INT6/EIF3E interacts with ATM and is required for proper execution of the DNA damage response in human cells

Altered expression of the INT6 gene, encoding the e subunit of the translational initiation factor eIF3, occurs in human breast cancers, but how INT6 relates to carcinogenesis remains unestablished. Here, we show that INT6 is involved in the DNA damage response. INT6 was required for cell survival following γ-irradiation and G(2)-M checkpoint control. RNA interference-mediated silencing of INT6 reduced phosphorylation of the checkpoint kinases CHK1 and CHK2 after DNA damage. In addition, INT6 silencing prevented sustained accumulation of ataxia telangiectasia mutated (ATM) at DNA damage sites in cells treated with γ-radiation or the radiomimetic drug neocarzinostatin. Mechanistically, this result could be explained by interaction of INT6 with ATM, which together with INT6 was recruited to the sites of DNA damage. Finally, INT6 silencing also reduced ubiquitylation events that promote retention of repair proteins at DNA lesions. Accordingly, accumulation of the repair factor BRCA1 was defective in the absence of INT6. Our findings reveal unexpected and striking connections of INT6 with ATM and BRCA1 and suggest that the protective action of INT6 in the onset of breast cancers relies on its involvement in the DNA damage response.

Innovative hybrid composite floor plate system

New materials technology has provided the potential for the development of an innovative Hybrid Composite Floor Plate System (HCFPS) with many desirable properties, such as light weight, easy to construct, economical, demountable, recyclable and reusable. Component materials of HCFPS include a central Polyurethane (PU) core, outer layers of Glass-fibre Reinforced Cement (GRC) and steel laminates at tensile regions. HCFPS is configured such that the positive inherent properties of individual component materials are combined to offset any weakness and achieve optimum performance. Research has been carried out using extensive Finite Element (FE) computer simulations supported by experimental testing. Both the strength and serviceability requirements have been established for this lightweight floor plate system. This paper presents some of the research towards the development of HCFPS along with a parametric study to select suitable span lengths.

Nagelschmidtite bioceramics with osteostimulation properties : material chemistry activating osteogenic genes and WNT signalling pathway of human bone marrow stromal cells

Bioactive materials with osteostimulation properties are of great importance to promote osteogenic differentiation of human bone marrow stromal cells (hBMSCs) for potential bone regeneration. We have recently synthesized nagelschmidtite (NAGEL, Ca7Si2P2O16) ceramic powders which showed excellent apatite-mineralization ability. The aim of this study was to investigate the interaction of hBMSCs with NAGEL bioceramic bulks and their ionic extracts, and to explore the osteostimulation properties of NAGEL bioceramics and the possible molecular mechanism. The cell attachment, proliferation, bone-related gene expression (ALP, OPN and OCN) and WNT signalling pathways (WNT3a, FZD6, AXIN2 and CTNNB) of hBMSCs cultured on NAGEL bioceramic disks were systematically studied. We further investigated the biological effects of ionic products from NAGEL powders on cell proliferation and osteogenic differentiation of hBMSCs by culturing cells with NAGEL extracts. Furthermore, the effect of NAGEL bioceramics on the osteogenic differentiation in hBMSCs was also investigated with the addition of cardamonin, a WNT inhibitor. The results showed that NAGEL bioceramic disks supported the attachment and proliferation of hBMSCs, and significantly enhanced the bone-related gene expression and WNT signalling pathway of hBMSCs, compared to conventional beta-tricalcium phosphate (β-TCP) bioceramic disks and blank controls. The ionic products from NAGEL powders also significantly promoted the proliferation, bone and WNT-related gene expression of hBMSCs. It was also identified that NAGEL bioceramics could bypass the action of the WNT inhibitor (10 μM) to stimulate the selected osteogenic genes in hBMSCs. Our results suggest that NAGEL bioceramics possess excellent in vitro osteostimulation properties. The possible mechanism for the osteostimulation may be directly related to the released Si, Ca and P-containing ionic products from NAGEL bioceramics which activate bone-related gene expression and WNT signalling pathway of hBMSCs. The present study suggests that NAGEL bioceramics are a potential bone regeneration material with significant osteostimulation capacity.

Near-Wall Turbulent Pressure Diffusion Modeling and Influence in Three-Dimensional Secondary Flows

The purpose of this paper is to develop a second-moment closure with a near-wall turbulent pressure diffusion model for three-dimensional complex flows, and to evaluate the influence of the turbulent diffusion term on the prediction of detached and secondary flows. A complete turbulent diffusion model including a near-wall turbulent pressure diffusion closure for the slow part was developed based on the tensorial form of Lumley and included in a re-calibrated wall-normal-free Reynolds-stress model developed by Gerolymos and Vallet. The proposed model was validated against several one-, two, and three-dimensional complex flows.

