Syntaxin 11 binds Vti1b and regulates late endosome to lysosome fusion in macrophages

Syntaxin 11 (Stx11) is a SNARE protein enriched in cells of the immune system. Loss or mutation of Stx11 results in familial hemophagocytic lymphohistiocytosis type-4 (FHL-4), an autosomal recessive disorder of immune dysregulation characterized by high levels of inflammatory cytokines along with defects in T-cell and natural killer cell function. We show here Stx11 is located on endosomalmembranes including late endosomes and lysosomes in macrophages. While Stx11 did not form a typical trans-SNARE complex, it did bind to the Q-SNARE Vti1b and was able to regulate the availability of Vti1b to form the Q-SNARE complexes Stx6/Stx7/Vtib and Stx7/Stx8/Vti1b. The mutant form of Stx11 sequestered Vti1b from forming the Q-SNARE complex that mediates late endosome to lysosome fusion. Depletion of Stx11 in activated macrophages leads to an accumulation of enlarged late endocytic compartments, increased trafficking to the cell surface and inhibition of late endosome to lysosome fusion. These phenotypes arerescued by the expression of an siRNA-resistant Stx11 construct in Stx11-depleted cells. Our results suggest that by regulating the availability of Vti1b, Stx11 regulates trafficking steps between late endosomes, lysosomes and the cell surface in macrophages.

The scalability and the strategy for EMR database encryption techniques

EMR (Electronic Medical Record) is an emerging technology that is highly-blended between non-IT and IT area. One methodology is to link the non-IT and IT area is to construct databases. Nowadays, it supports before and after-treatment for patients and should satisfy all stakeholders such as practitioners, nurses, researchers, administrators and financial departments and so on. In accordance with the database maintenance, DAS (Data as Service) model is one solution for outsourcing. However, there are some scalability and strategy issues when we need to plan to use DAS model properly. We constructed three kinds of databases such as plan-text, MS built-in encryption which is in-house model and custom AES (Advanced Encryption Standard) - DAS model scaling from 5K to 2560K records. To perform custom AES-DAS better, we also devised Bucket Index using Bloom Filter. The simulation showed the response times arithmetically increased in the beginning but after a certain threshold, exponentially increased in the end. In conclusion, if the database model is close to in-house model, then vendor technology is a good way to perform and get query response times in a consistent manner. If the model is DAS model, it is easy to outsource the database, however, some techniques like Bucket Index enhances its utilization. To get faster query response times, designing database such as consideration of the field type is also important. This study suggests cloud computing would be a next DAS model to satisfy the scalability and the security issues.

A new model to analyze metaphyseal bone healing in mice

Background: Despite the increasing clinical problems with metaphyseal fractures, most experimental studies investigate the healing of diaphyseal fractures. Although the mouse would be the preferable species to study the molecular and genetic aspects of metaphyseal fracture healing, a murine model does not exist yet. Using a special locking plate system, we herein introduce a new model, which allows the analysis of metaphyseal bone healing in mice. Methods: In 24 CD-1 mice the distal metaphysis of the femur was osteotomized. After stabilization with the locking plate, bone repair was analyzed radiologically, biomechanically, and histologically after 2 (n = 12) and 5 wk (n = 12). Additionally, the stiffness of the bone-implant construct was tested biomechanically ex vivo. Results: The torsional stiffness of the bone-implant construct was low compared with nonfractured control femora (0.23 ± 0.1 Nmm/°versus 1.78 ± 0.15 Nmm/°, P < 0.05). The cause of failure was a pullout of the distal screw. At 2 wk after stabilization, radiological analysis showed that most bones were partly bridged. At 5 wk, all bones showed radiological union. Accordingly, biomechanical analyses revealed a significantly higher torsional stiffness after 5 wk compared with that after 2 wk. Successful healing was indicated by a torsional stiffness of 90% of the contralateral control femora. Histological analyses showed new woven bone bridging the osteotomy without external callus formation and in absence of any cartilaginous tissue, indicating intramembranous healing. Conclusion: With the model introduced herein we report, for the first time, successful metaphyseal bone repair in mice. The model may be used to obtain deeper insights into the molecular mechanisms of metaphyseal fracture healing. © 2012 Elsevier Inc. All rights reserved.

