Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA

We report that tumor cells devoid of their mitochondrial genome (mtDNA) show delayed tumor growth and that tumor formation is associated with acquisition of mtDNA from host cells. This leads to partial recovery of mitochondrial function in cells derived from primary tumors grown from cells without mtDNA and a shorter lag in tumor growth. Cell lines from circulating tumor cells showed further recovery of mitochondrial respiration and an intermediate lag to tumor growth, while cells from lung metastases exhibited full restoration of respiratory function and no lag in tumor growth. Stepwise assembly of mitochondrial respiratory supercomplexes was correlated with acquisition of respiratory function. Our findings indicate horizontal transfer of mtDNA from host cells in the tumor microenvironment to tumor cells with compromised respiratory function to re-establish respiration and tumor-initiating efficacy. These results suggest a novel pathophysiological process for overcoming mtDNA damage and support the notion of high plasticity of malignant cells.

Integrated decoupling and matching network incorporated in the ground plane of a compact monopole array

Compact arrays enable various applications such as antenna beam-forming and multi-input, multi-output (MIMO) schemes on limited-size platforms. The reduced element spacing in compact arrays introduces high levels of mutual coupling which can affect the performance of the adaptive array. This coupling causes a mismatch at the input ports, which disturbs the performance of the individual elements in the array and affects the implementation of beam steering. In this article, a reactive decoupling network for a 3-element monopole array is used to establish port isolation while simultaneously matching input impedance at each port to the system impendence. The integrated decoupling and matching network is incorporated in the ground plane of the monopole array, providing further development scope for beamforming using phase shifters and power splitters in double-layered circuits.

A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010

BACKGROUND Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. METHODS We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. FINDINGS In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. INTERPRETATION Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.

High-throughput bone and cartilage micropellet manufacture, followed by assembly of micropellets into biphasic osteochondral tissue

Engineered biphasic osteochondral tissues may have utility in cartilage defect repair. As bone-marrow-derived mesenchymal stem/stromal cells (MSC) have the capacity to make both bone-like and cartilage-like tissues, they are an ideal cell population for use in the manufacture of osteochondral tissues. Effective differentiation of MSC to bone-like and cartilage-like tissues requires two unique medium formulations and this presents a challenge both in achieving initial MSC differentiation and in maintaining tissue stability when the unified osteochondral tissue is subsequently cultured in a single medium formulation. In this proof-of-principle study, we used an in-house fabricated microwell platform to manufacture thousands of micropellets formed from 166 MSC each. We then characterized the development of bone-like and cartilage-like tissue formation in the micropellets maintained for 8–14 days in sequential combinations of osteogenic or chondrogenic induction medium. When bone-like or cartilage-like micropellets were induced for only 8 days, they displayed significant phenotypic changes when the osteogenic or chondrogenic induction medium, respectively, was swapped. Based on these data, we developed an extended 14-day protocol for the pre-culture of bone-like and cartilage-like micropellets in their respective induction medium. Unified osteochondral tissues were formed by layering 12,000 osteogenic micropellets and 12,000 chondrogenic micropellets into a biphasic structure and then further culture in chondrogenic induction medium. The assembled tissue was cultured for a further 8 days and characterized via histology. The micropellets had amalgamated into a continuous structure with distinctive bone-like and cartilage-like regions. This proof-of-concept study demonstrates the feasibility of micropellet assembly for the formation of osteochondral-like tissues for possible use in osteochondral defect repair.

Building a "brain attack" team to administer thrombolytic therapy for acute ischemic stroke

Before tissue plasminogen activator (tPA) was licensed for use in Canada, in February 1999, the Calgary Regional Stroke Program spearheaded the development and organization of local resources to use thrombolytic therapy in patients who had experienced acute ischemic stroke. In 1996 special permission was obtained from the Calgary Regional Health Authority to use intravenously administered tPA for acute ischemic stroke, and ethical and scientific review boards approved the protocols. After 3 years our efforts have resulted in improved patient outcomes, shorter times from symptom onset to treatment and acceptable adverse event rates. Areas for continued improvement include the door-to-needle time and broader education of the public about the symptoms of acute ischemic stroke.