Eigenvoice modeling for cross likelihood ratio based speaker clustering : a Bayesian approach

This paper proposes the use of Bayesian approaches with the cross likelihood ratio (CLR) as a criterion for speaker clustering within a speaker diarization system, using eigenvoice modeling techniques. The CLR has previously been shown to be an effective decision criterion for speaker clustering using Gaussian mixture models. Recently, eigenvoice modeling has become an increasingly popular technique, due to its ability to adequately represent a speaker based on sparse training data, as well as to provide an improved capture of differences in speaker characteristics. The integration of eigenvoice modeling into the CLR framework to capitalize on the advantage of both techniques has also been shown to be beneficial for the speaker clustering task. Building on that success, this paper proposes the use of Bayesian methods to compute the conditional probabilities in computing the CLR, thus effectively combining the eigenvoice-CLR framework with the advantages of a Bayesian approach to the diarization problem. Results obtained on the 2002 Rich Transcription (RT-02) Evaluation dataset show an improved clustering performance, resulting in a 33.5% relative improvement in the overall Diarization Error Rate (DER) compared to the baseline system.

Effect of bone morphogenetic protein-4 (BMP-4) on the expression of Sox2, Oct-4 and c-Myc in human periodontal ligament cells during long-term culture

Recent studies demonstrated endogenous expression level of Sox2, Oct-4 and c-Myc is correlated with the pluripotency and successful induction of induced pluripotent stem cells (iPSCs). Periondontal ligament cells (PDLCs)have multi-lineage diferentiation capability and ability to maintain undifferentiated stage, which makes PDLCs a suitable cell source for tissue repair and regeneration. To elucidate the effect of in vitro culture condition on the stemness potential of PDLCs, we explored the cell growth, proliferation, cell cycle, and the expression of Sox2, Oct-4 and c-Myc in PDLCs from passage 1 to 7 with or without the addition of recombinant human BMP4(rhBMP4). Our results revealed that BMP-4 promoted cell growth and proliferation, arrested PDLCs in S phase of cell cycle and upregulated PI value. It was revealed that without the addition of rhBMP4, the expression of Sox2, Oct-4 and c-Myc in PDLCs only maintained nucleus location until passage 3, then lost nucleus location subsequently. The mRNA expression in PDLCs further confirmed that the level of Sox2 and Oct-4 peaked at passage 3, then decreased afterwards, whereas c-Myc maintained consistently upregulation along passages. after the treatment with rhBMP4, the expression of Sox2, Oct-4 and c-Myc in PDLCs maintained nucleus location even at passage 7 and the mRNA expression of Sox2 and Oct-4 significantly upregulated at passage 5 and 7. These results demonstrated that addition of rhBMP-4 in the culture media could improve the current culture condition for PDLCs to maintain in an undifferentiated stage.

The human dimension of nosocomial wound infection : a study in liminality

Nosocomial wound infection is a disease that has to date been primarily understood through the language of science and biomedicine. This paper reports on findings from a sociological, interpretive study that focused on the experiential dimension of this phenomenon. The illness experience of a nosocomial wound infection is examined within a cultural milieu that values the smooth, untroubled body and alternatively ascribes cultural meaning to a body that has a definable illness. Within this context the person with a chronic wound from nosocomial infection defies normative categorisation and is thus situated outside the patterning of society. The human dimension of nosocomial wound infection includes the private, existential and embodied aspects of living with a chronic, infected wound. This report indicates that the experiential dimension is characterised by an embodied state of liminality. People with this illness live an indeterminate existence that is in-between health and illness, cure and disease. As such they have no recognised place in the medical or social world.

Making sense of mental illness as a full human experience : Perspective of illness and recovery held by people with a mental illness living in the community.

Recovery is a highly contextualized concept amid divergent interpretations and unique experiences. There is substantial current interest in building evidence about recovery from mental illness in order to inform best practice founded in the ways people find to live productive and meaningful lives. This paper presents some accounts related to recovery and illness expressed by eight people through a Participatory Action Research project. The research facilitated entry to the subjective experiences of living in the community as an artist with a mental illness. The people in the research shared an integrated understanding of illness, recovery and identity. Their understanding provided insight into mental illness as an inseparable aspect of who they were. Further, specific issue was raised of recovery as a clinical term with a requirement to meet distinct conventions of recovery. This paper emphasizes that being ill and being well, for the person with a mental illness, is a dynamic and complex development not easily explained or transformed into uniform process or outcomes. Attempts to establish an integral or consensual approach to recovery has, to date, disregarded mental illness as a full human experience. This paper argues that broader frameworks for thinking and responding to the dynamic processes of mental illness and recovery are needed and require acknowledgment of competing and contradictory ideas.

