Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes

Senescence and genomic integrity are thought to be important barriers in the development of malignant lesions. Human fibroblasts undergo a limited number of cell divisions before entering an irreversible arrest, called senescence. Here we show that human mammary epithelial cells (HMECs) do not conform to this paradigm of senescence. In contrast to fibroblasts, HMECs exhibit an initial growth phase that is followed by a transient growth plateau (termed selection or M0; refs 3-5), from which proliferative cells emerge to undergo further population doublings (approximately 20-70), before entering a second growth plateau (previously termed senescence or M1; refs 4-6). We find that the first growth plateau exhibits characteristics of senescence but is not an insurmountable barrier to further growth. HMECs emerge from senescence, exhibit eroding telomeric sequences and ultimately enter telomere-based crisis to generate the types of chromosomal abnormalities seen in the earliest lesions of breast cancer. Growth past senescent barriers may be a pivotal event in the earliest steps of carcinogenesis, providing many genetic changes that predicate oncogenic evolution. The differences between epithelial cells and fibroblasts provide new insights into the mechanistic basis of neoplastic transformation.

Why trust the head? Key practices for transformational school leaders to build a purposeful relationship of trust

Trust is widely recognized as one of the key qualities that a successful leader needs to bring about change within his/her organization. Literature has also shown that trust plays a pivotal role in effective school leadership. However, little research has been undertaken to identify specific actions of a transformational school leader enabling him/her to develop purposeful relationships of trust with his/her staff and Chair of the school’s governing body. Using a theoretical framework of transformational leadership in the context of the independent schooling sector in Australia, a multicase study of four highly trusted, transformational school leaders revealed 10 key trust building practices in the Head–staff dyad and three practices in the Head–Chair dyad. These practices were independent of the leader’s personal attributes. The study also revealed an inextricable link between trust and transformational leadership.

Gender inequities in health research : an Australian perspective

This chapter presents the current challenges facing legislators, regulators, researchers, and ethics committees in determining how and when to include women appropriately in research, and ensure that sex analysis of research results is routinely performed. It offers five issues that require attention to address these challenges: that national regulatory statements could provide researchers with definitions of the terms ‘sex’ , ‘gender’, and ‘gender equity’ in research; that sex and gender analysis should be built into health research protocols; the lack of internationally comparable data regarding the rates of inclusion of men and women presents a major hurdle for analysing the efficacy of different regulatory strategies; the accessibility of data would be facilitated by a requirement for publication of the results of health research to include descriptions of sex analysis performed on research data; and that institutional review boards, research ethics committees, and researchers themselves require better education about the scientific and ethical importance of including of women in clinical research.

More than a backchannel : Twitter and television

Twitter is a social media service that has managed very successfully to embed itself deeply in the daily lives of its users. Its short message length (140 characters), and one-way connections (‘following’ rather than ‘friending’), lead themselves effectively to random and regular updates on almost any form of personal or professional activity. Thus, it has found uses from the interpersonal (e.g. Boyd et al., 2010) through crisis communication (e.g. Bruns et al., 2012), to political debate (e.g. Burgess & Bruns, 2012). In such uses, Twitter does not necessarily replace existing media channels, such as broadcasting or online mainstream media, but often complements them, providing its users with alternative opportunities to contribute more actively to the wider media sphere. This is true especially where Twitter is used alongside television, as a simple backchannel to live programming or for more sophisticated uses. In this article, we outline four aspects and dimensions, of the way that the old medium of television intersects, and in some cases, interacts with the new medium of Twitter. Tweeting about the television has always been a social media form. It has also consistently provided key ‘talking points’ for western societies...

MicroRNAs targeting mutant K-ras by electrotransfer inhibit human colorectal adenocarcinoma cell growth in vitro and in vivo