Factors influencing speeding in school zones : the role of mindfulness

Background Excessive speed contributes to the incidence and severity of road crashes. The Theory of Planned Behaviour (TPB) has successfully explained variance in speeding intentions and behaviour. However, studies have shown that more than 40% of the variance in outcome measures of speeding remains unexplained, thus, suggesting additional constructs may help to enhance the TPB’s predictive power. Therefore, this study examined mindfulness; a promising construct which has not yet been tested as an additional TPB predictor. Aims The aims of this study were to explore drivers’ beliefs about speeding in school zones using the extended TPB as a framework and to examine the effect that mindfulness had on driver speeding behaviour in school zones. Methods Australian drivers (N = 17) participated in one of four focus group discussions. The overall sample was comprised of five males and twelve females who were aged between 17 to56 years. All participants were recruited via purposive sampling among 1st year psychology students at a large South East Queensland University. The group discussions took approximately one hour and were guided by a structured interview schedule which sought to elicit drivers’ beliefs, thoughts and opinions on speeding in school zones and the factors which motivate such behaviour. Results Overall, thematic analysis revealed some similar issues emerged across the groups. . In particular and perhaps somewhat unsurprisingly, given public concerns regarding the want to ensure the safety of school children, there was much agreement that speeding in school zones was dangerous and unacceptable. Somewhat paradoxically however, some participants also agreed that they had unintentionally or mindlessly sped in school zones. There were several factors that drivers believed influenced their speeding in school zones including their current mood (e.g., if in a bad mood, anxious, or excited they may be more likely to drive without awareness of, and being attentive to, their driving environment) and the extent to which they were familiar with the environment (i.e., more familiar contexts, more likely to drive mindlessly). Thus, although drivers expressed a belief that speeding in school zones was dangerous and acceptable, the extent to which a driver is mindful does influence whether or not a driver may actually engage in speeding in this context. Discussion and conclusions This study highlights the potential role of mindfulness in helping to explain speeding behaviour in school zones. Mindless drivers may speed unintentionally and while unintentional still be endangering the safety and lives of school children. The findings of this research suggest that unintentional speeding, especially in school zones, may be reduced by countermeasures which heighten the extent to which drivers are mindful of approaching and/or driving through a school zone, such as street markings and engineering measures (e.g.,flashing lights and speed bumps).

Entrepreneurship : from denial to discovery in nonprofit art museums?

This research explores the function of entrepreneurship in nonprofit art museums. Traditionally, entrepreneurship literature features debates on customer orientation and innovation. This paper reviews a tension in entrepreneurship: the relationship between limited funding and the need to innovate in nonprofit art museums. The paper develops a construct by which to explain the structure of entrepreneurship in nonprofit art museums in Australia and New Zealand since 1975. From this discussion, different strategies and tensions are highlighted that nonprofit art museum directors have used. The dynamics are explored in ten large art museums and the managerial implications are developed.

Tinamous and moa flock together : mitochondrial genome sequence analysis reveals independent losses of flight among ratites

Ratites are large, flightless birds and include the ostrich, rheas, kiwi, emu, and cassowaries, along with extinct members, such as moa and elephant birds. Previous phylogenetic analyses of complete mitochondrial genome sequences have reinforced the traditional belief that ratites are monophyletic and tinamous are their sister group. However, in these studies ratite monophyly was enforced in the analyses that modeled rate heterogeneity among variable sites. Relaxing this topological constraint results in strong support for the tinamous (which fly) nesting within ratites. Furthermore, upon reducing base compositional bias and partitioning models of sequence evolution among protein codon positions and RNA structures, the tinamou–moa clade grouped with kiwi, emu, and cassowaries to the exclusion of the successively more divergent rheas and ostrich. These relationships are consistent with recent results from a large nuclear data set, whereas our strongly supported finding of a tinamou–moa grouping further resolves palaeognath phylogeny. We infer flight to have been lost among ratites multiple times in temporally close association with the Cretaceous–Tertiary extinction event. This circumvents requirements for transient microcontinents and island chains to explain discordance between ratite phylogeny and patterns of continental breakup. Ostriches may have dispersed to Africa from Eurasia, putting in question the status of ratites as an iconic Gondwanan relict taxon. [Base composition; flightless; Gondwana; mitochondrial genome; Palaeognathae; phylogeny; ratites.]