Eat Cook Grow : Mixing Human-Computer Interactions with Human-Food Interactions

Food has been a major agenda in political, socio-cultural, and environmental domains throughout history. The significance of food has been particularly highlighted in recent years with the growing public awareness of the unfolding impacts of climate change, challenging our understanding, practice, and expectations of our relationship with food. Parallel to this development has been the rise of web applications such as blogs, wikis, video and photo sharing sites, and social networking systems that are arguably more open, collaborative, and personalisable. These so-called ‘Web 2.0’ technologies have contributed to a more participatory Internet experience than what had previously been possible. An increasing number of these social applications are now available on mobile technologies where they take advantage of device-specific features such as sensors, location and context awareness, further expanding potential for the culture of participation and creativity. This international volume assembles a diverse collection of book chapters that contribute towards exploring and better understanding the opportunities and challenges provided by tools, interfaces, methods, and practices of social and mobile technology to enable engagement with people and creativity in the domain of food in contemporary society. It brings together an international group of academics and practitioners from a diverse range of disciplines such as computing and engineering, social sciences, digital media and human-computer interaction to critically examine a range of applications of social and mobile technology, such as social networking, mobile interaction, wikis, twitter, blogging, mapping, shared displays and urban screens, and their impact to foster a better understanding and practice of environmentally, socio-culturally, economically, and health-wise sustainable food culture.

Ideal victims in human trafficking awareness campaigns

Amidst a proliferation of bestseller books, blockbuster films, television documentaries and sensational news reports, public awareness campaigns have claimed their place in a growing chorus of concern about the crime of human trafficking. These campaigns aim to capture the public’s support in efforts to eliminate a ‘modern slave trade’ in which individuals seeking a better life are transported across borders and forced into exploitative labour conditions. Constrained by the limitations of primary campaign materials (posters, print ads, billboards) typically allowing for only a single image and minimal text, it is unlikely that these awareness campaigns can accurately convey the complexity of the trafficking problem. This chapter explores how the depictions of trafficking victims in awareness campaigns can exclude those who do not fit a restrictive narrative mould. Nils Christie’s pivotal work on the construction of society’s ideal victim is the lens through which this paper examines the literal ‘poster child’ of the anti-trafficking movement.

Re-imagining utopias: The bat/human project

The making of the modern world has long been fuelled by utopian images that are blind to ecologi- cal reality. Botanical gardens are but one example – who typically portray themselves as miniature, isolated 'edens on earth', whereas they are now in many cases self-evidently also the vital ‘lungs’ of crowded cities, as well as critical habitats for threat- ened biodiversity. In 2010 the 'Remnant Emergency Art lab' set out to question utopian thinking through a creative provocation called the 'Botanical Gardens ‘X-Tension’ - an imagined city-wide, distributed, network of 'ecological gardens' suited to both bat and human needs, in order to ask, what now needs to be better understood, connected and therefore ultimately conserved.

Use of a clay modeling task to reduce chocolate craving

Elaborated Intrusion theory (EI theory; Kavanagh, Andrade, & May, 2005) posits two main cognitive components in craving: associative processes that lead to intrusive thoughts about the craved substance or activity, and elaborative processes supporting mental imagery of the substance or activity. We used a novel visuospatial task to test the hypothesis that visual imagery plays a key role in craving. Experiment 1 showed that spending 10 min constructing shapes from modeling clay (plasticine) reduced participants' craving for chocolate compared with spending 10 min 'letting your mind wander'. Increasing the load on verbal working memory using a mental arithmetic task (counting backwards by threes) did not reduce craving further. Experiment 2 compared effects on craving of a simpler verbal task (counting by ones) and clay modeling. Clay modeling reduced overall craving strength and strength of craving imagery, and reduced the frequency of thoughts about chocolate. The results are consistent with EI theory, showing that craving is reduced by loading the visuospatial sketchpad of working memory but not by loading the phonological loop. Clay modeling might be a useful self-help tool to help manage craving for chocolate, snacks and other foods.