Mutations of K-ras have been found in 30-60% of colorectal carcinomas and are believed to be associated with tumor initiation, tumor progression and metastasis formation. Therefore, silencing of mutant K-ras expression has become an attractive therapeutic strategy for colorectal cancer treatment. The aim of our study was to investigate the effect of microRNA (miRNA) molecules directed against K-ras (miRNA-K-ras) on K-ras expression level and the growth of colorectal carcinoma cell line LoVo in vitro and in vivo. In addition, we evaluated electroporation as a gene delivery method for transfection of LoVo cells and tumors with plasmid DNA encoding miRNA-K-ras (pmiRNA-K-ras). Results of our study indicated that miRNAs targeting K-ras efficiently reduced K-ras expression and cell survival after in vitro electrotransfection of LoVo cells with pmiRNA-K-ras. In vivo, electroporation has proven to be a simple and efficient delivery method for local administration of pmiRNA-K-ras molecules into LoVo tumors. This therapy shows pronounced antitumor effectiveness and has no side effects. The obtained results demonstrate that electrogene therapy with miRNA-K-ras molecules can be potential therapeutic strategy for treatment of colorectal cancers harboring K-ras mutations. © 2010 Nature Publishing Group All rights reserved.

The rise of englightened shareholder primacy and its impact on US corporate self-regulation

Enlightened shareholder primacy (“ESP”) is a new approach in the corporate governance (“CG”) framework. The emergence of this approach is important owing to its role in answering a vital question: is the company really a private organisation to be seen only through the economic prism of contract? Or is it public and about a wider group of interests and underwritten by communitarian concern about social responsibility? Apart from answering this question, ESP explains the changes in corporate directors’ roles and self-regulation strategies of companies.

A study of governance arrangements for land use and natural resource management planning in Cape York Peninsula

Complex intersecting social, economic and environmental dilemmas in Australia's Cape York Peninsula present a number of challenges for planners seeking to develop and implement land use and natural resource management (NRM) plans. There have been five different attempts at land use and NRM planning in Cape York Peninsula over the last 20 years. These processes have (to greater or lesser extents) failed to deliver community-owned and government-supported plans to guide development and/or the management of the region's natural resources. The region is remote, sparsely populated, and home to a significant Indigenous population. Much of the contestation within the region surrounds the access, use and ownership of the region's internationally valuable natural resources. This paper reviews, from the literature, the relevancy and applicability of criteria for best practice planning and governance. A range of identified best practice governance and planning principles are applied to assess the governance arrangements for planning in the Peninsula. The paper finds that decision-making arrangements for land use and NRM planning in the Peninsula are still in their infancy and are inadequate to support effective outcomes. The paper concludes that broader attention to best practice principles in governance for planning is needed to improve planning outcomes.

Nanofiber orientation and surface functionalization modulate human mesenchymal stem cell behavior in vitro

Electrospun nanofiber meshes have emerged as a new generation of scaffold membranes possessing a number of features suitable for tissue regeneration. One of these features is the flexibility to modify their structure and composition to orchestrate specific cellular responses. In this study, we investigated the effects of nanofiber orientation and surface functionalization on human mesenchymal stem cell (hMSC) migration and osteogenic differentiation. We used an in vitro model to examine hMSC migration into a cell-free zone on nanofiber meshes and mitomycin C treatment to assess the contribution of proliferation to the observed migration. Poly (ɛ-caprolactone) meshes with oriented topography were created by electrospinning aligned nanofibers on a rotating mandrel, while randomly oriented controls were collected on a stationary collector. Both aligned and random meshes were coated with a triple-helical, type I collagen-mimetic peptide, containing the glycine-phenylalanine-hydroxyproline-glycine-glutamate-arginine (GFOGER) motif. Our results indicate that nanofiber GFOGER peptide functionalization and orientation modulate cellular behavior, individually, and in combination. GFOGER significantly enhanced the migration, proliferation, and osteogenic differentiation of hMSCs on nanofiber meshes. Aligned nanofiber meshes displayed increased cell migration along the direction of fiber orientation compared to random meshes; however, fiber alignment did not influence osteogenic differentiation. Compared to each other, GFOGER coating resulted in a higher proliferation-driven cell migration, whereas fiber orientation appeared to generate a larger direct migratory effect. This study demonstrates that peptide surface modification and topographical cues associated with fiber alignment can be used to direct cellular behavior on nanofiber mesh scaffolds, which may be exploited for tissue regeneration.

