Natural and engineered kallikrein inhibitors: an emerging pharmacopoeia

The kallikreins and kallikrein-related peptidases are serine proteases that control a plethora of developmental and homeostatic phenomena, ranging from semen liquefaction to skin desquamation and blood pressure. The diversity of roles played by kallikreins has stimulated considerable interest in these enzymes from the perspective of diagnostics and drug design. Kallikreins already have well-established credentials as targets for therapeutic intervention and there is increasing appreciation of their potential both as biomarkers and as targets for inhibitor design. Here, we explore the current status of naturally occurring kallikrein protease-inhibitor complexes and illustrate how this knowledge can interface with strategies for rational re-engineering of bioscaffolds and design of small-molecule inhibitors.

Homodimerization controls the fibroblast growth factor 9 subfamily's receptor binding and heparan sulfate-dependent diffusion in the extracellular matrix

Uncontrolled fibroblast growth factor (FGF) signaling can lead to human diseases, necessitating multiple layers of self-regulatory control mechanisms to keep its activity in check. Herein, we demonstrate that FGF9 and FGF20 ligands undergo a reversible homodimerization, occluding their key receptor binding sites. To test the role of dimerization in ligand autoinhibition, we introduced structure-based mutations into the dimer interfaces of FGF9 and FGF20. The mutations weakened the ability of the ligands to dimerize, effectively increasing the concentrations of monomeric ligands capable of binding and activating their cognate FGF receptor in vitro and in living cells. Interestingly, the monomeric ligands exhibit reduced heparin binding, resulting in their increased radii of heparan sulfate-dependent diffusion and biologic action, as evidenced by the wider dilation area of ex vivo lung cultures in response to implanted mutant FGF9-loaded beads. Hence, our data demonstrate that homodimerization autoregulates FGF9 and FGF20's receptor binding and concentration gradients in the extracellular matrix. Our study is the first to implicate ligand dimerization as an autoregulatory mechanism for growth factor bioactivity and sets the stage for engineering modified FGF9 subfamily ligands, with desired activity for use in both basic and translational research.

Living City 2010 Workshop

Living City 2010 was a three-day place-based urban design immersion workshop program held at Logan Road Conference Centre, Stones Corner, for 30 self-selected Year 11 Visual Art Students and 4 Teachers drawn from 11 state and private Brisbane Secondary Schools, that focused on the active Brisbane City Council redevelopment site of Stones Corner, specifically Logan Road, public spaces at Stones Corner Library and rehabilitation of the nearby creek corridor. The workshop, framed within notions of ecological, economic, social and cultural sustainability, aimed to raise awareness of the layered complexity and perspectives involved in the design of shared city spaces and to encourage young people to voice their own concerns as future citizens about the shape and direction of their city. On Day 1, Brisbane City Council Public Art Officers Brendan Doherty and Genevieve Searle, local landscape architect Peter Boyle (Verge) and artists Malcolm Enright and Barbara Heath provided students with an overview of the historic and future context of the area including proposed design and public art interventions, followed by a site walk. The afternoon session, led by Natalie Wright and QUT design staff and students, focused on design tools to assist in the tackling of the redesign of the Stones Corner library precinct, where students worked on ideas. On Day 2, students were mentored by artist Liam Key to participate in a computer animation activity using the built environment as a canvas, and by artist Sebastian Moody to participate in an activity using red helium balloons as a playful catalyst for interaction to activate and create new public space. Later, students worked in teams on their ideas for redevelopment of the site in preparation for their Day 3 presentations. The workshop culminated in an exchange of planning ideas with Georgina Aitchison from Brisbane City Council's Urban Renewal Division. Students were introduced to design methodology, team thinking strategies, the scope of design practices and professions, presentation skills and post-secondary pathways, while participating teachers acquired content and design learning strategies transferable in many other contexts.

Vibrational spectroscopic study of the copper silicate mineral kinoite Ca2Cu2Si3O10(OH)4

Kinoite Ca2Cu2Si3O10(OH)4 is a mineral named after a Jesuit missionary. Raman and infrared spectroscopy have been used to characterise the structure of the mineral. The Raman spectrum is characterised by an intense sharp band at 847 cm-1 assigned to the ν1 (A1g) symmetric stretching vibration. Intense sharp bands at 951, 994 and 1000 cm-1 are assigned to the ν3 (Eu, A2u, B1g) SiO4 antisymmetric stretching vibrations. Multiple ν2 SiO4 vibrational modes indicate strong distortion of the SiO4 tetrahedra. Multiple CaO and CuO stretching bands are observed. Raman spectroscopy confirmed by infrared spectroscopy clearly shows that hydroxyl units are involved in the kinoite structure. Based upon the infrared spectra, it is proposed that water is also involved in the kinoite structure. Based upon vibrational spectroscopy, the formula of kinoite is defined as Ca2Cu2Si3O10(OH)4•xH2O.