Efficient preconditioning of the method of lines for solving nonlinear two-sided space-fractional diffusion equations

A standard method for the numerical solution of partial differential equations (PDEs) is the method of lines. In this approach the PDE is discretised in space using �finite di�fferences or similar techniques, and the resulting semidiscrete problem in time is integrated using an initial value problem solver. A significant challenge when applying the method of lines to fractional PDEs is that the non-local nature of the fractional derivatives results in a discretised system where each equation involves contributions from many (possibly every) spatial node(s). This has important consequences for the effi�ciency of the numerical solver. First, since the cost of evaluating the discrete equations is high, it is essential to minimise the number of evaluations required to advance the solution in time. Second, since the Jacobian matrix of the system is dense (partially or fully), methods that avoid the need to form and factorise this matrix are preferred. In this paper, we consider a nonlinear two-sided space-fractional di�ffusion equation in one spatial dimension. A key contribution of this paper is to demonstrate how an eff�ective preconditioner is crucial for improving the effi�ciency of the method of lines for solving this equation. In particular, we show how to construct suitable banded approximations to the system Jacobian for preconditioning purposes that permit high orders and large stepsizes to be used in the temporal integration, without requiring dense matrices to be formed. The results of numerical experiments are presented that demonstrate the effectiveness of this approach.

Informed learning in online environments : supporting the higher education curriculum beyond Web 2.0

As boundaries between physical and online learning spaces become increasingly blurred in higher education, how can students gain full benefit of Web 2.0 social media and mobile technologies for learning? How can we, as information professionals and educators, best support the information literacy learning needs of students who are universally mobile and Google-focused? This chapter presents informed learning (Bruce, 2008) as a pedagogical construct with potential to support learning across the higher education curriculum, for Web 2.0 and beyond. After outlining the principles of informed learning and how they may enrich the higher education curriculum, we explain the role of library and information professionals in promoting informed learning for Web 2.0 and beyond. Then, by way of illustration, we describe recent experience at an American university where librarians simultaneously learned about and applied informed learning principles in reshaping the information literacy program.

Improving trust and securing data accessibility for e-health decision making by using data encryption techniques

In the medical and healthcare arena, patients‟ data is not just their own personal history but also a valuable large dataset for finding solutions for diseases. While electronic medical records are becoming popular and are used in healthcare work places like hospitals, as well as insurance companies, and by major stakeholders such as physicians and their patients, the accessibility of such information should be dealt with in a way that preserves privacy and security. Thus, finding the best way to keep the data secure has become an important issue in the area of database security. Sensitive medical data should be encrypted in databases. There are many encryption/ decryption techniques and algorithms with regard to preserving privacy and security. Currently their performance is an important factor while the medical data is being managed in databases. Another important factor is that the stakeholders should decide more cost-effective ways to reduce the total cost of ownership. As an alternative, DAS (Data as Service) is a popular outsourcing model to satisfy the cost-effectiveness but it takes a consideration that the encryption/ decryption modules needs to be handled by trustworthy stakeholders. This research project is focusing on the query response times in a DAS model (AES-DAS) and analyses the comparison between the outsourcing model and the in-house model which incorporates Microsoft built-in encryption scheme in a SQL Server. This research project includes building a prototype of medical database schemas. There are 2 types of simulations to carry out the project. The first stage includes 6 databases in order to carry out simulations to measure the performance between plain-text, Microsoft built-in encryption and AES-DAS (Data as Service). Particularly, the AES-DAS incorporates implementations of symmetric key encryption such as AES (Advanced Encryption Standard) and a Bucket indexing processor using Bloom filter. The results are categorised such as character type, numeric type, range queries, range queries using Bucket Index and aggregate queries. The second stage takes the scalability test from 5K to 2560K records. The main result of these simulations is that particularly as an outsourcing model, AES-DAS using the Bucket index shows around 3.32 times faster than a normal AES-DAS under the 70 partitions and 10K record-sized databases. Retrieving Numeric typed data takes shorter time than Character typed data in AES-DAS. The aggregation query response time in AES-DAS is not as consistent as that in MS built-in encryption scheme. The scalability test shows that the DBMS reaches in a certain threshold; the query response time becomes rapidly slower. However, there is more to investigate in order to bring about other outcomes and to construct a secured EMR (Electronic Medical Record) more efficiently from these simulations.