Association of a disintegrin and metalloprotease 33 (ADAM33) gene polymorphisms with the risk of COPD: An updated meta-analysis of 2,644 cases and 4,804 controls

A series of observational studies have been made to investigate the association of the ADAM33 gene polymorphisms with the risk of COPD, but their results were conflicting. Therefore, we performed an updated meta-analysis to quantitatively summarize the associations of ADAM33 gene polymorphisms with the risk of COPD. Thirteen case–control studies referring to nine SNPs were identified: V4 (rs2787094), T+1 (rs2280089), T2 (rs2280090), T1 (rs2280091), S2 (rs528557), S1 (rs3918396), Q−1 (rs612709), F+1 (rs511898) and ST+5 (rs597980). A dominant model (AA+Aa vs. aa), recessive model (AA vs. Aa+aa), additive model (AA vs. aa) and allelic model (A vs. a) were used to evaluate the association of ADAM33 polymorphism with the risk of COPD. The results indicated that significant associations were found for ADAM33 T1, T2, S1, Q−1, F+1 and ST+5 polymorphisms associated with the risk of COPD in different populations. However, no significant associations were found for V4, T+1 and S2 polymorphisms with the risk of COPD in all genetic models, even in the subgroup analysis by ethnicity. This meta-analysis provided evidence that the ADAM33 T1, T2, S1, Q−1, F+1 and ST+5 six locus polymorphisms association with the risk of COPD. Furthermore, T2, Q−1 and ST+5 indicated an association with the risk of COPD in the European populations, whereas T1, T2, S1, F+1 and Q−1 indicated an association with the risk of COPD in the Asian populations.

Postglacial Early Permian (late Sakmarian-early Artinskian) shallow-marine carbonate deposition along a 2000 km transect from Timor to west Australia

Late Sakmarian to early Artinskian (Early Permian) carbonate deposition was widespread in the marine intracratonic rift basins that extended into the interior of Eastern Gondwana from Timor in the north to the northern Perth Basin in the south. These basins spanned about 20° of paleolatitude (approximately 35°S to 55°S). This study describes the type section of the Maubisse Limestone in Timor-Leste, and compares this unit with carbonate sections in the Canning Basin (Nura Nura Member of the Poole Sandstone), the Southern Carnarvon Basin (Callytharra Formation) and the northern Perth Basin (Fossil Cliff Member of the Holmwood Shale). The carbonate units have no glacial influence and formed part of a major depositional cycle that, in the southern basins, overlies glacially influenced strata and lies a short distance below mudstone containing marine fossils and scattered dropstones (perhaps indicative of sea ice). In the south marine conditions became more restricted and were replaced by coal measures at the top of the depositional sequence. In the north, the carbonate deposits are possibly bryozoan–crinoidal mounds; whereas in the southern basins they form laterally continuous relatively thin beds, deposited on a very low-gradient seafloor, at the tops of shale–limestone parasequences that thicken upward in parasequence sets. All marine deposition within the sequence took place under very shallow (inner neritic) conditions, and the limestones have similar grain composition. Bryozoan and crinoidal debris dominate the grain assemblages and brachiopod shell fragments, foraminifera and ostracod valves are usually common. Tubiphytes ranged as far south as the Southern Carnarvon Basin, albeit rarely, but is more common to the north. Gastropod and bivalve shell debris, echinoid spines, solitary rugose corals and trilobite carapace elements are rare. The uniformity of the grain assemblage and the lack of tropical elements such as larger fusulinid foraminifera, colonial corals or dasycladacean algae indicate temperate marine conditions with only a small increase in temperature to the north. The depositional cycle containing the studied carbonate deposits represents a warmer phase than the preceding glacially influenced Asselian to early Sakmarian interval and the subsequent cool phase of the “mid” Artinskian that is followed by significant warming during the late Artinskian–early Kungurian. The timing of cooler and warmer intervals in the west Australian basins seems out-of-phase with the eastern Australian succession, but this may be a problem of chronostratigraphic miscorrelation due to endemic faunas and palynofloras.

More than thirty years of ultimatum bargaining experiments: Motives, variations, and a survey of the recent literature

Take-it or leave-it offers are probably as old as mankind. Our objective here is, first, to provide a, probably subjectively colored, recollection of the initial ultimatum game experiment, its motivation and the immediate responses. Second, we discuss extensions of the standard ultimatum bargaining game in a unified framework, and, third, we offer a survey of the experimental ultimatum bargaining literature containing papers published since the turn of the century. The paper argues that the ultimatum game is a versatile tool for research in bargaining and on social preferences. Finally, we provide examples for open research questions and directions for future studies.

