A voyage of discovery to the North Pacific Ocean, and round the world : in which the coast of north-west America has been carefully examined and accurately surveyed : Undertaken by His Majesty's command, principally with a view to ascertain the existence of any navigable communication between the North Pacific and North Atlantic Oceans, and performed in the years 1790, 1791, 1792, 1793, 1794, and 1795, in the Discovery sloop of war, and armed tender Chatham, under the command of Captain George Vancouver : in three volumes, Vol. III.

Mode of access: Internet.

A voyage of discovery to the North Pacific Ocean, and round the world : in which the coast of north-west America has been carefully examined and accurately surveyed : Undertaken by His Majesty's command, principally with a view to ascertain the existence of any navigable communication between the North Pacific and North Atlantic Oceans, and performed in the years 1790, 1791, 1792, 1793, 1794, and 1795, in the Discovery sloop of war, and armed tender Chatham, under the command of Captain George Vancouver : in three volumes, Vol. II.

Mode of access: Internet.

Boylston medical prize dissertations for the years 1819 and 1821. Experiments and observations on the communication between the stomach and the urinary organs, and on the propriety of administering medicine by injection into the veins.

Dissertation I. On the question, Is there any communication from the stomach to the bladder, more direct than that through the circulating system and the kidneys? Which obtained the Boylston premium in 1819.--Dissertation II. On the question, Can medicinal substances be safely and advantageously introduced into animal bodies through the medium of the veins? Which obtained the Boylston premium in 1821.

Gap-junction communication between subtypes of direction-selective ganglion cells in the developing retina

The On-Off direction-selective ganglion cells (DSGCs) in the rabbit retina comprise four distinct subtypes that respond preferentially to image motion in four orthogonal directions; each subtype forms a regular territorial array, which is overlapped by the other three arrays. In this study, ganglion cells in the developing retina were injected with Neurobiotin, a gap-junction-permeable tracer, and the DSGCs were identified by their characteristic type 1 bistratified (BiS1) morphology. The complex patterns of tracer coupling shown by the BiSl ganglion cells changed systematically during the course of postnatal development. BiSl cells appear to be coupled together around the time of birth, but, over the next 10 days, BiSl cells decouple from each other, leading to the mature pattern in which only one subtype is coupled. At about postnatal day 5, before the ganglion cells become visually responsive, each of the BiSl cells commonly showed tracer coupling both to a regular array of neighboring BiSl cells, presumably destined to be DSGCs of the same subtype, and to a regular array of overlapping BiSl cells, presumably destined to be DSGCs of a different subtype. The gap-junction intercellular communication between subtypes of DSGCs with different preferred directions may play an important role in the differentiation of their synaptic connectivity, with respect to either the inputs that DSGCs receive from retinal interneurons or the outputs that DSGCs make to geniculate neurons. (C) 2004 Wiley-Liss, Inc.

A feasibility study of email communication between the patient's family and the specialist burns team

We investigated whether the parents of burns patients could capture suitable clinical images with a digital camera and add the necessary text information to enable the paediatric burns team to provide follow-up care via email. Four families were involved in the study, each of whom sent regular email consultations for six months. The results were very encouraging. The burns team felt confident that the clinical information in 30 of the 32 email messages (94%) they received was accurate, although in I I of these 30 cases (37%) they stated that there was room for improvement (the quality was nonetheless adequate for clinical decision making). The study also showed that low-resolution images (average size 37 kByte) were satisfactory for diagnosis. Families were able to participate in the service without intensive training and support. The user survey showed that all four families found it easy and convenient to take the digital photographs and to participate in the study. The results suggest that the technique has potential as a low-cost telemedicine service in burns follow-up, and that it requires only modest investment in equipment, training and support.