"Participation" in participatory design research

This thesis is about defining participation in the context of fostering research cohesion in the field of Participatory Design. The systematic and incremental building of new knowledge is the process by which science and research is advanced. This process requires a certain type of cohesion in the way research is undertaken for new knowledge to be built from the knowledge provided by previous projects and research. To support this process and to foster research cohesion three conditions are necessary. These conditions are: common ground between practitioners, problem-space positioning, and adherence to clear research criteria. The challenge of fostering research cohesion in Participatory Design is apparent in at least four themes raised in the literature: the role of politics within Participatory Design epistemology, the role of participation, design with users, and the ability to translate theory into practice. These four thematic challenges frame the context which the research gap is situated. These themes are also further investigated and the research gap – a general lack of research cohesion – along with one avenue for addressing this gap – a clear and operationalizable definition for participation – are identified. The intended contribution of this thesis is to develop a framework and visual tool to address this research gap. In particular, an initial approximation for a clear and operationalizable definition for participation will be proposed such that it can be used within the field of Participatory Design to run projects and foster research cohesion. In pursuit of this contribution, a critical lens is developed and used to analyse some of the principles and practices of Participatory Design that are regarded as foundational. This lens addresses how to define participation in a way that adheres to basic principles of scientific rigour – namely, ensuring that the elements of a theory are operationalizable, falsifiable, generalizable, and useful, and it also treats participation as a construct rather than treating the notion of participation as a variable. A systematic analysis is performed using this lens on the principles and practices that are considered foundational within the field. From this analysis, three components of the participation construct – impact, influence, and agency – are identified. These components are then broken down into two constituent variables each (six in all) and represented visually. Impact is described as the relationship between the quality and use of information. Influence is described as the relationship between the amount and scope of decision making. Agency is described as the relationship between the motivation of the participant and the solidarity of the group. Thus, as a construct, participation is described as the relationship between a participant’s impact, influence, and agency. In the concluding section, the value of this participation construct is explored for its utility in enhancing project work and fostering research cohesion. Three items of potential value that emerge are: the creation of a visual tool through the representation of these six constituent variables in one image; the elaboration of a common language for researchers based on the six constituent variables identified; and the ability to systematically identify and remedy participation gaps throughout the life of the project. While future research exploring the applicability of the participation construct in real world projects is necessary, it is intended that this initial approximation of a participation construct in the form of the visual tool will serve as the basis for a cohesive and rigorous discussion about participation in Participatory Design.

Realizing benefits from enterprise architecture : a measurement model

Enterprise architecture (EA) management has become an intensively discussed approach to manage enterprise transformations. Despite the popularity and potential of EA, both researchers and practitioners lament a lack of knowledge about the realization of benefits from EA. To determine the benefits from EA, we explore the various dimensions of EA benefit realization and report on the development of a validated and robust measurement instrument. In this paper, we test the reliability and construct validity of the EA benefit realization model (EABRM), which we have designed based on the DeLone & McLean IS success model and findings from exploratory interviews. A confirmatory factor analysis confirms the existence of an impact of five distinct and individually important dimensions on the benefits derived from EA: EA artefact quality, EA infrastructure quality, EA service quality, EA culture, and EA use. The analysis presented in this paper shows that the EA benefit realization model is an instrument that demonstrates strong reliability and validity.