The rapid manufacture of uniform composite multicellular-biomaterial micropellets, their assembly into macroscopic organized tissues, and potential applications in cartilage tissue engineering

We and others have published on the rapid manufacture of micropellet tissues, typically formed from 100-500 cells each. The micropellet geometry enhances cellular biological properties, and in many cases the micropellets can subsequently be utilized as building blocks to assemble complex macrotissues. Generally, micropellets are formed from cells alone, however when replicating matrix-rich tissues such as cartilage it would be ideal if matrix or biomaterials supplements could be incorporated directly into the micropellet during the manufacturing process. Herein we describe a method to efficiently incorporate donor cartilage matrix into tissue engineered cartilage micropellets. We lyophilized bovine cartilage matrix, and then shattered it into microscopic pieces having average dimensions < 10 μm diameter; we termed this microscopic donor matrix "cartilage dust (CD)". Using a microwell platform, we show that ~0.83 μg CD can be rapidly and efficiently incorporated into single multicellular aggregates formed from 180 bone marrow mesenchymal stem/stromal cells (MSC) each. The microwell platform enabled the rapid manufacture of thousands of replica composite micropellets, with each micropellet having a material/CD core and a cellular surface. This micropellet organization enabled the rapid bulking up of the micropellet core matrix content, and left an adhesive cellular outer surface. This morphological organization enabled the ready assembly of the composite micropellets into macroscopic tissues. Generically, this is a versatile method that enables the rapid and uniform integration of biomaterials into multicellular micropellets that can then be used as tissue building blocks. In this study, the addition of CD resulted in an approximate 8-fold volume increase in the micropellets, with the donor matrix functioning to contribute to an increase in total cartilage matrix content. Composite micropellets were readily assembled into macroscopic cartilage tissues; the incorporation of CD enhanced tissue size and matrix content, but did not enhance chondrogenic gene expression.

The importance of connexin hemichannels during chondroprogenitor cell differentiation in hydrogel versus microtissue culture models

Appropriate selection of scaffold architecture is a key challenge in cartilage tissue engineering. Gap junction-mediated intercellular contacts play important roles in precartilage condensation of mesenchymal cells. However, scaffold architecture could potentially restrict cell-cell communication and differentiation. This is particularly important when choosing the appropriate culture platform as well as scaffold-based strategy for clinical translation, that is, hydrogel or microtissues, for investigating differentiation of chondroprogenitor cells in cartilage tissue engineering. We, therefore, studied the influence of gap junction-mediated cell-cell communication on chondrogenesis of bone marrow-derived mesenchymal stromal cells (BM-MSCs) and articular chondrocytes. Expanded human chondrocytes and BM-MSCs were either (re-) differentiated in micromass cell pellets or encapsulated as isolated cells in alginate hydrogels. Samples were treated with and without the gap junction inhibitor 18-α glycyrrhetinic acid (18αGCA). DNA and glycosaminoglycan (GAG) content and gene expression levels (collagen I/II/X, aggrecan, and connexin 43) were quantified at various time points. Protein localization was determined using immunofluorescence, and adenosine-5'-triphosphate (ATP) was measured in conditioned media. While GAG/DNA was higher in alginate compared with pellets for chondrocytes, there were no differences in chondrogenic gene expression between culture models. Gap junction blocking reduced collagen II and extracellular ATP in all chondrocyte cultures and in BM-MSC hydrogels. However, differentiation capacity was not abolished completely by 18αGCA. Connexin 43 levels were high throughout chondrocyte cultures and peaked only later during BM-MSC differentiation, consistent with the delayed response of BM-MSCs to 18αGCA. Alginate hydrogels and microtissues are equally suited culture platforms for the chondrogenic (re-)differentiation of expanded human articular chondrocytes and BM-MSCs. Therefore, reducing direct cell-cell contacts does not affect in vitro chondrogenesis. However, blocking gap junctions compromises cell differentiation, pointing to a prominent role for hemichannel function in this process. Therefore, scaffold design strategies that promote an increasing distance between single chondroprogenitor cells do not restrict their differentiation potential in tissue-engineered constructs.

Co-benefits of addressing climate change can motivate action around the world

Personal and political action on climate change is traditionally thought to be motivated by people accepting its reality and importance. However, convincing the public that climate change is real faces powerful ideological obstacles1, 2, 3, 4, and climate change is slipping in public importance in many countries5, 6. Here we investigate a different approach, identifying whether potential co-benefits of addressing climate change7 could motivate pro-environmental behaviour around the world for both those convinced and unconvinced that climate change is real. We describe an integrated framework for assessing beliefs about co-benefits8, distinguishing social conditions (for example, economic development, reduced pollution or disease) and community character (for example, benevolence, competence). Data from all inhabited continents (24 countries; 6,196 participants) showed that two co-benefit types, Development (economic and scientific advancement) and Benevolence (a more moral and caring community), motivated public, private and financial actions to address climate change to a similar degree as believing climate change is important. Critically, relationships were similar for both convinced and unconvinced participants, showing that co-benefits can motivate action across ideological divides. These relationships were also independent of perceived climate change importance, and could not be explained by political ideology, age, or gender. Communicating co-benefits could motivate action on climate change where traditional approaches have stalled.