Communication between the nucleotide binding domains of P-glycoprotein occurs via conformational changes that involve residue 508

Our aim is to provide molecular understanding of the mechanisms underlying the (i) interaction between the two nucleotide binding domains (NBDs) and (ii) coupling between NBDs and transmembrane domains within P-glycoprotein (Pgp) during a transport cycle. To facilitate this, we have introduced a number of unique cysteine residues at surface exposed positions (E393C, S452C, I500C, N508C, and K578C) in the N-terminal NBD of Pgp, which had previously been engineered to remove endogenous cysteines. Positions of the mutations were designed using a model based on crystallographic features of prokaryotic NBDs. The single cysteine mutants were expressed in insect cells using recombinant baculovirus and the proteins purified by metal affinity chromatography by virtue of a polyhistidine tag. None of the introduced cysteine residues perturbed the function of Pgp as judged by the characteristics of drug stimulated ATP hydrolysis. The role of residues at each of the introduced sites in the catalytic cycle of Pgp was investigated by the effect of covalent conjugation with N-ethyl-maleimide (NEM). All but one mutation (K578C) was accessible to labeling with [3H]-NEM. However, perturbation of ATPase activity was only observed for the derivitized N508C isoform. The principle functional manifestation was a marked inhibition of the "basal" rate of ATP hydrolysis. Neither the extent nor potency to which a range of drugs could affect the ATPase activity were altered in the NEM conjugated N508C isoform. The results imply that the accessibility of residue 508, located in the alpha-helical subdomain of NBD1 in Pgp, is altered by the conformational changes that occur during ATP hydrolysis.

Software Components for Serious Game Development

The presentation explains the approach of the RAGE project. It presents three examples of RAGE software components and how these can be easily reused for applied game development.

Software Components for Serious Game Development

The large upfront investments required for game development pose a severe barrier for the wider uptake of serious games in education and training. Also, there is a lack of well-established methods and tools that support game developers at preserving and enhancing the games’ pedagogical effectiveness. The RAGE project, which is a Horizon 2020 funded research project on serious games, addresses these issues by making available reusable software components that aim to support the pedagogical qualities of serious games. In order to easily deploy and integrate these game components in a multitude of game engines, platforms and programming languages, RAGE has developed and validated a hybrid component-based software architecture that preserves component portability and interoperability. While a first set of software components is being developed, this paper presents selected examples to explain the overall system’s concept and its practical benefits. First, the Emotion Detection component uses the learners’ webcams for capturing their emotional states from facial expressions. Second, the Performance Statistics component is an add-on for learning analytics data processing, which allows instructors to track and inspect learners’ progress without bothering about the required statistics computations. Third, a set of language processing components accommodate the analysis of textual inputs of learners, facilitating comprehension assessment and prediction. Fourth, the Shared Data Storage component provides a technical solution for data storage - e.g. for player data or game world data - across multiple software components. The presented components are exemplary for the anticipated RAGE library, which will include up to forty reusable software components for serious gaming, addressing diverse pedagogical dimensions.

An investigation of the relationship between the components of tumour microenvironment, signal transduction pathways and outcome in breast cancer