Creating heterogeneity: Evolving use of groupware in a network of freelancers

This contribution is a long-term study of the evolving use of the organization-wide groupware in a service network. We are describing the practices related to organization-wide groupware in conjunction with local groupware-related practices and how they have proceeded since the organization was established. In the discussion of these practices we are focussing on issues such as: 1. tendencies for proliferation and integration, 2. local appropriations of a variety of systems, 3. creative appropriations, including the creation of a unique heterogeneous groupware fabric, 4. the design strategy of multiple parallel experimental use an; 5. the relation between disparate local meanings and successful computer supported cooperative practice. As an overarching theme we are exploring the explanatory value of the concepts of objectification and appropriation as compared to the concepts of design vs. use.

The purposes of history? Curriculum studies, invisible objects and twenty-first century societies

A new intellectual epoch has generated new enterprises to suit changed beliefs and circumstances. A widespread sentiment in both formal historiography and curriculum studies reduces the “new” to the question of how knowledge is recognized as such, how it is gained, and how it is represented in narrative form. Whether the nature of history and conceptions of knowledge are, or ought to be, central considerations in curriculum studies and reducible to purposes or elevated as present orientated requires rethinking. This paper operates as an incitement to discourse that disrupts the protection and isolation of primary categories in the field whose troubling is overdue. In particular, the paper moves through several layers that highlight the lack of settlement regarding the endowment of objects for study with the status of the scientific. It traces how some “invisible” things have been included within the purview of curriculum history as objects of study and not others. The focus is the making of things deemed invisible into scientific objects (or not) and the specific site of analysis is the work of William James (1842-1910). James studied intensely both child mind and the ghost, the former of which becomes scientized and legitimated for further study, the latter abjected. This contrast opens key points for reconsideration regarding conditions of proof, validation criteria, and subject matters and points to opportunities to challenge some well-rehearsed foreclosures within progressive politics and education.

The post-illumination pupil response of melanopsin expressing retinal ganglion cells

Purpose The post-illumination pupil response (PIPR) has been quantified in the literature by four metrics. The spectral sensitivity of only one metric is known and this study quantifies the other three. To optimize the measurement of the PIPR in humans, we also determine the stimulus protocol producing the largest PIPR, the duration of the PIPR, and the metric(s) with the lowest coefficient of variation. Methods The consensual pupil light reflex (PLR) was measured with a Maxwellian view pupillometer (35.6° diameter stimulus). - Experiment 1: Spectral sensitivity of four PIPR metrics [plateau, 6 s, area under curve (AUC) early and late recovery] was determined from a criterion PIPR (n = 2 participants) to a 1 s pulse at five wavelengths (409-592nm) and fitted with Vitamin A nomogram (ƛmax = 482 nm). - Experiment 2: The PLR was measured in five healthy participants [29 to 42 years (mean = 32.6 years)] as a function of three stimulus durations (1 s, 10 s, 30 s), five irradiances spanning low to high melanopsin excitation levels (retinal irradiance: 9.8 to 14.8 log quanta.cm-2.s-1), and two wavelengths, one with high (465 nm) and one with low (637 nm) melanopsin excitation. Intra and inter-individual coefficients of variation (CV) were calculated. Results The melanopsin (opn4) photopigment nomogram adequately described the spectral sensitivity derived from all four PIPR metrics. The largest PIPR amplitude was observed with 1 s short wavelength pulses (retinal irradiance ≥ 12.8 log quanta.cm-2.s-1). Of the 4 PIPR metrics, the plateau and 6 s PIPR showed the least intra and inter-individual CV (≤ 0.2). The maximum duration of the sustained PIPR was 83.4 ± 48.0 s (mean ± SD) for 1 s pulses and 180.1 ± 106.2 s for 30 s pulses (465 nm; 14.8 log quanta.cm-2.s-1). Conclusions All current PIPR metrics provide a direct measure of intrinsic melanopsin retinal ganglion cell function. To measure progressive changes in melanopsin function in disease, we recommend that the intrinsic melanopsin response should be measured using a 1 s pulse with high melanopsin excitation and the PIPR should be analyzed with the plateau and/or 6 s metrics. That the PIPR can have a sustained constriction for as long as 3 minutes, our PIPR duration data provide a baseline for the selection of inter-stimulus intervals between consecutive pupil testing sequences.