Vibrational spectroscopic study of the copper silicate mineral ajoite (K,Na)Cu7AlSi9O24(OH)6•3H2O

Ajoite (K,Na)Cu7AlSi9O24(OH)6•3H2O is a mineral named after the Ajo district of Arizona. Raman and infrared spectroscopy were used to characterise the molecular structure of ajoite. The structure of the mineral shows disorder which is reflected in the difficulty of obtaining quality Raman spectra. The Raman spectrum is characterised by a broad spectral profile with a band at 1048 cm-1 assigned to the ν1 (A1g) symmetric stretching vibration. Strong bands at 962, 1015 and 1139 cm-1 are assigned to the ν3 SiO4 antisymmetric stretching vibrations. Multiple ν4 SiO4 vibrational modes indicate strong distortion of the SiO4 tetrahedra. Multiple AlO and CuO stretching bands are observed. Raman spectroscopy and confirmed by infrared spectroscopy clearly shows that hydroxyl units are involved in the ajoite structure. Based upon the infrared spectra, water is involved in the ajoite structure, probably as zeolitic water.

New organisational leadership capabilities : transitional engineer the new designer?

Traditionally, design has been centred within the manufacturing and production areas of companies and or as a styling afterthought. Increasingly, design is viewed as a vital and important strategic business resource (Dell’Era, Marchesi & Verganti, 2010) and consequently companies worldwide look to design to help them innovate, differentiate and compete in the global marketplace. The role of the professional designer is evolving to a point where they are needed to work beyond being a specialist in the manufacturing and aesthetics of an artefact (Wrigley & Bucolo, 2011). This paper challenges the values held by academics and industry regarding the traditional role of designers in business. It investigates the emerging transitional engineering framework and puts forward a proposal for the next generation designer in the future era of design. Questions surrounding how designers will develop these new skills and how the Authors’ new framework of design led innovation can contribute to the future of design will be presented. This research is needed to better equip future designers to have a more central role in business.

Psychology students’ beliefs about integrating Complementary and Alternative Therapy (CAT) into their future psychology practice

We investigated whether belief-based differences exist between students who have strong and weak intentions to integrate complementary and alternative therapy (CAT) into future psychology practice by recommending CAT or specific CAT practitioners to clients. A cross-sectional methodology was used. Psychology undergraduate students (N = 106) participated in a paper-based questionnaire design to explore their underlying beliefs related to CAT integration. The study was undertaken at a major university in Queensland, Australia. The theory of planned behaviour belief-based framework guided the study. Multivariate analyses of variance examined the influence of behavioural, normative, and control beliefs on the strong and weak intention groups. A multiple regression analysis investigated the relative importance of these belief sets for predicting intentions. We found that clear differences emerged between strong and weak intenders on behavioural and normative beliefs, but not control beliefs. Strong intenders perceived the positive outcomes of integrating CAT, such as being able to offer clients a more holistic practice and having confidence in the practitioners/practices, as more likely to occur than weak intenders, and perceived the negative outcome of compromising my professional practice as less likely. Strong in-tenders were more likely than weak intenders to perceive that a range of important referents (e.g., clients) would think they should integrate CAT. Results of the regression analysis revealed the same pattern of results in that behavioural and normative beliefs, but not control beliefs, significantly predicted intentions. The findings from this study can be used to inform policy and educational initiatives that aim to encourage CAT use in psychology practice.

Influence of grain boundaries on the vibrational properties of silver nanowires

Metal and semiconductor nanowires (NWs) have been widely employed as the building blocks of the nanoelectromechanical systems, which usually acted a resonant beam. Recent researches reported that nanowires are often polycrystalline, which contains grain boundaries (GBs) that transect the whole nanowire into a bamboo like structure. Based on the larger-scale molecular dynamics (MD) simulations, a comprehensive investigation of the influence from grain boundaries on the vibrational properties of doubly clamped Ag NWs is conducted. It is found that, the presence of grain boundary will result in significant energy dissipation during the resonance of polycrystalline NWs, which leads a great deterioration to the quality factor. Further investigation reveals that the energy dissipation is originated from the plastic deformation of polycrystalline NWs in the form of the nucleation of partial dislocations or the generation of micro stacking faults around the GBs and the micro stacking faults is found to keep almost intact during the whole vibration process. Moreover, it is observed that the closer of the grain boundary getting to the regions with the highest strain state, the more energy dissipation will be resulted from the plastic deformation. In addition, either the increase of the number of grain boundaries or the decrease of the distance between the grain boundary and the highest strain state region is observed to induce a lower first resonance frequency. This work sheds lights on the better understanding of the mechanical properties of polycrystalline NWs, which benefits the increasing utilities of NWs in diverse nano-electronic devices.