Breast cancer, the most commonly diagnosed type of cancer in women, is a major cause of morbidity and mortality in the western world. Well-established risk factors of breast cancer are mostly related to women’s reproductive history, such as early menarche, late first pregnancy and late menopause. Survival rates have improved due to a combination of factors, including better health education, early detection with large-scale use of screening mammogram, improved surgical techniques, as well as widespread use of adjuvant therapy. At initial presentation, clinicopathological features of breast cancer such as age, nodal status, tumour size, tumour grade, and hormonal receptor status are considered to be the standard prognostic and predictive markers of patient survival, and are used to guide appropriate treatment strategies. Lymphovascular invasion (LBVI), including lymphatic (LVI) and blood (BVI) vessel invasion, has been reported to be prognostic and merit accurate evaluation, particularly in patients with node negative tumours who might benefit from adjuvant chemotherapy. There is a lack of standard assessment and agreement on distinguishing LVI from BVI despite the major challenges in the field. A systematic review of the literatures, examining methods of detection and the prognostic significance of LBVI, LVI and BVI, was carried out. The majority of studies used haematoxylin and eosin (H&E) and classical histochemistry to identify LVI and BVI. Only few recent studies used immunohistochemistry (IHC) staining of the endothelium lining lymphatic and blood vessels, and were able to show clear differences between LVI and BVI. The prognostic significance of LBVI and LVI was well-documented and strongly associated with aggressive features of breast tumours, while the prognostic value and the optimal detection method of BVI were unclear. Assessment and prognostic value of LBVI on H&E sections (LBVIH&E) was examined and compared to that of LVI and BVI detected using IHC with D2-40 for LVI (LVID2–40) and Factor VIII for BVI (BVIFVIII) in patients with breast cancer including node negative and triple negative patients (n=360). LBVIH&E, LVID2–40 and BVIFVIII were present in 102 (28%), 127 (35%) and 59 (16%) patients respectively. In node negative patients (206), LBVIH&E, LVID2–40 and BVIFVIII were present in 41 (20%), 53 (26%) and 21 (10%) respectively. In triple negative patients (102), LBVIH&E, LVID2–40 and BVIFVIII were present in 35 (29%), 36 (35%) and 14 (14%) respectively. LBVIH&E, LVID2–40 and BVIFVIII were all significantly associated with tumour recurrence in all cohorts. On multivariate survival analysis, only LVID2–40 and BVIFVIII were independent predictors of cancer specific survival (CSS) in the whole cohort (P=0.022 and P<0.001 respectively), node negative (P=0.008 and P=0.001 respectively) and triple negative patients (P=0.014 and P<0.001 respectively). Assessment of LVI and BVI by IHC, using D2-40 and Factor VIII, improves prediction of outcome in patients with node negative and triple negative breast cancer and was superior to the conventional detection method. Breast cancer is recognised as a complex molecular disease and histologically identical tumours may have highly variable outcomes, including different responses to therapy. Therefore, there is a compelling need for new prognostic and predictive markers helpful of selecting patients at risk and patients with aggressive diseases who might benefit from adjuvant and targeted therapy. It is increasingly recognised that the development and progression of human breast cancer is not only determined by genetically abnormal cells, but also dependent on complex interactions between malignant cells and the surrounding microenvironment. This has led to reconsider the features of tumour microenvironment as potential predictive and prognostic markers. Among these markers, tumour stroma percentage (TSP) and tumour budding, as well as local tumour inflammatory infiltrate have received recent attention. In particular, the local environment of cytokines, proteases, angiogenic and growth factors secreted by inflammatory cells and stromal fibroblasts has identified crucial roles in facilitating tumour growth, and metastasis of cancer cells through lymphatic and/or blood vessel invasion. This might help understand the underlying process promoting tumour invasion into these vessels. An increase in the proportion of tumour stroma and an increase in the dissociation of tumour cells have been associated with poorer survival in a number of solid tumours, including breast cancer. However, the interrelationship between these variables and other features of the tumour microenvironment in different subgroups of breast cancer are not clear. Also, whether their prognostic values are independent of other components of the tumour microenvironment have yet to be identified. Therefore, the relationship between TSP, clinicopathological characteristics and outcome in patients with invasive ductal breast cancer, in particular node negative and triple negative disease was examined in patients with invasive ductal breast cancer (n=361). The TSP was assessed on the haematoxylin and eosin-stained tissue sections. With a cut-off value of 50% TSP, patients with ≤50% stroma were classified as the low-TSP group and those with >50% stroma were classified as the high-TSP group. A total of 109 (30%) patients had high TSP. Patients with high TSP were old age (P=0.035), had involved lymph node (P=0.049), Her-2 positive tumours (P=0.029), low-grade peri-tumoural inflammatory infiltrate (P=0.034), low CD68+ macrophage infiltrate (P<0.001), low CD4+ (P=0.023) and low CD8+ T-lymphocytes infiltrate (P=0.017), tumour recurrence (P=0.015) and shorter CSS (P<0.001). In node negative patients (n=207), high TSP was associated with low CD68+ macrophage infiltrate (P=0.001), low CD4+ (P=0.040) and low CD8+ T-lymphocytes infiltrate (P=0.016) and shorter CSS (P=0.005). In triple negative patients (n=103), high TSP was associated with increased tumour size (P=0.017) high tumour grade (P=0.014), low CD8+ T-lymphocytes infiltrate (P=0.048) and shorter CSS (P=0.041). The 15-year cancer specific survival rate was 79% vs 21% in the low-TSP group vs high-TSP group. On multivariate survival analysis, a high TSP was associated with reduced CSS in the whole cohort (P=0.007), node negative patients (P=0.005) and those who received systemic adjuvant therapy (P=0.016), independent of other pathological characteristics including local host inflammatory responses. Therefore, a high TSP in invasive ductal breast cancer was associated with recurrence and poorer long-term survival. The inverse relation with the tumour inflammatory infiltrate highlights the importance of the amount of tumour stroma on immunological response in patients with invasive ductal breast cancer. Implementing this simple and reproducible parameter in routine pathological examination may help optimise risk stratification in patients with breast cancer. Similarly, the relationship between tumour budding, clinicopathological characteristics and outcome was examined in patients with invasive ductal breast cancer (n=474), using routine pathological sections. Tumour budding was associated with several adverse pathological characteristics, including positive lymph node (P=0.009), presence of LVI (P<0.001), and high TSP (P=0.001) and low-grade general peri-tumural inflammatory infiltrative (P=0.002). In node negative patients, a high tumour budding was associated with presence of LVI (P<0.001) and low-grade general peri-tumural inflammatory infiltrative (P=0.038). On multivariate survival analysis, tumour budding was associated with reduced CSS (P=0.001), independent of nodal status, tumour necrosis, CD8+ and CD138+ inflammatory cells infiltrate, LVI, BVI and TSP. Furthermore, tumour budding was independently associated with reduced CSS in node negative patients (P=0.004) and in those who have low TSP (P=0.003) and high-grade peri-tumoural inflammatory infiltrative (P=0.012). A high tumour budding was significantly associated with shorter CSS in luminal B and triple negative breast cancer subtypes (all P<0.001). Therefore, tumour budding was a significant predictor of poor survival in patients with invasive ductal breast cancer, independent of adverse pathological characteristics and components of tumour microenvironment. These results suggest that tumour budding may promote disease progression through a direct effect on local and distant invasion into lymph nodes and lymphatic vessels. Therefore, detection of tumour buds at the stroma invasive front might therefore represent a morphologic link between tumour progression, lymphatic invasion, spread of tumour cells to regional lymph nodes, and the establishment of metastatic dissemination. Given the potential importance of the tumour microenvironment, the characterisation of intracellular signalling pathways is important in the tumour microenvironment and is of considerable interest. One plausible signalling molecule that links tumour stroma, inflammatory cell infiltrate and tumour budding is the signal transducer and activator of transcription (STAT). The relationship between total and phosphorylated STAT1 (ph-STAT1), and total and ph-STAT3 tumour cell expression, components of tumour microenvironment and survival in patients with invasive ductal breast cancer was examined. IHC of total and ph-STAT1/STAT3 was performed on tissue microarray of 384 breast cancer specimens. Cellular STAT1 and cellular STAT3 expression at both cytoplasmic and nuclear locations were combined and identified as STAT1/STAT3 tumour cell expression. These results were then related to CSS and phenotypic features of the tumour and host. A high ph-STAT1 and a high ph-STAT3 tumour cell expression was associated with increased ER (P=0.001 and P<0.001 respectively) and PR (all P<0.05), reduced tumour grade (P=0.015 and P<0.001 respectively) and necrosis (all P=0.001). Ph-STAT1 was associated with increased general peri-tumoural inflammatory infiltrate (P=0.007) and ph-STAT3 was associated with lower CD4+ T-lymphocyte infiltrate (P=0.024). On multivariate survival analysis, including both ph-STAT1 and ph-STAT3 tumour cell expression, only high ph-STAT3 tumour cell expression was significantly associated with improved CSS (P=0.010) independent of other tumour and host-based factors. In patients with high necrosis grade, high ph-STAT3 tumour cell expression was independent predictor of improved CSS (P=0.021). Ph-STAT1 and ph-STAT3 were also significantly associated with improved cancer specific survival in luminal A and B subtypes. STAT1 and STAT3 tumour cell expression appeared to be an important determinant of favourable outcome in patients with invasive ductal breast cancer. The present results suggest that STATs may affect disease outcome through direct impact on tumour cells, and the surrounding microenvironment. The above observations of the present thesis point to the importance of the tumour microenvironment in promoting tumour budding, LVI and BVI. The observations from STATs work may suggest that an important driving mechanism for the above associations is the presence of tumour necrosis, probably secondary to hypoxia. Further work is needed to examine the interaction of other molecular pathways involved in the tumour microenvironment, such as HIF and NFkB in patients with invasive ductal breast cancer.