Academics’ work and the concept of “profession” : an Australian case study

Universities in Australia and elsewhere have changed considerably in recent years. Inevitably, this has meant that the work of academics has also changed. Academics’ work is of importance because they are key players in universities and universities matter to the nation economically and intellectually in advancing knowledge and its practical application. Through the changes and challenges that have characterised academia in recent years, there is an assumption that academics’ work is representative of a profession. This research study investigates how academics construct their own perspectives regarding the academic "profession". The study is theoretically informed by Freidson’s theory that conceptualises professions as occupations if they are in control of their work rather than it being under the control of either the market or of their employing institutions. Two research questions guide this study. The first question investigates how academics might construct their work in ideal terms and the second one investigates the extent to which such constructions might constitute a "profession". A qualitative case study was conducted within two Australian universities. In all, twenty academics from ten disciplines took part in the study that consisted of a focus group and fifteen individual interviews. The study was conducted in three phases during which a conceptual framework of academics’ work was developed across three versions. This framework acted both a prompt to discussion and as a potential expression of academics’ work. The first version of the framework was developed from the literature during the first phase of the study. This early framework was used during the second phase of the study when five academics took part in a focus group. After the focus group, the second version of the framework was developed and used with fifteen academics in individual interviews during phase three of the study. The third version of the framework was the outcome of a synthesis of the themes that were identified in the data. The discussion data from the focus group and the individual interviews were analysed through a content analysis approach that identified four major themes. The first theme was that academics reported that their work would ideally be located within universities committed to using their expert knowledge to serve the world. The second theme was that academics reported that they wanted sufficient thinking time and reasonable workloads to undertake the intellectual work that they regard as their core responsibility, particularly in relation to undertaking research. They argued against heavy routine administrative workloads and sought a continuation of current flexible working arrangements. The third theme was that teaching qualifications should not be mandated but that there should be a continuation of the present practice of universities offering academics the opportunity to undertake formal teaching qualifications if they wish to. Finally, academics reported that they wanted values that have traditionally mattered to academia to continue to be respected and practised: autonomy, collegiality and collaborative relationships, altruism and service, and intellectual integrity. These themes are sympathetic to Freidson’s theory of professions in all but one matter: the non-mandatory nature of formal qualifications which he regards as absolutely essential for the performance of the complex intellectual work that characterises occupations that are professions. The study places the issue of academic professionalism on the policy agenda for universities wishing to identify academics’ work as a profession. The study contributes a theory-based and data-informed conceptual framework for academics’ work that can be considered in negotiating the nature and extent of their work. The framework provides a means of analysing what "academic professionalism" might mean; it adds specificity to such discussions by exploring a particular definition of profession, namely Freidson’s theory of professions as occupations that are in control of their own work. The study contributes to the development of theories around higher education concepts of academic professionalism and, in so doing, links that theoretical contribution to the wider professions field.

Development of a 3D culture system to study the skeletal metastasis of prostate cancer