The application of fiber Bragg grating sensor to high precision temperature measurement [基于光纤光栅的高精度测温传感器研究]

Basing on the character that Fiber Bragg Grating (FBG) is sensitive to both temperature and strain, by using Al and Fe-Ni alloy’s bimetal structure, we successfully design and manufacture a high accuracy FBG temperature sensor for earthquake premonition. Furthermore, we analyze the accuracy of the FBG sensors with enhanced sensitivity for the first time, and get its accuracy is up to ±0.05℃ with highest resolution ever in all FBG temperature sensors (0.0014℃/pm). This work experimentally proves the feasibility of using FBG in the earthquake premonition monitoring, and builds the foundation for the application of optic technology in earthquake premonition monitoring.

Protective effects of sweroside on human MG-63 cells and rat osteoblasts

Herbal Fructus Corni is a folk medicine with a long history of safe use for treating osteoporosis in postmenopausal women or elderly men in Asia. Sweroside is a bioactive herbal ingredient isolated from Fructus Corni, which has been widely used for the treatment of osteoporosis in traditional Chinese medicine (TCM). Unfortunately, the working mechanisms of this compound are difficult to determine and thus remain unclear. The aim of the study was performed to determine the potential molecular mechanism of the anti-osteoporotic effect of sweroside on the human MG-63 cells and rat osteoblasts. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was used to observe the effect of sweroside on cell proliferation. The activity of alkaline phosphatase (ALP) and the amount of osteocalcin were also assayed the cell differentiation. Sweroside significantly increased the proliferation of human MG-63 cells and rat osteoblasts (P<0.01). It increased the activity of ALP, and osteocalcin was also elevated in response to sweroside (P<0.05). Of note, flowcytometer assay showed that sweroside can attenuate and inhibit apoptosis. Sweroside has a direct osteogenic effect on the proliferation and differentiation of cultured human MG-63 cells and rat osteoblasts in vitro. These data will help in understanding the molecular mechanisms of therapeutic efficacy of sweroside, and highlight insights into drug discovery. In the current study, sweroside has been suggested to be a promising osteoporosis therapeutic natural product.

Advances in the systemic therapy of malignant pleural mesothelioma

Malignant pleural mesothelioma is an aggressive thoracic malignancy associated with exposure to asbestos, and its incidence is anticipated to increase during the first half of this century. Chemotherapy is the mainstay of treatment, yet sufficiently robust evidence to substantiate the current standard of care has emerged only in the past 5 years. This Review summarizes the evidence supporting the clinical activity of chemotherapy, discusses the use of end points for its assessment and examines the influence of clinical and biochemical prognostic factors on the natural history of malignant pleural mesothelioma. Early-phase clinical trials of second-line and novel agents are emerging from an increased understanding of mesothelioma cell biology. Coupled with high-quality translational research, such developments have real potential to improve the outlook of patients at a time of increasing incidence.

Targeting oxidative stress in cancer

Importance of the field: Reactive oxygen species (ROS) occur as natural by-products of oxygen metabolism and have important cellular functions. Normally, the cell is able to maintain an adequate balance between the formation and removal of ROS either via anti-oxidants or through the use specific enzymatic pathways. However, if this balance is disturbed, oxidative stress may occur in the cell, a situation linked to the pathogenesis of many diseases, including cancer. Areas covered in this review: HDACs are important regulators of many oxidative stress pathways including those involved with both sensing and coordinating the cellular response to oxidative stress. In particular aberrant regulation of these pathways by histone deacetylases may play critical roles in cancer progression. What the reader will gain: In this review we discuss the notion that targeting HDACs may be a useful therapeutic avenue in the treatment of oxidative stress in cancer, using chronic obstructive pulmonary disease (COPD), NSCLC and hepatocellular carcinoma (HCC) as examples to illustrate this possibility. Take home message: Epigenetic mechanisms may be an important new therapeutic avenue for targeting oxidative stress in cancer. © 2010 Informa UK, Ltd.