Ability of commonly used prediction equations to predict resting energy expenditure in children with inflammatory bowel disease

Background: Paediatric onset inflammatory bowel disease (IBD) may cause alterations in energy requirements and invalidate the use of standard prediction equations. Our aim was to evaluate four commonly used prediction equations for resting energy expenditure (REE) in children with IBD. Methods: Sixty-three children had repeated measurements of REE as part of a longitudinal research study yielding a total of 243 measurements. These were compared with predicted REE from Schofield, Oxford, FAO/WHO/UNU, and Harris-Benedict equations using the Bland-Altman method. Results: Mean (±SD) age of the patients was 14.2 (2.4) years. Mean measured REE was 1566 (336) kcal per day compared with 1491 (236), 1441 (255), 1481 (232), and 1435 (212) kcal per day calculated from Schofield, Oxford, FAO/WHO/UNU, and Harris-Benedict, respectively. While the Schofield equation demonstrated the least difference between measured and predicted REE, it, along with the other equations tested, did not perform uniformly across all subjects, indicating greater errors at either end of the spectrum of energy expenditure. Smaller differences were found for all prediction equations for Crohn's disease compared with ulcerative colitis. Conclusions: Of the commonly used equations, the equation of Schofield should be used in pediatric patients with IBD when measured values are not able to be obtained. (Inflamm Bowel Dis 2010;) Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.

Respite & Recoery at Al Wakra

International Design Competition for Qatar Psychiatric Hospital. The scheme for the Al Wakra Respite and Recovery Centre delivers on an all-in attitude toward evidence-based design. It sets new benchmarks in so many ways: the way it allows excellent separation between patient cohorts without unnecessary or visible restrictions; the way it allows sharing of most of the clinical kit and spaces; the way services reticulation and facilities management takes place without compromising security and safety; the ways It abandons the institutional axioms that are still so ubiquitous elsewhere, so it can appear as the friendly, welcoming and wholesome; the way it allows incredible flexibility to allow changes or flexion on the fly; the way it has such ‘good bones’ for more structural changes as the future unfolds. But most importantly, the scheme will be exemplary in the way the building itself plays a role in promoting the recovery and mental well-being of its residents. Like no other, the Centre will rise to the challenges of supporting and inspiring an exemplary mental health service and promote the well-being of the patients. The 160 bed scheme allows for 43,000m2 of landscape, packed with wholesome things to do and experience. The Aspire zone even has stables and a falconry, both to celebrate the love that Qatari people have for horses and birds.

Building creative connections: An analysis of a creative arts widening participation program

Widening participation or outreach agendas have been a major part of higher education policy since the early 2000s. These policies and programs seek to increase marginalised groups’ access to further study through activities, tutoring programs, workshops, and other provisions. Some programs openly state their intention to assist people from low socioeconomic backgrounds to become more civically engaged and socially mobile by improving their education, which creates an immediate link between education and social capital (see Morley 2012; Hillmert and Jacob 2010). Social capital refers to the ‘connections among individuals’ and the consequent value of the things they do together (Putnam 2000; Gauntlett 2011). Media and creative arts widening participation programs, arguably, are better equipped to build social capital than any other form of outreach, due to their relationship-building capacity (Gauntlett 2011; Kinder and Harland 2004). This article analyses Queensland University of Technology’s Creative Industries Widening Participation Program. It investigates social capital and its relationship with higher education in outreach initiatives in order to identify how media and creative arts widening participation programs have the capacity to influence the attitudes of low socioeconomic background students towards higher education.

Evidence of clustering in an aqueous electrolyte solution: a small-angle X-ray scattering study

The work reported hen was motivated by a desire to verify the existence of structure - specifically MP-rich clusters induced by sodium bromide (NaBr) in the ternary liquid mixture 3-methylpyridine (Mf) + water(W) + NaBr. We present small-angle X-ray scattering (SAXS) measurements in this mixture. These measurements were obtained at room temperature (similar to 298 K) in the one-phase region (below the relevant lower consolute points, T(L)s) at different values of X (i.e., X = 0.02 - 0.17), where X is the weight fraction of NaBr in the mixture. Cluster-size distribution, estimated on the assumption that the clusters are spherical, shows systematic behaviour in that the peak of the distribution shifts rewards larger values of cluster radius as X increases. The largest spatial extent of the clusters (similar to 4.5 nm) is seen at X = 0.17. Data analysis assuming arbitrary shapes and sizes of clusters gives a limiting value of cluster size (- 4.5 nm) that is not very sensitive to X. It is suggested that the cluster size determined may not be the same as the usual critical-point fluctuations far removed from the critical point (T-L). The influence of the additional length scale due to clustering is discussed from the standpoint of crossover from Ising to mean-field critical behaviour, when moving away from the T-L.