In the cancer research field, most in vitro studies still rely on two-dimensional (2D) cultures. However, the trend is rapidly shifting towards using a three-dimensional (3D) culture system. This is because 3D models better recapitulate the microenvironment of cells, and therefore, yield cellular and molecular responses that more accurately describe the pathophysiology of cancer. By adopting technology platforms established by the tissue engineering discipline, it is now possible to grow cancer cells in extracellular matrix (ECM)-like environments and dictate the biophysical and biochemical properties of the matrix. In addition, 3D models can be modified to recapitulate different stages of cancer progression for instance from the initial development of tumor to metastasis. Inevitably, to recapitulate a heterotypic condition, comprising more than one cell type, it requires a more complex 3D model. To date, 3D models that are available for studying the prostate cancer (CaP)-bone interactions are still lacking. Therefore, the aim of this study is to establish a co-culture model that allows investigation of direct and indirect CaP-bone interactions. Prior to that, 3D polyethylene glycol (PEG)-based hydrogel cultures for CaP cells were first developed and growth conditions were optimised. Characterization of the 3D hydrogel cultures show that LNCaP cells form a multicellular mass that resembles avascular tumor. In comparison to 2D cultures, besides the difference in cell morphology, the response of LNCaP cells to the androgen analogue (R1881) stimulation is different compared to the cells in 2D cultures. This discrepancy between 2D and 3D cultures is likely associated with the cell-cell contact, density and ligand-receptor interactions. Following the 3D monoculture study, a 3D direct co-culture model of CaP cells and the human tissue engineered bone (hTEBC) construct was developed. Interactions between the CaP cells and human osteoblasts (hOBs) resulted in elevation of Matrix Metalloproteinase 9 (MMP9) for PC-3 cells and Prostate Specific Antigen (PSA) for LNCaP cells. To further investigate the paracrine interaction of CaP cells and (hOBs), a 3D indirect co-culture model was developed, where LNCaP cells embedded within PEG hydrogels were co-cultured with hTEBC. It was found that the cellular changes observed reflect the early event of CaP colonizing the bone site. In the absence of androgens, interestingly, up-regulation of PSA and other kallikreins is also detected in the co-culture compared to the LNCaP monoculture. This non androgenic stimulation could be triggered by the soluble factors secreted by the hOB such as Interleukin-6. There are also decrease in alkaline phosphatase (ALP) activity and down-regulation of genes of the hOB when co-cultured with LNCaP cells that have not been previously described. These genes include transforming growth factor β1 (TGFβ1), osteocalcin and Vimentin. However, no changes to epithelial markers (e.g E-cadherin, Cytokeratin 8) were observed in both cell types from the co-culture. Some of these intriguing changes observed in the co-cultures that had not been previously described have enriched the basic knowledge of the CaP cell-bone interaction. From this study, we have shown evidence of the feasibility and versatility of our established 3D models. These models can be adapted to test various hypotheses for studies pertaining to underlying mechanisms of bone metastasis and could provide a vehicle for anticancer drug screening purposes in the future.

Low rank Runge-Kutta methods, symplecticity and stochastic Hamiltonian problems with additive noise

In this paper we extend the ideas of Brugnano, Iavernaro and Trigiante in their development of HBVM($s,r$) methods to construct symplectic Runge-Kutta methods for all values of $s$ and $r$ with $s\geq r$. However, these methods do not see the dramatic performance improvement that HBVMs can attain. Nevertheless, in the case of additive stochastic Hamiltonian problems an extension of these ideas, which requires the simulation of an independent Wiener process at each stage of a Runge-Kutta method, leads to methods that have very favourable properties. These ideas are illustrated by some simple numerical tests for the modified midpoint rule.

Hearing voice and silence during stressful economic times

Purpose - It is ironic that in stressful economic times, when new ideas and positive behaviors could be most valuable, employees may not speak up, leading to reduced employee participation, less organizational learning, less innovation and less receptiveness to change. The supervisor is the organization’s first line of defense against a culture of silence and towards a culture of openness. This research asks what helps supervisors to hear prosocial voice and notice defensive silence. Design/methodology/approach - We conducted a cross-sectional field study of 142 supervisors. Findings - Our results indicate that prosocial voice is increased by supervisor tension and trust in employees, while defensive silence is increased by supervisor tension but reduced by unionization of employees and trust in employees. This indicates that, as hypothesized by others, voice and silence are orthogonal and not opposites of the same construct. Research limitations/implications - The data is measured at one point in time, and further longitudinal study would be helpful to further understand the phenomena. Practical implications - This research highlights the potential for supervisors in stressful situations to selectively hear voice and silence from employees. Originality/value - This study adds to our knowledge of prosocial voice and defensive silence by testing supervisors’ perceptions of these constructs during difficult times. It provides valuable empirical insights to a literature dominated by conceptual non-empirical papers. Limited research on silence might reflect how difficult it is to study such an ambiguous and passive construct as silence (often simply viewed as a lack of speech). also contribute to trust literature by identifying its role in increasing supervisor’s perceptions of prosocial voice and reducing perceptions of defensive silence.