Padrão CQRS para sistemas distribuídos de larga escala

Esta tese pretende desenvolver o estudo de um padrão que utiliza um modelo de implementação fundamentado na natureza das operações que um sistema pretende executar. Estas operações são distinguidas pelo que realizam, portanto um sistema poderá ser dividido em duas grandes áreas: uma, de leitura de dados, e outra, de manipulação de dados. A maior parte dos sistemas atuais está a progredir, com o objetivo de conseguir suportar muitos utilizadores em simultâneo, e é neste aspeto que este padrão se diferencia porque vai permitir escalar, com muita facilidade e sem sobrecarga. Além disso, este estudo deverá facultar um conjunto de boas práticas e incidir sobre o facto de se pretender desenhar um sistema de raiz e não apenas em “migrar” de um sistema já existente. Ao estudar este padrão é essencial estudar e analisar a evolução da utilização futura dos sistemas, para determinar a utilidade e a aplicação crescente ou não, deste padrão. Interessa também saber, quem implementa atualmente este padrão, em que tipo de produtos, e enaltecer o seu sucesso de implementação, estimulando o desenvolvimento da sua utilização. Finalmente, demonstra-se a aplicabilidade e validade do padrão proposto, através de uma implementação modelo, com a ajuda de uma framework de forma a determinar quais as ferramentas existentes que possam ser úteis e contribuir para a implementação deste padrão. O objetivo final será demonstrar os principais componentes do sistema, como poderá prosseguir a sua evolução e como poderá ser melhorada e simplificada a comunicação entre os seus componentes, para uma utilização mais fácil, frequente e de interesse comum para todos: utilizadores e administradores.

MULTIDIMENSIONAL OPTIMAL DROOP CONTROL FOR WIND RESOURCES IN DC MICROGRIDS

Two important and upcoming technologies, microgrids and electricity generation from wind resources, are increasingly being combined. Various control strategies can be implemented, and droop control provides a simple option without requiring communication between microgrid components. Eliminating the single source of potential failure around the communication system is especially important in remote, islanded microgrids, which are considered in this work. However, traditional droop control does not allow the microgrid to utilize much of the power available from the wind. This dissertation presents a novel droop control strategy, which implements a droop surface in higher dimension than the traditional strategy. The droop control relationship then depends on two variables: the dc microgrid bus voltage, and the wind speed at the current time. An approach for optimizing this droop control surface in order to meet a given objective, for example utilizing all of the power available from a wind resource, is proposed and demonstrated. Various cases are used to test the proposed optimal high dimension droop control method, and demonstrate its function. First, the use of linear multidimensional droop control without optimization is demonstrated through simulation. Next, an optimal high dimension droop control surface is implemented with a simple dc microgrid containing two sources and one load. Various cases for changing load and wind speed are investigated using simulation and hardware-in-the-loop techniques. Optimal multidimensional droop control is demonstrated with a wind resource in a full dc microgrid example, containing an energy storage device as well as multiple sources and loads. Finally, the optimal high dimension droop control method is applied with a solar resource, and using a load model developed for a military patrol base application. The operation of the proposed control is again investigated using simulation and hardware-in-the-loop techniques.