Application of a digital elevation model for flood modeling for the Pagsangaan River in Leyte

Flood related scientific and community-based data are rarely systematically collected and analysed in the Philippines. Over the last decades the Pagsangaan River Basin, Leyte, has experienced several flood events. However, documentation describing flood characteristics such as extent, duration or height of these floods are close to non-existing. To address this issue, computerized flood modelling was used to reproduce past events where there was data available for at least partial calibration and validation. The model was also used to provide scenario-based predictions based on A1B climate change assumptions for the area. The most important input for flood modelling is a Digital Elevation Model (DEM) of the river basin. No accurate topographic maps or Light Detection And Ranging (LIDAR)-generated data are available for the Pagsangaan River. Therefore, the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) Global Digital Elevation Map (GDEM), Version 1, was chosen as the DEM. Although the horizontal spatial resolution of 30 m is rather desirable, it contains substantial vertical errors. These were identified, different correction methods were tested and the resulting DEM was used for flood modelling. The above mentioned data were combined with cross-sections at various strategic locations of the river network, meteorological records, river water level, and current velocity to develop the 1D-2D flood model. SOBEK was used as modelling software to create different rainfall scenarios, including historic flooding events. Due to the lack of scientific data for the verification of the model quality, interviews with local stakeholders served as the gauge to judge the quality of the generated flood maps. According to interviewees, the model reflects reality more accurately than previously available flood maps. The resulting flood maps are now used by the operations centre of a local flood early warning system for warnings and evacuation alerts. Furthermore these maps can serve as a basis to identify flood hazard areas for spatial land use planning purposes.

Selective cleavage of human sex hormone-binding globulin by kallikrein-related peptidases and effects on androgen action in LNCaP prostate cancer cells

Stimulation of the androgen receptor via bioavailable androgens, including testosterone and testosterone metabolites, is a key driver of prostate development and the early stages of prostate cancer. Androgens are hydrophobic and as such require carrier proteins, including sex hormone-binding globulin (SHBG), to enable efficient distribution from sites of biosynthesis to target tissues. The similarly hydrophobic corticosteroids also require a carrier protein whose affinity for steroid is modulated by proteolysis. However, proteolytic mechanisms regulating the SHBG/androgen complex have not been reported. Here, we show that the cancer-associated serine proteases, kallikrein-related peptidase (KLK)4 and KLK14, bind strongly to SHBG in glutathione S-transferase interaction analyses. Further, we demonstrate that active KLK4 and KLK14 cleave human SHBG at unique sites and in an androgen-dependent manner. KLK4 separated androgen-free SHBG into its two laminin G-like (LG) domains that were subsequently proteolytically stable even after prolonged digestion, whereas a catalytically equivalent amount of KLK14 reduced SHBG to small peptide fragments over the same period. Conversely, proteolysis of 5α-dihydrotestosterone (DHT)-bound SHBG was similar for both KLKs and left the steroid binding LG4 domain intact. Characterization of this proteolysis fragment by [(3)H]-labeled DHT binding assays revealed that it retained identical affinity for androgen compared with full-length SHBG (dissociation constant = 1.92 nM). Consistent with this, both full-length SHBG and SHBG-LG4 significantly increased DHT-mediated transcriptional activity of the androgen receptor compared with DHT delivered without carrier protein. Collectively, these data provide the first evidence that SHBG is a target for proteolysis and demonstrate that a stable fragment derived from proteolysis of steroid-bound SHBG retains binding function in vitro.

Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases

The Kallikrein (KLK) gene locus encodes a family of serine proteases and is the largest contiguous cluster of protease-encoding genes attributed an evolutionary age of 330 million years. The KLK locus has been implicated as a high susceptibility risk loci in numerous cancer studies through the last decade. The KLK3 gene already has established clinical relevance as a biomarker in prostate cancer prognosis through its encoded protein, prostate-specific antigen. Data mined through genome-wide association studies (GWAS) and next-generation sequencing point to many important candidate single nucleotide polymorphisms (SNPs) in KLK3 and other KLK genes. SNPs in the KLK locus have been found to be associated with several diseases including cancer, hypertension, cardiovascular disease and atopic dermatitis. Moreover, introducing a model incorporating SNPs to improve the efficiency of prostate-specific antigen in detecting malignant states of prostate cancer has been recently suggested. Establishing the functional relevance of these newly-discovered SNPs, and their interactions with each other, through in silico investigations followed by experimental validation, can accelerate the discovery of diagnostic and prognostic biomarkers. In this review, we discuss the various genetic association studies on the KLK loci identified either through candidate gene association studies or at the GWAS and post-GWAS front to aid researchers in streamlining their search for the most significant, relevant and therapeutically promising candidate KLK gene and/or SNP for future investigations.