual features that present a significantly better discriminative power than classical ones

Automatic detection of accommodation steps as an indicator of knowledge maturing

Jointly working on shared digital artifacts – such as wikis – is a well-tried method of developing knowledge collectively within a group or organization. Our assumption is that such knowledge maturing is an accommodation process that can be measured by taking the writing process itself into account. This paper describes the development of a tool that detects accommodation automatically with the help of machine learning algorithms. We applied a software framework for task detection to the automatic identification of accommodation processes within a wiki. To set up the learning algorithms and test its performance, we conducted an empirical study, in which participants had to contribute to a wiki and, at the same time, identify their own tasks. Two domain experts evaluated the participants’ micro-tasks with regard to accommodation. We then applied an ontology-based task detection approach that identified accommodation with a rate of 79.12%. The potential use of our tool for measuring knowledge maturing online is discussed

The cost effectiveness of integrated care for people living with HIV including antiretroviral treatment in a primary health care centre in Bujumbura, Burundi

The incremental cost effectiveness of an integrated care package (i.e., medical care including antiretroviral therapy (ART) and other services such as psychological and social support) for people living with HIV/AIDS was calculated in a not-for-profit primary health care centre in Bujumbura run by Society of Women against AIDS-Burundi (SWAA-Burundi), an African non-governmental organisation (NGO). Results are expressed as cost-effectiveness ratio 2007, constant US$per disability-adjusted life year (DALY) averted. Unit costs are estimated from the NGO's accounting data and activity reports, healthcare utilisation is estimated from the medical records of a cohort of 149 patients. Effectiveness is modelled on the survival of this cohort, using standard calculation methods. The incremental cost of integrated care for people living with HIV/AIDS in the Bujumbura health centre of SWAA-Burundi is 258 US$ per DALY averted. The package of care provided by SWAA-Burundi is therefore a very cost-effective intervention in comparison with other interventions against HIV/AIDS that include ART. It is however, less cost effective than other types of interventions against HIV/AIDS, such as preventive activities

Diamond electro-optomechanical resonators integrated in nanophotonic circuits

Diamond integrated photonic devices are promising candidates for emerging applications in nanophotonics and quantum optics. Here we demonstrate active modulation of diamond nanophotonic circuits by exploiting mechanical degrees of freedom in free-standing diamond electro-optomechanical resonators. We obtain high quality factors up to 9600, allowing us to read out the driven nanomechanical response with integrated optical interferometers with high sensitivity. We are able to excite higher order mechanical modes up to 115 MHz and observe the nanomechanical response also under ambient conditions.Comment: 15 pages, 4 figure

Nutritional Immunomodulation as an Approach to Decreasing the Negative Effects of Stress in Poultry Production

Stress can lead to changes in the immune response resulting in both increased and decreased resistance to opportunistic bacterial pathogens. Growth-promoting antibiotics have been a major tool in modulating hostpathogen interactions and limiting clinical and subclinical bacterial infection in confined animal production. Regulatory pressures to limit antibiotic use in poultry production and recent international marketing agreements that prohibit treating poultry with antibiotics have limited the disease-fighting tools available to poultry and livestock producers, particularly in Europe. There is a need to evaluate potential antibiotic alternatives to improve both production and disease resistance in high-intensity food animal production. Nutritional approaches to counteract the debilitating effects of stress and infection may provide producers with useful alternatives to antibiotics. Improving disease resistance in food animals, particularly in the absence of antibiotic treatment, is a key strategy in the effort to increase food safety. ARS research has demonstrated the efficacy of several nutritional immunomodulators, including vitamin D3 and yeast cell wall products, to protect against bacterial infection due to stress and challenge with opportunistic pathogens. These studies also provide an animal model for testing the efficacy of nutritional strategies that may affect the response to stress and related infection in humans