Product ecosystems : an emerging methodological approach to study the implementation of disruptive innovations : the case of the CityCar

The car has arguably had more influence on our lifestyle and urban environment than any other consumer product; allowing unprecedented freedom for living, working and recreation where and when we choose. However, problems of pollution, congestion, road trauma, inefficient land use and social inequality are associated with car use. Despite 100 years of design and technology refinements, the aforementioned problems are significant and persistent: many argue that resolving these problems requires a fundamental redesign of the car. Redesigned vehicles have been proposed such as the MIT CityCar and others such as the Renault Twizy, commercialized. None however have successfully brought about significant change and the study of disruptive innovation offers an explanation for this. Disruptive innovation, by definition, disrupts a market. It also disrupts the product ecosystem. The existing product ecosystem has co-evolved to support the conventional car and is not optimized for the new design: which will require a redesigned ecosystem to support it. A literature review identifies a lack of methodology for identifying the components of product ecosystems and the changes required for disruptive innovation implementation. This paper proposes such a methodology based on Design Thinking, Actor Network Theory, Disruptive Innovation and the CityCar scenarios.

Living City 2013 Workshop

Living City 2013 Workshop, as part of a school term’s design-based curriculum connected to the KGSC/QUT Design Excellence Program and run from 11 February – 1 May, 2013, was essentially a three-day place-based urban design immersion workshop program for 25 Year 11 Visual Art and Design Students and 2 Teachers from Kelvin Grove State College (KGSC) held at both Queensland University of Technology (QUT) Gardens Point Campus and The Edge, State Library of Queensland. Mentored by 4 design professionals, 2 tertiary design academics, 2 public artists, and 12 QUT tertiary design students, the workshop explored youth-inspired public space design solutions for the active Brisbane City Council redevelopment site of Queens Wharf Road precinct. As well as the face-to-face workshops, for Living City 2013, an interactive web environment was introduced to enable students to connect with each other and program mentors throughout the course of the program. The workshop, framed within notions of ecological, economic, social and cultural sustainability, aimed to raise awareness of the layered complexity and perspectives involved in the design of shared city spaces and to encourage young people to voice their own concerns as future citizens about the shape and direction of their city. The program commenced with an introductory student briefing by stakeholders and mentors at KGSC on 11 February, an introduction to site appraisal and site visit held at QUT and Queens Wharf Road on 20 February, and a follow up site analysis session on 6 March. Day 1 Workshop on April 17 at the Edge, State Library of Queensland, as part of the Design Minds partnership (http://designminds.org.au/kelvin-grove-state-college-excellence-in-art-design/), focused on mentoring team development of a concept design for a range of selected sites. Two workshops on April 22 and 23 at QUT, to develop these designs and presentation schemes, followed this. The workshop program culminated in a visual presentation of concept design ideas and discussion with a public audience in the Ideas Gallery on The Deck, King George Square during the Brisbane City Council City Centre Master Plan Ideas Fiesta on 1 May, 2013, as referenced in the Ideas Fiesta Wrap-up Report (http://www.brisbane.qld.gov.au/planning-building/planning-guidelines-tools/city-centre-master-plan/city-centre-master-plan-ideas-fiesta). Students were introduced to design methodology, team thinking strategies, the scope of design practices and professions, presentation skills and post-secondary pathways, while participating teachers acquired content and design learning strategies transferable in many other contexts. The program was fully documented on the Living City website (http://www.livingcity.net.au/LC2013x/index.html) and has been recognised by the Brisbane City Council Youth Strategy 2014-2019 as a best practice model for making Brisbane a well-designed, subtropical city.

Interpreting scratch assays using pair density dynamics and approximate Bayesian computation

Quantifying the impact of biochemical compounds on collective cell spreading is an essential element of drug design, with various applications including developing treatments for chronic wounds and cancer. Scratch assays are a technically simple and inexpensive method used to study collective cell spreading; however, most previous interpretations of scratch assays are qualitative and do not provide estimates of the cell diffusivity, D, or the cell proliferation rate,l. Estimating D and l is important for investigating the efficacy of a potential treatment and provides insight into the mechanism through which the potential treatment acts. While a few methods for estimating D and l have been proposed, these previous methods lead to point estimates of D and l, and provide no insight into the uncertainty in these estimates. Here, we compare various types of information that can be extracted from images of a scratch assay, and quantify D and l using discrete computational simulations and approximate Bayesian computation. We show that it is possible to robustly recover estimates of D and l from synthetic data, as well as a new set of experimental data. For the first time, our approach also provides a method to estimate the uncertainty in our estimates of D and l. We anticipate that our approach can be generalized to deal with more realistic experimental scenarios in which we are interested in estimating D and l, as well as additional relevant parameters such as the strength of cell-to-cell adhesion or the strength of cell-to-substrate adhesion.